Clinical evaluation of mezlocillin in neonates

Single-dose pharmacokinetic studies were performed in 64 infants, ranging in age from less than 1 day to 6 days, after intravenous infusion or intramuscular injection of approximately 75 mg/kg of mezlocillin. Mean serum concentrations at one hour were 107 micrograms/ml and 82.5 micrograms/ml for neonates less than or equal to 1 day of age and greater than or equal to 6 days of age, respectively. The serum clearance ranged from 3.0 to 6.4 hours. Based on data from the study, it is recommended that mezlocillin be administered to neonates with gram-negative bacterial infections in a single dose of 75 mg/kg, either as an intravenous infusion over 30 minutes or as an intramuscular injection, every 12 hours during the first week of life. Mezlocillin alone or in conjunction with penicillin was used in treating 165 neonates with suspected sepsis. Gram-negative organisms were recovered from 18 of the 27 neonates from whom pathogens were isolated. Three of these 18 strains, a Klebsiella oxytoca, an Acinetobacter anitratum, and a Haemophilus influenzae, were resistant to mezlocillin in vitro. Twenty-four of the 27 patients who satisfied criteria for evaluation achieved a bacteriological and a clinical cure. Cerebrospinal fluid permeation after multiple doses ranged from 18% to 45% of serum levels. No significant local or systemic side effects were seen. The results indicate that mezlocillin is an effective ureidopenicillin for the treatment of gram-negative bacterial infections.     

Dose-dependent pharmacokinetics of mezlocillin in rats.

The pharmacokinetics of mezlocillin were examined in rats following bolus intravenous doses of 20 or 200 mg/kg. Mezlocillin exhibited bi- or triexponential disposition profiles, and the area under the concentration-time curve increased nonproportionally with dose similar to reported findings in humans. Apparent total, renal, and nonrenal clearances and the volume of distribution at steady-state all decreased by 45 to 50% with the higher dose, and the elimination half-life was longer (8 +/- 2 versus 15 +/- 3 min). Mezlocillin exhibits low saturable binding in rat serum, ranging from 20 to 40% bound. Pharmacokinetic parameters based on free drug demonstrated dose-dependent characteristics similar to those with total drug. Use of the volume of distribution from the low dose allowed calculation of the true mean residence time. The linear relationship between dose and mean residence time from free concentrations yielded pooled Michaelis-Menten parameters. These were used as initial estimates in the simultaneous nonlinear fitting of the low- and high-dose mean free concentrations to a three-compartment model with sequential distribution and Michaelis-Menten elimination to describe the nonlinearity of mezlocillin disposition further.     

Pharmacokinetics of two multiple-dose mezlocillin regimens.

The pharmacokinetics of mezlocillin at two dosages were studied over the course of therapy in 12 patients receiving the drug for the treatment of infections. Patients received an initial dosing regimen of 4 g every 6 h or 5 g every 8 h, which was switched to the alternative regimen after 5 days of treatment. Both drug regimens demonstrated similar pharmacokinetic characteristics, which suggests that the reported dose-dependent elimination of mezlocillin is not an important factor in the clinical use of mezlocillin at the dosages currently used.     

Effect of saturable clearance during high-dose mezlocillin therapy.

As mezlocillin has been shown to display nonlinear pharmacokinetics in single-dose evaluations, we evaluated a crossover trial in patients with renal dysfunction the impact on serum clearance of fixed-dose versus fixed-interval administration of identical daily doses of the drug. In four patients with creatinine clearances of 0.00 to 1.78 liters/h per 1.73 m2, equal serum clearances were observed when the calculated daily total dose of mezlocillin was given either as a fixed dose of 5,000 mg at various intervals or every 4 h at various doses. We found that repetitive large daily doses that are equivalent to 30 g/day in patients with normal renal function can be administered to patients with impaired renal function as a reduced dose every 4 h instead of prolonging the dosing interval, as suggested by Mangione et al. (Antimicrob. Agents Chemother. 21:428-435, 1982). The observed serum clearances were equal for the two schedules, probably owing to the degree of continuing saturation of the nonlinear clearance mechanisms of mezlocillin.     

Kinetics of intravenous mezlocillin in chronic hemodialysis patients.

