Chapter 42: Infections: Bacterial & Spirochetal

GROUP A STREPTOCOCCAL INFECTIONS

General Considerations

Group A streptococci (GAS) are common gram-positive bacteria producing a wide variety of clinical illnesses, including acute pharyngitis, impetigo, cellulitis, and scarlet fever. GAS can also cause pneumonia, septic arthritis, osteomyelitis, meningitis, and other less common infections. GAS infections may also produce postinfectious sequelae (rheumatic fever and acute glomerulonephritis [AGN]).

Almost all GAS are β-hemolytic. These organisms may be carried without symptoms on the skin and in the pharynx, rectum, and vagina. All GAS are sensitive to penicillin. Resistance to erythromycin is common in some countries and has increased in the United States.

Prevention

GAS pharyngitis usually occurs after contact with respiratory secretions of a person infected with GAS. Crowding facilitates spread of GAS and outbreaks of pharyngitis and impetigo occur. Prompt recognition and institution of antibiotics may decrease spread. Treatment with antibiotics prevents acute rheumatic fever.

Clinical Findings

A. Symptoms and Signs

1. Respiratory infections

The onset is insidious, with mild symptoms (low-grade fever, serous nasal discharge, and pallor). Otitis media is common. Exudative pharyngitis and cervical adenitis are uncommon in this age group.

Classic GAS pharyngitis presents with the sudden onset of fever, sore throat, malaise, and often vomiting. On examination, tonsillar exudate and tender anterior cervical adenopathy are usually noted. Petechiae are frequently seen on the soft palate. In scarlet fever, the skin is diffusely erythematous and appears sunburned and roughened (sandpaper rash); most intense in the axillae, groin, and on the abdomen and trunk. It blanches except in the skin folds, which do not blanch and are pigmented (Pastia sign). The rash usually appears 24 hours after the onset of fever and rapidly spreads over the next 1–2 days. Desquamation begins on the face at the end of the first week and becomes generalized by the third week. Early in the infection, there is circumoral pallor and the surface of the tongue is coated white, with the papillae enlarged and bright red (white strawberry tongue). Subsequently desquamation occurs, and the tongue appears beefy red (strawberry tongue). Petechiae may be seen on any mucosal surfaces.

2. Impetigo

Streptococcal impetigo begins as a papule that vesiculates and then breaks, leaving a denuded area covered by a honey-colored crust. Both Staphylococcus aureus and GAS are isolated in some cases. The lesions spread readily and diffusely. Local lymph nodes may become swollen and inflamed. Although the child often lacks systemic symptoms, a high fever and toxicity may be present. If flaccid bullae are noted, the disease is called bullous impetigo and is caused by an epidermolytic toxin-producing strain of S aureus.

3. Cellulitis

The portal of entry is often an insect bite or superficial abrasion. A diffuse, rapidly spreading cellulitis occurs that involves the subcutaneous tissues and extends along the lymphatic pathways with only minimal local suppuration. Local acute lymphadenitis occurs. The child is usually acutely ill, with fever and malaise. In classic erysipelas, the involved area is bright red, swollen, warm, and very tender. The infection may extend rapidly from the lymphatics to the bloodstream.

Streptococcal perianal cellulitis is an entity peculiar to young children. Pain with defecation often leads to constipation, which may be the presenting complaint. The child is afebrile and otherwise well. Perianal erythema, tenderness, and painful rectal examination are the only abnormal physical findings. Scant rectal bleeding with defecation may occur. A perianal swab culture usually yields heavy growth of GAS. A variant of this syndrome is streptococcal vaginitis in prepubertal girls. Symptoms are dysuria and pain; marked erythema and tenderness of the introitus and blood-tinged discharge are seen.

4. Necrotizing skin and soft tissue infection

This dangerous disease is reported sporadically and may occur as a complication of varicella infection. GAS is the most common cause of necrotizing skin and soft tissue infection in children, followed by S aureus. The disease is characterized by extensive necrosis of superficial fasciae, undermining of surrounding tissue, and usually systemic toxicity. Initially the skin overlying the infection is tender and pale red without distinct borders, resembling cellulitis. Blisters or bullae may appear. The color deepens to a distinct purple or in some cases becomes pale. Tenderness out of proportion to the clinical appearance, skin anesthesia (due to infarction of superficial nerves), or “woody” induration suggest necrotizing fasciitis. Involved areas may develop mild to massive edema. Early recognition and aggressive debridement of necrotic tissue are essential.

5. Group A streptococcal infections in newborn nurseries

GAS epidemics occur occasionally in nurseries. The organism may be introduced into the nursery from the vaginal tract of a mother or from the throat or nose of a mother or a staff member. The organism then spreads from infant to infant. The umbilical stump is colonized while the infant is in the nursery. Most often, a colonized infant develops a chronic oozing omphalitis days later. The organism may spread from the infant to other family members. Serious and even fatal infections may develop, including sepsis, meningitis, empyema, septic arthritis, and peritonitis.

6. Streptococcal sepsis

Sepsis frequently occurs in conjunction with a focal source of infection, but can also manifest as isolated bacteremia. Rash and scarlet fever may or may not be present. Prostration and shock result in high mortality rates. Pharyngitis is uncommon as an antecedent illness. Underlying disease is a predisposing factor.

7. Streptococcal toxic shock syndrome (STSS)

Toxic shock syndrome (TSS) can be caused by GAS and is typically more severe than S aureus–associated toxic shock; multiorgan system involvement is a prominent part of the illness. The diagnostic criteria include (1) isolation of GAS from a normally sterile site, (2) hypotension or shock, and (3) at least two of the following: renal impairment (creatinine more than two times the upper limit of normal for age), thrombocytopenia (< 100,000/mm³) or coagulopathy, liver involvement (transaminases or bilirubin ≥ two times normal), acute respiratory distress syndrome, erythematous macular rash, or soft tissue necrosis (myositis, necrotizing fasciitis, gangrene). In cases that otherwise meet clinical criteria, isolation of GAS from a nonsterile site (throat, wound, or vagina) is indicative of a “probable case.”

B. Laboratory Findings

Leukocytosis with a marked shift to the left is seen early. β-Hemolytic streptococci are cultured from the throat or site of infection. For suspected GAS pharyngitis, the throat should be swabbed and the specimen sent for GAS testing (rapid antigen detection tests and/or culture for GAS) because the clinical features of some viral infections may overlap with the clinical features of GAS. In children and adolescents, negative rapid antigen tests should be backed up by a culture. Patients with positive rapid strep antigen tests do not need a confirmation by throat culture, since the specificities of antigen tests are high. The Food and Drug Administration (FDA) has recently approved nucleic acid amplification tests (NAATs) for the detection of GAS from throat swab specimens. The organism may be cultured from the skin and by needle aspiration from subcutaneous tissues and other involved sites such as infected nodes. Occasionally blood cultures are positive.

Antistreptolysin O (ASO) titers rise about 150 units within 2 weeks after acute infection. Elevated ASO and anti-DNase B titers may be useful in documenting prior throat infections in cases of acute rheumatic fever, although they may remain elevated for several months and even years after the original infection.

Proteinuria, cylindruria, and minimal hematuria may be seen early in children with streptococcal infection. True poststreptococcal glomerulonephritis is seen 1–4 weeks after the respiratory or skin infection.

Differential Diagnosis

Streptococcal infection in early childhood must be differentiated from adenovirus and other respiratory virus infections. The pharyngitis in herpangina (coxsackievirus A) is vesicular or ulcerative. Herpes simplex also causes ulcerative lesions, which most commonly involve the anterior pharynx, tongue, and gums. In infectious mononucleosis, the pharyngitis is also exudative, but splenomegaly and generalized adenopathy are typical, and laboratory findings are often diagnostic (atypical lymphocytes, a positive heterophile, or other serologic test for mononucleosis). Uncomplicated streptococcal pharyngitis improves within 24–48 hours if penicillin is given and by 72–96 hours without antimicrobials.

Arcanobacterium hemolyticum may cause pharyngitis with scarlatina-like or maculopapular truncal rash. In diphtheria, systemic symptoms, vomiting, and fever are less marked; pharyngeal pseudomembrane is confluent and adherent; the throat is less red; and cervical adenopathy is prominent. Pharyngeal tularemia causes white rather than yellow exudate; there is little erythema; and cultures for β-hemolytic streptococci are negative. A history of exposure to rabbits and a failure to respond to antimicrobials may suggest the diagnosis. Oral gonococcal infection may also cause pharyngitis with tonsillar exudate. Leukemia and agranulocytosis may present with pharyngitis and are diagnosed by bone marrow examination.

Scarlet fever must be differentiated from other exanthematous diseases, erythema due to sunburn, drug reactions, Kawasaki disease, TSS, and staphylococcal scalded skin syndrome (see also Table 40–3).

Complications

Suppurative complications of GAS infections include sinusitis, otitis, mastoiditis, cervical lymphadenitis, pneumonia, empyema, septic arthritis, sepsis, and meningitis. Spread of streptococcal infection from the throat to other sites—principally the skin (impetigo) and vagina—is common and should be considered in every instance of chronic vaginal discharge or chronic skin infection, such as that complicating childhood eczema. Both acute rheumatic fever and AGN are nonsuppurative complications of GAS infections.

A. Acute Rheumatic Fever

(See Chapter 20)

B. Acute Glomerulonephritis

Poststreptococcal glomerulonephritis (PSGN) can follow streptococcal infections of either the pharynx or the skin—in contrast to rheumatic fever, which follows pharyngeal infection (See Chapter 20). PSGN may occur at any age. The risk is higher in school-aged children and members of indigenous populations. In most reports of PSGN, males predominate by a ratio of 2:1. Rheumatic fever occurs with equal frequency in both sexes. Certain GAS strains are associated with PSGN (nephritogenic types).

The median period between infection and the development of glomerulonephritis is 10 days. In contrast, acute rheumatic fever occurs after a median of 18 days.

C. Poststreptococcal Reactive Arthritis

Following an episode of group A streptococcal (GAS) pharyngitis, reactive arthritis develops in some patients. This reactive arthritis is believed to be due to immune complex deposition and is seen about 1–2 weeks following the acute infection. Patients with poststreptococcal reactive arthritis do not have the full constellation of clinical and laboratory criteria needed to fulfill the Jones criteria for a diagnosis of acute rheumatic fever.

Treatment

A. Specific Measures

Treatment is directed toward both eradication of acute infection and prevention of rheumatic fever. In patients with pharyngitis, antibiotics should be started early to relieve symptoms and should be continued for 10 days to prevent rheumatic fever. Although early therapy has not been shown to prevent PSGN, it seems advisable to treat impetigo promptly in sibling contacts of patients with poststreptococcal nephritis. Neither sulfonamides nor trimethoprim-sulfamethoxazole (TMP-SMX) is effective in the treatment of streptococcal infections. Although topical therapy for impetigo with antimicrobial ointments (especially mupirocin) is as effective as systemic therapy, it does not eradicate pharyngeal carriage and is less practical for extensive disease.

1. Penicillin

For GAS pharyngitis, the following regimens can be used. Except for penicillin-allergic patients, penicillin V (phenoxymethyl penicillin) is the drug of choice. Penicillin resistance has never been documented. For children weighing less than 27 kg, the regimen is 250 mg, given orally two or three times a day for 10 days. For children or adults weighting more than 27 kg, 500 mg two or three times a day is recommended. Giving penicillin V twice daily is as effective as more frequent oral administration. Alternatively, amoxicillin 50 mg/kg/day as a single daily dose (maximum 1000 mg) can be used. Another alternative for treatment of pharyngitis and impetigo is a single dose of penicillin G benzathine given intramuscularly (600,000 units for children weighing ≤ 27 kg and 1.2 million units for children weighing > 27 kg). Intramuscular delivery ensures compliance, but is painful. Parenteral therapy is indicated if vomiting is present. Mild cellulitis due to GAS may be treated orally or intramuscularly. For severe or invasive GAS infections intravenous antibiotics are indicated.

GAS cellulitis requiring hospitalization can be treated with aqueous penicillin G (150,000 U/kg/day, given intravenously in four divided doses) or cefazolin (100 mg/kg/day, given intravenously in three divided doses) until there is marked improvement. Penicillin V (50 mg/kg/day in four divided doses) or cephalexin (50–75 mg/kg/day in four divided doses) may then be given orally to complete a 10-day course. Acute cervical lymphadenitis may require incision and drainage. Treatment of necrotizing fasciitis requires emergency surgical debridement followed by high-dose parenteral antibiotics appropriate to the organisms cultured.

2. Other antibiotics

Cephalexin and azithromycin are other effective oral antimicrobials. Clindamycin is also effective, but resistance is occasionally present (labs can check for susceptibility to clindamycin). For penicillin-allergic patients with pharyngitis or impetigo the following alternative regimens have been used: azithromycin (12 mg/kg/day on day 1 followed by 6 mg/kg/day for days 2–5; maximum 500 mg/day) or clindamycin (20–30 mg/kg/day in three divided doses; maximum 600 mg per dose) for 10 days. Patients with immediate, anaphylactic hypersensitivity to penicillin should not receive cephalosporins, because up to 15% will also be allergic to cephalosporins. Macrolide resistance rates vary and may be high in some areas of the world. In general, macrolide resistance rates in most areas of the United States are between 5% and 8%. In most studies, bacteriologic failures after cephalosporin therapy are less frequent than failures following penicillin. However, there are few conclusive data on the ability of these agents to prevent rheumatic fever. Therefore, penicillin remains the agent of choice for nonallergic patients. Many strains are resistant to tetracycline.

For serious infections requiring intravenous therapy, aqueous penicillin G (250,000 U/kg in six divided doses) given intravenously is usually the drug of choice. Cefazolin (100 mg/kg/day intravenously or intramuscularly in three divided doses), clindamycin (30–40 mg/kg/day intravenously in four divided doses), and vancomycin (40 mg/kg/day intravenously in four divided doses) are alternatives in penicillin-allergic pediatric patients. Clindamycin should not be used alone empirically for severe, suspected GAS infections because a small percentage of isolates in the United States are resistant.

3. Serious GAS disease

Serious GAS infections, such as pneumonia, osteomyelitis, septic arthritis, sepsis, endocarditis, meningitis, and STSS, require parenteral antimicrobial therapy. Penicillin G is the drug of choice for these invasive infections. Clindamycin, a protein synthesis inhibitor, is advocated by many experts for STSS or necrotizing fasciitis as a second agent along with penicillin G to inhibit toxin production. Necrotizing skin and soft tissue infection requires prompt surgical debridement. In STSS, volume status and blood pressure should be monitored and patients evaluated for a focus of infection, if not readily apparent. Intravenous immunoglobulin (in addition to antibiotics) has been used in severe cases.

4. Treatment failure

Even when compliance is perfect, organisms will be found in cultures in 5%–35% of children after cessation of therapy. Reculture is indicated only in patients with relapse or recrudescence of pharyngitis or those with a personal or family history of rheumatic fever. Repeat treatment at least once with an oral cephalosporin or clindamycin is indicated in patients with recurrent culture-positive pharyngitis.

5. Prevention of recurrences in patients with previous rheumatic fever

The preferred prophylaxis for rheumatic individuals is benzathine penicillin G, 1.2 million units (600,000 units for patients weighing < 27 kg) intramuscularly every 4 weeks. If the risk of streptococcal exposure is high, every 3-week dosing is preferred. One of the following alternative oral prophylactic regimens may be used: penicillin V, 250 mg twice daily; or sulfadiazine, 0.5 g once a day (if < 27 kg) or 1 g once a day (if > 27 kg). In patients allergic to both penicillin and sulfonamide drugs, erythromycin 250 mg twice daily orally can be used. If carditis is absent, continued prophylaxis is recommended for at least 5 years after the last episode of acute rheumatic fever or until 21 years of age (whichever is longer). Prophylaxis should be continued longer if the risk of contact with persons with GAS is high (eg, parents of school-aged children, pediatric nurses, and teachers). In the presence of carditis without residual heart or valvular disease, a minimum of 10 years after the last episode of acute rheumatic fever or until 21 years of age (whichever is longer) is the minimum duration. If the patient has residual valvular heart disease, many recommend lifelong prophylaxis. These patients should be at least 10 years from their last episode of rheumatic disease and at least 40 years of age before considering discontinuation of prophylaxis. Those with severe valvular heart disease or with risk of ongoing exposure to GAS may benefit from lifelong prophylaxis.

6. Poststreptococcal reactive arthritis

In contrast to rheumatic fever, nonsteroidal agents may not dramatically improve joint symptoms. However, like patients with rheumatic fever, some patients with poststreptococcal reactive arthritis have developed carditis several weeks to months after their arthritis symptoms began. Patients should be monitored for development of carditis for the next 1–2 years. Some experts recommend antibiotic prophylaxis of these patients (same prophylaxis regimens as in prevention of recurrences of acute rheumatic fever) for 1–2 years and monitoring for signs of carditis (see recommendations for prevention of recurrences of rheumatic fever, above). If carditis does not develop, prophylaxis could then be discontinued. If carditis develops, the patient should be considered to have acute rheumatic fever and prophylaxis continued as described above.

B. General Measures

Acetaminophen or ibuprofen is useful for pain or fever. Local treatment of impetigo may promote earlier healing. Crusts should first be soaked off. Areas beneath the crusts should then be washed with soap daily.

C. Treatment of Complications

Rheumatic fever is best prevented by early and adequate penicillin treatment of the streptococcal infection.

D. Treatment of Carriers

Identification and treatment of GAS carriers are difficult. There are no established clinical or serologic criteria for differentiating carriers from the truly infected. Up to 20% of school-aged children in some studies are asymptomatic pharyngeal carriers of GAS. Streptococcal carriers are individuals who do not mount an immune response to the organism and are therefore believed to be at low risk for nonsuppurative sequelae.

Some children receive multiple courses of antimicrobials, with persistence of GAS in the throat, leading to a “streptococcal neurosis” on the part of families.

In certain circumstances, eradication of carriage may be desirable: (1) when a family member has a history of rheumatic fever; (2) when an episode of STSS or necrotizing fasciitis has occurred in a household contact; (3) multiple, recurring, documented episodes of GAS in family members despite adequate therapy; and (4) during an outbreak of rheumatic fever or GAS-associated glomerulonephritis. Clindamycin (20–30 mg/kg/day, given orally in three divided doses; maximum dose 300 mg) or a combination of rifampin (20 mg/kg/day, given orally for 4 days) and penicillin in standard dosage given orally has been used to attempt eradication of carriage.

Prognosis

Death is rare except in infants or young children with sepsis, necrotizing infection, or pneumonia. The febrile course is shortened, and complications are eliminated by early and adequate treatment with penicillin.

GROUP B STREPTOCOCCAL INFECTIONS

Prevention

Many women of childbearing age possess type-specific circulating antibody to the polysaccharide antigens for group B Streptococcus (GBS). These antibodies are transferred to the newborn via the placental circulation. GBS carriers delivering healthy infants have significant serum levels of IgG antibody to this antigen. In contrast, women delivering infants who develop either early- or late-onset GBS disease rarely have detectable antibody in their sera. There is no licensed vaccine for GBS disease prevention. Vaccines have been studied in pregnant women, and research is ongoing.

CDC Recommendations for Prevention of Perinatal GBS Disease

1. Caregivers for pregnant women are referred to the Centers for Disease Control and Prevention (CDC) guidelines for screening of pregnant women for GBS and use of intrapartum antibiotic prophylaxis (IAP)—see CDC guidelines http://www.cdc.gov/mmwr/pdf/rr/rr5910.pdf and http://www.cdc.gov/groupbstrep/clinicians/obstetric-providers.html.

2. Indications and nonindications for IAP to prevent early-onset group B streptococcal (GBS) disease are given in Table 42–1.

3. Algorithm for secondary prevention of early-onset GBS disease among newborns (management of a newborn whose mother received IAP for prevention of GBS or suspected chorioamnionitis)—Figure 42–1.

Clinical Findings

The incidence of perinatal GBS disease has declined dramatically since screening of pregnant mothers and provision of IAP began. Although most patients with GBS disease are infants younger than 3 months, cases are seen in infants aged 4–5 months. Serious GBS infection also occurs in women with puerperal sepsis, immunocompromised patients, patients with cirrhosis and spontaneous peritonitis, and diabetic patients with cellulitis. Two distinct clinical syndromes distinguished by differing perinatal event and age at onset occur in infants.

A. Early-Onset Disease

“Early-onset” disease is observed in newborns younger than 7 days. Risk factors for early-onset disease include maternal GBS colonization, gestational age less than 37 weeks, rupture of membranes more than 18 hours prior to presentation, young maternal age, history of a previous infant with invasive GBS disease, African American or Hispanic ethnicity, and low or absent maternal GBS anticapsular antibodies. The onset of symptoms in the majority of these infants is in the first 48 hours of life, and most are ill within 6 hours. Respiratory abnormalities, irritability, lethargy, temperature instability, or poor perfusion may be presenting signs. Sepsis, shock, meningitis, and pneumonia are the most common clinical presentations. Although premature infants are at increased risk for the disease, most infants with early-onset infections are full term. Newborns with early-onset infection acquire GBS in utero as an ascending infection or during passage through the birth canal.

B. Late-Onset Disease

“Late-onset” disease occurs in infants between ages 7 and 89 days (median age at onset is about 4 weeks). Maternal obstetric complications are not usually associated with late-onset disease. However, young maternal age and prematurity remain risk factors. Late-onset disease is not prevented by IAP. The most common presentation of late-onset disease is bacteremia without focus, and compared to early-onset disease, a higher proportion presents with meningitis. Pneumonia, septic arthritis and osteomyelitis, otitis media, ethmoiditis, conjunctivitis, cellulitis (particularly of the face or submandibular area), lymphadenitis, breast abscess, empyema, and impetigo have also been described. The exact mode of transmission of the organisms is not well defined.

C. Laboratory Findings

Culture of GBS from a normally sterile site such as blood, pleural fluid, or CSF provides proof of diagnosis.

Treatment

Intravenous ampicillin and an aminoglycoside are the initial regimens of choice for newborns with presumptive invasive GBS disease. For neonates 7 days of age or younger with meningitis, the recommended ampicillin dosage is 200–300 mg/kg/day, given intravenously in three divided doses. For infants older than 7 days, the recommended ampicillin dosage is 300 mg/kg/day, given intravenously in four divided doses.

Penicillin G can be used alone once GBS is identified and clinical and microbiologic responses have occurred. GBS is less susceptible than other streptococci to penicillin, and high doses are recommended, especially for meningitis. In infants with meningitis, the recommended dosage of penicillin G varies with age: for infants 7 days or younger, 250,000–450,000 U/kg/day, given intravenously in three divided doses; for infants older than 7 days, 450,000–500,000 U/kg/day, given intravenously in four divided doses.

A second lumbar puncture after 24–48 hours of therapy is recommended by some experts to assess efficacy. Duration of therapy is 2 weeks for uncomplicated meningitis; at least 4 weeks for osteomyelitis, cerebritis, ventriculitis, or endocarditis, and 10 days for bacteremia. Therapy does not eradicate carriage of the organism.

Although streptococci have been universally susceptible to penicillins, increased minimum inhibitory concentrations (MICs) have been observed in some isolates. Resistance of isolates to clindamycin and erythromycin has increased significantly worldwide.

