Bacterial and Fungal Infections
Karen M. Puopolo
KEY POINTS
Risk factors for neonatal early-onset sepsis (EOS) include prematurity, documented maternal colonization with group B Streptococcus (GBS), intrapartum fever and other signs of chorioamnionitis, and prolonged rupture of membranes; risk is modified by the administration of intrapartum antibiotics.
Empiric antibiotic therapy includes broad coverage for organisms known to cause EOS, usually a β-lactam antibiotic and an aminoglycoside. The most common microbial causes of EOS include GBS, Escherichia coli, viridans streptococci, Enterococcus, and a variety of Enterobacteriaceae such as Klebsiella and Haemophilus spp.
Risk for neonatal late-onset sepsis (LOS) increases with lower gestational age and birth weight and with longer duration of central venous access, mechanical ventilation, and use of total parenteral nutrition.
Empiric antibiotic therapy for LOS should be tailored to the local microbiology of infection, which may include different relative contributions of coagulase-negative staphylococci, methicillin-sensitive and methicillin-resistant Staphylococcus aureus, β-lactam-resistant gram-negative organisms, and Candida spp.
I. BACTERIAL SEPSIS AND MENINGITIS
A. Introduction. Bacterial sepsis and meningitis continue to be major causes of morbidity and mortality in newborns, particularly in premature infants. Although improvements in neonatal intensive care have decreased the impact of early-onset sepsis (EOS) in term infants, preterm infants remain at high risk for both EOS and its sequelae. Very low birth weight (VLBW) infants are also at risk for late-onset (hospital acquired) sepsis. Neonatal survivors of sepsis can have severe neurologic sequelae due to central nervous system (CNS) infection as well as from secondary hypoxemia resulting from septic shock, persistent pulmonary hypertension, and severe parenchymal lung disease.
B. Epidemiology of EOS. The overall incidence of EOS has decreased significantly since the Centers for Disease Control and Prevention (CDC) first published recommendations for intrapartum antibiotic prophylaxis (IAP) against group B Streptococcus (GBS) in 1996. Studies conducted afterward
showed the overall incidence of EOS to be ≤1 case per 1,000 live births. The incidence is twice as high among moderately premature infants compared to term infants and highest among VLBW (<1,500 g) infants with recent reports ranging from 10 to 15 cases/1,000 VLBW births.
showed the overall incidence of EOS to be ≤1 case per 1,000 live births. The incidence is twice as high among moderately premature infants compared to term infants and highest among VLBW (<1,500 g) infants with recent reports ranging from 10 to 15 cases/1,000 VLBW births.
C. Risk factors for EOS. The pathogenesis of EOS is that of ascending colonization of the maternal genital tract and uterine compartment with gastrointestinal and genitourinary flora, and subsequent transition to invasive infection of the fetus or newborn. Maternal and infant characteristics associated with the development of EOS have been most rigorously studied with respect to GBS EOS. Maternal factors predictive of GBS disease include documented maternal GBS colonization, intrapartum fever (>38°C) and other signs of chorioamnionitis, and prolonged rupture of membranes (ROM) (>18 hours). Neonatal risk factors include prematurity (<37 weeks’ gestation) and low birth weight (BW) (<2,500 g). These factors are modified by the administration of intrapartum antibiotics.
D. Clinical presentation of EOS. Early-onset disease can manifest as asymptomatic bacteremia, generalized sepsis, pneumonia, and/or meningitis. The clinical signs of EOS are usually apparent in the first hours of life; >90% of infants are symptomatic by 24 hours of age. Respiratory distress is the most common presenting symptom. Respiratory symptoms can range in severity from mild tachypnea and grunting, with or without a supplemental oxygen requirement, to respiratory failure. Persistent pulmonary hypertension of the newborn (PPHN) can also accompany sepsis. Other less specific signs of sepsis include irritability, lethargy, temperature instability, poor perfusion, and hypotension. Disseminated intravascular coagulation (DIC) with purpura and petechiae can occur in more severe septic shock. Gastrointestinal symptoms can include poor feeding, vomiting, and ileus. Meningitis may present with seizure activity, apnea, and depressed sensorium but may complicate sepsis without specific neurologic symptoms, underscoring the importance of the lumbar puncture (LP) in the evaluation of sepsis.
