Single-dose kinetics and dosage of mecillinam in renal failure and haemodialysis

Mecillinam (amdinocillin) serum concentrations and urinary excretion of the drug and its degradation products were determined in 9 subjects: 1 with normal renal function, 4 with varying degrees of renal failure, and 4 on haemodialysis for end-stage renal failure. The results conform to first-order elimination kinetics. With decreasing glomerular filtration, renal clearance decreases sharply, and in severe renal failure approaches the value of creatinine clearance. However, elimination of the drug also takes place by non-renal clearance, which was found to be 48.8 +/- 9.1 (SD) ml/min. Concentrations of mecillinam and its degradation products were also determined in haemodialysis ultrafiltrate. From these data and other evidence, it is concluded that degradation of the drug is the chief mechanism of non-renal elimination. Based on the relationship between creatinine clearance and plasma clearance of mecillinam, and considering that the drug is a relatively non-toxic bactericidal antibiotic, the following dosage adjustment scheme is proposed: glomerular filtration rate over 30 ml/min: normal dosage; 10-30 ml/min: 50% of normal dosage; under 10 ml/min: 25% of normal dosage. Even when dosage is adjusted, therapeutic concentrations of the drug will appear in urine in most cases. During haemodialysis, which increases clearance of the drug by 100%, the dosage should, in principle, be doubled. Alternatively the treatment schedule may be modified by giving the dose just after each dialysis.