Clinical characteristics and antimicrobial therapy of healthcare-associated carbapenem-non-susceptible gram-negative bacterial meningitis: a 16-year retrospective cohort study.

OBJECTIVE: Healthcare-associated Gram-negative bacterial meningitis is a substantial clinical issue with poor outcomes, especially for neurosurgical patients. Here, we aimed to study the characteristics and treatment options of patients with healthcare-associated carbapenem-non-susceptible (Carba-NS) Gram-negative bacterial meningitis. METHODS: This observational cohort study was conducted at a teaching hospital from 2004 to 2019. The clinical characteristics of patients with meningitis with Carba-NS and carbapenem-susceptible (Carba-S) bacilli were compared, and the antimicrobial chemotherapy regimens and outcomes for Carba-NS Gram-negative bacterial meningitis were analyzed. RESULTS: A total of 505 patients were included, of whom 83.8% were post-neurosurgical patients. The most common isolates were Acinetobacter spp. and Klebsiella spp., which had meropenem-resistance rates of 50.6% and 42.5%, respectively, and showed a markedly growing carbapenem-resistance trend. Kaplan-Meier curve analysis revealed that Carba-NS Gram-negative bacilli were associated with a significantly higher in-hospital mortality rate (18.8%, 35/186) compared to the Carba-S group (7.4%, 9/122; P = 0.001). For Carba-NS Enterobacterales meningitis, aminoglycoside-based and trimethoprim-sulfamethoxazole-based regimens yielded significantly higher clinical efficacy rates than non-aminoglycoside-based and non-trimethoprim-sulfamethoxazole-based regimens (69.0% vs. 38.7%, P = 0.019 and 81.8% vs. 46.9%, P = 0.036, respectively). For Carba-NS A. baumannii complex meningitis, tetracycline-based (including doxycycline, minocycline, or tigecycline) therapy achieved a significantly higher clinical efficacy rate (62.9%, 22/35) than the non-tetracycline-based therapy group (40.4%, 19/47; P = 0.044). CONCLUSIONS: Our findings revealed that Carba-NS Gram-negative bacilli are associated with higher in-hospital mortality in patients with healthcare-associated meningitis. The combination therapies involving particular old antibiotics may improve patients' outcome. TRIAL REGISTRATION: This study was registered on the Chinese Clinical Trial Register under ChiCTR2000036572 (08/2020).

Determine the factors affecting the time to recovery of children with bacterial meningitis at Jigjiga university referral hospital in the Somali Regional State of Ethiopia: using the parametric shared frailty and AFT models.

BACKGROUND: Neisseria meningitides, Streptococcus pneumonia, and hemophilic influenza type B are frequently linked to bacterial meningitis (BM) in children. It's an infectious sickness that kills and severely mobilizes children. For a variety of reasons, bacterial meningitis remains a global public health concern; most cases and deaths are found in Sub-Saharan Africa, particularly in Ethiopia. Even though vaccination has made BM more preventable, children worldwide are still severely harmed by this serious illness. Age, sex, and co-morbidity are among the risk variables for BM that have been found. Therefore, the main objective of this study was to identify the variables influencing the time to recovery for children with bacterial meningitis at Jigjiga University referral hospital in the Somali regional state of Ethiopia. METHOD: A retrospective cohort of 535 children with bacterial meningitis who received antibiotic treatment was the subject of this study. Parametric Shared Frailty ty and the AFT model were employed with log likelihood, BIC, and AIC methods of model selection. The frailty models all employed the patients' kebele as a clustering factor. RESULTS: The number of cases of BM declined in young children during the duration of the 2 year, 11 month study period, but not in the elderly. Streptococcus pneumonia (50%), hemophilic influenza (30.5%), and Neisseria meningitides (15%) were the most frequent causes of BM. The time to recovery of patients from bacteria was significantly influenced by the covariates male patients (ϕ = 0.927; 95% CI (0.866, 0.984); p-value = 0.014), patients without a vaccination history (ϕ = 0.898; 95% CI (0.834, 0.965); P value = 0.0037), and patients who were not breastfeeding (ϕ = 0.616; 95% CI (0.404, 0.039); P-value = 0.024). The recovery times for male, non-breastfed children with bacterial patients are 7.9 and 48.4% shorter, respectively. In contrast to children with comorbidity, the recovery time for children without comorbidity increased by 8.7%. CONCLUSION: Age group, sex, vaccination status, co-morbidity, breastfeeding, and medication regimen were the main determinant factors for the time to recovery of patients with bacterial meningitis. Patients with co-morbidities require the doctor at Jigjiga University Referral Hospital to pay close attention to them.

