Dose ranging and fractionation of intravenous ciprofloxacin against Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of infection

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.

Section: Discussioncontrasting

confidence: 56%

mentioning

confidence: 99%

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

Campion¹,

Evans²

2004

“…Further doses of both agents did not reduce the bacterial counts. A ciprofloxacin C max /MIC greater than 10 in a dose ranging study in an in vitro model has been considered to be a strong predictor of clinical success against P. aeruginosa (27), an organism similarly saprophytic, multiresistant, and pathogenic for debilitated patients as S. maltophilia. In our study, only moxifloxacin led to upper values for the reference strains and the two MIC-related parameters were at least threefold higher for moxifloxacin than for ciprofloxacin.…”

Section: Discussionmentioning

confidence: 99%

Activities of Ciprofloxacin and Moxifloxacin against Stenotrophomonas maltophilia and Emergence of Resistant Mutants in an In Vitro Pharmacokinetic-Pharmacodynamic Model

Feghali

Arpin

et al. 2004

A two-compartment in vitro pharmacokinetic-pharmacodynamic model, with full computer-controlled devices, was used to accurately simulate human plasma pharmacokinetic profiles after multidose oral regimens of ciprofloxacin (750 mg every 12 h) and moxifloxacin (400 mg every 24 h) during 48 h. Pharmacodynamics of these drugs was investigated against three quinolone-susceptible strains of Stenotrophomonas maltophilia (MICs of ciprofloxacin and moxifloxacin of 0.5 to 2 and 0.0625 to 0.5 g/ml, respectively). The first dose of ciprofloxacin and moxifloxacin reduced the bacterial count by 1 and 2 log CFU/ml, respectively, prior to a bacterial regrowth that reached the plateau value of the growth control curve at 13 to 24 h versus 24 to 36 h and persisted despite repeated administration of both drugs. The surviving bacterial cells were quinoloneresistant mutants (2 to 128 times the MIC) that exhibited cross-resistance to unrelated antibiotics. Their antibiotic resistance probably resulted from the overproduction of different multidrug resistance efflux system(s). C max /MIC and area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC values were at least threefold higher for moxifloxacin than for ciprofloxacin. Moreover, integral parameters of ciprofloxacin and moxifloxacin, in particular the area under the killing and regrowth curve from 0 to 48 h (AUBC 0-48 , 342.3 to 401.3 versus 295.2 to 378.7 h ؋ log CFU/ml, respectively) and the area between the control growth curve and the killing and regrowth curve from 0 to 48 h (ABBC 0-48 , 40.4 to 101.1 versus 72.9 to 144.7 h ؋ log CFU/ml, respectively), demonstrated a better antibacterial effect of moxifloxacin than ciprofloxacin on S. maltophilia. However, selection of resistant mutants by both fluoroquinolones, although delayed with moxifloxacin, emphasizes the need to use maximal dosages and combined therapy in the treatment of systemic S. maltophilia infections.

“…Bacterial resistance has been studied infrequently using these models. Limited observations reported from earlier timekill studies (3,8,(21)(22)(23) precluded delineation of relationships of the area under the concentration-time curve (AUC)/MIC ratio with resistance because the ranges of the simulated AUCto-MIC ratios were too narrow. In fact, the first attempts to relate resistance to the AUC/MIC or peak concentration (C max )/MIC ratio were reported quite recently from studies that declared resistance analysis as a primary goal (1, 7, 17, 18, 20, 25-27, 30, 33, 34; A. MacGowan and K. Bowker, Abstr.…”

mentioning

confidence: 99%

In Vitro Pharmacodynamic Evaluation of the Mutant Selection Window Hypothesis Using Four Fluoroquinolones against Staphylococcus aureus

Firsov

Vostrov

Lubenko

et al. 2003

201

183

Examination of time-kill curves of antibiotic-exposed bacteria using in vitro dynamic models allows pharmacokinetically related comparisons of antimicrobial effects but may or may not directly reflect the selective enrichment of resistant mutants. Bacterial resistance has been studied infrequently using these models. Limited observations reported from earlier timekill studies (3, 8, 21-23) precluded delineation of relationships of the area under the concentration-time curve (AUC)/MIC ratio with resistance because the ranges of the simulated AUCto-MIC ratios were too narrow. In fact, the first attempts to relate resistance to the AUC/MIC or peak concentration (C max )/MIC ratio were reported quite recently from studies that declared resistance analysis as a primary goal (1,7,17,18,20,(25)(26)(27)30,33,34; A. MacGowan and K. Bowker, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., poster A-440, 2001). Despite wide ranges of AUC/MIC ratios simulated in some recent studies (17)(18)(19)(20)27,33; MacGowan and Bowker, 41st ICAAC), reasonable relationships with resistance were not established. The relatively few studies of these relationships can be classified as those that directly attempt to relate resistance to the simulated pharmacokinetics but do not (17,20) and those that imply the existence of relationships with the AUC/MIC ratio measured within a 24-h dosing interval (AUC 24 /MIC) or with the C max /MIC ratio but do not actually report them (26,27,30). One study did report a complex effect of AUC 24 /MIC and duration of moxifloxacin treatment on bacterial resistance (MacGowan and Bowker, 41st ICAAC), but the three-dimensional plots masked rather than highlighted these links. For example, according to an analysis of these data (A. Firsov, S. Vostrov, I. Lubenko, S. Zinner, and Y. Portnoy, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-1210Chemother., abstr. A- , p. 10, 2002, the reported 72-h area under the population analysis profile-time curve as an index of pneumococcal resistance did not correlate with simulated AUC 24 /MIC ratios (r 2 , 0.04).