azlocillin and Kidney-Diseases

The pharmacokinetics of azlocillin have been studied in healthy subjects and in patients, in children and in adults, using different doses, either single or repeated. Following intravenous injection of doses ranging from 1 to 5 g, plasma concentrations increase in relation to dosage. Maximum concentrations at the end of an injection or infusion average 100-200 micrograms/ml with 1 g and 400-500 micrograms/ml with 5 g. Azlocillin has a low degree of plasma protein binding: 30% to 40% depending on concentrations. Its volume of distribution is approximately 0.2 l/kg. Tissue distribution has been studied by various authors: with a 2 to 5 g dose, therapeutically active concentrations have been found in a variety of tissues, including bronchial secretions, bone, etc. Azlocillin crosses the placenta; the ratio of maternal to foetal plasma concentrations is 0.50. Azlocillin undergoes little metabolic degradation and its metabolites (penicilloates) amount to less than 15% of the dose administered. Most of the drug is excreted by the kidneys, 50% to 70% of the dose injected being recovered in the 24 h urines; the remainder is excreted in the bile, and biliary concentrations may be as high as 15-fold the corresponding plasma concentrations. Azlocillin is rapidly cleared. Its plasma half-life varies from 45 to 75 min according to different authors. The fact that it increases slightly with dosage suggests the kinetics of the drug might be dose-dependent. In view of the intervals between doses, this is certainly not of therapeutic importance. Total and renal clearance values are 150-200 ml/min and 100-140 ml/min respectively. In patients with renal impairment azlocillin is eliminated more slowly, with a half-life of up to 6-10 h when creatinine clearance is below 5 ml/min. The reduced urinary excretion may partly be compensated for by increased biliary excretion. The proportion of drug removed by haemodialysis is 40-50%. Azlocillin excretion is slowed down in children under 3 months of age, with half-lives of 4.5 h, 3.0 h and 2.0 h respectively in prematures, neonates and infants.

Topics: Azlocillin; Bile; Blood Proteins; Bone and Bones; Half-Life; Humans; Injections, Intravenous; Kidney; Kidney Diseases; Kinetics; Lung; Penicillins; Tissue Distribution

Cross-over studies on volunteers with several doses of azlocillin ranging from 1.0 to 5.0 g have shown that azlocillin is subject to dose dependent pharmacokinetics, the area under the serum curve becoming larger than expected as doses increase. There was also a tendency towards longer serum half-life values and excretion of more unchanged compound as the doses increase. The serum half-life varied between 0.9 h after 1.0 g increasing to 1.5 h after intravenous doses of 5.0 g given to adults. In neonates, values around 2.6 h have been observed, and they were slightly longer in premature babies at approximately twice the value in adults receiving similar doses per kg body weight. In normal adults protein binding lies between 35 and 40% for therapeutic concentrations. Approximately 60-75% of the dose appears as unchanged azlocillin in the urine, increasing with higher doses. Reduced renal function lowers urinary excretion, but concentrations are always above the break point for sensitivity of 32 mg/l in patients with creatinine clearances above 10 ml/min. In anephric subjects T1/2 of 2.5-6 h is observed. Dosage modifications only to one-third of normal are needed for a renal clearance of 10-25 ml/min. The concentrations of active compound are high in the bile in subjects with normal liver function.

Topics: Azlocillin; Cystic Fibrosis; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Infant, Newborn; Intestinal Absorption; Kidney Diseases; Kinetics; Liver Diseases; Penicillins; Pregnancy; Protein Binding; Renal Dialysis

Left-sided endocarditis caused by Pseudomonas aeruginosa is frequently associated with failure of medical therapy in man. The efficacy of ciprofloxacin and netilmicin + azlocillin has been studied in 79 rabbits with aortic valve endocarditis caused by a serum-resistant strain of P. aeruginosa. Infected animals received either: no therapy; ciprofloxacin (80 mg/kg/day); or netilmicin (6.5 mg/kg/day) + azlocillin (400 mg/kg/day). Ciprofloxacin significantly lowered vegetation titers of P. aeruginosa at days 6 and 10 of therapy compared with netilmicin + azlocillin (P less than 0.001). Similarly, ciprofloxacin was significantly more effective in sterilizing vegetations (P less than 0.005), curing P. aeruginosa endocarditis (P less than 0.001), and preventing bacteriological relapse after discontinuing antibiotic therapy (P less than 0.005). Both antibiotic regimens were equally effective in sterilizing renal abscesses. Resistance to azlocillin was occasionally observed in vivo among P. aeruginosa isolates within cardiac vegetations during the second week of therapy, but not to ciprofloxacin or netilmicin.

