A HIGHLY CEFTRIAXONE-RESISTANT SALMONELLA TYPHI IN BANGLADESH

Abstract

Enteric fever continues to be a public health problem in the Indian subcontinent including Bangladesh. In the early 1990s there were many reports about the increasing frequency of multiresistant strains of Salmonella typhi.1, 2 All these reports prompted the suggestion that ciprofloxacin1 or ceftriaxone3 should be the empiric treatment of choice for enteric fever. This suggestion and the availability of ciprofloxacin and ceftriaxone have drastically reduced the use of first line drugs [amoxicillin, trimethoprim-sulfamethoxazole (TMP-SMX) and chloramphenicol] and led to a significant decrease of multiresistant S. typhi strains in Bangladesh.4 However, because of the contraindication of fluoroquinolone use in children and reports about epidemics with ciprofloxacin-resistant strains,1, 5 ceftriaxone become the drug of choice for treatment of these patients, if parents could afford it. Until now there has been no report of resistance of S. typhi to ceftriaxone or other cephalosporins. We report here a strain of S. typhi highly resistant to ceftriaxone and other cephalosporins. Case report. A 11-month-old boy with high grade fever for 2 days was clinically diagnosed as enteric fever and empirically treated with ceftriaxone (100 mg/kg/day) for 7 days. The patient became afebrile on the fifth day of treatment. From the eighth day amoxicillin (75 mg/kg/day) was given for 15 days to prevent the carrier state. Fever recurred on the fourth day of amoxicillin therapy and the physician (SYT) obtained a blood specimen for culture and the Widal test. On the basis of the culture report the patient was successfully treated with ciprofloxacin (20 mg/kg/day) and two consecutive stool cultures for Salmonella at the end of treatment were negative. Microbiology. The Widal test of the patient was strongly positive6 and the antibody titer against both somatic and flagellar antigen of S. typhi (TO and TH) was 1/320. Blood culture by the lysis-centrifugation method7 yielded growth of numerous S. typhi per ml of blood. The strain was identified by biochemical tests and the analytical profile index (API 20 E, BioMérieux, Marcy l'Etoile, France) score was 4404540. Identification was confirmed by agglutination test with specific antisera (Murex, UK) (Specific information regarding the identification and suceptibility testing of the strain is available from Dr. Saha.). By the disc diffusion method the strain was resistant to amoxicillin, ceftriaxone and cefmenoxime. It was susceptible to TMP-SMX, chloramphenicol, ciprofloxacin (tested by nalidixic acid 30-μg disc as well5) and ceftazidime. The strain was beta-lactamase-positive when tested by nitrocefin disc (BBL, Cockeysville, MD) but resistant to amoxicillin/clavulanic acid. The MIC of the strain to several antibiotics (except ceftazidime) was determined by E test (AB Biodisk, Sweden). By repeated testing the strain showed high level resistance to ceftriaxone (MIC >256.0 μg/ml). It was also highly resistant to amoxicillin and cephalothin with the MIC value being >256.0 μg/ml for both antibiotics. This beta-lactamase-producing strain was also resistant to the combination of amoxicillin and clavulanic acid (MIC 64.0 μg/ml to amoxicillin combination). However, it was susceptible to other antibiotics such as TMP-SMX (MIC 0.047 μg/ml), chloramphenicol (MIC 3.00 μg/ml) and ciprofloxacin (MIC 0.032 μg/ml). The isolate was intermediately resistant to ceftazidime with a MIC of 16.00 μg/ml, as determined by microbroth dilution. Discussion. Typhoid is endemic in Bangladesh, where there is a high incidence in children. Reports about multidrug-resistant S. typhi strains have led to remarkably limited use of ampicillin, chloramphenicol and cotrimoxazole as the empiric drug of choice and increased the use of ceftriaxone for pediatric patients with enteric fever. In Bangladesh less use of first line antibiotics for empiric therapy of typhoid fever is reflected by a significantly decreasing trend of multiresistant S. typhi.4 It is not clear whether the high level (>256.0 μg/ml) resistance of this S. typhi strain to ceftriaxone developed during the course of treatment, as the blood culture was not done on the first occasion of fever. However, remission of fever on the fifth day of ceftriaxone therapy possibly indicates that the strain was initially either fully or partially susceptible, with an increased MIC, and it become highly resistant during the course of treatment with ceftriaxone. In our previous experiences we have isolated many pairs of S. typhi from recurrent cases8 treated with ceftriaxone, but all of them were susceptible to the drug on both the occasions. To our knowledge this is the first report of ceftriaxone-resistant S. typhi from any part of the world. Emergence of this resistance may be an indication that, like ciprofloxacin, antibiotic pressure can facilitate the emergence ceftriaxone-resistant S. typhi strains. Because of the lack of facilities we could not do the molecular characterization of this isolate and look forward to collaborating with other laboratories in that endeavor. Samir K. Saha, M.Sc., Ph.D. Sailah Y. Talukder, M.B.B.S., M.C.P.S. Maksuda Islam, B.A. Setarunnahar Saha, M.Sc., Ph.D. Department of Microbiology; Bangladesh Institute of Child Health; Dhaka Shishu (Children) Hospital (SKS, MI) Popular Diagnostic Centre (SKS, MI, SS) House #1D, Road #35, Gulshan (SYT) DPT Vaccine Production Laboratory; Institute of Public Health (SS) Dhaka, Bangladesh