Laboratory-Based Surveillance of Salmonella Serotype Typhi Infections in the United States:  Antimicrobial Resistance on the Rise FREE

Since the mid-1960s, the incidence of infections due to Salmonella serotype Typhi in the United States has been stable at about 0.2 cases per 100,000 persons per year. While the incidence has stabilized, the estimated proportion of cases diagnosed in the United States and acquired abroad increased from 33% in 1967-1972¹ to 62% in 1975-1984² and to 72% in 1985-1994.³

In the preantibiotic era, the typhoid fever case-fatality rate approached 20%. Treatment with effective antimicrobial agents—ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and, more recently, ciprofloxacin—has reduced the case-fatality rate to less than 1%.³

While the risk of acquiring typhoid fever remains low in the United States and other developed countries, the disease is common in countries where sanitation is poor. In some areas, the high rate of Salmonella Typhi transmission, together with widespread indiscriminate use of antimicrobial agents, has led to marked increases in infections with strains resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (multidrug-resistant Salmonella Typhi [MDRST]). Increased isolation rates of MDRST throughout India have been well documented since 1990,^4- 9 and reports from Vietnam, South Africa, China, and Pakistan describe similarly resistant isolates.^10- 13 However, despite documentation in the medical literature, clinicians in the United States may be unaware of the increase in drug resistance in Salmonella Typhi and the implications for treatment.

Since there is no coordinated global surveillance for antimicrobial resistance among Salmonella Typhi isolates, the actual geographic distribution of resistance is unknown. Although limited demographic information on many of the typhoid fever cases diagnosed in the United States is reported in Morbidity and Mortality Weekly Report, data on antimicrobial resistance are lacking. Thus, physicians who treat patients with typhoid fever have little information on which to base choices of empirical antimicrobial therapy. Some have suggested that patients with a history of travel to the Indian subcontinent should receive ciprofloxacin as first-line therapy.^14- 15 However, Salmonella Typhi strains that are resistant to ciprofloxacin and ceftriaxone have recently been reported,^6,8,16- 21 and ciprofloxacin is not approved for use in children, further complicating the choice of antimicrobial therapy for suspected infections.

To determine antimicrobial resistance patterns of Salmonella Typhi isolates from patients with acute typhoid fever in the United States and to define risk factors for infection with antimicrobial-resistant strains, the Foodborne and Diarrheal Diseases Branch of the Centers for Disease Control and Prevention (CDC) initiated laboratory-based surveillance for the 1-year period from June 1, 1996, through May 31, 1997.

During the study period, a standard questionnaire was administered by telephone or in person by state and local health department staff to patients with newly diagnosed Salmonella Typhi infection. A case was defined as an illness compatible with typhoid fever and isolation of Salmonella Typhi from a sterile site, stool specimen, or urine culture. If the patient was younger than 18 years, deceased, or unable to respond, the interview was conducted with a parent, guardian, or other adult family member. This questionnaire collected demographic and epidemiological information, including sex, age, US citizenship/residency, country of birth, and travel history, as well as clinical information, such as date of illness onset, symptoms, hospitalization, prior antimicrobial drug use, typhoid vaccination status, and type of antimicrobial therapy received. Persons with asymptomatic infections and those who were known carriers were excluded. Completed questionnaires were reviewed, coded, and entered into a database at the CDC. Informed consent was obtained from all study participants.

A travel-associated case was defined as typhoid fever in a person who had traveled outside the United States in the 6 weeks before illness onset. Travel-associated cases also included visitors from outside the United States whose illnesses were diagnosed in the United States. Cases were defined as domestically acquired if there was no history of travel outside the United States in the 6 weeks before illness onset. Cases that could not be classified into 1 of these 2 categories were considered to be of unknown origin. United States residents were defined as patients who reported both departure and arrival dates or who had no history of international travel; foreign visitors or immigrants to the United States were patients who reported only US arrival dates.

