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Dr Akinboyo is a pediatric infectious disease fellow at Johns Hopkins University School of Medicine, Baltimore, Maryland.
Dr Sardi is attending pediatric hospitalist at Children’s Hospital Los Angeles, California.
After an otherwise normal pregnancy, a male infant was born at 37 weeks gestational age via emergency cesarean delivery for decreased or absent fetal movement with multiple late and variable heart rate decelerations.
After an otherwise normal pregnancy, a male infant was born at 37 weeks gestational age via emergency cesarean delivery for decreased or absent fetal movement with multiple late and variable heart rate decelerations. Rupture of membranes occurred at delivery with copious thick meconium. The baby was limp and apneic, requiring intubation and tracheal suctioning for meconium aspiration and respiratory support immediately after birth.
The infant’s APGAR scores were 4, 6, and 8 at 1, 5, and 10 minutes. Cord blood gas was unavailable but initial arterial blood gas was pH 7.28, CO2 44. He developed worsening respiratory distress and was transferred to the neonatal intensive care unit (NICU).
The mother was a 28-year-old G3P2002, previously healthy female with gestational diabetes controlled on glyburide. Prenatal screening tests were unremarkable including Group B Streptococcus (GBS) culture obtained at delivery that was negative. The mother denied tobacco, alcohol, or illicit drug use. She had no infections or complications during her pregnancy. She had no known foreign travel history or exposures to uncooked food, and the only cheese she had consumed was processed cheese out of a can. After delivery, the mother developed a fever from presumed chorioamnionitis. She received a course of antibiotics, improved, and was discharged to home.
The baby weighed 2862 grams (~15th percentile for gestational age), with a head circumference of 34 cm (35th percentile) and length of 47.5 cm (10th percentile). On arrival to the NICU, he was afebrile with a heart rate of 206 beats per minute; blood pressure of 42/30 mm Hg; mean arterial pressure, 36 mm Hg; and 97% oxygen saturation on 100% fraction of inspired oxygen.
The patient was sedated on the oscillator but had some spontaneous movement. He was breathing over the oscillator with retractions and coarse breath sounds when the oscillator was paused. He had normal heart sounds but poor peripheral perfusion and decreased capillary refill with dusky extremities. No cardiac murmurs were appreciated. He had a normal abdominal exam and was nondysmorphic. No rash was noted.
The patient’s labs showed a white blood cell count of 2.4 k/cu mm; absolute neutrophil count, 700; 28% bands; platelets of 115 k/cu mm; hemoglobin, 15.9 g/dL; hematocrit, 47.8%; and C-reactive protein that was elevated at 15.5 mg/dL, then peaked to 17.9 mg/dL. Lactate peaked to 5.3 mmol/L. Basic metabolic panel was within normal limits except for a creatinine of 1 mg/dL. Aspartate aminotransferase and alanine aminotransferase were elevated at 239 U/L and 81 U/L, respectively. He was hypoglycemic at 32 mg/dL, and he received intravenous dextrose solution.
Chest and abdominal X-rays showed adequately aerated lungs with diffuse interstitial and alveolar opacities and a nonspecific bowel gas pattern without any radiographic evidence of obstruction, free air, pneumatosis, or portal venous gas.
The differential diagnosis for an early-term neonate with significant respiratory distress, hypoglycemia, and signs of hypoperfusion is broad. It includes congenital cardiothoracic abnormalities, central nervous system (CNS) disease, and perhaps most importantly, early-onset sepsis (EOS).1,2
Early-onset sepsis has been described as a systemic neonatal infection occurring in the first 3 to 7 days of life and is usually caused by vertical transmission of organisms that colonize the maternal genitourinary tract. The 2 most common causative organisms are GBS and Escherichia coli (E coli), which together account for approximately 70% of infections.2 Other culprits include Enterococcus, herpes simplex virus, Listeria, and other less common organisms such as Staphylococcus sp. Listeria is usually acquired by maternal exposure to contaminated foods leading to septicemia in neonates.
The infant in this case had many factors associated with an increased risk of EOS, including maternal chorioamnionitis, meconium aspiration, low APGAR scores (score of ≤6 at 5 min), and early-term status.2 Other risk factors for EOS that were not present in this patient include prolonged rupture of membranes, prematurity, maternal colonization with GBS, and previous delivery of an infant with GBS disease. The presence of leukopenia, bandemia, thrombocytopenia, opacities on chest X-ray, poor perfusion, and dusky appearance on exam all were very concerning for sepsis.
