|Year : 2014 | Volume
| Issue : 2 | Page : 161-163
Revised ciprofloxacin breakpoints for Salmonella Typhi: Its implications in India
V Balaji1, A Sharma1, P Ranjan1, A Kapil2
1 Department of Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||21-Aug-2013|
|Date of Acceptance||13-Dec-2013|
|Date of Web Publication||2-Apr-2014|
Department of Microbiology, Christian Medical College, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
The rise of multidrug resistant strains of Salmonella Typhi in the last decade of the previous century led to the use of fluoroquinolones as the drug of choice. However, over the past few years fluoroquinolone resistance has been increasingly reported. In accordance with the revised Clinical and Laboratory Standards Institute (CLSI) breakpoints, only 3% of the isolates were susceptible to ciprofloxacin in comparison to 95% as per the earlier guidelines when 488 isolates collected between 2010 and 2012 were re-interpreted. Interestingly, re-emergence of strains susceptible to chloramphenicol, ampicillin and cotrimoxazole is being seen. Amidst the changing susceptibility profile, azithromycin remains a promising alternative.
Keywords: Enteric fever, minimum inhibitory concentration, S . Typhi
|How to cite this article:|
Balaji V, Sharma A, Ranjan P, Kapil A. Revised ciprofloxacin breakpoints for Salmonella Typhi: Its implications in India. Indian J Med Microbiol 2014;32:161-3
|How to cite this URL:|
Balaji V, Sharma A, Ranjan P, Kapil A. Revised ciprofloxacin breakpoints for Salmonella Typhi: Its implications in India. Indian J Med Microbiol [serial online] 2014 [cited 2020 Mar 30];32:161-3. Available from: http://www.ijmm.org/text.asp?2014/32/2/161/129804
| ~ Introduction|| |
Enteric fever (typhoid and paratyphoid fever) is a systemic infection caused by the bacteria Salmonella enterica serovar Typhi (S. Typhi) or Salmonella enterica serovar Paratyphi (S. Paratyphi). In humans it is transmitted through the feco-oral route. Enteric fever is a major public health problem in the Indian subcontinent. There is a need for an efficacious, safe and affordable oral treatment. 
Is it time to abandon the prescription of ciprofloxacin as the drug of choice for S. Typhi infections?
The emergence of multidrug-resistant (MDR) strains (resistant to chloramphenicol, ampicillin and sulfamethoxazole-trimethoprim) became a major issue, resulting in widespread use of ciprofloxacin as first line therapy for adults infected with susceptible as well as MDR S. Typhi and S. Paratyphi A. 
Fluoroquinolone resistant strains then began to emerge and were identified by determining susceptibility to nalidixic acid. Earlier studies have shown that increase in nalidixic acid resistant S.Typhi (NARST) strains is associated with a consistent increase in the MIC levels of ciprofloxacin.  In the past decade, strains of the organism that show decreased ciprofloxacin susceptibility (DCS) have emerged in Asia. DCS is defined as ciprofloxacin MIC of 0.12 - 1 μg/mL.  Patients infected with DCS S. Typhi have not responded to fluoroquinolone therapy as effectively as previously or have failed to clear organisms in stool cultures. 
In view of the poor response to ciprofloxacin therapy for S. Typhi, Clinical and Laboratory Standards Institute (CLSI) published evidence-based revision of the ciprofloxacin MIC and the disc diffusion interpretative criteria in 2012. The revised criteria are as follows: Ciprofloxacin cut-off for susceptibility using disk diffusion was raised from 21 to 31 mm and the MIC value lowered from 1 to 0.06 μg/mL. Subsequently, in 2013, levofloxacin and ofloxacin disc diffusion zone diameter interpretative criteria for S. Typhi has been removed and MIC interpretative criteria has been revised. The cut-off for levofloxacin and ofloxacin MIC for S. Typhi has been lowered to ≤0.12 μg/mL susceptible, 0.25-1 μg/mL intermediate and ≥2 μg/mL resistant. It is noteworthy that ciprofloxacin, levofloxacin and ofloxacin disc diffusion and MIC breakpoints have been changed/deleted only for typhoidal Salmonella in the Enterobacteriaceae family.  Ciprofloxacin MIC was determined using E-test (Epsilometer test, bioMérieux, France) for 488 clinical isolates between 2010 and 2012. The E-test results were interpreted using both the current as well as the previous CLSI guidelines [Table 1]. As per the earlier (2011) guidelines, 466 isolates (95%) were susceptible. When re-evaluated as per the revised (2012) guidelines, only 14 isolates (3%) remained susceptible, while the majority (88%) fell in the intermediate or moderately susceptible zone. The MIC 50 and MIC 90 for ciprofloxacin were 0.25 and 0.5 μg/mL, respectively. As intermediate or moderately susceptible organisms fall in DCS category, they are well known to cause clinical failure in the treatment of typhoid fever.
