Rapid detection of microorganisms in blood cultures of newborn infants utilizing an automated blood culture system.

BACKGROUND: Neonatal sepsis is a low incidence, high-risk disease with many sepsis work-ups performed to detect a single case. Seventy-two hours of antibiotic therapy have been traditionally recommended pending negative culture results. Improved culture media and new technology integrated into blood culture systems could shorten incubation time required to detect positive culture results. This would then change the length of antibiotic therapy in the management of the newborn infant with suspected sepsis. In addition, previous data supporting the 72-hour recommendation were retrospectively acquired, utilized nonautomated systems, and reported in an era with a different population of microorganisms cultured in special care nurseries. OBJECTIVE: Evaluate the time of incubation to detect positive blood cultures from newborn infants with suspected sepsis using a computer-assisted, automated blood culture system, ESP (Trek Diagnostic Systems, Inc, Westlake, OH). DESIGN: Prospective, observational study. PATIENTS AND SETTING: All positive blood culture results that were obtained from term and preterm newborn infants born from November 1993 through June 1997 at a publicly funded hospital with over 6000 live births per year. METHODS: As positive blood culture results were identified, data were prospectively obtained from the patient's medical record. The computer algorithm in the automated blood culture system determined the time to positivity. Time to positivity was determined for blood cultures obtained before the initiation antimicrobial therapy and compared with those cultures obtained after beginning therapy. Time to positivity was also evaluated for clinically important Gram-positive and Gram-negative bacteria and yeast. RESULTS: Four hundred fifty-five positive blood culture results were obtained from 222 patients. Gram-positive organisms accounted for 80% (366/455) of the positive culture results, Gram-negative organisms accounted for 11% (48/455), and yeast for 9% (41/455). Virtually all cultures growing clinically significant Gram-positive and Gram-negative organisms were positive by 24 to 36 hours of incubation. Cultures growing Staphylococcus epidermidis were virtually all positive after 36 to 48 hours of incubation. Of cultures growing yeast, 88% (36/41) were positive by 48 hours of incubation. There was no difference in time to positivity in pretherapy or posttherapy obtained positive blood cultures. Prenatally administered antibiotics did not affect time to positivity in positive cultures drawn on the first day of life. In a selected group of microorganisms that are the frequent cause of bacteremia in term infants, 97% and 99% of cultures were positive by 24 to 36 hours of incubation when only pretherapy cultures are evaluated. CONCLUSIONS: The ESP blood culture system identified 77%, 89% and 94% of all microorganisms at 24, 36, and 48 hours of incubation in aerobic cultures obtained from both term and preterm infants. Introduction of antimicrobial therapy did not affect time to positivity. Reducing duration of antibiotic therapy to 24 to 36 hours should be considered in term, asymptomatic newborn infants undergoing evaluation for suspected sepsis for maternal indications. Confirmation of similar rapidity of detection using other blood culture systems should be undertaken.

Managing disagreements in the management of short bowel and hypoplastic left heart syndrome.

BACKGROUND AND OBJECTIVES: When innovative, not yet fully proven therapies are introduced, physicians may have neither experience nor sufficient data in the medical literature to assist in their decision to discuss them with and/or recommend them to patients. Little is known about how physicians deal with this uncertainty. Moreover, when multiple physicians caring for a single patient have reached different conclusions regarding this new therapy, the potential for disagreement exists that could give rise to ethical issues as well as cause confusion to the patient. To explore these topics, we investigated the attitudes of specialists to therapies for two life-threatening diseases: hypoplastic left heart syndrome (HLHS) and short bowel syndrome. METHODS: A forced choice questionnaire was distributed to the heads of neonatology, pediatric cardiology, and pediatric gastroenterology training programs asking about their outcome impressions and treatment recommendations and about the local availability of treatments. In addition, responses from specialists from the same institution were linked in a confidential manner to evaluate the frequency of disagreement within the same institution. Responses were analyzed using chi(2) and Wilcoxon matched pair analysis as appropriate. RESULTS: The overall rate of response was 79%. In institutions that had both neonatology and pediatric gastroenterology training programs, there was a 59% response rate compared with a 73% response rate from institutions that had both neonatology and cardiology programs. Significant differences were noted among specialists as to who would be involved in discussions of therapeutic options with patients in both HLHS and short bowel syndrome. Differences also were noted in the willingness of specialists to discuss and recommend therapies, in the perceived survival and quality of life by various specialists after transplant and palliative surgery, and in the local availability of various options. The neonatologists and gastroenterologists at the same institution disagreed on responses in 34% of the questions with only 1 of the 25 pairs in full agreement. In contrast, the neonatologists and pediatric cardiologists at the same institution disagreed in only 14% of the questions with 7 of the 28 pairs in full agreement. CONCLUSIONS: Substantial disagreement among specialists about new interventions was found. There seem to be fewer differences among specialists when dealing with the more mature therapy, HLHS. Two major ethical issues arise. First, there seems to be no accepted professional standard to which individuals can appeal when determining whether to discuss or recommend new, not-yet-fully-proven technologies. Second, there is the potential for much patient confusion when counseling physicians recommend different options. Colleagues as individuals and specialists as groups should talk to each other before individual discussions with families to ensure that there is a clear understanding of differing beliefs.

