Enteric Fever Treatment Failures: A Global Concern.

To the Editor: We read with great interest the report by Threlfall et al. (1) of decreased susceptibility to ciprofloxacin in Salmonella enterica serotype Typhi from the United Kingdom. The authors indicate that nalidixic acid-resistant S. Typhi with decreased susceptibility to ciprofloxacin is now endemic in India and neighboring countries, constituting a threat to global health. The data are consistent with previous studies from India (2-4). Despite the wide applications and broad-spectrum efficacy of fluoroquinolones, resistance is increasingly observed in many species of gram-negative organisms, including Salmonella. Detection in any part of the world of even a few resistant strains with higher MICs to ciprofloxacin is of concern to clinicians and microbiologists. We report our recent observations in cases of treatment failure of enteric fever caused by S. enterica serotypes Typhi and Paratyphi A.

Fluoroquinolones have been in use for [is greater than] 15 years and have remained an extremely important weapon against infections. Ciprofloxacin is used widely in India to treat many human infections, even without prescription, although recommendations limit its use to enteric cases caused by multidrug-resistant (MDR) strains. However, concern is increasing that widespread use of these and newer drugs will result in development of resistance against them. Recently, reports have increased worldwide concerning reduced activity of ciprofloxacin and allied drugs against many infectious agents, including Salmonella (2-4).

In an ongoing study of drug susceptibility following E-test, [is greater than] 12% of recent isolates of S. typhi in our institution have shown increased MICs to ciprofloxacin (range 1.0 to 2.0 [micro]g/mL), with 3% as high as 2.5 [micro]g/mL (3-4). Of [is greater than] 100 strains screened recently, 4 of 18 MDR strains had increased resistance to ciprofloxacin. Of the rest, 9 of 82 had higher MICs to ciprofloxacin alone but were not MDR, and 2 were cases of double infection with S. Typhi and S. Paratyphi A, common serotypes causing enteric fever in our region. Because resistance to the quinolone group of drugs (caused by gene mutations) develops independent of that in other drugs, which are plasmid encoded, it also may develop in otherwise sensitive strains.

However, our recent observations differ from those of Dr. Threlfall, as well as from past data from India. We have observed that treatment failures did not always correlate with higher MICs to nalidixic acid and ciprofloxacin alone. We have also noted a declining rate of MDR in S. Typhi, reflecting increased sensitivity to chloramphenicol, amoxicillin, and trimethoprim. However, S. Paratyphi A showed relatively increased resistance to these drugs. The increasing resistance to ciprofloxacin, to which enteric fever treatment failures are often attributed, is now mainly caused by strains susceptible to other common drugs.

Drs. Threlfall and Ward stated that [is greater than] 50% of strains with decreased susceptibility to ciprofloxacin were MDR (1). In contrast, our findings suggest that, despite prolonged doses of ciprofloxacin, treatment failures are still common with isolates sensitive to ciprofloxacin and nalidixic acid. Drs. Threlfall and Ward also emphasized that MDR cases with reduced sensitivity to ciprofloxacin are mainly transmitted by travelers returning from India and Pakistan. This conclusion would be justified as long as phage type E1, comprising MDR strains with higher MICs to ciprofloxacin, is endemic in India. However, problems of reduced action by ciprofloxacin are now thought to be independent of MDR, to result from many other factors, and thus to be of global origin and incidence. Overall, we observe a much higher rate than in the past of reduced susceptibility in S. Typhi and S. Paratyphi A in our region, causing delayed response in enteric patients. The increasing enteric fever treatment failures noted by our clinicians indicate the need for careful screening of recent isolates.

