A microscale HPLC-UV method for the determination of latamoxef in plasma: An adapted method for therapeutic drug monitoring in neonates.

Latamoxef, a broad-spectrum anti-bacterial agent of the ß-lactam antibiotics, is used off-label in treatment of neonatal sepsis. Large inter-individual variability and uncertainty of treatment make therapeutic drug monitoring (TDM) useful to optimize antimicrobial therapy. The objective of this study was to develop and validate a simple, selective and reliable HPLC method for the determination of latamoxef in small volumes of plasma, which could be used in neonatal TDM. After a simple protein precipitation, analytes were separated with liquid chromatography and quantified by UV detection, with tinidazole as the internal standard. The calibration range was linear from 3.0 to 60.0 µg/mL. Intra- and inter-day precisions were < 7.2%. The acceptance criteria of accuracy (between 85 and 115%, 120% for lower limit of quantification) were met in all cases. A plasma volume of 50 µL was required to achieve the limit of quantification of 3.0 µg/mL. The TDM results showed a large variability in trough concentrations. A large number of patients were underdosed, highlighting the unmet need for TDM to optimize latamoxef therapy in neonates.

Epimerization of moxalactam by albumin and simulation of in vivo epimerization by a physiologically based pharmacokinetic model.

We investigated the mechanism of epimerization (R to S or S to R) of moxalactam in serum of rats, dogs, and humans. The epimerization of moxalactam occurred in the serum of these animals, but not in the serum filtrate. The albumin fraction of human serum purified by gel filtration catalysed the epimerization of moxalactam at an identical rate to serum, but other fractions (i.e., lipoproteins and globulins) showed slower epimerization. alpha 1-acid glycoprotein, which was eluted in the same fraction with albumin by G-200 gel filtration, did not epimerize moxalactam. The presence of 2 mM warfarin decreased the binding of R- and S-moxalactam and decreased the epimerization of moxalactam in human serum. These results demonstrate moxalactam was epimerized on the warfarin binding site on albumin in serum. Additionally, a physiologically based pharmacokinetic model shows that the epimerization of moxalactam after administration in dogs is simulated by the epimerization in serum.

Improvement of the rectal bioavailability of latamoxef sodium by adjuvants following administration of a suppository.

The absorption of an antibiotic, latamoxef sodium (LMOX), following the rectal administration of a suppository containing adjuvants was investigated. A lipophilic base (Witepsol H15) was used. The rectal absorption of LMOX following the administration of a suppository without adjuvants was very low. Diclofenac sodium (DF) was used as an absorption promoter; it enhances rectal membrane permeability. The blood level of LMOX following the addition of DF(10 mg) to the base was increased only about 1.3-fold compared with that achieved with LMOX alone (difference not significant); even with a higher dose of DF, the absorption of LMOX was not sufficient. The release rate of LMOX from the base was slow. When Tween 80, a non-ionic surfactant, was added to improve the release rate of LMOX, the rate was sufficiently increased. The rectal absorption of LMOX on the addition of both Tween 80 and DF was markedly increased compared to that achieved with LMOX alone or with DF. These results indicate that the rectal absorption of LMOX after administration by a suppository was sufficiently improved by enhancing both the release rate from the base and the membrane permeability of the rectum. Lymphatic uptake and blood levels of LMOX were also investigated after the rectal administration of the LMOX preparation containing both Tween 80 and DF; the lymphatic uptake of LMOX was significantly enhanced compared with the LMOX preparation in which only DF was used as an adjuvant. The mechanism whereby adjuvants lead to the absorption of a non-absorbable drug, and the subsequent drug transportation routes through the membrane are discussed.

Epimerization kinetics of moxalactam in frozen urine and plasma samples.

The epimerization of moxalactam (LMOX) in frozen urine and plasma samples was studied during long-term storage. The R/S ratio at equilibrium [(R/S)eq] at -10 degrees C was similar in urine and in rat and human plasma ultrafiltrate but differed from that in water. The (R/S)eq values in human plasma and its ultrafiltrate differed slightly, while they were the same in rat plasma and in its ultrafiltrate. The difference for the human plasma and ultrafiltrate may result from differences in plasma protein binding between R- and S-epimers in the liquid region of the frozen plasma. The change of R/S ratio in frozen human plasma continued below the collapse temperature of LMOX aqueous solution, where the liquid region appeared still to exist as determined by NMR measurement. Consequently, the biological LMOX samples should be preserved at or below -70 degrees C to prevent changes in the R/S ratio.