Other diagnoses to be considered in the immediate newborn period in the infant with signs of sepsis include transient tachypnea of the newborn, meconium aspiration syndrome, intracranial hemorrhage, congenital viral disease, and congenital cyanotic heart disease. In infants presenting at more than 24 hours of age, closure of the ductus arteriosus in the setting of a ductal-dependent cardiac anomaly (such as critical coarctation of the aorta or hypoplastic left heart syndrome) can mimic sepsis. Other diagnoses that should be considered in the infant presenting beyond the first few hours of life with a sepsis-like picture include bowel obstruction, necrotizing enterocolitis (NEC), and inborn errors of metabolism.
E. Evaluation of the symptomatic infant for EOS. Laboratory evaluation of the symptomatic infant suspected of EOS includes at minimum a complete blood count (CBC) with differential and blood culture. Other laboratory abnormalities can include hyperglycemia and metabolic acidosis. Thrombocytopenia as well as evidence of DIC (elevated prothrombin time [PT], partial thromboplastin time [PTT], and international normalized ratio [INR]; decreased fibrinogen) can be found in more severely ill infants, particularly those born preterm. For infants with a strong clinical suspicion of sepsis, an LP for cerebrospinal fluid (CSF) cell count, protein and
glucose concentration, Gram stain, and culture should be performed before the administration of antibiotics if the infant is clinically stable. The LP may be deferred until after the institution of antibiotic therapy if the infant is clinically unstable, or if later culture results or clinical course demonstrates that sepsis was present.
glucose concentration, Gram stain, and culture should be performed before the administration of antibiotics if the infant is clinically stable. The LP may be deferred until after the institution of antibiotic therapy if the infant is clinically unstable, or if later culture results or clinical course demonstrates that sepsis was present.
Infants with respiratory symptoms should have a chest radiograph as well as other indicated evaluation such as arterial blood gas measurement. Radiographic abnormalities caused by retained fetal lung fluid or atelectasis usually resolve within 48 hours. Neonatal pneumonia will present with persistent focal or diffuse radiographic abnormalities and variable degrees of respiratory distress. Neonatal pneumonia (particularly that caused by GBS) can be accompanied by primary or secondary surfactant deficiency.
F. Treatment of EOS. Empiric antibiotic therapy includes broad coverage for organisms known to cause EOS, usually a β-lactam antibiotic and an aminoglycoside. In our institutions, we use ampicillin and gentamicin as initial therapy. We add a third-generation cephalosporin (cefotaxime or ceftazidime) to the empiric treatment of critically ill infants for whom there is a strong clinical suspicion for sepsis to optimize therapy for ampicillinresistant enteric gram-negative organisms, primarily ampicillin-resistant Escherichia coli (see Table 49.1 for treatment recommendations). Supportive treatments for sepsis include the use of mechanical ventilation, exogenous surfactant therapy for pneumonia and respiratory distress syndrome (RDS), volume and pressor support for hypotension and poor perfusion, sodium bicarbonate for metabolic acidosis, and anticonvulsants for seizures. Echocardiography may be of benefit in the severely ill, cyanotic infant to determine if significant pulmonary hypertension or cardiac failure is present. Infants born at ≥34 weeks with symptomatic pulmonary hypertension may benefit from treatment with inhaled nitric oxide (iNO). Extracorporeal membrane oxygenation (ECMO) can be offered to infants ≥34 weeks if respiratory and circulatory failure occurs despite all conventional measures of intensive care. ECMO is not generally available to infants <34 weeks’ gestation.
A variety of adjunctive immunotherapies for sepsis have been trialed since the 1980s to address deficits in immunoglobulin and neutrophil number and function. Double-volume exchange transfusions, granulocyte infusions, the administration of intravenous immunoglobulin (IVIG), and treatment with granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) have all been investigated with variable results.