Topics: Abscess; Animals; Anti-Infective Agents; Aortic Valve; Azlocillin; Ciprofloxacin; Drug Therapy, Combination; Endocarditis, Bacterial; Female; Kidney Diseases; Microbial Sensitivity Tests; Netilmicin; Penicillin Resistance; Pseudomonas Infections; Quinolines; Rabbits

Azlocillin serum concentrations were followed in 9 severely ill patients with various degrees of renal dysfunction after single and repetitive dosage. All patients were treated concomitantly with a cephalosporin and/or an aminoglycoside antibiotic. Elimination halflives (t1/2 beta) were highly variable (62-1, 194 min), but no significant increase occurred in patients with stable renal function during repetitive dosage due to previously described nonlinear pharmacokinetic behavior of azlocillin. However, drug accumulation was observed in patients with deterioration of renal and hepatic function. The rise in drug accumulation can be disproportionally high if both routes of elimination are affected. In such cases, careful dosage adjustment of azlocillin is required to avoid toxic side effects.

Topics: Adult; Aged; Azlocillin; Bacterial Infections; Drug Administration Schedule; Drug Therapy, Combination; Female; Half-Life; Humans; Kidney Diseases; Kinetics; Male; Middle Aged

Cefotaxime (CTX) kinetics, alone and in combination with azlocillin (AZ), were determined in 18 subjects with either normal or impaired renal function. After the single dose and with increasing renal insufficiency, total CTX clearance fell from 266 to 71 ml/min/1.73 m2. At the same time the terminal t1/2 rose from 1.1 to 2.8 hr. Regardless of the degree of renal function, CTX clearance in combination with AZ in all patients was only 50% to 60% of that with CTX alone. This reduction in total body clearance was due to a parallel decrease in renal and nonrenal clearance. In advanced renal failure, particularly after AZ, the terminal t1/2 of the CTX metabolites increased up to 1000% to 1500% of normal. On the basis of these findings, CTX dosage adjustment is recommended only in patients with a glomerular filtration rate (GFR) below 20 ml/min. After AZ, however, dosage reduction of CTX seems to be advisable at an earlier stage of renal impairment (GFR 40 ml/min).

Topics: Adult; Azlocillin; Cefotaxime; Drug Interactions; Female; Glomerular Filtration Rate; Half-Life; Humans; Kidney Diseases; Kinetics; Male; Middle Aged; Penicillins

The safety of azlocillin was evaluated in 631 patients treated for urinary tract or systemic infections in U.S.A. clinical trials. The mean azlocillin dose was 260 mg/kg/day and the mean duration of treatment was 11.1 days. Twenty patients (3.2%) experienced adverse local reactions and 92 patients (14.6%) experienced adverse systemic reactions. In thirty-one instances (4.9%) they led to premature termination of therapy, but only 14 of 135 reactions were classified as severe. All adverse reactions were reversible if adequate follow-up was done. Hypersensitivity reactions, manifest by rash, fever or eosinophilia occurred in 4.4%, 0.3% and 1.1% respectively. Hypokalaemia was noted in only three instances (0.5%). Hepatotoxicity occurred in 1.7%, diarrhoea in 1.9% and leukopenia in 0.3%. Transient chest discomfort was seen on rapid infusion on three occasions. Overall, azlocillin appeared well tolerated, and had no evident unique toxicity.

Topics: Adolescent; Adult; Aged; Azlocillin; Bacterial Infections; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Hypersensitivity; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kidney Diseases; Male; Middle Aged; Penicillins; Water-Electrolyte Imbalance

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.

Topics: Azlocillin; Creatinine; Drug Administration Schedule; Half-Life; Humans; Kidney Diseases; Models, Biological; Penicillins

Topics: Azlocillin; Creatinine; Half-Life; Humans; Kidney Diseases; Kinetics; Penicillins; Renal Dialysis