Gordon L. Brier

Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers.

Three separate single-dose studies were performed to define the disposition and pharmacokinetics of daptomycin in healthy volunteers. Daptomycin was administered as a single 14C-labeled dose (1.0 mg/kg of body weight) and as single doses between 0.5 and 6.0 mg/kg. All doses were intravenous. Antibacterial activity was determined from doses of 2.0, 3.0, 4.0, and 6.0 mg/kg against two strains of Staphylococcus aureus (one methicillin resistant) and one Enterococcus strain. After administration of 14C-labeled daptomycin, recovery of 14C in urine and feces accounted for 83% of the administered dose, with the greatest fraction (78%) appearing in the urine. Specific analysis for daptomycin in both urine and plasma indicated that metabolic products were present in urine, but total 14C in plasma consisted of daptomycin only. Doses between 0.5 and 6 mg/kg were linear, with a limited total body clearance (0.13 to 0.21 ml/min/kg) and a small volume of distribution (0.10 to 0.15 liter/kg). The small volume of distribution may be a factor of the high plasma protein binding (90 to 95%). Renal clearance made up 34 to 54% of total body clearance. Daptomycin demonstrated in vivo antibacterial activity against all three test strains, with the greatest activity observed against methicillin-resistant S. aureus. The predicted MIC for all three strains was approximately 13 micrograms/ml, corresponding to total (bound plus unbound) drug. On the basis of the drugs pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be effective.

Cefamandole: In Vitro and Clinical Pharmacokinetics

Cefamandole has a broader spectrum and greater potency than the other cephalosporins. It includes Haemophilus influenzae, most strains of Enterobacter, and many strains of indole-positive Proteus and Bacteroides, with a lower minimal inhibitory concentration for Escherichia coli, Klebsiella, etc. Concentrations of drug in the serum after the parenteral injection of cefamandole exceed manyfold the minimal inhibitory concentrations of over 82% of the bacteria studied. Approximately 65 to 85% is excreted in a biologically active form in the urine. This antibiotic offers advantages of antibacterial effectiveness and at the same time retains the safety of penicillin G and cephalothin in animals.

High-performance liquid chromatographic determination of loracarbef, a potential metabolite, cefaclor and cephalexin in human plasma, serum and urine

A high-performance liquid chromatographic (HPLC) method is reported for the determination of a new carbacephem antibiotic, loracarbef, a hydroxylated analogue, and two cephalosporins, cefaclor and cephalexin, in plasma, serum, and urine. The antibiotics are extracted from plasma by means of C18 solid-phase cartridges. Urine samples are diluted with water and directly injected on the HPLC system. The HPLC system utilizes a Supelcosil LC-18-DB (250 mm x 4.6 mm I.D.) reversed-phase column and ultraviolet detection at 265 nm. The limit of quantitation is 0.5 micrograms/ml for each compound. Excellent correlation of plasma concentrations is shown between results determined by HPLC and those obtained by microbiological agar-well diffusion assays. Stability studies of loracarbef in human plasma show the antibiotic to be stable for at least 24 h at room temperature and for at least twelve months at -20 degrees C.

Effect of Probenecid on the Blood Levels and Urinary Excretion of Cefamandole

Two oral 0.5-g doses of probenecid given 7 and 1 h before a single 1-g intramuscular dose of cefamandole resulted in higher serum levels of cefamandole than when cefamandole was given alone: 37 versus 20 μg per ml of serum, respectively. Cefamandole was not measurable (<0.3 μg/ml) at 8 h when it was given alone, whereas an average 8-h value of 2.9 μg/ml was obtained after pretreatment with probenecid. By prolonging the duration of these high cefamandole levels, probenecid should permit the treatment of more serious clinical infections, including those due to relatively resistant organisms, or permit a reduction in either the dosage of cefamandole or the frequency of administration.

Effect of probenecid on the pharmacokinetics of moxalactam.

The effects of probenecid on the pharmacokinetics of moxalactam were studied in normal volunteers administered a 2-min l-g intravenous infusion. The results showed that probenecid did not alter the plasma or urinary concentrations of moxalactam, its apparent volume of distribution, plasma elimination half-life, elimination rate constant, or plasma and renal clearances. Therefore, moxalactam appears to be eliminated primarily by the kidney via glomerular filtration.

Synergistic action of erythromycin and cefamandole against Bacteroides fragilis subsp. fragilis.

Erythromycin and cefamandole have exhibited synergistic activity against eight strains of Bacteroides fragilis subsp. fragilis. In concentrations of only 0.25 to 0.5 μg of erythromycin per ml (easily obtainable with oral therapy), less than 0.4 μg (0.015 to 1.0) of cefamandole per ml inhibited the B. fragilis strains. In the presence of the erythromycin, the potency of cefamandole was increased more than 100-fold. On the basis of the mechanism of action of these two antibiotics, the synergism may be related to inhibition of beta-lactamase formation by the erythromycin, removal of the bacterial cell wall by the cefamandole permitting erythromycin penetration to the ribosomal level, and decreasing inoculum effect.

Single- and multiple-dose pharmacokinetics of moxalactam in normal subjects.

The pharmacokinetics of moxalactam were studied in 86 normal adult male volunteers who received single or multiple doses intravenously or intramuscularly. The short absorption half-times and lag times indicate that the intramuscular dose is rapidly absorbed. The mean plasma half-life was 1.85 +/- 0.24 h for intravenous doses and 2.24 +/- 0.44 h for intramuscular doses. The mean renal clearances for intravenous doses were 0.052 and 0.067 liters/kg per h for intramuscular doses. Although moxalactam is eliminated primarily by the kidney a chromatogram of the feces from volunteers who received multiple doses showed that it is also excreted as the parent compound in to the feces via the biliary tract. The pharmacokinetics parameters of moxalactam when administered intravenously or intramuscularly in single and multiple doses clearly show the kinetics of moxalactam are linear over the dosage ranges studied and are independent of dose.

Bacterial L-phase growth as a possible complicating factor in certain bacteriological procedures.

Abstract Bacteria are converted to L-phase growth in the presence of antibiotics and serum. High concentrations of the antibiotics are not required for the L-phase conversion when human or horse serum is present, but instead, concentrations only slightly above that required for inhibition of classic growth forms are adequate. None of the currently available antibiotics tested in this study proved to have an inhibitory action on the growth of the L-phase.