1. Double-volume exchange transfusion and granulocyte infusion. Both of these approaches to replete neutrophils in neutropenic septic infants have been studied in small numbers of infants. Both present significant risks, including graft-versus-host disease; blood-group sensitization; and transmission of infections such as cytomegalovirus (CMV), HIV, and viral hepatitis. We do not currently use either of these treatments in the treatment of early- or late-onset sepsis (LOS).
2. IVIG. The use of IVIG in the acute treatment of neonatal sepsis has been studied in several small trials, with mixed results. A definitive trial including 3,493 infants was conducted in nine countries from 2001 to 2007. This was a randomized, placebo-controlled trial of IVIG
administration to infants with suspected or proven sepsis. The administration of IVIG resulted in no change in the primary outcome of death or major disability at 2 years of age, nor any change in a number of secondary outcomes, including second episodes of sepsis. IVIG is not recommended for treatment of neonatal sepsis.
administration to infants with suspected or proven sepsis. The administration of IVIG resulted in no change in the primary outcome of death or major disability at 2 years of age, nor any change in a number of secondary outcomes, including second episodes of sepsis. IVIG is not recommended for treatment of neonatal sepsis.
Table 49.1. Suggested Antibiotic Regimens for Sepsis and Meningitis* | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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3. Cytokines. Recombinant G-CSF and GM-CSF have been shown to restore neutrophil levels in small studies of neutropenic growth-restricted infants, ventilator-dependent neutropenic infants born to mothers with preeclampsia, and in neutropenic infants with sepsis. A rise in the absolute neutrophil count (ANC) above 1,500/mm3 occurred in 24 to 48 hours. To date, nine randomized, controlled trials of recombinant colony-stimulating factors have been reported, all enrolling small numbers of infants. Assessment of these trials is complicated by the use of different preparations, dosages, and durations of therapy as well as variable enrollment criteria. None of the trials included neurodevelopmental follow-up. These studies suggest that G-CSF may result in lower mortality among neutropenic, septic VLBW infants, but overall, there is currently insufficient evidence to support the routine use of these preparations in the acute treatment of neonatal sepsis.
4. Activated protein C (APC) and pentoxifylline. Both of these immunomodulatory preparations have been studied in adults with severe sepsis. Both are active in preventing the microvascular complications of sepsis, by promoting fibrinolysis (APC) and improving endothelial cell function (pentoxifylline), and both decrease the production of tumor necrosis factor (TNF). APC has not been studied in neonates in randomized trials and has been withdrawn from clinical production due to safety concerns in adult patients. Pentoxifylline has been studied in a small number of preterm infants with LOS with potential improvement in mortality. Neither medication can be recommended for use in neonates without further study.
G. Evaluation of the asymptomatic infant at risk for EOS. There are a number of clinical factors that place infants at risk for EOS. These factors also identify a group of asymptomatic infants who may have colonization or bacteremia that places them at risk for the development of symptomatic EOS. These infants include those born to mothers who have received inadequate IAP for GBS (see subsequent text) and those born to mothers with suspected chorioamnionitis. Blood cultures are the definitive determination of bacteremia. A number of laboratory tests have been evaluated for their ability to predict which of the at-risk infants will go on to develop symptomatic or culture-proven sepsis, but no single test has adequate sensitivity and specificity.
1. Blood culture. With advances in the development of computerassisted, continuous-read culture systems, most blood cultures will be positive within 24 to 36 hours of incubation if organisms are present. Most institutions, including ours, empirically treat infants for sepsis for a minimum of 48 hours with the assumption that true positive cultures will turn positive within that period. At least 1 mL (and up to 3 mL) of blood should be placed in most pediatric blood culture bottles. The use of two culture bottles for each sepsis evaluation aids in the distinction
of true bacteremia versus contaminants. Depending on the clinical scenario, one aerobic and one anaerobic culture bottle is optimal, despite the fact that most blood culture systems do not provide pediatricspecific anaerobic culture bottles. Certain organisms causing EOS (such as Bacteroides fragilis) will only grow under anaerobic conditions; 5% to 10% of culture-proven EOS in preterm infants is due to strictly anaerobic species when anaerobic blood culture is performed. NEC may also be complicated by anaerobic bacteremia. Additionally, GBS, staphylococci, and many gram-negative organisms grow in a facultative fashion, and the use of two culture bottles increases the likelihood of detecting low-level bacteremia with these organisms.
