Methodological features of clinical pharmacokinetic–pharmacodynamic studies of antibacterials and antifungals: a systematic review

Abstract

Abstract Background Pharmacokinetic (PK)–pharmacodynamic (PD) indices relate measures of drug exposure to antibacterial effect. Clinical PK–PD studies aim to correlate PK–PD indices with outcomes in patients. Optimization of dosing based on pre-clinical studies means that PK–PD relationships are difficult to establish; therefore studies need to be designed and reported carefully to validate pre-clinical findings. Objectives To describe the methodological features of clinical antibacterial and antifungal PK–PD studies that reported the relationship between PK–PD indices and clinical or microbiological responses. Methods Studies published between 1980 and 2015 were identified through systematic searches. Methodological features of eligible studies were extracted. Results We identified 85 publications containing 97 PK–PD analyses. Most studies were small, with fewer than 100 patients. Around a quarter were performed on patients with infections due to a single specific pathogen. In approximately one-third of studies, patients received concurrent antibiotics/antifungals and in some other studies patients received other treatments that may confound the PK–PD–outcome relationship. Most studies measured antimicrobial concentrations in blood/serum and only four measured free concentrations. Most performed some form of regression, time-to-event analysis or used the Hill/Emax equation to examine the association between PK–PD index and outcome. Target values of PK–PD indices that predict outcomes were investigated in 52% of studies. Target identification was most commonly done using recursive partitioning or logistic regression. Conclusions Given the variability in conduct and reporting, we suggest that an agreed set of standards for the conduct and reporting of studies should be developed.