BORDETELLA PERTUSSIS INFECTION (WHOOPING COUGH)
ESSENTIALS OF DIAGNOSIS
Predominantly in infants under age 2 years. Adolescents and adults are reservoirs of infection.
Two-week prodromal catarrhal stage of malaise, cough, coryza, and anorexia.
Paroxysmal cough ending in a high-pitched inspiratory “whoop.”
Absolute lymphocytosis, often striking; culture confirms diagnosis.
Pertussis is an acute infection of the respiratory tract caused by B pertussis that is transmitted by respiratory droplets. The incubation period is 7–17 days. Half of all cases occur before age 2 years. Neither immunization nor disease confers lasting immunity to pertussis. Consequently, adults are an important reservoir of the disease.
The symptoms of classic pertussis last about 6 weeks and are divided into three consecutive stages. The catarrhal stage is characterized by its insidious onset, with lacrimation, sneezing, and coryza, anorexia and malaise, and a hacking night cough that becomes diurnal. The paroxysmal stage is characterized by bursts of rapid, consecutive coughs followed by a deep, high-pitched inspiration (whoop). The convalescent stage begins 4 weeks after onset of the illness with a decrease in the frequency and severity of paroxysms of cough. The diagnosis often is not considered in adults, who may not have a typical presentation. Cough persisting more than 2 weeks is suggestive. Infection may also be asymptomatic.
The white blood cell count is usually 15,000–20,000/mcL (rarely, as high as 50,000/mcL or more), 60–80% of which are lymphocytes. The diagnosis is established by isolating the organism from nasopharyngeal culture. A special medium (eg, Bordet-Gengou agar) must be requested. Polymerase chain reaction assays for diagnosis of pertussis may be available in some clinical or health department laboratories.
Acellular pertussis vaccine is recommended for all infants, combined with diphtheria and tetanus toxoids (DTaP). Infants and susceptible adults with significant exposure should receive prophylaxis with an oral macrolide. In recognition of their importance as a reservoir of disease, vaccination of adolescents and adults against pertussis is recommended (see Table 30–7 and www.cdc.gov/vaccines/schedules). Two tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) products (BOOSTRIX, GlaxoSmithKline and ADACEL, Sanofi Pasteur) are licensed by the FDA. Adolescents aged 11–18 years (preferably between 11 and 12 years of age) who have completed the DTP or DTaP vaccination series should receive a single dose of either Tdap product instead of Td (tetanus and diphtheria toxoids vaccine) for booster immunization against tetanus, diphtheria, and pertussis. Adults of all ages (including those older than age 64 years) should receive a single dose of Tdap. In addition, pregnant women should receive a dose of Tdap during each pregnancy regardless of prior vaccination history. The optimal timing for such Tdap administration is between 27 and 36 weeks of gestation, in order to maximize the antibody response of the pregnant woman and the passive antibody transfer to the infant. For any woman who was not previously vaccinated with Tdap and for whom the vaccine was not given during her pregnancy, Tdap should be administered immediately postpartum. The CDC has eliminated the recommendation that a 2-year period window is needed between receiving the Td and Tdap vaccines based on data showing that there is not an increased risk of adverse events.
Antibiotic treatment should be initiated in all suspected cases. Treatment options include erythromycin, 500 mg four times a day orally for 7 days; azithromycin, 500 mg orally on day 1 and 250 mg for 4 more days; or clarithromycin, 500 mg orally twice daily for 7 days. Trimethoprim-sulfamethoxazole, 160 mg–800 mg orally twice a day for 7 days, also is effective. Treatment shortens the duration of carriage and may diminish the severity of coughing paroxysms. These same regimens are indicated for prophylaxis of contacts to an active case of pertussis that are exposed within 3 weeks of the onset of cough in the index case.
et al. Tdap vaccination during pregnancy and microcephaly and other structural birth defects in offspring. JAMA. 2016 Nov 1;316(17):1823–5.
et al. Association of Tdap vaccination with acute events and adverse birth outcomes among pregnant women with prior tetanus-containing immunizations. JAMA. 2015 Oct 20;314(15):1581–7.
et al. Effectiveness of prenatal versus postpartum tetanus, diphtheria, and acellular pertussis vaccination in preventing infant pertussis. Clin Infect Dis. 2017 Jan 1;64(1):3–8.
OTHER BORDETELLA INFECTIONS
Bordetella bronchiseptica is a pleomorphic gram-negative coccobacillus causing kennel cough in dogs. On occasion it causes upper and lower respiratory infection in humans, principally HIV-infected patients. Infection has been associated with contact with dogs and cats, suggesting animal-to-human transmission. Treatment of B bronchiseptica infection is guided by results of in vitro susceptibility tests.
ESSENTIALS OF DIAGNOSIS
Fever, headache, vomiting, delirium, convulsions.
Petechial rash of skin and mucous membranes in many.
Neck and back stiffness with positive Kernig and Brudzinski signs is characteristic.
Purulent spinal fluid with gram-negative intracellular and extracellular diplococci.
Culture of cerebrospinal fluid, blood, or petechial aspiration confirms the diagnosis.
Meningococcal meningitis is caused by Neisseria meningitidis of groups A, B, C, Y, and W-135, among others. Meningitis due to serogroup A is uncommon in the United States. Serogroup B generally causes sporadic cases. The frequency of outbreaks of meningitis caused by group C meningococcus has increased, and this serotype is the most common cause of epidemic disease in the United States. Up to 40% of persons are nasopharyngeal carriers of meningococci, but disease develops in relatively few of these persons. Infection is transmitted by droplets. The clinical illness may take the form of meningococcemia (a fulminant form of septicemia without meningitis), meningococcemia with meningitis, or meningitis. Recurrent meningococcemia with fever, rash, and arthritis is seen rarely in patients with certain terminal complement deficiencies.
High fever, chills, and headache; back, abdominal, and extremity pains; and nausea and vomiting are typical. Rapidly developing confusion, delirium, seizures, and coma occur in some. On examination, nuchal and back rigidity are typical. Positive Kernig and Brudzinski signs (Kernig sign is pain in the hamstrings upon extension of the knee with the hip at 90-degree flexion; Brudzinski sign is flexion of the knee in response to flexion of the neck) are specific but not sensitive findings. A petechial rash appearing in the lower extremities and at pressure points is found in most cases. Petechiae may vary in size from pinpoint lesions to large ecchymoses or even skin gangrene that may later slough if the patient survives.
Lumbar puncture typically reveals a cloudy or purulent cerebrospinal fluid, with elevated pressure, increased protein, and decreased glucose content. The fluid usually contains greater than 1000 cells/mcL, with polymorphonuclear cells predominating and containing gram-negative intracellular diplococci. The absence of organisms in a Gram-stained smear of the cerebrospinal fluid sediment does not rule out the diagnosis. The capsular polysaccharide can be demonstrated in cerebrospinal fluid or urine by latex agglutination; this is useful in partially treated patients, though sensitivity is 60–80%. The organism is usually demonstrated by smear and culture of the cerebrospinal fluid, oropharynx, blood, or aspirated petechiae.
Disseminated intravascular coagulation is an important complication of meningococcal infection and is typically present in toxic patients with ecchymotic skin lesions.
Meningococcal meningitis must be differentiated from other meningitides. In small infants and in older adults, fever or stiff neck is often missing, and altered mental status may dominate the picture.
Rickettsial, echovirus and, rarely, other bacterial infections (eg, staphylococcal infections, scarlet fever) also cause petechial rash.
Four meningococcal vaccines are available. There are two vaccines with coverage against meningococcal serogroups A, C, Y, and W-135 and two with coverage against meningococcal serogroup B. The two vaccines effective for meningococcal serogroups A, C, Y, and W-135 are the meningococcal polysaccharide vaccine (MPSV4) indicated for vaccination of persons over age 55 and the conjugate vaccine (MCV4) indicated for persons aged 2–55 years. The two vaccines against meningococcal serogroup B are MenB-FHbp and MenB-4C are approved for persons aged 10–25 years and are not interchangeable.
The Advisory Committee on Immunization Practices recommends immunization with a dose of MCV4 for preadolescents aged 11–12 with a booster at age 16 (see www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html). For ease of program implementation, persons aged 21 years or younger should have documentation of receipt of a dose of MCV4 not more than 5 years before enrollment to college. If the primary dose was administered before the sixteenth birthday, a booster dose should be administered before enrollment. Vaccine is also recommended as a two-dose primary series administered 2 months apart for persons aged 2 through 54 years with persistent complement deficiency, persons with functional or anatomic asplenia, and for adolescents with HIV infection. All other persons at increased risk for meningococcal disease (eg, military recruits, microbiologists, or travelers to an epidemic or highly endemic country) should receive a single dose. One of the meningococcal serogroup B vaccines may be administered to persons 10 years of age or older who are at increased risk for meningococcal disease. These persons include those with persistent complement component deficiencies; persons with anatomic or functional asplenia; microbiologists routinely exposed to isolates of Neisseria meningitidis; and persons identified to be at increased risk because of a serogroup B meningococcal disease outbreak. Vaccination of persons aged 16–23 years may provide short-term protection against most strains of serogroup B meningococcal disease; the MenB vaccine is preferred for persons aged 16–18 years.
