Neonatal Bacterial Meningitis: Single Reference Center Experience and Review of Current Literature: A Retrospective Cohort Study

OBJECTIVE: Despite improvements in neonatal care, neonatal bacterial meningitis is still an emerging problem worldwide with high rates of mortality. The present study evaluates data on suspectedand culture-proven neonatal bacterial meningitis in the light of a single tertiary reference center experience in Turkey in comparison with the globe. STUDY DESIGN: In this retrospective cohort study newborns admitted to Hacettepe University Ihsan Dogramaci Children’s Hospital Neonatal Intensive Care Unit during a 5-year-period between April 2014May 2019 and who underwent atraumatic lumbar puncture were included. RESULTS: Two hundred sixty-four patients fulfilled the inclusion criteria. Most common symptoms in all patients raised suspicion in favor of NBM and resulted in lumbar puncture were fever (34.5%, n=91), respiratory distress (31.1%, n=82), lethargy (31.1%, n=82), and apnea (26.1%, n=69). The incidence of culture-proven NBM among suspected patients was 5.7% (n=15/264); while the incidence is 3.1 per 1000 (15/4574) at all Neonatal Intensive Care Unit admissions. Respiratory distress (60.0%, n=9/15) and apnea (40.0%, n=6/15) were the most common symptoms in patients with NBM; which may be due to the predominance of premature newborns in the NBM group. The most common microorganisms in CSF cultures were coagulase-negative Staphylococci with Methicillin-resistant Staphylococcus epidermidis being most common among all. CONCLUSIONS: The present study underlines high rates of culture-proven neonatal bacterial meningitis among suspected newborns despite improvements in modern health care, which raises attention to careful evaluation of these patients and early administration of properly-selected antibiotics. Our incidence rates are in keeping with studies from the developed world.


Results
Within the study period, 4.574 newborns were admitted to NICU for different causes; 646 of them underwent an LP proceeding with suspicion of meningitis at admission or during the stay. Of these, 264 of them fulfilled the inclusion criteria owing to an atraumatic LP with the successful withdrawal of CSF. Among the patients included in the study, 48.1% (n=127) of them were female with the median week of gestation (GW) 36 (24-42) weeks, median birth weight (BW) 2500 (500-4.920) grams, and the median duration of stay 22  days. There was no significant variability regarding the demographical profile of the patients (Table I).
While numerous in-depth studies have addressed the aspects of NBM, large studies demonstrate that the epidemiology, etiology, treatment strategies, and outcome of NBM may vary with the changing setting; which is of importance in short-term care and long-term follow-up of newborns. In this study, we aimed to analyze suspected-and culture-proven NBM in the light of a single large tertiary reference center in Turkey, in comparison with other studies around the globe.

Material and Method
This retrospective cohort study included all newborns (chronologic age in 0-28 days, or corrected post-conceptual age under 40 weeks) who were admitted to Hacettepe University Ihsan Dogramaci Children's Hospital Neonatal Intensive Care Unit (NICU) during a 5-year-period between April 2014-May 2019, who underwent atraumatic lumbar puncture (LP) and successful withdrawal of CSF proceeding a suspicion of meningitis. Patients who were beyond the age limits and who had traumatic LP with blood contamination were excluded. Demographical features, clinical symptoms, culture findings (CSF, blood and urine samples), empirical antibiotic regimens, and duration of therapy were analyzed in a retrospective manner with Statistical Package for Social Sciences (SPSS) for Windows 20.0. The study was reviewed and approved by the ethics committee of Hacettepe University (ethics approval reference number: 2019/23-08). All procedures were performed according to the Declaration of Helsinki.  median timing of LP 25 (5-70) days (Table II). The median duration of antibiotics was 20 (14-32) days. The most preferred empirical antibiotic regime was the wide-spectrum regime [Ampicillin/Meropenem/Gentamycin/Fluconazole (prophylaxis)] (66.7%, n=10) (Table III). Most common symptoms included respiratory distress (60.0%, n=9), apnea (40.0%, n=6), lethargy (26.7%, n=4), abdominal distension (26.7%, n=4), and feeding difficulties (in patients with GW>34 weeks, 33.3%, n=3) (Table III).
Meningitis (n=15) and non-meningitis (n=249) groups did not differ significantly regarding demographical, epidemiological, and clinical profile (Table I and III); although respiratory distress as the preceding clinical symptom was more prominent in the meningitis group (60.0% vs. 29.2%, p=0.02) (Table III).  (Table V).
Although statistically not significant, the rate of mortality was higher in the meningitis group (13.3%, n=2 vs. 4.4%, n=11); while the overall mortality at all NICU admissions during the study period being 5.3% (Table II).

