The epidemiology, etiology and outcome of neonatal sepsis are changing over time. While monitoring longitudinal trends in neonatal sepsis in our institution, we encountered a case of late-onset neonatal sepsis due to Leclercia adecarboxylata. A Gram-negative rod previously not encountered in the clinical setting, L. adecarboxylata has recently emerged as a human pathogen, primarily in immunosuppressed patients. This report describes the clinical and laboratory features of this case of late-onset L. adecarboxylata sepsis, and reviews significant features of infection associated with this emerging pathogen.
Sepsis is a significant cause of morbidity and mortality in the neonatal period. Careful observation of longitudinal trends in neonatal sepsis aid in formulation of prevention and treatment strategies, with the ultimate goal of decreasing neonatal morbidity and mortality. Studies have demonstrated changing epidemiology, etiology and rates of late-onset neonatal sepsis.1 While monitoring trends in our institution, we encountered a case of late-onset neonatal sepsis due to Leclercia adecarboxylata in a preterm infant. L. adecarboxylata, a Gram-negative rod with phenotypic resemblance to Escherichia coli, has recently emerged as a human pathogen, primarily in immunosuppressed patients, frequently associated with polymicrobial infection.2, 3 This report describes the clinical and laboratory features of this case of late-onset L. adecarboxylata sepsis, and reviews significant features of infection associated with this emerging pathogen.
An 810-g appropriate-for-gestational age female neonate was delivered at 24 weeks gestation to a 28-year-old gravida 4, para 2 woman by repeat cesarean section. Pregnancy had been unremarkable until premature rupture of membranes with the onset of labor 7 h prior to delivery. Owing to clinical suspicion of chorioamnionitis, intravenous clindamycin and gentamicin were administered prior to delivery.
The patient suffered from respiratory distress syndrome treated with intratracheal surfactant and mechanical ventilation. Intravenous ampicillin and gentamicin were prescribed and discontinued after 48 h when admission blood and cerebrospinal fluid cultures demonstrated no growth. Parenteral nutrition and enteral feeds were introduced shortly after birth. Enteral feeding advancement was tolerated and parenteral fluids were discontinued on day 14 of life. A patent ductus arteriosus was closed with indomethacin on day 19 of life.
On day 31 of life, she developed apnea, lethargy, poor perfusion and a rigid, distended abdomen. Radiographs revealed a large amount of free intraperitoneal air. Enteral feeds were discontinued and intravenous fluids given. An endotracheal tube was placed and mechanical ventilation instituted. Blood cultures were obtained and intravenous ampicillin, gentamicin and clindamycin were prescribed. Exploratory laparotomy revealed a gastric perforation along the posterior wall of the mid-greater curvature of the stomach, treated with local debridement and primary closure of the perforation. A Broviac central venous catheter was placed.
Within 24 h of surgery, blood cultures yielded a Gram-negative rod, with biochemical features suggestive of L. adecarboxylata sensitive to ampicillin, cefotaxime and gentamicin. After 7 days of triple antibiotic therapy, treatment was continued with cefotaxime for a total of 21 days. Repeat blood cultures taken on days 33 and 35 of life yielded no growth.
The patient had a postoperative course complicated by respiratory failure necessitating high-frequency oscillatory ventilation, arrhythmias, protracted hypotension requiring dopamine, milrinone and glucocorticoid treatment, acute renal injury with prolonged oliguria, and disseminated intravascular coagulation requiring multiple transfusions of blood products. Despite the clearance of infection, she never fully recovered from the multiorgan failure caused by the late-onset septic shock. On day 54 of life, resuscitative efforts were discontinued and the patient died. Autopsy showed evidence of severe multisystem organ failure.
Confirmation of the biochemical identification of L. adecarboxylata in the blood culture was sought by 16S rRNA gene sequencing. Bacterial DNA was extracted and purified from colonies grown from the blood-culture isolate. Bacterial DNA was amplified using a primer pair designed to PCR amplify a fragment of the 16S rRNA gene of L. adecarboxylata (sense 5′-IndexTermCCTATCCCCTGTGTGCCTTGGCAGTCTCAGAAACTYAAAKGAATTGACGG-3′ antisense 5′-IndexTermCCATCTCATCCCTGCGTGTCTCCGACTCAGACGGGCGGTGTGTRC-3′). DNA amplicons underwent agarose gel electrophoresis with ethidium bromide staining and ultraviolet light visualization, followed by capillary-based nucleotide sequence analysis on a 3130XL Applied Biosystems (Grand Island, NY, USA) platform. Sequence data were subject to analysis, with the creation of a phylogenetic tree utilizing the tree builder application from the Ribosomal Database Project website (http://rdp.cme.msu.edu/).