Fulminant coronavirus disease 2019 meningitis in Iranian infants: a case series.

BACKGROUND: Pediatric coronavirus disease 2019 infection usually presents with respiratory and gastrointestinal symptoms. In this report we present fulminant meningitis as the main presentation of coronavirus disease 2019 without major signs and symptoms of other organs' involvement in 3 infants. CASES: The first case was a 4 months Iranian male infant with fulminant meningitis as the main presentation of coronavirus disease 2019 without other organ involvement. He was treated as suspected bacterial meningitis but CSF PCR and CSF culture were negative for common meningeal pathogens. On 3rd day, his coronavirus disease 2019 PCR test became positive, while it was negative on 1st day. The second case was a 13 months Iranian male infant with fever, irritability, and photophobia for 24 h before poorly controlled status epilepticus. CSF coronavirus disease 2019 PCR became positive while CSF PCR and CSF culture were negative for other common meningeal pathogens. Seizures were controlled with multiple anti-seizure medications. The third case was a 14 months Iranian female infant with fever and seizure1 hour before admission, leading to poorly controlled status epilepticus despite anti-epileptic therapy 10 h after admission. CSF coronavirus disease 2019 PCR became positive while CSF PCR and CSF culture were negative for other common meningeal pathogens. He was controlled with multiple anti-seizure medications. CONCLUSION: Meningitis of coronavirus disease 2019 should be considered in severely ill pediatric cases with poorly controlled seizures and RBC in CSF smear. Also, pediatricians can consider corticosteroids, remdesivir, and IVIG therapy in these cases.

Clinical Picture and Risk Factors for Poor Outcome in Streptococcus pneumoniae Meningitis of Childhood on Three Continents.

BACKGROUND: Streptococcus pneumoniae meningitis (SpM) remains a major health burden worldwide, particularly in low- and middle-income countries. Identifying the patients at highest risk for mortality and disabling sequelae may reveal potentially avoidable predisposing factors and identify patients most in need of intensive care. We searched for factors that do not require laboratory facilities. METHODS: This study was a secondary analysis of prospectively collected data from 5 clinical trials of childhood bacterial meningitis on 3 continents between 1984 and 2017. SpM cases were analyzed by study site and predictors for poor outcome (death or severe sequelae) were identified from the whole series, Latin America and Angola. RESULTS: Among a total of 1575 children (age range: 2 months to 15 years), 505 cases were due to pneumococci. Compared to other etiologies, SpM doubled the death rate (33% vs. 17%) and tripled poor outcome (15% vs. 6%). In SpM, Glasgow Coma Score <13 [odds ratio (OR): 4.73] and previous antibiotics in Angola (OR: 1.70) were independent predictors for death. Predictors for poor outcome were age <1 year (OR: 2.41) and Glasgow Coma Score <13 (OR: 6.39) in the whole series, seizures in Latin America (OR: 3.98) and previous antibiotics in Angola (OR: 1.91). Angolan children had a 17-fold increased risk for poor outcome when compared with Finnish children ( P = 0.011). CONCLUSIONS: Our study proved the severity of SpM when compared with other etiologies. The outcome was especially poor in Angola. Most patients at risk for poor outcome are easily identified by clinical factors on admission.

Development and validation of a novel multiplex digital PCR assay for identification of pathogens in cerebrospinal fluid of children with bacterial meningitis.