of true bacteremia versus contaminants. Depending on the clinical scenario, one aerobic and one anaerobic culture bottle is optimal, despite the fact that most blood culture systems do not provide pediatricspecific anaerobic culture bottles. Certain organisms causing EOS (such as Bacteroides fragilis) will only grow under anaerobic conditions; 5% to 10% of culture-proven EOS in preterm infants is due to strictly anaerobic species when anaerobic blood culture is performed. NEC may also be complicated by anaerobic bacteremia. Additionally, GBS, staphylococci, and many gram-negative organisms grow in a facultative fashion, and the use of two culture bottles increases the likelihood of detecting low-level bacteremia with these organisms.
2. White blood cell (WBC). The WBC and differential is readily available and commonly used to evaluate both symptomatic and asymptomatic infants at risk for sepsis. Interpretation of neonatal WBC has been compromised by the impact of differences mediated by gestational age, postnatal age, mode of delivery, and maternal conditions. Maternal fever, neonatal asphyxia, meconium aspiration syndrome, pneumothorax, and hemolytic disease have all been associated with neutrophilia; maternal pregnancy-induced hypertension and preeclampsia are associated with neonatal neutropenia as well as thrombocytopenia.
One finding common to all published neonatal WBC data is the “roller coaster” shape of the WBC and ANC and immature to total neutrophil ratio (I/T) curves in the first 72 hours of life. This suggests that optimal interpretation of WBC data to predict EOS should account for the natural rise and fall in WBC during this period. Recent studies support the use of CBC only after the first few hours of life, when placed in the proper clinical context and used as part of an algorithm to evaluate infants for sepsis risk. The WBC and ANC are most predictive of infection when these values were low (WBC <5,000 and ANC <1,000). An elevated WBC (>20,000) is neither worrisome nor reassuring in neonates. The I/T ratio is most informative if measured at 1 to 4 hours after birth, with low values (<0.15) reassuring, while elevated values (>0.3) are weakly associated with EOS. The combination of low ANC and elevated I/T ratio is the most predictive combination of WBC indices for EOS.
Although studies demonstrate that no component of the WBC is very sensitive among term and late preterm infants for the prediction of sepsis, there are little data to guide interpretation of the WBC among VLBW infants at risk for EOS. The WBC and its components may be of more value in the VLBW infant and/or in the evaluation of late-onset infection, especially if interpreted in relation to values obtained prior to the concern for infection.
3. C-reactive protein (CRP). CRP is a nonspecific marker of inflammation or tissue necrosis. Elevations in CRP are found in bacterial sepsis and meningitis. A single determination of CRP at birth lacks both sensitivity and specificity for infection. Serial CRP determinations at the time of blood culture, 12 to 24 hours and 48 hours later, have been used to manage infants at risk for LOS. Some centers use serial CRP measurements to determine length of antibiotic treatment for infants
with culture-negative clinical sepsis, despite the absence of data to support the efficacy of this practice.
with culture-negative clinical sepsis, despite the absence of data to support the efficacy of this practice.
4. Cytokine measurements. Advances in the understanding of the immune responses to infection and in the measurement of small peptide molecules have allowed investigation into the utility of these inflammatory molecules in predicting infection in neonates at risk. Serum levels of interleukin-6, interleukin-8, interleukin-10, interleukin-1 β, G-CSF, TNF-α, and procalcitonin (PCT), as well as measurements of inflammatory cell-surface markers such as CD64, have been variably correlated with culture-proven, clinical, and viral sepsis. The need for serial measurements and the availability of the specific assays so far limit the use of cytokine markers in diagnosing neonatal infection. PCT is increasingly available in clinical settings and correlates with bacterial infection; however, there is a natural rise in PCT levels in the hours after birth for all infants, normal ranges vary with gestational age, and like CRP, PCT levels rise in response to noninfectious inflammatory signals. In addition, most studies of biomarkers have been performed on infants who are symptomatic and being evaluated for sepsis. None of these has yet proven useful in predicting infection in initially well-appearing infants.
