INTRODUCTION — Nontyphoidal salmonellae are an important bacterial cause of diarrheal disease. The epidemiology and pathophysiology of nontyphoidal strains differ from typhoidal strains [1]. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
Issues related to the epidemiology, clinical microbiology, clinical manifestations, and treatment of nontyphoidal Salmonella bacteremia will be reviewed here. Nontyphoidal Salmonella gastrointestinal disease and typhoid fever are discussed in detail separately. (See "Nontyphoidal Salmonella: Gastrointestinal infection and carriage" and "Enteric (typhoid and paratyphoid) fever: Treatment and prevention".)
EPIDEMIOLOGY
Incidence — Invasive infections due to nontyphoidal Salmonella occur globally, but the burden varies by geographic location. Approximately 1 percent of enteric infections with nontyphoidal Salmonella result in bacteremia, although the true rate of bacteremia is unknown, as many primary enteric infections are not microbiologically diagnosed.
In a systematic review that extrapolated the global incidence of invasive nontyphoidal Salmonella infections based on 35 studies, there were an estimated 535,000 cases in 2017 (7.5 cases per 100,000 people worldwide) [2]. The greatest burden was in sub-Saharan Africa, which accounted for 79 percent of all cases globally [2] and where nontyphoidal Salmonella bacteremia is a leading cause of bacteremia in adults and children [3-8]. According to one systematic review, nontyphoidal Salmonella causes 8 to 39 percent of community-acquired bacteremia cases in sub-Saharan Africa, depending on the country [9]. In these areas, nontyphoidal Salmonella bacteremia may occur in epidemic waves (more common during and just after rainy seasons) and mortality may be very high.
Approximately 65 percent of cases worldwide are in children younger than five years of age.
Host risk factors — A number of host risk factors predispose to nontyphoidal Salmonella bacteremia [10-13]. Such risk factors include:
●Extremes of age
●Immunosuppressing conditions, including malignancy, rheumatologic disease, use of immunomodulatory drugs, transplantation, HIV infection, and congenital immune defects
●Chronic liver disease
●Hemoglobinopathies (especially sickle cell disease)
●Malaria
●Schistosomiasis
●Chronic granulomatous disease
Alteration of the gastrointestinal tract (eg, by suppression of gastric acid, malnutrition, recent antibiotic use, or rotavirus infection) also predisposes to progression from enteric to systemic salmonellosis [14]. (See "Pathogenesis of Salmonella gastroenteritis".)
The importance of predisposing host risk factors was illustrated in a series of 55 Malaysian adults with nontyphoidal Salmonella bacteremia, in which over 90 percent of patients had an underlying medical illness; 65 percent had severe immunosuppression, most commonly HIV infection or malignancy [3]. In a systematic review of global cases of invasive nontyphoidal Salmonella, 8 percent of cases were attributed to HIV in 2017 [2].
In sub-Saharan Africa, nontyphoidal Salmonella bacteremia most commonly occurs in patients with HIV, infants, and young children with malaria, anemia, and malnutrition [9]. The association with malaria may be related to increased intestinal permeability and bacterial translocation in the setting of malaria [15-17]. Relapsing bacteremia and higher mortality are observed in the setting of concurrent HIV infection.
However, among children with nontyphoidal bacteremia in resource-rich settings, most have associated gastroenteritis, have no underlying comorbid illness, and recover uneventfully [14,18,19]. In a series of 144 pediatric cases of nontyphoidal Salmonella bacteremia in Pittsburgh in the United States (median age 10.5 months), 82 percent of patients were previously healthy [18].
Risk by serotype — Although Salmonella enteritidis and Salmonella typhimurium are the most commonly isolated pathogenic serotypes overall and the most common causes of invasive nontyphoidal Salmonella infections, other serotypes have a greater predisposition for causing invasive disease [20]. These include Salmonella enterica serotypes Dublin, Choleraesuis, Virchow, Infantis, Newport, and Heidelberg [1,21]. In addition, antibiotic-resistant strains of S. typhimurium are associated with a two- to threefold increase in the risk of bacteremia [22,23].
