Prevalence of gyrA , gyrB , parC , and parE Mutations in Clinical Isolates of Streptococcus pneumoniae with Decreased Susceptibilities to Different Fluoroquinolones and Originating from Worldwide Surveillance Studies during the 1997-1998 Respiratory Season

Abstract

From 8,419 worldwide clinical isolates of Streptococcus pneumoniae obtained during 1997-1998, 69 isolates with reduced susceptibility or resistance to fluoroquinolones (FQs) were molecularly characterized. For the isolates in this prevalence study, only parC (Ser-793Tyr) and gyrA (Ser-813Phe or Tyr) mutations, especially in combination, were found to contribute significantly to resistance. These mutations influenced the FQ MICs to varying degrees, although the rank order of activity remains independent of mutation type, with ciprofloxacin the least active, followed by levofloxacin, gatifloxacin/grepafloxacin/moxifloxacin/sparfloxacin/trovafloxacin, and clinafloxacin/sitafloxacin. Efflux likely plays a crucial role in reduced susceptibility for new hydrophilic FQs.Streptococcus pneumoniae is a leading cause of illness in humans (32). Recent increases in resistance (4,8,9,(29)(30)(31) have spawned the development of several new fluoroquinolones (FQs) with improved in vitro antipneumococcal activity (1, 7, 10-12, 14, 15, 34, 35). In pneumococci, reports indicate mutations in gyrA, gyrB, parC, and parE to be associated with FQ resistance (16, 18, 20-23, 28, 33). Efflux is also reported to contribute significantly to reduced susceptibility for some hydrophilic FQs, such as ciprofloxacin, while more hydrophobic FQs, like grepafloxacin, appear less affected (5, 13).(This work was presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1999.) This work aimed to define the prevalence of predominant mutations conferring FQ resistance in pneumococci collected during 1 year. Mutations in genes conferring FQ resistance in S. pneumoniae (16, 18, 20-23, 28, 33) have been well studied, but studies have typically included either clinical isolates (few and locally derived) or laboratory-derived mutants. In contrast, this study, the largest molecular surveillance study of FQ resistance in S. pneumoniae to date, comprises clinically significant isolates from locations worldwide, providing the opportunity to characterize the prevalence of mutations globally and their impact on the MICs of several new FQs.A total of 8,419 clinically significant isolates of S. pneumoniae associated with lower respiratory tract or blood infections were derived from 519 geographically distinct hospital laboratories in

Benchmarking the In Vitro Activities of Moxifloxacin and Comparator Agents against Recent Respiratory Isolates from 377 Medical Centers throughout the United States

“…In concordance with this, the 11 fluoroquinolone-resistant isolates detected in this study possessed classic single or combination mutations in gyrA and parC responsible for conferring fluoroquinolone-resistant phenotypes. It is worth noting, however, that the effects of mutations in QRDRs are not always clear-cut and that considerable biovariation clearly occurs in clinical isolates of S. pneumoniae (18). This is apparent from strain 11, which, despite possessing ParC alterations Lys-1373Asn and Ser-793Phe and GyrA alteration Ser-813Phe, maintained a moxifloxacin-susceptible phenotype, although the MIC was close to the breakpoint.…”

“…In S. pneumoniae (18), as in S. aureus (37,38), mutations in the DNA gyrase subunit A (gyrA) and topoisomerase IV (parC or grlA in S. aureus) are mostly responsible for conferring reduced susceptibility to fluoroquinolone compounds. Most previous reports suggest that mutations in gyrA (Ser-813Phe or Tyr) and parC (Ser-793Tyr) are the most significant (17, 18, 25, 27-29, 31, 40, 45).…”

“…Alteration Lys-1373Asn in ParC was identified in five isolates, each in combination with GyrA Ser-813Phe and (except for isolate 1) with ParC Ser-793Phe (Table 2). We did not look for mutations in parE or gyrB, since these are considered not to play a significant role in conferring reduced susceptibility to the fluoroquinolones studied (18).…”

Use of antimicrobials in veterinary medicine and mechanisms of resistance

“…A wide variety of mutations has been detected in the various target genes of a wide range of gram-positive and gram-negative bacteria of human and veterinary importance [16,23,27]. The effect of the different mutations on resistance also differs with respect to the various fluoroquinolones [30]. The gyrA mutations are commonly located within what is referred to as a quinolone resistance-determining region of 130 bp [48].…”

Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001

“…As single parC or gyrA mutations in S. aureus (31) confer resistance to ciprofloxacin, the widespread use of this antibiotic may have already selected a population of organisms requiring only one further mutation for resistance to the new fluoroquinolones to occur. Similarly, with S. pneumoniae, mutations within the quinolone resistancedetermining region (QRDR) for both topoisomerases can lead to resistance for the new fluoroquinolones (18). Within the Asia-Pacific region, multidrug resistance and, specifically, fluoroquinolone resistance for both gram-positive and gram-negative organisms is relatively high (33).…”