• More than 95% of nontyphoid salmonellosis presents as uncomplicated acute gastroenteritis.
• The clinical presentation of different causes of gastroenteritis and diarrhea overlaps significantly.
• The physician should be familiar with groups of patients at risk for complicated salmonellosis.
• Specific diagnosis requires culture of the stool or blood.
• Focal complications are always suspect in high-risk patients who are blood culture positive for nontyphoid Salmonellae (e.g., aortitis or mycotic aneurysm in patients older than age 60 years with atherosclerosis).
• Fluid and electrolyte replacement is of paramount importance.
• The physician should avoid routine empiric antibiotic in acute uncomplicated patients.
• The physician should avoid antimotility agents for diarrhea presenting with fever or with mucus and blood present.
• More than 95% of patients with nontyphoid salmonellosis will get better on their own.
• Fluoroquinolone antibiotics should be reserved for when they are truly indicated clinically.
• Increasing resistance mandates sensitivity testing (including tests for ESBL) to guide therapy of bacteremia and its complications.
• Do not prescribe prophylactic antibiotics to prevent diarrhea in travelers.
• Stress personal hygiene and prudent food choice with proper preparation.
Abbreviation: ESBL = extended spectrum beta lactamases.
Salmonellosis refers to a group of infections caused by members of the genus Salmonella. This genus is named after Salmon, a pathologist who first isolated the organism, later designated as Salmonella choleraesuis, from the intestine of pigs with diarrhea. Salmonellae are widely distributed throughout nature and are adapted to a myriad of warm and cold-blooded hosts. In humans there are four main clinical presentations:
- Acute gastroenteritis
- Focal extraintestinal infection
- Chronic carriage (Table 1)
Clinical Presentations of Salmonellosis
Salmonellae are motile, gram-negative, nonspore-forming bacilli that are differentiated from other Enterobacteriaceae by inability to ferment lactose and sucrose while producing acid, hydrogen sulfide, and gas (except Salmonella typhi). Members of the genus were more accurately classified into serotypes using the Kauffman-White schema, which differentiated and grouped them serologically dependent on their lipopolysaccharide somatic (O) and flagellar (H) antigens.
More recently, DNA analysis has divided the genus into two species. Initially the first of the two species was named Salmonella choleraesuis and was divided into six subspecies, each of which was then divided into more than 2400 serotypes (serovars) by Kauffman- White methodology. The second species, Salmonella bongori, is inconsequential. Serotypes were named historically from the host or the geographic locale of the first isolate, such as Salmonella typhimurium or Salmonella dublin. However, under the new DNA division, choleraesuis was both a species and a serotype. To avoid confusion the name Salmonella enterica has been widely adopted. The first of the six subspecies (Group I) is also named enterica. It contains the more than 1400 serotypes that occur in warm-blooded animals.
Using nomenclature employed by the United States Centers for Disease Control (CDC) and the World Health Organization (WHO), the species and subspecies name is understood and the serotype is capitalized. Thus, the formal S. enterica subspecies enterica serotype typhimurium becomes simply S. Typhimurium, which except for the capital T is where we started!
In the last 25 years, the incidence of nontyphoid salmonellosis has increased two- to threefold, with approximately 1.5 million cases occurring annually in the United States. This is an underestimate because most cases are sporadic (endemic) and go unreported.
Children younger than 5 years of age have the highest incidence of gastroenteritis and constitute the greatest number of cases.
Animals are the source of nontyphoid salmonella infection in humans. Infection occurs from food of animal origin such as meat, poultry, eggs, and dairy products. Contamination may occur during the production, slaughter, processing, or distribution of these products. Outbreaks have been associated with eggs, ice cream, and processed meats. Increasingly there have been outbreaks associated with raw vegetables (e.g., scallions) that are crosscontaminated during growth and distribution. Restaurant or home outbreaks occur in the context of improper preparation, cooking, and refrigeration. Most of the outbreaks can be attributed to centralized mass production and preparation of food along with globalization of the food trade. Novel sources of human salmonella include pet turtles, lizards, iguanas, African hedgehogs, rattlesnakes, and even marijuana contaminated by manure.
