A Proposal of a Pharmacokinetic/pharmacodynamic (PK/PD) Index Map for Selecting an Optimal PK/PD Index from Conventional Indices (AUC/MIC, Cmax/MIC, and TAM) for Antibiotics

Abstract

A pharmacokinetic/pharmacodynamic (PK/PD) analysis is important in antibiotic chemotherapy. Basically, the in vivo efficacy of antibiotics that exert concentration-dependent effects can be predicted using conventional PK/PD indices such as the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC) and/or the ratio of the maximum plasma concentration to MIC (Cmax/MIC), whereas that of antibiotics with time-dependent effects can be determined using the period of time for which the drug concentration exceeds the MIC (time above MIC [TAM]). However, an optimal PK/PD index remains to be established for some antibiotics. Thus, a PK/PD model which describes the PK profile and effect of an antibiotic was developed, and the results obtained from this model were interpreted to form a PK/PD index map to assess the optimal PK/PD index for the antibiotic. The findings from the map were generally consistent with clinical outcomes even for the antibiotics which proved to be exceptions to the conventional classification. For example, AUC/MIC was an optimal index for azithromycin despite its time-dependent bactericidal activity, and Cmax/MIC was a poor index for arbekacin despite its concentration-dependent profile. Thus, the map would be useful for selecting the appropriate PK/PD index for an antibiotic.

Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs

“…The ability to predict the commonly employed PK/ PD indices for a range of antibiotics have however been confirmed previously (31), and the optimal PK/PD index has been shown to be mathematically dependent on the PK (27) which brings confidence to the presented results. For simplicity a 2-log kill target was used for making comparisons of drug effect between the studied scenarios, however the alternate 3-log kill target and the EX50 for each index (value for which half the maximum effect is reached) were investigated with similar results except for the high inoculate scenario where 3-log kill was not predicted to be achievable.…”

“…The PK/PD index most predictive of bacterial kill is known to be dependent on a complex interplay of PK and PD parameters such as the drug elimination rate and rates of kill and growth of the bacteria (27). In order to investigate how sensitive the selected index and target magnitude of meropenem is to variations in PK, PD and investigated dosages we expanded the in silico simulations in mouse and man.…”

The pharmacokinetic/pharmacodynamic paradigm for antimicrobial drugs in veterinary medicine: Recent advances and critical appraisal

“…Historically, the ratio of maximum free plasma concentration ( f Cmax) over MIC ( f Cmax/MIC) was used as the index of choice for aminoglycosides but f Cmax/MIC is not used by VetCAST (Toutain, et al., 2017) and not favoured by EUCAST (Mouton et al., 2012). These decisions are supported by simulations using a semi‐mechanistic PK/PD model, indicating that f Cmax/MIC was a poor index for aminoglycosides (Kitamura et al., 2014).…”

“…There are several circumstances when %f T > MIC is very sensitive to small differences in the measured MIC. The problem of using %f T > MIC as a predictor of efficacy was explored by simulation, using a semi‐mechanistic PK/PD model (Kitamura et al., 2014). These authors concluded that %f T > MIC should not be used, when the rate constant of AMD elimination was less than 0.2 per h (Kitamura et al., 2014) corresponding to a MRT of more than 5 hr.…”

Pharmacokinetics of enrofloxacinHCl‐2H2O (ENRO‐C),PK/PD, and Monte Carlo modeling vs. Leptospiraspp. in cows

“…Enrofloxacin is usually injected intramuscularly at doses ranging from 2.5 to 5 mg/kg, and it is recommended to repeat the treatment daily for at least 3–5 days (EMEA, ). In Latin America and in some textbooks (Plumb, ), dose recommendations reach 10 mg/kg or more, and these doses are more in accordance with the PK/PD ratios established for this concentration‐dependent antimicrobial drug that is, the ratio of maximum plasma concentration ( C max )/minimum inhibitory concentration (MIC) should ideally be ≥10 to 12, and the ratio of the area under the plasma concentration vs. time curve in 24 hr (AUC 0‐24 )/MIC should be ≥125 (Asín‐Prieto, Rodriguéz‐Gascón, & Istla, ; Kitamura, Yoshida, Kusama, & Sugiyama, ; Papich, ). Unfortunately, due to the lack of bioequivalence, many pharmaceutical preparations fail to achieve the same C max and AUC 0‐24 values (Sumano, Ocampo, & Gutiérrez, ).…”