Pharmacokinetics and safety of trovafloxacin (CP-99, 219), a new quinolone antibiotic, following adminstration of single oral doses to healthy male volunteers

The pharmacodynamic and pharmacokinetic properties of trovafloxacin were studied in a standardized murine model of established subcutaneous abscesses. Daily dosing regimens of 37.5 to 300 mg/kg every 8 h (q8h) or every 24 h (q24h) were started 3 days after inoculation with mixtures containing either Bacteroides fragilis-Escherichia coli-autoclaved cecal contents (ACC) or B. fragilis-vancomycin-resistant Enterococcus faecium (VREF)-ACC. Treatment was continued for 3 or 5 days. The efficacy of treatment was determined by the decrease in abscess bacterial counts and abscess weights, as well as by the reduction in inflammation (biodistribution of 99m Tc-HYNIC immunoglobulin G) compared to saline-treated controls. Trovafloxacin showed a significant dose-response effect on the bacterial counts, weight, and inflammation of B. fragilis-E. coli abscesses after 3 and/or 5 days of treatment. A maximum 3.4 and 3.1 log 10 reduction in CFU/abscess in the respective B. fragilis and E. coli bacterial counts was attained after 5 days of treatment with daily doses of 300 mg/kg. The peak serum concentration was more predictive for effect than the area under the concentration-time curve. The C max was the pharmacodynamic index most predictive for success, and the efficacy of the q24h regimens was significantly better than the q8h regimens. The antibiotic was ineffective against the VREF in mixed infection with B. fragilis, while the killing of the anaerobe in the same combination was significantly less than in the E. coli combination (P < 0.05). We conclude that this is a useful model for studying the activity of antimicrobials for the treatment of small (<1-cm), undrainable, mixed-infection abscesses. In addition, we have shown for the first time that a decrease in bacterial numbers also leads to a reduction in both abscess weight and inflammation.

Section: Discussionmentioning

confidence: 85%

In Vivo Efficacy of Trovafloxacin against Bacteroides fragilis in Mixed Infection with either Escherichia coli or a Vancomycin-Resistant Strain of Enterococcus faecium in an Established-Abscess Murine Model

Stearne

Gyssens

Goessens

et al. 2001

“…In addition, the effect of LVX at the AUC that corresponds to that achieved with its 750-mg dose was predicted. The necessary AUC ther s were calculated by using linear dose relationships (GEM [2], LVX [20], and MXF [38]) or curvilinear dose relationships (CIP [4], GAT [30], GRX [10], and TVA [41,46]) of the AUC. To consider the different levels of protein binding of CIP, GAT, GEM, GRX, LVX, MXF, and TVA, the AUC ther s were corrected by factors of 0.74, 0.80, 0.30, 0.57, 0.70, 0.60, and 0.28, respectively (the reported free fractions of the quinolones in plasma are presented in Table 2).…”

Section: Antimicrobial Agents Ciprofloxacin (Cip) Gatifloxacin (Gatmentioning

confidence: 99%

Antistaphylococcal Effect Related to the Area under the Curve/MIC Ratio in an In Vitro Dynamic Model: Predicted Breakpoints versus Clinically Achievable Values for Seven Fluoroquinolones

Firsov

Lubenko

Vostrov

et al. 2005

Prediction of comparative efficacies among fluoroquinolones is often based on the ratios of the clinically achievable area under the concentration-time curve (AUC) to the MIC, usually with incorporation of the MIC 50 or MIC 90 (31). In fact, these antimicrobial effect predictors rather than the effect itself are often used in these comparisons. Such a replacement might seem appropriate, although it would be correct only if it were assumed that the AUC/MIC-response relationships are antibiotic independent. However, our in vitro pharmacodynamic studies that simulate quinolone pharmacokinetics (13,18,19,43) did not support this assumption: a specific AUC/MICresponse relationship was shown to be inherent in each individual quinolone.The present study was designed to compare the pharmacodynamics of seven pharmacokinetically different fluoroquinolones against Staphylococcus aureus, to delineate AUC/MICresponse relationships, and to predict the respective AUC/ MIC breakpoints (BPs) relative to clinically achievable AUC/ MIC ratios.

“…Pharmacokinetic data from studies with adults demonstrate a terminal elimination half-life (t 1/2 ) of 10 h for trovafloxacin following administration of a single oral dose (14,16), with similar values observed following administration of a single intravenous dose of alatrofloxacin, the L-Ala-L-alanine prodrug of trovafloxacin (18). This prodrug is rapidly hydrolyzed to trovafloxacin in the patient's bloodstream.…”

mentioning

confidence: 80%

Pharmacokinetics of a Fluoronaphthyridone, Trovafloxacin (CP 99,219), in Infants and Children following Administration of a Single Intravenous Dose of Alatrofloxacin

Bradley

Kearns

Reed

et al. 2000

The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average ؎ standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 ؎ 1.4 g/ml. The primary pharmacokinetic parameters (average ؎ SD) analyzed were volume of distribution at steady state (1.6 ؎ 0.6 liters/kg), clearance (151 ؎ 82 ml/h/kg), and half-life (9.8 ؎ 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 ؎ 10.1 g ⅐ h/ml and the susceptibility (<0.5 g/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.