Sources of infection — Nontyphoidal Salmonella infection usually results from ingestion of contaminated food and water. It can also be acquired via the fecal-oral route, either from other humans or farm or pet animals. Sources of infection are discussed in detail elsewhere. (See "Nontyphoidal Salmonella: Microbiology and epidemiology", section on 'Modes of transmission'.)
MICROBIOLOGY AND DIAGNOSIS — Blood cultures should be drawn in patients with Salmonella gastroenteritis ill enough to require hospitalization. Nontyphoidal Salmonella are vigorous organisms that grow readily in aerobic and anaerobic blood culture bottles.
Serotype distribution varies greatly by location and over time. S. enteritidis and S. typhimurium are the most commonly isolated pathogenic serotypes; therefore, they are also most frequently isolated from the blood. Some less frequently isolated serotypes can be more invasive than others and are more likely to cause bacteremia (including S. enterica serotypes Dublin, Choleraesuis, Virchow, Infantis, Newport, and Heidelberg) [1,21]. (See "Nontyphoidal Salmonella: Microbiology and epidemiology".)
A "primary bacteremia" (ie, a positive blood culture in the absence of recent or current gastrointestinal symptoms of Salmonella infection) may be an initial signal of unappreciated immunological dysfunction. HIV infection should be considered; recurrent Salmonella infection was a relatively frequent AIDS-defining infection in the US prior to the availability of potent antiretroviral therapy (ART). Other more frequently encountered co-morbidities include malignancy, diabetes, and rheumatologic illness. Therapeutic immunosuppression with steroids and other immunomodulatory drugs is increasingly common.
COMPLICATIONS
Extraintestinal focal infection — Nontyphoidal salmonellae bacteremia can progress to development of infection at any site, including the urinary tract, lung, pleura, heart, long bones, joints, muscle, and central nervous system. After stool and blood, urinary isolates are encountered most frequently; these may reflect urologic abnormalities, bacteremia in the setting of chronic medical illness, and/or retrograde spread of infection [24,25].
In a case series of 229 children from an urban setting in Thailand with invasive salmonellosis, respiratory symptoms were surprisingly common (in about 25 percent) [26]. These and underlying hepatobiliary disease were associated with an increased risk of fatality.
Salmonella meningitis is a rare complication that typically occurs in neonates and children ≤1 year; for this reason, any form of nontyphoidal salmonellosis in infants should prompt immediate and attentive management [27,28]. Where HIV prevalence is high, nontyphoidal salmonella meningitis can also be seen in adults [29]. Mortality is high and survivors may not have complete neurological recovery. (See "Gram-negative bacillary meningitis: Treatment".)
Endovascular infection — Endovascular infection is an uncommon but serious complication of nontyphoidal Salmonella bacteremia. Initially noted in the 1970s, subsequent population-based studies have noted that approximately 10 to 20 percent of adults over 50 years of age with documented nontyphoidal Salmonella bloodstream infections have a suppurative endovascular focus of infection [30,31]. The organisms are presumed to home to existing atherosclerotic sites in large vessels in older adults; this is the rationale for a more aggressive approach to treatment of Salmonella gastroenteritis in older individuals. (See "Nontyphoidal Salmonella: Gastrointestinal infection and carriage".)
Endovascular infection was specifically linked to atherosclerosis in one Taiwanese study, in the absence of other clinical features or immunodeficiencies [32]. The abdominal aorta (especially infrarenal) is the most frequent site of vascular infection, though involvement of the thoracic aorta, other central arterial sites and endocarditis occur as well [33]. Subacute fever and abdominal and back pain are the typical presenting symptoms; a pulsatile mass is a late and ominous finding.
The diagnostic approach should consist of CT or MRI (preferably with contrast angiographic analysis) when an aortic or vascular focus is possible or suspected.
TREATMENT — Extraintestinal nontyphoidal Salmonella infections generally require surgical drainage or debridement and prolonged antimicrobial therapy.
Antibiotic selection — Fluoroquinolones are a reasonable empiric antibiotic choice for treatment of nontyphoidal Salmonella bacteremia (ciprofloxacin 400 mg intravenously twice daily or levofloxacin 500 to 750 mg intravenously once daily). Fluoroquinolones have excellent intracellular penetration and oral bioavailability, allowing transition to oral therapy with clinical improvement.