Infants diagnosed with GBS infection who are part of a multiple birth (twins, triplets, etc) define a risk for acquisition of invasive GBS disease in their siblings. Those siblings should be closely monitored and if signs of illness occur, promptly evaluated and antibiotics instituted for possible systemic infection.

STREPTOCOCCAL INFECTIONS WITH ORGANISMS OTHER THAN GROUP A OR B

General Considerations

Streptococci of groups other than A and B are part of the normal flora of humans and can occasionally cause disease. Group C or G organisms occasionally produce pharyngitis, but without risk of subsequent rheumatic fever. AGN may occasionally occur. Group D streptococci and Enterococcus species are normal inhabitants of the gastrointestinal tract and may produce urinary tract infections, meningitis, and sepsis in the newborn, as well as endocarditis.

Nosocomial infections caused by Enterococcus are frequent in neonatal and oncology units and in patients with central venous catheters. Nonhemolytic aerobic streptococci and β-hemolytic streptococci are normal flora of the mouth. They are involved in the production of dental plaque and probably dental caries and are the most common cause of subacute infective endocarditis. Finally, there are numerous anaerobic and microaerophilic streptococci, normal flora of the mouth, skin, and gastrointestinal tract, which alone or in combination with other bacteria may cause sinusitis, dental abscesses, brain abscesses, and intra-abdominal or lung abscesses.

Prevention

Streptococci (other than group A or B) are common normal flora in humans. Some disease caused by these organisms can be prevented by maintaining good oral hygiene. Spread of vancomycin-resistant enterococcal strains can be limited by good infection control practices in healthcare environments. Development of resistant strains can also be limited by antimicrobial stewardship. There are no vaccines that prevent infections with these organisms.

Treatment

A. Enterococcal Infections

Enterococcus faecalis and Enterococcus faecium are the two most common and most important strains causing human infections. In general, E faecalis is more susceptible to antibiotics than E faecium, but antibiotic resistance is commonly seen with both species. Invasive enterococcal infections should be treated with ampicillin if the isolate is susceptible or vancomycin in combination with gentamicin. Gentamicin should be discontinued if susceptibility testing demonstrates high-level resistance to gentamicin. Isolates that are resistant to both ampicillin and vancomycin necessitate other therapeutic options.

1. Infections with ampicillin-susceptible enterococci

Lower tract urinary infections can be treated with oral amoxicillin. Pyelonephritis should be treated intravenously with ampicillin. Sepsis or meningitis in the newborn should be treated intravenously with a combination of ampicillin and gentamicin. Peak serum gentamicin levels of 3–5 mcg/mL are adequate as gentamicin is functioning as a synergistic agent. Consult the American Heart Association guidelines for treatment recommendations for infective endocarditis.

2. Infections with ampicillin-resistant- or vancomycin-resistant enterococci

Ampicillin-resistant enterococci are often susceptible to vancomycin. Vancomycin-resistant enterococci are usually also resistant to ampicillin. Linezolid is the only agent approved for use in children for vancomycin-resistant E faecium infections. Daptomycin and tigecycline have been used off-label for vancomycin-resistant enterococci; quinupristin-dalfopristin has been used to treat vancomycin-resistant E faecium but is not effective against E faecalis. Isolates resistant to linezolid, daptomycin, and quinupristin-dalfopristin have been reported. Infectious disease consultation is recommended when use of these drugs is entertained or when vancomycin-resistant enterococcal infections are identified.

B. Viridans Streptococci Infections (Subacute Infective Endocarditis)

It is important to determine the penicillin sensitivity of the infecting strain as early as possible in the treatment of viridans streptococcal endocarditis. Resistant organisms are most commonly seen in patients receiving penicillin prophylaxis for rheumatic heart disease. Treatment of endocarditis varies depending on whether the patient has native valves or prosthetic valves/material and whether the organism is penicillin susceptible. Refer to the American Heart Guidelines on Infective Endocarditis for a complete discussion and recommendations.

C. Other Viridans Streptococci–Related Infections

Viridans streptococci are normal flora of the gastrointestinal tract, respiratory tract, and the mouth. In many cases, isolation of viridans streptococci from a blood culture is considered to be a “contaminant” in the absence of signs or symptoms of endocarditis or other invasive disease. However, in children who are immunocompromised, have congenital or acquired valvular heart disease, or who have indwelling lines, viridans streptococci may be a cause of serious morbidity. About one-third of bacteremias in patients with malignancies may be due to bacteria from the Streptococcus viridans group. Mucositis and gastrointestinal toxicity from chemotherapy are risk factors for developing disease. Even in children with normal immune systems, viridans streptococci sometimes cause serious infections. For example, viridans streptococci isolated from an abdominal abscess after rupture of the appendix represents a true pathogen. Streptococcus anginosus, a member of the Streptococcus viridans group, can cause intracranial abscess (often as a complication of sinusitis) and abdominal abscesses. In patients with risk factors or signs/symptoms for subacute endocarditis, isolation of one of the members of the Streptococcus viridans group should prompt consideration and evaluation for possible endocarditis (see previous section).

Increasing prevalence of penicillin resistance has been seen in isolates of the streptococci viridans group. Penicillin resistance varies with geographic region, institution, and the populations tested, but ranges from 30% to 70% in oncology patients. Cephalosporin resistance is also relatively common. Therefore, it is important to obtain antibiotic susceptibilities to the organism to select effective therapy. Vancomycin, linezolid, and quinupristin-dalfopristin remain effective against most isolates.

PNEUMOCOCCAL INFECTIONS

General Considerations

Sepsis, sinusitis, otitis media, pneumonitis, meningitis, osteomyelitis, cellulitis, arthritis, vaginitis, and peritonitis are part of the spectrum of pneumococcal infection. Clinical findings that correlate with occult bacteremia in ambulatory patients include age (6–24 months), degree of temperature elevation (> 39.4°C), and leukocytosis (> 15,000/μL). Although each of these findings is in itself nonspecific, a combination of them should arouse suspicion.

Streptococcus pneumoniae is a common cause of acute purulent otitis media and is the organism responsible for most cases of acute bacterial pneumonia in children. Effusions are common, although frank empyema is less common. Abscesses also occasionally occur.

The incidence of pneumococcal meningitis has decreased since incorporation of the pneumococcal conjugate vaccine into the infant vaccine schedule; however, sporadic cases still occur. Pneumococcal meningitis, sometimes recurrent, may complicate serious head trauma, particularly if there is persistent leakage of CSF.

Children with sickle cell disease, other hemoglobinopathies, congenital or acquired asplenia, and some immunoglobulin and complement deficiencies are unusually susceptible to pneumococcal sepsis and meningitis. They often have a catastrophic illness with shock and disseminated intravascular coagulation (DIC). The spleen is important in the control of pneumococcal infection. Autosplenectomy may explain why children with sickle cell disease are at increased risk of developing serious pneumococcal infections. Children with cochlear implants are at higher risk for pneumococcal meningitis.

S pneumoniae rarely causes serious disease in the neonate. However, occasionally pneumonia, sepsis, or meningitis may occur and clinically is similar to GBS infection.

Historically, penicillin was the agent of choice for pneumococcal infections, and some strains are still highly susceptible to penicillin. However, pneumococci with moderately increased resistance to penicillin are found in most communities. There is some evidence that rates of antibiotic resistant pneumococcus are declining because non–vaccine-covered serotypes are less likely to be resistant. Nevertheless, empiric antibiotic coverage for suspected invasive pneumococcal disease should always account for the possibility of resistance.

Prevention

Two pneumococcal vaccines are licensed for use in children in the United States: 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV13 was licensed in 2010 (replacing the 7-valent pneumococcal vaccine). It contains antigens from 13 pneumococcal serotypes and is currently recommended for routine use in the infant and childhood immunization schedule. These vaccines and indications for use (including use of pneumococcal vaccines in children at high risk for invasive pneumococcal disease) are discussed in detail in Chapter 10.

Clinical Findings

A. Symptoms and Signs

In pneumococcal sepsis, fever usually appears abruptly, often accompanied by chills. There may be no respiratory symptoms. In infants and young children with pneumonia, fever, and tachypnea without auscultatory changes are the usual presenting signs. Respiratory distress is manifested by nasal flaring, chest retractions, and tachypnea. Abdominal pain is common. In older children, the adult form of pneumococcal pneumonia with signs of lobar consolidation may occur, but sputum is rarely bloody. Inspiratory pain (from pleural involvement) is sometimes present, but is less common in children. With involvement of the right hemidiaphragm, pain may be referred to the right lower quadrant, suggesting appendicitis. Vomiting is common at onset but seldom persists. Convulsions are relatively common at onset in infants.

Meningitis is characterized by fever, irritability, convulsions, and neck stiffness. The most important sign in very young infants is a tense, bulging anterior fontanelle. In older children, fever, chills, headache, and vomiting are common. Classic signs are nuchal rigidity associated with positive Brudzinski and Kernig signs. With progression of untreated disease, the child may develop opisthotonos, stupor, and coma.

B. Laboratory Findings

Leukocytosis is often pronounced (20,000–45,000/μL), with 80%–90% polymorphonuclear neutrophils and levels of C-reactive protein and procalcitonin are typically very elevated. Neutropenia may be seen early in very serious infections. The presence of pneumococci in the nasopharynx is not a helpful finding, because up to 40% of normal children carry pneumococci in the upper respiratory tract. Large numbers of organisms are seen on Gram-stained smears of endotracheal aspirates from patients with pneumonia. In meningitis, CSF usually shows an elevated white blood cell (WBC) count of several thousand, chiefly polymorphonuclear neutrophils, with decreased glucose and elevated protein levels. Gram-positive diplococci may be seen on some (but not all) stained smears of CSF sediment. Isolation of S pneumoniae from a normally sterile site (eg, blood, CSF, joint fluid, middle ear fluid) or from a suppurative focus confirms the diagnosis. The diagnosis can also be confirmed using as polymerase chain reaction (PCR)—often in the context of multiplex-PCR assays of positive blood culture samples or in CSF.

Differential Diagnosis

There are many causes of high fever and leukocytosis in young infants other than invasive pneumococcal disease. The differential diagnosis includes viral infection, urinary tract infection, unrecognized focal infection elsewhere in the body, salmonellosis, or early acute shigellosis.

Staphylococcal pneumonia may be indistinguishable early in its course from pneumococcal pneumonia.

In primary pulmonary tuberculosis (TB), children do not have a toxic appearance, and radiographs show a primary focus associated with hilar adenopathy and often with pleural involvement. Miliary TB presents a classic radiographic appearance.

Pneumonia caused by Mycoplasma pneumoniae may result in a similar illness to pneumococcal disease, though onset is typically more insidious, with infrequent chills, low-grade fever, prominent headache and malaise, cough, and, often, striking radiographic changes. Marked leukocytosis (> 18,000/μL) is unusual.

Pneumococcal meningitis is diagnosed by lumbar puncture. Without a Gram-stained smear and culture of CSF, pneumococcal meningitis is not distinguishable from other types of acute bacterial meningitis.

Complications

Complications of sepsis include meningitis and osteomyelitis; complications of pneumonia include empyema, parapneumonic effusion, and, rarely, lung abscess. Mastoiditis, subdural empyema, and brain abscess may follow untreated pneumococcal otitis media. Both pneumococcal meningitis and peritonitis are more likely to occur independently without coexisting pneumonia. Shock, DIC, and Waterhouse-Friderichsen syndrome resembling meningococcemia are occasionally seen in pneumococcal sepsis, particularly in asplenic patients. Hemolytic-uremic syndrome (HUS) may occur as a complication of pneumococcal pneumonia or sepsis.

Treatment

A. Specific Measures

All S pneumoniae isolated from normally sterile sites should be tested for antimicrobial susceptibility. The term “nonsusceptible” is used to describe both intermediate and resistant isolates. Antimicrobial susceptibility breakpoints for S pneumoniae to penicillin and ceftriaxone are based on whether the patient has meningitis and the drug route (oral vs intravenous; Table 42–2). Therapy of meningitis, empyema, osteomyelitis, and endocarditis due to nonsusceptible S pneumoniae is challenging because penetration of antimicrobials to these sites is limited. Infectious disease consultation is recommended for advice regarding these problems. For empiric therapy of serious or life-threatening infections pending susceptibility test results, vancomycin and ceftriaxone are recommended.

1. Bacteremia

Prior to routine childhood immunization with conjugated pneumococcal vaccine, 3%–5% of blood cultures in patients aged younger than 2 years yielded S pneumoniae, but these percentages decreased with the current vaccine schedule. Some children with positive blood cultures were well-appearing; such “occult bacteremias” were often managed with oral antibiotics. This clinical scenario has largely disappeared with pneumococcal conjugate vaccination. All children with blood cultures that grow pneumococci should be reexamined as soon as possible. The child who has a focal infection, such as meningitis, or who appears septic should be admitted to the hospital to receive parenteral antimicrobials. If the child is afebrile and appears well or mildly ill, outpatient management is appropriate. Severely ill or immunocompromised children, in whom invasive infection with S pneumoniae is suspected, should be empirically treated with vancomycin (in addition to other appropriate antibiotics to cover other suspected pathogens). If meningitis is also suspected, use ceftriaxone in addition to vancomycin until the susceptibilities of the organism are known.

2. Pneumonia

For infants (≥ 1 month of age) with susceptible organisms, appropriate regimens include ampicillin (150–200 mg/kg/day intravenously in four divided doses) or ceftriaxone (50 mg/kg intravenously every 24 hours). If susceptibilities are not known and the patient is severely ill or immunocompromised, vancomycin should be used as part of the regimen to provide coverage for penicillin- or cephalosporin-resistant pneumococcus. Once results of susceptibility testing are available, the regimen can be tailored. Mild pneumonia may be treated with amoxicillin (80–90 mg/kg/day) for 7–10 days. Oral cephalosporins are alternatives for penicillin allergic patients, but many (eg, cefdinir) have unfavorable pharmacokinetics for severe infection. Alternative regimens for penicillin and cephalosporin allergies include fluoroquinolones.

3. Otitis media

Most experts recommend oral amoxicillin (80–90 mg/kg/day, divided in two doses) as first-line therapy. Children younger than 2 years require 10 days of treatment. Shorter courses (5–7 days) may be adequate for older children with mild or moderate otitis. Treatment failures may be treated with amoxicillin-clavulanate (80–90 mg/kg/day of the amoxicillin component in the 14:1 formulation), though the addition of a β-lactamase inhibitor does not improve activity against pneumococcus. Intramuscular administration of ceftriaxone may be required for refractory cases of presumed pneumococcal acute otitis media (AOM).

4. Meningitis

Until bacteriologic confirmation and susceptibility testing are completed, patients should receive vancomycin (60 mg/kg/day, given intravenously in four divided doses) and ceftriaxone (100 mg/kg/day intravenously in two divided doses). Patients with serious hypersensitivity to β-lactam antibiotics (eg, penicillins, cephalosporins) can be treated with a combination of vancomycin (see previous dosage) and levofloxacin or meropenem. These regimens provide additional gram-negative coverage until culture and susceptibility results are obtained. Corticosteroids (dexamethasone, 0.6 mg/kg/day, in four divided doses for 4 days) are recommended by many experts as adjunctive therapy for pneumococcal meningitis. A repeat lumbar puncture at 24–48 hours should be considered to ensure sterility of the CSF if resistant pneumococci were initially isolated or if the patient is not demonstrating expected improvement after 24–48 hours on therapy.

If the isolate is penicillin-susceptible, aqueous penicillin G can be administered (300,000–400,000 U/kg/day intravenously in four to six divided doses for 10–14 days). Alternatively, use of ceftriaxone is an acceptable alternative therapy for penicillin- and cephalosporin-susceptible isolates. Consult an infectious disease specialist or the Red Book (American Academy of Pediatrics, 2018) for a complete discussion of pneumococcal meningitis and for therapeutic options for isolates that are nonsusceptible to penicillin or cephalosporins.

Prognosis

In children, case fatality rates of less than 1% should be achieved except for meningitis, where rates of 5%–20% still prevail. The presence of large numbers of organisms without a prominent CSF inflammatory response or meningitis due to a penicillin-resistant strain indicates a poor prognosis. Serious neurologic sequelae, particularly hearing loss, are frequent following pneumococcal meningitis.

STAPHYLOCOCCAL INFECTIONS

General Considerations

Staphylococcal infections are common in childhood and range from mild localized infections to overwhelming systemic infections. Diseases caused by staphylococci include, but are not limited to, furuncles, carbuncles, scalded skin syndrome, osteomyelitis, pyomyositis, septic arthritis, pneumonia, bacteremia, endocarditis, meningitis, and TSS. Staphylococci are the major cause of skin, soft tissue, bone and joint infections, and are an uncommon but important cause of bacterial pneumonia. Staphylococci are frequent colonizers of the nasopharynx, and a common route of entry to the body is through disruptions in the skin.

S aureus is the most common pathogenic species and most S aureus strains produce coagulase. Staphylococci that do not produce the enzyme coagulase are termed coagulase-negative staphylococci. The latter rarely cause disease except in compromised hosts, the newborn, or patients with indwelling lines.

Most strains of S aureus elaborate β-lactamase that confers penicillin resistance. This can be overcome in clinical practice by the use of a cephalosporin or a penicillinase-resistant penicillin, such as oxacillin, nafcillin, cloxacillin, or dicloxacillin. Methicillin-resistant S aureus (MRSA) are resistant in vivo to all of these penicillinase-resistant penicillins and cephalosporins. MRSA has dramatically increased in prevalence globally as both a healthcare-associated and a community-associated pathogen. Health care–associated infections are likely to be multidrug resistant. Community-associated MRSA are most often susceptible to clindamycin and/or TMP-SMX, but resistance rates to these agents vary widely geographically. MRSA strains with intermediate susceptibility to vancomycin occur, and vancomycin-resistant strains have been isolated. The existence of such strains is of concern because of the inherent virulence of most strains of S aureus and limited choices for therapy.

S aureus produces a variety of exotoxins that contribute to specific disease manifestations. The exfoliatin toxin is largely responsible for bullous impetigo and scalded skin syndrome. Enterotoxin causes staphylococcal food poisoning. The exoprotein toxin most commonly associated with TSS has been termed TSST-1. Panton-Valentine leukocidin (PVL) is an exotoxin produced by some clinical isolates of methicillin-susceptible S aureus (MSSA) and MRSA strains. PVL is a virulence factor that causes leukocyte destruction and tissue necrosis. PVL-producing S aureus strains are often community-acquired and have most commonly produced boils and abscesses. However, they also have been associated with severe cellulitis, osteomyelitis, and deaths from necrotizing pneumonia.

Prevention

No licensed vaccines are available. Patients with recurrent skin infections with S aureus should practice good skin hygiene to try to prevent recurrences. Weekly baths with bleach (1 tsp per gallon or ¼ cup per ½ tub [∼20 gal]) or chlorhexidine 4% may decrease skin contamination. Household eradication regimens may also include treatment of the patient and family with intranasal antibiotics (eg, mupirocin) and hot water washing of clothes and linens. Keeping fingernails short, good skin hygiene, not sharing towels or other personal items, and use of a clean towel daily may also help prevent recurrences.

Clinical Findings

A. Symptoms and Signs

1. Staphylococcal skin diseases

Dermal infection with MRSA and MSSA causes pustules, furuncles, carbuncles, or cellulitis. Skin lesions can be seen anywhere on the body but are commonly seen on the buttocks in infants and young children. Factors that facilitate transmission of MRSA or MSSA include crowding, compromised skin (eg, eczema), participation on contact sports teams, day care attendance, bare skin contact with surfaces used by others (exercise mats, sauna benches), and sharing towels or other personal items.

S aureus are often found along with streptococci in impetigo. If the strains produce exfoliatin, localized lesions become bullous (bullous impetigo).

Scalded skin syndrome is a toxin-mediated illness caused by exfoliative toxins A and B produced by certain strains of S aureus. The initial infection may begin at any site but occurs most frequently in the nasopharynx, a site that is frequently colonized by S aureus. Skin erythema, often beginning around the nose and mouth, is accompanied by fever and irritability. The involved skin becomes tender to touch. A day or so later, exfoliation begins, usually around the mouth. The inside of the mouth is red, and a peeling rash is present around the lips, often in a radial pattern. Generalized, painful peeling may follow, involving the limbs and trunk but often sparing the feet. If erythematous but unpeeled skin is rubbed, superficial epidermal layers separate from deeper ones and slough (Nikolsky sign). Generally, if secondary infection does not occur, there is healing without scarring. In the newborn, the disease is termed Ritter disease and may be fulminant.

2. Osteomyelitis and septic arthritis

(See Chapter 26.) MRSA invasive disease including osteomyelitis and septic arthritis is increasingly common.

3. Staphylococcal pneumonia

Staphylococcal pneumonia is often characterized by a severe respiratory and systemic illness. In the lungs, the organism is necrotizing, producing bronchoalveolar destruction. Pneumatoceles, pyopneumothorax, and empyema are frequently encountered. Rapid progression of disease is characteristic. Purulent pericarditis occurs by direct extension in about 10% of cases, with or without empyema. MSSA and MRSA pneumonias are frequently encountered in the setting of a primary influenza infection, or in the context of a multifocal or disseminated staphylococcal infection associated with endovascular infection and persistent bacteremia.

Staphylococcal pneumonia can also occur in newborns, and though infection with coagulase-negative Staphylococcus is more common, infection with S aureus is more likely to result in a fulminant course. Most staphylococcal lung infections in newborns occur in susceptible infants with indwelling catheters, endotracheal tubes, and are part of a systemic infectious process.

4. Staphylococcal food poisoning

Staphylococcal food poisoning is a result of ingestion of preformed enterotoxin produced by staphylococci growing in undercooked or improperly stored food. The disease is characterized by vomiting, prostration, and diarrhea occurring 2–6 hours after ingestion of contaminated foods.

5. Endocarditis and endovascular infection

Although the presence of a damaged or artificial heart valve or endocardium in children with congenital or rheumatic heart disease predisposes to endocarditis, S aureus may also produce infection of normal heart valves. A major risk factor for pediatric staphylococcal endocarditis is the presence of intravascular foreign bodies, including indwelling central catheters. Recent studies have indicated that S aureus may now cause approximately 50% of all cases of endocarditis in children. Infection usually begins in an extracardiac focus, often the skin or a catheter insertion site. Involvement of the endocardium should be considered when blood cultures grow S aureus, particularly when cultures are persistently positive and/or in the presence of congenital heart disease.

The presenting symptoms in staphylococcal endocarditis are fever, weight loss, weakness, muscle pain or diffuse skeletal pain, poor feeding, pallor, and cardiac decompensation. Signs include splenomegaly, cardiomegaly, petechiae, hematuria, and a new or changing murmur. The course of S aureus endocarditis is rapid, although subacute disease occurs occasionally. Peripheral septic embolization and uncontrollable cardiac failure are common, even when optimal antibiotic therapy is administered and may be indications for surgical intervention (see section 5. Staphylococcal Endocarditis).

Septic thrombophlebitis can occur in the setting of localized primary infections such as osteomyelitis. Patients often progress to septic shock, respiratory failure, and multiorgan dysfunction due to persistent bacteremia and disseminated embolic foci. Imaging studies to identify infected thromboses should be considered in the presence of severe illness and persistent bacteremia.

