Neonates are at high risk of meningitis which might lead to neurologic complications. Severe neurodisability and milder motor and psychometric impairment result from NM19. Despite global awareness of the risk factors of maternal and infantile infection and increased early treatments over the past 10 years, E. coli remains the primary causative organism of NM in developed countries20–22.From a Large cohort studies, NM remains a substantial cause of sepsis-related morbidity and mortality in the term and near-term infant23. We described how meningitis-related pathogens have changed from 2001 to 2019 in a city located in China. Bacterial resistance to commonly used antibiotics has become a global problem24, and regional differences exist13,25. When selecting empirical antibiotics, clinicians should consider local epidemiology (if known), early vs. late disease onset, antimicrobial resistance patterns, and availability within resource constraints26.There are relatively rare data about NM from developing countries, and the bacterial profile may be quite different. We investigated the current research in a large third-class hospital in eastern China over the last two decades. The findings shows the ratio of meningitis caused by CoNS has significantly decreased in the NICU of studied hospital, and the ratio of GBS meningitis has significantly increased, although E. coli persists as the mian etiologic agent of NM in the hospital. The most common pathogens(E. coli and GBS) we reported here are similar to those reported by Wiswell et al27. A multi-center survey of neonatal purulent meningitis from 13 hospitals in northern China showed that E. coli was the most common pathogen of NM with a rate of 21.1% among the infants of NM28, which is lower than that in our study (33%,69/209). We found out that GBS become the first common pathogen in our region, possibly resulted from the dramatic socioeconomic changes happened in China due to industrialization. Due to industrialization, people are more accustomed to drink milk and thus more maternal colonization in vagina and breast of pregnant women. This usually result in neonatal infection.
In the past 10 years, the annual deliveries number in our hospital has increased obviously,with approximately 10,000 births per year. This makes our center one of the largest perinatal centers in eastern China, where substantial socioeconomic changes have taken place due to industrialization. In the last decade, more babies have been born in hospitals, although occasionally some pregnant women have given birth at home. Compared with the proportion in 2001–2006, the proportion of children with E. coli meningitis birthed at home significantly decreased from 2007 to 2012, and there were no cases of children with E. coli meningitis birthed at home from 2013 to 2019 (3/10, 2/24, and 0/35, respectively). E. coli usually colonizes the maternal reproductive tract and can cause early neonatal infection29,30. However, the multidrug-resistant ESBL-producing bacteria observed in a large-scale sub-Saharan Africa study are obtained from polluted hospital environments, which increase the risk of death18. Our results are consistent with these findings. All five children born at home during our study periods were term infants and were infected with ESBL-negative E. coli. The proportion of ESBL-producing E. coli isolated from infants with EOM was significantly lower than that of infants with LOM (15.0% and 40.0%, respectively). In a similar way as presented in the French national survey, EOM from E. coli was statistically less frequent than LOM from E. coli (18% and 33%, respectively, P < 0.01) 31.Notably, the antimicrobial resistance rate of E. coli isolated from infants with EOM and from infants with LOM increased with regard to third-generation cephalosporins for example cefotaxime (15% and 41.9%, respectively), and to second-generation cephalosporins such as cefuroxime (15% and 43.9%, respectively), both the difference were considered significant. This may due to ESBL-producing E. coli infection spreads in the community and contaminated hospital environment with the mobile genetic elements of E. coli strains, such as plasmids. A lasted research revealed that ESBL-producing E. coli spreaded frequently in households with babies and improving community health was helpful to prevent the spread of ESBL-producing E. coli32.
The incidence of NM was between 0.12‰-1‰ in infants carried to term and 3‰ in premature infants11,33,34. A regional retrospective study conducted in Sweden from 1987–1996 estimated at 0.3 per 1000 live births35. This is in accordance with the UK and Ireland where reported an incidence of 0.38 per 1000 live births36. The incidence of NM much higher at 0.8–6.1 per 1000 live births, with a mortality of 40–58% in developing countries13.The incidence of culture-confirmed NM in our perinatal center increased from 0.12 per 1000 live-births in 2001–2006 to 0.26 per 1000 live-births in 2007–2012, and a little decreased to 0.23 per 1000 live-births in 2013–2019, which is a little lower than the datas from industrialized countries. This may reason for cases of negative blood culture associated with a pleocytosis (≥ 10×106 cells/L) in the CSF associated with typical clinical manifestations and the anti-infection treatment effect is remarkable were excluded.
Neonatal E. coli causing meningitis is related to high mortality and morbidity37,38. In a French national survey about neonatal bacterial meningitis 444 Cases from 2001 to 2007, reported the neonatal mortality rate of bacterial meningitis was 13%,while the mortality rate was twice as high in preterm (26%) than in term infants (10%),and neonatal mortality rate with E. coli meningitis was 12% (15/123) 31. In 2015, it was reported that in Britain, the most common cause of neonatal meningitis caused by gram-negative bacteria was E. coli K1, with a mortality rate of 10–15%39. As reported from1997-2017 in Sweden, the pathogens with the highest NM mortality rate are gram-negative bacteria, Klebsiella pneumoniae (33%; 2/6), and E. coli (11%; 2/18) 40. The case-mortality rate of E. coli meningitis in our center remained relatively unchanged with 12.5% (3/24) in 2007–2012 and 11.4% (4/35) in 2013–2019, at about 12%. Which is similar to the estimated 10% mortality rate of neonatal meningitis in developed countries13.
