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

Alexandra Mcaleenan, Paul G Ambrose, Sujata M Bhavnani, George L Drusano, William W Hope, Johan W Mouton, Julian P T Higgins, Alasdair P Macgowan*

*Corresponding author for this work

Research output: Contribution to journalReview article (Academic Journal)

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.
Original languageEnglish
Article numberdkaa005
Number of pages16
JournalJournal of Antimicrobial Chemotherapy
DOIs
Publication statusPublished - 21 Feb 2020

Keywords

  • antibiotics
  • antifungal agents
  • infections
  • pharmacodynamics
  • pathogenic organism
  • antimicrobials
  • anti-bacterial agents
  • serum
  • data mining

Fingerprint Dive into the research topics of 'Methodological features of clinical pharmacokinetic–pharmacodynamic studies of antibacterials and antifungals: a systematic review'. Together they form a unique fingerprint.

  • Cite this