6. Toxic shock syndrome

TSS is characterized by fever, blanching erythroderma, diarrhea, vomiting, myalgia, prostration, hypotension, and multiorgan dysfunction. It is due to S aureus focal infection, usually without bacteremia. Large numbers of cases have been described in menstruating adolescents using vaginal tampons. TSS has also been reported with focal staphylococcal infections and in individuals with wound infections due to S aureus. Additional clinical features include sudden onset; conjunctival suffusion; mucosal hyperemia; desquamation of skin on the palms, soles, fingers, and toes during convalescence; DIC in severe cases; renal and hepatic functional abnormalities; and myolysis. The mortality rate with early treatment is now less than 1%. Recurrences during subsequent menstrual periods are not unusual, occurring in as many as 60% of untreated women who continue to use tampons.

7. Coagulase-negative staphylococcal infections

Localized and systemic coagulase-negative staphylococcal infections occur primarily in immunocompromised patients, high-risk (especially premature) newborns, and patients with intravascular foreign bodies. Coagulase-negative staphylococci are the most common nosocomial pathogen in hospitalized low-birth-weight neonates in the United States. Intravenous administration of lipid emulsions and indwelling central venous catheters are risk factors contributing to coagulase-negative staphylococcal bacteremia in newborns. Coagulase-negative staphylococci are a common cause of bacteremia and sepsis in patients with an artificial heart valve, a Dacron patch, a ventriculoperitoneal shunt, or a central venous catheter, often necessitating removal of the foreign material and protracted antibiotic therapy. Coagulase-negative staphylococci are also normal skin flora and are thus a common cause of blood culture contamination.

B. Laboratory Findings

Moderate leukocytosis (15,000–20,000/μL) with a shift to the left is occasionally found, although normal counts are common, particularly in infants, and leukopenia (< 5000/μL) can occur in severe cases. Markers of inflammation, including the C-reactive protein, procalcitonin and sedimentation rate are frequently elevated except in localized mild infections. Blood cultures are frequently positive in systemic staphylococcal disease and should always be obtained when it is suspected. Similarly, pus from sites of infection should always be aspirated or obtained surgically, examined with Gram stain, and cultured. This is particularly important when MRSA is a possible pathogen. There are no useful serologic tests for staphylococcal disease.

Differential Diagnosis

Staphylococcal skin disease takes many forms; therefore, the differential list is long. Bullous impetigo must be differentiated from chemical or thermal burns, drug reactions, and, in the very young, from the various congenital epidermolytic syndromes or herpes simplex infections. Staphylococcal scalded skin syndrome may resemble scarlet fever, Kawasaki disease, Stevens-Johnson syndrome, erythema multiforme, and other drug reactions. A skin biopsy may be critical in establishing the diagnosis. Varicella lesions may become superinfected with exfoliatin-producing staphylococci and produce a combination of the two diseases (bullous varicella).

Severe, rapidly progressing pneumonia with formation of abscesses, pneumatoceles, and empyemas is typical of S aureus infection and group A Streptococcus (GAS), but may occasionally be produced by pneumococci, Klebsiella pneumoniae and Haemophilus influenzae.

Staphylococcal food poisoning often occurs in clusters associated with a single food source. It is differentiated from other common-source gastroenteritis syndromes (Salmonella, Clostridium perfringens, and Vibrio parahaemolyticus) by the short incubation period (2–6 hours), the prominence of vomiting (as opposed to diarrhea), and the absence of fever. Food poisoning from Bacillus cereus can result in a vomiting illness clinically indistinguishable from S aureus.

Endocarditis is suspected with S aureus bacteremia, particularly when a significant heart murmur or preexisting cardiac disease is present (see Chapter 20).

Neonatal infections with S aureus and coagulase-negative staphylococci can resemble infections with streptococci and a variety of gram-negative organisms. Umbilical and respiratory tract colonization occurs with many pathogenic organisms (GBS, Escherichia coli, and Klebsiella), and both skin and systemic infections occur with virtually all of these organisms.

TSS must be differentiated from Rocky Mountain spotted fever, leptospirosis, Kawasaki disease, drug reactions, adenovirus, and measles (see Table 40–2).

Treatment

A. Specific Measures

The incidence of community-acquired MRSA isolates varies greatly geographically, but in many communities in the United States, MRSA is the most common pathogen isolated from skin and soft tissue infections. For empiric coverage of potentially life-threatening infections with suspected S aureus (in which susceptibilities are not known), initial therapy should include vancomycin in combination with either nafcillin or oxacillin (in addition to appropriate antibiotic therapy for other suspected pathogens). Antibiotic therapy can then be adjusted based on identification of the organism and susceptibility results.

Currently, most community-acquired MRSA strains are susceptible to TMP-SMX, and many are susceptible to clindamycin, though this varies geographically. Knowledge of local MRSA susceptibility patterns is useful in guiding empiric therapy. Less serious infections in nontoxic patients may be initially treated using TMP-SMX or clindamycin, while awaiting cultures and susceptibility data, if community MRSA resistance to these agents is low.

For MSSA strains, a β-lactamase–resistant penicillin is the drug of choice (oxacillin or nafcillin) and is preferred over vancomycin. In serious systemic disease, in osteomyelitis, and in the treatment of large abscesses, intravenous therapy is indicated initially (oxacillin or nafcillin, 100–150 mg/kg/day in four divided doses). In serious or life-threatening illness, consultation with an infectious disease physician is recommended.

Many cephalosporins are active against MSSA. Cefazolin, 100–150 mg/kg/day, given intravenously in three divided doses, or cephalexin, 50–100 mg/kg/day, given orally in four divided doses, can be used once a child is able to take oral antibiotics. The third-generation cephalosporins should not generally be used for proven staphylococcal infections.

For serious S aureus infections, initial therapy with vancomycin (15 mg/kg/dose intravenously every 6 hours) plus nafcillin or oxacillin is recommended until susceptibilities are available. For nosocomially acquired MRSA infections, vancomycin should be used until results of susceptibility testing are available to guide therapy. Newer antistaphylococcal antibiotics with activity against MRSA include daptomycin, linezolid, and ceftaroline; these drugs and may be used for severe infections under the guidance of infectious disease specialists. To date there is little pediatric data for the use of novel long half-life lipoglycopeptides (eg, oritavancin, dalbavancin). Rifampin is used occasionally for adjunctive treatment of persistent staphylococcal infections, particularly in the presence of foreign material, but it should never be used as monotherapy.

1. Skin infections

Treatment of skin and soft tissue infections depends, in part, on the extent of the lesion, immunocompetence of the host, and the toxicity of the patient. Afebrile, well-appearing patients with small abscesses may do well with incision and drainage (with or without the addition of oral antimicrobials). More serious infections or infections in immunocompromised patients should be treated more aggressively. Hospitalization and intravenous antibiotics may be required. Culture and susceptibility testing will help guide therapy.

For patients who are not sick enough to require hospitalization or intravenous therapy, selection of the best empiric antimicrobial depends on local rates of MRSA and local susceptibilities. β-Lactam antibiotics, such as penicillins and cephalosporins, can no longer depend on as single agents for the majority of cases in communities with high MRSA rates, but may be considered as initial treatment in milder infections where good follow-up can be assured. TMP-SMX or clindamycin (depending on local susceptibility patterns) may be used for empiric staphylococcal coverage. However, GAS may be resistant to TMP-SMX, and not all MSSA or MRSA will be covered by clindamycin. Many clinicians empirically use a combination of TMP-SMX and cefazolin/cephalexin for empiric treatment of skin and soft tissue infections.

2. Osteomyelitis and septic arthritis

Treatment should be begun intravenously, with antibiotics selected to cover the most likely organisms (staphylococci in hematogenous osteomyelitis; meningococci, pneumococci, Kingella kingae, staphylococci in children aged < 3 years with septic arthritis; staphylococci and gonococci in older children with septic arthritis). Knowledge of local MRSA rates will help guide empiric therapy. Antibiotic levels should be kept high at all times.

Clinical studies support the use of intravenous treatment for osteomyelitis until fever and local symptoms and signs and inflammatory markers are subsiding—usually at least 3–5 days—followed by oral therapy. For both osteomyelitis and joint infections, good compliance with oral therapy is important for successful cure.

Nafcillin or cefazolin can be used for intravenous therapy of MSSA strains. Clindamycin is an alternative agent if the organism is susceptible, and the patient does not have a severe or life-threatening infection or ongoing bacteremia. Cephalexin 100–150 mg/kg/day in four divided doses can be used when the patient is ready for oral therapy.

Vancomycin can be used initially for MRSA osteomyelitis, while awaiting final susceptibilities. Antibiotic regimens for MRSA osteomyelitis should be based on susceptibility results; isolates may be susceptible to clindamycin or linezolid, but susceptibility patterns vary geographically.

The C-reactive protein (in the first or second week after therapy is started) and the erythrocyte sedimentation rate (ESR) (usually measured weekly) are good indicators of response to therapy. Duration of therapy is typically 3–4 weeks for septic arthritis and 4–6 weeks for acute osteomyelitis. Surgical drainage of osteomyelitis or septic arthritis is often required (see Chapter 26).

3. Staphylococcal pneumonia

For MSSA pneumonia, nafcillin and oxacillin are the usual drugs of choice. Vancomycin can be used empirically until results of cultures and susceptibility tests are obtained if community or hospital MRSA rates are high. In sicker patients, vancomycin plus nafcillin can be used (in addition to coverage of other pathogens) until the etiologic agent and susceptibilities are established. Linezolid has been reported to be as efficacious as vancomycin for the treatment of resistant gram-positive pneumonia and soft tissue infections.

Empyema and pyopneumothorax require drainage. The choice of chest tube versus thoracoscopic drainage depends on local institutional practice. If staphylococcal pneumonia is treated promptly and empyema drained, resolution in children often is complete.

4. Staphylococcal food poisoning

Therapy is supportive and usually not required except in severe cases or for small infants with marked dehydration.

5. Staphylococcal endocarditis

The treatment of staphylococcal endocarditis depends on whether the patient has a prosthetic valve or material in the heart and on the susceptibilities of the organism. Please see the American Heart Association’s Guidelines on Infective Endocarditis: Diagnosis and Management, and consult an infectious disease physician for this serious and sometimes complicated problem. High-dose, prolonged parenteral treatment is indicated. Therapy lasts in all instances for at least 6 weeks.

Occasionally, medical treatment fails. Signs of treatment failure are: (1) recurrent fever without apparent treatable other cause (eg, thrombophlebitis, respiratory or urinary tract infection, drug fever), (2) persistently positive blood cultures, (3) intractable and progressive congestive heart failure, and (4) recurrent (septic) embolization. In such circumstances—particularly (2), (3), and (4)—evaluation for valve replacement becomes necessary. Antibiotics are continued for at least another 4 weeks after blood cultures are proven negative. Persistent or recurrent infection may require a second surgical procedure.

6. Toxic shock syndrome

Treatment is aimed at expanding blood volume, maintaining perfusion pressure with inotropic agents, ensuring prompt drainage of a focus of infection (or removal of tampons or foreign bodies), and giving intravenous antibiotics.

Vancomycin, in addition to a β-lactam antibiotic (oxacillin or nafcillin), can be used for empiric therapy because TSS can be challenging to discriminate from staphylococcal sepsis. Many experts also add clindamycin, since clindamycin is a protein synthesis inhibitor and may limit toxin production. Clindamycin should not be used empirically as a single agent until susceptibilities are known. Intravenous immunoglobulin has been used as adjunctive therapy for severe disease.

7. Vancomycin-resistant S aureus infections (VRSA)

Reports of VRSA isolates are rare but are likely to increase in frequency. Such isolates are sometimes susceptible to clindamycin or TMP-SMX. If not, therapeutic options include linezolid, ceftaroline or daptomycin, assuming the strain is susceptible to these agents. Consultation with an infectious disease specialist is recommended.

8. Coagulase-negative staphylococcal infections

Coagulase-negative staphylococci are frequently resistant to penicillins and cephalosporins. Bacteremia and other serious coagulase-negative staphylococcal infections are treated initially with vancomycin, with susceptibility results guiding subsequent therapy. Coagulase-negative staphylococci are uncommonly resistant to vancomycin (see Chapter 39 for dosing). Many drugs used for MRSA are also effective against these pathogens.

MENINGOCOCCAL INFECTIONS

General Considerations

Meningococci (Neisseria meningitidis) may be carried asymptomatically for months in the upper respiratory tract. Less than 1% of carriers develop disease. Meningitis and sepsis are the two most common forms of illness, but septic arthritis, pericarditis, pneumonia, chronic meningococcemia, otitis media, conjunctivitis, and vaginitis also occur. Meningococcal cases in the United States have continued to decline; currently there are an estimated 400–600 cases annually. The highest attack rate for meningococcal meningitis is in the first year of life, with a secondary peak during the teen years. The development of irreversible shock with multiorgan failure is a significant factor in the fatal outcome of acute meningococcal infections.

Meningococci are gram-negative organisms containing endotoxin in their cell walls. Endotoxins cause capillary vascular injury and leak as well as DIC. Meningococci are classified serologically into groups: A, B, C, Y, and W are the groups most commonly implicated in systemic disease. Currently in the United States, more than one-half of cases in infants, children, and adolescents are caused by serogroup B. Over the last few years, several outbreaks on college campus have been caused by serogroup B. Serogroup A causes epidemics in sub-Saharan Africa but rarely is associated with cases of meningococcal disease in the United States. N meningitidis with increased MICs to penicillin G are reported, but the clinical significance of this is unclear. A small number of these isolates are reported in the United States. Resistant isolates are susceptible to third-generation cephalosporins. Few isolates are resistant to rifampin. In recent years, fluoroquinolone-resistant N meningitidis has emerged.

Patients deficient in one of the late components of the complement pathway are uniquely susceptible to meningococcal infection. Deficiencies of early and alternative pathway complement components, anatomic or functional asplenia, eculizumab use, and human immunodeficiency virus (HIV) infection also are associated with increased susceptibility.

Prevention

A. Chemoprophylaxis

Household contacts, day care center contacts, and hospital personnel directly exposed to the respiratory secretions of patients are at increased risk for developing meningococcal infection and should be given chemoprophylaxis. The secondary attack rate among household members is about 500–800 times the attack rate in the general population. Children between the ages of 3 months and 2 years are at greatest risk, presumably because they lack protective antibodies. Secondary cases may occur in day care centers and in classrooms. Hospital personnel are not at increased risk unless they have had contact with a patient’s oral secretions, for example, during mouth-to-mouth resuscitation, intubation, or suctioning procedures. Approximately 50% of secondary cases in households have their onset within 24 hours of identification of the index case. Exposed contacts should be notified promptly. If they are febrile, they should be fully evaluated and given high doses of penicillin or another effective antimicrobial pending the results of blood cultures.

All high-risk contacts should receive chemoprophylaxis for meningococcal disease as soon as an index case is identified. High-risk contacts are defined as:

• All household contacts (especially children < 2 years of age)

• Persons with child care or preschool contact with the index patient at any time in the 7 days prior to illness onset

• Persons with direct exposure to index patients secretions (sharing of drinks, straws, cigarettes, toothbrushes, eating utensils, kissing) during the 7 days prior to illness onset

• Persons who have performed mouth-to-mouth resuscitation or performed unprotected endotracheal intubation of the index patient during the 7 days prior to illness onset

• Persons who have slept in the same dwelling as the index patient within 7 days of illness onset

• Passengers who were seated directly next to the index patient on a flight of more than 8 hours duration

The most commonly used agent for meningococcal chemoprophylaxis is oral rifampin given twice daily for 2 days (600 mg for adults; 15–20 mg/kg for children older than 1 month [maximum dosage 600 mg] and 5 mg/kg for infants younger than 1 month). Rifampin may stain a patient’s tears (and contact lenses), sweat, and urine orange; it may also affect the reliability of oral contraceptives, and alternative contraceptive measures should therefore be employed when rifampin is administered. Rifampin should not be given to pregnant women. Instead, intramuscular ceftriaxone is the preferred agent: 125 mg given as a single dose if the patient is younger than 15 years; 250 mg given as a single dose if the patient is aged 15 years or older. Penicillin and most other antibiotics (even with parenteral administration) are not effective chemoprophylactic agents, because they do not eradicate upper respiratory tract carriage of meningococci. Ciprofloxacin (20 mg/kg as a single dose, maximum dose 500 mg) effectively eradicates nasopharyngeal carriage in adults and children but is not recommended in pregnant women or in communities where fluoroquinolone-resistant strains of N meningitidis have been identified. Throat cultures to identify carriers are not useful.

B. Vaccine

Several types of vaccines are currently licensed in the United States for meningococcal disease prevention; 2-quadrivalent meningococcal conjugate vaccines (see Chapter 10) that cover serogroups A, C, Y, and W are available in the United States. Two serogroup B vaccines are licensed for ages 10–25 years. (See Chapter 10 for a discussion on meningococcal vaccines.)

Clinical Findings

A. Symptoms and Signs

Many children with clinical meningococcemia also have meningitis, and some have other foci of infection. All children with suspected meningococcemia should have a lumbar puncture.

1. Meningococcemia

A prodrome of upper respiratory infection is followed by high fever, headache, nausea, marked toxicity, and hypotension. Purpura, petechiae, and occasionally bright pink, tender macules or papules over the extremities, and trunk are seen. The rash usually progresses rapidly. Occasional cases lack rash. Fulminant meningococcemia is characterized by DIC, massive skin and mucosal hemorrhages, and shock. This syndrome also may be caused by H influenzae, S pneumoniae, or other bacteria. Chronic meningococcemia is a rare condition characterized by periodic bouts of fever, arthralgia or arthritis, and recurrent petechiae. Splenomegaly often is present. Patients may be free of symptoms between bouts. Chronic meningococcemia occurs primarily in adults and mimics Henoch-Schönlein purpura.

2. Meningitis

In many children, meningococcemia is followed within a few hours to several days by symptoms and signs of acute purulent meningitis, with severe headache, stiff neck, nausea, vomiting, and stupor. Children with meningitis generally fare better than children with meningococcemia alone, probably because they have survived long enough to develop clinical signs of meningitis.

B. Laboratory Findings

The peripheral WBC count may be either low or elevated. Thrombocytopenia may be present with or without DIC (see Chapter 30). If petechial or hemorrhagic lesions are present, meningococci can sometimes be seen microscopically in tissue fluid expressed from a punctured lesion. CSF is generally cloudy and contains more than 1000 WBCs/μL, with many polymorphonuclear neutrophils and gram-negative intracellular diplococci. A total hemolytic complement assay may reveal absence of late components as an underlying cause. PCR assays with high sensitivity and specificity are now available to detect N meningitidis, and can be useful, especially in cases where antibiotics were initiated before any cultures were obtained; however, culture remains the gold standard.

Differential Diagnosis

The skin lesions of H influenzae or pneumococci, enterovirus infection, endocarditis, leptospirosis, Rocky Mountain spotted fever, other rickettsial diseases, Henoch-Schönlein purpura, and blood dyscrasias may be similar to meningococcemia. Severe S aureus sepsis has been reported in some patients to present with purpura. Other causes of sepsis and meningitis are distinguished by appropriate Gram stain and cultures.

Complications

Meningitis may lead to permanent central nervous system (CNS) damage, with deafness, convulsions, paralysis, or impaired intellectual function. Hydrocephalus may develop and requires ventriculoperitoneal shunt. Subdural collections of fluid are common but usually resolve spontaneously. Extensive skin necrosis, loss of digits or extremities, intestinal hemorrhage, and late adrenal insufficiency may complicate fulminant meningococcemia.

Treatment

Blood cultures should be obtained for all children with fever and purpura or other signs of meningococcemia, and antibiotics should be administered immediately as an emergency procedure.

Children with meningococcemia or meningococcal meningitis should be treated as though shock were imminent even if their vital signs are stable when they are first seen. If hypotension is present, supportive measures should be aggressive, because the prognosis is grave in such situations. Treatment should be started emergently in an intensive care setting, but should not be delayed while transporting the patient. Shock may worsen following antimicrobial therapy due to endotoxin release. To minimize the risk of nosocomial transmission, patients should be placed in respiratory isolation for the first 24 hours of antibiotic treatment.

A. Specific Measures

Antibiotics should be initiated promptly. Because other bacteria, such as S pneumoniae, S aureus, or other gram-negative organisms, can cause identical syndromes, initial therapy should be broad. Vancomycin and cefotaxime (or ceftriaxone) are preferred initial coverage. Once N meningitidis has been isolated, penicillin G, cefotaxime, or ceftriaxone intravenously for 7 days are the drugs of choice. Relative penicillin resistance is uncommon but has been reported in the United States.

B. General Measures

Blood cultures should be drawn prior to initiation of antibiotic therapy; however antibiotic therapy should not be delayed in order to obtain a lumbar puncture as prompt treatment portends better outcomes due to the aggressive nature of this infection. Supportive care includes early and aggressive fluid resuscitation and vasopressor initiation.

Prognosis

Unfavorable prognostic features include shock, DIC, and extensive skin lesions. The case fatality rate in fulminant meningococcemia is over 30%. In uncomplicated meningococcal meningitis, the fatality rate is much lower (10%–20%). An invasive meningococcal infection may be the first indication of an underlying immunodeficiency, particularly defects in terminal complement function.

GONOCOCCAL INFECTIONS

General Considerations

Neisseria gonorrhoeae is a gram-negative diplococcus. Although morphologically similar to other Neisseriae, it differs in its ability to grow on selective media and to ferment carbohydrates. The cell wall of N gonorrhoeae contains endotoxin, which is liberated when the organism dies and stimulates the production of a cellular exudate. The incubation period is short, usually 2–5 days.

Reported cases of gonorrhea exceeded 555,000 in the United States in 2017 and have continued to increase since reaching historic lows in 2009. Gonococcal disease in children may be transmitted sexually or nonsexually. Prepubertal gonococcal infection outside the neonatal period should be considered presumptive evidence of sexual contact or child abuse. Prepubertal girls usually manifest gonococcal vulvovaginitis without cervicitis because of the neutral to alkaline pH of the vagina and thin vaginal mucosa.

In the adolescent or adult, the workup of every case of gonorrhea should include a careful and accurate inquiry into the patient’s sexual practices and appropriate cultures obtained, because pharyngeal and/or anorectal infections may be difficult to eradicate. Efforts should be made to identify and provide treatment to all sexual contacts. Programs of expedited partner treatment where prescriptions are provided without first examining the sexual contact increase successful treatment. Young women are at risk for serious health consequences including infertility due to gonococcal and chlamydia infection.

Clinical Findings

A. Symptoms and Signs

1. Asymptomatic gonorrhea

The ratio of asymptomatic to symptomatic gonorrheal infections in adolescents and adults is probably 3–4:1 in women and 0.5–1:1 in men. Asymptomatic infections are as infectious as symptomatic ones.

2. Uncomplicated genital gonorrhea

Urethral discharge is sometimes painful and bloody and may be white, yellow, or green. There may be associated dysuria. Epididymitis may present with acute scrotal swelling or pain. The patient usually is afebrile.

The only clinical findings initially may be dysuria and polymorphonuclear neutrophils in the urine. Vulvitis characterized by erythema, edema, and excoriation accompanied by a purulent discharge may follow.