The kinetics of intravenous mezlocillin was studied in 8 patients with creatinine clearances under 7 ml/min who were undergoing chronic hemodialysis. Kinetic parameters were determined using a 2-compartment linear model. The mezlocillin serum half-life (t 1/2) in these patients ranged from 2.9 to 7.8 hr (mean, 5.4). The t 1/2 decreased to 1.57 +/- 0.09 hr during dialysis. Approximately 18% of the dose was recovered in the dialysate in 4 hr of dialysis. There was a 30% reduction per hour in serum concentration. The kinetics of mezlocillin, due to removal by nonrenal mechanisms, more closely resemble the kinetics of penicillin G and ampicillin than of carbenicillin and ticarcillin. A dosage schedule for use of intravenous mezlocillin in patients undergoing hemodialysis is presented.     

Determination of mezlocillin and its penicilloate and penilloate by high-performance liquid chromatography and stability of mezlocillin at different temperatures.

A method is described for the determination of mezlocillin and its metabolites penicilloic acid and penilloic acid in biological fluids by high-performance liquid chromatography. The stability of mezlocillin in serum and buffer was studied at different temperatures (4, -20, -70, and -196 degrees C) over a period of 6 months. Mezlocillin remained stable at -70 and -196 degrees C, whereas degradation was observed at -20 and 4 degrees C in serum and buffer.     

Dose-dependent pharmacokinetics of mezlocillin in relation to renal impairment.

The dose dependence of mezlocillin pharmacokinetics was examined in relation to renal function after intravenous doses of 1 and 5 g in 16 subjects with various degrees of renal impairment. Dose and time-average model-independent physiological parameters were calculated from plasma concentration and urinary excretion data. Lack of superimposition of plasma concentration profiles occurred between dosage levels with a twofold exaggeration of areas under the curve produced between doses of 1 and 5 g. Decreased plasma clearances at the higher dose were caused partly by nonlinear renal clearance, but more markedly by dose dependence in nonrenal clearances. At each dosage level, these parameters were examined in relation to creatinine clearances. Plasma and renal clearances exhibited a typical linear correlation with creatinine clearance for each dose level. However, nonrenal clearances demonstrated a linear relationship with creatinine clearance at the 1-g dose, but apparent saturation of this pathway produced lower and relatively constant nonrenal clearance values at the 5-g dose. Mezlocillin pharmacokinetics are thus influenced by both dose and renal function over the dosage range of 1 to 5 g. Saturation in renal clearance and probably in biliary clearance explains the unusual disposition characteristics of mezlocillin observed in this and previously reported studies.     

Clinical evaluation of moxalactam.

We investigated the clinical efficacy of moxalactam for treatment of a variety of infectious disorders in 50 patients (38 males and 12 females). Patient ages ranged from 8 days to 98 years, with a median of 66 years. Infectious disorders were confirmed by isolation of etiological bacteria in all patients. Thirty-eight patients had gram-negative bacillary disease, nine had pneumococcal infection, and three had disorders caused by staphylococci or streptococci. Twenty-three patients had pneumonia, 17 had bacteremic diseases other than pneumonia, and 10 had miscellaneous infectious diseases. The overall efficacy of moxalactam was excellent. Forty-eight patients were cured by clinical criteria, and 45 were cured by bacteriological criteria. A total of 19 adverse reactions were associated with the use of moxalactam in 18 patients, but none were severe and only one necessitated discontinuation of treatment. Moxalactam promises to be an important addition to our therapeutic armamentarium, especially for therapy of gram-negative bacillary infections.     

Clinical evaluation of moxalactam.

Moxalactam was administered intravenously or intramuscularly or both in doses of 1 to 12 g/day to 45 patients with clinically significant infections (17 soft tissue or bone, 9 pleuropulmonary, 9 septicemic, 6 urinary tract, and 4 intraabdominal infections). Mean 0.5-h postinfusion levels were 105 micrograms/ml for a 4.0-g dose, 44.7 micrograms/ml for a 2.0-g dose, and 18 micrograms/ml for a 1.0-g dose. We identified 28 isolates of Enterobacteriaceae, 10 Pseudomonas aeruginosa isolates, 9 Staphylococcus aureus isolates, and 15 anaerobic bacterial isolates. A total of 15 patients were clinically cured, 8 patients improved, 13 patients improved initially but suffered subsequent relapses or superinfections, and 10 patients failed therapy. Toxicity was generally minimal (reversible eosinophilia, and mild liver function abnormalities, and elevated prothrombin time). The selection or emergence of resistant organisms in 17 patients during treatment (particularly Pseudomonas, enterococci, and Candida) was a disturbing feature of therapy. Our results were generally favorable, considering the complicated underlying medical problems of this group of patients.     

