Pomar et al. BMC Infectious Diseases (2020) 20:292 https://doi.org/10.1186/s12879-020-05023-5 RESEARCH ARTICLE Open Access Characteristics and outcome of spontaneous bacterial meningitis in patients with diabetes mellitus Virginia Pomar1*, Natividad de Benito1, Albert Mauri2, Pere Coll3, Mercè Gurguí1 and Pere Domingo1 Abstract Background: Studies on bacterial meningitis in diabetics patients versus non-diabetics are scarce. In patients with diabetes, bacterial meningitis may have a different presentation, etiology and course. We analyzed and compared the characteristics and outcome of spontaneous BM in adult patients with and without diabetes mellitus (DM). Methods: We performed a single-center, prospective observational cohort study, conducted between 1982 and 2017, in a tertiary university hospital in Barcelona (Spain). The primary outcome measure was in-hospital mortality. Results: We evaluated 715 episodes of bacterial meningitis; 106 patients (15%) had diabetes mellitus. Patients with diabetes were older (median 67 [IQR 17] vs 49 [IQR 40] years, p < 0.001) and more often had a Charlson comorbidity score of ≥3 (40% vs 15%, p < 0.001). Neck stiffness (56% vs 75%, p < 0.001), headache (41% vs 78%) p < 0.001), nausea and/or vomiting (32% vs 56% p < 0.001), and rash (12% vs 26%, p = 0.007) were less frequent in diabetics, whereas altered mental status was more common. Streptococcus pneumoniae and Listeria meningitis were the most common etiologic agents (24 and 18%, respectively). Listeria was more frequent (18% vs. 10%, p = 0.033), whereas meningococcal meningitis was less frequent (10% vs 32%, p < 0.001). Overall mortality was higher in patients with diabetes (26% vs 16%, p = 0.025) concerning non-diabetics. Conclusions: Patients with bacterial meningitis and diabetes mellitus are older, have more comorbidities, and higher mortality. S. pneumoniae and L. monocytogenes are the predominant pathogens, Listeria being more common, whereas Neisseria meningitidis is significantly less frequent than in non-diabetics. Keywords: Spontaneous meningitis, Bacterial meningitis, Bacterial infection of the central nervous system, Diabetes mellitus Background depends on the patient‘s age, geography, and season of Bacterial meningitis (BM) remains a significant cause of the year. Lately, vaccines against meningeal pathogens infection-related death worldwide [1, 2]. In industrialized have shown a meaningful impact, and will hopefully fur- countries, its estimated annual incidence is 4–6 cases ther modify this scenario shortly [7]. per 100,000 adults, and Streptococcus pneumoniae The International Diabetes Federation estimated that followed by Neisseria meningitidis rank first among the there were almost 400 million people living with dia- causative agents [1–6]. The prevalence of BM mainly betes mellitus (DM) around the world in 2016. Its preva- lence is expected to increase to more than 590 million * Correspondence: vpomar@santpau.cat people by the year 2035 [8]. There is a positive associ- 1 Infectious Diseases Unit (Department of Internal Medicine), Hospital de la Santa Creu i Sant Pau – Institut d’Investigació Biomèdica Sant Pau. ation between diabetes and the development of several Universitat Autònoma de Barcelona, Barcelona, Spain types of infection. Many aspects of immunity are altered Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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BMC Infectious Diseases (2020) 20:292 Page 2 of 9 in patients with DM, because hyperglycemia decreases The ethics committee approved the study and its sub- neutrophil and monocyte function, including impaired sequent amendments of the Hospital de la Santa Creu i chemotaxis, adherence, and phagocytosis. Therefore, Sant Pau. Verbal informed consent was obtained from patients with diabetes tend to be hospitalized for infec- all participants (patients, parents, or guardians) because tions more frequently than non-diabetics [9–16]. of the years and the kind of the study. Our ethic com- The incidence of spontaneous BM in diabetic patients mittee accepts this situation. is unknown since most of the previous reports have combined spontaneous and post-neurosurgical menin- Diagnosis gitis, or diabetes has not been the focus of the study The diagnosis of culture-proven BM was made on the [9, 17–19]. A recent study describes community- basis of consistent clinical findings, a positive CSF culture. acquired bacterial meningitis in patients with and If CSF culture was negative, culture-proven BM could still without diabetes, but this study focused on be diagnosed with CSF neutrophilic pleocytosis (= > 100 community-acquired, culture-proven meningitis [20]. neutrophils/cu mm), a positive CSF antigen test, or a posi- In our study, we included nosocomial infections and tive