Marion L. Thomas

Clinical evaluation of a new broad-spectrum oxa-beta-lactam antibiotic, moxalactam, in neonates and infants

Moxalactam, a new parenteral 1-oxa-beta-lactam antibiotics, is highly effective in vitro against gram-negative enteric bacilli, including isolated from neonates with meningitis. Studies with moxalactam in experimental coliform meningitis demonstrated favorable penetration, bioavailability, and antibacterial activity in CSF. The potential value of moxalactam for therapy of gram-negative enteric meningitis of infancy prompted this study. Pharmacokinetics of moxalactam were determined in 74 infants and serum concentration-time curves were characterized bay the two-compartment open-system kinetic model. The mean peak serum concentration at the end of 50 mg/kg, ten-minute infusions was approximately 125 micrograms/ml. Elimination half-life values correlated inversely with gestational and chronologic age. The mean half-lives were 6.2 hours in neonates less than one week of age, 4.4 hours in those one to 4 weeks, and 1.6 hours in infants one to 24 months of age. A mean CSF penetration of 30% was demonstrated after repeated doses of moxalactam in 11 infants with coliform meningitis. Thirteen neonates and two infants with gram-negative enteric bacillary infections were successfully treated with this agent. the drug was well tolerated and adverse effects were not observed. Moxalactam will be evaluated in a prospective, controlled study of gram-negative enteric meningitis by the Neonatal Meningitis Cooperative Study Group.

Pharmacologic studies in neonates given large dosages of ampicillin

The clinical pharmacology of ampicillin in neonates was studied. Ampicillin was effective in vitro against the common gram-pesitive pathogens and most E. coli causing neonatal bacterial diseases. Synergy was demonstrated in vitro for 40 per cent of E. coli using combinations of ampicillin and gentamicin. The pharmacokinetic properties of ampicillin in premature and full-term infants given 50, 75, or 100 mg. per kilogram per dose intramuscularly were investigated. Mean peak serum ampicillin values in premature infants 1 to 3 days of age were 104, 166, and 204 μg per milliter after 50, 75, and 100 mg. per kilogram per dose, respectively. There was no significant drug accumulation in serum and, half-life values were related inversely to postnatal age. Ampicillin levels in cerebrospinal fluid of 1 to 28 μg per milliliter after 40 to 70 mg. per kilogram per dose were 11 to 65 per cent, respectively, of the simultaneous serum values. Dosage recommendations are presented.

Clinical pharmacology of penicillin in newborn infants

The clinical pharmacology of penicillin was studied in 47 newborn infants. Serum dose-response curves were determined after intramuscular injection of penicillin G in doses of 16,650, 25,000, and 50,000 units per kilogram. Peak serum concentrations in infants under one week of age were 22 to 24.8 μg per milliliter after 16,650 and 25,000 units per kilogram per dose and 35.8 μg per milliliter after 50,000 units per kilogram per dose; antimicrobial activity was measurable for 8 to 12 hours. The halflife of penicillin in serum correlated inversely with age and clearance of creatinine and ranged from 3.2 hours in infants 0 to 6 days of age to 1.4 hours in infants 14 days of age or older. Excretion of penicillin in urine correlated directly with clearance of creatinine. Mean serum levels after a single daily intramuscular dose of 50,000 units per kilogram of procaine penicillin G to infants under one week of age were 7 to 8 μg per milliliter for 12 hours and 1.5 μg per milliliter at 24 hours after the dose.

Pharmacokinetics and bacteriological efficacy of moxalactam (LY127935), netilmicin, and ampicillin in experimental gram-negative enteric bacillary meningitis.

Moxalactam (LY127935) is a 1-oxa-beta-lactam which was active in vitro against the majority of 128 strains of gram-negative enteric bacilli isolated from meningitis in neonates. Pharmacokinetics and bacteriological efficacy of LY127935 were studied in a lapin meningitis model. The average penetration of this investigational oxa-cephalosporin into cerebrospinal fluid of infected rabbits was 23% compared with 25% for netilmicin and 11% for ampicillin. The cerebrospinal fluid concentrations of LY127935 produced median bactericidal titers of 1:64 to 1:128 against five coliform organisms (two Escherichia coli K1 strains, Klebsiella pneumoniae, Salmonella saint-paul, and Citrobacter diversus) used in these experiments compared with median titers of 1:2 to 1:8 for netilmicin and 1:2 to 1:4 for ampicillin. LY127935 was statistically significantly more effective than netilmicin or ampicillin in reducing cerebrospinal fluid bacterial colony counts and in sterilizing cerebrospinal fluid of experimentally infected rabbits. These results suggest that LY127935 has theoretical advantages over netilmicin and ampicillin for therapy of gram-negative bacillary meningitis.

Pharmacokinetics of cefotaxime in newborn infants.

The pharmacokinetics of cefotaxime were determined in newborn infants who were 1 to 7 days of age. Mean peak serum concentrations of 116 and 132 micrograms/ml were observed at completion of a 10-min intravenous infusion of 50 mg of cefotaxime per kg in low and average birth weight infants, respectively. The mean elimination half-lives were 4.6 and 3.4 h and rates of clearance from serum were 23 and 44 ml/min per 1.73 m2, respectively. A dosage schedule for cefotaxime in newborn infants is presented.