Pharmacokinetics of single-dose administration of moxalactam in unweaned calves.

Twenty-nine healthy 17- to 29-day-old unweaned Israeli-Friesian male calves were each given a single IV or IM injection of 10 or 20 mg of moxalactam disodium/kg of body weight. Serum concentrations were measured serially during a 12-hour period. Serum concentration vs time profiles were analyzed by use of linear least-squares regression analysis and the statistical moment theory. The elimination half-lives after IV administration were 143.7 +/- 30.2 minutes and 155.5 +/- 10.5 minutes (harmonic mean +/- SD) at dosages of 10 and 20 mg of moxalactam/kg of body weight, respectively. Corresponding mean residence time values were 153.1 +/- 26.8 minutes and 169.9 +/- 19.3 minutes (arithmetic mean +/- SD). Mean residence time values after IM administration were 200.4 +/- 17.5 minutes and 198.4 +/- 19.9 minutes at dosages of 10 and 20 mg/kg, respectively. The volumes of distribution at steady state were 0.285 +/- 0.073 L/kg and 0.313 +/- 0.020 L/kg and total body clearance values were 1.96 +/- 0.69 ml/min/kg and 1.86 +/- 0.18 ml/min/kg after administration of dosages of 10 and 20 mg/kg, respectively. Moxalactam was rapidly absorbed from the IM injection site and peak serum concentrations occurred at 1 hour. The estimated bioavailability ranged from 69.8 to 79.1%. The amount of serum protein binding was 53.4, 55.0, and 61.5% when a concentration of moxalactam was at 50, 10, and 2 micrograms/ml, respectively. The minimal inhibitory concentrations of moxalactam ranged from 0.01 to 0.2 micrograms/ml against Salmonella and Escherichia coli strains and from 0.005 to 6.25 micrograms/ml against Pasteurella multocida strains.

Ocular pharmacokinetics of latamoxef and cefaclor in rabbits. Penetration into aqueous humor.

Penetrations of latamoxef (LMOX) and cefaclor (CCL) into the aqueous humor after intravenous or oral administration were investigated in rabbits. Concentrations of antibiotics in plasma and aqueous humor after administration were determined periodically by microbiological assay. LMOX disappeared from plasma in a monoexponential manner with a half-life of 43 min after intravenous administration at a dose of 50 mg/kg. The maximum concentration of LMOX in aqueous humor (6.4 micrograms/ml) was observed 1 h after administration. When CCL was administered orally at a dose of 50 mg/kg, the maximum concentration of CCL in aqueous humor was 1.00 microgram/ml 1.5 h after administration, whereas the maximum plasma concentration of 19.2 micrograms/ml was observed at 30 min. Pharmacokinetic analysis (simultaneous simulation) of plasma and aqueous humor concentration-time courses was made using the best fitted compartment model examined (modified two-compartment model). Prediction of the concentration of antibiotics in aqueous humor from the plasma concentration profile was also examined using the same compartment model in a separate experiment. The predicted concentration in aqueous humor was proved to coincide reasonably well with the measured concentration.

Moxalactam vs tobramycin-clindamycin. A randomized trial in secondary peritonitis.

One hundred five patients with peritonitis were randomized to receive either tobramycin sulfate plus clindamycin phosphate or moxalactam alone before surgical intervention. Fifty-nine patients were evaluable. A mean of 3.1 (moxalactam) and 3.5 (tobramycin-clindamycin) pathogens per patient were identified. Overall success rate was 85% (tobramycin-clindamycin, 24/30; moxalactam, 26/29). When patients with appendicitis were excluded, there was an observed but not statistically significant advantage of moxalactam over tobramycin-clindamycin (85% vs 67%). There were five deaths (tobramycin-clindamycin, four; moxalactam, one). Other complications included hypoprothrombinemia (tobramycin-clindamycin, five; moxalactam, five), renal dysfunction (tobramycin-clindamycin, three; moxalactam, one), and superinfection (tobramycin-clindamycin, nine; moxalactam, six). More wound infections were noted in the group given tobramycin-clindamycin. These data suggest that moxalactam is as safe and efficacious as tobramycin plus clindamycin. The observed benefits of this agent warrant study in a larger sample to verify advantages of moxalactam over combination therapy.

Comparative serum bactericidal activity against test anaerobes in volunteers receiving imipenem, clindamycin, latamoxef and metronidazole.

