JAC Advance Access published online on September 4, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn362
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Research letter |
CTX-M-15-producing Escherichia coli in fatal neonatal meningitis: failure of empirical chemotherapy
1 Département de Microbiologie, CHU de Rouen, 1 rue de Germont, 76031 Rouen cedex, France 2 EA2656 GRAM, IHURBM, Faculté de Médecine, Université de Rouen, Rouen, France 3 Département de Microbiologie, Hôpital Robert Debré, 48 bd Sérurier, 75019 Paris, France 4 Département de Néonatalogie, CHU de Rouen, 1 rue de Germont, 76031 Rouen cedex, France
* Correspondence address. Département de Microbiologie, CHU de Rouen, 1 rue de Germont, 76031 Rouen cedex, France. Tel: +33-2-32-88-02-41; Fax: +33-2-32-88-80-98; E-mail: sophie.boyer{at}chu-rouen.fr
Key Words: ESBLs , very low birth weight , Enterobacteriaceae , resistance to cephalosporins
Escherichia coli is one of the most common bacterial agents in neonatal disease.1 Early- and late-onset meningitis remain a major cause of death and neurological sequelae in neonates, especially among very low birth weight (VLBW) infants. A recent study has reported the emergence of E. coli as the predominant organism responsible for early-onset sepsis, as well as an increased rate of E. coli ampicillin resistance after the initiation of intrapartum antimicrobial prophylaxis.2 Most E. coli strains remained susceptible to extended-spectrum cephalosporins (ESC). Extended-spectrum β-lactamases (ESBLs) are an increasingly important cause of resistance to ESC in E. coli, particularly the CTX-M-type enzymes. One of these enzymes, CTX-M-15, now occurs worldwide in strains responsible for outbreaks both in nosocomial and in community settings.3 To date, neonates with meningitis have remained free of these multidrug-resistant E. coli strains. The emergence of such strains would constitute a major problem for these patients for whom the choice of drugs is limited. In this context, we report one case of lethal neonatal meningitis due to CTX-M-15-producing E. coli resistant to fluoroquinolones in a VLBW infant linked to failure of initial therapeutic scheme.
We describe the case of an infant (Patient 1) born on day 1 after a programmed caesarean section before natural labour began because of severe intrauterine growth restriction at a gestational age of 30 weeks. The initial infectious assessment was negative, and this VLBW infant (1080 g) did not receive any antibiotics. The clinical evolution was satisfactory without any respiratory distress after birth and up to day 5. On day 6, the following appeared: hyperglycaemia, leucopenia and inflammatory syndrome (C-reactive protein increased to 66 mg/L). A first-line treatment was started with intravenous ceftazidime (100 mg/kg/day), vancomycin (20 mg/kg/day) and netilmicin (4 mg/kg/day) after three blood cultures and a lumbar puncture were collected. Direct examination after Gram staining of CSF was negative. The CSF cell count was 4 leucocytes/mL and 56 red blood cells/mL. The values of CSF protein and glucose level were, respectively, 0.72 g/L and 16.5 mmol/L (blood glucose level of 19.2 mmol/L). Moreover, there was a CSF lactic acid level of 6.3 mmol/L. Several hours later, the infant developed apnoea, haemodynamic instability and abdominal disorders. Metronidazole (20 mg/kg/day) was added on the assumption of necrotizing enterocolitis. One hour later, the infant was transferred to the intensive care unit because of refractory septic shock. The infant died at the end of day 6. On day 7, CSF and blood grew E. coli resistant to ESC, ciprofloxacin and trimethoprim/sulfamethoxazole, but susceptible to cefoxitin, imipenem and aminoglycosides. These strains exhibited an ESBL phenotype that had never been observed in clinical isolates in this neonatal ward. On day 8, a nasopharyngeal sample of a second baby (Patient 2) grew an E. coli strain with the same resistance phenotype, and this prompted an investigation of the outbreak. Screening for faecal and nasopharyngeal carriage of the 45 patients present in the neonatal department identified this second baby as the only infant colonized with ESBL E. coli.
The three ESBL strains from the CSF and the blood of Patient 1 and the nasopharyngeal sample of Patient 2 were indistinguishable using ERIC-2 PCR and ribotyping methods (Figure 1).4,5 Phylogenetic analysis revealed that these ESBL strains belonged to phylogenetic group B2, and virulence genotyping showed that they harboured only two virulence factors: aerobactin and yersiniabactin. PCR and sequencing5 of blaCTX-M, blaTEM and blaSHV demonstrated that the only β-lactamase present was CTX-M-15.
