Canadian national survey of prevalence of antimicrobial resistance among clinical isolates of Streptococcus pneumoniae. Canadian Bacterial Surveillance Network.

1996 ◽  
Vol 40 (9) ◽  
pp. 2190-2193 ◽  
Author(s):  
A E Simor ◽  
M Louie ◽  
D E Low
Keyword(s):  
Streptococcus Pneumoniae ◽  
Antimicrobial Agents ◽  
Clinical Isolates ◽  
Beta Lactam ◽  
Surveillance Network ◽  
Antibiotic Resistant ◽  
Intermediate Resistance ◽  
Resistant Strains ◽  
High Level ◽  
Level Resistance

The antimicrobial susceptibilities of 1,089 clinical isolates of Streptococcus pneumoniae obtained from 39 laboratories across Canada between October 1994 and August 1995 were determined. A total of 91 isolates (8.4%) demonstrated intermediate resistance (MIC, 0.1 to 1.0 microgram/ml) and 36 (3.3%) had high-level resistance (MIC, > or = 2.0 micrograms/ml) to penicillin. Penicillin-resistant strains were more likely to have been recovered from normally sterile sites (P = 0.005) and to be cross-resistant to several beta-lactam and non-beta-lactam antimicrobial agents (P < 0.05). These results indicate that there has been a recent significant increase in the prevalence of antibiotic-resistant S. pneumoniae in Canada.

scholarly journals Genetic Characterization of Fluoroquinolone-Resistant Streptococcus pneumoniae Strains Isolated during Ciprofloxacin Therapy from a Patient with Bronchiectasis

2003 ◽  
Vol 47 (4) ◽  
pp. 1419-1422 ◽  
Author(s):  
Adela G. de la Campa ◽  
María-José Ferrandiz ◽  
Fe Tubau ◽  
Román Pallarés ◽  
Federico Manresa ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Genetic Characterization ◽  
Susceptible Strain ◽  
Low Level ◽  
Resistant Strains ◽  
Resistant Mutants ◽  
High Level ◽  
Level Resistance

ABSTRACT Five Spain9V-3 Streptococcus pneumoniae strains were isolated from a patient with bronchiectasis who had received long-term ciprofloxacin therapy. One ciprofloxacin-susceptible strain was isolated before treatment, and four ciprofloxacin-resistant strains were isolated during treatment. The resistant strains were derived from the susceptible strain either by a parC mutation (low-level resistance) or by parC and gyrA mutations (high-level resistance). This study shows that ciprofloxacin therapy in a patient colonized by susceptible S. pneumoniae may select fluoroquinolone-resistant mutants.

scholarly journals Antimicrobial Resistance in Respiratory Tract Streptococcus pneumoniae Isolates: Results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002

2003 ◽  
Vol 47 (6) ◽  
pp. 1867-1874 ◽  
Author(s):  
George G. Zhanel ◽  
Lorraine Palatnick ◽  
Kimberly A. Nichol ◽  
Tracy Bellyou ◽  
Don E. Low ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Antimicrobial Resistance ◽  
Antibiotic Consumption ◽  
Multidrug Resistant ◽  
Medical Centers ◽  
Intermediate Resistance ◽  
Susceptibility Study ◽  
Resistant Strains ◽  
Canadian Provinces ◽  
High Level