Fluoroquinolone resistance usually results from mutations in genes for drug targets (gyrA and parC) or potential of the drug being marked as a substrate as a result of overexpression of drug-efflux pumps (5). Drug resistance attributable to efflux has been reported in a number of gram-negative species, including Salmonella and Pseudomonas. Strains expressing efflux mechanisms leading to fluoroquinolone resistance are cross-resistant to a number of structurally unrelated antimicrobial agents, permitting multidrug resistance to develop (6). Therefore, inhibition of efflux systems as targets of therapeutic intervention would help prevent emergence of resistance to fluoroquinolones and associated drugs and would further potentiate drug activity. Bacteria exposed to concentrations near their MIC values readily undergo selection for resistance to ciprofloxacin (7). Hence, dosing regimens accounting for both treatment efficacy and susceptibility of clinical pathogens should help control drug resistance that causes frequent treatment failures (8).

Emerging resistance to antimicrobial agents by interacting pathogens is not solely responsible for treatment failures, since many other factors may be involved, e.g., inappropriate antibiotic regimen and dose selection, poor patient compliance, and drug-drug and drug-host interactions. One clinically important drug interaction involving fluoroquinolones is not only by coadministration with other drugs but also results from chelation to divalent and trivalent cations, such as in antacids, iron compounds, or dairy products; such chelation prevents most of the drugs from being absorbed (9).

Efforts should be aimed at shortening treatment duration by adopting efficacious drugs, since rapid, complete eradication of an infecting organism may limit the development of drug resistance. In addition, the rapid and sensitive detection by molecular methods of invasive disease due to Salmonella may help avoid overtreatment for fever of unknown origin (10). Finally, development of newer drugs offering similar activity against both enzyme targets (DNA gyrase and topoisomerase-IV), as well as an improved therapeutic index, will definitely strengthen clinical practice.

The challenge ahead is to further our understanding of newer antimicrobial resistance mechanism possibilities stemming from the recent development of structurally modified fluoroquinolones. Additional studies should assess the relevance of pharmacodynamic modeling in determining dosing or predicting efficacy and clinical management for various indications in different patient populations.

Dinesh S. Chandel and Rama Chaudhry
All India Institute of Medical Sciences, New Delhi, India

References

(1.) Threlfall EJ, Ward LR. Decreased susceptibility to ciprofloxacin in Salmonella enterica serotype Typhi, United Kingdom. Emerg Infect Dis 2001;7:448-50.

(2.) Chandel DS, Chaudhry R, Dhawan B, Pandey A, Dey AB. Drug resistant Salmonella enterica serotype Paratyphi A in India. Emerg Infect Dis 2000;6:420-1.

(3.) Rodrigues C, Mehta A, Joshi VR. Nalidixic acid resistant Salmonella typhi in Mumbai. Nat Med J India 1999;12:188.

(4.) Chaudhry R, Chandel DS, Mehta G, Kapoor H, Pang T. Molecular characterisation of drug sensitive and drug resistant strains of Salmonella typhi. Med J Indonesia 1998; 7(S1):188.

(5.) Hooper DC. Emerging mechanisms of fluoroquinolone resistance. Emerg Infect Dis 2000;7:337-41.

(6.) Poole K. Efflux-mediated resistance to fluoroquinolones in gram-negative bacteria. Antimicrob Agents Chemother 2000; 44:2233-41.

(7.) Cullmann W, Steiglitz M, Baars B, Opferkuch W. Comparative evaluation of newly developed quinolone compounds, with a note on the frequency of resistant mutatants. Chemotherapy 1985;31:19-28.

(8.) Schentag JJ. Clinical pharmacology of the fluoroquinolones: studies in human dynamics/kinetic models. Clin Infect Dis 2000;31:S40-S44.

(9.) Borcherding SM, Stevens R, Nicholas RA, Corley CR, Self T. Quinolones: a practical review of clinical uses, dosing considerations and drug interactions. J Fam Pract 1996;42:69-78.

(10.) Chaudhry R, Laxmi BV, Nisar N, Ray K, Chandel DS. Standardisation of polymerase chain reaction for the detection of Salmonella typhi in typhoid fever. J Clin Pathol 1997;50:437-9.