Eliminating nasopharyngeal carriage of meningococci is an effective prevention strategy in closed populations and to prevent secondary cases in household or otherwise close contacts. Rifampin, 600 mg orally twice a day for 2 days, ciprofloxacin, 500 mg orally once, or one intramuscular 250-mg dose of ceftriaxone is effective. Cases of fluoroquinolone-resistant meningococcal infections have been identified in the United States. However, ciprofloxacin remains a recommended empiric agent for eradication of nasopharyngeal carriage. School and work contacts ordinarily need not be treated. Hospital contacts receive therapy only if intense exposure has occurred (eg, mouth-to-mouth resuscitation). Accidentally discovered carriers without known close contact with meningococcal disease do not require prophylactic antimicrobials.
Blood cultures must be obtained and intravenous antimicrobial therapy started immediately. This may be done prior to lumbar puncture in patients in whom the diagnosis is not straightforward and for those in whom MR or CT imaging is indicated to exclude mass lesions. Aqueous penicillin G is the antibiotic of choice (24 million units/24 h intravenously in divided doses every 4 hours). The prevalence of strains of N meningitidis with intermediate resistance to penicillin in vitro (MICs 0.1 to 1 mcg/mL) is increasing, particularly in Europe. At what level of resistance penicillin treatment failure can occur is not known. Penicillin-intermediate strains thus far remain fully susceptible to ceftriaxone and other third-generation cephalosporins used to treat meningitis, and these should be effective alternatives to penicillin. In penicillin-allergic patients or those in whom Haemophilus influenzae or gram-negative meningitis is a consideration, ceftriaxone, 2 g intravenously every 12 hours, should be used. Treatment should be continued in full doses by the intravenous route until the patient is afebrile for 5 days. Shorter courses—as few as 4 days if ceftriaxone is used—are also effective.
All patients with suspected meningococcal infection including meningitis and meningococcemia should be admitted for evaluation and empiric intravenous antibiotic therapy.
et al; Centers for Disease Control and Prevention (CDC). Use of serogroup B meningococcal vaccines in persons aged ≥10 years at increased risk for serogroup B meningococcal disease: recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. 2015 Jun 12;64(22):608–12. Erratum in: MMWR Morb Mortal Wkly Rep. 2015 Jul 31;64(29):806.
et al. Use of serogroup B meningococcal vaccines in adolescents and young adults: recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. 2015 Oct 23;64(41):1171–6.
INFECTIONS CAUSED BY HAEMOPHILUS SPECIES
H influenzae and other Haemophilus species may cause sinusitis, otitis, bronchitis, epiglottitis, pneumonia, cellulitis, arthritis, meningitis, and endocarditis. Nontypeable strains are responsible for most disease in adults. Alcoholism, smoking, chronic lung disease, advanced age, and HIV infection are risk factors. Haemophilus species colonize the upper respiratory tract in patients with chronic obstructive pulmonary disease and frequently cause purulent bronchitis.
Beta-lactamase–producing strains are less common in adults than in children. For adults with sinusitis, otitis, or respiratory tract infection, oral amoxicillin, 750 mg twice daily for 10–14 days, is adequate. For beta-lactamase–producing strains, use of the oral fixed-drug combination of amoxicillin, 875 mg, with clavulanate, 125 mg, is indicated. For the penicillin-allergic patient, oral cefuroxime axetil, 250 mg twice daily; or a fluoroquinolone (ciprofloxacin, 500 mg orally twice daily; levofloxacin, 500–750 mg orally once daily; or moxifloxacin, 400 mg orally once daily) for 7 days is effective. Azithromycin, 500 mg orally once followed by 250 mg daily for 4 days, is preferred over clarithromycin when a macrolide is the preferred agent. Trimethoprim-sulfamethoxazole (160/800 mg orally twice daily) can be considered, but resistance rates have been reported to be up to 25%.
In the more seriously ill patient (eg, the toxic patient with multilobar pneumonia), ceftriaxone, 1 g/day intravenously is recommended pending determination of whether the infecting strain is a beta-lactamase producer. A fluoroquinolone (see above for dosages) can be used for the penicillin-allergic patients for a 10- to 14-day course of therapy.
Epiglottitis is characterized by an abrupt onset of high fever, drooling, and inability to handle secretions. An important clue to the diagnosis is complaint of a severe sore throat despite an unimpressive examination of the pharynx. Stridor and respiratory distress result from laryngeal obstruction. The diagnosis is best made by direct visualization of the cherry-red, swollen epiglottis at laryngoscopy. Because laryngoscopy may provoke laryngospasm and obstruction, especially in children, it should be performed in an intensive care unit or similar setting, and only at a time when intubation can be performed promptly. Ceftriaxone, 1 g intravenously every 24 hours for 7–10 days, is the drug of choice. Trimethoprim-sulfamethoxazole or a fluoroquinolone (see above for dosage) may be used in the patient with serious penicillin allergy.
Meningitis, rare in adults, is a consideration in the patient who has meningitis associated with sinusitis or otitis. Initial therapy for suspected H influenzae meningitis should be with ceftriaxone, 4 g/day in two divided doses, until the strain is proved not to produce beta-lactamase. Meningitis is treated for at least 7 days. Dexamethasone, 0.15 mg/kg intravenously every 6 hours may reduce the incidence of long-term sequelae, principally hearing loss.
et al. Risk of invasive Haemophilus influenzae
infection during pregnancy and association with adverse fetal outcomes. JAMA. 2014 Mar 19;311(11):1125–32.
INFECTIONS CAUSED BY MORAXELLA CATARRHALIS
M catarrhalis is a gram-negative aerobic coccus morphologically and biochemically similar to Neisseria. It causes sinusitis, bronchitis, and pneumonia. Bacteremia and meningitis have also been reported in immunocompromised patients. The organism frequently colonizes the respiratory tract, making differentiation of colonization from infection difficult. If M catarrhalis is the predominant isolate, therapy is directed against it. M catarrhalis typically produces beta-lactamase and therefore is usually resistant to ampicillin and amoxicillin. It is susceptible to amoxicillin-clavulanate, ampicillin-sulbactam, trimethoprim-sulfamethoxazole, ciprofloxacin, and second- and third-generation cephalosporins.
ESSENTIALS OF DIAGNOSIS
Patients are often immunocompromised, smokers, or have chronic lung disease.
Scant sputum production, pleuritic chest pain, toxic appearance.
Chest radiograph: focal patchy infiltrates or consolidation.
Gram stain of sputum: polymorphonuclear leukocytes and no organisms.
Legionella infection ranks among the three or four most common causes of community-acquired pneumonia and is considered whenever the etiology of a pneumonia is in question. Legionnaires disease is more common in immunocompromised persons, in smokers, and in those with chronic lung disease. Outbreaks have been associated with contaminated water sources, such as showerheads and faucets in patient rooms and air conditioning cooling towers.
Legionnaires disease is one of the atypical pneumonias, so called because a Gram-stained smear of sputum does not show organisms. However, many features of Legionnaires disease are more like typical pneumonia, with high fevers, a toxic patient, pleurisy, and grossly purulent sputum. Classically, this pneumonia is caused by Legionella pneumophila, though other species can cause identical disease.
There may be hyponatremia, elevated liver enzymes, and elevated creatine kinase. Culture of Legionella species has a 80–90% sensitivity. The use of charcoal-yeast extract agar or similar enriched medium is the most sensitive method for diagnosis and permits identification of infections caused by species and serotypes other than L pneumophila serotype 1. Dieterle silver staining of tissue, pleural fluid, or other infected material is also a reliable method for detecting Legionella species. Direct fluorescent antibody stains and serologic testing are less sensitive because these will detect only L pneumophila serotype 1. In addition, making a serologic diagnosis requires that the host respond with sufficient specific antibody production. Urinary antigen tests, which are targeted for detection of L pneumophila serotype 1, are also less sensitive than culture.
Azithromycin (500 mg orally once daily), clarithromycin (500 mg orally twice daily), or a fluoroquinolone (eg, levofloxacin, 750 mg orally once daily), and not erythromycin, are the drugs of choice for treatment of legionellosis because of their excellent intracellular penetration and in vitro activity, as well as desirable pharmacokinetic properties that permit oral administration and once or twice daily dosing. Duration of therapy is 10–14 days, although a 21-day course of therapy is recommended for immunocompromised patients.
et al. Legionnaire’s disease since Philadelphia: lessons learned and continued progress. Infect Dis Clin North Am. 2017 Mar;31(1):1–5.
et al. Atypical presentation of Legionella
pneumonia among patients with underlying cancer: a fifteen-year review. J Infect. 2016 Jan;72(1):45–51.
GRAM-NEGATIVE BACTEREMIA & SEPSIS
Gram-negative bacteremia can originate in a number of sites, the most common being the genitourinary system, hepatobiliary tract, gastrointestinal tract, and lungs. Less common sources include intravenous lines, infusion fluids, surgical wounds, drains, and pressure injuries (formerly pressure ulcers).
Patients with potentially fatal underlying conditions in the short term such as neutropenia or immunoparesis have a mortality rate of 40–60%; those with serious underlying diseases likely to be fatal in 5 years, such as solid tumors, cirrhosis, and aplastic anemia, die in 15–20% of cases; and individuals with no underlying diseases have a mortality rate of 5% or less.