ABSTRACT A total of 6,991 unique patient isolates of Streptococcus pneumoniae were collected from October 1997 to June 2002 from 25 medical centers in 9 of the 10 Canadian provinces. Among these isolates, 20.2% were penicillin nonsusceptible, with 14.6% being penicillin intermediate (MIC, 0.12 to 1 μg/ml) and 5.6% being penicillin resistant (MIC, ≥2 μg/ml). The proportion of high-level penicillin-resistant S. pneumoniae isolates increased from 2.4 to 13.8% over the last 3 years of the study, and the proportion of multidrug-resistant S. pneumoniae isolates increased from 2.7 to 8.8% over the 5-year period. Resistant rates (intermediate and resistant) among non-β-lactam agents were as follows: macrolides, 9.6 to 9.9%; clindamycin, 3.8%; doxycycline, 5.5%; chloramphenicol, 3.9%; and trimethoprim-sulfamethoxazole, 19.0%. Rates of resistance to non-β-lactam agents were higher among penicillin-resistant strains than among penicillin-susceptible strains. No resistance to vancomycin or linezolid was observed; however, 0.1% intermediate resistance to quinupristin-dalfopristin was observed. The rate of macrolide resistance (intermediate and resistant) increased from 7.9 to 11.1% over the 5 years. For the fluoroquinolones, the order of activity based on the MICs at which 50% of isolates are inhibited (MIC50s) and the MIC90s was gemifloxacin > clinafloxacin > trovafloxacin > moxifloxacin > grepafloxacin > gatifloxacin > levofloxacin > ciprofloxacin. The investigational compounds ABT-773 (MIC90, 0.008 μg/ml), ABT-492 (MIC90, 0.015 μg/ml), GAR-936 (tigecycline; MIC90, 0.06 μg/ml), and BMS284756 (garenoxacin; MIC90, 0.06 μg/ml) displayed excellent activities. Despite decreases in the rates of antibiotic consumption in Canada over the 5-year period, the rates of both high-level penicillin-resistant and multidrug-resistant S. pneumoniae isolates are increasing in Canada.

scholarly journals Antimicrobial Resistance among Clinical Isolates ofStreptococcus pneumoniae in the United States during 1999–2000, Including a Comparison of Resistance Rates since 1994–1995

2001 ◽  
Vol 45 (6) ◽  
pp. 1721-1729 ◽  
Author(s):  
Gary V. Doern ◽  
Kristopher P. Heilmann ◽  
Holly K. Huynh ◽  
Paul R. Rhomberg ◽  
Stacy L. Coffman ◽  
...  
Keyword(s):  
United States ◽  
Antimicrobial Resistance ◽  
Antimicrobial Agents ◽  
Rank Order ◽  
The United States ◽  
Clinical Isolates ◽  
Beta Lactam ◽  
High Level ◽  
Resistance Rates

ABSTRACT A total of 1,531 recent clinical isolates of Streptococcus pneumoniae were collected from 33 medical centers nationwide during the winter of 1999–2000 and characterized at a central laboratory. Of these isolates, 34.2% were penicillin nonsusceptible (MIC ≥ 0.12 μg/ml) and 21.5% were high-level resistant (MIC ≥ 2 μg/ml). MICs to all beta-lactam antimicrobials increased as penicillin MICs increased. Resistance rates among non-beta-lactam agents were the following: macrolides, 25.2 to 25.7%; clindamycin, 8.9%; tetracycline, 16.3%; chloramphenicol, 8.3%; and trimethoprim-sulfamethoxazole (TMP-SMX), 30.3%. Resistance to non-beta-lactam agents was higher among penicillin-resistant strains than penicillin-susceptible strains; 22.4% of S. pneumoniae were multiresistant. Resistance to vancomycin and quinupristin-dalfopristin was not detected. Resistance to rifampin was 0.1%. Testing of seven fluoroquinolones resulted in the following rank order of in vitro activity: gemifloxacin > sitafloxacin > moxifloxacin > gatifloxacin > levofloxacin = ciprofloxacin > ofloxacin. For 1.4% of strains, ciprofloxacin MICs were ≥4 μg/ml. The MIC90s (MICs at which 90% of isolates were inhibited) of two ketolides were 0.06 μg/ml (ABT773) and 0.12 μg/ml (telithromycin). The MIC90 of linezolid was 2 μg/ml. Overall, antimicrobial resistance was highest among middle ear fluid and sinus isolates of S. pneumoniae; lowest resistance rates were noted with isolates from cerebrospinal fluid and blood. Resistant isolates were most often recovered from children 0 to 5 years of age and from patients in the southeastern United States. This study represents a continuation of two previous national studies, one in 1994–1995 and the other in 1997–1998. Resistance rates with S. pneumoniae have increased markedly in the United States during the past 5 years. Increases in resistance from 1994–1995 to 1999–2000 for selected antimicrobial agents were as follows: penicillin, 10.6%; erythromycin, 16.1%; tetracycline, 9.0%; TMP-SMX, 9.1%; and chloramphenicol, 4.0%, the increase in multiresistance was 13.3%. Despite awareness and prevention efforts, antimicrobial resistance with S. pneumoniae continues to increase in the United States.

scholarly journals Sparfloxacin Resistance in Clinical Isolates ofStreptococcus pneumoniae: Involvement of Multiple Mutations in gyrA and parC Genes