Symptomatic disease is characterized by a purulent, foul-smelling vaginal discharge, dysuria, and occasionally dyspareunia. Fever and abdominal pain are absent. The cervix is frequently hyperemic and tender when touched. This tenderness is not worsened by moving the cervix, nor is the adnexa tender to palpation.

Rectal gonorrhea often is asymptomatic. There may be purulent discharge, edema, and pain during evacuation.

3. Pharyngeal gonorrhea

Pharyngeal infection usually is asymptomatic. There may be some sore throat and, rarely, acute exudative tonsillitis with bilateral cervical lymphadenopathy and fever.

4. Conjunctivitis and iridocyclitis

Copious, usually purulent exudate is characteristic of gonococcal conjunctivitis. Newborns are symptomatic on days 2–4 of life. In the adolescent or adult, infection probably is spread from infected genital secretions by the fingers.

5. Pelvic inflammatory disease (salpingitis)

The interval between initiation of genital infection and its ascent to the uterine tubes is variable and may range from days to months. Menses frequently are the initiating factor. With the onset of a menstrual period, gonococci invade the endometrium, causing transient endometritis. Subsequently salpingitis may occur, resulting in pyosalpinx or hydrosalpinx. Rarely infection progresses to peritonitis or perihepatitis. Gonococcal salpingitis occurs in an acute, subacute, or chronic form. All three forms have in common tenderness on gentle movement of the cervix and adnexal tenderness during pelvic examination.

Gonococci or Chlamydia trachomatis are the cause of about 50% of cases of pelvic inflammatory disease. A mixed infection caused by enteric bacilli, Bacteroides fragilis, or other anaerobes occurs in the other 50%.

6. Gonococcal perihepatitis (Fitz-Hugh-Curtis syndrome)

Typically the patient presents with right upper quadrant tenderness in association with signs of acute or subacute salpingitis. Pain may be pleuritic and referred to the shoulder. Hepatic friction rub is a valuable but inconstant sign.

7. Disseminated gonorrhea

Dissemination follows asymptomatic more often than symptomatic genital infection, often from gonococcal pharyngitis or anorectal gonorrhea. The most common form of disseminated gonorrhea is the triad of polyarthralgia, tenosynovitis, and dermatitis (also referred to as arthritis-dermatitis syndrome) although patients may not present with all three. Septic arthritis is less common, and gonococcal endocarditis and meningitis are rare.

Disease usually begins with the simultaneous onset of low-grade fever, polyarthralgia, and malaise. After a day or so, joint symptoms become acute. Swelling, redness, and tenderness occur, frequently over the wrists, ankles, and knees but also in the fingers, feet, and other peripheral joints. The arthralgia may be migratory. Skin lesions may be noted at the same time. Discrete, tender, maculopapular lesions 5–8 mm in diameter appear that may become vesicular, pustular, and then hemorrhagic. They are few in number and noted on the fingers, palms, feet, and other distal surfaces. In patients with this form of the disease, blood cultures are often positive, but joint fluid rarely yields organisms. Skin lesions often are positive by Gram stain but rarely by culture. Genital, rectal, and pharyngeal cultures must be performed.

In this less common form of disseminated gonorrhea, fever is often absent. Arthritis evolves in one or more joints. Dermatitis usually does not occur. Systemic symptoms are minimal. Blood cultures are negative, but joint aspirates may yield gonococci on smear and culture. Genital, rectal, and pharyngeal cultures must be performed.

B. Laboratory Findings

Demonstration of gram-negative, kidney-shaped diplococci in smears of urethral exudate in males is presumptive evidence of gonorrhea. Positive culture confirms the diagnosis. Negative smears do not rule out gonorrhea. Gram-stained smears of cervical or vaginal discharge in girls are more difficult to interpret because of normal gram-negative flora, but they may be useful when technical personnel are experienced. NAAT on urine or genital specimens enable detection of N gonorrhoeae and C trachomatis. These tests have excellent sensitivity and are replacing culture in many laboratories. All children or adolescents with a suspected or established diagnosis of gonorrhea should have serologic tests for syphilis and HIV.

If cultures are obtained, use of a selective chocolate agar–containing antibiotics (eg, Thayer-Martin agar) is needed to suppress normal flora. If bacteriologic diagnosis is critical, suspected material should be cultured on chocolate agar as well. Because gonococci are labile, agar plates should be inoculated immediately and placed without delay in an atmosphere containing CO_2. When transport of specimens is necessary, material should be inoculated directly into an appropriate transport medium prior to shipment to the laboratory. In cases of possible sexual molestation, notify the laboratory that definite speciation is needed, because nongonococcal Neisseria species can grow on the selective media.

Differential Diagnosis

Urethritis in the male may be gonococcal or nongonococcal (NGU). NGU is a syndrome characterized by discharge (rarely painful), mild dysuria, and a subacute course. The discharge is usually scant or moderate and nonpurulent. C trachomatis is the most common cause of NGU. Doxycycline (100 mg orally twice a day for 7 days) is efficacious. Single-dose azithromycin, 1 g orally, may achieve better compliance. C trachomatis has been shown to cause epididymitis in males and salpingitis in females.

Vulvovaginitis in a prepubertal female may be due to infection caused by miscellaneous bacteria, including Shigella, GAS, Candida, and herpes simplex. Discharges may be caused by trichomonads, Enterobius vermicularis (pin-worm), candidiasis or foreign bodies. Symptom-free discharge (leukorrhea) normally accompanies rising estrogen levels.

Cervicitis in a postpubertal female, alone or in association with urethritis and involvement of Skene and Bartholin glands, may be due to infection caused by Candida, herpes simplex, Trichomonas, or discharge resulting from inflammation caused by foreign bodies (usually some form of contraceptive device). Leukorrhea may be associated with birth control pills.

Salpingitis may be due to infection with other organisms. The symptoms must be differentiated from those of appendicitis, urinary tract infection, ectopic pregnancy, endometriosis, or ovarian cysts or torsion.

Disseminated gonorrhea presents a differential diagnosis that includes meningococcemia, acute rheumatic fever, Henoch-Schönlein purpura, juvenile idiopathic arthritis, lupus erythematosus, leptospirosis, secondary syphilis, certain viral infections (particularly rubella, but also enteroviruses and parvovirus), serum sickness, type B hepatitis (in the prodromal phase), infective endocarditis, and even acute leukemia and other types of cancer.

Prevention

Prevention of gonorrhea is principally a matter of sex education, condom use, and identification and treatment of contacts.

Treatment

Antimicrobial-resistant gonococci are a serious problem. N gonorrhoeae infections resistant to tetracyclines, penicillins, and fluoroquinolones are common. In some cases, clinicians will have very limited choices for therapy. Many clinical laboratories do not routinely perform antimicrobial susceptibility tests on N gonorrhoeae, and many infections are documented by nonculture methods.

A. Uncomplicated Urogenital, Pharyngeal, or Rectal Gonococcal Infections in Adolescents

Ceftriaxone (250 mg intramuscularly in a single dose) and azithromycin (1 g orally in a single dose) is recommended. Fluoroquinolones are no longer recommended for therapy due to increasing rates of resistance. If ceftriaxone cannot be used, cefixime (400 mg orally in a single dose) and azithromycin (1 g orally in a single dose) is recommended. Doxycycline (100 mg orally twice daily for 7 days) can be used in place of azithromycin in these regimens, but azithromycin is preferred due to convenience and compliance advantages. Azithromycin (2 g orally once) in combination with either gemifloxacin (320 mg orally once) or gentamicin (240 mg intramuscularly once) can be used in cases of severe cephalosporin allergy.

A test-of-cure is not recommended for asymptomatic individuals who have received one of the recommended regimens for gonococcal infection. However, a patient receiving an alternative regimen for pharyngeal infection should be retested 14 days after completing treatment.

B. Disseminated Gonorrhea

Recommended regimens include ceftriaxone (1 g intramuscularly or intravenously once daily) plus azithromycin (1 g orally in a single dose). Alternative regimens include azithromycin (1 g orally in a single dose) plus either cefotaxime (1 g intravenously every 8 hours) or ceftizoxime (1 g intravenously every 8 hours). Oral therapy may follow parenteral therapy 24–48 hours after improvement. Recommended regimens include cefixime (400 mg) twice daily to complete 7 days of therapy. Fluoroquinolones are not recommended.

C. Pelvic Inflammatory Disease

Doxycycline (100 mg twice a day orally or intravenously) and either cefoxitin (2 g intravenously every 6 hours) or cefotetan (2 g intravenously every 12 hours) are given until the patient is clinically improved; then doxycycline is administered by mouth to complete 14 days of therapy. Clindamycin (900 mg intravenously every 8 hours) plus gentamicin (2 mg/kg loading dose intravenously or intramuscularly, followed by a maintenance dose 1.5 mg/kg every 8 hours) until the patient improves clinically may also be used. When tubo-ovarian abscess is present, either clindamycin (450 mg orally four times daily) or metronidazole (500 mg orally twice daily) should be used in addition to doxycycline for at least 14 days in order to provide better anaerobic coverage. In women with mild to moderate PID, an intramuscular plus oral regimen can be considered—see the CDC STD Treatment Guidelines for further details.

D. Prepubertal Gonococcal Infections

1. Uncomplicated genitourinary, rectal, or pharyngeal infections

These infections may be treated with ceftriaxone (25–50 mg/kg to a maximum of 125 mg intramuscularly in a single dose) in prepubertal children who weigh less than 45 kg. Children who weigh 45 kg or greater and are older than 8 years should receive ceftriaxone (250 mg intramuscularly in a single dose) and azithromycin (1 g orally in a single dose). The physician should evaluate all children for evidence of sexual abuse and coinfection with syphilis, Chlamydia, and HIV.

2. Disseminated gonorrhea

Prepubertal children wei­ghing less than 45 kg should be treated with ceftriaxone (50 mg/kg (max 1 g) once daily parenterally for 7 days. For prepubertal children who weigh 45 kg or greater, the regimen is the same as the adult regimen.

BOTULISM

General Considerations

Botulism is a paralytic disease caused by Clostridium botulinum, an anaerobic, gram-positive, spore-forming bacillus normally found in soil. The organism produces an extremely potent neurotoxin. Of the seven types of toxin (A–G), types A, B, and E cause most human diseases. The toxin, a polypeptide, is so potent that 0.1 mg is lethal for humans.

Food-borne botulism usually results from ingestion of toxin-containing food. Preformed toxin is absorbed from the gut and produces paralysis by preventing acetylcholine release from cholinergic fibers at neuromuscular junctions. Virtually any food will support the growth of C botulinum spores into vegetative toxin-producing bacilli if an anaerobic, nonacid environment is provided. The food may not appear or taste spoiled. The toxin is heat-labile, but the spores are heat-resistant. Inadequate heating during processing (temperature < 115°C) allows the spores to survive and later resume toxin production.

Infant botulism occurs in infants younger than 12 months. The toxin is produced by ingested C botulinum spores that germinate and produce toxin in the gastrointestinal tract.

Annually, 10–15 cases of wound botulism are reported. Most cases occur in drug abusers with infection in intravenous or intramuscular injection sites.

Prevention

Infant botulism is acquired by ingestion of botulism spores that then sporulate into C botulinum organisms that form botulinum toxin. Honey can contain botulism spores so it is recommended that honey not be consumed by infants younger than 12 months.

Food-borne botulism is acquired by ingesting preformed botulism toxin in food. In the United States, food-borne botulism is most commonly seen with ingestion of home-canned foods of low acidity (ie, corn, asparagus, green beans, potatoes). However, other foods have been associated with botulism. Persons who eat home-canned foods should consider boiling foods for at least 10 minutes or heating to 80°F for 30 minutes (can destroy potential toxin). Safe food handling practices include keeping foods either refrigerated (< 45°F) or hot (> 185°F), and disposing of any cracked jars or bulging/dented cans.

Clinical Findings

A. Symptoms and Signs

The incubation period for food-borne botulism may range from 2 hours to 12 days. The initial symptoms are lethargy and headache. These are followed by double vision, dilated pupils, ptosis, and within a few hours, difficulty with swallowing and speech. The mucous membranes often are very dry. Descending skeletal muscle paralysis may be seen. Death usually results from respiratory failure.

Botulism patients present with a “classic triad”: (1) afebrile; (2) symmetrical, flaccid, descending paralysis with prominent bulbar palsies; and (3) clear sensorium. Recognition of this triad is important in making the clinical diagnosis. Botulism is caused by a toxin; thus, there is no fever unless secondary infection (eg, aspiration pneumonia) occurs. Common bulbar palsies seen include dysphonia, dysphagia, dysarthria, and diplopia (four “Ds”).

Infant botulism is seen in infants younger than 12 months (peak onset 2–8 months). Infants younger than 2 weeks rarely develop botulism. The initial symptoms are usually constipation and progressive, often severe, hypotonia. Clinical findings include loss of facial expression, constipation, weak suck and cry, pooled oral secretions, cranial nerve deficits, generalized weakness, and, on occasion, apnea.

B. Laboratory Findings

The diagnosis is made by demonstration of C botulinum toxin in stool, gastric aspirate or vomitus, or serum. Serum and stool samples can be sent for toxin confirmation (done by toxin neutralization mouse bioassay at CDC or state health departments). In infant botulism, serum assays for C botulinum toxin are usually negative. The tests take time, and therapy should not be withheld awaiting testing results. Foods that are suspected to be contaminated should be kept refrigerated and given to public health personnel for testing. Laboratory findings, including CSF examination, are usually normal. Electromyography suggests the diagnosis if the characteristic brief, small abundant motor-unit action potentials (BSAP) abnormalities are seen. A nondiagnostic electromyogram does not exclude the diagnosis.

Differential Diagnosis

Guillain-Barré syndrome is characterized by ascending paralysis, sensory deficits, and elevated CSF protein without pleocytosis.

Other illnesses that should be considered include poliomyelitis, acute flaccid myelitis, post diphtheritic polyneuritis, certain chemical intoxications, tick paralysis, and myasthenia gravis. The history and elevated CSF protein characterize postdiphtheritic polyneuritis. Tick paralysis presents with a flaccid ascending motor paralysis. An attached tick should be sought. Myasthenia gravis usually occurs in adolescent girls. It is characterized by ocular and bulbar symptoms, normal pupils, fluctuating weakness, absence of other neurologic signs, and clinical response to cholinesterase inhibitors.

Complications

Difficulty in swallowing leads to aspiration pneumonia. Serious respiratory paralysis may be fatal despite assisted ventilation and intensive supportive measures.

Treatment

A. Specific Measures

Patients with suspected botulism should be hospitalized and monitored closely for signs of impending respiratory failure and inability to manage secretions. Early treatment of botulism with antitoxin is beneficial. The type of antitoxin treatment recommended differs depending on the type of botulism. Treatment should begin as soon as the clinical diagnosis is suspected (prior to microbiologic or toxin confirmation). Contact your state health department’s emergency 24-hour telephone number immediately when a case of botulism is suspected to assist in therapeutic decisions and to help obtain treatment product.

For treatment of suspected infant botulism, intravenous human botulism immunoglobulin (BabyBIG) is approved by the US FDA. BabyBIG contains neutralizing antibodies against types A and B toxin. A placebo-controlled clinical trial of BabyBIG use in infant botulism showed substantial reductions in the mean hospital stay, mechanical ventilation days, and intensive care days in the BabyBIG-treated group. BabyBIG is not indicated for use in any form of botulism (wound, food-borne) other than infant botulism. To obtain BabyBIG (in any state), contact the California Department of Public Health (24-hour telephone number: 510-231-7600; www.infantbotulism.org/). Antimicrobial agents are not recommended to treat infant botulism, except when bacterial complications occur (ie, pneumonia, line infection, etc).

For other types of botulism (noninfant botulism), patients should be treated with heptavalent botulinum antitoxin (HBAT), which was licensed by the FDA in 2013 for treatment of adult and pediatric botulism. HBAT is an equine-derived antitoxin that contains antibodies to all seven botulinum toxin types (A through G). The treatment protocol (available from the CDC) includes detailed instructions for intravenous administration of antitoxin. State health departments can assist practitioners in obtaining the antitoxin; if state health department officials are unavailable, the CDC (770-488-7100) can be contacted for help in obtaining the product and for consultation. In addition, epidemic assistance, and laboratory testing services are available from the CDC through state health departments. For wound botulism, penicillin or metronidazole can be considered, once HBAT has been given. Surgical debridement of involved tissue is recommended.

B. General Measures

General and supportive therapy consists of bed rest, ventilatory support (if necessary), fluid therapy, and enteral or parenteral nutrition. Aminoglycosides and clindamycin may exacerbate neuromuscular blockage and should be avoided.

Prognosis

The mortality rate has declined substantially in recent years and currently is about 3%–5%. The prospect for full recovery is good but may take weeks to months depending on the severity of the initial illness.

TETANUS

General Considerations

Tetanus is caused by Clostridium tetani, an anaerobic, gram-positive bacillus that produces a potent neurotoxin. In unimmunized or incompletely immunized individuals, infection follows contamination of a wound by soil-containing clostridial spores from animal manure. The toxin reaches the CNS by retrograde axon transport, is bound to cerebral gangliosides, and increases reflex excitability in neurons of the spinal cord by blocking function of inhibitory synapses. Intense muscle spasms result. Two-thirds of cases in the United States follow minor puncture wounds of the hands or feet. In many cases, no history of a wound can be obtained. IV drug use and diabetes may be risk factors (in individuals who are not tetanus-immune). In the newborn, usually in underdeveloped countries, infection generally results from contamination of the umbilical cord. The incubation period typically is 3–21 days but may be longer. In the United States, cases in young children are due to inadequate immunization. Eighty-five percent of cases occur in adults older than 25 years.

Prevention

A. Tetanus Toxoid

Active immunization with tetanus toxoid prevents tetanus. Immunity is almost always achieved after the third dose of vaccine. Tetanus immunoglobulin (TIG) is an additional agent used to prevent tetanus in persons who have received less than three doses of tetanus toxoid or in immunocompromised patients who do not make sufficient antibody (ie, HIV infection; see Chapter 10). A tetanus toxoid booster at the time of injury is needed if none has been given in the past 10 years—or within 5 years for heavily contaminated wounds. Nearly all cases of tetanus (99%) in the United States are in nonimmunized or incompletely immunized individuals. Many adolescents and adults lack protective antibody.

B. Wound Care and Prophylaxis for Tetanus-Prone Wounds

Wounds that are contaminated with soil, debris, feces, or saliva are at increased risk for tetanus. Puncture wounds, crush injuries, avulsions, frostbite, burns, or other wounds that contain devitalized tissue are also at increased risk of infection with C tetani. All wounds should be adequately cleaned, foreign material removed, and debrided if necrotic or devitalized tissue or residual foreign matter is present. The decision to use tetanus toxoid–containing vaccine, human TIG, or both depends on the type of injury and the tetanus immunization status of the patient (see Chapter 10; Table 10–5). TIG should be used in children with fewer than three previous tetanus toxoid immunizations (DPT, DTaP, DT, Td, Tdap) who have tetanus-prone wounds and in immune compromised children, including those with HIV, who have tetanus-prone wounds, regardless of their immunization history. When TIG is indicated for wound prophylaxis 250 units are given intramuscularly regardless of age. If tetanus immunization is incomplete, a dose of age-appropriate vaccine should be given. When both are indicated, tetanus toxoid and TIG should be administered concurrently at different sites using different syringes (see Chapter 10).

Prophylactic antimicrobials are useful if the child is unimmunized and TIG is not available.

Clinical Findings

A. Symptoms and Signs

The first symptom often is mild pain at the site of the wound, followed by hypertonicity and spasm of the regional muscles. Characteristically, difficulty in opening the mouth (trismus) is evident within 48 hours. In newborns, the first signs are irritability and inability to nurse. The infant may then develop stiffness of the jaw and neck, increasing dysphagia, and generalized hyperreflexia with rigidity and spasms of all muscles of the abdomen and back (opisthotonos). The facial distortion resembles a grimace (risus sardonicus). Difficulty in swallowing and convulsions triggered by minimal stimuli such as sound, light, or movement may occur. Individual spasms may last seconds or minutes. Recurrent spasms are seen several times each hour, or they may be almost continuous. In most cases, the temperature is normal or only mildly elevated. A high or subnormal temperature is a bad prognostic sign. Patients are fully conscious and lucid. A profound circulatory disturbance associated with sympathetic overactivity (elevated blood pressure, tachycardia, arrhythmia) may occur on the second to fourth day, which may contribute to the mortality rate.

B. Laboratory Findings

The diagnosis is made on clinical grounds. There may be a mild polymorphonuclear leukocytosis. The CSF is normal with the exception of mild elevation of opening pressure. Serum muscle enzymes may be elevated. Anaerobic culture and microscopic examination of pus from the wound can be helpful, but C tetani is difficult to grow.

Differential Diagnosis

Poliomyelitis is characterized by asymmetrical flaccid paralysis in an incompletely immunized child. The history of an animal bite and the absence of trismus may suggest rabies. Local infections of the throat and jaw should be easily recognized. Bacterial meningitis, phenothiazine reactions, decerebrate posturing, narcotic withdrawal, spondylitis, and hypocalcemic tetany may be confused with tetanus.

Complications

Complications include sepsis, malnutrition, pneumonia, atelectasis, asphyxial spasms, decubitus ulcers, and fractures of the spine due to intense contractions. They can be prevented in part by skilled supportive care.

Treatment of Tetanus

A. Specific Measures

Human TIG in a single dose of 3000–6000 units, intramuscularly, is given to children and adults. Some experts suggest that a dose of 500 units is just as effective. Infiltration of part of the TIG dose around the wound is recommended. If TIG is indicated, but not available, intravenous immunoglobulin in a dose of 200–400 mg/kg intravenously can be infused over several hours (although it is not licensed for this indication; see package insert for infusion instructions). In countries where TIG or immunoglobulins are not available, equine tetanus antitoxin may be available. Surgical debridement of wounds is indicated, but more extensive surgery or amputation to eliminate the site of infection is not necessary. Antibiotics are given in an attempt to decrease the bacterial load and subsequent toxin production: oral or intravenous metronidazole (30 mg/kg/day in four divided doses; maximum 4 g/day) for 10–14 days is the preferred agent. Parenteral penicillin G (100,000 U/kg/day in four to six divided doses; maximum 12 million U/day) is an alternative regimen. An age-appropriate tetanus toxoid containing vaccine should be administered in a different limb from the TIG administration site.

B. General Measures

Treatment of tetanus is usually best accomplished in an intensive care unit. The patient is kept in a quiet room with minimal stimulation. Control of spasms and prevention of hypoxic episodes are crucial. Benzodiazepines can be used to help control spasms and provide some sedation. Mechanical ventilation and muscle paralysis are necessary in severe cases. Nasogastric or intravenous feedings should be used to limit stimulation of feedings and prevent aspiration.

Prognosis

The fatality rate in newborns and heroin-addicted individuals is high. The overall mortality rate in the United States is 8%. The fatality rate depends on the quality of supportive care, the patient’s age, and the patient’s vaccination history. Many deaths are due to pneumonia or respiratory failure. If the patient survives 1 week, recovery is likely.