Emergence of antibiotic resistant species is a formidable problem. It is believed that resistance is driven worldwide by improper antibiotics use. However, in developed countries it is attributable to widespread use in animal feeds. Large numbers of transferable-resistance plasmids have been described. Resistance rates of more than 50% to ampicillin, chloramphenicol (Chloromycetin), and trimethoprim- sulfamethoxazole (TMP-SMZ) (Bactrim) occur in parts of Asia, Africa, and Latin America. One strain of S. Typhimurium (DT104) is resistant to five antimicrobials; the three mentioned previously plus tetracycline and streptomycin. This organism has spread widely in livestock throughout the United States, Canada, the United Kingdom, Europe, and the Middle East. Likewise, resistance to third-generation cephalosporins is increasing and is mediated by plasmids producing both regular and extended-spectrum beta-lactamases (ESBLs). Even more disturbing is fluoroquinolone resistance caused by mutated DNA gyrase, topoisomerase IV, or efflux pumps. The latter literally expel the quinolone from the bacterium before it can act on its target. Fluoroquinolone resistance is most pronounced in Southeast Asia, Europe, and the Middle East.
Human infection usually requires 106 organisms. Fewer organisms may cause disease in patients who have hypochlorhydria or achlorhydria, have impaired cellular immunity, are at the extremes of age, or are taking certain drugs (Table 2). Salmonellae predominately infect the terminal ileum and proximal colon through attachment.
Initially, host response is by neutrophils followed by lymphocytes and macrophages. Strains vary genetically in their virulence and invasiveness. The organisms can survive intracellularly, thus avoiding antibiotic agents that lack intracellular penetration. Bacteria that are not contained regionally in the gut or lymph nodes may enter the blood. There are many predisposing factors associated with this and subsequent focal complications (see Table 2).
Predisposing Factors for Salmonellosis
Acute gastroenteritis is by far the most common clinical presentation of salmonellosis. It should be emphasized that there is considerable overlap in its presentation with other infectious intestinal pathogens such as Campylobacter species. Given this, the incubation ranges from 6 to 96 hours but most commonly occurs between 12 and 48 hours.
Initial symptoms include nausea and vomiting, followed by headaches, myalgias, malaise, chills, low-grade fever, abdominal cramps, and diarrhea. High temperatures (40°C [104°F]) should alert the clinician to invasive disease. Stools may be merely loose or profuse and watery. On direct examination, they may or may not contain polymorphonuclear leukocytes or occult blood. The presence of mucus or gross blood in the absence of hemorrhoids or fissures should alert the clinician to organisms causing dysentery such as Shigella species. The white blood cell count is most often normal or slightly elevated, with a left shift containing 10 to 15 bands. Low white blood cell counts with greater numbers of bands should alert the clinician to possible bacteremia or enteric fever. The diagnosis can be confirmed only by stool or blood culture. Serum serology examinations are not helpful. Most healthy adults have a self-limited, uncomplicated course, with resolution of symptoms without treatment within 48 to 72 hours.
Fluid and Electrolyte Replacement
The sine qua non in the treatment of diarrhea is fluid and electrolyte replacement. In most cases increased oral intake of bland juices coupled with clear broth and temporary elimination of lactose- containing foods will suffice. Commercial electrolyte solutions (Pedialyte) may be useful. Although not readily available in the United States, rehydration salts are widely employed in many developing countries. WHO distributes packets containing its recommended formula of 90 mmol sodium, 20 mmol potassium, 80 mmol chloride, 30 mmol bicarbonate, along with 111 mmol glucose to dissolve in 1 L sterile or boiled water. This mixture should be consumed at a rate sufficient to compensate for diarrheal losses while maintaining an adequate output of dilute-appearing urine. Within 24 to 48 hours, the diet can be supplemented with bland, soft foods given in small, frequent feedings. If the patient has profuse vomiting or severe dehydration as determined by orthostatic changes in blood pressure, parenteral rehydration should be used. Frequently, this can be accomplished as an outpatient in an infusion room or with a home agency rather than through admission to hospital. When there is persistent emesis, profuse diarrhea, systemic toxicity, or abnormalities in serum electrolytes, parenteral rehydration in hospital is prudent.
