Antimicrobial Susceptibility Breakpoints
Antimicrobial Susceptibility Breakpoints
Clinical antimicrobial susceptibility breakpoints are used to predict the clinical outcome of antimicrobial treatment. In contrast, microbiologic breakpoints are used to identify isolates that may be categorized as susceptible when applying clinical breakpoints but harbor resistance mechanisms that result in their reduced susceptibility to the agent being tested. Currently, the National Committee for Clinical Laboratory Standards (NCCLS) guidelines utilize clinical breakpoints to characterize the activity of the fluoroquinolones against Streptococcus pneumoniae. To determine whether levofloxacin breakpoints can identify isolates that harbor recognized resistance mechanisms, we examined 115 S. pneumoniae isolates with a levofloxacin MIC of ≥2 µg/mL for first-step parC mutations. A total of 48 (59%) of 82 isolates with a levofloxacin MIC of 2 µg/mL, a level considered susceptible by NCCLS criteria, had a first-step mutation in parC. Whether surveillance programs that use levofloxacin data can effectively detect emerging resistance and whether fluoroquinolones can effectively treat infections caused by such isolates should be evaluated.
The emergence of Streptococcus pneumoniae resistance to ß-lactam and macrolide antimicrobial agents has led to recommendations that fluoroquinolones with increased activity against S. pneumoniae, such as levofloxacin, moxifloxacin, and gatifloxacin, be used to treat patients at risk for infection caused by such multidrug-resistant strains. Fluoroquinolone resistance in S. pneumoniae is primarily due to mutations in the genes encoding the target topoisomerase enzymes, namely parC, which encodes the A subunit of DNA topoisomerase IV, and gyrA, which encodes the A subunit of DNA gyrase. Mutations in parE and gyrB have been reported, but to a lesser extent. Most pneumococcal isolates with reduced susceptibilities to fluoroquinolones have amino acid substitutions in either ParC alone or ParC and GyrA. Resistance can also be mediated by active efflux , although the role of efflux in contributing to resistance by the newer fluoroquinolones is unclear.
The MIC of an antimicrobial agent is a value that has been used to determine breakpoints that predict the probability of clinical success, detect resistant populations, or both. Clinical breakpoints are dependent on the antimicrobial activity and pharmacology of the drug; such breakpoints are ascertained with the goals of eradicating the infection and ultimately achieving clinical success with the antimicrobial agent. In contrast, microbiologic breakpoints are established to identify isolates that may be categorized as susceptible when applying clinical breakpoints but harbor resistance mechanisms that result in their reduced susceptibility to the agent being tested. These microbiologic breakpoints are therefore useful in monitoring the emergence of resistance. The current National Committee for Clinical Laboratory Standards (NCCLS) guidelines make no distinction between these two interpretations of MIC, with clinical breakpoints used to characterize most antimicrobial agents, including the fluoroquinolones.
Levofloxacin has been used as a surrogate marker to predict fluoroquinolone susceptibility in clinical laboratories and surveillance studies. To establish whether current levofloxacin breakpoints are also able to function as microbiologic breakpoints, we determined the percentage of S. pneumoniae isolates with first-step parC mutations that would go undetected by using the current NCCLS breakpoints for levofloxacin.
Clinical antimicrobial susceptibility breakpoints are used to predict the clinical outcome of antimicrobial treatment. In contrast, microbiologic breakpoints are used to identify isolates that may be categorized as susceptible when applying clinical breakpoints but harbor resistance mechanisms that result in their reduced susceptibility to the agent being tested. Currently, the National Committee for Clinical Laboratory Standards (NCCLS) guidelines utilize clinical breakpoints to characterize the activity of the fluoroquinolones against Streptococcus pneumoniae. To determine whether levofloxacin breakpoints can identify isolates that harbor recognized resistance mechanisms, we examined 115 S. pneumoniae isolates with a levofloxacin MIC of ≥2 µg/mL for first-step parC mutations. A total of 48 (59%) of 82 isolates with a levofloxacin MIC of 2 µg/mL, a level considered susceptible by NCCLS criteria, had a first-step mutation in parC. Whether surveillance programs that use levofloxacin data can effectively detect emerging resistance and whether fluoroquinolones can effectively treat infections caused by such isolates should be evaluated.
The emergence of Streptococcus pneumoniae resistance to ß-lactam and macrolide antimicrobial agents has led to recommendations that fluoroquinolones with increased activity against S. pneumoniae, such as levofloxacin, moxifloxacin, and gatifloxacin, be used to treat patients at risk for infection caused by such multidrug-resistant strains. Fluoroquinolone resistance in S. pneumoniae is primarily due to mutations in the genes encoding the target topoisomerase enzymes, namely parC, which encodes the A subunit of DNA topoisomerase IV, and gyrA, which encodes the A subunit of DNA gyrase. Mutations in parE and gyrB have been reported, but to a lesser extent. Most pneumococcal isolates with reduced susceptibilities to fluoroquinolones have amino acid substitutions in either ParC alone or ParC and GyrA. Resistance can also be mediated by active efflux , although the role of efflux in contributing to resistance by the newer fluoroquinolones is unclear.
The MIC of an antimicrobial agent is a value that has been used to determine breakpoints that predict the probability of clinical success, detect resistant populations, or both. Clinical breakpoints are dependent on the antimicrobial activity and pharmacology of the drug; such breakpoints are ascertained with the goals of eradicating the infection and ultimately achieving clinical success with the antimicrobial agent. In contrast, microbiologic breakpoints are established to identify isolates that may be categorized as susceptible when applying clinical breakpoints but harbor resistance mechanisms that result in their reduced susceptibility to the agent being tested. These microbiologic breakpoints are therefore useful in monitoring the emergence of resistance. The current National Committee for Clinical Laboratory Standards (NCCLS) guidelines make no distinction between these two interpretations of MIC, with clinical breakpoints used to characterize most antimicrobial agents, including the fluoroquinolones.
Levofloxacin has been used as a surrogate marker to predict fluoroquinolone susceptibility in clinical laboratories and surveillance studies. To establish whether current levofloxacin breakpoints are also able to function as microbiologic breakpoints, we determined the percentage of S. pneumoniae isolates with first-step parC mutations that would go undetected by using the current NCCLS breakpoints for levofloxacin.
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