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Temocillin is a β-lactamase-resistant penicillin used for the treatment of multiple drug-resistant Gram-negative bacteria. To maximize efficacy and avoid adverse effects, the dose regimen has to be quickly adjusted to the clinical situations. This necessitates the development of a rapid, reliable and accurate analytical method. Temocillin and the stable isotopically labeled internal standard ([ 13 C 6 ]-amoxicillin) were extracted from either serum or cerebrospinal fluid by a turbulent flow liquid chromatographic method and eluted onto an octadecyl-silica phase with polar endcapping. Mass spectrometry was conducted using an exact mass determination method by electrospray positive ionization high-resolution mass spectrometry. The LLOQ and ULOQ of the present method were determined to be 0.4 and 200 μg/ml for serum and cerebrospinal fluid samples, respectively. The total analysis time was <7 min. The recovery ranged from 87.7 to 120.8%. Intra- and inter-day precision and trueness were tested at four concentration levels: 0.4, 8, 40 and 160 μg/ml. Values were 6.33 ± 1.53, 8.8 ± 1.3, 8.8 ± 0.36 and 2.1 ± 0.76%, and 5.0 ± 0.54, 9.9 ± 1.0, 5.8 ± 1.6 and 0.1 ± 1.1%, for inter- and intra-day analysis, respectively. Temocillin was found to be stable under all relevant laboratory conditions. The method was cross-validated with a microbiological assay. This method is suitable for accurate measurement of temocillin concentration in small volumes of serum or cerebrospinal fluid. Thanks to the online extraction procedure, the overall analytical time is compatible with high-throughput analysis for clinical application., (© 2019 John Wiley & Sons, Ltd.)

The renal secretion of carbenicillin (CBPC) was studied in rats. The results obtained in the in vivo study indicated very poor renal secretion of CBPC in rats, which was entirely different from those observed in humans and rabbits. In humans and rabbits, significant and stereoselective renal secretion of CBPC was observed in vivo. In order to verify the poor renal secretion of CBPC in rats, the transport characteristics of the organic anion transporters were studied in vitro using basolateral and brush border membrane vesicles. Transport of p-aminohippuric acid (PAH) into the basolateral membrane vesicles (BLMVs) was inhibited by CBPC, indicating that the organic anion transporter located at the BLM may have affinity to CBPC. In contrast, the transport of PAH into the brush border membrane vesicles (BBMVs) was not inhibited by CBPC, suggesting that the organic anion transporter located at the BBM may not have affinity to CBPC. Similar results were obtained for sulbenicillin (SBPC). Since CBPC and SBPC exist as di-anions at physiological pH, the organic anion transporter located at the rat renal BBM may not exhibit affinity to water-soluble di-anions, which in turn will result in poor renal secretion of these compounds.

A rapid and sensitive high performance liquid chromatographic method is described for the simultaneous determination of benzylpenicillin, ampicillin, phenoxymethylpenicillin, cloxacillin, dicloxacillin and nafcillin in small samples of human serum. The chromatographic system involves the use of a Spherisorb ODS reversed phase column and a gradient elution with 1 mM ammonium acetate buffer/acetonitrile (from 90:10 to 75:25 in 15 min). Detection and quantification are monitored by UV absorption at 208 nm. The compounds are extracted with dichloromethane, using tetrabutylammonium hydrogen sulfate neutralized with sodium hydroxide and buffered with borate as an ion pairing reagent; beta-hydroxyethyltheophylline is added as an internal standard. Our results show that the method is accurate and reproducible, allowing quantification of serum levels of assayed penicillins (0.5-50 micrograms/mL) without interference from other drugs commonly used in therapy. Recoveries were generally greater than 79.4%.

Ticarcillin (4 gm) and clavulanic acid (0.1 gm) were simultaneously administered as timentin to patients with cancer as therapy for infections. The pharmacokinetics of both ticarcillin and clavulanic acid were studied in 15 patients after 30-minute and 2-hour intravenous infusions. The mean (+/- SD) ticarcillin plasma peak concentrations after the two infusions were 341 +/- 76 and 210 +/- 60 micrograms/ml. The plasma terminal t1/2 values of ticarcillin were 80 +/- 32 and 56 +/- 12 minutes. The AUCs were 631 +/- 189 and 601 +/- 230 mg/L X hr. The volumes of distribution of the area were 15 +/- 5 and 21 +/- 7 L and total clearances were 115 +/- 36 and 127 +/- 54 ml/min. The corresponding values for clavulanic acid after the infusions are as follows: mean peak concentrations, 5 +/- 1 and 4 +/- 1 micrograms/ml; plasma terminal t1/2 values, 84 +/- 24 and 74 +/- 36 minutes; AUCs, 11 +/- 3 and 11 +/- 6 mg/L X hr; volumes of distribution of the area, 22 +/- 3 and 32 +/- 6 L; and total clearances, 170 +/- 58 and 175 +/- 68 ml/min.