An outbreak of M serotype 1 group A Streptococcus in a neonatal intensive care unit.

OBJECTIVE: To describe the investigation and control of an outbreak of M serotype 1, Streptococcus pyogenes (group A Streptococcus, GAS) infections in a neonatal intensive care unit (NICU). STUDY DESIGN: The study was conducted in an NICU in a large urban university-affiliated hospital. Retrospective review was performed of all infants and health care workers in the NICU, especially those either colonized or infected with GAS during the outbreak and the prospective surveillance period (July through September 1994). Prospective epidemiologic investigation, including cultures of throat, umbilicus, and anorectum (infants), or throat and anus (NICU personnel), identified a possible common source of the disease in case infants. Antimicrobial susceptibility testing and serotyping of all GAS strains were performed; M serotype 1 isolates were examined by DNA analysis with restriction fragment length polymorphism. The M-1 GAS isolates were tested for streptococcal pyrogenic exotoxin (SPE) A and SPE B production. A retrospective chart review and analysis of infants with GAS infection or colonization was conducted. RESULTS: During a 1-week period, two very low birth weight infants more than 3 weeks of age had GAS septicemia and focal infection. Two additional very low birth weight infants with asymptomatic throat colonization were identified during the first week of surveillance. Benzathine penicillin G was administered to all NICU infants, but failed to eradicate throat colonization in the four case subjects. Seven days after completing parenteral antibiotic therapy, the index patient had a recurrence of GAS septicemia that was fatal. Eradication of throat colonization in the remaining three infants was achieved with a 10-day course of intravenous clindamycin therapy. Among 103 NICU personnel, five (4.9%) had asymptomatic GAS colonization with strains that were uniformly susceptible to penicillin. Each colonized adult was successfully treated with oral clindamycin therapy. Serotyping revealed that five isolates of GAS from four infants and one NICU respiratory therapist were M-1 isolates; DNA analysis confirmed that these were the same strain. The five M-1 isolates produced both SPE A and SPE B. CONCLUSIONS: The previously documented increase in prevalence of M-1 strains of GAS in the United States is likely to be associated with their introduction into closed populations including NICUs. Control of such outbreaks may be achieved by isolation, cohorting of case subjects and possible carriers, and successful eradication of colonization in case subjects and carriers. Although GAS organisms are uniformly susceptible to penicillin G, eradication may require agents other than penicillin.

Is surgical ligation of a patent ductus arteriosus the preferred initial approach for the neonate with extremely low birth weight?

The optimal approach to a patent ductus arteriosus (PDA) in an extremely low birth weight (ELBW) neonate, whether initial surgical ligation or a trial of indomethacin, has not been established. The authors reviewed the records of 82 ELBW premature infants who had surgical ligation of a PDA during a 2-year period. Thirty-one received indomethacin before ligation. Bronchopulmonary dysplasia (BPD) occurred in 33% of the infants. Predictors of BPD were prolonged positive pressure ventilation, severe intraventricular hemorrhage (IVH) and lower birth weight (BW). Seventy-seven percent of the infants survived. Predictors of mortality were severe IVH, lower BW, and the occurrence of necrotizing enterocolitis (NEC). The indomethacin-treated infants had a lower incidence of NEC and IVH. Overall, 16% of the patients had perioperative morbidity, and 10% of the patients died. The study shows that a trial of indomethacin therapy is not associated with increased complications in ELBW infants with PDA.

Diffusion of innovative approaches to managing hypoplastic left heart syndrome.