BACKGROUND AND AIMS: Identifying the pathogens of bacterial meningitis (BM) is crucial for its diagnosis and treatment. The aim of this study is to develop and validate a novel method for detecting pathogens in cerebrospinal fluid (CSF) of children with BM using a digital polymerase chain reaction (dPCR) assay. MATERIALS AND METHODS: A novel multiplex dPCR assay method has been developed and validated. The diagnostic performance of the dPCR assay was compared with that of synchronous CSF culture, and the factors affecting its performance were analyzed. RESULTS: A total of 69 children with BM were enrolled prospectively. The sensitivity of the dPCR assay was 94.44 %, specificity was 100 %, coincidence rate was 98.55 %, Kappa value was 0.959, and net reclassification improvement was 61.11 %. Compared with the CSF culture assay, the dPCR assay had higher sensitivity in different bacterial groups. Multiple factors affected its performance, including previous use of antibiotics, sampling time, BM complications, and levels of inflammatory biomarkers in CSF and blood (all P < 0.05). Patients who required intensive care and died had a higher bacterial DNA loads identified by dPCR assay (both P < 0.05). CONCLUSION: This novel assay has better pathogen detection ability than CSF culture. Its performance was influenced by sampling time, previous use of antibiotics, and disease severity.

Diagnostic accuracy of clinical and laboratory characteristics in suspected non-surgical nosocomial central nervous system infections.

BACKGROUND: The diagnosis of meningitis in non-surgical hospitalized patients is often difficult and diagnostic accuracy of clinical, laboratory, and radiological characteristics is unknown. AIM: To assess diagnostic accuracy for individual clinical characteristics of patients suspected of non-surgical nosocomial central nervous system (CNS) infections. METHODS: In a prospective multi-centre cohort study in the Netherlands with adults suspected of CNS infections, consecutive patients who underwent a lumbar puncture for the suspicion of a non-surgical nosocomial CNS infection were included. All episodes were categorized into five final clinical diagnosis categories, as reference standard: CNS infection, CNS inflammatory disease, systemic infection, other neurological disease, or non-systemic, non-neurological disease. FINDINGS: Between 2012 and 2022, 114 out of 1275 (9%) patients included in the cohort had suspected non-surgical nosocomial CNS infection: 16 (14%) had a confirmed diagnosis, including four (25%) with bacterial meningitis, nine (56%) with viral CNS infections, two (13%) fungal meningitis, and one (6%) parasitic meningitis. Diagnostic accuracy of individual clinical characteristics was generally low. Elevated CSF leucocyte count had the highest sensitivity (81%; 95% confidence interval (CI): 54-96) and negative predictive value (NPV) (96%; 95% CI: 90-99). When combining the presence of abnormalities in neurological or CSF examination, sensitivity for diagnosing a CNS infection was 100% (95% CI: 79-100) and NPV 100% (95% CI: 78-100). CSF examination changed clinical management in 47% of patients. CONCLUSION: Diagnostic accuracy for individual clinical characteristics was low, with elevated CSF leucocyte count having the highest sensitivity and NPV.

Clinical Characteristics, Treatment, and Outcomes of Veterans with Cerebrospinal Fluid Culture Positive for Gram-Negative Rod Bacteria: A Retrospective Analysis over 18 Years in 125 Veterans Health Administration Hospitals.

Optimal management for patients with bacterial ventriculitis/meningitis due to Gram-negative rods (GNRs) has yet to be well investigated. We assessed the clinical characteristics, treatment, and outcomes of patients with a positive cerebrospinal fluid (CSF) culture for GNRs. We conducted a retrospective cohort study of all patients with a positive CSF culture within the Veterans Health Administration (VHA) system during 2003-2020. Clinical and microbiological characteristics between the true meningitis and contamination groups were compared. Of the 5919 patients with positive CSF cultures among 125 nationwide VHA acute-care hospitals, 297 (5.0%) were positive for GNRs. Among 262 patients analyzed, 156 (59.5%) were assessed as patients with true meningitis, and 106 (40.5%) were assessed as patients with contaminated CSF cultures. Patients with true meningitis had a significantly higher CSF protein (median 168 vs 57 mg/dL, p < 0.001), CSF white blood cell count (median 525 vs 3/µL, p = 0.008) and percentage of neutrophils in CSF (median 88 vs 4%, p < 0.001). Enterobacterales were more common in the true meningitis group, while unidentified GNR or polymicrobial CSF cultures were more common in the contamination group. The all-cause 90-day mortality was 25.0% (39/156) in patients with true meningitis and 10.4% (11/106) in those with contaminated CSF cultures. None of the 11 patients with contaminated CSF cultures who died were considered due to missed meningitis. More than 40% of patients with a positive CSF culture with GNR did not receive treatment without negative consequences. Careful clinical judgment is required to decide whether to treat such patients.