Antimotility and Antinausea Agents
The use of agents such as atropine-diphenoxylate (Lomotil) or loperamide (Imodium) should be discouraged. Although they may result in symptomatic improvement in cramps and diarrhea, they can increase complications and even predispose to bacteremia. In general, if the patient has a fever and the diarrhea contains blood or mucus, their use should be eschewed. Most pediatricians feel they should never be used in children younger than 5 years of age. An alternative is bismuth subsalicylate (Pepto-Bismol). The adult dose is 1 ounce (2 tablespoons) or 2 tablets (262.5 mg) every 30 minutes for 8 hours. The pediatric dose is 1.1 mL/kg at 4-hour intervals for up to 5 days.
Although nausea and vomiting are occasional presenting symptoms with enterocolitis, they rarely persist. Prochlorperazine (Compazine) or trimethobenzamide (Tigan) may be helpful. Both are available in oral, suppository, or parenteral form, even though injectable prochlorperazine (Compazine) has been in short supply.
Suppositories usually stimulate further diarrhea. Vomiting may preclude oral administration. A singular muscular injection of prochlorperazine (Compazine) 5 to 10 mg, is often all that is needed. This may be repeated every 4 to 6 hours as needed. Promethazine hydrochloride (Phenergan) is more frequently used in children and may be used orally (0.5 mg/pound or 1 mg/kg every 6 hours) or intramuscularly in the same doses. A 5-HT3 receptor antagonist such as ondansetron (Zofran)1 is expensive and inefficacious.
The routine empiric use of antibiotics, especially fluoroquinolones, for any and all cases of diarrhea is not only unjustifiable but should be decried. Certainly antibiotics are not needed in the treatment of uncomplicated Salmonella gastroenteritis in otherwise healthy children or adults. Studies have shown that they neither shorten the course nor improve symptoms. No doubt some of this usage is patient driven.
However, overuse is contributing to the emergence of resistance, and may increase risk of symptomatic and bacteriologic relapse. Indeed, antibiotic use may actually prolong the convalescent excretion or contribute to chronic carriage of the organism. Postponing antibiotic therapy until the return of a stool culture often provides the physician with a way to avert the frequent demand for antibiotic therapy. Often patients are better by the time results become available. Nevertheless, high-risk patients, as previously identified (see Table 2), should receive treatment to prevent potential complications from bacteremia. Additionally, if patients are sick enough to require hospitalization, antibiotic therapy should be considered.
Appropriate antibiotic therapy should be guided by susceptibility testing. Initially, TMP-SMZ (cotrimoxazole, Bactrim, or Septra)1 may be administered to the nonsulfonamide-sensitive patient. The dose is 5 to 8 mg/kg trimethoprim every 12 hours for children or 1 double- strength tablet (160 mg trimethoprim/800 mg sulfamethoxazole) every 12 hours for adults. Although widely used, trimethoprim- sulfamethoxazole has not yet received FDA approval. If the organism is susceptible, ampicillin, 50 mg/kg orally to 100 mg/kg/day intravenously, each in four divided doses for children, or 2 to 4 g/day in four divided doses for adults, may be administered. Amoxicillin (Amoxil)1 in equivalent oral dosage may be substituted. The duration of therapy is generally 5 days.
Newer fluoroquinolone antibiotics, such as ciprofloxacin,1 ofloxacin,1 and norfloxacin,1 are among the most effective agents, with excellent oral bioavailability and intracellular concentration. They are contraindicated in prepubertal children and pregnant women. Adult doses are ciprofloxacin (Cipro), 500 mg twice daily; ofloxacin (Floxin), 400 mg twice daily; or norfloxacin (Noroxin), 400 mg twice daily. It must be emphasized that the trend in the United States to use these agents empirically for all suspected bacterial diarrhea should be vigorously resisted by the thoughtful clinician.
Bacteremia and Focal Infection
Bacteremia in acute uncomplicated Salmonella gastroenteritis is infrequent. Therefore, blood cultures are not routinely necessary except for patients who are in high-risk categories. Shaking chills or high fever (40°C [104°F]) should alert the clinician to possible bacteremia. Focal suppurative infection following bacteremia is also infrequent but may occur at any site. Thus, Salmonella has been associated with bronchopneumonia, soft tissue infection, aortic mycotic aneurysms, endocarditis, septic arthritis, splenic or hepatic abscesses, meningitis, and osteomyelitis. The clinician should suspect an endovascular mycotic aneurysm in all blood culture–positive patients older than 50 years of age. Salmonella should always be suspected in individuals with sickle cell disease in whom bone and joint infection is the most frequent cause of extraintestinal infection.