OBJECTIVE: To study the perceptions of outcome and the diffusion into practice of innovative approaches such as palliative surgery and heart transplantation to treat hypoplastic left heart syndrome. DESIGN: A forced-choice questionnaire was sent to 108 US neonatology section heads. Responses were analyzed using Wilcoxon matched pairs, chi 2 analysis, and multivariant logistic regression. RESULTS: Ninety-three questionnaires (86%) were returned. All respondents discussed palliative surgery or transplantation or both with parents; 71 (76%) of 93 also discussed comfort care. Nineteen (24%) of 80 recommended comfort care only, 51 (64%) of 80 recommended surgery only, and 10 (12%) of 80 recommended both. Of the 61 respondents recommending one or both surgical procedures, palliative surgery was recommended by 44 and transplantation by 33. Respondents perceived that transplantation was associated with a lower 1-year mortality than palliative surgery (P < .001) and with a better quality of life (P < .001). CONCLUSIONS: Palliative surgery and transplantation are widely used to treat hypoplastic left heart syndrome. The continued availability of comfort care suggests that these surgical procedures are still in transition from experimental technology to standard of care.

Description of an adenovirus type 8 outbreak in hospitalized neonates born prematurely.

An adenovirus (Ad) type 8 outbreak was prospectively studied in a neonatal intensive care unit. Nasopharyngeal secretions were cultured weekly for viruses and clinical information was obtained daily in each infant. Eleven of 112 neonates were infected with Ad; 8 of 9 available isolates represented one variant of Ad 8. The median age at infection was 54 days and the median duration of virus shedding was 2 days. Seven of 11 infants had onset of new symptoms and/or required acute respiratory support; only 2 infants had eye disease. Maternal characteristics, race, gender, age at entry into study and respiratory distress syndrome at birth were similar for both groups. Ad-infected infants tended to have earlier gestations and lower birth weights. Ad-infected neonates stayed longer in the neonatal intensive care unit, required more days of respiratory support and were more likely to develop bronchopulmonary dysplasia. Thus an association was established between lung disease in premature neonates and Ad infection.

Reduced mortality in small premature infants treated at birth with a single dose of synthetic surfactant.

A randomized controlled trial of Exosurf Neonatal, a synthetic exogenous surfactant, was performed. Exosurf was given to premature infants weighing 700-1350 g, by instillation down the endotracheal tube during mechanical ventilation, within 1 h of birth. Control infants were treated with air. Dose administration was performed in secrecy by clinicians who maintained the blind for 2 years. A total of 109 infants received air and 109 received Exosurf; 19 infants with congenital pneumonia or major malformations were excluded from the primary efficacy analysis. By the age of 28 days there were 14 deaths in the air group and 4 deaths in the Exosurf group, a 69% reduction with Exosurf (P = 0.020). Survival without bronchopulmonary dysplasia at the age of 28 days was significantly improved by 15% (P = 0.050). By the age of 1 year post-term there were 19 deaths in the air group and 10 deaths in the Exosurf group, a 42% reduction with Exosurf (P = 0.104). There were no significant changes in the incidence of bronchopulmonary dysplasia, pulmonary air leaks, intraventricular haemorrhage, patent ductus arteriosus, necrotizing enterocolitis or infection. The reduction in mortality indicates important results in high risk premature infants treated soon after birth with a single dose of Exosurf.

Evaluation of an intravenous immunoglobulin preparation for the prevention of viral infection among hospitalized low birth weight infants.

An intravenous immunoglobulin (IVIG) preparation was evaluated prospectively in hospitalized low birth weight infants for the prevention of respiratory virus infection. Premature neonates were evaluated from October 19, 1987, through July 31, 1988. Nasopharyngeal secretions were cultured weekly for viruses and clinical information was obtained daily on each infant. Ninety-one infants with birth weights between 500 and 1750 g were randomized to receive either IVIG, 500 mg/kg (46 infants), or 5% albumin-normal saline (placebo), 10 ml/kg (45 infants), between Days 3 and 7 of life, 7 days later and every 14 days thereafter for a maximum of 5 doses. Demographic and life event data during pregnancy were similar for IVIG and placebo groups. Birth weight, gestational age, gender, age at entry into the study and incidence of respiratory distress syndrome at birth were also similar in both groups of premature infants. Twenty-six viruses were isolated from 25 infants. There were 13 and 12 infections in the IVIG and placebo groups, respectively. Severity of disease, as measured by clinical factors and outcomes of virus-infected infants were no different in IVIG-treated and placebo groups. Adenoviruses and cytomegalovirus accounted for 57.7 and 23.1%, respectively, of the viral isolates. In this study the use of IVIG did not prevent or modify adenovirus and cytomegalovirus infections in premature infants.