A Rare Case of Meningitis Caused by Streptococcus gallolyticus subsp. pasteurianus in an Immunocompetent Young Adult.

Bacterial meningitis is a life-threatening condition that is mainly caused by Streptococcus pneumoniae and Neisseria meningitis. Although Streptococcus gallolyticus subsp. pasteurianus (Sgp) is also known to cause meningitis, its frequency is quite low, especially in adults. We herein report the first immunocompetent Japanese adult patient (20-year-old woman) with bacterial meningitis caused by Sgp. The patient showed dramatic improvement after antibiotic treatment. Although previous reports have described an association between Sgp infection and an immunosuppressive status, bowel and hepatobiliary diseases, or strongyloidiasis, our case did not demonstrate any of these conditions, suggesting that Sgp can cause meningitis even in young immunocompetent adults.

Noniatrogenic Meningitis Caused by Streptococcus salivarius Associated with Early Esophageal Cancer and Early Gastric Cancer.

Streptococcus salivarius is part of the normal oral cavity and gastrointestinal tract microflora and an unusual cause of acute bacterial meningitis. We herein report an 81-year-old man with S. salivarius meningitis, which led to a diagnosis of early esophageal cancer and early gastric cancer. S. salivarius infection may occur through the gastrointestinal mucosa when it is disrupted in association with early gastrointestinal cancer. To our knowledge, this is the first report describing S. salivarius meningitis associated with multiple early gastrointestinal cancers in the absence of other sources of infection.

Pre-hospital symptoms associated with acute bacterial meningitis differs between children and adults.

Community acquired bacterial meningitis (CABM) is a medical emergency requiring timely appropriate action. More knowledge about pre-hospital symptoms is needed. Retrospective observational study of pre-hospital management in patients with CABM between 2016 and 2021 admitted to a hospital in the Capital Region of Denmark. Reported symptoms were extracted from archived audio files of the initial phone call to emergency medical service. The majority of the 209 patients (82%) were adults. The most common symptoms were altered mental state (58%) and fever (57%), while neck stiffness was less common (9%). Children more often presented with fever, fatigue, rashes, and neck stiffness, while adults more often presented with altered mental state, and leg pain. Most patients (85%) reported at least 1 of the 3 symptoms in the classical triad of meningitis, while 3% reported all 3. Children more often presented at least 2 of 3 symptoms in the triad. One child (3%) and 7 adults (4%) received antibiotics pre-admission. Patients with CABM reported a variety of symptoms that differed significantly in children and adults. The classic triad was rare. Very few patients received antibiotics pre-admission. We suggest that questioning relevant symptoms should be done in febrile or mentally altered patients.

Diagnostic Utility of Cerebrospinal Fluid White Blood Cell Components for the Identification of Bacterial Meningitis in Infants.