1998 ◽  
Vol 42 (9) ◽  
pp. 2193-2196 ◽  
Author(s):  
Hideki Taba ◽  
Nobuchika Kusano
Keyword(s):  
Streptococcus Pneumoniae ◽  
Amino Acid ◽  
Antimicrobial Susceptibility ◽  
Susceptibility Testing ◽  
Clinical Isolates ◽  
Amino Acid Substitutions ◽  
Sequencing Analysis ◽  
High Level ◽  
Additional Nucleotide ◽  
Level Resistance

ABSTRACT Antimicrobial susceptibility testing revealed among 150 clinical isolates of Streptococcus pneumoniae 4 pneumococcal isolates with resistance to fluoroquinolones (MIC of ciprofloxacin, ≥32 μg/ml; MIC of sparfloxacin, ≥16 μg/ml). Gene amplification and sequencing analysis of gyrA andparC revealed nucleotide changes leading to amino acid substitutions in both GyrA and ParC of all four fluoroquinolone-resistant isolates. In the case of strains 182 and 674 for which sparfloxacin MICs were 16 and 64 μg/ml, respectively, nucleotide changes were detected at codon 81 in gyrA and codon 79 in parC; these changes led to an Ser→Phe substitution in GyrA and an Ser→Phe substitution in ParC. Strains 354 and 252, for which sparfloxacin MICs were 128 μg/ml, revealed multiple mutations in both gyrA and parC. These strains exhibited nucleotide changes at codon 85 leading to a Glu→Lys substitution in GyrA, in addition to Ser-79→Tyr and Lys-137→Asn substitutions in ParC. Moreover, strain 252 showed additional nucleotide changes at codon 93, which led to a Trp→Arg substitution in GyrA. These results suggest that sparfloxacin resistance could be due to the multiple mutations in GyrA and ParC. However, it is possible that other yet unidentified mutations may also be involved in the high-level resistance to fluoroquinolones in S. pneumoniae.

scholarly journals Genetic Analyses of Mutations Contributing to Fluoroquinolone Resistance in Clinical Isolates ofStreptococcus pneumoniae

2001 ◽  
Vol 45 (12) ◽  
pp. 3517-3523 ◽  
Author(s):  
L. M. Weigel ◽  
G. J. Anderson ◽  
R. R. Facklam ◽  
F. C. Tenover
Keyword(s):  
Amino Acid ◽  
Antimicrobial Agents ◽  
Clinical Isolates ◽  
Fluoroquinolone Resistance ◽  
Cross Resistance ◽  
Genetic Analyses ◽  
High Level ◽  
Susceptibility Profiles ◽  
Level Resistance

ABSTRACT Twenty-one clinical isolates of Streptococcus pneumoniae showing reduced susceptibility or resistance to fluoroquinolones were characterized by serotype, antimicrobial susceptibility, and genetic analyses of the quinolone resistance-determining regions (QRDRs) of gyrA,gyrB, parC, and parE. Five strains were resistant to three or more classes of antimicrobial agents. In susceptibility profiles for gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, ofloxacin, sparfloxacin, and trovafloxacin, 14 isolates had intermediate- or high-level resistance to all fluoroquinolones tested except gemifloxacin (no breakpoints assigned). Fluoroquinolone resistance was not associated with serotype or with resistance to other antimicrobial agents. Mutations in the QRDRs of these isolates were more heterogeneous than those previously reported for mutants selected in vitro. Eight isolates had amino acid changes at sites other than ParC/S79 and GyrA/S81; several strains contained mutations in gyrB, parE, or both loci. Contributions to fluoroquinolone resistance by individual amino acid changes, including GyrB/E474K, ParE/E474K, and ParC/A63T, were confirmed by genetic transformation of S. pneumoniae R6. Mutations in gyrB were important for resistance to gatifloxacin but not moxifloxacin, and mutation of gyrAwas associated with resistance to moxifloxacin but not gatifloxacin, suggesting differences in the drug-target interactions of the two 8-methoxyquinolones. The positions of amino acid changes within the four genes affected resistance more than did the total number of QRDR mutations. However, the effect of a specific mutation varied significantly depending on the agent tested. These data suggest that the heterogeneity of mutations will likely increase as pneumococci are exposed to novel fluoroquinolone structures, complicating the prediction of cross-resistance within this class of antimicrobial agents.