Role of intravenous immunoglobulin in prevention of late-onset infection in low-birth-weight neonates. The Neonatal IVIG Study Group.

As a result of inadequate placental transport of maternal IgG, preterm neonates of less than 32 weeks' gestation, especially those with birth weights less than 1,500 g, are profoundly hypogammaglobulinemic at birth, a condition that worsens during the first several weeks of life. This hypogammaglobulinemia is believed to contribute to their high frequency of late-onset sepsis, with its accompanying morbidity and mortality. Animal studies suggest that human immunoglobulin prepared for intravenous use (IVIG) improves host defense against pathogens that cause neonatal infections, but studies of IVIG in human neonates have been inconclusive because of the small numbers of infants included, lack of suitable controls, use of clinical rather than strict microbiologic definition of sepsis, and performance only in a single hospital outside the United States. A double-blind, randomized, placebo-controlled multicenter trial in the United States is in progress to determine the efficacy of IVIG in the prevention of late-onset infections in infants with birth weights between 500 and 1,750 g. Infants are infused with 500 mg of IVIG/kg or albumin-saline placebo at 3-7 days of age, 7 days later, and every 14 days for five doses. Efficacy parameters include mortality, number of proved infectious episodes (bacterial, fungal, or viral), and infection-related morbidity. Definitive guidelines for the possible use of prophylactic IVIG in low-birth-weight neonates should result from this evaluation of 500 to 700 infants in the United States.

Disposition of an immunoglobulin intravenous preparation in very low birth weight neonates.

To assess the disposition, tolerance, and toxicity of an intravenous preparation of immunoglobulin (IGIV) in very low birth weight (VLBW) neonates, we administered single doses of 500 or 750 mg/kg to 20 neonates with birth weights between 750 and 1500 g during the first week of life. The infusion of this product was well tolerated. Modest changes in hemoglobin, hematocrit, and total hemolytic complement occurred as expected. Hepatic toxic effects were not detected. Mean peak IgG concentrations were 1564 and 1316 mg/dL for the high-dose and low-dose groups, respectively. Mean IgG concentrations were very similar for both groups on postinfusion days 1, 4, 7, 14, 21, and 28. IgG concentrations remained above 300 mg/dL in seven of 10 infants in each group by day 21, and in six of the high-dose group and seven of the low-dose group by day 28. Mean elimination half-lives were 22.6 and 22.8 days in the high-dose and low-dose groups, respectively. These data provide a basis for assessment of potential efficacy of IGIV in the prevention of late-onset infection in VLBW neonates.

Response of the patent ductus arteriosus to indomethacin treatment.

The purposes of this study were to examine the response of the patent ductus arteriosus (PDA) to indomethacin, using serial two-dimensional and pulsed Doppler echocardiographic studies, and to correlate the response to treatment with serum indomethacin levels. Nineteen preterm infants (gestational age, 26 to 31 weeks [mean, 28 weeks]; weight, 600 to 1680 g [mean, 1060 g]) were treated with indomethacin. Two-dimensional and pulsed Doppler echocardiograms were obtained before administration of indomethacin and daily thereafter until the day after the last dose. Ductal responses to treatment were graded as open, constricted, or closed, and serum indomethacin levels were obtained 24 hours after the last dose. The PDA initially closed in 11 (58%) of 19 infants; however, in four of the 11, PDA reopened and three of four required surgical ligation. In seven (37%) of 19 patients, the PDA initially constricted, but five of seven subsequently reopened and required ligation. In one patient, indomethacin had no effect on the PDA. The mean indomethacin level for the whole group was 622 ng/mL. There was no difference in indomethacin level between the group with initial closure vs those with constriction (580 vs 590 ng/mL), nor between those who eventually required ligation and those who did not. This study demonstrates that the majority of premature infants respond to indomethacin treatment with ductal constriction or closure but that reopening occurs frequently. The initial response does not mean that the ductus will remain constricted or closed, and surgical intervention may still be necessary. A serum indomethacin level of more than 250 ng/mL does not ensure ductal closure.

Necrotizing enterocolitis: incidence, operative care, and outcome.

