Population pharmacokinetic modeling and Monte Carlo simulation of varying doses of intravenous metronidazole.

Population pharmacokinetic modeling and Monte Carlo simulation (MCS) are approaches used to determine probability of target attainment (PTA) of antimicrobial therapy. The objectives of this study were 1) to determine a population pharmacokinetic model (PPM) using metronidazole and hydroxy-metronidazole concentrations from healthy subjects and critically ill patients, and 2) to determine the probability of attaining the pharmacodynamic target area under the plasma concentration (AUC)/MIC ratio >or=70 against 218 clinical isolates of Bacteroides fragilis using MCS. Eighteen healthy subjects were randomized to 3 dosages of intravenous metronidazole (500 mg every 8 h, 1000 mg day(-1), 1500 mg day(-1)) in an open-label 3-way crossover fashion. Serial blood samples were collected over 25.5 h on the 3rd day of each study period. An additional of 8 critically ill patients received intravenous metronidazole 500 mg every 8 h. Serial blood samples were collected over 8 h after the 2nd day of dosing. Plasma metronidazole and hydroxy-metronidazole concentrations were analyzed using a high-performance liquid chromatographic assay. The 834 plasma concentrations from 62 data sets were simultaneously modeled with Non-Parametric Adaptive Grid population modeling program. A 4-compartment model with a metabolite and zero-order infusion into the central compartment was used. The mean parameter vector and covariance matrix from PPM were inserted into the simulation module of ADAPT II. A 10,000-subject MCS was performed to determine the probability of PTA for a total drug AUC to MIC ratio >or=70 against 218 isolates of B. fragilis (MIC range, 0.125-2.0 mg L(-1)). Mean parameter values were CL(non-OH), 3.08 L h(-1); Vc, 35.4 L; K(OH), 0.04 h(-1); CL(OH), 2.78 L h(-1); and V(OH), 9.66 L. The regression values of the observed versus predicted concentrations (r2) of metronidazole and hydroxy-metronidazole were 0.972 and 0.980, respectively. The PTA for metronidazole 1500 mg day(-1) or 500 mg every 8 h (taken together) and 1000 mg day(-1) were 99.9% and 99.8%, respectively, over the reported MIC distribution range. For an MIC of 4 mg L(-1), the predicted PTA decreased to 80.0% and 28.5%, respectively. A PPM was determined by comodeling metronidazole and hydroxy-metronidazole concentrations from healthy subjects and critically ill patients. Based on this model, attainment of the target pharmacodynamic parameter (AUC/MIC ratio >or=70) against B. fragilis isolates is >99% when MICs are <2 mg L(-1), irrespective of the dosing interval of 24 h.

Safety and tolerability of fluoroquinolones.

Clinical trials in patients with community- and hospital-acquired infections have established that the clinical effectiveness and safety of fluoroquinolones are similar to beta-lactam and macrolide agents. The most common drug-related adverse effects (AEs) with fluoroquinolone therapy involve the gastrointestinal tract and central nervous system and are usually transient and mild to moderate in severity. However, serious toxic reactions have led to the limited and restrictive use of trovafloxacin in the United States and the withdrawal of temafloxacin and grepafloxacin from worldwide markets. In addition, postmarketing spontaneous AE reports have imposed updates in the precautions and warning sections of product package inserts of selected fluoroquinolones. This article reviews the AEs associated with the fluoroquinolones and compares the safety profiles of ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin.

Levofloxacin plus metronidazole administered once daily versus moxifloxacin monotherapy against a mixed infection of Escherichia coli and Bacteroides fragilis in an in vitro pharmacodynamic model.

Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre- and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8- to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B. fragilis infection. A once-daily regimen of levofloxacin plus metronidazole looks promising for the treatment of intra-abdominal infections.

Pharmacokinetics and pharmacodynamics of intravenous levofloxacin at 750 milligrams and various doses of metronidazole in healthy adult subjects.

The purpose of this investigation was to evaluate the steady-state pharmacokinetics, pharmacodynamics, and safety of intravenous levofloxacin at 750 mg administered once daily combined with three different dosages of intravenous metronidazole (500 mg every 8 h [q8h], 1,000 mg q24h, and 1,500 mg q24h). Eighteen healthy adult subjects received all three combinations in a randomized, crossover fashion. Serial blood and urine samples were collected on the third day of each study period. The 24-h areas under the inhibitory (AUIC(0-24)) and bactericidal (AUBC(0-24)) curves of these three combination regimens were determined against clinical isolates of Bacteroides fragilis, Bacteroides thetaiotaomicron, Peptostreptococcus asaccharolyticus, and Escherichia coli. The mean concentrations of levofloxacin were not different between study periods and were similar to those previously published. The mean (+/- standard deviation) areas under the metronidazole plasma concentration-time curve (AUC(0-24)) for 1,500-mg q24h (338 +/- 105 mg.h/liter) and 500-mg q8h (356 +/- 68 mg.h/liter) regimens were not different (P > 0.05), but both were significantly higher than the 1,000-mg q24h AUC(0-24) (P < 0.05, 227 +/- 57 mg.h/liter). Mean (+/- standard deviation) total body clearance and renal clearance values were similar among the 500-mg q8h, 1,000-mg q24, and 1,500-mg q24h regimens (62 +/- 7, 67 +/- 13, and 67 +/- 14 and 11 +/- 3, 12 +/- 2, and 12 +/- 5 ml/min/1.73 m2, respectively). Levofloxacin at 750 mg q24h plus metronidazole at 500 mg q8h or 1,500 mg q24h resulted in similar AUIC(0-24) and AUBC(0-24) values with one exception: the AUIC(0-24) for the 1,500-mg q24h regimen against B. thetaiotamicron was significantly higher (P < 0.05) than those of the other regimens. Overall, the combination of levofloxacin at 750 mg once daily and metronidazole at 500 mg q8h or 1,500 mg q24h appeared to have greater AUIC(0-24) and AUBC(0-24) values than did the 1,000-mg q24h regimen. All combination regimens of levofloxacin and metronidazole were well tolerated, and no serious drug-related adverse effects were reported. The pharmacokinetic, safety, and pharmacodynamic data from our study suggest that a once-daily regimen of intravenous levofloxacin at 750 mg and metronidazole at 1,500 mg warrants further clinical investigation.