State public health laboratories forwarded Salmonella Typhi isolates obtained from clinical laboratories to the Foodborne and Diarrheal Diseases Laboratory Section at the CDC. Antimicrobial susceptibility testing on all confirmed Salmonella Typhi isolates was performed at the CDC. All Salmonella Typhi isolates were tested by the disk-diffusion method for resistance to the following 12 antimicrobial agents: chloramphenicol, trimethoprim-sulfamethoxazole, tetracycline, ciprofloxacin, nalidixic acid, ampicillin, sulfisoxazole, streptomycin, kanamycin, gentamicin, ceftriaxone, and cephalothin.²² Isolates resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole were defined as MDRST and isolates resistant to nalidixic acid were defined as nalidixic acid–resistant Salmonella Typhi (NARST). Isolates sensitive to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and nalidixic acid were defined as susceptible. Isolates resistant to nalidixic acid by disk diffusion were tested for minimum inhibitory concentration (MIC) of nalidixic acid and ciprofloxacin.²³

Rates of typhoid fever among travelers to specific regions and individual countries were calculated using available 1996 air passenger data from the Tourism Industries, International Trade Administration, US Department of Commerce.²⁴

Logistic regression and the Fisher exact test were used to examine relationships between independent variables and typhoid fever infection. Differences in medians were compared with the Wilcoxon 2-sample test. Logistic regression modeling was conducted using SAS Version 6.12 software (SAS Institute Inc, Cary, NC). Variables that were significantly associated with illness by univariate analysis at P≤.10 were entered into a forward-stepwise multiple logistic regression model.²⁵

During the 1-year study, 364 newly diagnosed typhoid fever cases were reported by 45 state and territorial health departments and public health laboratories. We obtained isolates for 350 patients (96%) and epidemiological information for 306 (83%), including 293 corresponding pairs (ie, an isolate and information from the same patient; 80%). Pairs were received from 31 states, the District of Columbia, and New York City (Table 1). Unless otherwise specified, results presented herein pertain to the 293 pairs.

Among the 293 pairs, median age was 21 years (range, 3 months–84 years) and 56% were male. Although 123 (52%) of 238 patients reported US citizenship, only 91 (37%) were reportedly born in the United States. Among 237 patients for whom such information was reported, 17 (7%) had received malaria chemoprophylaxis; 20 (9%) of 224 had received antimicrobial therapy in the 6 weeks before illness onset.

Fever was the most frequent symptom reported by patients, followed by malaise, chills, and anorexia (Table 2). Two hundred twenty-eight patients (80%) were hospitalized for a median duration of 7 days (range, 1-35 days). Two patients died (case-fatality rate, 0.6%); 1 was an unvaccinated traveler to Egypt and the other had not traveled.

For 229 (81%) of 282 patients, typhoid fever was associated with travel; 53 infections (19%) were domestically acquired. Of the 216 patients who had traveled to a single country, 142 (65%) had traveled to 1 of 4 countries: India, Pakistan, Bangladesh, or Haiti (Table 3). Most travelers were either foreign-born US residents who visited friends or family in their country of origin (40%) or foreign visitors or immigrants to the United States (26%). Of the 130 US residents traveling to a single country with known departure and arrival dates, the median duration of their trip was 34 days (range, 1-362 days). Only 6 travelers (4%) reported receiving a typhoid fever vaccination before travel; the 4 vaccinated US residents all reported receiving the oral typhoid fever vaccine.

Overall, the typhoid fever infection rate was 0.93 cases per 100,000 air travelers arriving in the United States from typhoid-endemic regions (ie, all countries except Canada, Japan, and countries in Europe and Oceania). For Latin America, the rate was 0.33 cases per 100,000 travelers; for Africa, the rate was 1.5 cases per 100,000 travelers; and for Asia, the rate was 3.0 cases per 100,000 travelers. Rates were similar among US residents and nonresidents (0.91 per 100,000 US resident travelers compared with 0.99 per 100,000 foreign visitors or immigrants to the United States). For countries for which data were available, individual rates for US resident travelers varied greatly, ranging from 0.30 cases per 100,000 US resident travelers to Mexico to 8.0 cases per 100,000 US resident travelers to Haiti and 16.7 cases per 100,000 US resident travelers to India.