blood culture. Meningococcal meningitis was diag- also unknown etiology BM. The underrepresentation nosed, in addition to those culture-proven, in patients of these patients in the Netherland cohort may lead with CSF gram-negative diplococci identified together to prevalence and mortality underestimation. with with a petechial or purpuric rash and a fulminant In previous studies we observed that DM increases course [27]. among older patients, and that DM was the associated Unknown etiology BM was diagnosed in patients with comorbidity in 13% of adults [4, 21]. a compatible clinical picture together with neutrophilic Moreover, compared to non-diabetic patients, the pleocytosis and decreased CSF glucose (defined as CSF/ presentation and course of common infections in dia- blood glucose ratio < 0.40) or elevated CSF proteins betic patients may vary, leading to a possible delay in (defined as > 0.5 g/l) [3, 6, 28]. diagnosis and therapy. The causative organisms may also Patients with a history of neurosurgical procedures or differ from those identified in the general population, traumatic head/spinal injuries and cases of viral, fungal, depending on the glycemic control, local nosocomial or mycobacterial meningitis were excluded. trends, and specific vulnerabilities created by other asso- ciated underlying comorbidities, such as alcoholism and Microbiology methods cancer or DM-related complications [18–20]. Diabetic Isolate identification and susceptibility tests performance patients seem to be at particularly high risk of infection have been described elsewhere [4, 21, 25, 26, 29–31]. with certain bacterial microorganisms, such as Strepto- coccus agalactiae, Klebsiella spp, Salmonella enteritidis, Definitions and Staphylococcus aureus [22–24]. Majority of the variables have been defined in other pub- Our study aims to compare BM characteristics and lished works [4, 21, 25, 26]. outcome in patients with and without DM for 36 years. The Charlson Comorbidity Index was used to assess Such a piece of knowledge may improve the medical comorbidity [32, 33]. Comorbid conditions were consid- management, prognosis, and mortality of these patients. ered to be present if the patient had a confirmed diagno- sis of one or more. A diagnosis of DM was based on information provided Methods by the patient or his/her family, recorded on medical Setting and study population charts or due to the presence of diagnostic criteria for We collected data from 1982 through 2017 at the DM at the time of admission (glycosylated hemoglobin Hospital de la Santa Creu i Sant Pau (Barcelona, Spain), [HbA1c] ≥ 6.5% or a fasting plasma glucose level ≥ 126 a 540-bed tertiary university hospital serving an esti- mg/dl [7 mmol/L] or the 2-h plasma glucose value after mated population of 450,000 in a predominantly urban 75 g oral glucose tolerance test > 200 mg/dl [11,1 mmol/ area. We included all consecutive adult patients (> 14 L] or in a patient with classic symptoms of hypergly- years) with spontaneous bacterial meningitis. cemia [polyuria, polydipsia or polyphagia] or hypergly- The characteristics of this cohort have been described cemic crisis, random plasma glucose ≥200 mg/dL [11.1 elsewhere [4, 21, 25, 26], and also how we identified the mmol/L]) [34]. We included type 1 and 2. cases. Data were collected during the hospitalization and A primary distant focus of infection was considered the patient was monitored after discharge by one of the when a patient had clinical symptoms and signs consist- authors (PD or VP). Follow-up always included a neuro- ent with a focal infection distant from the central ner- logical exam, neuropsychological testing, complement, vous system, and the same pathogenic bacterium was and immunoglobulin levels, and audiometry. isolated from the primary focus of infection or a blood Pomar et al. BMC Infectious Diseases (2020) 20:292 Page 3 of 9 culture. Communication of the subarachnoid space with systemic inflammatory response syndrome (SIRS) to the skin, sinuses, or mucosal surfaces, and upper respira- infection with 2 or more of temperature > 38 °C or < tory tract infection (frequent in meningococcal disease) 36 °C, heart rate > 90, respiratory rate > 20/min or were not considered distant foci of infection [24]. pCO2 < 32 mmHg or white blood cell count > 12,000/ The symptoms-admission interval (SAI) was the mm3 or < 4000/mm3 or > 10% immature bands. Septic interval, in hours, between onset of signs and symptoms shock was defined as sepsis induced hypotension persist- of BM and admission to hospital was. When the onset of ing despite adequate fluid resuscitation. Disseminated symptoms could not be precisely determined, we calcu- intravascular coagulation is primarily a laboratory diag- lated the mean interval between the last time the patient