scholarly journals Antimicrobial Resistance among Clinical Isolates of Streptococcus pneumoniae in Canada during 2000

2002 ◽  
Vol 46 (5) ◽  
pp. 1295-1301 ◽  
Author(s):  
Donald E. Low ◽  
Joyce de Azavedo ◽  
Karl Weiss ◽  
Tony Mazzulli ◽  
Magdalena Kuhn ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Antimicrobial Resistance ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Central Laboratory ◽  
Resistant Strains ◽  
Resistance Rates

ABSTRACT A total of 2,245 clinical isolates of Streptococcus pneumoniae were collected from 63 microbiology laboratories from across Canada during 2000 and characterized at a central laboratory. Of these isolates, 12.4% were not susceptible to penicillin (penicillin MIC, ≥0.12 μg/ml) and 5.8% were resistant (MIC, ≥2 μg/ml). Resistance rates among non-β-lactam agents were the following: macrolides, 11.1%; clindamycin, 5.7%; chloramphenicol, 2.2%; levofloxacin, 0.9%; gatifloxacin, 0.8%; moxifloxacin, 0.4%; and trimethoprim-sulfamethoxazole, 11.3%. The MICs at which 90% of the isolates were inhibited (MIC90s) of the fluoroquinolones were the following: gemifloxacin, 0.03 μg/ml; BMS-284756, 0.06 μg/ml; moxifloxacin, 0.12 μg/ml; gatifloxacin, 0.25 μg/ml; levofloxacin, 1 μg/ml; and ciprofloxacin, 1 μg/ml. Of 578 isolates from the lower respiratory tract, 21 (3.6%) were inhibited at ciprofloxacin MICs of ≥4 μg/ml. None of the 768 isolates from children were inhibited at ciprofloxacin MICs of ≥4 μg/ml, compared to 3 of 731 (0.6%) from those ages 15 to 64 (all of these >60 years old), and 27 of 707 (3.8%) from those over 65. The MIC90s for ABT-773 and telithromycin were 0.015 μg/ml for macrolide-susceptible isolates and 0.12 and 0.5 μg/ml, respectively, for macrolide-resistant isolates. The MIC of linezolid was ≤2 μg/ml for all isolates. Many of the new antimicrobial agents tested in this study appear to have potential for the treatment of multidrug-resistant strains of pneumococci.

scholarly journals Penicillin-binding proteins 2b and 2x of Streptococcus pneumoniae are primary resistance determinants for different classes of beta-lactam antibiotics.

1996 ◽  
Vol 40 (4) ◽  
pp. 829-834 ◽  
Author(s):  
T Grebe ◽  
R Hakenbeck
Keyword(s):  
Streptococcus Pneumoniae ◽  
Clinical Isolate ◽  
Binding Proteins ◽  
Point Mutations ◽  
Clinical Isolates ◽  
Single Amino Acid ◽  
Beta Lactam ◽  
Penicillin Binding Proteins ◽  
Beta Lactam Antibiotics ◽  
High Level

High-level resistance to beta-lactam antibiotics in Streptococcus pneumoniae is mediated by successive alterations in essential penicillin-binding proteins (PBPs). In the present work, single amino acid changes in S. pneumoniae PBP 2x and PBP 2b that result in reduced affinity for the antibiotic and that confer first-level beta-lactam resistance are defined. Point mutations in the PBP genes were generated by PCR-derived mutagenesis. Those conferring maximal resistance to either cefotaxime (pbp2x) or piperacillin (pbp2b) were obtained after transformation of the susceptible laboratory strain R6 with the PCR-amplified PBP genes and selection on agar with various concentrations of the antibiotic. In the case of PBP 2x, transformants for which the cefotaxime MIC was 0.16 microgram/ml contained the substitution of a Thr for an Ala at position 550 (Thr550-->Ala), close to the PBP homology box Lys547SerGly, a mutation frequently observed in laboratory mutants and in a high-level cefotaxime-resistant clinical isolate as well. After further selection, transformants resisting 0.3 microgram of cefotaxime per ml were obtained; they contained the substitution Gly550 as the result of two mutations in the same codon. In PBP 2b, Thr446-->Ala, adjacent to another homology box Ser443SerAsn, was the mutation selected with piperacillin. This substitution has been described in all clinical isolates with a low-affinity PBP 2b but was distinct from point mutations found in laboratory mutants. Both pbp2b with the single mutation and a mosaic pbp2b of a clinical isolate conferred a twofold increase in piperacillin resistance. Attempts to select PBP 2b variants at higher piperacillin concentrations were unsuccessful. The mutated PBP 2b also markedly reduced the lytic response to piperacillin, suggesting that such a mutation is an important step in resistance development in clinical isolates.

