Levofloxacin-Resistant Invasive Streptococcus pneumoniae in the United States: Evidence for Clonal Spread and the Impact of Conjugate Pneumococcal Vaccine

Abstract

The emergence of fluoroquinolone resistance in sterile-site isolates of Streptococcus pneumoniae is documented in this study characterizing all invasive levofloxacin-resistant (MIC, >8 mg/liter) S. pneumoniae isolates (n ‫؍‬ 50) obtained from the Centers for Disease Control and Prevention Active Bacterial Core Surveillance from 1998 to 2002. Resistance among all isolates increased from 0.1% in 1998 to 0.6% in 2001 (P ‫؍‬ 0.008) but decreased to 0.4% in 2002, while resistance among vaccine serotypes continued to increase from 0.3% in 1998 to 1.0% in 2002, suggesting that fluoroquinolones continue to exert selective pressure on these vaccine serotypes. Only 22% of resistant isolates were not covered by the conjugate vaccine serogroups. Multilocus sequence typing revealed that 58% of resistant strains were related to five international clones identified by the Pneumococcal Molecular Epidemiology Network, with the Spain 23F -1 clone being most frequent (16% of all isolates). Thirty-six percent of the isolates were coresistant to penicillin, 44% were coresistant to macrolides, and 28% were multiresistant to penicillin, macrolides, and fluoroquinolones. Fifty percent of the isolates were resistant to any three drug classes. Ninety-four percent of the isolates had multiple mutations in the quinolone resistance-determining regions of the gyrA, gyrB, parC, and parE genes. In 16% of the isolates, there was evidence of an active efflux mechanism. An unusual isolate was found that showed only a single parE mutation and for which the ciprofloxacin MIC was lower (2 mg/liter) than that of levofloxacin (8 mg/liter). Our results suggest that invasive pneumococcal isolates resistant to levofloxacin in the United States show considerable evidence of multiple resistance and of clonal spread.

Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens

“…On the other hand, in S. pneumoniae, even within what appeared to be a clonal lineage, there were multiple events of gain and loss of resistance determinants both by point mutations and by horizontal gene transfer (43). In the extreme case, there may be very little clonal spread of a particular resistance phenotype but rather repeated appearance in multiple lineages, as appears to occur for fluoroquinolone resistance in S. pneumoniae (123,124).…”

Relative Fitness of Fluoroquinolone-resistantStreptococcus pneumoniae

“…The emergence of quinolone-resistant S. pneumoniae (QRSP) appears to be more dependent on fluoroquinolone selection of de novo spontaneous point mutations in the quinolone resistance-determining regions (QRDRs) of the topoisomerase genes gyrA and parC than on clonal dissemination (9-13). However, some studies reported occurrences of clonal relatedness among QRSP (11,(14)(15)(16).…”

“…The emergence of quinolone-resistant S. pneumoniae (QRSP) appears to be more dependent on fluoroquinolone selection of de novo spontaneous point mutations in the quinolone resistance-determining regions (QRDRs) of the topoisomerase genes gyrA and parC than on clonal dissemination (9-13). However, some studies reported occurrences of clonal relatedness among QRSP (11,(14)(15)(16).To investigate the relative fitness of QRSP, we conducted a competition study of a fluoroquinolone-susceptible clinical strain of S. pneumoniae (EF3030) with 2 of its fluoroquinolone-resistant isogenic mutants that had 2 common QRDR point mutation combinations. These 3 strains were analyzed by using an in vitro growth model, an in vivo nasopharyngeal colonization model, and an in vivo pneumonia model.…”

Impact of a 16-Community Trial to Promote Judicious Antibiotic Use in Massachusetts

“…1,2 The rapid increase in resistance among common bacterial pathogens, such as Streptococcus pneumoniae, [3][4][5][6] is widely believed to be fueled by high rates of antibiotic use, much of which is unnecessary. [7][8][9][10][11] Because of the communicability of bacterial pathogens, the consequences of resis-tance have an impact on communities in addition to individual carriers.…”