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  Table of Contents  
Year : 2019  |  Volume : 37  |  Issue : 4  |  Page : 600-601

Will the recently reinstated clsi 2020 breakpoints of norfloxacin for urinary isolates work for India? – Tertiary care experience and evidence

Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission03-Apr-2020
Date of Acceptance29-Apr-2020
Date of Web Publication18-May-2020

Correspondence Address:
Dr. Rani Diana Sahni
Department of Clinical Microbiology, Christian Medical College, Vellore - 632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_20_142

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How to cite this article:
Sahni RD, Veeraraghavan B, Dhiviya Prabaa M S, Jacob JJ. Will the recently reinstated clsi 2020 breakpoints of norfloxacin for urinary isolates work for India? – Tertiary care experience and evidence. Indian J Med Microbiol 2019;37:600-1

How to cite this URL:
Sahni RD, Veeraraghavan B, Dhiviya Prabaa M S, Jacob JJ. Will the recently reinstated clsi 2020 breakpoints of norfloxacin for urinary isolates work for India? – Tertiary care experience and evidence. Indian J Med Microbiol [serial online] 2019 [cited 2020 Sep 30];37:600-1. Available from:

Dear Editor,

Norfloxacin (NOR), an oral broad-spectrum, second-generation fluoroquinolone (FQ), has been reinstated in the M-100CLSI 2020 guidelines for urinary tract infections (UTI)[1] after its complete removal in 2019, with the same clinical breakpoints as in the earlier editions. NOR with a half-life of 2.3–5.5 h reaches a peak serum concentration of 1.5–2.0 μg/ml in 1–1.5 h, and 30% of the drug gets excreted renally, unchanged. FQs with their excellent bioavailability are, however, second-line options in the management of UTI (IDSA, 2011) due to collateral damage on the intestinal microbiota and their contraindications in pregnancy and children. Yet, in comparison with pivmecillinam, a first-line choice, NOR, is preferred due to its more pronounced effect with no major disturbances on the periurethral and vaginal microbiota.[2] Currently, the increased use of FQ's, in general, led to the gradual development of resistance over time. Studies have, therefore, recommended that FQs be reserved for the use in patients who have no alternative treatment options.[3]

In India, where the antimicrobial resistance burden is already high, the efficacy of NOR for treating UTI is uncertain as most contemporary urinary pathogens showed decreased susceptibility to this drug class. To demonstrate the current efficacy of NOR, we carried out susceptibility testing on contemporary, consecutive urinary isolates between February 24th and March 24th, 2020, at Christian Medical College, Vellore, Tamil Nadu, India. Urinary bacterial isolates of Escherichia coli, Klebsiella spp., Pseudomonas spp., Serratia spp., Morganella spp., Providencia spp., Proteus spp., Enterobacter spp., Citrobacter spp., Staphylococcus spp. and Enterococcus spp. were tested by the Kirby–Bauer disk diffusion method with 10 μg NOR and compared with 5 μg ciprofloxacin.[1] The antimicrobial susceptibility testing reveals a 91.3% concordance with ciprofloxacin and an overall 64.4% resistance to the agents. Specifically, among our major pathogens, >70% of the E. coli, >80% of Enterococcus spp. and 50% of Klebsiella and Pseudomonas isolates were resistant to the FQ's. A 10-year analysis of uropathogens at our centre reveals non-susceptibility to FQ between 63.2% and 52.2%. Similarly, Varughese et al. reported high-level resistance to NOR among E. coli clinical isolates.[4] Another study showed a high rate of resistance to NOR among Enterococcus sp., with higher resistance among Enterococcus faecium isolates than Enterococcus faecalis (85 vs 58.8%).[5]

A detailed analysis of the FQ resistance mechanism among clinical isolates of E. coli, Klebsiella spp. and Staphylococcus spp. from our centre revealed double/triple mutations in quinolone resistance-determining regions. E. coli mutations in gyr A (S83L, D87N and D87Y) and par C (S80I) were found to be the primary cause of quinolone resistance, whilst efflux-mediated FQ resistance (oqx A/B) seems to be the common mechanism in Klebsiella spp. Remarkably, previous studies from India have shown that NOR Minimum inhibitory concentrations (MICs) for most of the double mutants (codons 83 and 87 of gyrase A) were >1024 μg/ml, whereas that of ciprofloxacin is 256 μg/ml.[4] However, among Gram-positive organisms, stepwise mutations play a crucial role in raising MICs to NOR. In Staphylococcus, strains with gyr A (S84L) and grl A (S80F, S80Y) substitutions resulted in quinolone resistance. The first step mutation occurs in parC (Ser-80-Phe) for Staphylococcus aureus raising NOR MIC level to 4 μg/ml. Additional mutation at Ser-84-Leu further raises MIC to 16 μg/ml, and a third step mutation in gyrA pushes the MIC further up to 128 μg/ml.[6] The higher MIC for NOR compared to ciprofloxacin, ofloxacin and levofloxacin in both Gram-negative and Gram-positive probably evidence the inappropriateness of NOR for contemporary clinical isolates.

In conclusion, NOR testing may not be useful due to the current FQ resistance among contemporary uropathogens. It is suggested that antimicrobial testing guidelines be based on geographical locations, as this scenario may not be the same globally.

Financial support and sponsorship

This work received no specific external funding, and the work was carried out depending on the resources of the Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India.

Conflicts of interest

There are no conflicts of interest.

 ~ References Top

Wayne PA. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. CLSI Supplement M100. 30th ed. Wayne P.A: Clinical and Laboratory Standards Institute; 2020.  Back to cited text no. 1
Norinder BS, Norrby R, Palmgren AC, Hollenberg S, Eriksson U, Nord CE. Microflora changes with norfloxacin and pivmecillinam in women with recurrent urinary tract infection. Antimicrob Agents Chemother 2006;50:1528-30.  Back to cited text no. 2
Van TT, Minejima E, Chiu CA, Butler-Wu SM. Don't get wound up: Revised fluoroquinolone breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa. J Clin Microbiol 2019;57. pii: e02072-18.  Back to cited text no. 3
Varughese LR, Rajpoot M, Goyal S, Mehra R, Chhokar V, Beniwal V. Analytical profiling of mutations in quinolone resistance determining region of gyrA gene among UPEC. PLoS One 2018;13:e0190729.  Back to cited text no. 4
Abamecha A, Wondafrash B, Abdissa A. Antimicrobial resistance profile of Enterococcus species isolated from intestinal tracts of hospitalized patients in Jimma, Ethiopia. BMC Res Notes 2015;8:213.  Back to cited text no. 5
Sierra JM, Marco F, Ruiz J, Jiménez de Anta MT, Vila J. Correlation between the activity of different fluoroquinolones and the presence of mechanisms of quinolone resistance in epidemiologically related and unrelated strains of methicillin-susceptible and -resistant Staphylococcus aureus. Clin Microbiol Infect 2002;8:781-90.  Back to cited text no. 6


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