Antimicrobial susceptibility testing was performed on all 350 isolates. Two hundred sixty-five isolates (76%) were sensitive to all 12 antimicrobial agents. Eighty-five (24%) were resistant to at least 1 agent; 56 (16%) were MDRST isolates. All 56 MDRST isolates were resistant to at least 2 additional agents, most commonly streptomycin (100%), tetracycline (98%), or sulfisoxazole (98%). Twelve MDRST isolates (21%) and 11 non-MDRST isolates (4%) were NARST isolates. No resistance to ciprofloxacin, gentamicin, kanamycin, or ceftriaxone was observed.

Resistance patterns of the 293 pairs reflected the overall resistance characteristics. Two hundred nineteen isolates (75%) were sensitive to all antimicrobial agents tested. Seventy-four (25%) were resistant to at least 1 agent; 51 (17%) were MDRST isolates. Twelve (24%) of the 51 MDRST isolates and 8 (5%) of the 242 non-MDRST isolates were NARST isolates. All 20 NARST isolates had nalidixic acid MICs greater than 256 µg/mL (resistant, ≥32 µg/mL). None of these 20 isolates were resistant to ciprofloxacin. Ciprofloxacin disk-diffusion zones ranged from 21 to 27 mm and MICs ranged from 0.125 to 0.38 µg/mL (resistant, ≥4.0 µg/mL). However, NARST isolates appeared less sensitive to ciprofloxacin than did nalidixic acid sensitive isolates; the median ciprofloxacin disk-diffusion zone of NARST isolates was 23 mm compared with 30 mm from nalidixic acid–sensitive isolates (P<.001).

Among these 293 Salmonella Typhi isolates, 200 (83%) of 240 isolates obtained from a single site were from blood cultures, 36 (15%) were from stool specimens, 2 (1%) were from urine cultures, 1 (0.5%) was from bone marrow, and 1 (0.5%) was from liver. All 46 patients in whom Salmonella Typhi was isolated from more than 1 site had positive blood cultures; secondary sites of isolation included 43 (96%) from stool, 1 (2%) from both stool and urine, 1 (2%) from gallbladder, and 1 (2%) from appendix.

Multidrug-Resistant Salmonella Typhi. The median age of the 51 patients with MDRST infections was 18 years (range, 1-61 years); 51% were male. Reported symptoms and clinical course were similar to those of the 229 patients with susceptible infections; 76% vs 82% were hospitalized and none died. In the 6 weeks before illness onset, 49 (98%) of 50 patients had traveled outside the United States. Only 2 (4%) of the 50 patients with MDRST infections reported receiving typhoid immunization. Forty-six (94%) travel-associated cases of MDRST could be linked to 5 countries: India (n=26 cases), Pakistan (n=12), Vietnam (n=4), Bangladesh (n=3), and Haiti (n=1). All 3 of the remaining persons with travel-associated cases had traveled to India but had also visited 1 additional country (Holland, Turkey, or England). One of the remaining 2 patients with MDRST infection was a 3-year-old child with non–English-speaking parents and may have been a recent Asian immigrant to the United States, whereas the other patient denied recent overseas travel but had been born in Laos. The most frequent agents used for the initial treatment of MDRST were third-generation cephalosporins (43%), fluoroquinolones (38%), and ampicillin (10%).

In univariate analysis, travel outside the United States in the 6 weeks before illness onset was strongly associated with MDRST infection, especially travel to the Indian subcontinent (Bangladesh, India, or Pakistan) and Vietnam, as was malaria chemoprophylaxis (Table 4). However, in a multiple logistic regression model including travel outside the United States and malaria chemoprophylaxis, only travel to the Indian subcontinent (odds ratio [OR], 29.3; 95% confidence interval [CI], 6.8-126.7; P<.001) and travel to Vietnam (OR, 178.0; 95% CI, 12.4-2554.0; P<.001) remained independently associated with MDRST infection.