Most patients have fevers and chills, often with abrupt onset. However, 15% of patients are hypothermic (temperature 36.4°C or less) at presentation, and 5% never develop a temperature above 37.5°C. Hyperventilation with respiratory alkalosis and changes in mental status are important early manifestations. Hypotension and shock, which occur in 20–50% of patients, are unfavorable prognostic signs.
Neutropenia or neutrophilia, often with increased numbers of immature forms of polymorphonuclear leukocytes, is the most common laboratory abnormality in septic patients. Thrombocytopenia occurs in 50% of patients, laboratory evidence of coagulation abnormalities in 10%, and overt disseminated intravascular coagulation in 2–3%. Both clinical manifestations and the laboratory abnormalities are nonspecific and insensitive, which accounts for the relatively low rate of blood culture positivity (approximately 20–40%). If possible, three blood cultures from separate sites should be obtained in rapid succession before starting antimicrobial therapy. The chance of recovering the organism in at least one of the three blood cultures is greater than 95%. The false-negative rate for a single culture of 5–10 mL of blood is 30%. This may be reduced to 5–10% (albeit with a slight false-positive rate due to isolation of contaminants) if a single volume of 30 mL is inoculated into several blood culture bottles. Because blood cultures may be falsely negative, when a patient with presumed septic shock, negative blood cultures, and inadequate explanation for the clinical course responds to antimicrobials, therapy should be continued for 10–14 days.
Several factors are important in the management of patients with sepsis.
A. Removal of Predisposing Factors
This usually means decreasing or stopping immunosuppressive medications and, in certain circumstances, giving granulocyte colony-stimulating factor (filgrastim; G-CSF) to the neutropenic patient.
B. Identifying the Source of Bacteremia
By simply finding the source of bacteremia and removing it (central venous catheter) or draining it (abscess), a fatal disease becomes easily treatable.
The use of fluids, vasopressors, and corticosteroids in septic shock are discussed in Chapter 14; management of disseminated intravascular coagulation is discussed in Chapter 13.
Antibiotics should be given as soon as the diagnosis is suspected, since delays in therapy have been associated with increased mortality rates, particularly once hypotension develops. In general, bactericidal antibiotics should be used and given intravenously to ensure therapeutic serum levels. Penetration of antibiotics into the site of primary infection is critical for successful therapy—ie, if the infection originates in the central nervous system, antibiotics that penetrate the blood-brain barrier should be used—eg, third- or fourth-generation cephalosporin—but not first-generation cephalosporins or aminoglycosides, which penetrate poorly. Sepsis caused by gram-positive organisms cannot be differentiated on clinical grounds from that due to gram-negative bacteria. Therefore, initial therapy should include antibiotics active against both types of organisms.
The number of antibiotics necessary remains controversial and depends on the cause. Table 30–4 provides a guide for empiric therapy. Although a combination of antibiotics is often recommended for “synergism,” combination therapy has not been shown to be superior to a single-drug regimen with any of several broad-spectrum antibiotics (eg, a third-generation cephalosporin, piperacillin-tazobactam, carbapenem). If multiple drugs are used initially, the regimen should be modified and coverage narrowed based on the results of culture and sensitivity testing.
et al; Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Patient and organizational factors associated with delays in antimicrobial therapy for septic shock. Crit Care Med. 2016 Dec;44(12):2145–53.
et al. Time to appropriate antibiotic therapy is an independent determinant of postinfection ICU and hospital lengths of stay in patients with sepsis. Crit Care Med. 2015 Oct;43(10):2133–40.
Salmonellosis includes infection by any of approximately 2000 serotypes of salmonellae. The taxonomy of Salmonella species has been confusing. All Salmonella serotypes are members of a single species, Salmonella enterica. Human infections are caused almost exclusively by S enterica subsp enterica, of which three serotypes—typhi, typhimurium, and choleraesuis—are predominantly isolated. Three clinical patterns of infection are recognized: (1) enteric fever, the best example of which is typhoid fever, due to serotype typhi; (2) acute enterocolitis, caused by serotype typhimurium, among others; and (3) the “septicemic” type, characterized by bacteremia and focal lesions, exemplified by infection with serotype choleraesuis. All types are transmitted by ingestion of the organism, usually from contaminated food or drink.
1. Enteric Fever (Typhoid Fever)
ESSENTIALS OF DIAGNOSIS
Gradual onset of malaise, headache, nausea, vomiting, abdominal pain.
Rose spots, relative bradycardia, splenomegaly, and abdominal distention and tenderness.
Slow (stepladder) rise of fever to maximum and then slow return to normal.
Leukopenia; blood, stool, and urine cultures positive for salmonella.
Enteric fever is a clinical syndrome characterized by constitutional and gastrointestinal symptoms and by headache. It can be caused by any Salmonella species. The term “typhoid fever” applies when serotype typhi is the cause. Infection is transmitted by consumption of contaminated food or drink. The incubation period is 5–14 days. Salmonella is an intracellular pathogen. Infection begins when organisms breach the mucosal epithelium of the intestines by transcytosis, an organism-mediated transport process through the cell via an endocytic vesicle. Having crossed the epithelial barrier, organisms invade and replicate in macrophages in Peyer patches, mesenteric lymph nodes, and the spleen. Serotypes other than typhi usually do not cause invasive disease, presumably because they lack the necessary human-specific virulence factors. Bacteremia occurs, and the infection then localizes principally in the lymphoid tissue of the small intestine (particularly within 60 cm of the ileocecal valve). Peyer patches become inflamed and may ulcerate, with involvement greatest during the third week of disease. The organism may disseminate to the lungs, gallbladder, kidneys, or central nervous system.
During the prodromal stage, there is increasing malaise, headache, cough, and sore throat, often with abdominal pain and constipation, while the fever ascends in a stepwise fashion. After about 7–10 days, it reaches a plateau and the patient is much more ill, appearing exhausted and often prostrated. There may be marked constipation, especially early, or “pea soup” diarrhea; marked abdominal distention occurs as well. If there are no complications, the patient’s condition will gradually improve over 7–10 days. However, relapse may occur for up to 2 weeks after defervescence.
During the early prodrome, physical findings are few. Later, splenomegaly, abdominal distention and tenderness, relative bradycardia, and occasionally meningismus appear. The rash (rose spots) commonly appears during the second week of disease. The individual spot, found principally on the trunk, is a pink papule 2–3 mm in diameter that fades on pressure. It disappears in 3–4 days.
Leukopenia is typical. Typhoid fever is best diagnosed by blood culture, which is positive in the first week of illness in 80% of patients who have not taken antimicrobials. The rate of positivity declines thereafter, but one-fourth or more of patients still have positive blood cultures in the third week. Cultures of bone marrow occasionally are positive when blood cultures are not. Stool culture is unreliable because it may be positive in gastroenteritis without typhoid fever.
Enteric fever must be distinguished from other gastrointestinal illnesses and from other infections that have few localizing findings. Examples include tuberculosis, infective endocarditis, brucellosis, lymphoma, and Q fever. Often there is a history of recent travel to endemic areas, and viral hepatitis, malaria, or amebiasis may be in the differential as well.
Complications occur in about 30% of untreated cases and account for 75% of deaths. Intestinal hemorrhage, manifested by a sudden drop in temperature and signs of shock followed by dark or fresh blood in the stool, or intestinal perforation, accompanied by abdominal pain and tenderness, is most likely to occur during the third week. Appearance of leukocytosis and tachycardia should suggest these complications. Urinary retention, pneumonia, thrombophlebitis, myocarditis, psychosis, cholecystitis, nephritis, osteomyelitis, and meningitis are less often observed.
Immunization is not always effective but should be considered for household contacts of a typhoid carrier, for travelers to endemic areas, and during epidemic outbreaks. A multiple-dose oral vaccine and a single-dose parenteral vaccine are available. Their efficacies are similar, but oral vaccine causes fewer side effects. Boosters, when indicated, should be given every 5 years and 2 years for oral and parenteral preparations, respectively.
Adequate waste disposal and protection of food and water supplies from contamination are important public health measures to prevent salmonellosis. Carriers cannot work as food handlers.
Because of increasing antimicrobial resistance, fluoroquinolones—such as ciprofloxacin 750 mg orally twice daily or levofloxacin 500 mg orally once daily, 5–7 days for uncomplicated enteric fever and 10–14 days for severe infection—are the agents of choice for treatment of salmonella infections. Ceftriaxone, 2 g intravenously for 7 days, is also effective. Although resistance to fluoroquinolones or cephalosporins occurs uncommonly, the prevalence is increasing. When an infection is caused by a multidrug-resistant strain, select an antibiotic to which the isolate is susceptible in vitro. Alternatively, increasing the dose of ceftriaxone to 4 g/day and treating for 10–14 days or using azithromycin 500 mg orally for 7 days in uncomplicated cases may be effective. In years past, ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole had been effective treatments but resistance has spread globally.
Ciprofloxacin, 750 mg orally twice a day for 4 weeks, has proved to be highly effective in eradicating the carrier state. Cholecystectomy may also achieve this goal. When the isolate is susceptible, treatment of carriage with ampicillin, trimethoprim-sulfamethoxazole, or chloramphenicol may be successful.
The mortality rate of typhoid fever is about 2% in treated cases. Elderly or debilitated persons are likely to do worse. With complications, the prognosis is poor. Relapses occur in up to 15% of cases. A residual carrier state frequently persists in spite of chemotherapy.
et al. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2014 Jan 2;1:CD001261.