scholarly journals Activities of Newer Fluoroquinolones against Streptococcus pneumoniae Clinical Isolates Including Those with Mutations in the gyrA, parC, and parELoci

1999 ◽  
Vol 43 (2) ◽  
pp. 329-334 ◽  
Author(s):  
J. H. Jorgensen ◽  
L. M. Weigel ◽  
M. J. Ferraro ◽  
J. M. Swenson ◽  
F. C. Tenover
Keyword(s):  
Streptococcus Pneumoniae ◽  
Amino Acid ◽  
Amino Acid Sequences ◽  
Clinical Isolates ◽  
Single Amino Acid ◽  
Single Mutation ◽  
Topoisomerase Iv ◽  
In Vitro Susceptibility ◽  
Resistant Strains ◽  
Level Resistance

ABSTRACT Resistance to fluoroquinolone (FQ) antibiotics inStreptococcus pneumoniae has been attributed primarily to specific mutations in the genes for DNA gyrase (gyrA andgyrB) and topoisomerase IV (parC andparE). Resistance to some FQs can result from a single mutation in one or more of the genes encoding these essential enzymes. A group of 160 clinical isolates of pneumococci was examined in this study, including 36 ofloxacin-resistant isolates (MICs, ≥8 μg/ml) recovered from patients in North America, France, and Belgium. The susceptibilities of all isolates to clinafloxacin, grepafloxacin, levofloxacin, sparfloxacin, and trovafloxacin were examined by the National Committee for Clinical Laboratory Standards reference broth microdilution and disk diffusion susceptibility testing methods. Among the ofloxacin-resistant strains, 32 of 36 were also categorized as resistant to levofloxacin, 35 were resistant to sparfloxacin, 29 were resistant to grepafloxacin, and 19 were resistant to trovafloxacin. In vitro susceptibility to clinafloxacin appeared to be least affected by resistance to the other FQs. Eight isolates with high- and low-level resistance to the newer FQs were selected for DNA sequence analysis of the quinolone resistance-determining regions (QRDRs) ofgyrA, gyrB, parC, andparE. The DNA and the inferred amino acid sequences of the resistant strains were compared with the analogous sequences of reference strain S. pneumoniae ATCC 49619 and FQ-susceptible laboratory strain R6. Reduced susceptibilities to grepafloxacin and sparfloxacin (MICs, 1 to 2 μg/ml) and trovafloxacin (MICs, 0.5 to 1 μg/ml) were associated with either a mutation inparC that led to a single amino acid substitution (Ser-79 to Phe or Tyr) or double mutations that involved the genes for both GyrA (Ser-81 to Phe) and ParE (Asp-435 to Asn). High-level resistance to all of the compounds except clinafloxacin was associated with two or more amino acid substitutions involving both GyrA (Ser-81 to Phe) and ParC (Ser-79 to Phe or Ser-80 to Pro and Asp-83 to Tyr). No mutations were observed in the gyrB sequences of resistant strains. These data indicate that mutations in pneumococcal gyrA,parC, and parE genes all contribute to decreased susceptibility to the newer FQs, and genetic analysis of the QRDR of a single gene, either gyrA or parC, is not predictive of pneumococcal resistance to these agents.

scholarly journals Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.

