The novel therapeutic implications of azlocillin's dose-dependent pharmacokinetics: contributing physiologic mechanisms and a prospective, cross-over designed trial.

Azlocillin is an important acylureido penicillin antibiotic for the management of complex gram-negative infections particularly those caused by Pseudomonas species. The current studies demonstrate that it manifests dose-dependent pharmacokinetics during the usual regimens of clinical dosing, that enterohepatic recirculation does not occur and that renal tubular secretion (maximum renal tubular secretory capacity 300 +/- 30 micrograms/min) and hepatic metabolism appear to be the dominant contributors to the dose-dependent nature of azlocillin. The possible therapeutic implications of azlocillin's dose dependency were evaluated by undertaking a six-day randomized, prospective, cross-over design study to evaluate the pharmacokinetic disposition of the drug during a 3-g q4h (typically used in adults) regimen versus a 5-g q8h regimen. By using the area under the serum-time concentration curve (AUC) as the major comparative parameter for these two regimens, the results demonstrate that both regimens provide approximately equal quantitative amounts of the drug systemically as a result of azlocillin's dose dependency. The AUC values, although not therapeutic end points, nonetheless correlate well with clinical response to antibiotic therapy. The 5-g q8h regimen was well tolerated. It is less disruptive for patients, requires half the number of intravenous administrations, 17% less drug, and is more cost effective than the 3-g q4h regimen.

The influence of renal functional changes on the intrarenal distribution and urinary kinetics of amdinocillin.

The maintenance of effective therapeutic concentrations of antibiotics within the renal parenchyma is an important issue in the management of acute and chronic pyelonephritis. Available clinical data indicate that an important clinical-therapeutic correlation exists between the physiologic state of the kidney and the antibiotic concentrations that can be achieved in the medulla and papilla. Using a healthy canine model, we evaluated the influence of hydration and the state of acid-base balance upon the intrarenal distribution and urinary clearance of the semisynthetic penicillin amdinocillin. Renal physiologic activity significantly modulates the intrarenal distribution pattern of this compound. During the production of maximally acid and concentrated urine, the highest renal parenchyma levels of amdinocillin are achieved. During the latter circumstances the antibiotic undergoes distal tubular nonionic diffusion, which appears to be an important contributing factor to the high medullary and papillary concentrations of the drug. Nonetheless, at all levels of tested renal physiologic activity tissue and urine drug concentrations are adequate for the treatment of sensitive urinary pathogens.

Pharmacokinetics of azlocillin in normal renal function: single and repetitive dosing studies.

Systemic and urinary pharmacokinetic studies of the disposition of azlocillin were performed in seven male and six female healthy volunteers. Four separate studies identified the kinetics of the drug following a single 2, 3 or 4 g administration and during the repetitive administrations of 3 g of the drug over a five-day period. Peak plasma concentrations were 174 +/- 19 mg/l, 214 +/- 17 mg/l and 286 +/- 11 mg/l in the 2, 3 and 4 g single dose studies respectively. Trough values at 4 h post-dosing were 6 +/- 1 mg/l, 10 +/- 1 mg/l and 26 +/- 3 mg/l respectively. The plasma half-life of azlocillin was approximately 60 min. A dose-dependent phenomenon was observed. This was characterized by a slight but significant progressive increase in the plasma half-life of the drug as increasing amounts of drug were given and as the same amount was given repeatedly. No significant systemic accumulation of azlocillin was noted during the repetitive dosing study. The urinary excretion of the compound was prompt with most of the bioactive drug being eliminated in the first 4-6 h following dosing. The apparent volume of distribution of azlocillin was slightly greater than the extracellular fluid compartment. For the therapy of systemic infections in adults with normal renal function a 4 h or 6 h dosing cycle would be appropriate.

Azlocillin kinetics during extracorporeal haemodialysis and peritoneal dialysis.

The kinetic disposition of azlocillin in patients with end stage renal failure was evaluated in six individuals maintained on chronic extracorporeal haemodialysis and in six individuals on peritoneal dialysis. In the absence of renal function the plasma half-life of azlocillin was extended from the normal value of approximately 60 min to 235 +/- 30 min. During peritoneal dialysis the plasma half-life was reduced to 148 +/- 15 min and during extracorporeal haemodialysis it was further reduced to 112 +/- 11 min. Azlocillin was readily dialysed during haemodialysis but its removal rate during peritoneal dialysis was substantially less.

An azlocillin dosing nomogram for renal insufficiency.

We have developed an azlocillin dosing nomogram suitable for use in patients with various degrees of renal functional impairment. A total of 50 kinetic studies undertaken by us and an additional 60 similar kinetic investigations as reported in the literature formed the basis for the construction of our nomogram. This renal failure dosing nomogram gives immediate information to the physician who needs to give azlocillin to a patient with renal failure.