Fluoroquinolones are frequently avoided in children because of cartilage abnormalities observed in developing animals, although data suggest that fluoroquinolones may be used in children over short courses [34]. Treatment of serious Salmonella infections is a reasonable indication for use of fluoroquinolones in children, especially if other agents are not readily available [35]. (See "Fluoroquinolones".)
Third generation cephalosporins are a reasonable alternative to fluoroquinolones (eg, ceftriaxone 1 to 2 g intravenously once daily or cefotaxime 2 g intravenously every eight hours).
Other reasonable antibiotic alternatives include trimethoprim-sulfamethoxazole (8 to 10 mg/kg/day of the trimethoprim component divided three times per day) and ampicillin (2 g IV every 4 hours).
Reduced susceptibility and frank resistance to fluoroquinolones and third generation cephalosporins is increasing [36,37]. Resistance has been reported frequently in Asia and history of travel to this region should be considered in clinical management [38]. In the United States, the number of ceftriaxone-resistant blood isolates has approximately doubled, from 2.5 percent (1996 to 2007) to approximately 5 percent (2003 to 2013), as reported to the Centers for Disease Control and Prevention's National Antimicrobial Resistance Monitoring System [39]. Importantly, these resistance patterns correlate with findings in ground beef, cattle, and poultry [40].
Antibiotics must be tailored to susceptibility data once available, and infectious disease consultation may be helpful. Although nalidixic acid disc resistance screening had been previously used as a marker for relative resistance to fluoroquinolones, direct testing for sensitivity to ciprofloxacin or other clinically used fluoroquinolones is now recommended, when possible, for cases of invasive salmonellosis [37]. Break points for susceptibility have been lowered such that fully-fluoroquinolone susceptible organisms are now defined as those with a minimum inhibitory concentration (MIC) of 0.06 mcg/mL or less.
Nalidixic acid resistance testing does not detect all mechanisms of fluoroquinolone resistance.
For management of infections due to highly resistant organisms, infectious disease consultation is advisable. Carbapenems are appropriate agents for treatment of infection due to highly resistant organisms [41,42]; resistance to carbapenems has rarely been noted in case reports [43,44].
Azithromycin is another possible alternative in exceptional cases, although there are no standard NCCLS antimicrobial susceptibility break points reported for salmonellae. Azithromycin resistance has been reported in Salmonella choleraesuis from Cambodia [45].
Surgical management of complications — Extraintestinal nontyphoidal Salmonella infections generally warrant surgical drainage or debridement in addition to prolonged antimicrobial therapy.
In particular, for patients with endovascular infection, medical therapy alone is inadequate; surgery is required [46,47]. Experienced vascular surgeons should be consulted. Because of the morbidity of extra-anatomic bypass, most experts perform in-situ debridement and grafting despite the risk of leak and relapsed infection. There are a variety of specific surgical approaches and grafts, depending on the site involved, intraoperative findings, and degree of debridement deemed necessary and achieved. Small surgical series of up to 26 patients have demonstrated a 60 to 100 percent survival rate [19,47,48]. As an example, in a European retrospective registry of patients with mycotic aneurysm who underwent endovascular repair, among the 15 documented nontyphoidal Salmonella cases, four of six deaths occurred within 90 days, and the five-year survival among those surviving 90 days was 90 percent [49]. This survival rate appeared superior to those with other infectious etiologies.
Antibiotics are an essential component of therapy, but the duration of therapy is debated. (See 'Antibiotic selection' above and 'Extraintestinal focal infections and endovascular infection' below.)
Duration of antibiotic therapy
Bacteremia — The optimal duration of antimicrobial therapy for nontyphoidal Salmonella bacteremia in the absence of extraintestinal focal infection depends upon the immune status of the host. A 14 day course of antimicrobial therapy for otherwise healthy individuals is likely appropriate. Patients with Salmonella gastroenteritis hospitalized with the suspicion of bacteremia should have blood cultures drawn and empiric treatment initiated while awaiting culture results. In such circumstances, prompt initiation of antibiotic therapy is of greater clinical importance than the possibility of prolonging fecal carriage, especially in older patients. (See "Nontyphoidal Salmonella: Gastrointestinal infection and carriage".)
