Fluoroquinolone Resistance in
Streptococcus pneumoniae
in United States since 1994-1995
Authors: Brueggemann Angela B. , Coffman Stacy L. , Rhomberg Paul , Huynh Holly , Almer Laurel , Nilius Angela , Flamm Robert , Doern Gary V. 
Published: July 2002

The in vitro activities of ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin against a large collection of clinical isolates of
Streptococcus pneumoniae
(
n
= 4,650) obtained over a 5-year period, 1994-1995 through 1999-2000, were assessed as part of a longitudinal multicenter U.S. surveillance study of antimicrobial resistance. Three sampling periods were used during this investigation, the winter seasons of 1994-1995, 1997-1998, and 1999-2000; and 1,523, 1,596 and 1,531 isolates were collected during these three periods, respectively. The overall rank order of activity of the four fluoroquinolones examined in this study was moxifloxacin > gatifloxacin > levofloxacin = ciprofloxacin, in which moxifloxacin (MIC at which 90% of isolates are inhibited [MIC
90
], 0.25 μg/ml; modal MIC, 0.12 μg/ml) was twofold more active than gatifloxacin (MIC
90
, 0.5 μg/ml; modal MIC, 0.25 μg/ml), which in turn was fourfold more active than either levofloxacin (MIC
90
, 1 μg/ml; modal MIC, 1 μg/ml) or ciprofloxacin (MIC
90
, 2 μg/ml; modal MIC, 1 μg/ml). Changes in the in vitro activities of fluoroquinolones against
S. pneumoniae
strains in the United States over the 5-year period of the survey were assessed by comparing the MIC frequency distributions of the study drugs against the isolates obtained during the three sampling periods encompassing this investigation. These comparisons revealed no evidence of changes in the in vitro activities of the fluoroquinolones. In addition, the percentages of isolates in the three sampling periods for which MICs were above the resistance breakpoints were compared. Low percentages of resistant strains were detected, and there was no evidence of resistance rate changes over time. For example, by use of a ciprofloxacin MIC of ≥4 μg/ml to define resistance, the proportions of isolates from the three sampling periods for which MICs were at or above this breakpoint were 1.2, 1.6, and 1.4%, respectively. A total of 164 unique isolates (
n
= 58 from 1994-1995, 65 from 1997-1998, and 42 from 1999-2000) were examined for evidence of mutations in the quinolone resistance-determining regions (QRDRs) of the
parC
and the
gyrA
genes. Forty-nine isolates harbored at least one mutation in the QRDRs of one or both genes (1994-1995,
n
= 15; 1997-1998,
n
= 19; 1999-2000,
n
= 15). Among the 4,650 isolates of
S. pneumoniae
examined in the study, we estimated that 0.3% had mutations in both the
parC
and
gyrA
loci. The majority of mutations (67.3% of the mutations in 49 isolates with mutations) were amino acid substitutions in the
parC
locus only. Four isolates had a mutation in the
gyrA
locus only, and 12 isolates had mutations in both genes (8.2 and 24.5% of isolates with mutations, respectively). There was no significant difference in the number of isolates with
parC
and/or
gyrA
mutations detected during each study period. Finally, because of the magnitude of the study, we had reasonably large numbers of pneumococcal isolates with genotypically defined mechanisms of fluoroquinolone resistance and were thus able to determine the effects of specific resistance mutations on the activities of different fluoroquinolones. In general, isolates with mutations in
parC
only were resistant to ciprofloxacin but remained susceptible to levofloxacin, gatifloxacin, and moxifloxacin, whereas isolates with mutations in
gyrA
only and isolates with mutations in both
parC
and
gyrA
were resistant to all four fluoroquinolones tested.