Ten healthy volunteers received on separate days the following regimens: imipenem 500 mg, clindamycin 600 mg, latamoxef 1 g, and metronidazole 500 mg. The antibiotics were given intravenously as an infusion over 15 min. Blood samples were obtained before and 30 min, 1 and 6 h after the start of the infusion. Serum bacteriostatic and bactericidal activities were measured against the following strains of strict anaerobes: two strains of Bacteroides fragilis, one strain each of B. vulgatus, B. thetaiotaomicron, B. oralis, Fusobacterium symbiosum, Eubacterium lentum, Clostridium perfringens, and Peptostreptococcus magnus. Sera from patients receiving clindamycin showed the highest inhibitory and bactericidal activities except against B. thetaiotaomicron and F. symbiosum. Imipenem had similar inhibitory and bactericidal activity to that shown by latamoxef. Metronidazole had a moderate activity against all strains although the activity persisted for 6 h. Latamoxef was the most active antibiotic against the test strain of C. perfringens.

Effects of various doses of latamoxef (moxalactam) on haemostasis.

The effects of intravenous latamoxef therapy at two doses of 3g and 6g daily for 7 days was assessed by various haemostatic parameters. With both doses, the prothrombin time, thrombin time and activated partial thromboplastin time remained within the normal range throughout the study. However, with the 6g day-1 dose there was a marked prolongation of the bleeding time associated with defective platelet aggregation to adenosine diphosphate and low dose collagen after 7 days therapy. With the 3g day-1 dose of latamoxef, there was no prolongation of the bleeding time and only minor changes in platelet aggregation responses.

Human vitreous levels of cefamandole and moxalactam.

We gave 2-g intravenous doses of either cefamandole or moxalactam to 22 patients before vitrectomy. At 1 1/2 to 2 1/2 hours after administration, cefamandole vitreous concentrations varied from 0.36 to 2.05 micrograms/ml (mean, 0.94 micrograms/ml). Individual levels above the minimum inhibitory concentration of cefamandole for 90% (MIC90) of Staphylococcus aureus were found in five of 11 patients. Levels above the MIC90 for S. epidermidis were found in only two of 11 samples. Vitreous concentrations above the MIC90 of cefamandole for common gram-negative pathogens were found in only two patients. Moxalactam concentrations in the vitreous varied from 1.1 to 4 micrograms/ml 30 minutes to six hours after administration. These levels were not above moxalactam's MIC90 for S. aureus or S. epidermidis but were many times higher than the MIC90 of moxalactam for Enterobacteriaceae excluding Pseudomonas.

A double beta-lactam combination versus an aminoglycoside-containing regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients.

The double beta-lactam combination of moxalactam plus piperacillin was compared with the aminoglycoside-containing regimen of moxalactam plus amikacin in a prospective, randomized trial of empiric therapy for 302 febrile episodes in granulocytopenic cancer patients. The moxalactam/piperacillin regimen was found to be as effective as the moxalactam/amikacin regimen (70 percent overall responses); responses with moxalactam/piperacillin and moxalactam/amikacin were similar for microbiologically documented infections (24 of 37, 65 percent, versus 20 of 35, 57 percent), for the subgroup with bacteremias (19 of 32 versus 14 of 28), and for clinically documented infections (41 of 58, 71 percent, versus 40 of 48, 83 percent). Responses were similar also for bacteremia in patients with persistent, profound (less than 100/microliter) granulocytopenia. Among profoundly (less than 100/microliter) granulocytopenic patients with gram-negative bacteremia, an increase in the granulocyte count to more than 100/microliter during therapy and a peak bactericidal activity of 1:16 or more (the latter noted in seven of nine moxalactam/piperacillin trials and six of nine moxalactam/amikacin trials) correlated with a favorable clinical response in 85 percent (p less than or equal to 0.00003) and 92 percent (p less than or equal to 0.044), respectively. Although serious side effects were minimal with either regimen, the double beta-lactam combination was associated with significantly less frequent nephrotoxicity (two of 145 versus 12 of 130; p less than or equal to 0.003) and ototoxicity (none of 34 versus seven of 34; p less than or equal to 0.006). The double beta-lactam combination of moxalactam plus piperacillin was found to be as effective as moxalactam plus amikacin but to have significantly less nephro- and ototoxicity.

Pharmacokinetics of cefotaxime, moxalactam, and cefoperazone in the early puerperium.