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, DNA molecular weight marker; lanes 2 and 3, ESBL strains from CSF and blood of Patient 1; lane 4, ESBL strain from pharyngeal site of Patient 2; lanes 1, 5, 6, 7 and 8, unrelated strains.The emergence of CTX-M-15-producing E. coli in perinatal care is a major concern, and this is the first report of lethal neonatal meningitis in a VLBW infant. In Algeria, there have been five cases of infection with E. coli CTX-M-15 in a neonatal ward; two of them were non-fatal meningitis.6 First-line treatment of neonatal infections due to E. coli usually combines ESC and aminoglycoside because the strains are mostly susceptible to these antibiotics. In our case, the E. coli strain was resistant to ESC by production of ESBL CTX-M-15, the most prevalent CTX-M-type enzyme encountered in France.3,5 CTX-M-15 E. coli strains belonging to phylogenetic group B2 have been reported in Europe and Canada and are responsible for outbreaks of nosocomial and community-acquired urinary tract infections, mainly in the elderly,7 but not in children. Interestingly, the virulence genotype harboured by our B2 strains was identical to that reported in CTX-M-15-producing epidemic B2 strains in long-term care facilities in France, suggesting dissemination of a multiresistant clone.
For neonates, both CTX-M-15 enzyme and virulence factors in highly pathogenic group B2 E. coli frequently involved in neonatal meningitis are an additional fear and may have important implications for physicians treating neonates with invasive E. coli infections. Nevertheless, in this case, the process was so rapid that, even with the use of appropriate antibiotics, the outcome was unlikely to have been any different. However, fluoroquinolone resistance, frequently encountered in CTX-M-15-positive isolates7 is another therapeutic challenge. Fluoroquinolones, indeed, are widely added because of their excellent brain tissue penetration and their bactericidal activity to avoid abscess complications frequently observed in neonatal meningitis due to Gram-negative bacilli.8 Finally, this report highlights the need to track the emergence of such unprecedented resistant strains of E. coli in neonates in order to adapt first-line and second-line empirical chemotherapy. As CTX-M-producing E. coli are emerging in young adults, there is a need to establish the prevalence of ESBL-producing strains from vaginal swabs in pregnant women and the corresponding attack rate of this infection in neonates. This would inform future possible prevention strategies such as universal screening.
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This work was financed with a grant from the Ministère de l'Education Nationale et de la Recherche, Faculté de Médecine de Rouen (UPRES, EA 2656 GRAM, IFR23), France.
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None to declare.
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1 . Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med (2002) 347:240–7.
2
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Bizzarro MJ, Dembry LM, Baltimore RS, et al. Changing patterns in neonatal Escherichia coli sepsis and ampicillin resistance in the era of intrapartum antibiotic prophylaxis. Pediatrics (2008) 121:689–96.
3
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Livermore DM, Canton R, Gniadkowski M, et al. CTX-M: changing the face of ESBLs in Europe. J Antimicrob Chemother (2007) 59:165–74.
4 . Bonacorsi S, Clermont O, Houdouin V, et al. Molecular analysis and experimental virulence of French and North American Escherichia coli neonatal meningitis isolates: identification of a new virulent clone. J Infect Dis (2003) 187:1895–906.[CrossRef][Web of Science][Medline]
5
.
Eckert C, Gautier V, Saladin-Allard M, et al. Dissemination of CTX-M-type β-lactamases among clinical isolates of Enterobacteriaceae in Paris, France. Antimicrob Agents Chemother (2004) 48:1249–55.
6
.
Ramdani-Bouguessa N, Mendonça N, Leitao J, et al. CTX-M-3 and CTX-M-15 extended-spectrum β-lactamases in isolates of Escherichia coli from a hospital in Algiers, Algeria. J Clin Microbiol (2006) 44:4584–6.
7
.
Pitout JD, Nordmann P, Laupland KB, et al. Emergence of Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) in the community. J Antimicrob Chemother (2005) 56:52–9.
8 . Leibovitz E. The use of fluoroquinolones in children. Curr Opin Microbiol (2006) 18:64–70.
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