5. Other strategies. Urine latex particle agglutination testing for GBS remains available at some institutions; we do not use this test due to very poor predictive value. Latex particle testing of CSF for both GBS and E. coli K1 can be of use in evaluating CSF after the institution of antibiotic treatment.
6. LP. The use of routine LP in the evaluation of asymptomatic neonates at risk for EOS remains controversial. A retrospective review of 13,495 infants born at all gestational ages from 150 neonatal intensive care units (NICUs) on whom an LP was performed found 46 cases of cultureproven GBS meningitis. In 9 out of 46 cases, the accompanying blood culture was sterile. Another retrospective study of CSF taken from a population of 169,849 infants identified 8 infants with culture-positive CSF but with negative blood cultures and no CNS symptoms. In both studies, the authors concluded that the selective use of LP in the evaluation of EOS might lead to missed diagnoses of meningitis. However, in both studies, infants were not all evaluated for sepsis in the absence of symptoms, and the subjects were drawn from large numbers of hospitals with likely disparate culture systems. Another study reviewed the results of sepsis evaluations in a population of 24,452 infants from a single institution. This study found 11 cases of meningitis, all in symptomatic infants; 10 of 11 corresponding blood cultures were positive for the same organism. No cases of meningitis were found in 3,423 asymptomatic infants evaluated with LP.
Current national guidelines from the United States and Great Britain for evaluation of infants at risk for EOS endorse the selective use of LP when there is strong clinical suspicion for sepsis and/or specifically for meningitis. We do not perform LPs for the evaluation of asymptomatic term infants at risk for EOS. It is our current policy to perform LPs only on (i) infants with positive blood cultures and (ii) symptomatic infants with a high risk for EOS whose condition
is stable enough to tolerate LP and (iii) infants with negative blood cultures who are treated empirically for the clinical diagnosis of sepsis.
is stable enough to tolerate LP and (iii) infants with negative blood cultures who are treated empirically for the clinical diagnosis of sepsis.
When LPs are performed after the administration of antibiotics, a clinical evaluation of the presence of meningitis is made, taking into account the blood culture results, the CSF cell count, protein, and glucose levels as well as the clinical scenario. We recommend sending two separate CSF samples for cell count from the same LP in these circumstances to account for the role of possible fluctuation in CSF cell count measurements. Interpretation of CSF WBC values can be challenging. Normal CSF WBC counts in term, noninfected infants are variable, with most studies reporting a mean of <20 cells/mm3, with ranges of up to 90 cells, and widely varying levels of polymorphonuclear cells on the differential. One recent study assessed CSF parameters among neonate without bacterial or viral blood or CSF infection, in CSF samples with <500 red blood cell (RBC)/mm3. This study reported a mean CSF WBC 3/mm3 with an upper reference limit of 14 cells; no significant differences were found between term and preterm infants. Another study of culture-proven early-onset meningitis demonstrated only 80% sensitivity and specificity for CSF WBC values >20. The presence of blood in the CSF, due to subarachnoid or intraventricular hemorrhage, or to blood contamination of CSF samples by “traumatic” LPs, can yield abnormal cell counts that may be due to the presence of blood in the CSF rather than true infection. Adjustment of the WBC in “traumatic” LP results (those with >500 RBC/mm3) using different algorithms has not been shown to substantially improve the sensitivity and specificity of the WBC in predicting culture-confirmed meningitis.
