Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model

Kang, Sangrim; Rybak, Michael J.; McGrath, B J; Kaatz, Glenn W.; Seo, Susan M.

doi:10.1128/aac.38.12.2702

Cited by 69 publications

(32 citation statements)

References 38 publications

(50 reference statements)

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“…Our findings are consistent with an earlier study where no resistance occurred when S. aureus was exposed to levofloxacin daily doses of 400 to 800 mg in an in vitro glass infection model (21). Our results are similar to those of another study where a levofloxacin-susceptible (MIC, 0.5 g/ml) S. aureus strain was exposed to a simulated levofloxacin regimen of 500 mg every 24 h in a hollow-fiber in vitro system (25).…”

Section: Discussionsupporting

confidence: 83%

Pharmacodynamic Modeling of the Evolution of Levofloxacin Resistance in Staphylococcus aureus

Campion¹,

Chung

Titlow³

et al. 2005

Antimicrob Agents Chemother

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Previously, we demonstrated the importance of low-level-resistant variants to the evolution of resistance in Staphylococcus aureus exposed to ciprofloxacin in an in vitro system and developed a pharmacodynamic model which predicted the emergence of resistance. Here, we examine and model the evolution of resistance to levofloxacin in S. aureus exposed to simulated levofloxacin pharmacokinetic profiles. Enrichment of subpopulations with mutations in grlA and low-level resistance varied with levofloxacin exposure. A regimen producing average steady-state concentrations (C avg ss ) just above the MIC selected grlA mutants with up to 16-fold increases in the MIC and often additional mutations in grlA/grlB and gyrA. A regimen providing C avg ss between the MIC and the mutant prevention concentration (MPC) suppressed bacterial numbers to the limit of detection and prevented the appearance of bacteria with additional mutations or high-level resistance. Regimens producing C avg ss above the MPC appeared to eradicate low-level-resistant variants in the cultures and prevent the emergence of resistance. There was no relationship between the time concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of mutations that appeared in grlA/B or gyrA. Our pharmacodynamic model described the growth and levofloxacin killing of the parent strains and the most resistant grlA mutants in the starting cultures and correctly predicted conditions that enrich subpopulations with low-level resistance. These findings suggest that the pharmacodynamic model has general applicability for describing fluoroquinolone resistance in S. aureus and further demonstrate the importance of low-level-resistant variants to the evolution of resistance.In previous work, we examined the evolution of resistance when ciprofloxacin-susceptible (S) Staphylococcus aureus strains were exposed in an in vitro hollow-fiber system to simulated clinical and experimental ciprofloxacin pharmacokinetic profiles (4). We found that with increasing average steady-state concentrations (C avg ss ), the rate of initial killing approached a maximum, and the rate of regrowth decreased. Enrichment of subpopulations with mutations in grlA and low-level resistance also varied depending on the pharmacokinetic environment. A regimen producing C avg ss slightly above the MIC selected resistant (R) variants with grlA mutations that did not evolve to higher levels of resistance. Clinical regimens which provided C avg ss intermediate between the MIC and mutant prevention concentration (MPC) resulted in the emergence of subpopulations with gyrA mutations and higher levels of resistance and a regimen producing C avg ss greater than or equal to the MPC selected grlA mutants, but the appearance of subpopulations with higher levels of resistance was delayed. A regimen designed to maintain ciprofloxacin concentrations entirely above the MPC appeared to eradicate low-level-resistant variants in the inoculum and prevent the emergence of high-level-re...