Meningitis occurs primarily in infants younger than 5 months of age. The diagnosis of a Salmonella bacteremia in HIV patients will almost always be accompanied by recurrent episodes.
Bacteremia and localized suppurative infection require antibiotic therapy. The choice of effective treatment is less predictable with the emergence of resistance. Therapy must be altered according to the results of susceptibility testing. Therefore the recovery of the organism is extremely important, and adequate cultures of blood or infected material must be obtained before initiation of therapy.
Parenteral ampicillin, 100 to 200 mg/kg/day divided into four doses, or TMP/SMZ,1 8 to 10 mg/kg of trimethoprim per day in three divided doses, may be used. In the case of resistance or allergy to the foregoing, third-generation cephalosporins such as cefotaxime (Claforan) or ceftriaxone (Rocephin) have reasonable activity, but intracellular concentrations are not optimal. Cefotaxime, 1 to 2 grams every 6 to 8 hours for adults, or 100 to 200 mg/kg/day in three or four divided doses for children, has been found effective in bacteremia, osteomyelitis, septic arthritis, and a variety of other focal Salmonella infections. The use of chloramphenicol (Chloromycetin) is not recommended, but a preparation of it in oil (Typhomycine)2 is in use in developing countries. Ciprofloxacin (Cipro)1 7.5 mg/kg intravenously twice daily is becoming a favored agent; not only is it effective, but oral bioequivalence facilitates the change to 500 to 750 mg by mouth twice daily. If fluoroquinolone resistance is encountered, imipenem (Primaxin)1 may be tried. Efficacy data for it or other agents such as azithromycin (Zithromax)1 are scant.
Focal infection often requires surgery. Often this is as simple as the drainage of localized suppuration or lavage of a septic joint. However, in the case of infected aortic aneurysms, extensive resection and vascular reconstruction are required. Infected prosthetic grafts must be removed in nearly all cases, with courses of antibiotics before and after surgery.
The duration of therapy for simple bacteremia is 10 to 14 days.
Septic arthritis is usually treated for 4 weeks whereas osteomyelitis and endovascular infections require 6 weeks. Oral fluoroquinolones such as ciprofloxacin (Cipro), 500 mg twice daily, may be helpful in treating osteomyelitis. TMP-SMZ (Bactrim)1 can also be used in this manner. Both have adequate blood levels after oral administration. I have had to use continuous prophylaxis of either TMP-SMZ or ciprofloxacin in several HIV patients to prevent recurrent bacteremia. Because prophylactic TMP-SMZ is used chronically for Pneumocystis, it may be preferred.
The clinical picture of nontyphoid Salmonella enteric fever is indistinguishable from that of typhoid fever, which is discussed elsewhere in this publication. However, the following discussion also applies to enteric fever caused by nontyphoid Salmonellae.
The adjunct and antibiotic therapy of nontyphoid enteric fever parallels that of the treatment of typhoid. Antibiotics should be adjusted and altered once the results of susceptibility testing are available. Acceptable regimens include ampicillin, amoxicillin,1 and TMP-SMZ (Bactrim),1 along with third-generation cephalosporins and fluoroquinolone antibiotics. My preference was cefotaxime (Claforan)1 in the same doses as for bacteremic salmonellosis. The duration is 10 to 14 days. Relapse rates are low, and relapse is seen within 2 to 6 weeks. Relapse requires an equivalent course of therapy in both dose and duration. Currently, I prefer ciprofloxacin (Cipro)1 intravenously 7.5 mg/kg every 12 hours continued until the patient is afebrile and clinically able to start taking it orally. Comparative studies are ongoing, using both third-generation cephalosporins, such as ceftriaxone (Rocephin)1 or cefixime (Suprax),1 and oral fluoroquinolones in short-course therapy of typhoid as well as nontyphoid enteric fever. Although these show some promise, they are currently not the standard of practice in the United Nevertheless, a strong case can be made for oral fluoroquinolones use, with obvious cost saving. Otherwise healthy young adults may be treated orally as outpatients. This advantage, if for no other reason, should prevent the physician from prescribing quinolones for uncomplicated gastroenteritis or other self-limited diarrheas of bacterial origin.