Twelve geldings were used to evaluate serum levels of penicillin following the intravenous (iv) and intramuscular (im) injection of benzylpenicillin, im procaine penicillin and im fortified benzathine penicillin, at a variety of dose rates. Blood samples were collected up to 7 h after iv and im benzylpenicillin, up to benzathine penicillin. Results were analysed using an analysis of variance and regression analyses were used to calculate the time taken for the serum penicillin concentration to decline to 0.5 micrograms/ml. As a result of the experiments the following dosage regimes could be recommended for each drug. Benzylpenicillin should be administered im at a dose rate of 10,000 iu/kg at the commencement of treatment. Procaine penicillin should be injected at a dose rate of 15,000 iu/kg every 12 h or 30,000 iu/kg every 24 h. In serious infections 10,000 iu/kg of benzylpenicillin im should be used concomitantly to begin therapy. Fortified benzathine penicillin appears to have little value for antimicrobial therapy in the horse.

Piperacillin was administered to normal, healthy volunteers by an intravenous infusion over 30 min at dosage regimens of 12 gm daily (4 gm every 8 hr) and 24 gm daily (6 gm every 6 hr) for 5 consecutive days. Mean peak serum level after 12 gm daily was 244 +/- 24 (SE) microgram/ml and after 24 gm daily, 353 +/- 7 microgram/ml. After infusion the serum level declined monoexponentially in most subjects. On the 12-gm daily dosage mean values were 60 min for half-life (t1/2), 16 1 for volume of distribution, 188 ml/min for body clearance, and 139 ml/min for renal clearance. The same values on day 4 were 47 min, 12 1, 181 ml/min, and 125 ml/min; the volume of distribution was lower than on day 1. On the 24-gm daily dosage regimen, t1/2 was 60 min; volume of distribution, 16 1; body clearance, 183 ml/min; and renal clearance, 101 ml/min on day 1 compared to 68 min, 15 1, 148 ml/min, and 71 ml/min on day 4, the last 2 being significantly lower than on day 1. High renal clearance values were observed at low serum concentrations and vice versa, suggesting saturation of the tubular secretion process at high piperacillin concentrations in serum.

The kinetics of the antipseudomonas penicillin, azlocillin, was studied after intravenous injection in 9 patients with creatinine clearance under 7 ml/min. All were on long-term hemodialysis; 3 were also studied during a dialysis-free period. Kinetic parameters were derived using a 2-compartment open model. The mean serum azlocillin half-life (t 1/2) was 1.93 hr in patients on dialysis and approximately 5 hr off dialysis. Thirty percent of the dose was recovered in the dialysate during a 4-hr period. An approach to the use of azlocillin in patients undergoing dialysis is presented.

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.

1. Plasma, peripheral and thoracic lymph concentrations of penicillin V, phenethicillin, carbenicillin, ampicillin, cloxacillin, penicillin G, chloramphenicol and sulphadiazine were determined at various time intervals up to 6 h following intramuscular administration of 50 mg/kg to dogs.2. Peak plasma concentrations of the penicillins occurred within half an hour after administration with the peak lymphatic concentrations occurring 1.5 to 3 h afterwards. For the remaining period of the test the concentration in the lymph exceeded the corresponding concentration in the plasma. Sulphadiazine gave concentrations in thoracic lymph equal to the plasma concentration, but the peripheral lymph concentrations were lower while the concentrations of chloramphenicol in both peripheral and thoracic lymph were always lower than the plasma concentrations.3. After the peak concentrations were reached, the concentration curves for penicillins in lymph followed the same pattern as found in plasma, the penicillin concentrations declining exponentially. Sulphadiazine produced more persistent levels both in lymph and in plasma while the concentrations of chloramphenicol were still rising 6 h after administration.4. The free concentrations of penicillin in lymph were equal to the free concentrations in plasma, whereas the concentrations of free sulphadiazine and chloramphenicol in lymph were less than those in the plasma.