At Jefferson Davis Hospital, the incidence of necrotizing enterocolitis (NEC) was three per 1,000 live births, and 30 per 1,000 low birth weight births. The occurrence of NEC was sporadic and no epidemics occurred. NEC occurred most frequently in infants weighing between 750 and 1,500 g, and the smaller infant with NEC was more likely to require surgical intervention. As the survival of small birth weight infants improved over the 4 years of the study, the patient population developing NEC became smaller. The age at operation also increased in the period between 1982 and 1984. Those infants who developed NEC after 30 days of age typically had more extensive disease and a less favorable prognosis. In this series, 31% of infants with acute NEC required surgical intervention. An additional 11% of those infants treated nonoperatively eventually required surgical intervention for late sequelae of NEC. The overall survival of infants with NEC was 75%. While the survival of all infants operated for NEC was 68%, the survival for those with the acute syndrome was 63% and those operated on for late sequelae was 87%. Primary anastomosis in selected patients did not adversely affect mortality and simplified the postoperative care of these infants with severe complications. Indeed, enterostomy closure in an infant who had previously had NEC was an extensive procedure that carried significant risk. Our results indicated that the trained pediatric surgeon could predict at the operating table which infants could safely undergo resection and anastomosis and that, with experience, the percent undergoing primary anastomosis increased to approximately 50%.

Single-dose pharmacokinetics of imipenem-cilastatin in neonates.

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin), a beta-lactam antibiotic, used in combination with cilastatin, a renal dehydropeptidase I inhibitor, were evaluated in 10 neonates 1 to 8 days of age. The imipenem-cilastatin combination was given intravenously over a 15-min period at a dose of 15 or 25 mg/kg. Drug concentrations in serum, urine, and cerebrospinal fluid (when available) were determined by high-pressure liquid chromatography, and plasma disposition of the drugs was described by a two-compartment open model. The mean peak plasma levels of imipenem 30 min postinfusion were 55.4 and 27.2 micrograms/ml, and the mean t1/2 beta values were 2.1 and 1.8 h at doses of 25 and 15 mg/kg, respectively. The calculated volume of distribution was 0.41 liters/kg. In two patients from whom cerebrospinal fluid was obtained 1.5 h postinfusion, imipenem levels were 5.6 and 1.1 micrograms/ml at doses of 25 and 15 mg/kg, respectively, representing 10 and 4% of the 1-h serum levels. No side effects attributable to a single dose of imipenem-cilastatin were noted.

Survival of low-birth-weight infants with neonatal intraventricular hemorrhage. Outcome in the preschool years.

Twenty-nine low-birth-weight infants who survived neonatal intraventricular hemorrhage (IVH) were followed up prospectively and were last examined at a mean age of 3 1/2 years. The mean gestational age (+/- SD) of the group was 28.9 weeks (+/- 2.4 weeks), and the mean birth weight (+/- SD) was 1,167 g (+/- 292 g). Ten patients (34%) had normal neurologic outcome, and four (14%) had minimal abnormalities. Nine children (31%) were categorized as moderately abnormal, and six (21%) had severe abnormalities on neurologic examination. Intellectual performance was normal for 14 patients (48%), mildly delayed for seven (24%), and in the retarded range for eight (28%). Twelve children (41%), at 3 years of age, had handicapping conditions severe enough to warrant admission to special education programs in the public school. The grade of IVH was related significantly to neurologic outcome; both grade of hemorrhage and birth weight were correlated significantly with need for special education. Intellectual performance was related not only to grade of hemorrhage and birth weight, but also to paternal social class.

The hyaline membrane disease-intraventricular hemorrhage relationship in the very low birth weight infant: perinatal aspects.

A large retrospective clinical study is reported confirming pathologic studies upon the effect of hyaline membrane disease on the occurrence of intraventricular hemorrhage in very low birth weight infants. Two hundred and twenty infants with birth weight less than or equal to 1 500 g and gestational age less than or equal 32 weeks were studied. Infants with hyaline membrane disease (112) had 56% incidence of intraventricular hemorrhage whereas of those without hyaline membrane disease (108) only 31% developed intraventricular hemorrhage (p less than 0.001). When controlled for gestational age, the more immature infants (less than or equal to 1 000 g) exhibited no difference in the occurrence of intraventricular hemorrhage whether hyaline membrane disease coexisted or not. In the 1 001-1 500 g group, the occurrence of hyaline membrane disease with intraventricular hemorrhage was significant (p less than 0.001). The association of lower Apgar scores and the influence of intermittent positive pressure ventilation in infants with intraventricular hemorrhage is discussed. Extreme immaturity negates all perinatal clinical expertise in determining neonatal outcome. Therefore, carrying pregnancies beyond 28 weeks gestation is mandatory. Beyond 28 weeks, pulmonary maturity and the influence of therapeutic modalities and maternal transport become increasingly important.