Additional confirmation of L. adecarboxylata in the blood-culture isolate was developed. A pair of primers (sense 5′-IndexTermAATGATACGGCGACCACCGAAGRGTTTGATCMTGGCTCAG-3′ antisense 5′-IndexTermCAAGCAGAAGACGGCATACGATACGGYTACCTTGTTAYGACTT-3′) were designed to PCR amplify a 1504 bp fragment unique to L. adecarboxylata. The same processes of PCR amplification, electrophoresis and DNA sequencing were performed. DNA sequence was analyzed with the Basic Local Alignment Search Tool algorithm.4
Phylogenetic trees were constructed from a clustalw alignment of RecN protein sequences of L. adecarboxylata and other members of the Enterobacteriaceae family by neighbor joining using blosum62 with jalview (http://www.jalview.org/).
DNA sequence analysis from 16S rRNA gene sequencing ranked L. adecarboxylata as the most likely bacterial species with extended sequence homology to other Enterobacteriaceae. Sequence analysis of the amplicons designed for a unique region of L. adecarboxylata confirmed it as the source of the amplified DNA.
The Gram-negative rod now known as L. adecarboxylata was first described in 1962 by Leclerc,3, 5 who originally designated this type of pigmented Enterobacteriaceae as ‘Escherichia adecarboxylata’ or ‘Enteric group 41’. In 1986, Tamura et al.6 renamed the species to its current name after phenotypic and DNA relatedness evidence distinguished the bacterium as a separate organism from other members of the Enterobacteriaceae family. Figure 1 demonstrates the phylogenetic relationships between L. adecarboxylata and other members of the Enterobacteriaceae family commonly associated with neonatal sepsis. L. adecarboxylata is a Gram-negative, facultative-anaerobic, mesophilic, oxidase-negative, peritrichous-flagellated bacillus.3 Found widely in nature, including in food, water, soil and other environmental sources, it has been isolated from the skin and gastrointestinal tract of normal humans.7, 8 Previously unreported, approximately two dozen cases of L. adecarboxylata infection have been described in the last 10 years,2, 9 primarily as an opportunistic pathogen in immunosuppressed patients, often associated with polymicrobial infection.2
L. adecarboxylata is typically sensitive to treatment with a wide variety of antibiotics including most beta-lactams, aminoglycosides and the quinolones.10 However, two resistant isolates have recently been reported, one from a man with a chemical burn9 and another from a man with acute myelogenous leukemia.11 Both isolates exhibited characteristics of extended-spectrum beta-lactamase-producing strains with resistance to ceftazidime, cefotaxime, aztreonam and cefepime, as well as several aminoglycosides, penicillin, piperacillin and other agents. The isolate isolated from the patient with leukemia carried an SHV-12 beta-lactamase gene, which confers resistance via a transposable element. Identification of extended-spectrum beta-lactamase resistance in L. adecarboxylata is worrisome due to the possibility of horizontal transfer to other bacteria. As L. adecarboxylata is so frequently associated with polymicrobial infection, this could lead to widespread alterations in antibiotic susceptibility patterns.
There have been five cases of L. adecarboxylata infection reported in pediatric patients (Table 1).10, 12, 13, 14, 15 All five cases involved patients with serious underlying medical problems, many of which were chronic and involved some degree of immunosuppression, and were due to pansensitive isolates of L. adecarboxylata. The previously reported pediatric cases were all treated successfully with resolution of symptoms and clearance of bacteria from infected sites.
Unfortunately in this case, the severe damage associated with this patient’s L. adecarboxylata sepsis led to an overwhelming multisystem organ failure, making this the first pediatric case associated with mortality. The patient’s extreme prematurity and her gastric perforation likely contributed to her susceptibility to infection with L. adecarboxylata, and the profound severity of her illness.
L. adecarboxylata is emerging as an agent of serious human infection, including late-onset neonatal sepsis. 16S rRNA gene sequencing may facilitate or confirm L. adecarboxylata as the etiological agent of infection.
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This Study was supported in part by a grant from the NICHD, T32 HD007094.
The authors declare no conflict of interest.
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Nelson, M., Maksimova, Y., Schulz, V. et al. Late-onset Leclercia adecarboxylata sepsis in a premature neonate. J Perinatol 33, 740–742 (2013). https://doi.org/10.1038/jp.2013.34
- late-onset sepsis
- Gram-negative rod
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