Kinetics of mezlocillin and carbenicillin

The kinetics of mezlocillin, a semisynthetic acylureido penicillin, more active than carbenicillin against many gram-negative bacteria, were compared with those of carbenicillin. Following an intravenous infusion of 4 gm in 5 min to 8 normal men there was an average serum level of 294 microgram/ml for mezlocillin and 365 microgram/ml for carbenicillin. The t1/2 for mezlocillin was 47 min and that for carbencillin was 70 min. The apparent volume of distribution was 13.4 L for mezlocillin and 14.4 L for carbenicillin. The mean urinary recovery of mezlocillin was 72% and that for carbenicillin was 92%. Constant infusion of 5 mg of mezlocillin over 2 hr gave steady-state levels of 234 microgram/ml. Half-life, apparent volume of distribution, and serum and renal clearance of mezlocillin after constant infusion were in the same range as those after rapid infusion.     

Pharmacokinetics of mezlocillin in pleural fluid

Mezlocillin concentrations in the pleural fluid and serum of six patients with malignant pleural effusion were determined following administration of 10 g mezlocillin over 30 minutes as a rapid infusion. Thirty minutes and eight hours after the infusion had been completed, concentrations of the active ingredient in the pleural fluid were 36.44 micrograms/ml and 112 micrograms/ml respectively; in the serum the respective values were 777.89 micrograms/ml and 44.22 micrograms/ml. The concentrations of active ingredient in the pleural fluid exceed the MIC for clinically significant pathogenic germs. The elimination half-life of mezlocillin in malignant pleural effusion is prolonged.     

Clinical study of mezlocillin for the treatment and prevention of postoperative obstetric and gynecological infections

Twenty-one women were given mezlocillin for the treatment or prevention of infections after obstetric and gynecological surgery. Ten women had active infections caused by Escherichia coli, Klebsiella species, Proteus mirabilis, Pseudomonas aeruginosa, or Streptococcus faecalis. They had a 90% rate of recovery after an average of seven days of treatment with 6 to 15 gm/day of mezlocillin. The other 11 women were given mezlocillin prophylactically, 2 gm every 12 hours for seven days. All had good postoperative courses without complications caused by infections. Among both groups only three adverse reactions occurred, two instances of rash and one case of moderate diarrhea. All resolved spontaneously without discontinuation of treatment.     

Comparative pharmacokinetics of two multiple-dose mezlocillin regimens in normal volunteers.

Mezlocillin was previously reported to exhibit dose-dependent pharmacokinetics. These reports suggest that it may be possible to administer a relatively large dose at a longer interval than is usual and still achieve therapeutic concentrations in serum. In a randomized, crossover study, we compared concentrations of mezlocillin in serum after a single dose and at steady state in 12 healthy volunteers who received 4 g every 6 h and 5 g every 8 h. A slight, but statistically significant, dose-dependent effect was observed upon the area under the concentration-time curve and total body clearance. No accumulation was observed with either schedule. Although concentrations in serum were higher after the 5-g dose, the more frequent administration of the 4-g dose schedule produced serum concentrations above the MIC for susceptible bacteria for a greater portion of the day. In the absence of clear guidelines from human studies which relate serum concentrations to clinical response, the available data indicate that the more frequent dosage schedule is appropriate for severe infections.     

Sulbactam in combination with mezlocillin, piperacillin or cefotaxime. Clinical and bacteriological results in the treatment of severe bacterial infections

An open multicenter study on inpatients of 12 german hospitals was performed to investigate efficacy and safety of sulbactam in combination with mezlocillin, piperacillin or cefotaxim in severe bacterial infections. In total 155 patients were enrolled. The following infections were diagnosed: 48 lower respiratory tract infections, 66 intraabdominal infections, 34 skin/soft tissue infections including post operative wound infections and 5 complicated urinary tract infections. 55 patients received 3 daily doses of 4 g mezlocillin + 1 g sulbactam, 52 patients received 3 daily doses of 4 g piperacillin + 1 g sulbactam and 48 patients received 3 daily doses of 2 g cefotaxim + 1 g sulbactam. Antibiotics and sulbactam were administered concomitantly via intravenous short infusion. Mean duration of therapy was 8 days. Endpoints for assessment of therapeutic efficacy were cure (complete resolution of pretreatment signs and symptoms of the infection) or improvement (marked reduction or partial disappearance or pretreatment signs and symptoms, no further antibiotic therapy required) as well as eradication of pretreatment pathogens. 141 (92%) of 153 evaluable patients were successfully treated (98 cures and 43 improvements), therapy failed in 12 patients (7.8%). Success rates of the 3 sulbactam combinations were almost identical: 91% for mezlocillin/sulbactam, 92% for piperacillin/sulbactam and 93% for cefotaxim/sulbactam. 106 patients (68.4%) were also bacteriologically evaluable. In these patients 192 bacterial pathogens were isolated prior to study therapy, 55 patients had mixed infections. In 96 patients (90%) pretreatment pathogens were eradicated (180 strains = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic properties of mezlocillin in newborn infants

