Population pharmacokinetics and dosing optimization of latamoxef in neonates and young infants.

OBJECTIVES: There has been recent renewed interest in historical antibiotics because of the increased antibiotic-resistant bacterial strains. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has recently been brought back into use for treatment of infections in newborns; however, it is still used off-label in neonatal clinical practice due to the lack of an evidence-based dosing regimen. This study was performed to evaluate the pharmacokinetics of latamoxef in neonates and young infants, and to provide an evidence-based dosing regimen for newborns based on developmental pharmacokinetics-pharmacodynamics (PK-PD). METHODS: Opportunistic blood samples from newborns treated with latamoxef were collected to determine the latamoxef concentration by high-performance liquid chromatography with UV detection. Population PK-PD analysis was conducted using NONMEM and R software. A total of 165 plasma samples from 128 newborns (postmenstrual age range 28.4-46.1 weeks) were available for analysis. RESULTS: A two-compartment model with first-order elimination showed the best fit with the data. Current body weight, birth weight, and postnatal age were identified as significant covariates influencing latamoxef clearance. Simulation indicated that the current dosing regimen (30 mg/kg q12h) is adequate with an MIC of 1 mg/L. For an MIC of 4 mg/L, 30 mg/kg q8h was required to achieve a target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval. CONCLUSIONS: Based on the developmental PK-PD analysis of latamoxef, a rational dosing regimen of 30 mg/kg q12h or q8h was required in newborns, depending on the pathogen.

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.

Improved measurement of drug exposure in the brain using drug-specific correction for residual blood.

A major challenge associated with the determination of the unbound brain-to-plasma concentration ratio of a drug (K(p,uu,brain)), is the error associated with correction for the drug in various vascular spaces of the brain, i.e., in residual blood. The apparent brain vascular spaces of plasma water (V(water), 10.3 microL/g brain), plasma proteins (V(protein), 7.99 microL/g brain), and the volume of erythrocytes (V(er), 2.13 microL/g brain) were determined and incorporated into a novel, drug-specific correction model that took the drug-unbound fraction in the plasma (f(u,p)) into account. The correction model was successfully applied for the determination of K(p,uu,brain) for indomethacin, loperamide, and moxalactam, which had potential problems associated with correction. The influence on correction of the drug associated with erythrocytes was shown to be minimal. Therefore, it is proposed that correction for residual blood can be performed using an effective plasma space in the brain (V(eff)), which is calculated from the measured f(u,p) of the particular drug as well as from the estimates of V(water) and V(protein), which are provided in this study. Furthermore, the results highlight the value of determining K(p,uu,brain) with statistical precision to enable appropriate interpretation of brain exposure for drugs that appear to be restricted to the brain vascular spaces.

Antibiotic deactivation by a dizinc beta-lactamase: mechanistic insights from QM/MM and DFT studies.

Hybrid quantum mechanical/molecular mechanical (QM/MM) methods and density functional theory (DFT) were used to investigate the initial ring-opening step in the hydrolysis of moxalactam catalyzed by the dizinc L1 beta-lactamase from Stenotrophomonas maltophilia. Anchored at the enzyme active site via direct metal binding as suggested by a recent X-ray structure of an enzyme-product complex (Spencer, J.; et al. J. Am. Chem. Soc. 2005, 127, 14439), the substrate is well aligned with the nucleophilic hydroxide that bridges the two zinc ions. Both QM/MM and DFT results indicate that the addition of the hydroxide nucleophile to the carbonyl carbon in the substrate lactam ring leads to a metastable intermediate via a dominant nucleophilic addition barrier. The potential of mean force obtained by SCC-DFTB/MM simulations and corrected by DFT/MM calculations yields a reaction free energy barrier of 23.5 kcal/mol, in reasonable agreement with the experimental value of 18.5 kcal/mol derived from kcat of 0.15 s(-1). It is further shown that zinc-bound Asp120 plays an important role in aligning the nucleophile, but accepts the hydroxide proton only after the nucleophilic addition. The two zinc ions are found to participate intimately in the catalysis, consistent with the proposed mechanism. In particular, the Zn(1) ion is likely to serve as an "oxyanion hole" in stabilizing the carbonyl oxygen, while the Zn(2) ion acts as an electrophilic catalyst to stabilize the anionic nitrogen leaving group.

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.