Ceftriaxone pharmacokinetics in newborn infants.

Ceftriaxone pharmacokinetics were determined in 40 newborn infants who were 1 to 45 days of age. Mean peak plasma concentrations of 136 to 173 micrograms/ml were observed at the completion of a 15-min intravenous infusion of 50 mg of ceftriaxone per kg. Mean half-life values were 5.2 to 8.4 h, and mean plasma clearances were 0.7 to 1.8 ml/min. Rectal swab cultures from 14 of 16 infants had either reduced numbers of aerobic and anaerobic bacteria or no growth during therapy. A once-daily dosage schedule is suggested for ceftriaxone therapy in newborn infants.

Pharmacokinetics and therapeutic efficacy of imipenem, ceftazidime, and ceftriaxone in experimental meningitis due to an ampicillin- and chloramphenicol-resistant strain of Haemophilus influenzae type b

The pharmacokinetics and therapeutic efficacy of imipenem, ceftazidime, and ceftriaxone were compared with those of ampicillin and chloramphenicol in rabbits with experimental meningitis due to an ampicillin- and chloramphenicol-resistant strain of Haemophilus influenzae type b. The mean bacterial colony counts in cerebrospinal fluid were reduced by 49% (-1.85 log10 CFU/ml), 92% (-3.37 log10 CFU/ml), and 92% (-4.30 log10 CFU/ml) after a single dose of imipenem, ceftazidime, and ceftriaxone, respectively. The median peak cerebrospinal fluid bactericidal titers against this multiply resistant strain of H. influenzae were 1:4 for thienamycin, 1:16 for ceftazidime, and 1:256 for ceftriaxone. By contrast, no bactericidal activity was observed in cerebrospinal fluid and the mean concentrations of H. influenzae were either unchanged or slightly increased in animals treated with ampicillin or chloramphenicol.

Pharmacokinetic Properties of Netilmicin in Newborn Infants

Netilmicin and gentamicin susceptibilities of 258 gram-negative organisms and 25 strains of Staphylococcus aureus were nearly identical. The pharmacokinetic properties of netilmicin were evaluated in 101 newborn infants and related to birth weight, gestational age, chronological age, and route of administration. Mean peak serum concentrations of 5.6 to 6.9 and 7.8 to 8.4 μg/ml were observed 30 min after 3- and 4-mg/kg doses, respectively, were given intramuscularly. The peak concentrations were directly related to gestational age. The average serum half-life values varied from 3.4 to 4.7 h and in general were inversely related to birth weight, gestational age, and postnatal age. The pharmacokinetics of netilmicin in 10 infants were similar after intramuscular and intravenous administration. A comparative study of netilmicin and gentamicin in seven neonates revealed greater variability in serum concentrations of gentamicin and a shorter half-life for netilmicin. There was evidence of accumulation of netilmicin in 12 low-birth weight, premature infants who received 4-mg/kg doses for an average of 6.4 days. Serum and urine levels of netilmicin were measured up to 11 days after discontinuation of the drug. These data are well characterized by a two-compartment model. Additional studies of efficacy and long-term toxicity of netilmicin in neonates are necessary.

Pharmacokinetics of ceftazidime in newborn infants.

Doses of 50 mg of ceftazidime per kg were administered intravenously to 29 newborn infants every 8 or 12 h for 3 to 5 days. Mean peak concentrations in plasma ranged from 102 to 124 micrograms/ml. Mean elimination half-life values ranged from 2.9 to 6.7 h and varied inversely with gestational age and plasma clearances. Peak and trough plasma bactericidal titers against an Escherichia coli and a group B streptococcus strain were at least 1:16 and 1:32, respectively.

Bioavailability of cephalexin in children: Relationship to drug.formulations and meals

PHYSICIANS frequently prescribe oral antibiotics for children without instructions about when to give these drugs in relation to meals. Absorption of drugs from the gastrointestinal tract may be diminished or delayed, or both, when food is coadministered because of slowed gastric emptying, dilution of intestinal contents, changes in drug solubility, or alteration of intestinal pH, motility, and blood flow?, 2 The factors influencing bioavailability (the rate and degree to which a drug is absorbed into the systemic circulation) of orally administered antimicrobial agents have not been adequately studied in infants and children. In the present study cephalexin monohydrate suspension or capsules were administered to fasting and nonfasting children. The pharmacokinetic properties of the drug were measured to determine if the two formations were bioequivalent and if concomitant food intake affected absorption. Previous studies showed smaller peak concentrations of cephalexin in serum of adults receiving capsules with food compared to individuals given the drug on an empty stomach?, �9 PATIENTS AND METHODS The project was conducted on the wards of Childrens Medical Center and Parkland Memorial Hospital, Dallas. Study patients were part of an ongoing evaluation of oral antibiotic therapy in the management of osteomyelitis and septic arthritis of childhood. Informed, Written consent was obtained from the patients parents or guardians.