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Section: Discussionsupporting

confidence: 83%

Pharmacodynamic Modeling of the Evolution of Levofloxacin Resistance in Staphylococcus aureus

Campion¹,

Chung

Titlow³

et al. 2005

Antimicrob Agents Chemother

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“…Our results differ from those of others who examined the killing and regrowth of S. aureus exposed to ciprofloxacin in in vitro systems (6,17,31,35). The discrepancies between our results in which resistance (often high level) emerged and those of others in which resistance did not emerge may be due to factors such as the type of in vitro system used, phenotypic and genotypic heterogeneity of the bacteria tested, methods of drug administration, and the duration of the experiments.…”

Section: Discussioncontrasting

confidence: 56%

Evolution of Ciprofloxacin-Resistant Staphylococcus aureus in In Vitro Pharmacokinetic Environments

Campion¹,

Evans²

2004

Antimicrob Agents Chemother

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The development of novel antibacterial agents is decreasing despite increasing resistance to presently available agents among common pathogens. Insights into relationships between pharmacodynamics and resistance may provide ways to optimize the use of existing agents. The evolution of resistance was examined in two ciprofloxacin-susceptible Staphylococcus aureus strains exposed to in vitro-simulated clinical and experimental ciprofloxacin pharmacokinetic profiles for 96 h. As the average steady-state concentration (C avg ss ) increased, the rate of killing approached a maximum, and the rate of regrowth decreased. The enrichment of subpopulations with mutations in grlA and low-level ciprofloxacin resistance also varied depending on the pharmacokinetic environment. A regimen producing values for C avg ss slightly above the MIC selected resistant variants with grlA mutations that did not evolve to higher levels of resistance. Clinical regimens which provided values for C avg ss intermediate to the MIC and mutant prevention concentration (MPC) resulted in the emergence of subpopulations with gyrA mutations and higher levels of resistance. A regimen producing values for C avg ss close to the MPC selected grlA mutants, but the appearance of subpopulations with higher levels of resistance was diminished. A regimen designed to maintain ciprofloxacin concentrations entirely above the MPC appeared to eradicate low-level resistant variants in the inoculum and prevent the emergence of higher levels of resistance. There was no relationship between the time that ciprofloxacin concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of ciprofloxacin-resistance mutations that appeared in grlA or gyrA. Regimens designed to eradicate low-level resistant variants in S. aureus populations may prevent the emergence of higher levels of fluoroquinolone resistance.

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“…Those authors found that the activity of each drug showed antagonism when combined together, yet substantial SBA remained (264). Kang et al also could not show rifampin-ciprofloxacin in vitro synergy, but the addition of rifampin prevented the emergence of ciprofloxacin-resistant S. aureus isolates (138). The rifampin-quinolone in vitro data suggest that the combination does not appear to offer any substantial benefit against S. aureus other than perhaps preventing quinolone resistance.…”

Section: Staphylococcimentioning

confidence: 88%

Rifampin Combination Therapy for Nonmycobacterial Infections

2010

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SUMMARY The increasing emergence of antimicrobial-resistant organisms, especially methicillin-resistant Staphylococcus aureus (MRSA), has resulted in the increased use of rifampin combination therapy. The data supporting rifampin combination therapy in nonmycobacterial infections are limited by a lack of significantly controlled clinical studies. Therefore, its current use is based upon in vitro or in vivo data or retrospective case series, all with major limitations. A prominent observation from this review is that rifampin combination therapy appears to have improved treatment outcomes in cases in which there is a low organism burden, such as biofilm infections, but is less effective when effective surgery to obtain source control is not performed. The clinical data support rifampin combination therapy for the treatment of prosthetic joint infections due to methicillin-sensitive S. aureus (MSSA) after extensive debridement and for the treatment of prosthetic heart valve infections due to coagulase-negative staphylococci. Importantly, rifampin-vancomycin combination therapy has not shown any benefit over vancomycin monotherapy against MRSA infections either clinically or experimentally. Rifampin combination therapy with daptomycin, fusidic acid, and linezolid needs further exploration for these severe MRSA infections. Lastly, an assessment of the risk-benefits is needed before the addition of rifampin to other antimicrobials is considered to avoid drug interactions or other drug toxicities.

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Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model

Cited by 69 publications

References 38 publications

Pharmacodynamic Modeling of the Evolution of Levofloxacin Resistance in Staphylococcus aureus

Pharmacodynamic Modeling of the Evolution of Levofloxacin Resistance in Staphylococcus aureus

Evolution of Ciprofloxacin-Resistant Staphylococcus aureus in In Vitro Pharmacokinetic Environments

Rifampin Combination Therapy for Nonmycobacterial Infections

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