For infected infants < 60 days of age, the World Health Organization recommends using penicillins (such as ampicillin or penicillin) and aminoglycosides such as gentamicin or third-generation cephalosporins (such as ceftriaxone or cefotaxime)13. In the current study, 83.3% of all E. coli isolates from infants with meningitis from 2007 to 2012 were resistant to ampicillin, and 50% were resistant to third-generation cephalosporins (such as cefotaxime or ceftazidime). These rates were significantly higher than the percentages of resistance from 2001 to 2006, although the resistance rate of E. coli to ampicillin and cefotaxime or ceftazidime significantly decreased from 2013 to 2019. Our data showed that approximately one-third (21/65) of the cerebrospinal fluid isolates from infants with E. coli in our NICU were multidrug-resistant because of the production of ESBL. No ESBL-producing multidrug-resistant strains of E. coli were isolated from 2001 to 2006. An increasing number of ESBL-producing multidrug-resistant E. coli strains were isolated from 2007 to 2012, comprising 50% of strains (12/24), while the number of ESBL-producing multidrug-resistant E. coli strains significantly decreased from 2013 to 2019, comprising 29% of strains (9/31). This may be a result of China’s strict control of antibiotic using over the past 10 years, particularly for children, which has influenced the formulation of a series of regulations to restrict the use of antibiotics, such as expert consensus on the diagnosis and management of neonatal sepsis. In our NICU, the management guidelines for antibiotic using are strictly implemented. According to the guidelines of neonatal septicemia in America41, neonatologists grasp the indications for the use and discontinuation of antibacterial drugs. When antibiotics are used in children with high-risk factors, if no infection symptoms (e.g., fever, poor reaction and feeding), exist for 48 h, and a blood culture produces no alarming results, then the use of antibiotics is to be stopped immediately. For children with meningitis, penicillin combined with antibiotics, such as Rorschach's third-generation cephalosporins such as cefotaxime, is a combination that is also used empirically, and antibiotics are adjusted according to the drug sensitivity of the E. coli strain.
A study on neonatal septicemia and meningitis from 26 countries in Africa between 2008 and 2018 reported a non-susceptibility of E. coli isolates from NM to ampicillin was 89%, and gentamicin of 47%18. This data is higher than that from our center, in which 83.3% from 2007 to 2012 and 66.7% from 2013 to 2019 of E. coli isolates were resistant to ampicillin, and a non-susceptibility to gentamicin of 40.7% between 2013 and 2019. The widespread use of carbapenems has caused a notable spread of carbapenem-resistant42. However, to date, all E. coli strains isolated from infants with meningitis in our NICU have still been sensitive to cefoperazone-sulbactam and carbapenem antibiotics.
Compared to term infants, the percentage of premature infants among E. coli NM cases had increased and they are more susceptible to infections. A study form France has reported E coli is the most common cause of late premature infants and very early premature infants31. A prospective French survey collected data of 325 children hospitalized globally with E. coli meningitis from 2001 to 2013. The results of this study showed that 65.2% of these children were born at term, 22.4% were late premature infant, and 12.5% were very early premature infant43. Our results were in line with those from the French study. The percentage of term infants with E. coli meningitis 75.4% (52/69), late premature infants11.6% (8/69), and very premature or very early premature infants accounted for 13% (9/69) of our study population. Additionally, the proportion of premature infants with E. coli meningitis who were birth weight < 1500 gm in our NICU increased from 4.2–11.4%, which may be the result of the comprehensive actions of many factors. With the general progress of neonatal nursing and the improvement of NICU doctors' clinical skills, an increasing number of extremely premature infants have been successfully treated. In addition, this should related to most maternal immunoglobulins do not cross the placenta before 32 weeks gestation, the extremely preterm infants are at significantly higher risk for infections.44 Furthermore,early initiation of breastfeeding may be protective against infections which due to transfer of immunoglobulin A, however, term infants usually with breastfeeding at home45.
Interestingly, E. coli is one of the most common microorganisms producing L-asparaginase, and L- glutamine releases ammonia through enzymatic reaction, which makes E. coli obtain acid resistance. In a recent study, which revealed the divalent cations except magnesium almost completely inhibited L-asparaginase, such as Ca2+, Zn2+ and Cu2+ have been demonstrated as inhibitors of E. cloacae enzyme and reduce its activity by about 95 %46. We assume that Zn2+ may be a choice to supplementary treatment of E. coli causing neonatal meningitis in the near future, and furthermore studies are needed to validate this suppose.