|Table 1: Comparison and interpretation according to the breakpoints recommended by Earlier CLSI, CLSI|
2012, EUCAST against S. typhi isolates
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Azithromycin MIC was determined for all the ciprofloxacin non-susceptible strains by E-test and all (100%) were found to be susceptible. The MIC values were between 2.0 and 8.0 μg/mL.
Decline in MDR strains: Reverting susceptibility profile
Interestingly, in the past few years ciprofloxacin MIC has been on a steady rise, while a significant decline in the MDR S. Typhi rates over the last one and a half decades was observed. [Figure 1] represents the sustained decrease in MDR S. Typhi isolates over the past 15 years. This, most probably, is attributable to the long-term disuse of ampicillin, cotrimoxazole and chloramphenicol, hence these drugs can be considered as alternatives for the treatment of typhoid fever.
|Figure 1: Sustained fall in MDR S. typhi isolates over the past 15 years in a tertiary care centre|
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Are cephalosporins a good choice for S. Typhi?
Third-generation cephalosporins, particularly ceftriaxone, remain highly effective alternative treatment of typhoid fever in this country and elsewhere. However, the high cost and parenteral route of administration associated with ceftriaxone make its usage less practical. Oral third-generation cephalosporin like cefixime is also used. Unfortunately S. Typhi isolates resistant to cephalosporins have begun to appear.  Comparative trials between fluoroquinolones and cephalosporins show that much higher rates of clinical failure and relapse has occurred with cephalosporins, , justifying it may not be an effective alternative.
Is azithromycin a promising alternative?
Azithromycin, possesses many characteristics for effective treatment of typhoid fever, including excellent penetration into most tissues, achievement of concentrations in macrophages and neutrophils that are 100-fold higher than concentrations in serum and a long elimination half-life. 
In comparative trials, patients treated with azithromycin fared equally well or better than patients treated with fluoroquinolones, ceftriaxone, chloramphenicol with respect to cure rate and average time to defervescence against infections caused by bacteria with DCS, prevention of faecal carriage and relapse.  Clinical responses in non-comparative trials were that 61 of 64 patients (95%) treated with azithromycin were afebrile within 7 days of therapy and were considered to be cured. , Combining results of the six comparative trials, ,,,, none (0%) of the 416 patients who received azithromycin showed relapse. The dosage of azithromycin was 10 or 20 mg/kg for children and 500 or 1 g/day in adults, given orally for 7 days in four trials and 5 days in two trials. Relapse was seen in 6 out of 280 (2.14%) patients receiving fluoroquinolones and 9 of 66 (19.63%) patients receiving ceftriaxone. The concentration of azithromycin within cells and its secretion into the biliary tree, in conjunction with the long half-life of the drug, is likely to explain why relapses have not occurred when treating a principally intracellular infection such as typhoid fever. 
To surmise, the implications of revised CLSI ciprofloxacin breakpoints for S. Typhi in India are as follows.
Re-interpreting the MIC results with revised breakpoints indicates that we are reaching the end of the road for ciprofloxacin as the drug of choice for S. Typhi; sustained decrease in MDR rates over the past years and concurrently increasing susceptibility to ampicillin, chloramphenicol and cotrimoxazole is being observed making them alternative choices; azithromycin seems to be a preferred alternative over other anti-S. Typhi drugs as delineated in [Table 2].
|Table 2: Advantages and limitations of commonly prescribed drugs for typhoid fever|
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| ~ Acknowledgement|| |
We thank ICMR's for funding (Funding no. Adhoc/8362/2009) Multicenter study on antimicrobial resistance monitoring of Salmonella Typhi and Salmonella Paratyphi A - An attempt to make national guidelines to treat Enteric fever.
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[Table 1], [Table 2]
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