The patient’s chest X-ray ruled out many of the diagnoses in Table, including congenital diaphragmatic hernia and pneumothorax. His laboratory evaluation showed no evidence of significant anemia, polycythemia, or electrolyte abnormalities other than acidosis. An echocardiogram ruled out congenital heart disease and his exam (lack of stridor, micrognathia, dysmorphic features) made etiologies such as anatomic airway abnormalities and Pierre Robin syndrome less likely to be contributing to this patient’s illness. His presentation was most consistent with sepsis.
Blood cultures, collected on day-of-life (DOL) 1 were positive for Gram-positive rod bacteria, confirming sepsis as the underlying etiology. Because this was an uncommon pathogen, further tests to clarify the specific organism were needed.
The infant was severely ill for many days. He was intubated and received surfactant at birth but he required high-frequency oscillatory ventilator support and inhaled nitric oxide for the first days of life. Multiple fluid boluses and vasopressors were administered. After cultures and labs were obtained on DOL 1, ampicillin and cefotaxime were initiated for empiric antimicrobial coverage consistent with hospital guidelines for management of neonatal sepsis in cases where there is a concern for meningitis.
Final identification of Listeria monocytogenes (L monocytogenes) was made 4 days later. It was sensitive to ampicillin and penicillin. At that time, the pediatric infectious disease team was consulted. They recommended using meningitic dosing of ampicillin and switching cefotaxime to gentamicin, the preferred agent for synergy against Listeria. They also recommended at least 21 days of antibiotics, a conservative measure to treat for presumed meningitis because the patient was too hemodynamically unstable for a lumbar puncture to evaluate CNS infection. All subsequent blood cultures were negative.
Neonatal EOS remains a challenge for clinicians who care for infants in the first week of life. Clinical findings vary considerably, but pneumonia is often the presenting infection and respiratory symptoms (tachypnea, grunting, retractions) can be prominent.2 Other signs include hypothermia, lethargy, cyanosis, poor perfusion, and acidosis.
The Centers for Disease Control and Prevention (CDC) has recommended that all infants with clinical signs suggestive of sepsis should receive a full diagnostic workup and empirical therapy with ampicillin and gentamicin.3 The reason for this recommendation is multifactorial. First, despite increased intrapartum maternal prophylaxis to prevent GBS transmission, GBS continues to be a leading cause of neonatal EOS and meningitis in the United States.2,3 Secondly, although there is increasing prevalence of extended-spectrum beta-lactamase producers as etiologic agents of neonatal sepsis, most neonatal infections secondary to E coli in the United States are community acquired and remain gentamicin susceptible.2 Finally, ampicillin and gentamicin have demonstrated a synergistic effect in laboratory and animal models of L monocytogenes. Therefore, the combination of ampicillin and gentamicin is recommended to treat infants for EOS because it provides adequate bactericidal activity against GBS, E coli, other streptococci, Enterococcus, and Listeria. Cefotaxime may be added empirically or substituted for gentamicin if there is concern for meningitis because it has excellent cerebrospinal fluid penetration.4
Listeria monocytogenes is a rare but dangerous neonatal pathogen. It is a Gram-positive coccobacillus (or rod) that expresses a hemolytic exotoxin, and it is usually isolated from soil, water, and food. It is an intracellular pathogen that is typically acquired by ingesting unpasteurized dairy products, soft cheeses, ready-to-eat deli meats, pates, and smoked foods.4
Listeria monocytogenes infections have been linked to premature delivery, miscarriage, and stillbirths, and can present as EOS for up to 4 weeks after delivery.5 Early-onset neonatal infection usually occurs from vertical transmission (ie, mother to child) at about 2 to 5 days after delivery. In a review of worldwide articles with pregnancy-associated listeriosis, Okike and colleagues found that about 75% of listeriosis occurred in patients aged younger than 1 week, and only 5 of 456 cases (1%) occurred in infants aged between 1 and 3 months.6 Silk et al analyzed data from the Foodborne Diseases Active Surveillance Network (FoodNet) and concluded that of 68 listeriosis cases in infants from 2004 to 2009, 78% occurred by 2 weeks, also suggesting that early-onset disease is more common.7
In the United States, Listeria is rare and often associated with food outbreaks. The largest listeriosis outbreak in US history was in 2011, when 147 illnesses, 33 deaths, and 1 miscarriage occurred among residents of 28 states. The outbreak was associated with consumption of cantaloupe from a single farm.8
Although the CDC notes that the annual incidence of Listeria in the United States is low (0.26 per 100,000 individuals),9 pregnant women are at up to 13 times greater risk than the general population.10 In pregnancies complicated by listeriosis, up to two-thirds of infants may be affected, and of these, 25% to 44% can present with meningitis.7,11 As with the infant in this case, patients may be severely ill with a risk of death of up to 30%, even with effective treatment.12
Given that neonatal listeriosis is seen infrequently, at least 1 study has questioned the validity of continuing to use ampicillin for empiric coverage in neonates with clinical signs of sepsis.4 However, empiric use of ampicillin remains important to provide coverage not just for Listeria but also as the treatment of choice for GBS and to cover enterococci infections that are not responsive to cephalosporins such as cefotaxime.