Discussion
Despite improvements in neonatal routine-and intensivecare, neonatal bacterial meningitis (NBM) is still a great concern worldwide due to its higher incidence and mortality compared to any other age (1)(2)(3)10,12,13). This recent retrospective cohort evaluates culture-proven NBM while presenting data over patients with clinically-suspected NBM, in the light of a single tertiary reference center experience in Turkey in comparison with the globe.
The present study included some important data that was not encountered in other studies during our routine literature review. The most common symptoms which raised suspicion in favor of NBM and resulted in LP were found to be fever, respiratory distress, lethargy, and apnea. While interpreting this finding, we realized that these symptoms led us to be more of a priority in making an LP decision in late-onset NBM. Among patients clinically suspected of NBM, the incidence of culture-proven NBM was 5.7%. We appraised this incidence to be high, which draws attention to being more attentive while evaluating a newborn suspected of NBM. This also further underlines the importance of early administration of properly-selected antibiotics whenever needed.
Literature reveals that the incidence and mortality rates of culture-proven NBM range between 0.2-0.3 vs. 0.8-6.1 per 1000 live births and 10-15% vs. 11-58% in respect to developed vs. developing countries (1)(2)(3)(4)(5)(6)(7)(8)(13)(14)(15). Direct comparison of the present study with the world in terms of NBM incidence was not possible due to the fact that our NBM incidence was calculated from NICU admissions rather than live births. On the other hand, the incidence of 3.1 per 1000 at all NICU admissions in the present study was in keeping with a recent study from Canada (2.2-3.5 per 1000 NICU admissions) and lower than a native study from Turkey (9 per 1000 admissions) (11,12). Mortality rates among patients with NBM in the present study (13.3%) were in concurrence with the developed world (13.3% vs. 10-15%) (1-3,8).
Many variables have been shown as risk factors of NBM in multiple studies; which in turn affect the site of presentation (community-or hospital-based), the most common symptom at presentation, most preferred empirical antibiotic regimen, and most commonly isolated microorganisms in CSF cultures (1)(2)(3)9,12). The patients diagnosed with NBM in the present study were predominantly composed of premature newborns [GW 34 (25-41) weeks] with a relatively long duration of stay [37 (16-130) days]. Many of them had concomitant congenital CNS (meningomyelocele, hydrocephalus) or non-CNS (cardiac, gastrointestinal) defects with multiple invasive procedures (Table I). In our understanding, this may explain the relatively high rate of hospital-based NBM (73.3%). Respiratory distress and apnea were found to be the most common symptoms in patients with NBM; which may also be explained by prematurity and which is also in concurrence with current knowledge of NBM in premature newborns (1,2).
Wide-spectrum with multiple antibiotics was the regime of choice, as the patients were suspected of late-onset meningitis with a possible risk of resistance patterns. The most common bacteria isolated in CSF cultures (coagulase-negative Staphylococci) were in concurrence with the current literature and also with microorganisms related to late-onset meningitis (1,2,9,11). A variety of studies reported up to 50.0% of blood culture negativity in patients diagnosed with NBM and some of them even suggested multiple blood samples to be withdrawn to increase sensitivity (1)(2)(3)(4)(5)(6)11,12). The present study has also detected a comparatively high rate of negative blood cultures (53.3%) parallel to previous studies.
An important limitation was the difficulty encountered during the comparison of the present study with other studies around the globe owing to varieties in study design. A forthcoming new prospective study would address this issue by evaluating NBM incidence at live births by means of a new study architecture.
In conclusion, NBM continues to be a great concern both where CSF cultures still stand to be the gold standard for definitive diagnosis. Our findings regarding incidence are in keeping with studies from the developed world. Despite improvements in neonatal health care in recent years, the rate of culture-proven NBM is still high among suspected newborns, which raises attention to careful evaluation of patients with apparent symptoms and early administration of properly-selected antibiotics.