EijkmanWinkler Institute for Medical Microbiology, Utrecht University, The Netherlands
Sir,
In recent years there have been increasing numbers of reports of the emergence of resistance tociprofloxacin. 1 This development is regarded as the inevitable consequence of the exposure of bacterialpopulations to progressively greater quantities of this antibiotic. There is, therefore, a need fornew quinolones with reduced propensities for promoting resistance and improved activities against Gram-positive bacteria, whilst retaining broad-spectrum activity against aerobic Gram-negative bacilli.
Gatifloxacin and trovafloxacin are novel quinolones that meet these criteria and are active against a broad range of Gram-positive and Gram-negative bacteria. Gatifloxacin is afluoroquinolone with a 3-methylpiperazine group at position 7 of the quinolone ring and amethoxy group at position 8, 2 while trovafloxacin possesses a novel 3-azabicyclohexyl substituent at the C-7 position. 3
The SENTRY Antimicrobial Surveillance Programme is a longitudinal surveillance programme that was created for the purpose of monitoring the antimicrobial resistance patterns of the principal causes of nosocomial and community-acquired infections bothnationally and internationally; included among these infections are bacteraemias,outpatient respiratory tract infections caused by fastidious organisms, nosocomial pneumonias, wound infections and urinary tract infections. This initiative was employed in the present study, which was undertaken before the launch of gatifloxacin and trovafloxacin, to monitor the levelsof resistance to quinolone antibiotics in 12 European countries and to investigate geographical differences in the emergence of resistant strains.
Three of the predominant causes of severe bacterial infections, namely Staphylococcus aureus, Escherichia coli and Klebsiella spp., were selected as the main foci of the study; only methicillin-susceptible S. aureus (MSSA) isolates were included, since, across Europe, all but 10% of the methicillin-resistant S. aureus isolates tested (n = 369) were resistant to ciprofloxacin. The strains studied therefore included 1179 MSSA, 1894 E. coli and 520 Klebsiella spp. clinical isolates collected between April 1997 (the start of the European SENTRYprogramme) and April 1998; these strains comprised nearly 35% of the organisms tested duringthe first year of the programme. The isolates were referred to the EijkmanWinklerInstitute for Medical Microbiology, Utrecht, The Netherlands, which served as the regionalco-ordinating centre for 20 university hospitals in the 12 European countries. The susceptibilitiesof the isolates to ciprofloxacin, gatifloxacin and trovafloxacin were determined by a referencemicrobroth dilution method recommended by the National Committee for Clinical Laboratory Standards. 4
The susceptibility data for the isolates are summarized in the Table. The
activities ofgatifloxacin
and trovafloxacin against the MSSA strains were comparable (MIC
90s 1 mg/L) and superior to that of ciprofloxacin (MIC
90 >2 mg/L); on the basis of an MIC breakpoint of 1 mg/L,
4 a mean of c. 87% of all MSSA isolates were
categorized as susceptible to ciprofloxacin. The prevalence ofquinolone resistance among the
MSSA isolates was high in the participating hospitals inFrance, Italy, Portugal and the UK and in
one of the three hospitals inSpain.
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Although the percentages of susceptible strains belonging to some species varied markedlyfrom one university hospital to another, the relative activities of the quinolones tested weresimilar in each institution; this reflects cross-resistance to the quinolones among differentbacterial species. In general, ciprofloxacin resistance was associated with reduced susceptibilityto the newer quinolones.
There are several explanations for the observed regional variations in susceptibility tociprofloxacin, including differences in the sources of the isolates referred for susceptibilitytesting (i.e. different wards and patient populations) and differences in quinolone usage withinthe various hospitals. Case-control studies have demonstrated that the emergence offluoroquinolone resistance correlates with extensive use of these drugs and that previoustreatment with ciprofloxacin is a major risk factor for the isolation of ciprofloxacin-resistantbacteria. 5 Quinolone resistance is also frequently associated with specific centres or wards. Once aresistant clone emerges, the rate of quinolone resistance usually increases rapidly within thatspecific hospital setting as the result of clonal spread. 6 In addition to quinolone usage, this clonal spread might account for the differences in theprevalence of ciprofloxacin-resistant MSSA, E. coli and Klebsiella spp. in the 20 European hospitals. Further epidemiological typing studies are underway toanalyse the clonal relatedness of these resistant bacteria and to clarify the role of antibiotic usagein promoting quinolone resistance in different hospitals.
In summary, compared with ciprofloxacin, gatifloxacin and trovafloxacin exhibited superiorin-vitro activities against S. aureus, and ciprofloxacin and gatifloxacin were more active than trovafloxacin against E. coli and Klebsiella spp. Pre-existing ciprofloxacin resistance was associated with reduced susceptibility to thenewer quinolones. Finally, geographical differences in the prevalence of quinolone-resistantbacteria might be explained by extensive quinolone usage and/or horizontal clonal spread ofresistant bacteria in the various hospitals.
Acknowledgments
This work was funded by Bristol Myers Squibb Pharmaceuticals. We thank MaritaHautvast, Miriam Klootwijk, Carlijn Kusters and Stefan de Val for their expert technicalassistance. The SENTRY Participants Group includes H. Mittermayer, M. Struelens, J. Acar, V.Jarlier, J. Etienne, R. Courcol, F. Daschner, U. Hadding, N. Legakis, G.-C. Schito, C. Mancini, P.Heczko, W. Hyrniewicz, D. Costa, E. Perea, F. Baquero, R. M. Alvarez, J. Bille and G.French.
Notes
* Corresponding address. Institute for Medical Microbiology and
Virology,Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1,
Geb. 22.21,D-40225 Düsseldorf, Germany. Tel/Fax: +49-2132-72040.
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