Adjunctive measures are of importance, including attention to fluid and electrolyte balance and nutrition. As in typhoid, the routine use of corticosteroids is controversial. Use in patients who are steroid dependent or believed to be hypoadrenal is indicated. In those who are delirious, obtunded, comatose, or in shock it may be warranted, but there are little supportive data. It has been my overall impression that nontyphoid enteric fever is somewhat milder than typhoid itself, and complications such as gastrointestinal bleeding or ileal perforation are exceedingly rare.
Asymptomatic excretion of organisms invariably occurs following clinical Salmonella gastroenteritis. It exceeds 8 weeks in 5% to 10% of patients. Chronic carriage, either in the stool or urine, is defined as excretion of the organism for more than 1 year. Its incidence is stated to be 1% in adults and 5% in children younger than 5 years of age.
This is somewhat less than that seen with S. typhi. Convalescent excreters need only maintain strict personal hygiene to prevent transmission of the organism. Those involved in food preparation or in child care and health care should be kept off work until three successive cultures are negative at intervals required by the public health department. It goes without saying that all positive cases of salmonellosis are reportable by law to local public health authorities.
Recently, oral quinolones have been used (ciprofloxacin [Cipro],1 500 to 750 mg twice daily for 5 to 14 days) to curtail institutional outbreaks, as in nursing homes or psychiatric facilities. Although this may be expeditious, eliminating or preventing the source of the outbreak in a prospective fashion is preferable. In the case of food handlers and health care or child care workers, some feel that quinolone therapy eliminates the problem of convalescent excretion, hence individuals may return to work without delay. The data are debatable and the successive negative stool requirement will not be obviated.
The management of the chronic carriage of nontyphoidal salmonellosis is the same as that of S. typhi, which is discussed in detail elsewhere. A 4- to 6-week course of oral antibiotics may be tried when no evidence of gallbladder disease exists. However, if chronic cholecystitis and/or cholelithiasis are present, cholecystectomy is almost always necessary. Despite cholecystectomy, a certain number of individuals will continue to excrete organisms thought to be of hepatobiliary origin. Chronic carriage is seen, albeit rarely, in the United States with either Schistosoma mansoni or Schistosoma haematobium. When these parasites are treated, subsequent therapy of the Salmonella results in termination of the stool or urinary carrier state.
Prevention of salmonellosis has both personal and public health dimensions. Food and leftovers should be rapidly refrigerated. I recommend separate plastic (not wood) cutting boards for meats and vegetables and washing them after each use. Spillage of raw animal juices should be immediately cleaned. All preparation surfaces should be washed and dried after each meal. Detergent rather than antibacterial cleaners should be used; bleach is beautiful.
Public health surveillance is essential via regular inspection of restaurants, food retailers, and industrial food processors. National efforts to coordinate and computerize surveillance systems such as FoodNet should be expanded and fully funded so as to guarantee our food supply. Preservation technologies, including irradiation, need study.
Finally, the practicing physician should take the time to reiterate to patients with HIV or malignancies or other immune-compromised patients (see Table 2) how they can avoid food-borne pathogens.
1. Brenner F.W., Villar R.G., Angulo F.J., et al. Salmonella nomenclature. J Clin Microbiol. 2000;38:2465.
2. Fierer J., Swancutt M. Non-typhoid Salmonella: A review. In: Remington J.S., Swartz M.N., eds. Current Clinical Topics in Infectious Diseases 20. Boston: Blackwell Science; 2000:134–157.
3. Herikstad H., Hayes P., Mokhtar M., et al. Emerging quinolone- resistant Salmonella in the United States. Emerg Infect Dis. 1997;3:371–372.
4. Molbak K. Human health consequences of antimicrobial drug resistant Salmonella and other foodborne pathogens. Clin Infect Dis. 2005;41:1613–1620.
5. Sirinivan S., Garner P. Antibiotics for treating Salmonella gut infections. Cochrane Database Sys Rev. 2000;93: CD001167.
6. Su L.H., Chiu C.H., Chu C.S., et al. Antimicrobial resistance in nontyphoid Salmonella: A global challenge. Clin Infect Dis. 2004;39:546–551.
7. Voetsch A.C., Van Gilder T.J., Angulo F.J., et al. FoodNet estimate of the burden of illness caused by nontyphoidal Salmonella infections in the United States. Clin Infect Dis. 2004;38(Suppl. 3):S127–S134.
1 Not FDA approved for this indication.
2 Not available in the United States.