GAS GANGRENE

General Considerations

Gas gangrene (clostridial myonecrosis) is a necrotizing infection that follows trauma or surgery and is caused by several anaerobic, gram-positive, spore-forming bacilli of the genus Clostridium. Occasionally the source is the gastrointestinal tract, and muscles are hematogenously seeded. The spores are found in soil, feces, and vaginal secretions. In devitalized tissue, the spores germinate into vegetative bacilli that proliferate and produce toxins, causing thrombosis, hemolysis, and tissue necrosis. C perfringens, the species causing approximately 80% of cases of gas gangrene, produces at least eight toxins. The areas involved most often are the extremities, abdomen, and uterus. Clostridium septicum may also cause myonecrosis and causes septicemia in patients with neutropenia. Nonclostridial infections with gas formation can mimic clostridial infections and are more common. Neutropenia is a risk factor for this severe infection.

Prevention

Gas gangrene can be prevented by the adequate cleansing and debridement of all wounds. It is essential that foreign bodies and dead tissue be removed. A clean wound does not provide a suitable anaerobic environment for the growth of clostridial species.

Clinical Findings

A. Symptoms and Signs

The onset of gas gangrene usually is sudden, often 1 day after trauma or surgery, but can be delayed up to 20 days. Pain and swelling usually are intense. The skin around the wound becomes discolored (pale, red, or purple), with hemorrhagic bullae, serosanguineous exudate, and crepitus may be observed the subcutaneous tissues. The absence of crepitus does not rule out the diagnosis. Systemic illness appears early and progresses rapidly to intravascular hemolysis, jaundice, shock, toxic delirium, and renal failure.

B. Laboratory Findings

Isolation of the organism requires anaerobic cultures. The wound exudate, soft tissue, muscle and blood can be cultured. Gram-stained smears may demonstrate many gram-positive rods and few inflammatory cells.

C. Imaging

Radiographs may demonstrate gas in tissues, but this is a late finding and is also seen in infections with other gas-forming organisms or may be due to air introduced into tissues during trauma or surgery.

D. Operative Findings

Direct visualization of the muscle at surgery may be necessary to diagnose gas gangrene. Early, the muscle is pale and edematous and does not contract normally; later, the muscle may be frankly gangrenous.

Differential Diagnosis

Gangrene and cellulitis caused by other organisms and clostridial cellulitis (not myonecrosis) must be distinguished. Necrotizing fasciitis may resemble gas gangrene.

Treatment

A. Specific Measures

Penicillin G (300,000–400,000 U/kg/day intravenously in six divided doses) should be given. Clindamycin, metronidazole, meropenem, and ertapenem are alternatives for penicillin-allergic patients. Some experts recommend a combination of penicillin and clindamycin; clindamycin may inhibit toxin production.

B. Surgical Measures

Surgery should be prompt and extensive, with removal of all necrotic tissue. Compartment syndromes can occur even if there are few cutaneous findings. Checking compartment pressures in patients with severe pain and any signs of compartment syndrome is prudent.

C. Hyperbaric Oxygen

Hyperbaric oxygen therapy is controversial, but good outcomes have been reported in nonrandomized studies using hyperbaric oxygen in combination with surgery and antibiotics.

Prognosis

Clostridial myonecrosis is fatal if untreated. With early diagnosis, antibiotics, and surgery, the mortality rate is 20%–60%. Involvement of the abdominal wall, leukopenia, intravascular hemolysis, renal failure, and shock are ominous prognostic signs.

DIPHTHERIA

General Considerations

Diphtheria is an acute infection of the upper respiratory tract or skin caused by toxin-producing Corynebacterium diphtheriae. Diphtheria in the United States is rare; between 2004 and 2017, two cases have been reported. However, significant numbers of elderly adults and unimmunized children are susceptible to infection. Diphtheria still occurs in epidemics in countries where immunization is not universal. Unimmunized travelers to these areas may acquire the disease.

Corynebacteria are gram-positive, club-shaped rods with a beaded appearance on Gram stain. The capacity to produce exotoxin is conferred by a lysogenic bacteriophage and is not present in all strains of C diphtheriae. In immunized communities, infection probably occurs through spread of the phage among carriers of susceptible C diphtheriae rather than through spread of phage-containing bacteria themselves. Diphtheria toxin kills susceptible cells by irreversible inhibition of protein synthesis.

The toxin is absorbed into the mucous membranes and causes destruction of epithelium and a superficial inflammatory response. The necrotic epithelium becomes embedded in exuded fibrin with WBCs and RBCs (red blood cells), forming a grayish pseudomembrane over the tonsils, pharynx, or larynx. Any attempt to remove the membrane exposes and tears the capillaries, resulting in bleeding. The diphtheria bacilli within the membrane continue to produce toxin, which is absorbed and may result in toxic injury to the heart muscle, liver, kidneys, and adrenals, and is sometimes accompanied by hemorrhage. The toxin also produces neuritis, resulting in paralysis of the soft palate, eye muscles, or extremities. Death may result from respiratory obstruction or toxemia and circulatory collapse. The patient may succumb after a somewhat longer time as a result of cardiac damage. The incubation period is 2–5 days.

Clinical Findings

A. Symptoms and Signs

1. Pharyngeal diphtheria

Early manifestations of diphtheritic pharyngitis are mild sore throat, moderate fever, and malaise, followed fairly rapidly by prostration and circulatory collapse. The pulse is more rapid than the fever would seem to justify. A pharyngeal membrane forms and may spread into the nasopharynx or the trachea, producing respiratory obstruction. The membrane is tenacious and gray, and is surrounded by a narrow zone of erythema and a broader zone of edema. The cervical lymph nodes become swollen, which is associated with brawny edema of the neck (so-called bull neck). Laryngeal diphtheria presents with stridor, which can progress to airway obstruction.

2. Other forms

Cutaneous, vaginal, and wound diphtheria cases account for up to one-third and are characterized by ulcerative lesions with membrane formation.

B. Laboratory Findings

Diagnosis requires culture of C. diphtheriae obtained from the nose, throat, or skin lesions, if present. Specialized culture media is required so laboratory personnel should be notified if diphtheria is suspected. A toxigenicity test should be performed to differentiate toxigenic from nontoxigenic strains of C. diphtheriae. New non–culture-based methods such as PCR or matrix-assisted laser desorption/ionization (MALDI-TOF) mass spectroscopy can be useful as cultures may be negative in individuals who have received antibiotics. The WBC count usually is normal, but hemolytic anemia and thrombocytopenia are frequent.

Differential Diagnosis

Pharyngeal diphtheria resembles pharyngitis secondary to β-hemolytic Streptococcus, Epstein-Barr virus, or other viral respiratory pathogens. A nasal foreign body or purulent sinusitis may mimic nasal diphtheria. Other causes of laryngeal obstruction include epiglottitis and viral croup. Guillain-Barré syndrome, poliomyelitis, or acute poisoning may mimic the neuropathy of diphtheria.

Complications

A. Myocarditis

Diphtheritic myocarditis is characterized by a rapid, thready pulse; indistinct heart sounds, ST-T-wave changes, conduction abnormalities, dysrhythmias, or cardiac failure; hepatomegaly; and fluid retention. Myocardial dysfunction may occur from 2 to 40 days after the onset of pharyngitis.

B. Polyneuritis

Neuritis of the palatal and pharyngeal nerves occurs during the first or second week. Nasal speech and regurgitation of food through the nose are seen. Diplopia and strabismus occur during the third week or later. Neuritis may also involve peripheral nerves supplying the intercostal muscles, diaphragm, and other muscle groups. Generalized paresis usually occurs after the fourth week.

C. Bronchopneumonia

Secondary pneumonia is common in fatal cases.

Prevention

A. Immunization

Immunization with diphtheria toxoid combined with pertussis and tetanus toxoids (DTaP) should be used routinely for infants and children (see Chapter 10).

B. Care of Exposed Susceptibles

Children exposed to diphtheria should be examined, and nose and throat cultures obtained. Immunized asymptomatic individuals who have not received a diphtheria toxoid booster within 5 years and inadequately immunized individuals all should receive a diphtheroid toxoid vaccine. Regardless of immunization status, close contacts should receive either erythromycin orally (40 mg/kg/day in four divided doses) for 7–10 days or a single dose of benzathine penicillin G intramuscularly (600,000 units for children weighing < 30 kg, and 1.2 million units for children weighing ≥ 30 kg and for adults) and be closely observed.

Treatment

A. Specific Measures

1. Antitoxin

Suspected diphtheria should be reported promptly to the Centers for Disease Control Emergency Center (770-488-7100) so diphtheria antitoxin can be obtained. Diphtheria antitoxin is no longer commercially available. To be effective, diphtheria antitoxin should be administered within 48 hours (see Chapter 9).

2. Antibiotics

Acceptable regimens include erythromycin (40 mg/kg/day, maximum 2g/day) given parenterally or orally, or procaine penicillin G intramuscularly (300,000 units every 12 hours for those weighing ≤ 10 kg, and 600,000 units every 12 hours for those weighing > 10 kg). Treatment should be given for 14 days.

B. General Measures

Patients should receive a diphtheria toxoid–containing vaccine during convalescence as infection does not confer immunity. Observation of patients in the hospital for 10–14 days is usually required. All patients must be strictly isolated for 1–7 days until respiratory secretions are noncontagious. Isolation may be discontinued when two successive nose and throat cultures at 24-hour intervals are negative. These cultures should not be taken until at least 24 hours have elapsed since the cessation of antibiotic treatment.

C. Treatment of Carriers

All carriers should receive either erythromycin (40 mg/kg/day orally in three or four divided doses) for 10–14 days or a single dose of benzathine penicillin G (600,000 units for children weighing < 30 kg, and 1.2 million units for children weighing ≥ 30 kg or for adults), and they must be quarantined. Before release from quarantine carriers must have two negative cultures of both the nose and the throat taken 24 hours apart and obtained at least 24 hours after the cessation of antibiotic therapy. If follow-up cultures remain positive, they should receive another 10 day course of erythromycin.

Prognosis

Mortality varies from 3% to 25% and is particularly high in the presence of early myocarditis. Neuritis is reversible. Diphtheria is fatal if an intact airway and adequate respiration cannot be maintained. Permanent heart damage from myocarditis occurs rarely.

INFECTIONS DUE TO ENTEROBACTERIACEAE

General Considerations

Enterobacteriaceae are a family of gram-negative bacilli that are normal flora in the gastrointestinal tract of people and animals that contaminate water and soil. They cause gastroenteritis, urinary tract infections, neonatal sepsis and meningitis, and opportunistic infections. E coli is the organism in this family that most commonly causes infection in children, but Klebsiella, Morganella, Enterobacter, Serratia, Proteus, and other genera are also important, particularly in hospitalized persons or immune compromised hosts. Shigella and Salmonella are discussed in separate sections.

E coli strains capable of causing diarrhea were originally termed enteropathogenic E coli (EPEC) and were recognized by serotype. It is now known that E coli may cause diarrhea by several distinct mechanisms. Classic EPEC strains cause a characteristic histologic injury in the small bowel termed adherence and effacement. Enterotoxigenic E coli (ETEC) causes a secretory, watery diarrhea. ETEC adheres to enterocytes and secretes one or more plasmid-encoded enterotoxins. One of these, heat-labile toxin, resembles cholera toxin in structure, function, and mechanism of action. Enteroinvasive E coli (EIEC) are very similar to Shigella in their pathogenetic mechanisms. Shigella-toxin producing E coli (STEC) cause hemorrhagic colitis and the HUS. The STEC serotype is O157:H7 that is particularly virulent, although several other serotypes cause the same syndrome. These strains elaborate one of several cytotoxins, closely related to Shiga toxin produced by Shigella dysenteriae. Outbreaks of HUS associated with STEC have followed consumption of inadequately cooked ground beef. Thorough heating to 71°C (160°F) is considered preventative. Unpasteurized fruit juice, various uncooked vegetables, flour, and contaminated water also have caused infections and epidemics. The common source for STEC in all of these foods and water is the feces of cattle or several other animals. Person-to-person spread including spread in day care centers by the fecal-oral route has been reported. Over 7000 cases of STEC were reported in the United States in 2016, although many more cases are estimated to have occurred. E coli defined by their tendency to aggregate on the surface of human epithelial cells in tissue culture are termed enteroaggregative E coli (EAEC). EAEC causes diarrhea by a distinct but unknown mechanism. Eighty percent of E coli strains causing neonatal meningitis possess a specific capsular polysaccharide (K1 antigen), which, alone or in association with specific somatic antigens, confers virulence.

Klebsiella, Enterobacter, Serratia, and Morganella are normally found in the gastrointestinal tract and in soil and water. Klebsiella may cause a bronchopneumonia with cavity formation. Klebsiella, Enterobacter, and Serratia are often hospital-acquired opportunists associated with antibiotic usage, debilitated states, and chronic respiratory conditions. They frequently cause urinary tract infection or sepsis. Many of these infections are difficult to treat because of antibiotic resistance. Carbapenem-resistant Enterobacteriaceae (CRE) are a serious concern due to limited options for therapy. Antibiotic susceptibility tests are necessary. Parenteral third-generation cephalosporins are usually more active than ampicillin, but resistance due to extended-spectrum β-lactamase (ESBL) may occur. Aminoglycoside antibiotics are usually effective but require monitoring of serum levels to ensure therapeutic and nontoxic levels.

Clinical Findings

A. Symptoms and Signs

1. E coli gastroenteritis

E coli may cause diarrhea of varying types and severity. ETEC usually produce mild, self-limiting illness without significant fever or systemic toxicity, often known as traveler’s diarrhea. However, diarrhea may be severe in newborns and infants, and occasionally an older child or adult will have a cholera-like syndrome. EIEC strains, which cause a shigellosis-like illness, characterized by fever, systemic symptoms, blood and mucus in the stool, are uncommon in the United States. STEC strains cause hemorrhagic colitis. Diarrhea initially is watery and fever usually is absent. Abdominal pain and cramping occur; diarrhea progresses to blood streaking or grossly bloody stools. HUS occurs within a few days of diarrhea in 2%–5% of children with STEC diarrhea, with a rate of 15% in children with O157:H7, and is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure (see Chapter 24). STEC encoding a gene for Shiga toxin 2 are more virulent than those with only Shiga toxin 1.

2. Neonatal sepsis

Findings include jaundice, hepatosplenomegaly, fever, temperature lability, apneic spells, irritability, and poor feeding. Respiratory distress develops when pneumonia occurs; it may appear indistinguishable from respiratory distress syndrome in preterm infants. Meningitis is associated with bacteremia in 25%–40% of cases. Other metastatic foci of infection may be present, including pneumonia and pyelonephritis. Sepsis may lead to severe metabolic acidosis, shock, DIC, and death.

3. Neonatal meningitis

Findings include high fever, full fontanelles, vomiting, coma, convulsions, pareses or paralyses, poor or absent Moro reflex, opisthotonos, and occasionally hypertonia or hypotonia. Sepsis coexists or precedes meningitis in most cases. Thus, signs of sepsis often accompany those of meningitis. CSF usually shows a cell count of over 1000 WBC/μL, mostly polymorphonuclear neutrophils, and bacteria on Gram stain. CSF glucose concentration is low (usually less than half that of blood), and the protein is elevated above the levels normally seen in newborns and premature infants (> 150 mg/dL).

4. Acute urinary tract infection

Symptoms include dysuria, increased urinary frequency, and fever in the older child. Nonspecific symptoms such as anorexia, vomiting, irritability, failure to thrive, and unexplained fever are seen in children younger than age 2 years. Young infants may present with jaundice. As many as 1%–3% of school-aged girls and 0.5% of boys have asymptomatic bacteriuria. Screening for and treatment of asymptomatic bacteriuria is not recommended.

B. Laboratory Findings

Because E coli are normal flora in the stool, a positive stool culture alone does not prove that the E coli in the stool are causing disease. Multiplex PCR tests are available to rapidly diagnose STEC and other enteropathogens. Rapid immunologic assays such as enzyme immunoassays (EIA) and immunochromatographic assays are available to detect Shiga toxin. Blood cultures are positive in neonatal sepsis. Cultures of CSF and urine should also be obtained. The diagnosis of urinary tract infections is discussed in Chapter 24.

Differential Diagnosis

The clinical picture of E coli infection may resemble that of other enteric infections such as salmonellosis, shigellosis, or viral gastroenteritis. Neonatal sepsis and meningitis caused by E coli can be differentiated from other causes of neonatal infection only by blood and CSF culture.

Treatment

A. Specific Measures

1. E coli gastroenteritis

Gastroenteritis seldom requires antimicrobial treatment. Fluid and electrolyte therapy, preferably given orally, may be required to avoid dehydration. Antibiotics are generally not recommended because of potential selection for resistant organisms, risks and side effects of antibiotics, and the fact that diarrhea will typically resolve spontaneously. Traveler’s diarrhea may be treated with azithromycin in children and with fluoroquinolones in adults, although resistance to these drugs is increasing. The risk of HUS is not proven to be increased by antimicrobial therapy of STEC cases, but most experts recommend no antimicrobial treatment of suspected cases.

2. E coli sepsis and pneumonia

The drugs of choice are ampicillin (150–200 mg/kg/day intravenously or intramuscularly in divided doses every 4–6 hours), ceftriaxone (50–100 mg/kg/day parenterally as single dose or in two divided doses), and gentamicin (6–7.5 mg/kg/day intramuscularly or intravenously in divided doses every 8 hours). Initial therapy often includes at least two drugs until microbial etiology is established and susceptibility testing is completed. Treatment is continued for 10–14 days. Amikacin or tobramycin may be used instead of gentamicin if the strain is susceptible. Third-generation cephalosporins are often an attractive alternative as single-drug therapy and do not require monitoring for toxicity.

3. E coli meningitis

Third-generation cephalosporins such as ceftriaxone (100 mg/kg/day intravenously) are given for a minimum of 3 weeks. Ampicillin (300–400 mg/kg/day intravenously in four to six divided doses) and gentamicin (7.5 mg/kg/day intramuscularly or intravenously in three divided doses) also are effective for susceptible strains. Serum levels need to be monitored. Treatment with intrathecal and intraventricular aminoglycosides does not improve outcome.

4. Acute urinary tract infection

(See Chapter 24.)

Prognosis

Death due to gastroenteritis leading to dehydration can be prevented by early fluid and electrolyte therapy. Effective treatment has reduced mortality from neonatal sepsis with meningitis to 10%–20%; however, many survivors have some degree of residual disability. Most children with recurrent urinary tract infections do well if they have no underlying anatomic defects. The mortality rate in opportunistic infections usually depends on the severity of infection and the underlying immune compromising condition.

PSEUDOMONAS INFECTIONS

General Considerations

Pseudomonas aeruginosa is an aerobic gram-negative rod with versatile metabolic requirements. The organism may grow in distilled water and in commonly used disinfectants, complicating infection control in medical facilities. P aeruginosa is both invasive and destructive to tissue as well as toxigenic due to secreted exotoxins, all factors that contribute to virulence. Other genera previously classified as Pseudomonas frequently cause nosocomial infections and infections in immunocompromised children. Stenotrophomonas maltophilia (previously Pseudomonas maltophilia) and Burkholderia cepacia (previously Pseudomonas cepacia) are the most frequent.

P aeruginosa is an important cause of infection in children with cystic fibrosis, neoplastic disease, neutropenia, or extensive burns and in those receiving antibiotic therapy. Infections of the urinary and respiratory tracts, ears, mastoids, paranasal sinuses, eyes, skin, meninges, and bones are seen. Pseudomonas pneumonia is a common nosocomial infection in patients receiving assisted ventilation.

P aeruginosa sepsis may be accompanied by characteristic peripheral lesions called ecthyma gangrenosum. Ecthyma gangrenosum also may occur by direct invasion through intact skin in the groin, axilla, or other skinfolds. P aeruginosa is an infrequent cause of sepsis in previously healthy infants and may be the initial sign of underlying medical problems. Osteomyelitis of the calcaneus or other foot bones, which occurs after punctures such as stepping on a nail, is commonly due to P aeruginosa.

P aeruginosa is a frequent cause of malignant external otitis media and of chronic suppurative otitis media. Outbreaks of vesiculopustular skin rash have been associated with exposure to contaminated water in whirlpool baths and hot tubs.

P aeruginosa infects the tracheobronchial tree of nearly all patients with cystic fibrosis. Mucoid exopolysaccharide, an exuberant capsule, is characteristically overproduced by isolates from patients with cystic fibrosis. Although bacteremia seldom occurs, patients with cystic fibrosis often ultimately succumb to chronic lung infection with P aeruginosa. Infection due to B cepacia has caused a rapidly progressive pulmonary disease in some colonized patients and may be spread by close contact.

Clinical Findings

The clinical findings depend on the site of infection and the patient’s underlying disease. Sepsis with these organisms resembles gram-negative sepsis with other organisms, although the presence of ecthyma gangrenosum suggests the etiologic diagnosis. The diagnosis is made by culture. Pseudomonas infection should be suspected in neonates and neutropenic patients with clinical sepsis. A severe necrotizing pneumonia occurs in patients on ventilators.

Patients with cystic fibrosis have a persistent bronchitis that progresses to bronchiectasis and ultimately to respiratory failure. During exacerbations of illness, cough and sputum production increase along with low-grade fever, malaise, and diminished energy.

The purulent aural drainage without fever in patients with chronic suppurative otitis media is not distinguishable from that due to other causes.

Prevention

A. Infections in Debilitated Patients

Colonization of extensive second- and third-degree burns by P aeruginosa can lead to fatal septicemia. Aggressive debridement and topical treatment with 0.5% silver nitrate solution, 10% mafenide cream, or silver sulfadiazine will greatly inhibit P aeruginosa contamination of burns. (See Chapter 12 for a discussion of burn wound infections and prevention.)

B. Nosocomial Infections

Faucet aerators, communal soap dispensers, disinfectants, improperly cleaned inhalation therapy equipment, infant incubators, and many other sources that usually are associated with wet or humid conditions all have been associated with Pseudomonas epidemics. Patient-to patient transmission by hospital staff carrying Pseudomonas on the hands occurs in some units where hand hygiene is inadequate. Careful maintenance of equipment and enforcement of infection control procedures are essential to minimize nosocomial transmission.

C. Patients with Cystic Fibrosis

Chronic infection of the lower respiratory tract occurs in nearly all patients with cystic fibrosis. The infecting organism is seldom cleared from the respiratory tract, even with intensive antimicrobial therapy, and the resultant injury to the lung eventually leads to pulmonary insufficiency. Treatment is aimed at controlling signs and symptoms of the infection.

Treatment

P aeruginosa is inherently resistant to many antimicrobials and may develop resistance during therapy. Mortality rates in hospitalized patients exceed 50%, owing both to the severity of underlying illnesses in patients predisposed to Pseudomonas infection and to the limitations of therapy. Antibiotics effective against Pseudomonas include the aminoglycosides, ureidopenicillins (piperacillin), β-lactamase inhibitor with a ureidopenicillin (piperacillin-tazobactam), expanded-spectrum cephalosporins (ceftazidime and cefepime), monobactams (aztreonam), carbapenems (doripenem, meropenem), and fluoroquinolones (ciprofloxacin, levofloxacin). Aminoglycosides may be used as an adjunct to the above regimen, but not as monotherapy except in the case of urinary tract infections. Colistin has been used in some children with multidrug resistance. Antimicrobial susceptibility patterns vary from area to area, and sometimes by unit within a hospital. Resistance tends to appear as new drugs become popular. Treatment of infections is best guided by clinical response and susceptibility tests.