2. Salmonella Gastroenteritis
By far the most common form of salmonellosis is acute enterocolitis caused by numerous Salmonella serotypes. The incubation period is 8–48 hours after ingestion of contaminated food or liquid.
Symptoms and signs consist of fever (often with chills), nausea and vomiting, cramping abdominal pain, and diarrhea, which may be grossly bloody, lasting 3–5 days. Differentiation must be made from viral gastroenteritis, food poisoning, shigellosis, amebic dysentery, and acute ulcerative colitis. The diagnosis is made by culturing the organism from the stool.
The disease is usually self-limited, but bacteremia with localization in joints or bones may occur, especially in patients with sickle cell disease.
In most cases, treatment of uncomplicated enterocolitis is symptomatic only. However, patients who are malnourished or severely ill, patients with sickle cell disease, and patients who are immunocompromised (including those who are HIV-positive) should be treated with ciprofloxacin, 500 mg orally twice a day; ceftriaxone, 1 g intravenously once daily; trimethoprim-sulfamethoxazole, 160 mg/80 mg orally twice a day; or azithromycin, 500 mg orally once daily for 7–14 days (14 days for immunocompromised patients).
et al. Salmonella
in the tropical household environment—everyday, everywhere. J Infect. 2015 Dec;71(6):642–8.
Salmonella infection may be manifested by prolonged or recurrent fevers accompanied by bacteremia and local infection in bone, joints, pleura, pericardium, lungs, or other sites. Mycotic abdominal aortic aneurysms may also occur. Serotypes other than typhi usually are isolated. This complication tends to occur in immunocompromised persons and is seen in HIV-infected individuals, who typically have bacteremia without an obvious source. Treatment is the same as for typhoid fever, plus drainage of any abscesses. In HIV-infected patients, relapse is common, and lifelong suppressive therapy may be needed. Ciprofloxacin, 750 mg orally twice a day, is effective both for therapy of acute infection and for suppression of recurrence. Incidence of infections caused by drug-resistant strains may be on the rise.
et al. Epidemiology, clinical presentation, laboratory diagnosis, antimicrobial resistance, and antimicrobial management of invasive salmonella infections. Clin Microbiol Rev. 2015 Oct;28(4):901–37.
et al. Control of invasive salmonella disease in Africa: is there a role for human challenge models? Clin Infect Dis. 2015 Nov 1;61(Suppl 4):S266–71.
ESSENTIALS OF DIAGNOSIS
Diarrhea, often with blood and mucus.
Crampy abdominal pain and systemic toxicity.
White blood cells in stools; organism isolated on stool culture.
Shigella dysentery is a common disease, often self-limited and mild but occasionally serious. S sonnei is the leading cause in the United States, followed by S flexneri. S dysenteriae causes the most serious form of the illness. Shigellae are invasive organisms. The infective dose is 102–103 organisms. There has been a rise in strains resistant to multiple antibiotics.
The illness usually starts abruptly, with diarrhea, lower abdominal cramps, and tenesmus. The diarrheal stool often is mixed with blood and mucus. Systemic symptoms are fever, chills, anorexia and malaise, and headache. The abdomen is tender. Sigmoidoscopic examination reveals an inflamed, engorged mucosa with punctate and sometimes large areas of ulceration.
The stool shows many leukocytes and red cells. Stool culture is positive for shigellae in most cases, but blood cultures grow the organism in less than 5% of cases.
Bacillary dysentery must be distinguished from salmonella enterocolitis and from disease due to enterotoxigenic Escherichia coli, Campylobacter, and Yersinia enterocolitica. Amebic dysentery may be similar clinically and is diagnosed by finding amoebas in the fresh stool specimen. Ulcerative colitis is also an important cause of bloody diarrhea.
Temporary disaccharidase deficiency may follow the diarrhea. Reactive arthritis is an uncommon complication, usually occurring in HLA-B27 individuals infected by Shigella. Hemolytic-uremic syndrome occurs rarely.
Treatment of dehydration and hypotension is lifesaving in severe cases. Recommended empiric antimicrobial therapy is either a fluoroquinolone (ciprofloxacin, 750 mg orally twice daily for 7–10 days, or levofloxacin, 500 mg orally once daily for 3 days) or ceftriaxone, 1 g intravenously once daily for 5 days. If the isolate is susceptible, trimethoprim-sulfamethoxazole, 160/80 mg orally twice daily for 5 days or azithromycin, 500 mg orally once daily for 3 days, is also effective. High rates of resistance to amoxicillin make it a less effective treatment option.
et al. Shigellosis in men who have sex with men: an overlooked opportunity to counsel with pre-exposure prophylaxis for HIV. Int J STD AIDS. 2016 Nov;27(13):1236–8.
GASTROENTERITIS CAUSED BY ESCHERICHIA COLI
E coli causes gastroenteritis by a variety of mechanisms. Enterotoxigenic E coli (ETEC) elaborates either a heat-stable or heat-labile toxin that mediates the disease. ETEC is an important cause of traveler’s diarrhea. Enteroinvasive E coli (EIEC) differs from other E coli bowel pathogens in that these strains invade cells, causing bloody diarrhea and dysentery similar to infection with Shigella species. EIEC is uncommon in the United States. Neither ETEC nor EIEC strains are routinely isolated and identified from stool cultures because there is no selective medium. Antimicrobial therapy against Salmonella and Shigella, such as ciprofloxacin 500 mg orally twice daily, shortens the clinical course, but the disease is self-limited.
Shiga-toxin–producing E coli (STEC) infection can result in asymptomatic carrier stage, nonbloody diarrhea, hemorrhagic colitis, hemolytic-uremic syndrome, or thrombotic thrombocytopenic purpura. Although E coli O157:H7 is responsible for most cases of STEC infection in the United States, other STEC strains that cause severe disease (such as E coli O104:H4) have been reported in Europe. E coli O157:H7 has caused several outbreaks of diarrhea and hemolytic-uremic syndrome related to consumption of undercooked hamburger, unpasteurized apple juice, and spinach, while E coli O145 was linked to the consumption of contaminated lettuce. Older individuals and young children are most affected, with hemolytic-uremic syndrome being more common in the latter group. STEC identification can be difficult and the CDC recommends that all stools submitted for routine testing from patients with acute community-acquired diarrhea be simultaneously cultured for E coli O157:H7 and tested with an assay that detects Shiga toxins to detect non-O157 STEC, such as E coli O145. Antimicrobial therapy does not alter the course of the disease and may increase the risk of hemolytic-uremic syndrome. Treatment is primarily supportive. Hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura occurring in association with a diarrheal illness suggests the diagnosis and should prompt evaluation for STEC. Confirmed infections should be reported to public health officials.
et al; Centers for Disease Control and Prevention (CDC). Preliminary incidence and trends of infection with pathogens transmitted commonly through food—Foodborne Diseases Active Surveillance Network, 10 U.S. sites, 2006–2014. MMWR Morb Mortal Wkly Rep. 2015 May 15;64(18):495–9.
C. Antimicrobial therapy of acute diarrhoea: a clinical review. Expert Rev Anti Infect Ther. 2016;14(2):193–206.
ESSENTIALS OF DIAGNOSIS
History of travel in endemic area or contact with infected person.
Voluminous diarrhea (up to 15 L/day).
Characteristic “rice water stool.”
Rapid development of marked dehydration.
Positive stool cultures and agglutination of vibrios with specific sera.
Cholera is an acute diarrheal illness caused by certain serotypes of Vibrio cholerae. The disease is toxin-mediated, and fever is unusual. The toxin activates adenylyl cyclase in intestinal epithelial cells of the small intestines, producing hypersecretion of water and chloride ion and a massive diarrhea of up to 15 L/day. Death results from profound hypovolemia. Cholera occurs in epidemics under conditions of crowding, war, and famine (eg, in refugee camps) and where sanitation is inadequate. Infection is acquired by ingestion of contaminated food or water. For over a century, cholera was rarely seen in the Western Hemisphere until an outbreak occurred in Peru, starting in the early 1990s and ending by 2001; the outbreak resulted in almost 400,000 cholera cases and more than 4000 deaths. Cholera again became a rare disease in the Western Hemisphere until late 2010, when there was a massive earthquake in Haiti followed by a cholera outbreak that has continued and resulted in thousands of deaths.
Cholera is characterized by a sudden onset of severe, frequent watery diarrhea (up to 1 L/h). The liquid stool is gray; turbid; and without fecal odor, blood, or pus (“rice water stool”). Dehydration and hypotension develop rapidly. Stool cultures are positive, and agglutination of vibrios with specific sera can be demonstrated.
A vaccine is available that confers short-lived, limited protection and may be required for entry into or reentry after travel to some countries. It is administered in two doses 1–4 weeks apart. A booster dose every 6 months is recommended for persons remaining in areas where cholera is a hazard.
Vaccination programs are expensive and not particularly effective in managing outbreaks of cholera. When outbreaks occur, efforts should be directed toward establishing clean water and food sources and proper waste disposal.
Treatment is by replacement of fluids. In mild or moderate illness, oral rehydration usually is adequate. A simple oral replacement fluid can be made from 1 teaspoon of table salt and 4 heaping teaspoons of sugar added to 1 L of water. Intravenous fluids are indicated for persons with signs of severe hypovolemia and those who cannot take adequate fluids orally. Lactated Ringer infusion is satisfactory.