H. Algorithm for the evaluation of the infant born at ≥35 weeks’ gestation at risk for EOS. Assessing risk of EOS among term and late preterm infants is a common clinical task in birth centers. Depending on the local structure of neonatal care, EOS evaluation may be performed by pediatric residents, community pediatricians, newborn hospitalists, midwives, and/or neonatal intensive care specialists. The use of an algorithm to guide assessment can ensure consistency among caregivers. An example of such an algorithm which has been used at the Brigham and Women’s Hospital (BWH) is shown in Figure 49.1. Algorithms should (i) establish criteria for EOS evaluation based on established risk factors for EOS, (ii) specify laboratory testing standards, and (iii) provide guidance for empiric administration of antibiotics. At our institutions, EOS risk assessment is informed by guidelines set forth by the CDC 2010 GBS prevention guidelines and the American Academy of Pediatrics. Risk factors used to identify newborns at risk for EOS include maternal intrapartum fever ≥38°C and other signs of chorioamnionitis, gestational age <37 weeks, inadequate indicated GBS prophylaxis, and premature and/or prolonged duration of ROM. A total WBC <5,000 or an I/T ratio >0.3 is used to guide treatment decisions in the evaluation of the well-appearing infant at risk for sepsis. A single CBC determination is used in most cases to avoid multiple blood draws from otherwise asymptomatic infants; as noted earlier, WBC values may have better predictive value when performed after 1 hour of age. These guidelines are based on a delivery service for which a screening-based approach to GBS
prophylaxis has been in place since 1996 and for which the vast majority of vaginal deliveries involve epidural placement (which alone can cause lowgrade intrapartum fever).
prophylaxis has been in place since 1996 and for which the vast majority of vaginal deliveries involve epidural placement (which alone can cause lowgrade intrapartum fever).
 Figure 49.1. Algorithm for sepsis evaluations in at-risk asymptomatic infants ≥35 weeks’ gestation. |
EOS algorithms based on risk factor threshold values are limited by an inability to account for interactions between risk factors and do not utilize the full value of information that falls just below or well above threshold values. A recent study used a cohort of >600,000 infants born ≥34 weeks’ gestation to develop a multivariate predictive model of sepsis risk using established risk factors. This model provides estimates of individual infant EOS risk using only objective clinical data available at the time of birth, combined with the infant’s clinical condition in the first 6 hours of life. The model provides as Sepsis Risk Score and is available as a web-based calculator at https://www.dor.kaiser.org/external/DORExternal/research/infectionprobabilitycalculator.aspx and http://newbornsepsiscalculator.org. The care recommendations provided are those used in a large integrated health care system in the United States and may not be universally appropriate. The Sepsis Risk Score is best used considering the local incidence of EOS and local structure of newborn care.
I. Specific organisms causing EOS. The bacterial species responsible for EOS vary by locality and time period. In the United States since the 1980s, GBS has been the leading cause of neonatal EOS. Despite the implementation of IAP against GBS, it remains the leading cause of EOS in term infants. However, coincident with the increased use of IAP for GBS, gramnegative enteric bacteria have become the leading cause of EOS in preterm infants. Enteric bacilli causing EOS include E. coli, other Enterobacteriaceae (Klebsiella, Pseudomonas, Haemophilus, and Enterobacter spp.) and the anaerobe B. fragilis. Less common organisms that can cause serious early-onset disease include Listeria monocytogenes and Citrobacter diversus. Staphylococci and enterococci can be found in EOS but are more commonly causes of nosocomial sepsis and are discussed under that heading in the subsequent text. Fungal species can cause EOS primarily in preterm infants; this is also discussed separately in the subsequent text.
1. GBS. GBS (Streptococcus agalactiae) frequently colonizes the human genital and gastrointestinal tracts and the upper respiratory tract in young infants. In addition to causing neonatal disease, GBS is a frequent cause of urinary tract infection (UTI), chorioamnionitis, postpartum endometritis, and bacteremia in pregnant women. There is some evidence suggesting that vaginal colonization with a high inoculum of GBS during pregnancy contributes to premature birth.
a. Microbiology. GBS are facultative diplococci that are easily cultivated in selective laboratory media. GBS are primarily identified by the Lancefield group B carbohydrate antigen and are further subtyped into 10 distinct serotypes (types Ia, Ib, II-IX) by analysis of capsular polysaccharide composition. Most neonatal diseases in the United States are currently caused by types Ia, Ib, II, III, and V GBS. Type III GBS are associated with the development of meningitis and are commonly a cause of late-onset GBS disease.
