New Sources and Spread of Multidrug Resistant Salmonella typhi

Abstract & Commentary

Synopsis: A careful assessment of bacterial isolates obtained from patients with acute typhoid fever in the United States has shown clear shifts in the sources of this infection, as well as evolving and worrisome antimicrobial resistance patterns of Salmonella typhi.

Source: Akers M-L, et al. Laboratory-based surveillance of Salmonella serotype typhi infections in the United States. JAMA 2000;283:2668-2673.

Comprehensive information on both the incidence and sources of antimicrobial resistant S. typhi isolates in the United States are presented in this article. Akers and associates review the recent surveillance data for typhoid fever (TF) cases and bacterial isolates reported to the Foodborne and Diarrheal diseases Branch of the U.S. Centers for Disease Control. Each year, approximately 16 million new cases of TF occur worldwide and about 300 laboratory-confirmed cases are reported in the United States. While the number of reported U.S. TF cases has remained fairly stable during the last 20 years, the proportion of TF cases ascribed to travel outside the United States has increased from 62% in 1975-1984 to 81% in the current study, which covers 1996-1997. During this same timeframe, the proportion of TF cases attributed to exposures in Mexico decreased from 46% in 1985 to 6%. In contrast, cases associated with exposures on the Indian subcontinent (India, Pakistan, and Bangladesh) increased from 25% in 1985 to 57% currently.

In a follow-up, this trend was confirmed in a presentation at the 38th meeting of the Infectious Diseases Society of America in New Orleans in September.1 The data from the National Antimicrobial Resistance Monitoring System (NARMS) for enteric bacteria were obtained in a 1999 surveillance study in which up to 63% of travel-associated Salmonella typhi isolates were documented as acquired in India. From June 1996 to May 1997, 350 S. typhi isolates were tested for their antimicrobial sensitivity patterns. Seven percent were resistant to nalidixic acid, the parent drug for the fluoroquinolone class of antibiotics. This resistance pattern represents the potential harbinger of decreased ciprofloxacin sensitivity, which will have major clinical significance.

From 1999 to the present, ongoing surveillance detected 166 patients with TF. Two-thirds of cases were associated with travel. The mean age was 22, and 51% were female. Twenty-five percent were children. Approximately two-thirds were blood isolates and one-third were obtained from stool, with 3% of isolates from urine. Fully 19% of S. typhi isolates were resistant to nalidixic acid in the most recent study, although none were found to be resistant to ciprofloxacin or ceftriaxone. While there have been no reported U.S. cases of ciprofloxacin-resistant S. typhi, nalidixic acid resistance has clearly been increasing—that is not good news.

To make matters worse, a research letter published in the Lancet has already described increasing numbers of treatment failures using ciprofloxacin for the treatment of TF in the United Kingdom, even when strains appeared to be sensitive.2 In 1998, strains with decreased sensitivity to ciprofloxacin accounted for 32 of 151 S. typhi isolates (21%). All strains with decreased sensitivity to ciprofloxacin were still fully sensitive to cephalosporin antibiotics, such as ceftriaxone or cefotaxime. The majority had been obtained from patients with a history of a recent return trip from India or Pakistan. Apparently, nalidixic acid-resistant strains of S. typhi with decreased susceptibility to ciprofloxacin are now endemic in both India and Pakistan.

Comment by Maria D. Mileno, MD

Multidrug resistance of S. typhi (MDRST) to traditional antimicrobial agents (i.e., ampicillin chloramphenicol, trimethoprim-sulfamethoxazole) has been increasing at an alarming pace. From 1985 to 1989, just 0.6% of U.S. strains represented MDRST. From 1996 to 1997, nearly one in every five S. typhi isolates (17%) were MDRST, and 7% (including 12 strains of MDRST) were also resistant to nalidixic acid, the parent drug for the fluoroquinolones, including ciprofloxacin. By 1999, resistance to nalidixic acid had reached 19% among U.S. isolates of S. typhi. Reports of TF treatment failures with ciprofloxacin from the United Kingdom suggest we may see this occurring soon in the United States. Where to look?

The answers are becoming clearer as the majority of reported TF cases in the United States are travel-associated and the majority (61%) of those are now clearly related to travel on the Indian subcontinent. Travel medicine consultants might consider offering typhoid vaccine, even to individuals embarking upon short stays in that region, given the high proportion of all cases originating from there.

Children are at high risk for TF and those younger than 18 years accounted for 44% of all cases, including 42% of travel-associated cases in the earlier surveillance study. The median age of children in that group was 8 years. Neither MDRST nor nalidixic acid-resistant strains were more common in children than in adults; however, fluoroquinolones are not approved for use in children, which leaves us with limited therapeutic options for them.

During the pre-antibiotic era, TF case-fatality ratios approached 20%. Treatment with effective antimicrobial agents has reduced rates to less than 1%. Should antimicrobial therapeutic options fail, the more serious manifestations of TF may emerge. TF can include hepatitis, characterized by jaundice and elevated transaminase levels, which occur in approximately 10% of affected adults and children. On rare occasions, encephalopathy results. Patients with TF who have both jaundice and encephalopathy may present with a picture that mimics fulminant hepatic failure resulting from other conditions, notably hepatotropic viruses and drugs. This form of hepatitis is described in the reference originating from the Department of Gastroenterology at St. John’s Medical College and Hospital, Bangalore, India.3  


1. Steinberg EB, et al. Antimicrobial resistance of Salmonella typhi in the United States—the National Antimicrobial Monitoring System, 1999. Abstracts of the IDSA Annual Meeting 2000, New Orleans, September 2000, page 40, abstract #3.

2. Threlfall J, et al. Ciprofloxacin-resistant Salmonella typhi and treatment failure. Lancet 1999;353:1590-1591.

3. Kamath PS, et al. Differentiation of typhoid fever from fulminant hepatic failure in patients presenting with jaundice and encephalopathy. Mayo Clin Proc 2000;75: 462-466.