Antimicrobial therapy will shorten the course of illness. Antimicrobials active against V cholerae include tetracycline, ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, fluoroquinolones, and azithromycin. Multiple drug-resistant strains are increasingly encountered, so susceptibility testing, if available, is advisable. A single 1 g oral dose of azithromycin is effective for severe cholera caused by strains with reduced susceptibility to fluoroquinolones, but resistance is emerging to this drug as well.
et al. Efficacy of a single-dose, inactivated oral cholera vaccine in Bangladesh. N Engl J Med. 2016 May 5;374(18):1723–32.
INFECTIONS CAUSED BY OTHER VIBRIO SPECIES
Vibrios other than V cholerae that cause human disease are Vibrio parahaemolyticus, V vulnificus, and V alginolyticus. All are halophilic marine organisms. Infection is acquired by exposure to organisms in contaminated, undercooked, or raw crustaceans or shellfish and warm (greater than 20°C [82.4°F]) ocean waters and estuaries. Infections are more common during the summer months from regions along the Atlantic coast and the Gulf of Mexico in the United States and from tropical waters around the world. Oysters are implicated in up to 90% of food-related cases. V parahaemolyticus causes an acute watery diarrhea with crampy abdominal pain and fever, typically occurring within 24 hours after ingestion of contaminated shellfish. The disease is self-limited, and antimicrobial therapy is usually not necessary. V parahaemolyticus may also cause cellulitis and sepsis, though these findings are more characteristic of V vulnificus infection.
V vulnificus and V alginolyticus—neither of which is associated with diarrheal illness—are important causes of cellulitis and primary bacteremia following ingestion of contaminated shellfish or exposure to sea water. Cellulitis with or without sepsis may be accompanied by bulla formation and necrosis with extensive soft tissue destruction, at times requiring debridement and amputation. The infection can be rapidly progressive and is particularly severe in immunocompromised individuals—especially those with cirrhosis—with death rates as high as 50%. Patients with chronic liver disease and those who are immunocompromised should be cautioned to avoid eating raw oysters.
Tetracycline at a dose of 500 mg orally four times a day for 7–10 days is the drug of choice for treatment of suspected or documented primary bacteremia or cellulitis caused by Vibrio species. V vulnificus is susceptible in vitro to penicillin, ampicillin, cephalosporins, chloramphenicol, aminoglycosides, and fluoroquinolones, and these agents may also be effective. V parahaemolyticus and V alginolyticus produce beta-lactamase and therefore are resistant to penicillin and ampicillin, but susceptibilities otherwise are similar to those listed for V vulnificus.
et al. Antibiotic use for Vibrio
infections: important insights from surveillance data. BMC Infect Dis. 2015 Jun 11;15:226.
et al. Correlations between clinical features and mortality in patients with Vibrio vulnificus
Infection. PLoS One. 2015 Aug 14;10(8):e0136019.
INFECTIONS CAUSED BY CAMPYLOBACTER SPECIES
Campylobacter organisms are microaerophilic, motile, gram-negative rods. Two species infect humans: Campylobacter jejuni, an important cause of diarrheal disease, and C fetus subsp fetus, which typically causes systemic infection and not diarrhea. Dairy cattle and poultry are an important reservoir for campylobacters. Outbreaks of enteritis have been associated with consumption of raw milk. Campylobacter gastroenteritis is associated with fever, abdominal pain, and diarrhea characterized by loose, watery, or bloody stools. The differential diagnosis includes shigellosis, Salmonella gastroenteritis, and enteritis caused by Y enterocolitica or invasive E coli. The disease is self-limited, but its duration can be shortened with antimicrobial therapy. Either azithromycin, 1 g orally as a single dose, or ciprofloxacin, 500 mg orally twice daily for 3 days, is effective therapy. However, fluoroquinolone resistance among C jejuni isolates has been increasing, particularly in Southeast Asia, and susceptibility testing should be routinely performed.
C fetus causes systemic infections that can be fatal, including primary bacteremia, endocarditis, meningitis, and focal abscesses. It infrequently causes gastroenteritis. Patients infected with C fetus are often older, debilitated, or immunocompromised. Closely related species, collectively termed “campylobacter-like organisms,” cause bacteremia in HIV-infected individuals. Systemic infections respond to therapy with gentamicin, chloramphenicol, ceftriaxone, or ciprofloxacin. Ceftriaxone or chloramphenicol should be used to treat infections of the central nervous system because of their ability to penetrate the blood-brain barrier.
et al. Global epidemiology of Campylobacter
infection. Clin Microbiol Rev. 2015 Jul;28(3):687–720.
et al. Campylobacteriosis: the role of poultry meat. Clin Microbiol Infect. 2016 Feb;22(2):103–9.
ESSENTIALS OF DIAGNOSIS
History of animal exposure, ingestion of unpasteurized milk or cheese.
Insidious onset: easy fatigability, headache, arthralgia, anorexia, sweating, irritability.
Intermittent and persistent fever.
Cervical and axillary lymphadenopathy; hepatosplenomegaly.
Lymphocytosis, positive blood culture, positive serologic test.
The infection is transmitted from animals to humans. Brucella abortus (cattle), B suis (hogs), and B melitensis (goats) are the main agents. Transmission to humans occurs by contact with infected meat (slaughterhouse workers), placentae of infected animals (farmers, veterinarians), or ingestion of infected unpasteurized milk or cheese. The incubation period varies from a few days to several weeks. Brucellosis is a systemic infection that may become chronic. In the United States, brucellosis is very rare. Almost all US cases are imported from countries where brucellosis is endemic (eg, Mexico, Mediterranean Europe, Spain, South American countries).
The onset may be acute, with fever, chills, and sweats, but more often is insidious with symptoms of weakness, weight loss, low-grade fevers, sweats, and exhaustion upon minimal activity. Headache, abdominal or back pain with anorexia and constipation, and arthralgias are also common. The chronic form may assume an undulant nature, with periods of normal temperature between acute attacks; symptoms may persist for years, either continuously or intermittently.
Fever, hepatosplenomegaly, and lymphadenopathy are the most common physical findings. Infection may present with or be complicated by specific organ involvement with signs of endocarditis, meningitis, epididymitis, orchitis, arthritis (especially sacroiliitis), spondylitis, or osteomyelitis.
The organism can be recovered from cultures of blood, cerebrospinal fluid, urine, bone marrow, or other sites. Cultures are more likely to be negative in chronic cases. The diagnosis often is made by serologic testing.
Brucellosis must be differentiated from any other acute febrile disease, especially influenza, tularemia, Q fever, mononucleosis, and enteric fever. In its chronic form it resembles Hodgkin disease, tuberculosis, HIV infection, malaria, and disseminated fungal infections such as histoplasmosis and coccidioidomycosis.
The most frequent complications are bone and joint lesions such as spondylitis and suppurative arthritis (usually of a single joint), endocarditis (often culture negative), and meningoencephalitis. Less common complications are pneumonitis with pleural effusion, hepatitis, and cholecystitis.
Single-drug regimens are not recommended because the relapse rate may be as high as 50%. Combination regimens of two or three drugs are most effective. Regimens of doxycycline (200 mg/day orally for 6 weeks) plus rifampin (600 mg/day orally for 6 weeks) or streptomycin (1 g/day intramuscularly for 2 weeks) or gentamicin (240 mg intramuscularly once daily for 7 days) have the lowest recurrence rates. Longer courses of therapy may be required to prevent relapse of meningitis, osteomyelitis, or endocarditis.
et al. Brucella
arteritis: clinical manifestations, treatment, and prognosis. Lancet Infect Dis. 2014 Jun;14(6):520–6.
et al. Brucellosis in pregnancy: clinical aspects and obstetric outcomes. Int J Infect Dis. 2015 Sep;38:95–100.
ESSENTIALS OF DIAGNOSIS
History of contact with rabbits, other rodents, and biting ticks in summer in endemic area.
Fever, headache, nausea, and prostration.
Papule progressing to ulcer at site of inoculation.
Enlarged regional lymph nodes.
Serologic tests or culture of ulcer, lymph node aspirate, or blood confirm the diagnosis.
Tularemia is a zoonotic infection of wild rodents and rabbits caused by Francisella tularensis. Humans usually acquire the infection by contact with animal tissues (eg, trapping muskrats, skinning rabbits) or from a tick or insect bite. Hamsters and prairie dogs also may carry the organism. An outbreak of pneumonic tularemia on Martha’s Vineyard in Massachusetts was linked to lawn-mowing and brush-cutting as risk factors for infection, underscoring the potential for probable aerosol transmission of the organism. F tularensis has been classified as a high-priority agent for potential bioterrorism use because of its virulence and relative ease of dissemination. Infection in humans often produces a local lesion and widespread organ involvement but may be entirely asymptomatic. The incubation period is 2–10 days.
Fever, headache, and nausea begin suddenly, and a local lesion—a papule at the site of inoculation—develops and soon ulcerates. Regional lymph nodes may become enlarged and tender and may suppurate. The local lesion may be on the skin of an extremity or in the eye. Pneumonia may develop from hematogenous spread of the organism or may be primary after inhalation of infected aerosols, which are responsible for human-to-human transmission. Following ingestion of infected meat or water, an enteric form may be manifested by gastrointestinal symptoms, stupor, and delirium. In any type of involvement, the spleen may be enlarged and tender and there may be nonspecific rashes, myalgias, and prostration.
