Effects of impaired renal function, hemodialysis, and peritoneal dialysis on the pharmacokinetics of mezlocillin

The pharmacokinetics of a single 1-g intravenous dose of mezlocillin were examined in six functionally anephric patients undergoing hemodialysis. Hemodialysis clearance calculated by plasma extraction ratios across the dialyzer membrane and by dialysis fluid output agreed well, averaging 26 and 32 ml/min.Dialyzer extraction ratios averaged 0.16 + 0.07, and 23.3 ± 9.6% of the dose was measured in the dialysate. Plasma clearances (104 ± 45 ml/min) and steady-state volumes of distribution (0.22 ± 0.07 liter/kg) of mezlocillin showed good agreement with literature values. The nonrenal clearance (4.25 ± 2.30 liters/h per 1.73 m2) of mezlocillin was appreciable. Drug loss by hemodialysis is small and should have little effect on therapeutic dosage needs.The risk of serious infection and electrolyte imbalance is increased in hemodialysis patients. An antibiotic such as mezlocillin, with a wide spectrum of action, a low sodium content (1.78 meq/g as compared to 5.0 meq/g for carbenicillin and ticarcillin), and a low incidence of toxicity, has potential usefulness in this group of patients (3,14,16).As a step toward rational design of therapeutic dosing regimens for chronic hemodialysis patients, we examined the pharmacokinetics of mezlocillin in this patient population. To human research committees, and informed consent was obtained from each subject.Study design. After an equilibration period of 30 min from the start of dialysis, a single 1.0-g dose of mezlocillin (Miles Pharmaceuticals, batch 10523-34) was administered as a 10% solution in sterile water for injection into the venous return of the artificial kidney over a 5-min interval. Blood samples were collected from the arterial inlet and venous outlet of the dialyzer at 0, 0.25, 0.5, 1.0, 1.5, 2.0, and 4.0 h from the beginning of the infusion. Arterial and venous blood samples were also obtained just before the termination of hemodialysis. All dialysate fluid was collected from the outflow drain from the start of the infusion until the end of dialysis. At the end of dialysis, all excreted urine was collected from subjects capable of urine output. Additionally, up to four venous blood samples were collected between dialysis sessions (2.0, 4.0, and 6.0 h postdialysis and at the beginning of the next scheduled dialysis period) to determine the off-dialysis half-life.

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confidence: 55%

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confidence: 99%

Mezlocillin disposition in chronic hemodialysis patients

Janicke¹,

Mangione²,

Schultz³

et al. 1981

“…Although pharmacokinetic data for mezlocillin are available for adults with normal and/or impaired renal function (1)(2)(3)(4)(5)8), similar data for infants or children are scarce (6,9,11 Meziocillin administration and specimen collection. Mezlocillin was administered over a 30-min period by an infusion pump at doses ranging from 12.2 to 125 mg/kg every 4 h. Blood samples were obtained for one dosage interval at steady state, usually during day 3 or 4 of therapy.…”

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confidence: 99%

Mezlocillin pharmacokinetics in pediatric oncology patients

Kramer¹,

Pickering²,

Culbert³

et al. 1984

“…The pharmacokinetics of mezlocillin must be understood to design dosage regimens which provide drug concentrations in serum above the MIC for the target organism. In addition, it may be important in some instances to determine the mezlocillin concentration at or near the site of infection, for example, in urine or cerebrospinal fluid (1,2,7,8).High-pressure liquid chromatographic (HPLC) assays are frequently used for pharmacokinetic studies of antibiotics because of their specificity, sensitivity, speed, and range of linearity. A number of HPLC methods for determination of mezlocillin levels have been described previously (3)(4)(5)(6).…”

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confidence: 99%

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confidence: 99%

Improved micromethod for mezlocillin quantitation in serum and urine by high-pressure liquid chromatography

Fiore¹,

Auger²,

Drusano³

et al. 1984

A rapid, sensitive, and specific method of analysis for mezlocillin in serum and urine by high-pressure liquid chromatography is described. A solid-phase extraction column was used to remove interfering substances from samples before chromatography. Quantitation included the use of an internal standard, nafcillin. Mezlocillin was chromatographed with a phosphate buffer-acetonitrile (73:27) mobile phase and a C-18 reverse-phase column and detected at a wavelength of 220 nm. The assay had a sensitivity of 1.6 ,ug/ml and a linearity of up to 600 ,ug/ml and 16 mg/ml in serum and urine, respectively, with only 0.1 ml of sample. The interday and intraday coefficients of variation for replicate analyses of spiked serum and urine specimens were less than 6.5%.Mezlocillin is a relatively new member of the ureidopenicillin class of antibiotics. It possesses a broader spectrum of activity against aerobic and anaerobic bacteria than the older semisynthetic penicillins. The pharmacokinetics of mezlocillin must be understood to design dosage regimens which provide drug concentrations in serum above the MIC for the target organism. In addition, it may be important in some instances to determine the mezlocillin concentration at or near the site of infection, for example, in urine or cerebrospinal fluid (1,2,7,8).High-pressure liquid chromatographic (HPLC) assays are frequently used for pharmacokinetic studies of antibiotics because of their specificity, sensitivity, speed, and range of linearity. A number of HPLC methods for determination of mezlocillin levels have been described previously (3)(4)(5)(6). One method requires a time-consuming extraction step and results in poor recovery (<50%) of mezlocillin (4). The other two HPLC procedures (3,6) are relatively simple, sensitive, and specific for mezlocillin in serum or plasma; however, they require a sample volume of at least 0.5 ml, and none of these methods use an internal standard.The objective of this study was to develop a more rapid, specific, and sensitive HPLC assay for the measurement of mezlocillin in serum and urine with an internal standard and small sample volumes (0.1 ml).HPLC The buffer solution used throughout the study was 0.07 M potassium dihydrogen phosphate adjusted to pH 5.0 with 5 M sodium hydroxide. Nafcillin, the internal standard, was prepared at a concentration of 190 Fig/ml in buffer and frozen in 1-ml portions in disposable polypropylene tubes (Bio-Rad Laboratories, Richmond, Calif.). Serum standards for mezlocillin were prepared from a stock solution of 6,040 ,ug/ml in blank serum to contain 6, 12, 48, 97, 242, 423, or 604 p.g of mezlocillin per ml. Urine standards were prepared from a * Corresponding author. stock solution of 73 mg/ml to contain 0.5, 1.0, 3.0, 6.0, 9.2, or 16.2 mg of mezlocillin per ml. Portions of the serum (0.25 ml) and urine (0.25 ml after 1:10 dilution with buffer) standards were stored at -25°C in polypropylene tubes, where they were stable for at least 3 weeks.A volume of 0.10 ml of serum or urine (after 1:10 dilution with ...