BACKGROUND: To evaluate the diagnostic and predictive utility of cerebrospinal fluid (CSF) white blood cell (WBC) components in the diagnosis of bacterial meningitis in infants discharged from the neonatal intensive care unit (NICU). METHODS: We identified a cohort of infants discharged from a Pediatrix NICU between 1997 and 2020 who did not have an immunodeficiency, had at least 1 CSF culture collected within the first 120 days of life, and at least 1 CSF laboratory specimen obtained on the day of culture collection. We only included an infant's first CSF culture and excluded cultures from CSF reservoirs and those growing contaminants or nonbacterial organisms. We examined the utility of CSF WBC components to diagnose or predict bacterial meningitis by calculating sensitivity, specificity, positive and negative predictive values, likelihood ratios, and area under the receiver operating curve (AUC) at different cutoff values for each parameter. We performed subgroup analysis excluding infants treated with antibiotics the day before CSF culture collection. RESULTS: Of the 20 756 infants that met the study inclusion criteria, 320 (2%) were diagnosed with bacterial meningitis. We found (AUC [95% CI]) CSF WBC count (0.76 [0.73-0.79]), CSF neutrophil count (0.74 [0.70-0.78]), and CSF neutrophil percent (0.71 [0.67-0.75]) had the highest predictive values for bacterial meningitis, even when excluding infants with early antibiotic administration. CONCLUSIONS: No single clinical prediction rule had the optimal discriminatory power for predicting culture-proven bacterial meningitis, and clinicians should be cautious when interpreting CSF WBC parameters in infants with suspected meningitis.

The usefulness of hematological parameters and cerebrospinal fluid indexes in the differential diagnosis of acute bacterial from viral meningitis.

Central nervous system (CNS) infection is a medical emergency with an important cause of mortality worldwide. The 79 patients with confirmed acute CNS infection (48 bacterial and 31 viral meningitis) were evaluated. Bacterial meningitis score, cerebrospinal fluid (CSF)/serum glucose ratio, and CSF/serum albumin ratio had the highest area under the curves (0.873, 0.843, 0.810, respectively) for discriminating bacterial meningitis. Neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte ratio (PLR) and CSF lactate dehydrogenase have a good ability for the differential diagnosis of bacterial meningitis. CSF/serum glucose ratio, NLR (with a cut-off value> 8.87), large unstained cell, total protein, albumin, and procalcitonin levels were found to be predictors for mortality. NLR can be used as a biomarker to differentiate bacterial meningitis from viral meningitis and to predict the prognosis of CNS infection. CSF/serum albumin ratio and CSF lactate dehydrogenase can be used to predict bacterial meningitis as well as CSF/serum glucose ratio.

Cerebrospinal Fluid Lactate as a Differential Biomarker for Bacterial and Viral Meningitis.

Meningitis is a critical public health problem demanding immediate diagnosis and effective treatment due to high mortality rates. Cerebrospinal Fluid (CSF) lactate concentration is a promising test to distinguish bacterial from viral meningitis. This study aimed to assess the performance and usefulness of CSF lactate as a biomarker to differentiate between bacterial and viral meningitis, and to determine its optimal level to differentiate between them. This prospective study included 50 patients, presented to Abbassia Fever Hospital with clinical findings consistent with meningitis. Patients were divided into two groups: Group1 included 30 patients with bacterial meningitis. Group 2 included 20 patients with viral meningitis. CSF lactate and other conventional CSF parameters were recorded. For CSF culture, Streptococcus pneumoniae was identified in 53.3% of the bacterial meningitis group. The polymerase chain reaction (PCR) indicated that S. pneumoniae was present in 26/50 (52%) and 3/50 (6%) patients were PCR negative. Among bacterial meningitis patients, S. pneumoniae was the most pervasive organism 26/30 (86.7%). The mean CSF lactate level was 9.3 mmol/l ±5.0 (2.2-17.6). There was a statistically significant strong agreement (Kappa=0.957) between types of meningitis diagnosed by PCR, culture, and CSF lactate at cutoff level of 7.2 mmol/L. This cutoff value was the best to differentiate between bacterial and viral meningitis. The validity of CSF lactate as a differentiating tool showed sensitivity, specificity, positive predictive value, and negative predictive value of 93.3%, 100%, 100%, and 90.9%, respectively. In conclusion, CSF lactate could be a valuable, sensitive, specific, and rapid marker for identifying the most dangerous bacterial causes of CNS infection, especially S. pneumoniae. CSF lactate can be routinely used as an early biochemical warning marker and a useful point-of-care test. CSF lactate at cutoff level of >7.2 mmol/L can accurately detect S. pneumoniae, the most prevalent organism in Egypt.

