Prenatal exposures and congenital heart defects in Down syndrome infants.

The purpose of this study was to determine whether there are important differences in maternal and environmental prenatal risk factors between liveborn Down syndrome infants with congenital heart defects and Down syndrome infants without heart defects. Using a case control study design, we evaluated the risk associated with maternal illness, drug ingestion, substance usage, and chemical exposures in the home or workplace. The period of risk selected was 3 months before and 3 months after the last menstrual period, because cardiac development occurs early, before the mother may become aware of her pregnancy. Because fetal survival in Down syndrome may be more vulnerable to various exposures, controls were selected who also had trisomy 21. Of 171 infants studied, 89 were cases with congenital heart disease, and 82 were controls without heart disease. All interviews were performed by one nurse practitioner using a structured standardized questionnaire. Cases and controls had similar maternal ages, family incomes, parental education levels, and contraceptive practices before pregnancy. No differences were found between case and control mothers for maternal illness, medication use, or consumption of caffeinated beverages, cigarettes, or alcohol. Reporting of recreational drug usage was infrequent, may reflect underreporting, and did not differ between cases and controls. Maternal exposures were commonly reported for pesticides (50%), hair dyes (22%), craft paints (8%), varnishes (7%), and solvents (3.5%). However, in none of the categories was maternal exposure significantly more prevalent among case mothers than among control mothers. The failure of this study to identify risk factors for cardiac malformations may be attributable to the small differences in reported frequencies reducing statistical power or to the possibility that cardiac malformation in Down syndrome is a direct result of chromosomal duplication.

Significance of a positive urine group B streptococcal latex agglutination test in neonates.

We assessed the clinical significance of a reactive urine latex agglutination (LA) test in neonates without bacteriologically confirmed group B streptococcal (GBS) infection. In a retrospective review of a 3 1/2-month period, during which 367 urine specimens from newborn infants evaluated for suspected sepsis were tested by LA, 25 infants (6.9%) with sterile blood cultures but positive urine LA test results were compared with a control group of 112 infants with both blood cultures and urine LA test results negative for GBS. When the data were studied with stepwise discriminant analysis, the only variables significantly associated with a positive urine LA test result were immature to total neutrophil ratios greater than or equal to 0.16 at 0 and 12 hours. The influence of mucosal GBS colonization on urine LA test results was then investigated prospectively in 98 healthy infants (83 born to mothers colonized with GBS and 15 born to mothers with negative GBS cultures). Eight (8.2%) of the infants studied, or 8 of 52 (15.4%) infants colonized with GBS, had a positive urine LA test result. GBS was isolated from urine cultures of all infants with a positive urine LA test result. A positive urine LA test result was associated with positive GBS rectal and vaginal cultures and with increased density of colonization at those sites. We conclude that contamination of bag specimens of urine with GBS from perineal and rectal colonization may produce a positive urine LA test result in an infant with no systemic sign of infection.

Molecular analysis of the fetal IgM response to Treponema pallidum antigens: implications for improved serodiagnosis of congenital syphilis.

Western blot analysis of the fetal IgM response to Treponema pallidum antigens was examined among 39 pairs of maternal/infant sera; this included 12 mothers and infants with active syphilis (group I), 9 mothers with active syphilis and their infants with uncertain infection (group II), and 18 mothers treated for syphilis before delivery and their asymptomatic infants (group III). A fetal IgM response to T. pallidum antigens with apparent molecular masses of 72, 47, 45, 42, 37, 17, and 15 kDa was observed among sera of infants with congenital syphilis. Fractionation of sera into IgM and IgG components by high performance liquid chromatography confirmed that fetal IgM antibodies in every case were directed specifically against a 47-kDa antigen. Two asymptomatic infants from group II also showed serum IgM reactivities with the 47-kDa antigen, thereby appearing to confirm in utero infection. The combined data suggest that fetal serum IgM reactivity with the 47-kDa antigen of T. pallidum can be used as an important molecular marker for the diagnosis of congenital syphilis.

Pharmacokinetics and plasma bactericidal activity of aztreonam in low-birth-weight infants.