The overall rate of MDRST infections was only 0.20 per 100,000 air travelers arriving in the United States from typhoid-endemic areas compared with a rate of 0.73 non-MDRST infections per 100,000 travelers. However, this gap narrowed for certain countries. For example, in India, MDRST infection rates (5.6 cases per 100,000 travelers) were approximately half the rates of non-MDRST infections (11.3 cases per 100,000 travelers).

Nalidixic Acid–Resistant Salmonella Typhi. Twelve (60%) of the 20 NARST isolates were MDRST isolates; the remaining 8 were resistant only to nalidixic acid. The median age of NARST patients was 30 years (range, 7-61 years); 59% were hospitalized. All 20 patients reported travel outside the United States in the 6 weeks before illness onset. Among the 19 patients who reported travel to a single country, 17 traveled to India, 1 to the Philippines, and 1 to Pakistan. The remaining patient had traveled to India and Turkey. Twelve patients were US residents who traveled to India.

As with MDRST infections, travel outside the United States in the 6 weeks before illness onset, travel to the Indian subcontinent, and malaria chemoprophylaxis were strongly associated with NARST infection in univariate analysis (Table 4). In addition, older age, being foreign-born, and a lower rate of hospitalization were associated with NARST infection (Table 4). However, in a multiple logistic regression model, only travel to the Indian subcontinent (OR, 35.9; 95% CI, 3.4-377.3; P<.001), malaria chemoprophylaxis (OR, 9.6; 95% CI, 2.0-45.5; P<.001), and older age (OR, 1.05; 95% CI, 1.01-1.1; P=.008) remained independently associated with infection.

Fifty-three patients (19%) did not travel abroad in the 6 weeks before illness onset and were considered to have domestically acquired infections. Patient median age was 17 years (range, 3 months–84 years); 59% were male. Seventy-seven percent were hospitalized and 1 died. Only 1 isolate (2%) was MDRST; 48 (91%) were pansensitive, 3 (6%) were resistant to streptomycin, 1 (2%) to trimethoprim-sulfamethoxazole, and 1 (2%) to cephalothin. No resistance to nalidixic acid was detected. Although all patients denied having traveled abroad, anecdotal information from 15 patients noted contact with visitors from outside the United States or consumption of food from typhoid-endemic countries before illness onset.

Our study, the first national laboratory-based surveillance of typhoid fever to our knowledge, provides comprehensive information on the incidence of antimicrobial resistance among Salmonella Typhi isolates in the United States and on risk factors for MDRST and NARST infections. Although the number of reported US typhoid fever cases has remained fairly stable during the last 20 years, the sources of infection and patterns of antimicrobial resistance have changed substantially. The proportion of typhoid fever cases ascribed to travel outside the United States has increased from 62% for 1975-1984 to 72% for 1985-1994 and to 81% in the current study from mid-1996 through mid-1997.^2- 3 The proportion of typhoid fever cases attributed to exposure in Mexico has steadily decreased, from 46% in 1985² to 6% in the current study. In contrast, the proportion of typhoid fever cases attributed to exposure in the Indian subcontinent increased from 25% in 1985² to 57% in the current study.

Our data also confirm that resistance to antimicrobial agents and, in particular, to traditional agents (ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole) has continued to increase at an alarming pace. From 1985 to 1989, 0.6% of US strains were reportedly MDRST, and from 1990 to 1994, MDRST accounted for 12% of strains.³ In our study, 17% or nearly 1 of every 5 Salmonella Typhi isolates was MDRST. The prevalence of MDRST among travelers who acquired typhoid fever in India increased from 30% in 1990-1994³ to 35% in the current study, and 4 (80%) of 5 travelers who acquired typhoid fever in Vietnam were infected with MDRST. Only 2% of cases that were domestically acquired infections were due to MDRST. Therefore, we recommend that ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole not be used for empirical treatment of typhoid fever among persons with a history of travel outside the United States in the 6 weeks before illness onset; however, these agents may still be useful for empirical treatment of domestically acquired cases.

