Full case: A preterm infant presents with neonatal respiratory distress | Image credit: Contemporary Pediatrics

The Case

A 32 weeks and 6/7 days, 1970 g infant was born via meconium-stained vaginal delivery to a 37-year-old G2P1 mother who recently immigrated from India. The mother presented with preterm premature rupture of membranes (PPROM) for 11 hours prior to eventual vaginal delivery. Maternal history was otherwise notable for rubella nonimmune, advanced maternal age, and a prior history of intrauterine fetal demise 4 years prior. Prior to delivery, the mother received 1 dose of ampicillin given unknown Group B streptococcus (GBS) status, and a single dose of betamethasone to accelerate fetal lung maturity. After delivery, the infant was vigorous with delayed cord clamping of 1 minute. The Apgar scores were 8 and 8 at 1 and 5 minutes of life, respectively. There was mildly increased respiratory effort in the delivery room for which CPAP respiratory support was begun. The child was brought to the NICU on CPAP 5, 30% FiO2.

Examination and studies

Initial vital signs included a temperature of 98.9F, heart rate of 165, respirations of 58, blood pressure of 47/18 with a mean of 28 and oxygen saturation of 97% on CPAP 5, 30% FiO2. Her physical exam was unremarkable except for mild intermittent tachypnea and subcostal retractions. Umbilical venous and umbilical arterial catheters were placed, a NS bolus was administered, and the child was begun on empiric ampicillin and gentamicin given preterm labor and PPROM. The admission chest x-ray was notable for moderate diffuse haziness bilaterally without focal infiltrates and no pneumothorax. Initial arterial blood gas at 1 hour of life was consistent with a respiratory acidosis with a pH of 7.08, CO2 of 85, and base of -6. Interval blood gases were monitored with rapid improvement of respiratory acidosis on CPAP6 respiratory support which was weaned to CPAP6 21% by 12 hours of life. A CBC obtained after birth was within normal limits including a white blood cell count of 12, hematocrit of 42, and platelet count of 312,000 with a differential that included 52% Neutrophils, 2% Bands, 26% Lymphocytes, 18% Monocytes, and 2% Eosinophils.

Within 18 hours of life, the initial blood culture was positive for gram negative rods with suggestion of extended spectrum beta-lactamase (ESBL).

Differential diagnosis

The initial presentation was most notable for preterm birth of unclear etiology, mild respiratory distress, and an initial blood culture that returned positive within the first 24 hours of life suggestive of early onset sepsis. The differential diagnosis for this infant’s initial presentation included respiratory distress syndrome/surfactant deficiency, meconium aspiration, transient tachypnea of the newborn, pneumonia/sepsis and more as listed in Table 1.

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Typical bacterial pathogens for early-onset sepsis, defined by blood or cerebrospinal fluid (CSF) culture bacterial growth in the first 72 hours of life, include Group B streptococcus (GBS), Escherichia coli, coagulase-negative Staphylococcus, Haemophilus influenza, and Listeria monocytogenes.¹ Among these bacteria, E Coli is the most common pathogen isolated and accounts for approximately half of reported cases nationally.

Actual diagnosis

Sensitivity analysis for this infant’s initial positive blood culture confirmed E. coli with ESBL profile including resistance to ampicillin, ampicillin/sulbactam, cephalosporins, and gentamicin.

The condition

Extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL) strains have been implicated in severe and often lethal neonatal sepsis cases. A 2018 study from Alabama noted 3 cases of ESBL E. coli sepsis in neonates born to mothers originating from South Asia and Southeast Asia.² In all 3 cases, the patients became critically ill including respiratory failure that required intubation and disseminated intravascular coagulation with pulmonary hemorrhage. All 3 cases were managed with β-lactams and aminoglycosides. Two deteriorated rapidly and passed away despite vigorous resuscitative efforts. However, early use of meropenem in the third patient led to a favorable outcome.

ESBL enzymes are characterized by the ability to hydrolyze third-generation cephalosporins (such as ceftriaxone and cefixime) and aztreonam.³ Resistance rates to ampicillin are as high as 66% to 78% in invasive neonatal E. coli isolates.⁴ Less data still exists worldwide regarding ESBL resistance towards aminoglycosides but the overall increasing rate of resistance to gentamicin now surpasses 10% in the United States and Europe.⁵ ESBL colonization exceeds just over 10% worldwide though approaches at least double that figure in certain parts of the world such as India, Southeast Asia, and Africa.⁶

Analysis of neonatal E. coli bacteremia isolates in the United States from 2006 to 2016 found 67% resistance to ampicillin, 14% to gentamicin, 2% to ceftriaxone, and 0% to amikacin and carbapenems.⁷

Management

The combination of ampicillin and gentamicin is the first choice for empirical antibiotic therapy when early onset sepsis is suspected. This targeted combination of gram positive and gram negative coverage addresses the most common bacterial pathogens in early onset neonatal sepsis. Broader spectrum antibiotics are reserved for rarer cases such as the one presented here. When selecting or adjusting appropriate antibiotic coverage, clinical context must be taken into account including demographics, clinical course, and available susceptibility patterns.

Patient course

Pediatric infectious disease was consulted and antibiotic coverage was changed from ampicillin and gentamicin to meropenem with the first dose administered by 24 hours of life. Repeat blood culture at 48 hours of life remained positive with a first negative blood culture at 72 hours of life. A lumbar puncture was performed on day of life number 4. Cerebrospinal fluid (CSF) culture pretreated with meropenem was negative, but concerning for elevated white blood cells of 97/mm³ with protein of 296 mg/dL. A 21 day course of meropenem was therefore completed. The infant remained on noninvasive respiratory support throughout the NICU course and was eventually weaned to room air by 5 weeks of life. The remainder of the NICU hospital course was remarkable for mild hyperbilirubinemia, anemia of prematurity, immature retinal exam in zones 2 and 3, and an occlusive thrombus in the right great saphenous vein likely secondary to a right lower extremity PICC. At the time of discharge at 46 days of life and 39 weeks corrected gestational age, the patient’s weight was 2775 grams. She was stable on room air and tolerating ad lib feeds of maternal milk fortified to 22kcal per ounce.

Discussion

Neonatal sepsis is the leading cause of death in preterm newborns worldwide, with an estimated annual mortality rate of 203,000.⁸ A systematic review in 2017 comparing 23 global studies, with a total of 3,381 laboratory-confirmed bloodstream infection cases, found the prevalence of extended-spectrum ß-lactamase producing Escherichia coli (ESBL-PE) infections to be 11% among neonates.⁷ These cases were pooled from Africa, South America, India, Asia, and Europe in order of descending prevalence. Surprisingly there were no North American cases in this review. However, between 1990 to 2011 the number of ESBL cases tripled in the United States.⁹

Early onset sepsis with ESBL has historically demonstrated relatively high mortality rates especially among the preterm neonatal population. These alarming statistics highlight the dangers and increasing frequency of ESBL infections in the vulnerable newborn population. Clinicians should have a high index of suspicion for ESBL E. coli sepsis in infants whose clinical status does not improve on typical empiric antibiotic coverage and/or in the context of infants born to mothers from high-risk regions. We believe that in our case early initiation of meropenem was life saving for this infant.

References

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9. Logan LK, Braykov NP, Weinstein RA, Laxminarayan R; CDC Epicenters Prevention Program. Extended-Spectrum β-Lactamase-Producing and Third-Generation Cephalosporin-Resistant Enterobacteriaceae in Children: Trends in the United States, 1999-2011. J Pediatric Infect Dis Soc. 2014;3(4):320-328. doi:10.1093/jpids/piu010