Gentamicin or tobramycin (5.0–7.5 mg/kg/day intramuscularly or intravenously in three divided doses) or amikacin (15–22 mg/kg/day in two or three divided doses) in combination with piperacillin (240–300 mg/kg/day intravenously in four to six divided doses) or with another antipseudomonal β-lactam antibiotic is recommended for treatment of serious Pseudomonas infections. Ceftazidime (150–200 mg/kg/day in four divided doses) or cefepime (150 mg/kg/day in three divided doses) has activity against susceptible strains. Treatment should be continued for 10–14 days. Treatment with two active drugs is recommended for all serious infections. Aerosolized anti-pseudomonal antibiotics, tobramycin, and aztreonam have been very useful adjunctive therapy for patients with cystic fibrosis.

Pseudomonas osteomyelitis due to punctures requires thorough surgical debridement and antimicrobial therapy. Pseudomonas folliculitis does not require antibiotic therapy.

Oral or intravenous ciprofloxacin is also effective against susceptible P aeruginosa but is not approved by the FDA for use in children except in the case of urinary tract infection. Nonetheless, in some circumstances of antimicrobial resistance, or when the benefits clearly outweigh the small risks, ciprofloxacin may be used.

Chronic suppurative otitis media may be treated with topical ofloxacin or ciprofloxacin and aural toilet. Failure of treatment with conservative measures may necessitate oral or parenteral antibiotic therapy guided by culture results. Swimmer’s ear may be caused by P aeruginosa and responds well to topical drying agents (alcohol–vinegar mix) and cleansing.

Prognosis

Because debilitated patients are most frequently affected, the mortality rate is high. These infections may have a protracted course, and eradication of the organisms may be difficult.

SALMONELLA GASTROENTERITIS

General Considerations

Salmonellae are gram-negative rods that frequently cause food-borne gastroenteritis and occasionally bacteremic infection of bone, meninges, and other foci. Approximately 2400 serotypes of Salmonella enterica are recognized. Salmonella typhimurium is the most frequently isolated serotype in most parts of the world. Although 51,400 cases were reported in 2014, it is estimated that more than 1 million cases occur yearly in the United States, as only a small percent of patients are cultured.

Salmonellae are able to penetrate the mucin layer of the small bowel and attach to epithelial cells. Organisms penetrate the epithelial cells and multiply in the submucosa. Infection results in fever, vomiting, and watery diarrhea; the diarrhea occasionally includes mucus and polymorphonuclear neutrophils in the stool. Salmonella infections in childhood occur in two major forms: (1) gastroenteritis (including food poisoning), which may be complicated by sepsis and focal suppurative complications; and (2) enteric fever (typhoid fever and paratyphoid fever) (see section Typhoid Fever & Paratyphoid Fever). Although the incidence of typhoid fever has decreased in the United States, the incidence of Salmonella gastroenteritis has greatly increased in the past 15–20 years. The highest attack rates occur in children younger than 6 years, with a peak in the age group from 6 months to 2 years.

Salmonellae are widespread in nature, infecting domestic and wild animals. Fowl and reptiles have a particularly high carriage rate. Outbreaks have been associated with petting zoos and keeping reptiles or backyard chickens as pets. Transmission occurs by the fecal-oral route via contaminated food, water, fomites, and sometimes person to person. Numerous foods, especially milk and egg products, are associated with outbreaks.

Because salmonellae are susceptible to gastric acidity, elderly, infants, and patients taking antacids or H₂-blocking drugs are at increased risk for infection. Most cases of Salmonella meningitis (80%) and bacteremia occur in infancy. Newborns may acquire the infection from their mothers during delivery and may precipitate outbreaks in nurseries. Newborns are at special risk for developing meningitis.

Clinical Findings

A. Symptoms and Signs

There is a very wide range of severity of infection. Infants usually develop fever, vomiting, and diarrhea. The older child also may complain of headache, nausea, and abdominal pain. Stools are often watery or may contain mucus and, in some instances, blood, suggesting shigellosis. Drowsiness and disorientation may be associated with meningismus. Convulsions occur less frequently than with shigellosis. Splenomegaly occasionally occurs. In the usual case, diarrhea is moderate and subsides after 4–5 days, but it may be protracted.

B. Laboratory Findings

Diagnosis is made by isolation in culture or by PCR of the organism from stool, blood, or, in some cases from urine, CSF, or pus from a suppurative lesion. The WBC count usually shows a polymorphonuclear leukocytosis but may show leukopenia. Salmonella isolates should be reported to public health authorities for epidemiologic purposes.

Differential Diagnosis

In staphylococcal food poisoning, the incubation period is shorter (2–4 hours) than in Salmonella food poisoning (12–24 hours), fever is absent, and vomiting rather than diarrhea is the main symptom. In shigellosis, many polymorphonuclear leukocytes usually are seen on a stained smear of stool, and the peripheral WBC count is more likely to slow a marked left shift, although some cases of salmonellosis are indistinguishable from shigellosis. Campylobacter gastroenteritis commonly resembles salmonellosis. Culture or PCR of stool is necessary to distinguish the causes of bacterial gastroenteritis.

Complications

Unlike most causes of infectious diarrhea, salmonellosis is frequently accompanied by bacteremia, especially in newborns and infants. Septicemia with extraintestinal infection is seen, most commonly with Salmonella choleraesuis but also with S enterica, S typhimurium, and S paratyphi serotypes. The organism may spread to any tissue and may cause arthritis, osteomyelitis, cholecystitis, endocarditis, meningitis, pericarditis, pneumonia, or pyelonephritis. Patients with sickle cell anemia or other hemoglobinopathies have a predilection for the development of osteomyelitis. Severe dehydration and shock are more likely to occur with shigellosis but may occur with Salmonella gastroenteritis.

Prevention

Measures for the prevention of Salmonella infections include thorough cooking of foodstuffs derived from contaminated sources, adequate refrigeration, control of infection among domestic animals, and meticulous meat and poultry inspections. Raw and undercooked fresh eggs or uncooked flour should be avoided. Food handlers and child care workers with salmonellosis should have three negative stool cultures before resuming work. Asymptomatic children, who have recovered from Salmonella infection, do not need school or day-care exclusion.

Treatment

A. Specific Measures

In uncomplicated Salmonella gastroenteritis, antibiotic treatment does not shorten the course of the clinical illness and may prolong convalescent carriage of the organism. Colitis or secretory diarrhea due to Salmonella may improve with antibiotic therapy. Azithromycin (10 mg/kg/day × 3 days) may be effective for moderate to severe colitis and is often used empirically for traveler’s diarrhea.

Because of the higher risk of sepsis and focal disease, antibiotic treatment is recommended in infants younger than 3 months, in severely ill children, and in children with sickle cell disease, liver disease, recent gastrointestinal surgery, cancer, depressed immunity, or chronic renal or cardiac disease. Infants younger than 3 months with positive stool cultures or suspected salmonellosis sepsis should be admitted to the hospital, evaluated for focal infection including cultures of blood and CSF, and given treatment intravenously. A third-generation cephalosporin is usually recommended due to frequent resistance to ampicillin and TMP-SMX. Older patients developing bacteremia during the course of gastroenteritis should receive parenteral treatment initially, and a careful search should be made for additional foci of infection. After signs and symptoms subside, these patients should receive oral medication. Parenteral and oral treatment should last a total of 7–10 days. Longer treatment is indicated for specific complications. If susceptibility tests indicate resistance to ampicillin, third-generation cephalosporins or TMP-SMX should be given if susceptible. Fluoroquinolones or azithromycin are used for strains resistant to multiple other drugs.

Outbreaks on pediatric wards are difficult to control. Strict hand washing, cohorting of patients and personnel, and, ultimately, closure of the unit may be necessary.

B. Treatment of the Carrier State

About one-half of patients may have positive stool cultures after 4 weeks. Infants tend to remain convalescent carriers for up to 1 year. Antibiotic treatment of carriers is not effective.

C. General Measures

Careful attention must be given to maintaining fluid and electrolyte balance, especially in infants.

Prognosis

In gastroenteritis, the prognosis is good. In sepsis with focal suppurative complications, the prognosis is more guarded. The case fatality rate of Salmonella meningitis is high in infants. There is a tendency to relapse if treatment is not continued for at least 4 weeks.

TYPHOID FEVER & PARATYPHOID FEVER

General Considerations

Typhoid fever is caused by the gram-negative bacillus S enterica serotype typhi and paratyphi. Children have a shorter incubation period than do adults (usually 5–8 days instead of 8–14 days). The organism enters the body through the walls of the intestinal tract and, following a transient bacteremia, multiplies in the reticuloendothelial cells of the liver and spleen. Persistent bacteremia and symptoms then follow. Reinfection of the intestine occurs as organisms are excreted in the bile. Bacterial emboli produce the characteristic skin lesions (rose spots). Typhoid fever is transmitted by the fecal-oral route and by contamination of food or water. Unlike other Salmonella species, there are no animal reservoirs of typhoid; each case is the result of direct or indirect contact with the organism or with an individual who is actively infected or a chronic carrier.

About 300 cases per year were reported in the United States in 2015, 79% of which were acquired during foreign travel. Multidrug-resistant S enterica serotype typhi isolates are an increasing global problem.

Clinical Findings

A. Symptoms and Signs

In children, the onset of typhoid fever usually is sudden rather than insidious, with malaise, headache, cough, crampy abdominal pains and distention, and sometimes constipation followed within 48 hours by diarrhea, high fever, and toxemia. An encephalopathy may be seen with irritability, confusion, delirium, and stupor. Vomiting and meningismus may be prominent in infants and young children. The classic lengthy three-stage disease seen in adult patients often is shortened in children. The prodrome may last only 2–4 days, the toxic stage only 2–3 days, and the defervescence stage 1–2 weeks.

During the prodromal stage, physical findings may be absent, but abdominal distention and tenderness, meningismus, mild hepatomegaly and splenomegaly may be present. The typical typhoidal rash (rose spots) is present in 10%–15% of children. It appears during the second week of the disease and may erupt in crops for the succeeding 10–14 days. Rose spots are erythematous maculopapular lesions 2–3 mm in diameter that blanch on pressure. They are found principally on the trunk and chest, and they generally disappear within 3–4 days. The lesions usually number fewer than 20.

B. Laboratory Findings

Typhoid bacilli can be isolated from many sites, including blood, stool, urine, and bone marrow. Blood cultures are positive in 50%–80% of cases during the first week and less often later in the illness. Stool cultures are positive in about 30% of cases after the first week. Urine and bone marrow cultures also are valuable. Most patients will have negative cultures (including stool) by the end of a 6-week period. Serologic tests (Widal reaction) are not as useful as cultures because both false-positive and false-negative results occur. Leukopenia is common in the second week of the disease, but in the first week, leukocytosis may be seen. Proteinuria, mild elevation of liver enzymes, thrombocytopenia, and DIC are common.

Differential Diagnosis

Typhoid and paratyphoid fevers must be distinguished from other serious prolonged fevers. These include typhus, brucellosis, malaria, tularemia, TB, psittacosis, vasculitis, lymphoma, mononucleosis, and Kawasaki disease. Prolonged fever is a common presentation of typhoid in a returning traveler. The diagnosis of typhoid fever often is made clinically in developing countries, but the accuracy of clinical diagnosis is variable. In developed countries, where typhoid fever is uncommon and physicians are unfamiliar with the clinical picture, the diagnosis often is not suspected until late in the course. Positive cultures confirm the diagnosis.

Complications

The most serious complications of typhoid fever are gastrointestinal hemorrhage (2%–10%) and perforation (1%–3%). They occur toward the end of the second week or during the third week of the disease.

Intestinal perforation is one of the principal causes of death. The site of perforation generally is the terminal ileum or cecum. The clinical manifestations are indistinguishable from those of acute appendicitis, with pain, tenderness, and rigidity in the right lower quadrant.

Bacterial pneumonia, meningitis, septic arthritis, abscesses, and osteomyelitis are uncommon complications, particularly if specific treatment is given promptly. Shock and electrolyte disturbances may lead to death.

About 1%–3% of patients become chronic typhoid carriers. Chronic carriage is defined as excretion of typhoid bacilli for more than a year, but carriage is often lifelong. Adults with underlying biliary or urinary tract disease are much more likely than children to become chronic carriers.

Prevention

Routine typhoid vaccine is not recommended in the United States but should be considered for foreign travel to endemic areas. An attenuated oral typhoid vaccine produced from strain Ty21a has better efficacy and causes minimal side effects but is not approved for children younger than 6 years. The vaccine is repeated after 5 years. A capsular polysaccharide vaccine (ViCPS) requires one intramuscular injection and may be given to children 2 years and older. (See Chapter 10.)

Treatment

A. Specific Measures

Third-generation cephalosporins such as ceftriaxone (50 mg/kg/dose every 24 hours), azithromycin (10 mg/kg on day 1, followed by 5 mg/kg on subsequent days), or a fluoroquinolone are used for presumptive therapy. Antimicrobial susceptibility testing and local experience are used to direct subsequent therapy. Typical courses of treatment are at least 7 days. Alternative regimens for susceptible strains include the following: TMP-SMX (10 mg/kg trimethoprim and 50 mg/kg sulfamethoxazole per day orally in two or three divided doses), amoxicillin (100 mg/kg/day orally in four divided doses), and ampicillin (100–200 mg/kg/day intravenously in four divided doses). These regimens generally require longer durations (14–21 days) than azithromycin or fluoroquinolone-based regimens. Aminoglycosides and first- and second-generation cephalosporins are clinically ineffective regardless of in vitro susceptibility results. Patients may remain febrile for 3–5 days even with appropriate therapy.

B. General Measures

General support of the patient is exceedingly important and includes rest, good nutrition and hydration, and careful observation, with particular regard to evidence of intestinal bleeding or perforation. Blood transfusions may be needed even in the absence of frank hemorrhage.

Prognosis

A prolonged convalescent carrier stage may occur in children. Three negative cultures after all antibiotics have been stopped are required before contact precautions are stopped. With early antibiotic therapy, the prognosis is excellent, and the mortality rate is less than 1%. Relapse occurs 1–3 weeks later in 10%–20% of patients despite appropriate antibiotic treatment.

SHIGELLOSIS (BACILLARY DYSENTERY)

General Considerations

Shigellae are nonmotile gram-negative rods of the family Enterobacteriaceae that are closely related to E coli. The genus Shigella is divided into four species: S dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei. An estimated 500,000 cases of Shigella diarrhea occur every year in the United States. S sonnei followed by S flexneri are the most common isolates. S dysenteriae, which causes the most severe diarrhea of all species and the greatest number of extraintestinal complications, accounts for less than 1% of all Shigella infections in the United States.

Shigellosis may be a serious disease, particularly in young children, and without supportive treatment an appreciable mortality rate results. In older children and adults, the disease tends to be self-limited and milder. Shigella is usually transmitted by the fecal-oral route. Food- and water-borne outbreaks are increasing in occurrence, but are less important overall than person-to-person transmission. The disease is very communicable—as few as 200 bacteria can produce illness in an adult volunteer. The secondary attack rate in families is high, and shigellosis is a serious problem in day care centers and custodial institutions. Shigella organisms produce disease by invading the colonic mucosa, causing mucosal ulcerations and microabscesses.

Clinical Findings

A. Symptoms and Signs

The incubation period of shigellosis is usually 1–3 days. Onset is abrupt, with abdominal cramps, urgency, tenesmus, chills, fever, malaise, and diarrhea. Hallucinations and seizures sometimes accompany high fever. In severe forms, blood and mucus are seen in small stools. In older children, the disease may be mild and characterized by watery diarrhea without blood. In young children, a fever of 39.4°C–40°C is common. Rarely there is rectal prolapse. Symptoms generally last 3–7 days.

B. Laboratory Findings

The total WBC count varies, but often there is a marked left shift. The stool may contain gross blood and mucus, and many neutrophils are seen if mucus from the stool is examined microscopically. Stool cultures are usually positive; however, they may be negative because the organism is somewhat fragile and present in small numbers late in the disease. Multiplex PCR tests are available for rapid diagnosis of Shigella and other enteropathogens.

Differential Diagnosis

Usually children with viral gastroenteritis are not as febrile or toxic as those with shigellosis, and the stool does not contain gross blood or neutrophils. Intestinal infections caused by Salmonella or Campylobacter are differentiated by culture or PCR. Grossly bloody stools in a patient without fever or stool leukocytes suggest E coli O157:H7 infection. Amebic dysentery is diagnosed by antigen detection or microscopic examination of fresh stools or sigmoidoscopy specimens. Intussusception is characterized by an abdominal mass with so-called currant jelly stools without leukocytes, and by absence of initial fever. Mild shigellosis is not distinguishable clinically from other forms of infectious diarrhea.

Complications

Dehydration, acidosis, shock, and renal failure are the major complications. In some cases, a chronic form of dysentery occurs, characterized by mucoid stools and poor nutrition. Bacteremia and metastatic infections are rare but serious complications. Febrile seizures are common. Fulminating fatal dysentery and HUS occur rarely. Reactive arthritis may follow Shigella infection in patients with HLA-B27 genotype.

Treatment

A. Specific Measures

Milder infections may not require antibiotic treatment. Antibiotic resistance in Shigella is an increasing problem, including to TMP-SMX, ampicillin and more recently to fluoroquinolones. Azithromycin (12 mg/kg/day on day 1, then 6 mg/kg/day for 2 days) is usually effective, as is ciprofloxacin, though the latter should not be used routinely in children. Parenteral ceftriaxone (50 mg/kg/day) is an option for severe infections. Successful treatment reduces the duration of fever, cramping, and diarrhea and terminates fecal excretion of Shigella. Presumptive therapy should be limited to children with classic shigellosis or known outbreaks.

B. General Measures

In severe cases, immediate rehydration is critical. A mild form of chronic malabsorption syndrome may supervene and require prolonged dietary control. Zinc supplementation may aid recovery in populations at risk of deficiency.

Prognosis

The prognosis is excellent if vascular collapse is prevented or treated promptly by adequate fluid therapy. The mortality rate is high in very young, malnourished infants who do not receive fluid and electrolyte therapy. Convalescent fecal excretion of Shigella lasts 1–4 weeks in patients not receiving antimicrobial therapy. Long-term carriers are rare.

CHOLERA

General Considerations

Cholera is an acute diarrheal disease caused by the gram-negative organism Vibrio cholerae. It is transmitted by contaminated water or food, especially contaminated shellfish. Epidemics are common in impoverished areas where hygiene and safe water supply are limited. Typical disease is generally so dramatic that in endemic areas the diagnosis is obvious. Individuals with mild illness and young children may play an important role in transmission of the infection.

Asymptomatic infection is far more common than clinical disease. In endemic areas, rising titers of vibriocidal antibody are seen with increasing age. Infection occurs in individuals with low titers. The age-specific attack rate is highest in children younger than 5 years and declines with age. Cholera is unusual in infancy.

Cholera toxin is a protein enterotoxin that is responsible for symptoms. Cholera toxin binds to a regulatory subunit of adenylyl cyclase in enterocytes, causing increased cyclic adenosine monophosphate and an outpouring of NaCl and water into the lumen of the small bowel.

Nutritional status is an important factor determining the severity of the diarrhea. Duration of diarrhea is prolonged in adults and children with severe malnutrition.

Cholera is endemic in India and southern and Southeast Asia and in parts of Africa. The most recent pandemic, caused by the El Tor biotype of V cholerae 01, began in 1961 in Indonesia. Epidemic cholera spread in Central and South America, with a total of 1 million cases and 9500 deaths reported through 1994. A severe cholera outbreak in Haiti began in October 2010 and many cases continue to occur. A recent outbreak in Yemen demonstrates the vulnerability of populations to cholera emergence in conflict settings. Cholera in the United States occurs after foreign travel or rarely as a result of consumption of contaminated imported food.

V cholerae is a natural inhabitant of shellfish and copepods in estuarine environments. Seasonal multiplication of V cholerae may provide a source of outbreaks in endemic areas. Chronic cholera carriers are rare. The incubation period is short, usually 1–3 days.

Clinical Findings

A. Symptoms and Signs

Many patients infected with V cholerae have mild disease, with 1%–2% developing severe diarrhea. During severe cholera, there is a sudden onset of massive, frequent, watery stools, generally light gray in color (so-called rice-water stools) and containing some mucus but no pus. Vomiting may be projectile and is not accompanied by nausea. Within 2–3 hours, the tremendous loss of fluids results in life-threatening dehydration, hypochloremia, and hypokalemia, with marked weakness and collapse. Renal failure and irreversible peripheral vascular collapse will occur if fluid therapy is not administered. The illness lasts 1–7 days and is shortened by appropriate antibiotic therapy.

B. Laboratory Findings

Markedly elevated hemoglobin (20 g/dL) and marked acidosis, hypochloremia, and hyponatremia are seen. Culture confirmation requires specific media and takes 16–18 hours for a presumptive diagnosis and 36–48 hours for a definitive bacteriologic diagnosis.

Prevention

A live attenuated oral cholera vaccine was approved in the United States in 2016 for adults traveling to cholera endemic areas. It is estimated to provide 80%–90% protection. Other cholera vaccines are available outside of the United States and provides 50%–75% efficacy. Protection lasts 3–6 months. Tourists visiting endemic areas are at little risk if they exercise caution in what they eat and drink and maintain good personal hygiene. In endemic areas, all water must be boiled, shellfish should be thoroughly cooked, food and drink protected from flies, and sanitary precautions observed. Foods should be promptly refrigerated whenever possible after meals. Simple filtration of water is highly effective in reducing cases. All patients with cholera should be isolated.

Chemoprophylaxis (tetracycline 500 mg/day for 5 days) can limit secondary cases in a household if administered rapidly. It should be initiated as soon as possible after the onset of the disease in the index patient. TMP-SMX may be substituted in children.

Treatment

Replacement and maintenance of fluids and electrolytes hydration are the most important aspects of cholera treatment. Physiologic saline or lactated Ringer solution should be administered intravenously in large amounts to restore blood volume and urine output and to prevent irreversible shock. Potassium supplements are required. Sodium bicarbonate, given intravenously, also may be needed initially to overcome profound metabolic acidosis from bicarbonate loss in the stool. Moderate dehydration and acidosis can be corrected in 3–6 hours by oral therapy alone, because the active glucose transport system of the small bowel is normally functional. The optimal composition of the oral solution is described in Table 45–5.

Antibiotic treatment can also shorten the duration and decrease the severity of cholera. First-line treatment for children in the United States is doxycycline (4.4 mg/kg/day divided twice daily). Azithromycin (10 mg/kg/day in one dose for 1–5 days) is also effective. Antibiotic treatment prevents clinical relapse but is not as important as fluid and electrolyte therapy.

Prognosis

With early and rapid replacement of fluids and electrolytes, the case fatality rate is 1%–2% in children. If significant symptoms appear and no treatment is given, the mortality rate is over 50%.

CAMPYLOBACTER INFECTION

General Considerations

Campylobacter species are small gram-negative, curved or spiral bacilli that are commensals or pathogens in many animals. Campylobacter jejuni frequently causes acute enteritis in humans. In the United States gastroenteritis due to C jejuni affects an estimated 1.3 million people annually and is more common than that due to Salmonella or Shigella. Campylobacter fetus causes bacteremia and meningitis in immunocompromised patients. C fetus may cause maternal fever, abortion, stillbirth, and severe neonatal infection.