b. Pathogenesis. Neonatal GBS infection is acquired in utero or during passage through the birth canal. Because not all women are colonized
with GBS, documented colonization with GBS is the strongest predictor of GBS EOS. Approximately 20% to 30% of American women are colonized with GBS at any given time. A longitudinal study of GBS colonization in a cohort of primarily young, sexually active women demonstrated that 45% of initially GBS-negative women acquired colonization at some time over a 12-month period. In the absence of IAP, approximately 50% of infants born to mothers colonized with GBS are found to be colonized with this organism at birth. Approximately 1% to 2% of all colonized infants develop invasive GBS disease, with clinical factors such as gestational age and duration of ROM contributing to risk for any individual infant (see subsequent text). Lack of maternally derived, protective capsular polysaccharide-specific antibody is associated with the development of invasive GBS disease. Other factors predisposing the newborn to GBS disease are less well understood, but relative deficiencies in complement, neutrophil function, and innate immunity may be important.
with GBS, documented colonization with GBS is the strongest predictor of GBS EOS. Approximately 20% to 30% of American women are colonized with GBS at any given time. A longitudinal study of GBS colonization in a cohort of primarily young, sexually active women demonstrated that 45% of initially GBS-negative women acquired colonization at some time over a 12-month period. In the absence of IAP, approximately 50% of infants born to mothers colonized with GBS are found to be colonized with this organism at birth. Approximately 1% to 2% of all colonized infants develop invasive GBS disease, with clinical factors such as gestational age and duration of ROM contributing to risk for any individual infant (see subsequent text). Lack of maternally derived, protective capsular polysaccharide-specific antibody is associated with the development of invasive GBS disease. Other factors predisposing the newborn to GBS disease are less well understood, but relative deficiencies in complement, neutrophil function, and innate immunity may be important.
c. Clinical risk factors for GBS EOS (Table 49.2). GBS bacteriuria during pregnancy is associated with heavy colonization of the rectovaginal tract and is considered a significant risk factor for EOS. Black race and maternal age <20 years are associated with higher rates of GBS EOS, although it is not entirely clear whether this reflects only higher rates of GBS colonization in these populations. Multiple gestation is not an independent risk factor for GBS EOS.
d. Prevention of GBS infection. Multiple trials have demonstrated that the use of intrapartum penicillin or ampicillin significantly reduces the rate of neonatal colonization with GBS and the incidence of early-onset GBS disease. IAP for the prevention of GBS EOS can be administered to pregnant women during labor based on (i) specific risk factors for
early-onset GBS infection or (ii) the results of antepartum screening of pregnant women for GBS colonization. Beginning in 1996, the CDC issued guidelines recommending the use of IAP to prevent neonatal GBS EOS. The most recent CDC guidelines were published in 2010 (http://www.cdc.gov/groupbstrep/guidelines/guidelines.html). These guidelines recommend universal screening of pregnant women for GBS by rectovaginal culture at 35 to 37 weeks’ gestation and management of IAP based on screening results. Pregnant women with documented GBS bacteriuria during pregnancy or who previously delivered an infant who developed invasive GBS disease need not be screened because these women should be given IAP regardless of current GBS colonization status. IAP is also recommended for all women who present in preterm labor with unknown GBS status. For women in labor at ≥37 weeks’ gestation with unknown GBS status, IAP is recommended if intrapartum maternal fever ≥100.5°F occurs, or if duration of ROM is ≥18 hours prior to delivery. The 2010 guidelines provide recommendations for the management of neonates at risk for EOS; recommendations for antibiotic choices for GBS IAP; specific recommendations for mothers who experience preterm labor and premature ROM; expanded laboratory methods for the detection of GBS including use of alternate culture-based detection methods; and for the first time, endorsed intrapartum nucleic acid amplification testing (NAAT) as an alternative to culture-based detection of maternal GBS colonization.