Culturing the organism from blood or infected tissue requires special media. For this reason and because cultures of F tularensis may be hazardous to laboratory personnel, the diagnosis is usually made serologically. A positive agglutination test (greater than 1:80) develops in the second week after infection and may persist for several years.
Tularemia must be differentiated from rickettsial and meningococcal infections, cat-scratch disease, infectious mononucleosis, and various bacterial and fungal diseases.
Hematogenous spread may produce meningitis, perisplenitis, pericarditis, pneumonia, and osteomyelitis.
Streptomycin is drug of choice for treatment of tularemia. The recommended dose is 7.5 mg/kg intramuscularly every 12 hours for 7–14 days. Gentamicin, which has good in vitro activity against F tularensis, is generally less toxic than streptomycin and probably just as effective. Doxycycline (200 mg/day orally) is also effective but has a higher relapse rate. A variety of other agents (eg, fluoroquinolones) are active in vitro but their clinical effectiveness is less well established.
et al. Francisella tularensis
group A.I, United States. Emerg Infect Dis. 2014 May;20(5):861–5.
ESSENTIALS OF DIAGNOSIS
History of exposure to rodents in endemic area.
Sudden onset of high fever, muscular pains, and prostration.
Axillary, cervical, or inguinal lymphadenitis (bubo).
Pustule or ulcer at inoculation site.
Pneumonia or meningitis is often fatal.
Positive smear and culture from bubo and positive blood culture.
Plague is an infection of wild rodents with Yersinia pestis, a small bipolar-staining gram-negative rod. It is endemic in California, Arizona, Nevada, and New Mexico. It is transmitted among rodents and to humans by the bites of fleas or from contact with infected animals. Following a fleabite, the organisms spread through the lymphatics to the lymph nodes, which become greatly enlarged (buboes). They may then reach the bloodstream to involve all organs. When pneumonia or meningitis develops, the outcome is often fatal. The patient with pneumonia can transmit the infection to other individuals by droplets. The incubation period is 2–10 days. Because of its extreme virulence, its potential for dissemination and person-to-person transmission, and efforts to develop the organism as an agent of biowarfare, plague bacillus is considered a high-priority agent for bioterrorism.
The onset is sudden, with high fever, malaise, tachycardia, intense headache, delirium, and severe myalgias. The patient appears profoundly ill. If pneumonia develops, tachypnea, productive cough, blood-tinged sputum, and cyanosis also occur. There may be signs of meningitis. A pustule or ulcer at the site of inoculation and lymphangitis may be observed. Axillary, inguinal, or cervical lymph nodes become enlarged and tender and may suppurate and drain. With hematogenous spread, the patient may rapidly become toxic and comatose, with purpuric spots (black plague) appearing on the skin.
Primary plague pneumonia is a fulminant pneumonitis with bloody, frothy sputum and sepsis. It is usually fatal unless treatment is started within a few hours after onset.
The plague bacillus may be found in smears from aspirates of buboes examined with Gram stain. Cultures from bubo aspirate or pus and blood are positive but may grow slowly. In convalescing patients, an antibody titer rise may be demonstrated by agglutination tests.
The lymphadenitis of plague is most commonly mistaken for the lymphadenitis accompanying staphylococcal or streptococcal infections of an extremity, sexually transmitted diseases such as lymphogranuloma venereum or syphilis, and tularemia. The systemic manifestations resemble those of enteric or rickettsial fevers, malaria, or influenza. The pneumonia resembles other bacterial pneumonias, and the meningitis is similar to those caused by other bacteria.
Avoiding exposure to rodents and fleas in endemic areas is the best prevention strategy. Drug prophylaxis may provide temporary protection for persons exposed to the risk of plague infection, particularly by the respiratory route. Doxycycline, 100 mg twice daily for 7 days, is effective. No vaccine is available at this time.
Therapy should be started immediately once plague is suspected. Either streptomycin (the agent with which there is greatest experience), 1 g every 12 hours intravenously, or gentamicin, administered as a 2-mg/kg loading dose, then 1.7 mg/kg every 8 hours intravenously, is effective. Alternatively, doxycycline, 100 mg orally or intravenously, may be used. The duration of therapy is 10 days. Patients with plague pneumonia are placed in strict respiratory isolation, and prophylactic therapy is given to any person who came in contact with the patient.
et al; Centers for Disease Control and Prevention (CDC). Outbreak of human pneumonic plague with dog-to-human and possible human-to-human transmission—Colorado, June–July 2014. MMWR Morb Mortal Wkly Rep. 2015 May 1;64(16):429–34.
ESSENTIALS OF DIAGNOSIS
Purulent, profuse urethral discharge with dysuria, especially in men; yields positive smear.
Men: epididymitis, prostatitis, periurethral inflammation, proctitis.
Women: cervicitis with purulent discharge, or asymptomatic, yielding positive culture; vaginitis, salpingitis, proctitis also occur.
Disseminated disease: fever, rash, tenosynovitis, and arthritis.
Gram-negative intracellular diplococci seen in a smear or cultured from the urethra, cervix, pharynx, or rectum.
Gonorrhea is caused by Neisseria gonorrhoeae, a gram-negative diplococcus typically found inside polymorphonuclear cells. It is transmitted during sexual activity and has its greatest incidence in the 15- to 29-year-old age group. The incubation period is usually 2–8 days.
A. Urethritis and Cervicitis
Initial symptoms seen in men include burning on urination and a serous or milky discharge. One to 3 days later, the urethral pain is more pronounced and the discharge becomes yellow, creamy, and profuse, sometimes blood-tinged. The disorder may regress and become chronic or progress to involve the prostate, epididymis, and periurethral glands with painful inflammation. Chronic infection leads to prostatitis and urethral strictures. Rectal infection is common in men who have sex with men. Atypical sites of primary infection (eg, the pharynx) must always be considered. Asymptomatic infection is common and occurs in both sexes.
Gonococcal infection in women often becomes symptomatic during menses. Women may have dysuria, urinary frequency, and urgency, with a purulent urethral discharge. Vaginitis and cervicitis with inflammation of Bartholin glands are common. Infection may be asymptomatic, with only slightly increased vaginal discharge and moderate cervicitis on examination. Infection may remain as a chronic cervicitis—an important reservoir of gonococci. It can progress to involve the uterus and tubes with acute and chronic salpingitis, with scarring of tubes and sterility. In pelvic inflammatory disease, anaerobes and chlamydiae often accompany gonococci. Rectal infection may result from spread of the organism from the genital tract or from anal coitus.
Nucleic acid amplification tests are the preferred method for diagnosing all types of gonorrhea given their excellent sensitivity and specificity. In women with suspected cervical infection, endocervical or vaginal swabs (clinician- or self-collected) as well as first catch am urine specimen (later specimens have 10% reduced sensitivity) are options. In men with urethral infection, first catch am urine is recommended. Nucleic acid amplification tests are also recommended by the CDC for oropharyngeal and rectal sites testing although they are not FDA approved for these specimen types. Gram stain of urethral discharge in men, especially during the first week after onset, shows gram-negative diplococci in polymorphonuclear leukocytes. Gram stain is less often positive in women. Cultures should still be obtained when evaluating a treatment failure to assess for antimicrobial resistance.
Systemic complications follow the dissemination of gonococci from the primary site via the bloodstream. Two distinct clinical syndromes—either purulent arthritis or the triad of rash, tenosynovitis, and arthralgias—are commonly observed in patients with disseminated gonococcal infection, although overlap can be seen. The skin lesions can range from maculopapular to pustular or hemorrhagic, which tend to be few in number and peripherally located. The tenosynovitis is often found in the hands and wrists and feet and ankles. These unique findings can help distinguish among other infectious syndromes. The arthritis can occur in one or more joints. Gonococci are isolated by culture from less than half of patients with gonococcal arthritis. Rarely, gonococcal endocarditis or meningitis develops.
The most common form of eye involvement is direct inoculation of gonococci into the conjunctival sac. In adults, this occurs by autoinoculation of a person with genital infection. The purulent conjunctivitis may rapidly progress to panophthalmitis and loss of the eye unless treated promptly. A single 1-g dose of ceftriaxone is effective.
Gonococcal urethritis or cervicitis must be differentiated from nongonococcal urethritis; cervicitis or vaginitis due to Chlamydia trachomatis, Gardnerella vaginalis, Trichomonas, Candida, and many other pathogens associated with sexually transmitted diseases; and pelvic inflammatory disease, arthritis, proctitis, and skin lesions. Often, several such pathogens coexist in a patient. Reactive arthritis (urethritis, conjunctivitis, arthritis) may mimic gonorrhea or coexist with it.
Prevention is based on education and mechanical or chemical prophylaxis. The condom, if properly used, can reduce the risk of infection. Effective drugs taken in therapeutic doses within 24 hours of exposure can abort an infection. Partner notification and referral of contacts for treatment has been the standard method used to control sexually transmitted diseases. Expedited treatment of sex partners by patient-delivered partner therapy is more effective than partner notification in reducing persistence and recurrence rates of gonorrhea and chlamydia.
Therapy typically is administered before antimicrobial susceptibilities are known. The choice of which regimen to use should be based on the national prevalences of antibiotic-resistant organisms. Nationwide, strains of gonococci that are resistant to penicillin, tetracycline, or ciprofloxacin have been increasingly observed. Consequently, these drugs can no longer be considered first-line therapy. All sexual partners should be treated and tested for HIV infection and syphilis, as should the patient.