Longer courses of antimicrobial therapy (4 to 6 weeks) are warranted for patients with significant immunosuppression for whom recurrence or relapse is likely (eg, such as in the setting of HIV/AIDS, solid organ transplant, or bone marrow transplant) [4,50,51]. If infection and/or bacteremia occurs at an immunological nadir in these patients, the infection may become established within the immunologically compromised reticuloendothelial system. Relapse may occur even after an asymptomatic interval and in the absence of a known focus of infection (such as osteomyelitis or an abnormal biliary or urinary system) [48].
A period of suppressive therapy may also be appropriate for patients with significant immunosuppression, especially if relapse of bacteremia is documented after an initial successful treatment.
Extraintestinal focal infections and endovascular infection — In general, complete debridement and drainage of soft tissue or visceral foci of infection should be followed by a minimum of 3 weeks of antimicrobial therapy if there are no clinical complications. Extraintestinal foci are virtually always seeded by bacteremic spread, so the issues discussed in the preceding section apply.
Longer courses of therapy (6 to 12 weeks) may be advisable depending upon the site, adequacy of surgical debridement achieved, presence of any prosthetic material (vascular grafts, joints, screws, plates, valves or other hardware), presence or absence remaining fluid collections or devitalized tissue, immunological status, and age of the patient. Duration of therapy should be commensurate with standard courses for the site of infection at a minimum; for example, a brain abscess, endocarditis, or osseous infection should be treated for at least 6 to 8 weeks if Salmonella are present.
Salmonella are hardy organisms that adapt to stressful environments and may be difficult to eradicate, especially if devitalized tissue or prosthetic material is present. Chronic suppressive therapy may be appropriate for patients with infection of prosthetic joints, heart valves, or vascular grafts where the potential consequences of relapsed infection may be dire. Reasonable suppressive regimens (depending on the sensitivity of the organism) include trimethoprim-sulfamethoxazole (one DS tablet once daily), levofloxacin (500 mg once daily) or ciprofloxacin (750 mg once daily). Consultation with infectious disease expertise is recommended.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults" and "Society guideline links: Acute diarrhea in children".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Salmonella infection (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Bacteremia and other forms of extraintestinal Salmonella infection are serious complications that may not be suspected in the setting of mild primary infection. Factors affecting the incidence of bacteremia include Salmonella serotype, geographic location, time of year, and host factors including extremes of age and immunosuppressing conditions. (See 'Epidemiology' above.)
●Nontyphoidal Salmonella bacteremia can progress to development of infection at any site, including any visceral organ, long bones, joints, muscle, and central nervous system. After stool and blood, urinary isolates are encountered most frequently. Salmonella meningitis is a rare complication that typically occurs in neonates and children ≤1 year. (See 'Extraintestinal focal infection' above.)
●Endovascular infection is a serious complication of nontyphoidal Salmonella bacteremia. The abdominal aorta (particularly the infrarenal aorta) is the most frequent site of infection. When a vascular focus of infection is suspected, CT or MRI with contrast should be performed. (See 'Endovascular infection' above.)
●Reasonable empiric antibiotics for treatment of nontyphoidal Salmonella bacteremia include fluoroquinolones (ciprofloxacin 400 mg intravenously twice daily or levofloxacin 500 to 750 mg intravenously once daily) or third generation cephalosporins (ceftriaxone 1 to 2 g intravenously once daily or cefotaxime 2 g intravenously every eight hours). Stable patients may receive fluoroquinolones orally, as they have excellent oral bioavailability (ciprofloxacin 500 mg twice daily or levofloxacin 500 to 750 mg once daily). (See 'Treatment' above and 'Antibiotic selection' above.)
●A 14 day course of antimicrobial therapy is likely adequate for otherwise healthy individuals with uncomplicated bacteremia accompanying gastroenteritis. Longer courses of antimicrobial therapy (4 to 6 weeks or more) are warranted for patients with significant immunosuppression for whom recurrence or relapse is likely. Suppressive therapy may also be appropriate for some patients, especially if relapse of bacteremia is documented after an initial successful treatment or prosthetic materials are present. (See 'Bacteremia' above.)
●Extraintestinal nontyphoidal Salmonella infections generally require surgical drainage or debridement and prolonged antimicrobial therapy. (See 'Surgical management of complications' above and 'Extraintestinal focal infections and endovascular infection' above.)
