Serum Level Monitoring of Antibacterial Drugs

Abstract

Serum concentration measurements of antibacterial agents are increasingly used to optimise drug dosage regimens. However, this approach is only justified for drugs with a low therapeutic index and poor predictability of serum concentrations, such as the aminoglycosides, chloramphenicol and vancomycin, whereas the penicillins and cephalosporins can safely be applied well above their minimum inhibitory concentrations. Wide interpatient variation in distribution and elimination are the main reasons for the unpredictability of aminoglycoside serum concentrations. It has been shown that in patients with normal creatinine clearance, the apparent elimination half-life of gentamicin varies from 0.4 to 7.6 hours. The pharmacokinetics of the aminoglycosides are most adequately described by a 3-compartment open model where the slow terminal half-life reflects elimination from the deep tissue compartment. The accumulation of the aminoglycosides in this compartment, which includes the kidneys and inner ear, is probably an important factor in their potential toxicity in these organs. Careful serum level monitoring may reduce, but cannot totally avoid, the risk of side effects. However, maintenance of effective drug levels appears to be at least an equally important goal of aminoglycoside serum level monitoring. Chloramphenicol is also a potentially toxic antibacterial agent. Its therapeutic range is usually considered to be 15 to 25 mg/L. The most important side effects are the 'grey baby syndrome' and bone marrow toxicity. Chloramphenicol is metabolised to several microbiologically inactive products. It also shows wide interpatient variability of its pharmacokinetics, especially in young children, and serum levels should therefore be followed in these patients. Vancomycin, a highly effective agent for staphylococcal and enterococcal infections, may also exhibit nephrotoxic and ototoxic side effects. A well-defined therapeutic range has not yet been established but in view of its minimum inhibitory concentrations it seems reasonable to maintain vancomycin serum concentrations between 15 and 50 mg/L. Since this drug is excreted unchanged in the urine, serum levels should particularly be monitored in patients with impaired renal function. The advances in routine therapeutic drug monitoring are directly related to rapid developments in technologies associated with the quantification of these agents. Microbiological plate diffusion assays are now often replaced by more specific immunoassays (radioimmunoassay, enzyme immunoassay, and fluorescence immunoassay) and chromatographic techniques.