In the United States, the incidence of NTS infection has doubled in the past 2 decades; the 2009 figure is ∼14 million cases annually. In 2007, the incidence of NTS infection in this country was 14.9 per 100,000 persons—the highest rate among the 11 food-borne enteric pathogens under active surveillance. Five serotypes accounted for one-half of U.S. infections in 2007: typhimurium (19%), enteritidis (14%), Newport (9%), Javiana (5%), and Heidelberg (4%).
The incidence of nontyphoidal salmonellosis is highest during the rainy season in tropical climates and during the warmer months in temperate climates, coinciding with the peak in food-borne outbreaks. Rates of morbidity and mortality associated with NTS are highest among the elderly, infants, and immunocompromised individuals, including those with hemoglobinopathies, HIV infection, or infections that cause blockade of the reticuloendothelial system (e.g., bartonellosis, malaria, schistosomiasis, and histoplasmosis).
Unlike S. typhi and S. paratyphi, whose only reservoir is humans, NTS can be acquired from multiple animal reservoirs. Transmission is most commonly associated with animal food products, especially eggs, poultry, undercooked ground meat, dairy products, and fresh produce contaminated with animal waste.
S. enteritidis infection associated with chicken eggs emerged as a major cause of food-borne disease during the 1980s and 1990s. S. enteritidis infection of the ovaries and upper oviduct tissue of hens results in contamination of egg contents before shell deposition. Infection is spread to egg-laying hens from breeding flocks and through contact with rodents and manure. Of the 997 outbreaks of S. enteritidis with a confirmed source that were reported to the CDC in 1985–2003, 75% were associated with raw or undercooked eggs. After peaking at 3.9 cases per 100,000 U.S. population in 1995, the incidence of S. enteritidis infection declined substantially to 1.7 per 100,000 in 2003; this decrease probably reflected improved on-farm control measures, refrigeration, and education of consumers and food-service workers. Transmission via contaminated eggs can be prevented by cooking eggs until the yolk is solidified and through pasteurization of egg products.
Centralization of food processing and widespread food distribution have contributed to the increased incidence of NTS in developed countries. Manufactured foods to which recent Salmonella outbreaks have been traced include peanut butter; milk products, including infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods. Large outbreaks have also been linked to fresh produce, including alfalfa sprouts, cantaloupe, fresh-squeezed orange juice, and tomatoes; these items become contaminated by manure or water at a single site and then are widely distributed.
An estimated 6% of sporadic Salmonella infections in the United States are attributed to contact with reptiles and amphibians, especially iguanas, snakes, turtles, and lizards. Reptile-associated Salmonella infection more commonly leads to hospitalization and more frequently involves infants than do other Salmonella infections. Other pets, including African hedgehogs, snakes, birds, rodents, baby chicks, ducklings, dogs, and cats, are also potential sources of NTS.
Increasing antibiotic resistance in NTS species is a global problem and has been linked to the widespread use of antimicrobial agents in food animals and especially in animal feed. In the early 1990s, S. typhimurium definitive phage type 104 (DT104), characterized by resistance to ≥5 antibiotics (ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracyclines; R-type ACSSuT), emerged worldwide. In 2005, resistance to at least ACSSuT was the most common MDR phenotype among NTS isolates in the United States. Acquisition is associated with exposure to ill farm animals and to various meat products, including uncooked or undercooked ground beef. Although probably no more virulent than susceptible S. typhimurium strains, DT104 strains are associated with an increased risk of bloodstream infection and hospitalization. NAR and trimethoprim-resistant DT104 strains are emerging, especially in the United Kingdom.
Because of increased resistance to conventional antibiotics such as ampicillin and TMP-SMX, extended-spectrum cephalosporins and fluoroquinolones have emerged as the agents of choice for the treatment of MDR NTS infections. In 2005, 2% of all NTS strains and 12.6% of S. Newport strains were resistant to ceftriaxone. Most ceftriaxone-resistant isolates were from children <18 years of age, in whom ceftriaxone is the antibiotic of choice for treatment of invasive NTS infection. These strains contained plasmid-encoded AmpC β-lactamases that were probably acquired by horizontal genetic transfer from Escherichia coli strains in food-producing animals—an event linked to the widespread use of the veterinary cephalosporin ceftiofur.
Resistance to nalidixic acid and fluoroquinolones also has begun to emerge and is most commonly associated with point mutations in the DNA gyrase genes gyrA and gyrB. Nalidixic acid resistance is a good predictor of reduced susceptibility to clinically useful fluoroquinolones. From 1996–2005, the rate of NAR NTS isolates in the United States increased fivefold (from 0.5–2.4%). In Denmark, infection with NAR S. typhimurium DT104 has been linked to swine and associated with a threefold higher risk of invasive disease or death within 90 days. In Taiwan in 2000, a strain of ciprofloxacin-resistant (MIC, ≥4 mcg/mL) S. choleraesuis caused a large outbreak of invasive infections that was linked to the use of enrofloxacin in swine feed.