early-onset GBS infection or (ii) the results of antepartum screening of pregnant women for GBS colonization. Beginning in 1996, the CDC issued guidelines recommending the use of IAP to prevent neonatal GBS EOS. The most recent CDC guidelines were published in 2010 (http://www.cdc.gov/groupbstrep/guidelines/guidelines.html). These guidelines recommend universal screening of pregnant women for GBS by rectovaginal culture at 35 to 37 weeks’ gestation and management of IAP based on screening results. Pregnant women with documented GBS bacteriuria during pregnancy or who previously delivered an infant who developed invasive GBS disease need not be screened because these women should be given IAP regardless of current GBS colonization status. IAP is also recommended for all women who present in preterm labor with unknown GBS status. For women in labor at ≥37 weeks’ gestation with unknown GBS status, IAP is recommended if intrapartum maternal fever ≥100.5°F occurs, or if duration of ROM is ≥18 hours prior to delivery. The 2010 guidelines provide recommendations for the management of neonates at risk for EOS; recommendations for antibiotic choices for GBS IAP; specific recommendations for mothers who experience preterm labor and premature ROM; expanded laboratory methods for the detection of GBS including use of alternate culture-based detection methods; and for the first time, endorsed intrapartum nucleic acid amplification testing (NAAT) as an alternative to culture-based detection of maternal GBS colonization.
Table 49.2. Risk Factors for Early-Onset Group B Streptococcus (GBS) Sepsis in the Absence of Intrapartum Antibiotic Prophylaxis | ||||||||||||||||
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Penicillin and ampicillin are the recommended antibiotics for GBS IAP. The document addresses the challenges to providing adequate IAP to the roughly 10% of women who report penicillin allergy. There is no data directly supporting the efficacy of any antibiotic other than penicillin, ampicillin, or cefazolin for GBS IAP. Because a significant proportion of GBS isolates (15% to 40%) are resistant to macrolide antibiotics, it is recommended that any GBS isolates identified on screening of penicillin-allergic women be tested for antibiotic susceptibility including specific testing for inducible clindamycin resistance. For the woman with a non-life-threatening penicillin allergy, cefazolin is the recommended antibiotic for IAP. If a woman has a documented history of anaphylactic penicillin or cephalosporin allergy (including urticaria, angioedema, and/or respiratory distress), clindamycin is recommended if the colonizing isolate is fully susceptible to this antibiotic; otherwise, vancomycin is the recommended agent. For the purpose of infant management, however, the 2010 guideline does not consider the administration of clindamycin or vancomycin to constitute fully adequate IAP.
e. Current status of GBS EOS. CDC active surveillance data for the United States in 2014 demonstrates that the overall incidence of GBS EOS has fallen to 0.24 cases per 1,000 live births (compared to 1.7 cases per 1,000 live births in 1993). There is ongoing racial disparity with the incidence among black infants roughly three times that of white infants. Approximately one-quarter of all GBS EOS now occurs among infants born at <37 weeks’ gestation. We evaluated the reasons for persistent GBS EOS despite the use of a screening-based approach to IAP at the BWH. We found that most GBS EOS in term infants now occurs in infants born to women with negative antepartum screens
for GBS colonization. Subsequent CDC multistate surveillance studies from 2003 to 2004 found that 61% of GBS disease among term infants occurred in infants born to mother who screened GBS negative. These “false-negative” screens may be due to improper culture technique or acquisition of GBS between the time of culture and start of labor.
for GBS colonization. Subsequent CDC multistate surveillance studies from 2003 to 2004 found that 61% of GBS disease among term infants occurred in infants born to mother who screened GBS negative. These “false-negative” screens may be due to improper culture technique or acquisition of GBS between the time of culture and start of labor.
Bacterial culture remains the CDC-recommended standard for detection of maternal GBS colonization. The 2010 revision includes recommendations for the use of chromogenic GBS detection media and for the use of direct broth detection methods by latex agglutination, probe detection, or NAAT methods. These approaches may shorten the time to GBS identification. In 2002, the U.S. Food and Drug Administration (FDA) approved the first PCR-based rapid NAAT diagnostic for detection of maternal GBS colonization directly from vaginal/rectal swab specimens. Different kits are commercially available, and the 2010 guideline endorses the optional use of these NAATs for the management of women whose GBS status is unknown at the time of delivery. Recent data demonstrates that NAATs are more sensitive than antenatal culture in predicting intrapartum GBS status, but real-time use is compromised by a 10% incidence of nonresults due to technical issues. Due to the costs and technicalities of providing continuous support for a real-time PCR-based diagnostic, as well as the inherent time delay in an intrapartum diagnostic, most obstetric services continue to rely on antenatal culture-based screening programs.
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