A. Uncomplicated Gonorrhea
Due to increasing resistance of N gonorrhoeae to cephalosporins, the CDC recommends a higher dose of intramuscular ceftriaxone in combination with a second drug (azithromycin or doxycycline) regardless of concern for possible secondary infection with chlamydia. For uncomplicated gonococcal infections of the cervix, urethra, and rectum, the recommended treatment is ceftriaxone (250 mg intramuscularly) plus azithromycin (1000 mg orally as a single dose). In cases where an oral cephalosporin is the only option, cefixime, 400 mg orally as a single dose, can be combined with azithromycin as above. When azithromycin is not an option, doxycycline at 100 mg orally twice daily for 7 days can be substituted. Fluoroquinolones are no longer recommended for treatment due to high rates of microbial resistance. Spectinomycin, 1 g intramuscularly once, may be used for the penicillin-allergic patient but is not currently available in the United States. Pharyngeal gonorrhea is also treated with ceftriaxone (250 mg intramuscularly) plus azithromycin (1000 mg orally as a single dose) but for conjunctival gonorrhea the recommendation is for ceftriaxone (1 g intramuscularly) plus azithromycin (1000 mg orally as a single dose).
B. Treatment of Other Infections
Disseminated gonococcal infection (including arthritis and arthritis-dermatitis syndromes) should be treated with ceftriaxone (1 g intravenously daily) plus azithromycin (1000 mg orally as a single dose), until 48 hours after improvement begins, at which time therapy may be switched to cefixime (400 mg orally daily) to complete at least 1 week of antimicrobial therapy. Endocarditis should be treated with ceftriaxone (2 g every 24 hours intravenously) for at least 4 weeks.
Pelvic inflammatory disease requires cefoxitin (2 g parenterally every 6 hours) or cefotetan (2 g intravenously every 12 hours) plus doxycycline (100 mg every 12 hours). Clindamycin (900 mg intravenously every 8 hours) plus gentamicin (administered intravenously as a 2-mg/kg loading dose followed by 1.5 mg/kg every 8 hours) is also effective. Ceftriaxone (250 mg intramuscularly as a single dose) or cefoxitin (2 g intramuscularly) plus probenecid (1 g orally as a single dose) plus doxycycline (100 mg twice a day for 14 days), with or without metronidazole (500 mg twice daily for 14 days) is an effective outpatient regimen.
et al. Failure of dual antimicrobial therapy in treatment of gonorrhea. N Engl J Med. 2016 Jun 23;374(25):2504–6.
et al; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1–137. Erratum in: MMWR Recomm Rep. 2015 Aug 28;64(33):924.
Chancroid is a sexually transmitted disease caused by the short gram-negative bacillus Haemophilus ducreyi. The incubation period is 3–5 days. At the site of inoculation, a vesicopustule develops that breaks down to form a painful, soft ulcer with a necrotic base, surrounding erythema, and undermined edges. There may be multiple lesions due to autoinoculation. The adenitis is usually unilateral and consists of tender, matted nodes of moderate size with overlying erythema. These may become fluctuant and rupture spontaneously. With lymph node involvement, fever, chills, and malaise may develop. Balanitis and phimosis are frequent complications in men. Women may have no external signs of infection. The diagnosis is established by culturing a swab of the lesion onto a special medium.
Chancroid must be differentiated from other genital ulcers. The chancre of syphilis is clean and painless, with a hard base. Mixed sexually transmitted disease is very common (including syphilis, herpes simplex, and HIV infection), as is infection of the ulcer with fusiforms, spirochetes, and other organisms.
A single dose of either azithromycin, 1 g orally, or ceftriaxone, 250 mg intramuscularly, is effective treatment. Effective multiple-dose regimens are erythromycin, 500 mg orally four times a day for 7 days, or ciprofloxacin, 500 mg orally twice a day for 3 days.
et al; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1–137. Erratum in: MMWR Recomm Rep. 2015 Aug 28;64(33):924.
Granuloma inguinale is a chronic, relapsing granulomatous anogenital infection due to Calymmatobacterium (Donovania) granulomatis. The pathognomonic cell, found in tissue scrapings or secretions, is large (25–90 mcm) and contains intracytoplasmic cysts filled with bodies (Donovan bodies) that stain deeply with Wright stain.
The incubation period is 8 days to 12 weeks. The onset is insidious. The lesions occur on the skin or mucous membranes of the genitalia or perineal area. They are relatively painless infiltrated nodules that soon slough. A shallow, sharply demarcated ulcer forms, with a beefy-red friable base of granulation tissue. The lesion spreads by contiguity. The advancing border has a characteristic rolled edge of granulation tissue. Large ulcerations may advance onto the lower abdomen and thighs. Scar formation and healing occur along one border while the opposite border advances.
Superinfection with spirochete-fusiform organisms is common. The ulcer then becomes purulent, painful, foul-smelling, and extremely difficult to treat.
Several therapies are available. Because of the indolent nature of the disease, duration of therapy is relatively long. The following recommended regimens should be given for 3 weeks or until all lesions have healed: doxycycline, 100 mg orally twice daily; or azithromycin, 1 g orally once weekly; or ciprofloxacin, 750 mg orally twice daily; or erythromycin, 500 mg orally four times a day.
et al; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1–137. Erratum in: MMWR Recomm Rep. 2015 Aug 28;64(33):924.
Bartonella species are responsible for a wide variety of clinical syndromes. Bacillary angiomatosis, an important manifestation of bartonellosis, is discussed in Chapter 31. A variety of atypical infections, including retinitis, encephalitis, osteomyelitis, and persistent bacteremia and endocarditis (especially consider in culture-negative endocarditis) have been described.
Trench fever is a self-limited, louse-borne relapsing febrile disease caused by B quintana. The disease has occurred epidemically in louse-infested troops and civilians during wars and endemically in residents of scattered geographic areas (eg, Central America). An urban equivalent of trench fever has been described among the homeless. Humans acquire infection when infected lice feces enter sites of skin breakdown. Onset of symptoms is abrupt and fever lasts 3–5 days, with relapses. The patient complains of weakness and severe pain behind the eyes and typically in the back and legs. Lymphadenopathy, splenomegaly, and a transient maculopapular rash may appear. Subclinical infection is frequent, and a carrier state is recognized. The differential diagnosis includes other febrile, self-limited states such as dengue, leptospirosis, malaria, relapsing fever, and typhus. Recovery occurs regularly even in the absence of treatment.
Cat-scratch disease is an acute infection of children and young adults caused by Bartonella henselae. It is transmitted from cats to humans as the result of a scratch or bite. Within a few days, a papule or ulcer will develop at the inoculation site in one-third of patients. One to 3 weeks later, fever, headache, and malaise occur. Regional lymph nodes become enlarged, often tender, and may suppurate. Lymphadenopathy from cat scratches resembles that due to neoplasm, tuberculosis, lymphogranuloma venereum, and bacterial lymphadenitis. The diagnosis is usually made clinically. Special cultures for bartonellae, serology, or excisional biopsy, though rarely necessary, confirm the diagnosis. The biopsy reveals necrotizing lymphadenitis and is itself not specific for cat-scratch disease. Cat-scratch disease is usually self-limited, requiring no specific therapy. Encephalitis occurs rarely.
Disseminated forms of the disease—bacillary angiomatosis, peliosis hepatis, and retinitis—occur most commonly in immunocompromised patients such as persons with late stages of HIV or solid organ transplant recipients. The lesions are vasculoproliferative and histopathologically distinct from those of cat-scratch disease. Unexplained fever in patients with late stages of HIV infection is not uncommonly due to bartonellosis. B quintana, the agent of trench fever, can also cause bacillary angiomatosis and persistent bacteremia or endocarditis (which will be “culture-negative” unless specifically sought), the latter two entities being associated with homelessness. Due to the fastidious nature of the organism and its special growth requirements, serologic testing (eg, demonstration of a high antibody titer in an indirect immunofluorescence assay) or nucleic acid amplification tests are often required to establish a diagnosis.
The disseminated forms of the disease (bacillary angiomatosis, peliosis hepatis, and retinitis) require a prolonged course of antibiotic therapy often in combination with a second agent. Bacteremia and endocarditis can be effectively treated with a 6-week course of doxycycline (200 mg orally or intravenously in two divided doses per day) plus either gentamicin 3 mg/kg/day intravenously or rifampin 600 mg/day orally in two divided doses. Relapse may occur.
et al. Bartonella
, a common cause of endocarditis: a report on 106 cases and review. J Clin Microbiol. 2015 Mar;53(3):824–9.
Elizabethkingia species (previously known as Flavobacterium and Chryseobacterium species) are gram-negative rods that cause infection primarily in patients with compromised immune systems or multiple other comorbidities. Outbreaks due to the subspecies E meningoseptica and E anopheles have been associated with contaminated water sources and have often occurred in health care facilities. Meningitis and bacteremia as well as skin and bone infections have developed in patients infected with Elizabethkingia. Empiric treatment is piperacillin/tazobactam 4.5 g intravenously four times daily. However, Elizabethkingia species can be resistant to multiple antimicrobials. When an outbreak of Elizabethkingia species infections occurs in a health care setting, the facility’s infection control specialists must search for and eliminate the contaminated water source.
et al. Waterborne Elizabethkingia meningoseptica
in adult critical care. Emerg Infect Dis. 2016 Jan;22(1):9–17.