Aztreonam (30 mg/kg) was administered intravenously every 12 h during week 1 and every 8 h during weeks 2 to 4 of life to 26 low-birth-weight (less than 2,000 g) infants, and plasma concentration-time curves were measured on two occasions. The pharmacokinetics were described equally well by one-compartment and noncompartment models, and the values on day 1 were similar to those measured during the steady state on days 3 to 6. The mean peak plasma concentrations at completion of the 10-min infusion were from 65 to 83 micrograms/ml, the higher concentrations being seen in the larger infants. The half-lives of aztreonam ranged from 5.4 to 8.6 h and did not change significantly with birth weight. The median peak and trough plasma bactericidal titer against a strain of Escherichia coli (MBC, 10 micrograms/ml) was 1:16. Against a strain of Pseudomonas aeruginosa (MBC, 16 micrograms/ml), the median peak and trough bactericidal titers were 1:8 to 1:16 and 1:4, respectively. The urinary concentrations of aztreonam on day 1 of therapy were from 24 to 460.7 micrograms/ml (mean +/- 1 standard deviation, 254 +/- 113 micrograms/ml).

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.

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.

Moxalactam therapy for neonatal meningitis due to gram-negative enteric bacilli. A prospective controlled evaluation.

Moxalactam and ampicillin sodium therapy were compared with amikacin sulfate and ampicillin therapy for meningitis due to gram-negative enteric bacilli in 63 infants enrolled in the Third Neonatal Meningitis Cooperative Study. The population characteristics and causative organisms were comparable for the two treatment groups. Cultures of CSF were positive for approximately three days in both study groups. Case-fatality rates were 23% and 15% for moxalactam-treated infants and ampicillin- and amikacin-treated infants, respectively. Developmental or neurological abnormalities were found in about 40% of survivors, and the rates were comparable for both treatment groups. Computed tomograms in 44 infants were interpreted as normal in 13 (30%); hydrocephalus, abscesses, and low-density areas were the most frequent abnormalities. We conclude that moxalactam is a suitable alternative for treatment of meningitis due to gram-negative enteric bacilli.

Pharmacokinetic properties of mezlocillin in newborn infants.

The pharmacokinetic properties of mezlocillin were evaluated in newborn infants. Mean peak and trough concentrations of drug in plasma, after 75 mg of mezlocillin per kg given intravenously, were 252 and 72 micrograms/ml, respectively, in infants who were less than 38 weeks gestation and less than or equal to 7 days old, compared with 139 and 9 micrograms/ml, respectively, in infants greater than or equal to 38 weeks gestation and greater than 7 days old. The mean elimination half-life values were from 4.5 h in preterm infants who were less than or equal to 7 days old to 1.8 h in term infants greater than or equal to 7 days old. Median peak and trough bactericidal titers of drug in plasma from neonates treated with mezlocillin were 1:8 and 1:4, respectively, against a resistant (minimal bactericidal concentration, 512 micrograms/ml) Escherichia coli strain and 1:64 and 1:32, respectively, against a susceptible (minimal bactericidal concentration, 2 micrograms/ml) E. coli strain. We propose a dosage schedule of 75 mg of mezlocillin per kg administered every 12 h to preterm (gestational age less than 38 weeks) infants less than or equal to 7 days old, every 8 h to preterm infants greater than 7 days old or term infants less than or equal to 7 days old, and every 6 h to term infants greater than 7 days old.

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.

Single-dose penicillin prophylaxis of neonatal group-B-streptococcal disease.

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.

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 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. Report of the Second Neonatal Meningitis Cooperative Study Group.

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.

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 mug/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.

Intravenous administration of kanamycin and gentamicin in newborn infants.

The pharmacokinetics of kanamycin and gentamicin were studied after intramuscular (IM) and intravenous (IV) (constant infusion over 20 minutes) administration in newborn infants. The serum concentrations, half-lives, area-under-the-curve values, and volumes of distribution were similar for each drug after both routes of administration. Based on these pharmacological similarities, it is likely that these aminoglycosides can be given safely and effectively as constant IV infusions to neonates in whom IM injections are not feasible.

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.