Final Diagnosis: Salmonella typhi septicemia (Typhoid Fever)
Typhoid fever affects approximately 21.5 million people yearly in the developing world. It is uncommon in the United States with approximately 400 cases occurring yearly and 75% of these cases being associated with foreign travel. Patients generally present with severe, debilitating fever and headache. Frequently, diarrhea is not a symptom of Salmonella typhi infection. Humans are the only reservoir and can be asymptomatic carriers, often in the biliary tract. In contrast, non-typhoidal Salmonella infections are much more common in the United States. Gastroenteritis is the most common manifestation, and patients present with diarrhea, abdominal cramps, and fever. Bacteremia and systemic infections can occur but are uncommon in the absence of immunocompromise.
Salmonella organisms are gram-negative, flagellate, non-sporulating, facultative anaerobic bacilli that ferment glucose and reduce nitrate to nitrite. They are ingested in food and survive passage through the gastric acid barrier. They subsequently invade the mucosa of the small and large intestines and produce toxins. Non-typhoidal strains induce an inflammatory response with cytokine production and diarrhea. Salmonella typhi possesses virulence factors allowing it to be more rapidly invasive through the mucosa. It multiplies within mononuclear phagocytic cells of the liver, spleen, lymph nodes, and Peyer's patches and quickly goes on to cause systemic infection.
Salmonella are members of the Enterobacteriaceae family, and two species are identified: Salmonella enterica and Salmonella bongori. Salmonella enterica is subdivided into six subspecies: I, II, IIIa, IIIb, IV, and VI. Salmonella bongori was previously known as subspecies V. Subspecies I strains are usually isolated from human hosts whereas the others are found in cold-blooded animals and in the environment. There are approximately 2,500 serotypes, most of which belong to Salmonella enterica subspecies I. The two most commonly isolated serotypes in the United States are Typhimurium and Enteritidis. Subspecies are serotyped according to their O (somatic), Vi (capsular), and H (flagellar) antigens.
Serotype typhi will have a positive slide agglutination test with polyvalent O antigen antiserum or group D antiserum (which contains antibodies to O antigens 9 and 12). Slide agglutination testing should also be positive with Vi antigen antiserum. Vi antigen expression is variable but tends to be more frequent in freshly isolated cultures than in cultures that have been subcultured. The Vi capsular polysaccharide can mask the O antigen thus inhibiting its reaction with its respective antiserum. If slide agglutination studies are positive for the Vi antigen but negative for the O antigen, the suspension should be heated in boiling water for fifteen minutes and retested. This maneuver will inactivate the heat labile Vi antigen and allow expression of the heat stable O antigen. typhi strains typically express only one flagellar antigen, the Hd antigen.
Serotype typhi most often has a characteristic reactivity on triple sugar iron media. The H2S reactivity occurs as a ring just at the slant as shown in Figure 3. If an organism displays this characteristic pattern on triple sugar iron, is urease negative, and reacts in O antigen group D antiserum or Vi antigen antiserum, then a presumptive diagnosis of Salmonella enterica serotype typhi can be made. Confirmation can be made with H antigen and further biochemical testing.
This patient showed clinical improvement with resolution of laboratory abnormalities after 4-5 days of IV ciprofloxacin. He was discharged on oral ciprofloxacin to complete a two-week course. He resumed his full level of activity with only mild fatigue after excessive exertion. One month after his initial presentation, blood cultures were drawn to confirm clearance of the bacteria despite his lack of symptoms. The cultures were positive for Salmonella enterica serotype typhi in two out of two bottles. Sensitivity testing to nalidixic acid was performed and is shown below.
Figure 4 shows the patient's sample exhibiting resistance to nalidixic acid as compared to a laboratory strain of group D non-typhoidal Salmonella (Figure 5), which is sensitive. Nalidixic acid has been shown to be the prototypic agent in testing for Salmonella resistance to fluoroquinolones. Resistance to nalidixic acid on in vitro tests can indicate emerging resistance to fluoroquinolones and is felt to most closely represent in vivo antibiotic efficacy. In this case, the patient appeared to be sensitive to ciprofloxacin via Kirby Bauer testing but tested as resistant to nalidixic acid suggesting an in vivo resistance to fluoroquinolones. These results were supported clinically as he did not clear his bacteremia after a two-week course of ciprofloxacin. He was subsequently given a two-week course of ceftriaxone, which did clear his bacteremia. He remains asymptomatic, and follow-up stool cultures show no evidence of a carrier state.
Contributed by James T Edinger, MD and A William Pasculle, ScD