Anaerobic bacteria comprise the majority of normal human flora. Normal microbial flora of the mouth (anaerobic spirochetes, Prevotella, fusobacteria), the skin (anaerobic diphtheroids), the large bowel (bacteroides, anaerobic streptococci, clostridia), and the female genitourinary tract (bacteroides, anaerobic streptococci, fusobacteria) produce disease when displaced from their normal sites into tissues or closed body spaces.
Anaerobic infections tend to be polymicrobial and abscesses are common. Pus and infected tissue often are malodorous. Septic thrombophlebitis and metastatic infection are frequent and may require incision and drainage. Diminished blood supply that favors proliferation of anaerobes because of reduced tissue oxygenation may interfere with the delivery of antimicrobials to the site of anaerobic infection. Cultures, unless carefully collected under anaerobic conditions, may yield negative results.
Important types of infections that are most commonly caused by anaerobic organisms are listed below. Treatment of all these infections consists of surgical exploration and judicious excision in conjunction with administration of antimicrobial drugs.
1. Head & Neck Infections
Prevotella melaninogenica (formerly Bacteroides melaninogenicus) and anaerobic spirochetes are commonly involved in periodontal infections. These organisms, fusobacteria, and peptostreptococci may cause chronic sinusitis, peritonsillar abscess, chronic otitis media, and mastoiditis. F necrophorum has been recognized as a common cause of pharyngitis in adolescents and young adults. F necrophorum infection has been associated with septic internal jugular thrombophlebitis (Lemierre syndrome) and causes septic pulmonary embolization. Hygiene, drainage, and surgical debridement are as important in treatment as antimicrobials. Oral anaerobic organisms have been uniformly susceptible to penicillin, but there has been a recent trend of increasing penicillin resistance, usually due to beta-lactamase production. Therefore, ampicillin/sulbactam 1.5–3 g intravenously every 6 hours (if parenteral therapy is required) or amoxicillin/clavulanic acid 875 mg/125 mg orally twice daily, or clindamycin can be used (600 mg intravenously every 8 hours or 300 mg orally every 6 hours). Antimicrobial treatment is continued for a few days after symptoms and signs of infection have resolved. Indolent, established infections (eg, mastoiditis or osteomyelitis) may require prolonged courses of therapy, eg, 4–6 weeks or longer.
Usually in the setting of poor oral hygiene and periodontal disease, aspiration of saliva (which contains 108 anaerobic organisms per milliliter in addition to aerobes) may lead to necrotizing pneumonia, lung abscess, and empyema. Polymicrobial infection is the rule and anaerobes—particularly P melaninogenica, fusobacteria, and peptostreptococci—are common etiologic agents. Most pulmonary infections respond to antimicrobial therapy alone. Percutaneous chest tube or surgical drainage is indicated for empyema.
Penicillin-resistant Bacteroides fragilis and P melaninogenica are commonly isolated and have been associated with clinical failures. Clindamycin, 600 mg intravenously once, followed by 300 mg orally every 6–8 hours, is the treatment of choice for these infections. Metronidazole does not cover facultative streptococci, which often are present, and if used, a second agent that is active against streptococci, such as ceftriaxone 1 g intravenously or intramuscularly daily, should be added. Penicillin, 2 million units intravenously every 4 hours, followed by amoxicillin, 500 mg every 8 hours orally, is an alternative; however, increasing prevalence of beta-lactamase producing organisms is a concern. Moxifloxacin, 400 mg orally or intravenously once daily, may be used. Because these infections respond slowly, a prolonged course of therapy (eg, 4–6 weeks) is generally recommended.
3. Central Nervous System
Anaerobes are a common cause of brain abscess, subdural empyema, or septic central nervous system thrombophlebitis. The organisms reach the central nervous system by direct extension from sinusitis, otitis, or mastoiditis or by hematogenous spread from chronic lung infections. Antimicrobial therapy—eg, ceftriaxone, 2 g intravenously every 12 hours, plus metronidazole, 500 mg intravenously every 8 hours—is an important adjunct to surgical drainage. Duration of therapy is 6–8 weeks but should be based on follow-up imaging. Some small multiple brain abscesses can be treated with antibiotics alone without surgical drainage.
4. Intra-abdominal Infections
In the colon there are up to 1011 anaerobes per gram of content—predominantly B fragilis, clostridia, and peptostreptococci. These organisms play a central role in most intra-abdominal abscesses following trauma to the colon, diverticulitis, appendicitis, or perirectal abscess and may also participate in hepatic abscess and cholecystitis, often in association with aerobic coliform bacteria. The bacteriology includes anaerobes as well as enteric gram-negative rods and on occasion enterococci. Therapy should be directed both against anaerobes and gram-negative aerobes. Agents that are active against B fragilis include metronidazole, chloramphenicol, moxifloxacin, tigecycline, ertapenem, imipenem, doripenem, ampicillin-sulbactam, ticarcillin-clavulanic acid, piperacillin-tazobactam, and ceftolozane/tazobactam. Resistance to cefoxitin, cefotetan, and clindamycin is increasingly encountered. Most third-generation cephalosporins have poor efficacy.
Table 33–6 summarizes the antibiotic regimens for management of moderate to moderately severe infections (eg, patient hemodynamically stable, good surgical drainage possible or established, low APACHE score, no multiple organ failure) and severe infections (eg, major peritoneal soilage, large or multiple abscesses, patient hemodynamically unstable), particularly if drug-resistant organisms are suspected. An effective oral regimen for patients able to take it is presented also.
Table 33–6.Treatment of anaerobic intra-abdominal infections. |Favorite Table|Download (.pdf) Table 33–6. Treatment of anaerobic intra-abdominal infections.
Moxifloxacin 400 mg every 24 hours
Moderate to moderately severe infections:
Ertapenem 1 g every 24 hours
Ceftriaxone 1 g every 24 hours (or ciprofloxacin 400 mg every 12 hours, if penicillin allergic) plus metronidazole 500 mg every 8 hours
Imipenem, 0.5 g every 6–8 hours or meropenem 1 g every 8 hours or doripenem 0.5 g every 8 hours or piperacillin/tazobactam 3.75 g every 6 hours
Imipenem, 0.5 g every 6–8 hours or meropenem 1 g every 8 hours or doripenem 0.5 g every 8 hours or piperacillin/tazobactam 4.5 g every 6 hours
Ceftazidime or cefepime 2 g every 8 hours plus metronidazole 0.5 g every 8 hours
et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015 May 21;372(21):1996–2005.
5. Female Genital Tract & Pelvic Infections
The normal flora of the vagina and cervix includes several species of bacteroides, peptostreptococci, group B streptococci, lactobacilli, coliform bacteria, and, occasionally, spirochetes and clostridia. These organisms commonly cause genital tract infections and may disseminate from there.
While salpingitis is often caused by gonococci and chlamydiae, tubo-ovarian and pelvic abscesses are associated with anaerobes in most cases. Postpartum infections may be caused by aerobic streptococci or staphylococci, but anaerobes are often found, and the worst cases of postpartum or postabortion sepsis are associated with clostridia and bacteroides. These have a high mortality rate, and treatment requires both antimicrobials directed against anaerobes and coliforms and abscess drainage or early hysterectomy.
et al. Antibiotic regimens for postpartum endometritis. Cochrane Database Syst Rev. 2015 Feb 2;2:CD001067.
6. Bacteremia & Endocarditis
Anaerobic bacteremia usually originates from the gastrointestinal tract, the oropharynx, pressure injuries (formerly pressure ulcers), or the female genital tract. Endocarditis due to anaerobic and microaerophilic streptococci and bacteroides originates from the same sites. Most cases of anaerobic or microaerophilic streptococcal endocarditis can be effectively treated with 12–20 million units of penicillin G daily for 4–6 weeks, but optimal therapy of other types of anaerobic bacterial endocarditis must rely on laboratory guidance. Propionibacteria, clostridia, and bacteroides occasionally cause endocarditis.
7. Skin & Soft Tissue Infections
Anaerobic infections of the skin and soft tissue usually follow trauma, inadequate blood supply, or surgery and are most common in areas that are contaminated by oral or fecal flora. These infections also occur in injection drug users and persons sustaining animal bites. There may be progressive tissue necrosis (Figure 33–5) and a putrid odor.
Left foot gangrene, with plantar extension. (Used, with permission, from Dean SM, Satiani B, Abraham WT. Color Atlas and Synopsis of Vascular Diseases. McGraw-Hill, 2014.)
Several terms, such as bacterial synergistic gangrene, synergistic necrotizing cellulitis, necrotizing fasciitis, and non-clostridial crepitant cellulitis, have been used to classify these infections. Although there are some differences in microbiology among them, their differentiation on clinical grounds alone is difficult. All are mixed infections caused by aerobic and anaerobic organisms and require aggressive surgical debridement of necrotic tissue for cure. Surgical consultation is obligatory to assist in diagnosis and treatment.
Broad-spectrum antibiotics active against both anaerobes and gram-positive and gram-negative aerobes (eg, vancomycin plus piperacillin-tazobactam) should be instituted empirically and modified by culture results (see Table 30–5). They are given for about a week after progressive tissue destruction has been controlled and the margins of the wound remain free of inflammation.