Campylobacter colonizes domestic and wild animals, especially poultry. Numerous cases have been associated with sick puppies or other animal contacts. Contaminated food and water, undercooked poultry, and person-to-person spread by the fecal-oral route are common routes of transmission. Outbreaks associated with day care centers, contaminated water supplies, and raw milk have been reported. Newborns may acquire the organism from their mothers at delivery. Campylobacter is a major cause of diarrhea in travelers to low- and middle-income countries.

Clinical Findings

A. Symptoms and Signs

C jejuni enteritis can be mild or severe. In tropical countries, asymptomatic stool carriage is common. The incubation period is usually 1–7 days. The disease usually begins with sudden onset of high fever, malaise, headache, abdominal cramps, nausea, and vomiting. Diarrhea follows and may be watery or bile stained, mucoid, and bloody. The illness is self-limiting, lasting 2–7 days, but relapses may occur. Without antimicrobial treatment, the organism remains in the stool for 1–6 weeks. Immune compromised patients may suffer prolonged or relapsing disease or complications due to bacteremia.

B. Laboratory Findings

The peripheral WBC count generally is elevated, with many band forms. Microscopic examination of stool reveals erythrocytes and leukocytes.

Isolation of C jejuni from stool is not difficult but requires selective agar and incubation conditions. Multiplex PCR tests are available for rapid diagnosis of Campylobacter and other enteropathogens.

Differential Diagnosis

Campylobacter enteritis may resemble viral gastroenteritis, salmonellosis, shigellosis, amebiasis, or other infectious diarrheas. Because it also mimics ulcerative colitis, Crohn disease, intussusception, and appendicitis, mistaken diagnosis can lead to unnecessary diagnostic testing or surgery.

Complications

The most common complication is dehydration. Other uncommon complications include erythema nodosum, convulsions, reactive arthritis, bacteremia, urinary tract infection, and cholecystitis. Campylobacter is the most commonly identified cause of Guillain-Barré syndrome (estimated to occur in 1 in 1000 cases) that typically follows C jejuni infection by 1–3 weeks.

Prevention

No vaccine is available. Hand washing and adherence to basic food sanitation practices help prevent disease. Hand washing and cleaning of kitchen utensils after contact with raw poultry are important. Adequate cooking of poultry is important.

Treatment

Treatment of fluid and electrolyte disturbances is important and in milder cases is the only required intervention. Antimicrobial therapy given early in the course of the illness will shorten the duration of symptoms. Treatment with azithromycin (10 mg/kg/day orally once daily) for 3 days, or ciprofloxacin terminates fecal excretion and may limit spread in households. Fluoroquinolone-resistant C jejuni are now common worldwide.

Prognosis

The outlook is excellent if dehydration is corrected, and misdiagnosis does not lead to inappropriate diagnostic or surgical procedures.

TULAREMIA

General Considerations

Tularemia is caused by Francisella tularensis, a gram-negative organism usually acquired directly from infected animals or by the bite of an infected tick or deer fly. Occasionally infection is acquired from infected domestic dogs or cats; by contamination of the skin or mucous membranes with infected blood or tissues; by inhalation of infected material; or by ingestion of contaminated meat or water. The incubation period is short, usually 3–7 days, but may vary from 2 to 25 days. In the United States 239 cases of tularemia were reported in 2017.

Ticks (dog tick, wood tick, lone star tick) are important vectors of tularemia transmission and rabbits are the classic vector. It is important to seek a history of rabbit hunting, skinning, or food preparation in any patient who has a febrile illness with tender lymphadenopathy, often in the region of a draining skin ulcer.

Prevention

Children should be protected from insect bites, especially those of ticks and deer flies, by the use of proper clothing and repellents. Because rabbits are the source of most human infections, the dressing and handling of such game should be performed with great care. Rubber gloves should be worn by hunters or food handlers when handling carcasses of wild rabbits. Care should be taken to avoid mowing over dead animals. If contact occurs, thorough washing with soap and water is indicated. For postexposure prophylaxis of F tularensis (such as might occur in a bioterrorism event), a 14-day course of doxycycline is recommended.

Clinical Findings

A. Symptoms and Signs

Several clinical types of tularemia occur in children. Sixty percent of infections are of the ulceroglandular form that starts as a relatively nonpainful, reddened papule that may be pruritic and quickly ulcerates. Soon, the regional lymph nodes become large and tender. Fluctuance quickly follows. There may be marked systemic symptoms, including high fever, chills, weakness, and vomiting. Pneumonitis occasionally accompanies the ulceroglandular form or may be seen as the sole manifestation of infection (pneumonic form). A detectable skin lesion may be absent, and localized lymphoid enlargement may exist alone (glandular form). Oculoglandular and oropharyngeal forms also occur. The latter is characterized by tonsillitis, often with membrane formation, cervical adenopathy, and high fever. In the absence of a primary ulcer or localized lymphadenitis, a prolonged febrile disease reminiscent of typhoid fever can occur (typhoidal form). Splenomegaly is common in all forms.

B. Laboratory Findings

F tularensis can be recovered from ulcers, regional lymph nodes, blood, and sputum of patients with the pneumonic form. However, the organism grows only on an enriched medium (blood-cystine-glucose agar), and laboratory handling is dangerous owing to the risk of airborne transmission to laboratory personnel. PCR or immunofluorescent staining of biopsy material or aspirates of involved lymph nodes is diagnostic.

The WBC count is not remarkable. The diagnosis is typically confirmed with serologic testing. Antibodies are usually present during the second week of illness. In the absence of a positive culture, a tube agglutination antibody titer of 1:160 or greater or a microagglutination titer of 1:128 or greater is presumptively positive for the diagnosis of tularemia. Confirmation of disease is established by demonstration of a fourfold antibody titer rise between acute and convalescent serum samples. PCR of blood, lymph node aspirate, or tissue may be available through state health departments.

Differential Diagnosis

The typhoidal form of tularemia may mimic typhoid, brucellosis, miliary TB, Rocky Mountain spotted fever, and mononucleosis. Pneumonic tularemia resembles atypical pneumonia. The ulceroglandular type of tularemia resembles pyoderma caused by staphylococci or streptococci, plague, anthrax, and cat-scratch fever. The oropharyngeal type must be distinguished from streptococcal or diphtheritic pharyngitis, mononucleosis, herpangina, or other viral pharyngitides.

Treatment

A. Specific Measures

Historically, streptomycin was the drug of choice. However, gentamicin (5 mg/kg/day) is efficacious, more available, and familiar to clinicians. A 10-day course is usually sufficient, although more severe infections may need longer therapy. Ciprofloxacin also can be used in patients with less severe disease. Doxycycline is often effective but is a static (as opposed to cidal) agent and is associated with higher relapse rates.

B. General Measures

Antipyretics and analgesics may be given as necessary. Skin lesions are best left open. Glandular lesions occasionally require incision and drainage.

Prognosis

The prognosis is excellent in most cases of tularemia that are recognized early and treated appropriately.

PLAGUE

General Considerations

Plague is an extremely serious acute infection caused by a gram-negative bacillus, Yersinia pestis. It is a disease of rodents that is transmitted to humans by flea bites. Plague bacilli have been isolated from ground squirrels, prairie dogs, and other wild rodents in many of the western and southwestern states in the United States. Most cases have come from New Mexico, Arizona, Colorado, and California. Direct contact with rodents, rabbits, or domestic dogs and cats provides exposure to fleas infected with plague bacilli. Contact with an infected dog caused a cluster of four cases in 2014. Most cases occur from June through September. Human plague in the United States appears to occur in cycles that reflect cycles in wild animal reservoirs. On average, seven cases per year are reported in the United States.

Prevention

Proper disposal of household and commercial wastes and control of rats and other animals are basic elements of plague prevention. Flea control is also important. Children vacationing in remote areas should be warned not to handle dead or dying animals. Domestic cats that roam freely in suburban areas may contact infected wild animals and acquire infected fleas. There is no commercially available vaccine for plague.

All persons exposed to plague in the previous 6 days (via personal contact with an infected person, contact with plague infected fleas, or exposure to infected tissues) should be given antimicrobial prophylaxis or be instructed to report fever or other symptoms to their physician. Persons who have close personal contact (< 2 m) with a person with pneumonic plague should receive antimicrobial prophylaxis for 7 days from the last exposure. Doxycycline or ciprofloxacin are the recommended agents for prophylaxis. Patients on prophylaxis should still seek prompt medical care for onset of fever or other illness.

Clinical Findings

A. Symptoms and Signs

Plague assumes several clinical forms; the two most common are bubonic and septicemic. Pneumonic plague is uncommon.

1. Bubonic plague

After an incubation period of 2–8 days, there is the sudden onset of high fever, chills, headache, vomiting, and marked delirium or clouding of consciousness. A less severe form also exists, with a less precipitous onset, but with progression over several days to severe symptoms. Although the flea bite is rarely seen, the regional lymph node, usually inguinal and unilateral, is/are painful and tender, 1–5 cm in diameter. The node usually suppurates and drains spontaneously after 1 week. Plague bacilli produce endotoxin that causes vascular necrosis. Bacilli may overwhelm regional lymph nodes and enter the circulation to produce septicemia. Severe vascular necrosis results in widely disseminated hemorrhage in skin, mucous membranes, liver, and spleen. Myocarditis and circulatory collapse may result from damage by the endotoxin. Plague meningitis or pneumonia may occur following bacteremic spread from an infected lymph node.

2. Septicemic plague

Plague may initially present as septicemia without evidence of lymphadenopathy. In some series, 25% of cases are initially septicemic. Septicemic plague carries a worse prognosis than bubonic plague, largely because it is not recognized and treated early. Patients may present with a nonspecific febrile illness characterized by fever, myalgia, chills, and anorexia. Septicemic plague may be complicated by secondary seeding of the lung causing plague pneumonia. Necrosis of distal body parts such as the fingers, toes, and nose tip may occur.

3. Primary pneumonic plague

Inhalation of Y pestis bacilli causes primary plague pneumonia. This form of plague is transmitted from human to human and to humans from cats or dogs with pneumonic plague and would be the form of plague most likely seen after aerosolized release of Y pestis in a bioterrorist incident. After an incubation of 1–6 days, the patient develops fever; cough; shortness of breath; and bloody, watery, or purulent sputum. Gastrointestinal symptoms are sometimes prominent. Because the initial focus of infection is the lung, buboes are usually absent; occasionally cervical buboes may be seen.

B. Laboratory Findings

Aspirate from a bubo contains bipolar-staining gram-negative bacilli. Pus, sputum, and blood all yield the organism. Rapid diagnosis can be made with fluorescent antibody detection or PCR on clinical specimens (available through state health departments). Confirmation is made by culture or serologic testing. Cultures are usually positive within 48 hours. Paired acute and convalescent sera may be tested for a fourfold antibody rise. Automated bacterial identification systems have been known to misidentify Y pestis and are unreliable.

Differential Diagnosis

The septic phase of the disease may be confused with illnesses such as meningococcemia, sepsis caused by other bacteria, and rickettsioses. The bubonic form resembles tularemia, anthrax, cat-scratch fever, lymphadenitis, and cellulitis.

Treatment

A. Specific Measures

Streptomycin or gentamicin for 10–14 days (or until several days after defervescence) is effective. For patients not requiring parenteral therapy, doxycycline, ciprofloxacin, TMP-SMX, or chloramphenicol may be given.

Every effort should be made to effect resolution of buboes without surgery. Pus from draining lymph nodes is infectious.

B. General Measures

State health officials should be notified immediately about suspected cases of plague. Pneumonic plague is highly infectious, and droplet isolation is required until the patient has been on effective antimicrobial therapy for 48 hours. Laboratory personnel should be notified if suspicion for plague exists in order to exercise precaution and prevent occupational acquisition.

Prognosis

The mortality rate in untreated bubonic plague is about 50%. The mortality rate for treated pneumonic plague is 50%–60%. Recent mortality rates in New Mexico were 3% for bubonic plague and 71% for the septicemic form.

HAEMOPHILUS INFLUENZAE TYPE B INFECTIONS

General Considerations

H influenzae is classified by its polysaccharide capsule into six serotypes (a–f), and those without a polysaccharide capsule are considered nontypeable. H influenzae type b (Hib) that was a common cause of invasive disease, such as meningitis, bacteremia, epiglottitis, septic arthritis, periorbital and facial cellulitis, pneumonia, and pericarditis, has become uncommon because of widespread immunization in early infancy. The 99% reduction in incidence seen in many parts of the United States is due to high rates of vaccine coverage and reduced nasopharyngeal carriage after vaccination. Now, non–type b and nontypeable H influenzae cause the majority of invasive disease. Non–type b serotypes may cause meningitis, bacteremia and other diseases previously caused by Hib.

Unencapsulated, nontypeable H influenzae frequently colonize the mucous membranes and cause otitis media, sinusitis, bronchitis, and pneumonia in children and adults. Unencapsulated, nontypeable H influenzae also cause invasive disease. Neonatal sepsis similar to early-onset GBS is recognized and is more common in preterm and low-birth-weight infants. Obstetric complications of chorioamnionitis and bacteremia are usually the source of neonatal cases.

Ampicillin resistance occurs in 25%–40% of nontypeable H influenzae. β-Lactamase-negative, ampicillin-resistant (BLNAR) H influenzae has emerged as a clinically important pathogen in Europe, Japan, and Canada. In the United States, the prevalence of BLNAR strains currently remains at around 3%.

Among children younger than 5 years, American Indian and Alaska Native children have a substantially higher incidence of invasive H influenzae disease, greater than five times the rate of other races.

Prevention

Several carbohydrate protein conjugate Hib vaccines are currently available (see Chapter 10).

The risk of invasive Hib disease is highest in unimmunized, or partially immunized, household contacts of a Hib patient when the contact is younger than 4 years. The following situations require rifampin chemoprophylaxis of all household contacts (except pregnant women) to eradicate potential nasopharyngeal colonization with Hib and limit risk of invasive disease: (1) families where at least one household contact is younger than 4 years and either unimmunized or incompletely immunized against Hib; (2) an immunocompromised child (of any age or immunization status) resides in the household; or (3) a child younger than 12 months resides in the home and has not received the primary series of the Hib vaccine. Preschool and day care center contacts may need prophylaxis if more than one case has occurred in the center in the previous 60 days (discuss with state health officials). The index case also needs chemoprophylaxis if the patient is younger than 2 years or if the patient resides in a household with a household contact at risk of disease (as described above) and if treated with an antibiotic regimen other than ceftriaxone or cefotaxime (both are effective in eradication of Hib from the nasopharynx). Household contacts and index cases older than 1 month who need chemoprophylaxis should be given rifampin, 20 mg/kg per dose (maximum adult dose, 600 mg) orally, once daily for 4 successive days. Infants who are younger than 1 month should be given oral rifampin (10 mg/kg per dose once daily for 4 days). Rifampin should not be used in pregnant females. Chemoprophylaxis may be considered for household contacts of children with invasive disease caused by H influenzae type A. For other strains, including nontypeable H influenzae, chemoprophylaxis is generally not recommended because secondary cases are rare.

Clinical Findings

A. Symptoms and Signs Hib and Non–Type B Invasive Disease

1. Meningitis

Infants usually present with fever, irritability, lethargy, poor feeding with or without vomiting, and a high-pitched cry.

2. Acute epiglottitis

The most useful clinical finding in the early diagnosis of Haemophilus epiglottitis is evidence of dysphagia, characterized by a refusal to eat or swallow saliva and by drooling. This finding, plus the presence of a high fever in a toxic child—even in the absence of a cherry-red epiglottis on direct examination—should strongly suggest the diagnosis and lead to prompt intubation. Stridor is a late sign (see Chapter 19).

3. Septic arthritis

In the prevaccine era, Hib was a common cause of septic arthritis in unimmunized children younger than 4 years in the United States. The child is febrile and refuses to move the involved joint and limb. Examination reveals swelling, warmth, redness, tenderness on palpation, and severe pain on attempted movement of the joint.

4. Cellulitis

Cellulitis due to Hib occurs almost exclusively in children between the ages of 3 months and 4 years but is now uncommon as a result of immunization. The cheek or periorbital (preseptal) area is often involved.

B. Laboratory Findings

The WBC count in Hib infections may be high or normal with a shift to the left. A positive culture of blood, CSF, aspirated pus, or fluid from the involved site proves the diagnosis. In untreated meningitis, CSF smear may show the characteristic pleomorphic gram-negative rods. Recently, the FDA approved a multiplex PCR test for CSF that includes H influenzae among the pathogens that can be detected.

C. Imaging

A lateral view of the neck may suggest the diagnosis in suspected acute epiglottitis, but misinterpretation is common. Intubation should not be delayed to obtain radiographs.

Differential Diagnosis

A. Meningitis

Meningitis must be differentiated from head injury, brain abscess, tumor, lead encephalopathy, and other forms of meningoencephalitis, including mycobacterial, viral, fungal, and bacterial agents.

B. Acute Epiglottitis

In croup caused by viral agents (parainfluenza 1, 2, and 3, respiratory syncytial virus, influenza A, adenovirus), the child has more definite upper respiratory symptoms, cough, hoarseness, slower progression of obstructive signs, and lower fever. Spasmodic croup usually occurs at night in a child with a history of previous attacks. Sudden onset of choking and paroxysmal coughing suggests foreign-body aspiration. Retropharyngeal abscess may have to be differentiated from epiglottitis.

C. Septic Arthritis

Differential diagnosis includes acute osteomyelitis, prepatellar bursitis, cellulitis, rheumatic fever, and fractures and sprains.

D. Cellulitis

Erysipelas, streptococcal cellulitis, insect bites, and trauma (including popsicle panniculitis or other types of freezing injury) may mimic Hib cellulitis. Periorbital cellulitis must be differentiated from paranasal sinus disease without cellulitis, allergic inflammatory disease of the lids, conjunctivitis, and herpes zoster infection.

Complications

A. Meningitis

(See Chapter 25)

B. Acute Epiglottitis

The disease may rapidly progress to complete airway obstruction with complications owing to hypoxia (see Chapter 25). Mediastinal emphysema and pneumothorax may occur.

C. Septic Arthritis

Septic arthritis may result in rapid destruction of cartilage and ankylosis if diagnosis and treatment are delayed. Even with early treatment, the incidence of residual damage and disability after septic arthritis in weight-bearing joints may be as high as 25%.

D. Cellulitis

Bacteremia from a cutaneous source may lead to meningitis or pyarthrosis.

Treatment

All patients with bacteremic or potentially bacteremic H influenzae diseases require hospitalization for treatment. The drug of choice in hospitalized patients is a third-generation cephalosporin (cefotaxime or ceftriaxone) until the sensitivity of the organism is known. Meropenem is an alternative choice. Persons with invasive Hib disease should be in droplet isolation for 24 hours after initiation of parenteral antibiotic therapy.

A. Meningitis

Therapy is begun as soon as bacterial meningitis is suspected. Empiric intravenous therapy recommended for meningitis (until organism identified) is vancomycin in combination with ceftriaxone. Once the organism has been identified as H influenzae and the susceptibilities are known, the antibiotic regimen can be tailored accordingly. Most isolates will be susceptible to ceftriaxone, and some to ampicillin. Therapy should be given intravenously for the entire course. Ceftriaxone may be given intramuscularly if venous access becomes difficult.

Duration of therapy is 10 days for uncomplicated meningitis. Longer treatment is reserved for children who respond slowly or have complications.

Dexamethasone given immediately after diagnosis and continued for up to 4 days may reduce the incidence of hearing loss in children with Hib meningitis. The use of dexamethasone is controversial, but when it is used, the dosage is 0.6 mg/kg/day in four divided doses for 2–4 days. Starting dexamethasone more than 6 hours after antibiotics have been initiated is unlikely to provide benefits.

Repeated lumbar punctures are usually not necessary in Hib meningitis. They should be obtained in the following circumstances: unsatisfactory or questionable clinical response, seizure occurring after several days of therapy, if the neurologic examination is abnormal or difficult to evaluate, or prolonged (7 days) or recurrent fever.

B. Acute Epiglottitis

(See Chapter 19)

C. Septic Arthritis

Initial therapy should include an effective antistaphylococcal antibiotic and cefotaxime or ceftriaxone until identification of the organism is made and continued, once the isolate is known to be Haemophilus and susceptibilities are known (see Chapter 19). If a child is improved following initial intravenous therapy, the patient can be transitioned to oral therapy based on susceptibilities. Possible oral agents should be chosen based on susceptibilities but might include amoxicillin/clavulanate (90–100 mg/kg/day of amoxicillin component in four divided doses every 6 hours). Alternative agents include second- or third-generation cephalosporins. Antibiotics should be administered to complete a 2- to 4-week course (longer if complications or signs and symptoms are unresolved). Drainage of infected joint fluid is an essential part of treatment. In joints other than the hip, this can often be accomplished by one or more needle aspirations. In hip infections—and in arthritis of other joints when treatment is delayed or clinical response is slow—surgical drainage is advised.

D. Cellulitis, Including Orbital Cellulitis

Initial therapy for orbital cellulitis should be broad spectrum antibiotics. Once the organism is identified as H influenzae and susceptibilities are known, cefotaxime, ceftriaxone, or meropenem can be used depending on susceptibilities. Mixed infections are common and may require additional agents. Therapy is given parenterally for at least 3–7 days followed by oral treatment. There is usually marked improvement after 72 hours of treatment. The total antibiotic course will vary with the severity of the infection, response to therapy, the presence of an abscess, and whether drainage was performed. A minimum course of 21 days is reasonable in uncomplicated cases without abscess and good therapeutic response, assuming all signs of orbital cellulitis have completely resolved. In cases with severe ethmoid sinusitis and evidence of boney destruction at least a 4-week treatment course is advisable. Complicated cases may require longer treatment courses.

Prognosis

The case fatality rate for invasive H influenzae is 15% but may be higher depending on the serotype. Young infants and older adults have the highest mortality rate. Hearing loss or other neurologic sequelae develop in 15%–30% of patients with Hib meningitis. Patients with Hib meningitis should have their hearing checked during the course of the illness or shortly after recovery. Children in whom invasive Hib infection develops despite appropriate immunization should have tests to investigate immune function and to rule out HIV. Deaths from epiglottitis are associated with bacteremia and the rapid development of airway obstruction. The prognosis for the other diseases requiring hospitalization is good with the early institution of adequate antibiotic therapy.

PERTUSSIS (WHOOPING COUGH)

General Considerations

Pertussis is an acute, highly communicable infection of the respiratory tract caused by Bordetella pertussis that is characterized by severe bronchitis. Children usually acquire the disease from symptomatic family contacts. Adults and adolescents who have mild respiratory illness, not recognized as pertussis, frequently are the source of infection. Asymptomatic carriage of B pertussis has not been demonstrated. Infectivity is greatest during the catarrhal and early paroxysmal cough stage (for about 4 weeks after onset).

In the United States, more than 48,000 cases were reported in 2012, but rates in recent years have declined to approximately to 18,000—20,000/year; many cases go unreported. Pertussis is most severe in the very young. Fifty percent of children younger than 1 year with a diagnosis of pertussis are hospitalized. Fatality rates in infants younger than 2 months are approximately 2% and approximately 1% for infants in their first year of life.