National surveillance data have not previously included information on fluoroquinolone resistance or resistance to the related quinolone agent, nalidixic acid. Although no ciprofloxacin-resistant strains were detected in this study, a total of 23 (7%) of 350 strains, including 12 strains of MDRST (21%), were resistant to nalidixic acid. As expected, these isolates had reduced sensitivity to ciprofloxacin. Although nalidixic acid is not a treatment for typhoid fever, this resistance may be clinically important. Recent case reports and a hospital-based study have demonstrated decreased efficacy of ciprofloxacin in treating patients with NARST infections.^6,16,20,26

Our data identify 2 groups in need of typhoid vaccination: foreign-born US residents returning to their country of origin and children. Although data were not available for all typhoid fever cases in our study, only 9 cases (4%) were known to have occurred in traditional tourists. Foreign-born US residents visiting their country of origin may be less likely to avail themselves of prevention measures geared toward traditional tourists, such as travel clinics that inform travelers of infectious disease risks and offer vaccinations. In addition, persons returning to their country of origin with spouses and children may not consider foods, beverages, and water in the areas they visit as unsafe or requiring special precautions.²⁷

Children are at high risk for typhoid fever. In our study, persons younger than 18 years accounted for 44% of all cases and 42% of travel-associated cases. The median age of children with travel-associated typhoid fever was 8 years, indicating that most were preschool- or school-aged children in the care of pediatricians and family practitioners. Only 1% of children with typhoid fever were younger than 1 year, but 25% were aged 1 through 4 years, 34% were aged 5 through 9 years, and 40% were aged 10 through 17 years. Multidrug-resistant Salmonella Typhi or NARST infections were not more common in children than in adults; however, because fluoroquinolones are not approved for use in children, therapeutic options are more limited. Previously, physicians may have opted not to immunize children with the heat-phenol–inactivated parenteral vaccine because of the high frequency of adverse effects. However, 2 more recently licensed typhoid vaccines, the oral live attenuated typhoid vaccine and the parenteral capsular polysaccharide vaccine (ViCPS), have fewer adverse effects and can be given to children safely. The oral live attenuated typhoid vaccine is licensed for use in children aged 6 years or older and ViCPS is licensed for children aged 2 years or older. Both vaccines provide protection to 50% to 80% of recipients.²⁸ Therefore, we strongly advise that clinicians consider offering typhoid vaccination to young travelers.

This study had several limitations. Although we attempted to obtain isolates from all Salmonella Typhi infections diagnosed in the United States, a small number of isolates were inadvertently discarded or could not be traced. Epidemiological data for some patients could not be obtained because of difficulty locating and interviewing foreign visitors and immigrants. However, based on reports from state health departments, we believe that we obtained isolates for 96% of newly diagnosed typhoid infections, epidemiological information for 83%, and both types of information for 80% during the study period. Therefore, although there could be some bias in effect estimation, it is unlikely to change our overall conclusions. Country-specific rates of travel-associated typhoid fever are subject to bias because the denominators for travelers are taken from embarkation cards showing the country of departure and not necessarily the country of origin or other countries visited. In addition, using air passenger data for denominators overestimates the risk for travelers to and visitors from Mexico, Central America, and the Caribbean, who are more likely than travelers from other regions to enter the United States via land or sea. However, our estimates are in general agreement with those from earlier studies.

The incidence of drug-resistant Salmonella Typhi infections in the United States reflects travel to and from the Indian subcontinent and Vietnam. Chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole are no longer useful as first-line treatment for Salmonella Typhi infections acquired in these countries, and the evidence from this study and other case reports suggests that ciprofloxacin, other fluoroquinolones, and ceftriaxone may soon be of limited value as well. However, currently, ciprofloxacin and ceftriaxone still remain appropriate choices for empirical therapy for suspected typhoid fever in travelers. The high incidence of infection among travelers to the Indian subcontinent, along with the increasing resistance in the strains they acquire there, indicate that these travelers are in particular need of pretravel vaccination. Continued monitoring of antimicrobial resistance among Salmonella Typhi strains will help inform vaccination and treatment policies.