Twelve parturient women volunteered to receive 1 g of cefotaxime on the second or third day postpartum by intravenous infusion over 3 min. Blood was taken from the antecubital vein of the contralateral arm at 0.25, 0.5, 0.75, 1, 2, 4, and 6 h. The concentration of cefotaxime in serum was assayed by agar diffusion, with Sarcina lutea ATCC 9341 as the indicator strain. The same 12 women received an identical dose of antibiotic 4 months after the first dose, and blood was taken at the same time intervals as in the first study to measure antibiotic levels. An additional 24 women participated in identical studies with either moxalactam or cefoperazone. Cefoperazone afforded the highest concentration in serum of the three drugs, followed by moxalactam. These differences in the concentration in serum were seen both early postpartum and 4 months later. However, the concentration in serum of all three drugs was diminished 2 and 3 days postpartum compared with 4 months postpartum. Most pharmacokinetic parameters were also significantly altered early in the puerperium relative to those obtained 4 months later. The altered pharmacokinetic behavior of antibiotics associated with pregnancy appears to persist into the early puerperium.

Antibiotic prophylaxis in vascular surgery: pharmacokinetic study of four commonly used cephalosporins.

Plasma levels of antibiotics often do not correlate well with their tissue levels. To determine optimal antibiotic coverage for prophylactic effect in vascular surgery, we studied the tissue pharmacokinetics of four cephalosporins in dogs: cefazolin, cefoxitin, cefamandole, and moxalactam for 3 hours after a single (25 mg/kg) intravenous injection. The minimal inhibitory concentration (MIC) of these antibiotics for the three most common pathogens involved in graft infections (Staphylococcus aureus, S. albus, and Escherichia coli) and their tissue concentration (TC) in the plasma, muscle, subcutaneous tissue, and aortic wall were assayed. The data are presented as TC/MIC ratio. Cefoxitin and moxalactam failed to achieve an effective therapeutic TC/MIC ratio (greater than 10) for S. aureus and S. albus in all the tissues studied whereas cefoxitin and cefamandole were above therapeutic levels. All antibiotics achieved an effective therapeutic ratio against E. coli, but cefamandole performed better (p less than 0.05) than cefoxitin; the latter reached effective levels at 3 hours. Cefamandole attained the most effective bioactive aortic tissue levels when the three most common pathogens were considered together and should therefore be considered as an antibiotic agent of choice for prophylaxis in vascular surgery.

A novel pharmacokinetic method for analysis of placental transfer of latamoxef in humans.

A novel pharmacokinetic method was developed for analysing the behaviour of a drug in tissues. The absolute transfer ratio of a drug to a tissue was defined using the pharmacokinetic parameters obtained by this method. Composite data of latamoxef (moxalactam) concentration in maternal blood, umbilical cord blood and amniotic fluid following a 2g intravenous injection to pregnant women at delivery were analysed by this method to study the drug behaviour in pregnant women, fetuses and amniotic fluid. Latamoxef kinetics in pregnant women at full term were generally similar to that in previously reported healthy subjects. The concentration of latamoxef in umbilical cord blood peaked about 2 hours after dosing then decreased in parallel with the maternal blood concentration. The amniotic fluid concentration peaked about 7 hours after administration, then decreased slowly. The absolute transfer ratios to fetus and amniotic fluid were calculated to be about 2.5 and 0.37% respectively.

Serum kinetics of intraperitoneal moxalactam.

Continuous intraperitoneal administration of antibiotics has been recommended as treatment for peritonitis. The necessity of simultaneous systemic administration of antibiotics remains undefined but usually is performed. Moxalactam kinetics in serum were studied in dogs receiving 15 mg/kg intravenously; 15 mg/kg intraperitoneally; 5 mg/kg hourly with peritoneal lavage; 15 mg/kg intravenously followed by 5 mg/kg hourly intraperitoneally; 15 mg/kg intraperitoneally after 24 hours of peritonitis; and 5 mg/kg hourly by peritoneal lavage after 24 hours of peritonitis. Intraperitoneally administered moxalactam resulted in sustained serum levels compared with intravenously administered drugs. Repeated exchanges in lavage fluid resulted in progressively higher serum levels with each exchange. Peritonitis results in statistically higher levels of serum antibiotic concentration when compared with controls. Continuous intraperitoneal lavage with antibiotics would not appear to require concomitant systemic drug therapy.