Neonatal listeriosis can be a serious disease resulting in long-term morbidity and mortality. It frequently presents soon after birth but it is clinically indistinguishable from other causes of serious bacterial infection in neonates. It continues to be important to provide immediate empiric coverage for pathogens causing early-onset neonatal sepsis including Group B Streptococcus, non–beta-lactamase-producing E coli, and Listeria any time that sepsis is suspected.
The infant’s clinical course was complicated by persistent pulmonary hypertension (with near systemic right-sided heart pressures and moderate cardiac dysfunction), presumed meconium aspiration syndrome, and a large inferior vena cava clot. He was discharged home after more than 1 month of hospitalization, 11 days of vasopressor support, and 12 days of mechanical ventilation.
At the time of discharge to an outside facility, the patient was well appearing and weaning medications for iatrogenic narcotic dependence, working on feeding, and completing his course of anticoagulation and antibiotics. He completed his anticoagulation medications at 7 months of age, and reportedly he is doing well.
1. Warren JB, Anderson JM. Newborn respiratory disorders. Pediatr Rev. 2010;31(12):487-495.
2. Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014;27(1):21-47.
3. Committee on Infectious Diseases; Committee on Fetus and Newborn; Baker CJ, Byington CL, Polin RA. Policy statement-Recommendations for the prevention of perinatal group B streptococcal (GBS) disease. Pediatrics. 2011;128(3):611-616.
4. Polin RA; Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics. 2012;129(5):1006-1015.
5. Hassoun A, Stankovic C, Rogers A, et al. Listeria and enterococcal infections in neonates 28 days of age and younger: is empiric parenteral ampicillin still indicated? Pediatr Emerg Care. 2014;30(4):240-243.
6. Okike IO, Lamont RF, Heath PT. Do we really need to worry about listeria in newborn infants? Pediatr Infect Dis J. 2013;32(4):405-406.
7. Silk BJ, Date KA, Jackson KA, et al. Invasive listeriosis in the Foodborne Diseases Active Surveillance Network (FoodNet), 2004-2009: further targeted prevention needed for higher-risk groups. Clin Infect Dis. 2012;54 suppl 5:S396-S404.
8. Centers for Disease Control and Prevention (CDC). Vital signs: incidence and trends of infection with pathogens transmitted commonly through food-Foodborne Diseases Active Surveillance Network, 10 US sites, 1996- 2010. MMWR Morb Mortal Wkly Rep. 2011;60(22):749-755.
9. Crim SM, Iwamoto M, Huang JY, et al; Centers for Disease Control and Prevention (CDC). Incidence and trends of infection with pathogens transmitted commonly through food-Foodborne Diseases Active Surveillance Network, 10 US sites, 2006-2013. MMWR Morb Mortal Wkly Rep. 2014;63(15):328-332.
10. Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Committee opinion no. 614: management of pregnant women with presumptive exposure to Listeria monocytogenes. Obstet Gynecol. 2014;124(6):1241-1244.
11. Mylonakis E, Paliou M, Hohmann EL, Calderwood SB, Wing EJ. Listeriosis during pregnancy: a case series and review of 222 cases. Medicine (Baltimore). 2002;81(4):260-269.
12. Center for Food Security and Public Health, Iowa State University. Listeriosis. Available at: www.cfsph.iastate.edu/Factsheets/pdfs/listeriosis.pdf. Updated May 2005. Accessed April 5, 2016.
Dr Akinboyo is a pediatric infectious disease fellow at Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr Sardi is attending pediatric hospitalist at Children’s Hospital Los Angeles, California. The authors have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.