Sequential changes in the prostatic fluid level of latamoxef in patients with acute bacterial prostatitis.

The sequential expressed prostatic secretion (EPS) levels of latamoxef (LMOX) were measured in 14 patients with acute bacterial prostatitis to evaluate the diffusion of this antibiotic from the plasma into the prostatic fluid. All patients received 2 g of LMOX on the 1st, 4th, and 7th days of hospitalization. The mean LMOX level in EPS and the EPS/serum ratio were 16.4 micrograms/ml and 0.24 on the 1st day, 5.5 micrograms/ml and 0.08 on the 4th day, and 3.5 micrograms/ml and 0.04 on the 7th day, respectively. The mean value of prostatic fluid was 7.7, 7.8, and 7.8, respectively. Thus, both the EPS level of LMOX and the EPS/serum ratio decreased along with the recovery from acute bacterial prostatitis and did not correlate with the pH gradient between prostatic fluid and plasma.

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.

Penetration of intravenous antibiotics into brain abscesses.

INTRA-ABSCESS CONCENTRATIONS OF the intravenously administered latamoxef (LMOX, moxalactam in the United States) and cefotetan (CTT), were studied in 11 patients with intracranial abscess. None of these patients underwent surgical ablation of the abscess. In all cases, the abscess was aspirated, and multiple aspirations were required in five patients. Antibiotic concentrations in 18 aspirates were, therefore, determined by the agar well method. LMOX concentrations in 16 aspirates drawn from nine brain abscess cases ranged from 0 to 10.9 micrograms/ml, with a mean (standard deviation) of 4.18 (3.04) micrograms/ml. The CTT concentration in one patient with a brain abscess was 8.51 micrograms/ml, and the LMOX concentration in the one remaining patient with subdural empyema was 5.20 micrograms/ml. In one patient, the serum-to-pus penetration rate of LMOX was estimated to be 0.11 against the peak value of the concentration in serum or 0.44 against the simultaneously obtained level in serum. Significantly higher concentrations of LMOX were produced in abscess cavities with multiple-dose administration or by prior drainage of pus. More-advanced stages of local inflammation, as demonstrated by computed tomography, correlated with higher concentrations. However, the routine indexes of systemic inflammation, such as body temperature, white blood cell count, and level of C-reactive protein in serum, cannot be used to predict the concentration present in intracerebral pus. A tendency for LMOX concentrations in pus obtained after single dose-administration to decrease with increasing duration from symptom onset to sampling was observed but was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Diffusion of cefmenoxime and latamoxef into prostatic fluid in the patients with acute bacterial prostatitis.

Twenty-two patients with acute bacterial prostatitis were treated with cefmenoxime (CMX) or latamoxef (LMOX), which have susceptibilities against various gram-negative bacteria. First 11 patients received a 5- to 12-day course of cefmenoxime and the next 11 received a 6- to 13-day course of latamoxef. All patients were treated successfully except 1 patient with a drug allergy. Diffusion of CMX or LMOX into prostatic fluid in these patients and healthy controls were evaluated. The mean value of CMX in the expressed prostatic fluid was 12.8 micrograms/ml in the patients receiving 2 g of CMX intravenously and 0.7 micrograms/ml in the controls. The mean value of LMOX was 14.0 micrograms/ml in the patients receiving 2 g of LMOX intravenously and 1.2 micrograms/ml in the controls. The diffusion of CMX and LMOX into prostatic fluid in the patients with acute bacterial prostatitis was strikingly higher than that of controls.

[Clinical study concerning of latamoxef concentration in the obstructed urinary tract].

Urinary LMOX concentration was studied in 18 patients with unilateral ureteral obstruction. The concentration of LMOX in the urine from the mild obstructed kidney was 124 to 2,140 micrograms/ml and 10 micrograms/ml in the severely obstructed ones. The difference was probably due to the intensity and the duration of the obstruction. The patient with 99mTc-DMSA renal uptake of less than 3% also had a urinary LMOX concentration of less than 7 micrograms/ml. The above results seem to show that 7 micrograms/ml in urinary LMOX concentration is a significant figure for treatment of UTI. 99mTc-DMSA renal uptake and renal echogram were used to estimate the excretion rate of antibiotics into the urine.

Therapeutic studies of cefepime (BMY 28142) in murine meningitis and pharmacokinetics in neonatal rats.