Purulent meningitis and secondary epilepsy caused by Mycobacterium iranicum infection: A case report.

Mycobacterium iranicum is characterized by rapid growth and orange-pigmented scotochromogenic colonies. However, it is uncommon for M. iranicum to invade the central nervous system. A man nearly 60 years old was referred to our hospital because of a seizure and unconsciousness. After admission, the patient had fever and dizziness without obvious abnormalities in the cerebrospinal fluid, except for an increase in neutrophils. Metagenomic next-generation sequencing and DNA testing were positive for M. iranicum. The patient was treated with imipenem, minocycline, moxifloxacin, and linezolid, and he gradually recovered during follow-up.

Neonatal Meningitis-Causing Escherichia coli Induces Microglia Activation which Acts as a Double-Edged Sword in Bacterial Meningitis.

Bacterial meningitis is a devastating disease occurring worldwide, with up to half of survivors left with permanent neurological sequelae. Neonatal meningitis-causing Escherichia coli (NMEC) is the most common Gram-negative bacillary organism that causes meningitis, particularly during the neonatal period. Here, RNA-seq transcriptional profiles of microglia in response to NMEC infection show that microglia are activated to produce inflammatory factors. In addition, we found that the secretion of inflammatory factors is a double-edged sword that promotes polymorphonuclear neutrophil (PMN) recruitment to the brain to clear the pathogens but, at the same time, induces neuronal damage, which may be related to the neurological sequelae. New neuroprotective therapeutic strategies must be developed for the treatment of acute bacterial meningitis. We found that transforming growth factor-ß (TGF-ß) may be a strong candidate in the treatment of acute bacterial meningitis, as it shows a therapeutic effect on bacterial-meningitis-induced brain damage. Prevention of disease and early initiation of the appropriate treatment in patients with suspected or proven bacterial meningitis are the key factors in reducing morbidity and mortality. Novel antibiotic and adjuvant treatment strategies must be developed, and the main goal for new therapies will be dampening the inflammatory response. Based on this view, our findings may help develop novel strategies for bacterial meningitis treatment.

A Refined, Controlled 16S rRNA Gene Sequencing Approach Reveals Limited Detection of Cerebrospinal Fluid Microbiota in Children with Bacterial Meningitis.

Advances in both laboratory and computational components of high-throughput 16S amplicon sequencing (16S HTS) have markedly increased its sensitivity and specificity. Additionally, these refinements have better delineated the limits of sensitivity, and contributions of contamination to these limits, for 16S HTS that are particularly relevant for samples with low bacterial loads, such as human cerebrospinal fluid (CSF). The objectives of this work were to (i) optimize the performance of 16S HTS in CSF samples with low bacterial loads by defining and addressing potential sources of error, and (ii) perform refined 16S HTS on CSF samples from children diagnosed with bacterial meningitis and compare results with those from microbiological cultures. Several bench and computational approaches were taken to address potential sources of error for low bacterial load samples. We compared DNA yields and sequencing results after applying three different DNA extraction approaches to an artificially constructed mock-bacterial community. We also compared two postsequencing computational contaminant removal strategies, decontam R and full contaminant sequence removal. All three extraction techniques followed by decontam R yielded similar results for the mock community. We then applied these methods to 22 CSF samples from children diagnosed with meningitis, which has low bacterial loads relative to other clinical infection samples. The refined 16S HTS pipelines identified the cultured bacterial genus as the dominant organism for only 3 of these samples. We found that all three DNA extraction techniques followed by decontam R generated similar DNA yields for mock communities at the low bacterial loads representative of CSF samples. However, the limits of detection imposed by reagent contaminants and methodologic bias precluded the accurate detection of bacteria in CSF from children with culture-confirmed meningitis using these approaches, despite rigorous controls and sophisticated computational approaches. Although we did not find current DNA-based diagnostics to be useful for pediatric meningitis samples, the utility of these methods for CSF shunt infection remains undefined. Future advances in sample processing methods to minimize or eliminate contamination will be required to improve the sensitivity and specificity of these methods for pediatric meningitis. IMPORTANCE Advances in both laboratory and computational components of high-throughput 16S amplicon sequencing (16S HTS) have markedly increased its sensitivity and specificity. These refinements have better delineated the limits of sensitivity, and contributions of contamination to these limits, for 16S HTS that are particularly relevant for samples with low bacterial loads such as human cerebrospinal fluid (CSF). The objectives of this work were to (i) optimize the performance of 16S HTS in CSF samples by defining and addressing potential sources of error, and (ii) perform refined 16S HTS on CSF samples from children diagnosed with bacterial meningitis and compare results with those from microbiological cultures. We found that the limits of detection imposed by reagent contaminants and methodologic bias precluded the accurate detection of bacteria in CSF from children with culture-confirmed meningitis using these approaches, despite rigorous controls and sophisticated computational approaches.