The pharmacokinetic properties of mezlocillin were evaluated in newborn infants. Mean peak and trough concentrations of drug in plasma, after 75 mg of mezlocillin per kg given intravenously, were 252 and 72 micrograms/ml, respectively, in infants who were less than 38 weeks gestation and less than or equal to 7 days old, compared with 139 and 9 micrograms/ml, respectively, in infants greater than or equal to 38 weeks gestation and greater than 7 days old. The mean elimination half-life values were from 4.5 h in preterm infants who were less than or equal to 7 days old to 1.8 h in term infants greater than or equal to 7 days old. Median peak and trough bactericidal titers of drug in plasma from neonates treated with mezlocillin were 1:8 and 1:4, respectively, against a resistant (minimal bactericidal concentration, 512 micrograms/ml) Escherichia coli strain and 1:64 and 1:32, respectively, against a susceptible (minimal bactericidal concentration, 2 micrograms/ml) E. coli strain. We propose a dosage schedule of 75 mg of mezlocillin per kg administered every 12 h to preterm (gestational age less than 38 weeks) infants less than or equal to 7 days old, every 8 h to preterm infants greater than 7 days old or term infants less than or equal to 7 days old, and every 6 h to term infants greater than 7 days old.     

Dose-dependent pharmacokinetics of azlocillin compared to mezlocillin

The pharmacokinetics of azlocillin at intravenous doses of 1.0, 2.0 and 5.0 g and of 2.0 g mezlocillin were studied in a cross-over study on 10 healthy volunteers. The serum concentrations and total area under the serum curves for azlocillin increased more than expected from the multiples of the dose size. Likewise, the percentage of urinary excretion of an antibacterially active agent increased steadily with higher doses. The same applied to the serum half-life (t 1/2), whereas the total body clearance was reduced. All these characteristics are indicative of dose-dependent, i.e. capacity-limited pharmacokinetics. The t 1/2 was 0.89, 0.98, and 1.53 h for each dose. For 2.0 g mezlocillin, the serum values, urinary recovery, and t 1/2 were lower than the values after the same dose of azlocillin. The t 1/2 was 0.64 h. The total body clearance was 12,0, 9.2, and 6.4 liters/h for the three doses of azlocillin and 14.4 liters/h for 2. g mezlocillin. Dose dependence appears to be more pronounced with azlocillin than found previously with mezlocillin. Unchanged azlocillin and its biotransformation products are excreted more slowly than mezlocillin and its metabolites.     

Effect of dose on pharmacokinetics and serum bactericidal activity of mezlocillin.

Mezlocillin is subject to dose-dependent pharmacokinetics. Previous studies have examined the pharmacokinetic but not the pharmacodynamic aspects of this effect. The pharmacokinetic disposition of mezlocillin was determined in eight healthy volunteers in a randomized, crossover fashion after single infusions of 50 and 80 mg of mezlocillin per kg of body weight. Plasma and urine were assayed with a specific high-pressure liquid chromatography assay and analyzed by noncompartmental methods. Pharmacodynamic (bactericidal) effects were evaluated from serial serum bactericidal titers obtained after each dose by using the area under the bactericidal activity curve method. The mean mezlocillin total body clearance decreased from 203.6 +/- 36.2 ml/min after the 50-mg/kg dose to 171.7 +/- 42.1 ml/min after the 80-mg/kg dose (P, 0.01). The decreased clearance was reflected by a decrease in nonrenal clearance only (108.9 +/- 20.0 to 77.9 +/- 23.5 ml/min, respectively; P, 0.001). Mean areas under the curve for concentration in plasma versus time normalized to the 50-mg/kg dose were 314 +/- 73 and 375 +/- 64 micrograms X h/ml for the low and high doses, respectively (P, 0.01). No significant changes were observed in the steady-state volume of distribution or elimination half-life. Mean areas under the bactericidal activity curve were 100 +/- 77 and 244 +/- 143 for the 50- and 80-mg/kg doses, respectively. The decrease in mezlocillin clearance and the disproportionate increase in the area under the curve for concentration in plasma versus time, coupled with the observed prolonged bactericidal effects of the 80-mg/kg dose, lend support for administration of mezlocillin at a higher dose less frequently (e.g., 5 g every 8 h). Clinical trials with the higher-dose regimen are warranted to validate these observations.