Cefepime (BMY 28142) was compared with ceftazidime, cefotaxime, and moxalactam for efficacy in treating experimental meningitis in mice and neonatal rats. Mice were infected intracranially with Streptococcus pneumoniae, S. agalactiae, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa and treated intramuscularly. Five- to eight-day-old neonatal rats were injected intracisternally with Haemophilus influenzae, S. pneumoniae, and S. agalactiae and treated intraperitoneally. Cefepime was found to be the most active compound against induced meningitis in mice infected with S. agalactiae. Cefepime was as active as cefotaxime against Staphylococcus aureus meningitis, slightly more active than cefotaxime against S. pneumoniae and E. coli, and as active as ceftazidime against K. pneumoniae and P. aeruginosa meningitis. Cefepime was found to be the most active compound against S. pneumoniae and S. agalactiae meningitis in neonatal rats. Against H. influenzae, cefepime was as active as moxalactam and cefotaxime. Ceftazidime was the least active compound. The pharmacokinetics of cefepime in neonatal rats were similar to those of ceftazidime. Both compounds penetrated well into cerebrospinal fluid and brain tissues of uninfected neonatal rats. Relative concentrations were twice as high as those of cefotaxime and moxalactam.

[Comparison of preoperative and postoperative chemotherapy in the treatment of advanced ovarian cancer].

Temporary blockage of uterine and ovarian vessels with forceps led to an approximately two-fold increase in the transfer of LMOX and Carboplatin to uterine muscle, ovarian tissue and pelvic lymph-nodes after the release of forceps. This result suggests the importance of preserving these main vessels for the effective transfer of chemotherapeutic agents to target tissues. Ten cases in stage III or IV underwent cytoreductive surgery followed by three courses of CDDP, ADM, CPA chemotherapy and SLO (postop. group). A further 27 cases were given diagnostic laparotomy followed by the same chemotherapy and SLO (preop. group). Examination of both groups revealed the following: The efficacy rate of the CAP regimen was 77.8% in the preop. group and 50.0% in the postop. group; the surgical extirpation rate exceeding 90% at SLO was 76.1% and 50.0% in the preop. and postop. groups respectively. The survival period was longer in the preop. group, ie., two years in 69% versus 40% and three years 43% v 20% of the preop. and postop. groups, respectively. Preoperative (Neo-adjuvant) chemotherapy followed by aggressive surgery was concluded to be preferable to carrying out enforced reduction surgery first on such advanced cases where the mass of the residual disease cannot be left untouched is unavoidable.

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 humans. Penetration into aqueous humor.

Penetrations of latamoxef (LMOX) and cefaclor (CCL) into the aqueous humor after intravenous or oral administration were investigated in patients admitted with cataract. Concentrations of antibiotics in plasma and aqueous humor were determined periodically by microbiological assay. LMOX disappeared from plasma in a monoexponential manner with a half-life of 2.7 h after intravenous administration at a dose of 1000 mg. The maximum concentration of LMOX in aqueous humor (4.7 micrograms/ml) was observed 2 h after administration. When CCL was administered orally at a dose of 500 mg, the maximum concentration of CCL in aqueous humor was 0.53 microgram/ml 2 h after administration, whereas the maximum plasma concentration of 8.4 micrograms/ml was observed at 1 h. Pharmacokinetic analysis (simultaneous simulation) of plasma and aqueous humor concentration-time courses was done by using the best-fitting 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 fit reasonably with the measured concentration.

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.

Transcervical amnioinfusion of antibiotics: a basic study for managing premature rupture of membranes.

To determine the best method of preventing ascending infection in the management of premature rupture of membranes, antibiotics such as latamoxef sodium, cefoperazone sodium, and cefotaxime sodium were infused directly into the amniotic cavity in 64 patients undergoing induction of labor at term. A single infusion of 100 or 500 mg of each drug resulted in a concentration of 200 to 1000 micrograms/ml immediately after infusion, and the concentration remained above 10 micrograms/ml for about 24 hours without significant increase in fetal or maternal blood levels. Consequently, a daily single dose of 100 mg or more is probably effective prophylaxis in cases of premature rupture of membranes. When intrauterine infection is suspected, the dose can be increased to 500 mg or more, and transplacental administration may be added to achieve a higher concentration in fetal blood. The present study simulates well premature rupture of membranes, and an amnioinfusion of antibiotics will be reliable and effective in managing premature rupture of membranes.