Infection with NTS most often results in gastroenteritis indistinguishable from that caused by other enteric pathogens. Nausea, vomiting, and diarrhea occur 6–48 h after the ingestion of contaminated food or water. Patients often experience abdominal cramping and fever (38–39°C; 100.5–102.2°F). Diarrheal stools are usually loose, nonbloody, and of moderate volume. However, large-volume watery stools, bloody stools, or symptoms of dysentery may occur. Rarely, NTS causes pseudoappendicitis or an illness that mimics inflammatory bowel disease.
Gastroenteritis caused by NTS is usually self-limited. Diarrhea resolves within 3–7 days and fever within 72 h. Stool cultures remain positive for 4–5 weeks after infection and—in rare cases of chronic carriage (<1%)—for >1 year. Antibiotic treatment usually is not recommended and may prolong fecal carriage. Neonates, the elderly, and immunosuppressed patients (e.g., transplant recipients, HIV-infected persons) with NTS gastroenteritis are especially susceptible to dehydration and dissemination and may require hospitalization and antibiotic therapy. Acute NTS gastroenteritis was associated with a threefold increased risk of dyspepsia and irritable bowel syndrome at 1 year in a recent study from Spain.
Bacteremia and Endovascular Infections
Up to 8% of patients with NTS gastroenteritis develop bacteremia; of these, 5–10% develop localized infections. Bacteremia and metastatic infection are most common with S. choleraesuis and S. Dublin and among infants, the elderly, and immunocompromised patients. NTS endovascular infection should be suspected in high-grade or persistent bacteremia, especially with preexisting valvular heart disease, atherosclerotic vascular disease, prosthetic vascular graft, or aortic aneurysm. Arteritis should be suspected in elderly patients with prolonged fever and back, chest, or abdominal pain developing after an episode of gastroenteritis. Endocarditis and arteritis are rare (<1% of cases) but are associated with potentially fatal complications, including valve perforation, endomyocardial abscess, infected mural thrombus, pericarditis, mycotic aneurysms, aneurysm rupture, aortoenteric fistula, and vertebral osteomyelitis. In some areas of sub-Saharan Africa, NTS may be among the most common causes—or even the most common cause—of bacteremia in children. NTS bacteremia among these children is not associated with diarrhea and has been associated with nutritional status and HIV infection.
Intraabdominal infections due to NTS are rare and usually manifest as hepatic or splenic abscesses or as cholecystitis. Risk factors include hepatobiliary anatomic abnormalities (e.g., gallstones), abdominal malignancy, and sickle cell disease (especially with splenic abscesses). Eradication of the infection often requires surgical correction of abnormalities and percutaneous drainage of abscesses.
Central Nervous System Infections
NTS meningitis most commonly develops in infants 1–4 months of age. It often results in severe sequelae (including seizures, hydrocephalus, brain infarction, and mental retardation) with death in up to 60% of cases. Other rare central nervous system infections include ventriculitis, subdural empyema, and brain abscesses.
NTS pulmonary infections usually present as lobar pneumonia, and complications include lung abscess, empyema, and bronchopleural fistula formation. The majority of cases occur in patients with lung cancer, structural lung disease, sickle cell disease, or glucocorticoid use.
Urinary and Genital Tract Infections
Urinary tract infections caused by NTS present as either cystitis or pyelonephritis. Risk factors include malignancy, urolithiasis, structural abnormalities, HIV infection, and renal transplantation. NTS genital infections are rare and include ovarian and testicular abscesses, prostatitis, and epididymitis. Like other focal infections, both genital and urinary tract infections can be complicated by abscess formation.
Bone, Joint, and Soft Tissue Infections
Salmonella osteomyelitis most commonly affects the femur, tibia, humerus, or lumbar vertebrae and is most often seen in association with sickle cell disease, hemoglobinopathies, or preexisting bone disease (e.g., fractures). Prolonged antibiotic treatment is recommended to decrease the risk of relapse and chronic osteomyelitis. Septic arthritis occurs in the same patient population as osteomyelitis and usually involves the knee, hip, or shoulder joints. Reactive arthritis (Reiter's syndrome) can follow NTS gastroenteritis and is seen most frequently in persons with the HLA-B27 histocompatibility antigen. NTS rarely can cause soft tissue infections, usually at sites of local trauma in immunosuppressed patients.
The diagnosis of NTS infection is based on isolation of the organism from freshly passed stool or from blood or another ordinarily sterile body fluid. All salmonellae isolated in clinical laboratories should be sent to local public health departments for serotyping. Blood cultures should be done whenever a patient has prolonged or recurrent fever. Endovascular infection should be suspected if there is high-grade bacteremia (>50% of three or more positive blood cultures). Echocardiography, CT, and indium-labeled white cell scanning are used to identify localized infection. When another localized infection is suspected, joint fluid, abscess drainage, or cerebrospinal fluid should be cultured, as clinically indicated.
