Fluoroquinolone resistance among recent clinical isolates of Streptococcus pneumoniae

J Antimicrob Chemother 1999; 43: 428–429

Arthur L. Barry*, Steven D. Brown and Peter C. Fuchs

The Clinical Microbiology Institute, Wilsonville, OR 97070,USA

Sir,

Recent studies of Streptococcus pneumoniae have defined the appearance of ciprofloxacin-resistant pneumococci in vitro and in vivo. 1,2 Two types of mutation have been identified: mutations of parC typically display low-level resistance (MIC 4.0–8.0 mg/L), while further mutations in thegene(s) encoding DNA gyrase, usually gyrA, result in high-level resistance (MIC 16–64 mg/L). These two types of mutational eventmust occur in sequence to result in high-level resistance to ciprofloxacin and to otherfluoroquinolones. 1 The clinical relevance of low-level resistance is not entirely clear, but continued exposure tofluoroquinolones could select mutants with high-level resistance.

The purpose of this study was to define the normal distribution of fluoroquinolone MICsagainst 600 contemporary isolates of S. pneumoniae gathered from 11 medical centres in North America during the 1996–97 winter season. Each facility contributed 30–81 separate isolates of pneumococci that were thought to be clinically relevant; duplicate isolates from the same patient episode were excluded. Only 68% of the strains were penicillin-susceptible, 15% were intermediate in susceptibility and 17%were penicillin-resistant; 17% were also macrolide-resistant.

We performed broth microdilution susceptibility tests as described by the NationalCommittee for Clinical Laboratory Standards. 3 Ciprofloxacin, ofloxacin, levofloxacin and sparfloxacin were studied. The population statisticsfor MICs of each fluoroquinolone (Table) describe normal distributions that might beexpected if one strain were retested 600 times or 600 strains were tested once. For eachfluoroquinolone, >99% of all MICs were within the range defined by the mode ± one doubling concentration and >1% of all MICs were two doubling concentrations from the mode.


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Table. Distribution of fluoroquinolone MICs against 600 recent isolates of S. pneumoniae recovered from patients in 11 different medical centres throughout North America during the 1996- 97 winter months
 
In the case of levofloxacin and sparfloxacin, the MIC mode is two doubling concentrations below the susceptible breakpoint and, consequently, only one or two strains gave MICs in the intermediate range (mode + 2 doubling concentrations) and none were in the resistantcategory.

The modal MICs of ciprofloxacin and of ofloxacin are located at their susceptiblebreakpoints of 1.0 and 2.0 mg/L, respectively. Consequently, repeated testing should shift asubstantial number of strains from the susceptible to the intermediate category or vice versa, but rarely from susceptible to resistant, or vice versa. For <1% of all pneumococci, ciprofloxacin MICs were in the upper portion of the resistant pneumococci represent first-step (parC) mutants, we would expect them to show cross-resistance to other fluoroquinolones and that was not observed consistently.

We are unaware of any evidence that supports or refutes the assumption that pneumococciwith ciprofloxacin MICs of 4.0 mg/L are likely to fail to respond to therapy. We do not yet knowwhether any of those strains are progeny from parents that have undergone the first-step parC mutation and are now ready to undergo a second-step mutation that can lead to high-levelresistance. Among the pneumococci that we collected from 11 USA medical centres, there wereno strains with ciprofloxacin MICs >8.0 mg/L; thus the prevalence of high-level resistance is <0.2% (<1 in 600). Pneumococci with a ciprofloxacin MIC of 4.0 mg/L (low-level resistance?) occurred in about 1% of our pneumococci. That is consistent with the findings of Simor et al. 4 who evaluated 1089 clinical isolates from Canadian medical centres. Of the 600pneumococci, 11.8% had ciprofloxacin-intermediate MICs of 2.0 mg/L: the clinical significanceof strains in this category remains unclear.

Acknowledgments

We wish to thank the following individuals for their cooperation in selecting the isolatesincluded in this study. T. Cleary, University of Miami, Miami, FL; M. J. Ferraro, MassachusettsGeneral Hospital, Boston, MA; D. Hardy, University of Rochester Medical Center, Rochester,NY; J. Hindler, UCLA Medical Center, Los Angeles, CA; S. Jenkins, Carolinas Medical Center,Charlotte, NC; J. McLaughlin, University of New Mexico Medical Center, Albuquerque, NM;M. Pfaller, University of Iowa College of Medicine, Iowa City, IA; R. Rennie, University ofAlberta Hospital, Edmonton, Alberta, Canada; D. Sahm, Jewish Hospital, Washington UniversityMedical Center, St Louis, MO; K. Waites, University of Alabama, Birmingham, AL; and J.Washington, The Cleveland Clinic Foundation, Cleveland, OH. This study was made possible bya grant from the Bayer Corporation, Pharmaceutical Division, West Haven, CT,USA.

Notes

* Corresponding address. 9725 SW Commerce Circle, Suite A1, Wilsonville, OR 97070, USA. Tel: +1-503-682-3232; Fax: +1-503-682-2065 or 682-4548; E-mail: cmi{at}hevanet.com Back

References

1 . Janoir, C., Zeller, V., Kitzis, M.-D., Moreau, N. J. & Gutmann, L. (1996). High levelfluoroquinolone resistance in Streptococcus pneumoniae requires mutations in par C and gyr A. Antimicrobial Agents and Chemotherapy 40, 2760–4.[Abstract]

2 . Tankovic, J., Perichon, B., Duval, J. & Courvalin, P. (1996). Contribution of mutations ingyrA and parC genes to fluoroquinolone resistance of mutants of Streptococcus pneumoniae obtained in vivo and in vitro. Antimicrobial Agents and Chemotherapy40 , 2505–10.[Abstract]

3 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests of Bacteria that Grow Aerobically.Approved Standard M7-A4, 4th edn. NCCLS, Wayne, PA.

4 . Simor, A. E., Lovie, M., The Canadian Bacterial Surveillance Network, & Low, D. E.(1997). Canadian national survey of prevalence of antimicrobial resistance among clinicalisolates of Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 40, 2190–3.[Abstract]