Prevalence, aetiology, vaccination coverage and spatio-temporal pattern among patients admitted with acute bacterial meningitis to the sentinel hospital surveillance network in Yemen, 2014-20, before and during the civil war.

BACKGROUND: Acute bacterial meningitis (ABM) is a serious health issue in Yemen where civil war, which continues unabated, has crippled the healthcare system. We conducted a nationwide retrospective observational study in Yemeni sentinel hospitals to identify the prevalence, aetiology, vaccination coverage and spatio-temporal pattern of ABM in children aged <5 years before and during the civil war, 2014-20. METHODS: Cerebrospinal fluid samples were collected from hospitalized children and were analysed macroscopically for appearance and microscopically by Gram stain and white blood cell count. Culture and latex agglutination tests were performed. Data on the prevalence of and vaccination coverage for ABM were obtained from the Ministry of Health. Joinpoint regression was used to assess the annual percent change (APC) of ABM prevalence and vaccination coverage. Pearson's correlation was used to evaluate the association between ABM prevalence and vaccination coverage. RESULTS: In total, 11 339 hospitalized children had suspected cases of ABM (prevalence, 40.07/100 000 of the whole Yemeni population) and 2.6% (293/11 339) of suspected ABM cases were confirmed (prevalence, 1.04/100 000 of the whole Yemeni population). The dominant pathogens were Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b (Hib). The civil war reduced the Hib and pneumococcal vaccination coverage (APC = -1.92), reaching its lowest (79.5%) in 2018. The prevalence of suspected ABM increased (APC = 3.46), reaching its maximum (6.08/100 000 of the whole Yemeni population) in 2019. The conflict inversely correlated with the ABM prevalence and vaccination coverage (Pearson correlation coefficient (r), -0.69 to -0.53). Ta'izz region, which was severely affected by the civil war, had the highest prevalence of suspected ABM (120.90/100 000 of the whole Yemeni population) and lowest vaccination coverage (60%). CONCLUSIONS: The civil war had a negative impact on vaccination coverage and coincided with increasing prevalence of ABM in Yemen. Streptococcus pneumoniae is the dominant causative pathogen.

Inactive Trojan Bacteria as Safe Drug Delivery Vehicles Crossing the Blood-Brain Barrier.

Escherichia coli K1 (EC-K1) can bypass the blood-brain barrier (BBB) and cause meningitis. Excitingly, we find the "dead EC-K1" can safely penetrate the BBB because they retain the intact structure and chemotaxis of the live EC-K1, while losing their pathogenicity. Based on this, we develop a safe "dead EC-K1"-based drug delivery system, in which EC-K1 engulf the maltodextrin (MD)-modified therapeutics through the bacteria-specific MD transporter pathway, followed by the inactivation via UV irradiation. We demonstrate that the dead bacteria could carry therapeutics (e.g., indocyanine green (ICG)) and together bypass the BBB after intravenous injection into the mice, delivering ∼3.0-fold higher doses into the brain than free ICG under the same conditions. What is more, all mice remain healthy even after 14 days of intravenous injection of ∼109 CFU of inactive bacteria. As a proof of concept, we demonstrate the developed strategy enables the therapy of bacterial meningitis and glioblastoma in mice.