Because of increasing antimicrobial resistance and the shortage of new antibiotics, there is a growing need to optimize the use of old and new antibiotics. Modelling of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of antibiotics can support the optimization of dosing regimens. Antimicrobial efficacy is determined by susceptibility of the drug to the microorganism and exposure to the drug, which relies on the PK and the dose. Population PK models describe relationships between patients characteristics and drug exposure. This article highlights three clinical applications of these models applied to antibiotics: 1) dosing evaluation of old antibiotics, 2) setting clinical breakpoints and 3) dosing individualization using therapeutic drug monitoring (TDM). For each clinical application, challenges regarding interpretation are discussed. An important challenge is to improve the understanding of the interpretation of modelling results for good implementation of the dosing recommendations, clinical breakpoints and TDM advices. Therefore, also background information on PK/PD principles and approaches to analyse PK/PD data are provided.

In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared with treatment with SM-RIF for 4 weeks followed by treatment with RIF-clarithromycin (CLA) for 4 weeks. The extent of the interaction of RIF and CLA combined on the pharmacokinetics of the two compounds is unknown in this population and was therefore studied in a subset of patients. Patients received CLA at a dose of 7.5 mg/kg of body weight once daily, rounded to the nearest 125 mg. RIF was administered at a dose of 10 mg/kg, rounded to the nearest 150 mg. SM was given at a dose of 15 mg/kg once daily as an intramuscular injection. Plasma samples were drawn at steady state and analyzed by liquid chromatography-tandem mass spectroscopy. Although many antimycobacterial agents appeared to be effective against Mycobacterium ulcerans infections in in vitro and in animal models (4,11,27,30), clinical evidence of the effectiveness of antimicrobial treatment was predominantly based on a small study conducted with patients in Ghana (15). Conceivably, using antimycobacterial agents results not only in preventing bacilli from replicating and killing microorganisms but also in halting the production of the toxin mycolactone (36). This toxin that causes the tissue damage is produced by enzymes encoded by the pMUM001 plasmid (33). Current WHO recommendations suggest 8 or more weeks of treatment with rifampin (RIF) plus streptomycin (SM) for all clinical forms of active Buruli ulcer disease (BUD). Daily injections with streptomycin are problematic, as most patients live in remote areas with limited health care facilities. Proper hygiene with these injections, as well as intrinsic ototoxicity and renal toxicity, is a concern. Therefore, an oral treatment schedule is urgently needed to reduce the number of injections and to improve the tolerability and safety of the proposed regimen. Pregnant women might also benefit from treatment without aminoglycosides. This problem was addressed by comparing 8 weeks of SM (15 mg/kg of body weight) and RIF (10 mg/kg) treatment (8SR arm) and 4 weeks of streptomycin and rifampin treatment followed by 4 weeks of RIF plus clarithromycin (CLA; 7.5 mg/kg) treatment (4SR/4CR arm) in a randomized controlled trial (the BURULICO trial) (26). CLA was chosen for inclusion in the treatment regimen because of in vitro data suggesting that this drug is active against M. ulcerans, for which the MICs range from Ͻ0.125 to 2.0 mg/liter (30). In a pharmacokinetic (PK) study with adults who received doses of 500 mg twice daily, plasma CLA concentrations (5) were well above the MIC for most M. ulcerans isolates.The clinical effectiveness of macrolides is only partly explained by pharmacokinetics, because these drugs typically accumulate in inflammatory cells, especially macrophages, at the site of infection (1). Although M. ulcerans infection has long been regarded a predominantly extracellular infection (20), evidence has emerged from animal models that M. ulcera...

The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency.

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