Treatment: Nontyphoidal Salmonellosis
Antibiotics should not be used routinely to treat uncomplicated NTS gastroenteritis. The symptoms are usually self-limited, and the duration of fever and diarrhea is not significantly decreased by antibiotic therapy. In addition, antibiotic treatment has been associated with increased rates of relapse, prolonged gastrointestinal carriage, and adverse drug reactions. Dehydration secondary to diarrhea should be treated with fluid and electrolyte replacement.
Preemptive antibiotic treatment (Table 153-2) should be considered for patients at increased risk for invasive NTS infection, including neonates (probably up to 3 months of age); persons >50 years of age with suspected atherosclerosis; and patients with immunosuppression, cardiac valvular or endovascular abnormalities, or significant joint disease. Treatment should consist of an oral or IV antibiotic administered for 48–72 h or until the patient becomes afebrile. Immunocompromised persons may require up to 7–14 days of therapy. The <1% of persons who develop chronic carriage of NTS should receive a prolonged antibiotic course, as described above for chronic carriage of S. typhi.
Table 153-2 Antibiotic Therapy for Nontyphoidal Salmonella Infection in Adults
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Table 153-2 Antibiotic Therapy for Nontyphoidal Salmonella Infection in Adults
|Indication||Agent||Dosage (Route)||Duration, Days|
|Ciprofloxacinb||500 mg bid (PO)||2–3|
|Ciprofloxacin||500 mg bid (PO) or 400 mg q12h (IV)||3–7|
|Trimethoprim-sulfamethoxazole||160/800 mg bid (PO)|
|Amoxicillin||1 g tid (PO)|
|Ceftriaxone||1–2 g/d (IV)|
|Ceftriaxoned||2 g/d (IV)||7–14|
|Ciprofloxacin||400 mg q12h (IV), then 500 mg bid (PO)|
|Endocarditis or Arteritis|
|Ceftriaxone||2 g/d (IV)||42|
|Ciprofloxacin||400 mg q8h (IV), then 750 mg bid (PO)|
|Ampicillin||2 g q4h (IV)|
|Ceftriaxone||2 g q12 h (IV)||14–21|
|Ampicillin||2 g q4h (IV)|
|Other Localized Infection|
|Ceftriaxone||2 g/d (IV)||14–28|
|Ciprofloxacin||500 mg bid (PO) or 400 mg q12h (IV)|
|Ampicillin||2 g q6h (IV)|
Because of the increasing prevalence of antibiotic resistance, empirical therapy for life-threatening NTS bacteremia or focal NTS infection should include a third-generation cephalosporin or a fluoroquinolone (Table 153-2). If the bacteremia is low-grade (<50% of positive blood cultures), the patient should be treated for 7–14 days. Patients with HIV/AIDS and NTS bacteremia should receive 1–2 weeks of IV antibiotic therapy followed by 4 weeks of oral therapy with a fluoroquinolone. Patients whose infections relapse after this regimen should receive long-term suppressive therapy with a fluoroquinolone or TMP-SMX, as indicated by bacterial sensitivities.
If the patient has endocarditis or arteritis, treatment for 6 weeks with an IV β-lactam antibiotic (such as ceftriaxone or ampicillin) is indicated. IV ciprofloxacin followed by prolonged oral therapy is an option, but published experience is limited. Early surgical resection of infected aneurysms or other infected endovascular sites is recommended. Patients with infected prosthetic vascular grafts that cannot be resected have been maintained successfully on chronic suppressive oral therapy. For extraintestinal nonvascular infections, a 2- to 4-week course of antibiotic therapy (depending on the infection site) is usually recommended. In chronic osteomyelitis, abscess, or urinary or hepatobiliary infection associated with anatomic abnormalities, surgical resection or drainage may be required in addition to prolonged antibiotic therapy for eradication of infection.
Despite widespread efforts to prevent or reduce bacterial contamination of animal-derived food products and to improve food-safety education and training, recent declines in the incidence of NTS in the United States have been modest compared with those of other food-borne pathogens. This observation probably reflects the complex epidemiology of NTS. Identifying effective risk-reduction strategies requires monitoring of every step of food production, from handling of raw animal or plant products to preparation of finished foods. Contaminated food can be made safe for consumption by pasteurization, irradiation, or proper cooking. All cases of NTS infection should be reported to local public health departments, since tracking and monitoring of these cases can identify the source(s) of infection and help authorities anticipate large outbreaks. Lastly, the prudent use of antimicrobial agents in both humans and animals is needed to limit the emergence of MDR Salmonella.