1996 ◽  
Vol 40 (5) ◽  
pp. 1208-1213 ◽  
Author(s):  
G V Doern ◽  
A Brueggemann ◽  
H P Holley ◽  
A M Rauch
Keyword(s):  
Streptococcus Pneumoniae ◽  
Antimicrobial Agents ◽  
Clinical Laboratory ◽  
Rank Order ◽  
The United States ◽  
Penicillin Resistance ◽  
National Committee ◽  
Medical Centers ◽  
Resistant Strains ◽  
High Level

A total of 1,527 clinically significant outpatient isolates of Streptococcus pneumoniae were prospectively collected in 30 different U.S. medical centers between November 1994 and April 1995. Overall, 23.6% of strains were not susceptible to penicillin, with 14.1% intermediate and 9.5% high-level resistant. The frequencies of recovery of intermediate and high-level resistant strains varied considerably between different medical centers and in different geographic areas. In general, intermediate and high-level penicillin resistance was most common with isolates of S. pneumoniae recovered from pediatric patients. The in vitro activities of 22 other antimicrobial agents were assessed against this collection of isolates. Ampicillin was consistently 1 twofold dilution less active than penicillin. Amoxicillin and amoxicillin-clavulanate were essentially equivalent to penicillin in activity. The rank order of activity for cephalosporins was cefotaxime = ceftriaxone > or = cefpodoxime > or = cefuroxime > cefprozil > or = cefixime > cefaclor = loracarbef > cefadroxil = cephalexin. The National Committee for Clinical Laboratory Standards [Performance Standards for Antimicrobial Susceptibility Testing, Sixth Information Supplement (M100-S6), 1995] has established MIC breakpoints for resistance (i.e., > or = 2 micrograms/ml) with three cephalosporins versus S. pneumoniae, namely, cefotaxime, ceftriaxone, and cefuroxime. The overall percentages of strains resistant to these three antimicrobial agents were 3, 5, and 12, respectively. The overall frequency of resistance was 10% with all three macrolides examined in this study, clarithromycin, erythromycin, and azithromycin. The overall percentages of chloramphenicol, tetracycline, and trimethoprim-sulfamethoxazole resistance were 4.3, 7.5, and 18, respectively. The resistance percentages among the cephalosporins, macrolides, chloramphenicol, tetracycline, and trimethoprim-sulfamethoxazole were consistently higher among penicillin-intermediate strains than among susceptible isolates and even higher still among organisms expressing high-level penicillin resistance. Multiply resistant strains represented 9.1% of the organisms examined in this study. Finally, rifampin resistance was uncommon (i.e., 0.5%), and vancomycin resistance was not detected. The quinopristin-dalfopristin combination was consistently active at concentrations of 0.25 to 4 micrograms/ml, but rates of resistance could not be determined in the absence of established interpretive criteria for MIC results.

scholarly journals High-level fluoroquinolone resistance in Streptococcus pneumoniae requires mutations in parC and gyrA.

1996 ◽  
Vol 40 (12) ◽  
pp. 2760-2764 ◽  
Author(s):  
C Janoir ◽  
V Zeller ◽  
M D Kitzis ◽  
N J Moreau ◽  
L Gutmann
Keyword(s):  
Streptococcus Pneumoniae ◽  
Quinolone Resistance ◽  
Fluoroquinolone Resistance ◽  
Clinical Samples ◽  
Low Frequencies ◽  
Low Level ◽  
Resistant Strains ◽  
High Level ◽  
Level Resistance

The mechanism of high-level fluoroquinolone resistance was studied in strains of Streptococcus pneumoniae, either selected in vitro or isolated from clinical samples. By using DNA from these high-level-resistant strains, low-level-resistant transformants (MIC of pefloxacin, > or = 32 micrograms/ml; MIC of ciprofloxacin, 4 micrograms/ml; MIC of sparfloxacin, 0.50 micrograms/ml) were obtained at high frequencies (ca.10(-2)), while high-level-resistant transformants (MIC of pefloxacin, > or = 64 micrograms/ml; MIC of ciprofloxacin, 16 to 64 micrograms/ml; MIC of sparfloxacin, > or = 8 micrograms/ml) were obtained only at low frequencies (ca.10(-4)). This suggested that mutations in at least two unlinked genes were necessary to obtain high-level resistance. Low-level resistance was associated with ParC mutations (change from Ser to Tyr at position 79 [Ser79Tyr], Ser79Phe, or Asp83Gly). ParC mutations were associated, in high-level-resistant strains and transformants, with alterations in the quinolone resistance-determining region of GyrA (Ser84Tyr, Ser84Phe, and/or Glu88Lys). Low-level resistance was shown to be necessary for expression of the gyrA mutations. No mutation in the region corresponding to the quinolone resistance-determining region of GyrB and no alteration of drug accumulation were found.

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