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  Table of Contents  
Year : 2014  |  Volume : 32  |  Issue : 2  |  Page : 161-163

Revised ciprofloxacin breakpoints for Salmonella Typhi: Its implications in India

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 Submission21-Aug-2013
Date of Acceptance13-Dec-2013
Date of Web Publication2-Apr-2014

Correspondence Address:
V Balaji
Department of Microbiology, Christian Medical College, Vellore, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0255-0857.129804

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 ~ Abstract 

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 Jul 2];32:161-3. Available from:

 ~ Introduction Top

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. [1]

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. [2]

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. [3] 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. [4] 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. [4]

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. [6] 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. [7] Comparative trials between fluoroquinolones and cephalosporins show that much higher rates of clinical failure and relapse has occurred with cephalosporins, [2],[8] 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. [9]

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. [5] 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. [10],[11] Combining results of the six comparative trials, [8],[12],[13],[14],[15] 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. [9]

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 Top

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.

 ~ References Top

1.Pandit A, Arjyal A, Day JN, Paudyal B, Dangol S, Zimmerman MD, et al. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS One 2007;2:e542.  Back to cited text no. 1
2.Butler T, Sridhar CB, Daga MK, Pathak K, Pandit RB, Khakhria R, et al. Treatment of typhoid fever with azithromycin versus chloramphenicol in a randomized multicentre trial in India. J Antimicrob Chemother 1999;44:243-50.  Back to cited text no. 2
3.Kadhiravan T, Wig N, Renuka K, Kapil A, Kabra SK, Misra A. Is nalidixic acid resistance linked to clinical virulence in Salmonella enterica serovar Typhi infections? J Med Microbiol 2008;57:1046-8.  Back to cited text no. 3
4.Kadhiravan T, Wig N, Kapil A, Kabra SK, Renuka K, Misra A. Clinical outcomes in typhoid fever: Adverse impact of infection with nalidixic acid-resistant Salmonella Typhi. BMC Infect Dis 2005;5:37.  Back to cited text no. 4
5.Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty third Informational Supplement. CLSI document M100-23. Wayne: Clinical and Laboratory Standards Institute; 2013;30:47.  Back to cited text no. 5
6.Butler T. Treatment of typhoid fever in the 21 st century: Promises and shortcomings. Clin Microbiol Infect 2011;17:959-63.  Back to cited text no. 6
7.Gokul BN, Menezes GA, Harish BN. ACC-1 beta-Lactamase-producing Salmonella enterica Serovar Typhi, India. Emerg Infect Dis 2010;16:1170-1.  Back to cited text no. 7
8.Frenck RW Jr, Nakhla I, Sultan Y, Bassily SB, Girgis YF, David J, et al. Azithromycin versus ceftriaxone for the treatment of uncomplicated typhoid fever in children. Clin Infect Dis 2000;31:1134-8.  Back to cited text no. 8
9.Tribble D, Girgis N, Habib N, Butler T. Efficacy of azithromycin for typhoid fever. Clin Infect Dis 1995;21:1045-6.  Back to cited text no. 9
10.Islam MN, Rahman ME, Rouf MA, Islam MN, Khaleque MA, Siddika M, et al. Efficacy of azithromycin in the treatment of childhood typhoid fever. Mymensingh Med J 2007;16:149-53.  Back to cited text no. 10
11.Frenck RW Jr, Mansour A, Nakhla I, Sultan Y, Putnam S, Wierzba T, et al. Short-course azithromycin for the treatment of uncomplicated typhoid fever in children and adolescents. Clin Infect Dis 2004;38:951-7.  Back to cited text no. 11
12.Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX, Diep TS, et al. A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrobial Agents Chemother 2000;44:1855-9.  Back to cited text no. 12
13.Parry CM, Ho VA, Phuong le T, Bay PV, Lanh MN, Tung le T, et al. Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother 2007;51:819-25.  Back to cited text no. 13
14.Girgis NI, Butler T, Frenck RW, Sultan Y, Brown FM, Tribble D, et al. Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance. Antimicrob Agents Chemother 1999;43:1441-4.  Back to cited text no. 14
15.Phuong XT, Kneen R, Nguyen TA, Truong DL, White NJ, Parry CM. A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group. Pediatr Infect Dis J 1999;18:245-8.  Back to cited text no. 15


  [Figure 1]

  [Table 1], [Table 2]

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