Population pharmacokinetics and target attainment analysis of moxifloxacin in patients with diabetic foot infections

Abstract

The objective of this study was to provide a pharmacokinetic/pharmacodynamic (PK/PD) analysis of moxifloxacin in patients with diabetic foot infections (DFI). The plasma concentration-time courses were determined in 50 DFI patients on day 1 and 3 after intravenous moxifloxacin 400 mg once-daily. A two-compartment population pharmacokinetic model was developed, identifying as covariates total body weight on central and peripheral volume of distribution (V1, V2) and ideal body weight on clearance (CL), respectively. For a 70 kg patient V1 was 68.1 L (interindividual variability, CV: 27.4%), V2 44.6 L, and CL 12.1 L/h (25.6%). Simulations were performed to calculate the probability of target attainment (PTA) for Gram-positive and Gram-negative pathogens with fAUC/MIC targets of ≥30 and ≥100, respectively. PTA was 0.68-1 for susceptible (MIC ≤0.5 mg/L according to EUCAST) Gram-positive, but <0.25 for Gram-negative pathogens with MIC ≥0.25 mg/L. With the exception of the first 24 hours of therapy, obesity affected PTA only marginally. Pharmacokinetic parameters in DFI patients were similar to those reported for healthy volunteers, indicating the appropriateness of the standard dose of moxifloxacin. Overall clinical efficacy has been shown previously, but PTA is limited in a subpopulation infected with formally susceptible Gram-negative pathogens close to the EUCAST breakpoint.

Is Moxifloxacin a Treatment Option for Pancreatic Infections? A Pharmacometric Analysis of Serum and Pancreatic Juice

“…Individually different and partly substantial volumes of intravenous infusion were given to the patients, which might have affected the initial distribution of MXF. Yet infusion volume could not be identified as a predictive covariate on V1 or Q. MXF clearance was comparably small and in line with previous findings, 20,21 indicating that the pancreatic juice drainage did not substantially contribute to MXF clearance. However, we acknowledge that the clearance of pancreatic juice drainage was not formally estimated due to the lack of cumulated volume of pancreatic juice in this study.…”

“…For the PK analysis, the population approach was chosen, which allowed for evaluating all available data (rich and sparse sampling) and could be exploited for simulation. The mean serum PK characteristics of MXF in the studied patient population were in a similar range of previous PK studies . However, of note is that the PK analysis revealed substantial unexplained interindividual variability of the V1 and Q, being considerably higher than previously observed.…”

“…Due to the considerably low total number of isolates with MIC values around the susceptibility breakpoint, no difference in the target attainment rate was observed between serum and pancreatic juice. Yet if the anticipated PTA was also calculated as a function of MIC (Figure ), a trend toward a one log 2 ‐fold higher susceptibility breakpoint for pancreatic juice was detected due to the approximately 2‐fold higher AUC values in pancreatic juice compared to those in serum, with serum PTA being in agreement with previously determined PTA . The susceptibility breakpoint for MXF in pancreatic juice might lie in the range of 0.25 mg/L for gram‐negative and 1.0 mg/L for gram‐positive organisms.…”

“…The mean serum PK characteristics of MXF in the studied patient population were in a similar range of previous PK studies. 20,21 However, of note is that the PK analysis revealed substantial unexplained interindividual variability of the V1 and Q, being considerably higher than previously observed. One possibility to explain this observation may originate from perioperative infusion therapy.…”

“…Yet if the anticipated PTA was also calculated as a function of MIC ( Figure 5), a trend toward a one log 2 -fold higher susceptibility breakpoint for pancreatic juice was detected due to the approximately 2-fold higher AUC values in pancreatic juice compared to those in serum, with serum PTA being in agreement with previously determined PTA. 21 The susceptibility breakpoint for MXF in pancreatic juice might lie in the range of 0.25 mg/L for gramnegative and 1.0 mg/L for gram-positive organisms. Our study employs PK/PD indices as surrogate markers for the antibacterial effect.…”