The duration of immunity following natural pertussis is not known but is not lifelong. Reinfections are usually mild. Immunity following vaccination wanes in 5–10 years; thus the majority of young adults in the United States are susceptible to pertussis infection, and disease is probably common but unrecognized. Decreased efficacy of acellular vaccines (now standard in the United States) compared to whole-cell vaccines and low rates of immunization due to vaccine hesitancy in some communities have contributed significantly to pertussis epidemics in the United States.

Bordetella parapertussis and Bordetella holmesii cause a similar but milder syndrome.

B pertussis organisms attach to the ciliated respiratory epithelium and multiply there; deeper invasion does not occur. Disease is due to several bacterial toxins, the most potent of which is pertussis toxin, which is responsible for the typical lymphocytosis.

Clinical Findings

A. Symptoms and Signs

The onset of pertussis is insidious, with catarrhal upper respiratory tract symptoms (rhinitis, sneezing, and an irritating cough). Fever above 38.3 is unusual and suggests an alternative diagnosis. After about 2 weeks, cough becomes paroxysmal, characterized by repeated forceful coughing ending with a loud inspiration (the whoop). Infants and adults with severe pertussis, as well as patients with milder pertussis, may lack the characteristic whoop. Vomiting commonly follows a paroxysm. Coughing may be accompanied by cyanosis, sweating, prostration, and exhaustion. Coughing fits occur more frequently at night. This stage lasts for 2–4 weeks, with gradual improvement. Paroxysmal coughing may continue for some months and may worsen with intercurrent viral respiratory infection. In adults, older children, and partially immunized individuals, symptoms may consist only of irritating cough lasting 1–2 weeks. Clinical pertussis is milder in immunized children.

B. Laboratory Findings

WBC counts of 20,000–30,000/μL with 70%–80% lymphocytes typically appear near the end of the catarrhal stage, and the degree of lymphocytosis correlates with the severity of disease. Severe pulmonary hypertension and hyperleukocytosis (> 70,000/μL) are associated with severe disease and death in young children with pertussis. The blood picture may resemble lymphocytic leukemia or leukemoid reactions. Many older children and adults with mild infections never demonstrate lymphocytosis.

The preferred method of diagnosis in most centers is identification of B pertussis by PCR from nasopharyngeal specimens. The organism may be found in the respiratory tract in diminishing numbers beginning in the catarrhal stage and ending about 2 weeks after the beginning of the paroxysmal stage. After several weeks of symptoms, PCR testing is frequently negative. Culture requires specialized media, careful attention to specimen collection and transport, and is now unavailable in many labs.

The chest radiograph reveals thickened bronchi and sometimes shows a “shaggy” heart border.

Differential Diagnosis

In the catarrhal phase, pertussis is extremely difficult to discriminate from viral causes of upper respiratory infection. The differential diagnosis of pertussis includes bacterial (particularly M pneumoniae), tuberculous, chlamydial, and viral pneumonia. The absence of fever in pertussis differentiates this disease from most bacterial infections. Cystic fibrosis and foreign-body aspiration may be considerations with chronic cough. Adenoviruses and respiratory syncytial virus may cause paroxysmal coughing with an associated elevation of lymphocytes in the peripheral blood, mimicking pertussis.

Complications

Bronchopneumonia due to superinfection is the most common serious complication. It is characterized by abrupt clinical deterioration during the paroxysmal stage, accompanied by high fever and sometimes a striking leukemoid reaction with a shift to predominantly polymorphonuclear neutrophils. Intercurrent viral respiratory infection is also a common complication and may provoke worsening or recurrence of paroxysmal coughing. Otitis media is common. Residual chronic bronchiectasis is an infrequent but serious complication. Apnea and sudden death may occur during a particularly severe paroxysm. Rib fractures may occur due to the force of coughing. Seizures complicate 1.5% of cases, and encephalopathy occurs in 0.1%. The encephalopathy frequently is fatal. Anoxic brain damage, cerebral hemorrhage, or pertussis neurotoxins are suggested contributors, but anoxia is most likely the cause. Epistaxis and subconjunctival hemorrhages are common. Rib fractures may occur due to forceful coughing.

In infants, choking, apnea, poor feeding, and failure to thrive are common.

Prevention

Active immunization (see Chapter 10) with DTaP (diphtheria, tetanus, and acellular pertussis) vaccine should be given in early infancy. The occurrence and increased recognition of disease in adolescents and adults contribute to the increasing number of cases. A booster dose of vaccine for adolescents between the ages of 11 and 18 years is recommended. Subsequent booster doses of Tdap are recommended for adults aged 18–60 years to replace Td boosters. Immunization of pregnant women in the last trimester prior to 36 weeks’ gestation, new mothers, care givers of infants younger than 6 months, and health care workers of young children is also recommended.

Chemoprophylaxis with azithromycin should be considered for exposed family, household, and hospital contacts who are within 21 days since the onset of cough in the index case, particularly for pregnant women, children younger than 12 months, and people with chronic medical problems. Hospitalized children with pertussis should be isolated because of the great risk of transmission to patients and staff. Several large hospital outbreaks have been reported.

Treatment

A. Specific Measures

Antibiotics may ameliorate early infections (ie, in the catarrhal phase) but have no effect on clinical symptoms in the paroxysmal stage. Thus, treatment should be initiated as quickly as possible and should not wait for confirmatory testing in cases where the diagnosis is strongly suspected. Azithromycin (10 mg/kg/dose up to 500 mg on day 1, followed by 5 mg/kg/dose up to 250 mg daily for 4 more days) is the drug of choice because it promptly terminates respiratory tract carriage of B pertussis. Erythromycin given four times daily for 14 days is acceptable but not preferred. Resistance to macrolides has been rarely reported. TMP-SMX may also be used for erythromycin-intolerant patients. Erythromycin has been associated with pyloric stenosis in infants younger than 1 month, and azithromycin is preferred in this age. The risk of pyloric stenosis after azithromycin treatment is likely less, but cases have occurred. Parents of infants younger than 1 month who require treatment with azithromycin should be informed of this risk and counseled on the signs of pyloric stenosis.

B. General Measures

Nutritional support during the paroxysmal phase is important. Frequent small feedings, tube feeding, or parenteral fluid supplementation may be needed. Minimizing stimuli that trigger paroxysms is probably the best way of controlling cough. Though numerous medications have been proposed, including albuterol, corticosteroids, and diphenhydramine, there are no adequate clinical trials that identify an effective treatment for cough paroxysms.

C. Treatment of Complications

Respiratory insufficiency due to pneumonia or other pulmonary complications should be treated with oxygen and assisted ventilation if necessary. Convulsions are treated with appropriate supportive care and anticonvulsants. Bacterial pneumonia or otitis media may require additional antibiotics. Infants with an extremely high WBC count (> 70,000/μL) are at high risk of death and may benefit from extracorporeal membrane oxygenation (ECMO).

Prognosis

The prognosis for patients with pertussis has improved in recent years because of excellent nursing care, treatment of complications, attention to nutrition, and modern intensive care. However, the disease is still very serious in infants younger than 1 year; most deaths occur in this age group. Children with encephalopathy have a poor prognosis.

LISTERIOSIS

General Considerations

Listeria monocytogenes is a gram-positive, non–spore-forming aerobic rod distributed widely in animals and in food, dust, and soil. It causes systemic infections in newborn infants and immunosuppressed older children. In pregnant women, infection is relatively mild, with fever, aches, and chills, but is accompanied by bacteremia and sometimes results in intrauterine or perinatal infection with grave consequences for the fetus or newborn. Pregnant women are particularly susceptible to listeriosis, and 20% of affected pregnancies end in stillbirth or neonatal death. In the United States, pregnant Hispanic women are 24 times more likely to contract listeriosis than the general population. Outbreaks of listeriosis have been associated with multiple foods, particularly unpasteurized dairy products including homemade Mexican-style cheese and prepared meats. Though cases have decreased since the adoption of strict regulations for ready-to-eat foods, outbreaks continue to occur in the United States; eight cases in four states associated with deli meats were reported by the CDC in 2019.

Clinical Findings

A. Symptoms and Signs

In the early neonatal form, symptoms of listeriosis usually appear on the first day of life and always by the third day. Fetal distress is common, and infants frequently have signs of severe disease at birth. Respiratory distress, diarrhea, and fever occur. On examination, hepatosplenomegaly and a papular rash are found. A history of maternal fever is common. Meningitis may accompany the septic course. The late neonatal form usually occurs after 9 days until as late as 5 weeks. Meningitis is common, characterized by irritability, fever, and poor feeding.

Listeria infections are rare in older children and usually are associated with immunodeficiency including treatment with tumor necrosis factor-α inhibitors. Signs and symptoms are those of meningitis or meningoencephalitis, often with insidious onset.

B. Laboratory Findings

In all patients except those receiving white cell depressant drugs, the WBC count is elevated, with 10%–20% monocytes. The characteristic CSF cell count in meningitis is high (> 500/μL) with a predominance of polymorphonuclear neutrophils, though monocytes may predominate in up to 30% of cases. Listeria are typically gram-positive rods, though they can be gram variable, and may be mistaken for “diphtheroids.” Gram-stained smears of CSF are frequently negative. The chief pathologic feature in severe neonatal sepsis is miliary granulomatosis with microabscesses in the liver, spleen, CNS, lung, and bowel.

Culture results are frequently positive from multiple sites, including blood from the infant and the mother.

Differential Diagnosis

Early-onset neonatal disease resembles hemolytic disease of the newborn, GBS sepsis or severe cytomegalovirus infection or toxoplasmosis. Late-onset disease must be differentiated from meningitis due to echovirus and coxsackievirus, GBS, and gram-negative enteric bacteria.

Prevention

Immunosuppressed, pregnant, and elderly patients can decrease the risk of Listeria infection by avoiding soft unpasteurized cheeses, by thoroughly reheating or avoiding delicatessen and ready-to-eat foods, by avoiding raw meat and milk, and by thoroughly washing fresh vegetables.

Treatment

Ampicillin is the drug of choice in most cases of listeriosis. Gentamicin has a synergistic effect with ampicillin and should be given in serious infections and to patients with immune deficits; doses depend on age and birth weight. If ampicillin cannot be used, TMP-SMX is effective and achieves adequate levels in the CNS. Meropenem and linezolid are also active and may be used in certain scenarios. Vancomycin may be substituted for ampicillin when empirically treating meningitis. Cephalosporins are not active. Treatment of severe disease should continue for at least 2 weeks; meningitis is treated 21 days.

Controversy exists about the need for empiric Listeria coverage for a febrile neonate; factors such as disease severity, maternal illness, maternal risk factors (eg, exposure to unpasteurized cheese, early/severe onset of infection or suspected meningitis) make empiric coverage more prudent.

Prognosis

In a recent outbreak of early-onset neonatal disease, the mortality rate was 27% despite aggressive and appropriate management. Meningitis in older infants has a good prognosis.

TUBERCULOSIS

General Considerations

Tuberculosis (TB) is a granulomatous disease caused by Mycobacterium tuberculosis (MTb). It is a leading cause of death throughout the world. Children younger than 5 years are most susceptible with highest risk in the first year of life. Primary infection occurs via the lungs with subsequent lymphohematogenous dissemination to extrapulmonary sites, including lymph nodes, the brain and meninges, bones and joints, kidneys, intestine, larynx, eyes, and skin. A greater proportion of pediatric TB disease is extrapulmonary compared to adults. Though TB is rare in many US communities, outbreaks in pediatric populations, particularly in schools do occur. Exposure to an infected adult is the most important risk factor for a pediatric patient. Groups at highest risk of TB infection are those who were born or lived in TB endemic countries and, to a lesser extent, US-born children with family members from endemic countries. Additional epidemiologic risk factors may include exposure to foreign-born persons, prisoners, residents of nursing homes, indigents, migrant workers, and health care providers. Rates of TB in American Indians, Asian, Hawaiian and Pacific Islanders, and Hispanic people are substantially greater than in Caucasians. Nationally about 1% if the TB cases are multiple drug resistant (MDR). HIV infection and other immune compromising diseases are important risk factors for both development and spread of disease.

An important distinction is the difference between TB infection and disease. In infection, there are no clinical or radiographic signs of active disease. This scenario is frequently referred to as latent tuberculosis infection (LTBI) and may affect up to one-quarter of the world population. LTBI may progress (quickly in the very young, and often after decades of infection in older children and adults) to symptomatic disease that requires aggressive multidrug therapy.

Mycobacterium bovis infection is clinically identical to M tuberculosis, though extrapulmonary disease (particularly gastrointestinal) is more common with M bovis. M bovis may be acquired from unpasteurized dairy products obtained outside the United States.

Clinical Findings

A. Symptoms and Signs

1. Latent Tuberculosis Infection

By definition, there are no symptoms or signs of LTBI, and diagnosis occurs in the context of a positive skin or blood test on TB screening.

2. Pulmonary

(See Chapter 19.)

3. Miliary

This manifestation of disseminated disease is common in young children and can be rapidly progressive. Affected children have fever, weight loss, or failure to thrive, and can become systemically unwell. Diagnosis is suggested by the classic “snowstorm” or “millet seed” appearance of lung fields on radiograph, although early in the course the chest radiograph may show only subtle abnormalities. Other tissues may be infected to produce osteomyelitis, arthritis, meningitis, tuberculomas of the brain, enteritis, or infection of the kidneys and liver.

4. Meningitis

Symptoms include fever, vomiting, headache, lethargy, and irritability, with signs of meningeal irritation and increased intracranial pressure, cranial nerve palsies, convulsions, and coma.

5. Lymphatic

Enlarged cervical lymph nodes usually present in a subacute manner. Involved nodes may become fixed to the overlying skin, suppurate, and drain.

B. Laboratory Findings

For decades, the tuberculin skin test (TST) has been the standard diagnostic tool for TB. However, the skin test has a number of disadvantages: Placement of TST can be difficult, measurement of induration can be subjective, it requires two health care visits to complete, the amount of induration that indicates a positive reaction varies with the epidemiologic risk and immune status of the patient (Table 42–3), and both false-positive and false-negative results occur. False-positive reactions are most common in children previously vaccinated with bacille Calmette-Guerin (BCG), though exposure to nontuberculous mycobacteria (NTM) can also lead to TST positivity. Approximately 75% of positive TSTs in BCG-vaccinated individuals (children and adults) may be due to the BCG rather than latent TB. This has significant implications for screening populations from TB endemic countries where the majority of children receive BCG. False-negative reactions are also a concern, occurring in malnourished patients, those with overwhelming disease, and in 10% of children with isolated pulmonary disease. Temporary suppression of tuberculin reactivity may be seen with viral infections (eg, measles, influenza, varicella, and mumps), after live virus immunization, and during corticosteroid or other immunosuppressive drug therapy. For these reasons, a negative TST does not exclude the diagnosis of TB.

IGRAs measure in vitro release of interferon-γ from blood lymphocytes in response to TB-specific antigens. These assays, which have much higher specificity for MTb, do not react with antigens in BCG and the majority of NTM. IGRAs are done on blood obtained by venipuncture and require only a single visit. These tests are preferred in adults and BCG-immunized children older than 2 years. IGRAs are reported as positive, negative, or indeterminate.

Definitive diagnosis of TB disease requires microbiologic or molecular identification of M tuberculosis. However, children have pauci-bacillary disease and at young age are less able to produce sputa, even with induction. Cultures of pooled early morning gastric aspirates from 3 successive days will yield M tuberculosis in about 40% of cases, but smears on gastric specimens are usually negative. Biopsy may be necessary to establish the diagnosis, but it may be difficult to justify invasive tests in mildly ill or asymptomatic children. Therapy should not be delayed in suspected cases. The CSF in tuberculous meningitis shows slight to moderate pleocytosis (50–300 WBCs/μL, predominantly lymphocytes), decreased glucose, and increased protein.

Acid-fast bacilli can be demonstrated on microscopy from patient samples. Culture for definitive identification and susceptibilities remains a mainstay of laboratory diagnosis, though nucleic amplification tests including the Xpert MTB/RIF are increasingly available and are able to rapidly identify Mtb genes associated with antimicrobial susceptibilities direct patient samples. Current World Health Organization (WHO) guidelines recommend utilization of Xpert testing on all sputa tested for TB.

C. Imaging

Chest radiograph should be obtained in all children with suspicion of TB at any site or with a positive TB test. Segmental consolidation with some volume loss and hilar adenopathy are common findings in children. Paratracheal adenopathy is a classic presentation. Pleural effusion also occurs with primary infection. Cavities and apical disease are unusual in children but are common in adolescents and adults. Computed tomography (CT) scanning more clearly demonstrates pathology in questionable cases but is unnecessary in the majority of cases.

Differential Diagnosis

Pulmonary TB must be differentiated from fungal, parasitic, mycoplasmal, and bacterial pneumonias; lung abscess; foreign-body aspiration; lipoid pneumonia; sarcoidosis; and mediastinal cancer. Cervical lymphadenitis is most likely due to streptococcal or staphylococcal infections. Cat-scratch fever and infection with atypical mycobacteria may need to be distinguished from tuberculous lymphadenitis. Viral meningoencephalitis, head trauma (child abuse), lead poisoning, brain abscess, acute bacterial meningitis, brain tumor, and disseminated fungal infections must be excluded in tuberculous meningitis. A positive TST or IGRA in the patient or family contacts is frequently valuable in suggesting the diagnosis of TB. A negative TST or IGRA does not exclude TB.

Prevention

A. BCG Vaccine

BCG vaccines are live-attenuated strains of M bovis. Although neonatal and childhood administration of BCG is carried out in countries with a high prevalence of TB, protective efficacy varies greatly with vaccine potency and method of delivery. BCG protects infants and toddlers against disseminated TB and meningitis but does not protect against pulmonary TB later in childhood or adolescence. In the United States where rates of TB are low among US-born children, BCG vaccination is not recommended, in part because of challenges posed by potential false positive TST reactions in BCG-vaccinated children.

B. LTBI Treatment and Window Prophylaxis

Children with LTBI should be treated to prevent future development of TB disease. Traditionally, treatment with 9 months of isoniazid (9H) as been utilized, but shorter regimens of daily rifampin (15–20 mg/kg/day) for 4 months or once-weekly isoniazid/rifapentine (15 mg/kg/dose) are now preferred by many experts. These regimens have equal efficacy and better completion rates compared to 9H. Because it can take up to 8 weeks for IGRA or skin tests to convert after infection and disease can progress quickly in young children, exposed asymptomatic children younger than 5 years should receive treatment as for LTBI until repeat testing can be performed at least 8 weeks after the last exposure (window prophylaxis). If follow-up testing is positive, they can simply complete the LTBI treatment.

C. Other Measures

Prevention of TB in children requires identification and treatment of infectious adult cases in a community or within a household. Because children are not generally contagious, a pediatric case indicates an active adult case, often a family member in the household. Contact tracing through public health agencies and TB screening of high-risk individuals are the most effective ways to prevent pediatric TB cases. Routine TB testing is not recommended for children without risk factors who reside in communities with a low incidence of TB. Children with travel or immigration from a country with a high incidence of infection should be tested on entry to the United States or upon presentation to health care providers.

Treatment

A. Specific Measures

Most children with suspected active TB do not require hospitalization. If the infecting organism has not been isolated from the presumed source (and therefore susceptibility testing is unavailable), reasonable attempts should be made to obtain it from the child using morning gastric aspirates, sputum, bronchoscopy, thoracentesis, or biopsy when appropriate. Unfortunately, cultures are frequently negative in children, and the risk of these procedures must be weighed against the yield.

Directly observed administration of all doses of antituberculosis therapy by a trained healthcare professional is essential to ensure compliance with therapy.

Most regimens for active TB infection begin with four drug therapy for the first 2 months. For example, children with active pulmonary disease receive isoniazid (10 mg/kg/day), rifampin (20 mg/kg/day), pyrazinamide (35 mg/kg/day), and ethambutol (20 mg/kg/day) in single daily oral doses for 2 months, followed by isoniazid plus rifampin (either in a daily or thrice-weekly regimen) for 4 months. This is effective for eliminating isoniazid-susceptible organisms. For more severe disease, such as miliary or CNS infection, higher doses of drugs are used, and the duration of the two drug continuation phase is increased to 10 months or more. The duration of therapy is prolonged in immunocompromised children and if drug resistance necessitates alternative regimens and such patients should be managed in consultation with a TB specialist. TB meningitis is often treated with additional IV medications to achieve better CSF penetration, including levofloxacin, linezolid, and amikacin.

Drugs to treat TB are generally better tolerated in children than adults. Clinically significant hepatotoxicity is rare, and routine monitoring or liver function tests in otherwise healthy children is generally not required. Peripheral neuropathy associated with pyridoxine deficiency is rare in children, and it is not necessary to add pyridoxine unless significant malnutrition coexists or if the child is strictly breast-fed. Rifampin causes an orange color of urine and secretions, which is benign but may stain contact lenses or clothes. Rifampin alters the kinetics of many medications including some anticonvulsants and oral contraceptives.

Optic neuritis is the major side effect of ethambutol in adults; thus, there has been concern with use in children too young to screen for color discrimination. However, optic neuritis is rare and usually occurs in adults receiving more than the recommended dosage of 25 mg/kg/day. Since documentation of optic neuritis in children is lacking despite considerable worldwide experience, many four-drug regimens for children now include ethambutol.

B. Chemotherapy for Drug-Resistant Tuberculosis

The incidence of drug resistance is increasing and reaches 10%–20% in some areas of the United States. Transmission of MDR and extensively drug-resistant strains to contacts has occurred in some epidemics. Therapy should continue for 18 months or longer. Often, four to six first- and second-line medications including parenteral formulations are needed. Consultation with a local expert in treating TB is recommended.

C. General Measures

Corticosteroids may be used for suppressing inflammatory reactions in meningeal, pleural, and pericardial TB and for the relief of bronchial obstruction due to hilar adenopathy. Prednisone is given orally, 1 mg/kg/day for 2 weeks, with gradual withdrawal over the next 4–6 weeks. The use of corticosteroids may mask progression of disease. Accordingly, the clinician needs to be sure that an effective regimen is being used.

Prognosis

If bacteria are sensitive and treatment is completed, most children are cured with minimal sequelae. Repeat treatment is more difficult and less successful. Without treatment, the mortality rate in both miliary TB and tuberculous meningitis is almost 100%. In the latter form, about two-thirds of patients receiving treatment survive, but there may be a high incidence of neurologic abnormalities among survivors if treatment is started late.

INFECTIONS WITH NONTUBERCULOUS MYCOBACTERIA

General Considerations

More than 130 species of acid-fast mycobacteria other than M tuberculosis may cause subclinical infections and occasionally clinical disease resembling TB. Strains of NTM are common in soil, food, and water. Organisms enter the host by small abrasions in skin, oral mucosa, or gastrointestinal mucosa.

Mycobacterium avium complex (MAC), Mycobacterium kansasii, Mycobacterium fortuitum, Mycobacterium abscessus, Mycobacterium marinum, and Mycobacterium chelonae are most commonly encountered. M fortuitum, M abscessus, and M chelonae are “rapid growers” requiring 3–7 days for recovery in culture, whereas other mycobacteria require up to several weeks. After inoculation they form colonies closely resembling M tuberculosis morphologically.