Norma Threlkeld

Single-dose penicillin prophylaxis against neonatal group B streptococcal infections. A controlled trial in 18,738 newborn infants.

Neonatal Group B streptococcal infections may not respond to antimicrobial therapy and have been associated with case fatality rates of 50 per cent or greater. We evaluated the effect on colonization and disease rates of a single intramuscular dose of aqueous penicillin G given at birth in a prospectively controlled study of 18,738 neonates during a 25-month period. The colonization rate in the mothers was 26.6 per cent, with 50 per cent concordance in the untreated infants and 12.2 per cent in the penicillin-treated infants (P < 0.001). There was a significant decrease in the incidence of disease caused by all penicillin-susceptible organisms in the penicillin group (0.64 vs. 2.26 cases per thousand live births, P = 0.005). Disease caused by penicillin-resistant pathogens was increased in the penicillin-treated group during the first year of the study but was unaffected during the second year. Routine administration of parenteral penicillin at birth cannot be recommended until the effect on the incidence of disease caused by penicillin-resistant pathogens is fully defined.

INTRAVENTRICULAR GENTAMICIN THERAPY IN GRAM-NEGATIVE BACILLARY MENINGITIS OF INFANCY

In a multicentre controlled trial in the U.S.A. and Latin America 52 infants with meningitis and ventriculitis were randomly assigned to receive either systemic ampicillin and gentamicin or intraventricular gentamicin plus systemic antimicrobial agents. The aetiological agents most often encountered were Escherichia coli in the U.S. infants and Salmonella spp. in Latin American infants. Infants receiving systemic antibiotics plus intraventricular gentamicin had a significantly higher mortality rate (42.9%) than those who received systemic therapy only (12.5%). Duration of positive CSF cultures and morbidity rates were not significantly different in the two treatment groups. The concentrations of gentamicin in ventricular and lumbar CSF 1--6 h after an intraventricular dose of 2.5 mg gentamicin were 10--130 microgram/ml and 8--85 microgram/ml, respectively. The study was terminated early because of the higher mortality rate in the intraventricular-therapy group. Intraventricular gentamicin should not be used as routine treatment for neonatal meningitis caused by gram-negative enteric bacilli.

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.

SINGLE-DOSE PENICILLIN PROPHYLAXIS OF NEONATAL GROUP-B STREPTOCOCCAL DISEASE: Conclusion of a 41 Month Controlled Trial

The efficacy of a single dose of aqueous penicillin G in preventing neonatal group-B streptococcal infections was demonstrated in a randomised study conducted over 41 months. 16 082 infant received a single dose of penicillin within one hour of delivery, and 15 976 infants who received tetracycline ophthalmic ointment served as the control group. Group-B streptococcal systemic infections were significantly less common in the penicillin-treated infants (0.6 vs 1.7 cases per 100 live birth, p = 0.004). The incidence of infection caused by penicillin-resistant pathogen was insignificantly increased in the penicillin group (2.2 vs 1.6 cases per thousand live birth, p = 0.32). this difference was accounted for almost completely by the events of the first 12 months of the study period when, for unexplained reasons, there was a considerable increase in the number of penicillin-resistant infections in the penicillin group (3.6 vs 1.4 cases per 1000 live births, p = 0.09). The mortality associated with penicillin-susceptible pathogens was higher in the control group (0.1 vs 0.4 per 1000 live births, p = 0.18). However, the mortality associated with penicillin-resistant pathogens was increased in the penicillin (0.4 vs 1.0 per 1000 live births, p = 0.06). The combined mortality rates for all pathogens were not significantly different (1.1 vs 0.7 per 1000 liver births, p = 0.27, for the penicillin and control groups, respectively) and were nearly equivalent when the excess number of deaths associated with penicillin-resistant infections in the penicillin group during the first study year was excluded from analysis. The incidence of gonococcal ophthalmia and conjunctivitis was unaffected by the use of intramuscular penicillin at birth.

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 of imipenem-cilastatin in neonates.

Imipenem and its renal dehydropeptidase I inhibitor, cilastatin, were coadministered intravenously in a 1:1 ratio to 30 newborns. Five infants each received single doses of 10, 15, or 20 mg/kg of both drugs. Concentrations in plasma were proportional to the administered dose, and cilastatin achieved consistently higher concentrations than did equivalent doses of imipenem because of its smaller volume of distribution. The pharmacokinetics of both drugs were best described by a one-compartment model. The plasma half-lives of imipenem were 1.7 to 2.4 h, whereas those of cilastatin were 3.9 to 6.3 h. The plasma clearance of cilastatin was approximately one-quarter of that of imipenem in the dose range tested. The urinary concentrations of imipenem were 50% of those of cilastatin despite its higher clearance from plasma. Fifteen additional newborns received five to eight doses of imipenem-cilastatin at 20 mg/kg per dose every 12 h. There was no accumulation of either drug in plasma after repeated administrations, and the mean concentrations in plasma were similar when measured on the first and last days of the multiple-dose study. There was marked intersubject variability, more so for cilastatin. The pharmacokinetics of both drugs in neonates resembled those observed in adults with moderate to severe renal insufficiency. Because the effects of enzyme inhibition on neonates are unknown, additional studies with imipenem-cilastatin (primaxin) are recommended.

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.

Clinical pharmacology of methicillin in neonates

The pharmacokinetic properties of methicillin were investigated in 59 newborn infants. Concentrations of methicillin in serum were approximately 58 and 80 microng/ml at one hour after 25 and 50 mg/kg doses, respectively. The average serum half-life values ranged from one to three hours and were inversely correlated with birth weight and chronologic age. The half-life values, volumes of distribution, and plasma clearances of methicillin are shown in relationship to gestational age and chronologic age. A dosage of 25 mg/kg is recommended for therapy of most neonatal staphylococcal diseases; the frequency of administration is altered on the basis of birth weight and chronologic age.