nosis, based on the combination of elevated fibrin- was asymptomatic, observed by a household member, related markers (FRM), with decreased procoagulant and the first time the patient was seen ill [35]. factors and platelets. The admission-therapy interval (ATI) was the inter- Sequelae were defined as any disability, disorder, or val, in hours, between hospital admission and first dose injury demonstrated during hospital stay or upon dis- of antibiotics for the treatment of meningitis. charge from hospital that was not present before the Impaired mental status, seizures and focal neurological episode of BM and persisted at 6 months after dis- signs (motor, sensory or cranial nerve disturbances) charge [42]. detected on admission or subsequently were considered neurological complications. Coma was defined as a Statistical analysis score of 6 or less on the Glasgow Coma Scale in the Qualitative variables were expressed as absolute num- absence of sedation [36]. bers and percentages, whereas quantitative variables The development of septic shock, acute respiratory were expressed as means and standard deviation (SD). failure, acute renal failure, and/or consumption coagu- The comparison of continuous variables was per- lopathy was considered a systemic complication if it formed through Student’s t-test or Mann-Whitney U was related to bacterial meningitis and was apparent on test, whereas categorical data were compared by c2 test admission or shortly afterwards [24, 37]. or Fisher’s exact test. Adequate antibiotic treatment was defined as the Independent predictive factors for mortality were intravenous administration of any antimicrobial agents explored through logistic regression analysis with adjust- to which isolated bacteria were sensitive following sus- ment for clinically relevant covariates was used, and the ceptibility testing at local laboratories, which crossed the outcome shown sed as adjusted odds ratios. The propor- blood-brain barrier in adequate amounts, were adminis- tion of the total variation of the outcome explained by a tered in a dose recommended for acute BM treatment model was assessed through Nagelkerke’s R2. and commenced on the day of admission or before All the tests were two-tailed. Significance was estab- deterioration of neurological and systemic conditions in lished by a p-value < 0.05. Statistical Product and Service inpatients [24, 38, 39]. Solutions (SPSS) software, version 19 (SPSS Inc., Chi- Dexamethasone therapy was only considered when its cago, IL) was used for all the statistical calculations. first dose of at least 10 mg/24 h was administered prior to or concomitant with the first antibiotic dose. Steroids Results administered after starting antibiotic therapy were not During the 36-year study period we diagnosed 715 epi- considered [40]. sodes of spontaneous acute bacterial meningitis. The Nosocomial meningitis was defined as developing median age were 55 years (IQR 38) and etiology was more than 48 h after admission or within one week of established in 583 cases (81.5%). N. meningitidis was the discharge [41]. most common microorganism overall (28.7%), followed Inpatient mortality was considered to be due to BM by S. pneumoniae (25.6%), L. monocytogenes (11.6%) and when meningitis was the underlying and immediate gram-negative bacilli other than Haemophilus influenzae cause of death. BM-related death was defined and (5.9%). recorded if there were no other cause and if there were Of these 715 adults included in the study, 106 (15%) agreement between the reviewing physician and the had diabetes mellitus: 45 (42%) diagnosed between 1982 underlying cause of death recorded on the medical and 1999, and 61 (58%) between 2000 and 2017 (p < records. We classified the causes of death in two 0.002). categories: neurological causes (intractable seizures, brain herniation, cerebrovascular complications or Characteristics of spontaneous bacterial meningitis (BM) coma) and systemic causes (septic shock, respiratory in patients with diabetes mellitus failure, disseminated intravascular coagulation or mul- The demographic characteristics and clinical features of tiple organ failure) [37, 42]. Sepsis resulted from a host’s the population are summarized in Table 1. Patients with Pomar et al. BMC Infectious Diseases (2020) 20:292 Page 4 of 9 Table 1 Demographics and clinical features of spontaneous bacterial meningitis episodes in diabetic patients Characteristics Diabetic Patients Other Patients P value (n = 106) (n = 609) Male sex 53 (50) 298 (48.9) 0.916 Age – years, median (IQR) 67 (17) 49 (40) < 0.001 Recurrent meningitis 6 (5.7) 26 (4.3) 0.455 Comorbid conditionsa 106 (100) 284 (46.6) < 0.001 • Hypertension 19 (17.9) 61 (10) 0.028 • Cancer 17 (16) 89 (14.8) 0.541 • Chronic lung disease b 13 (8.2) 39 (6.4) 0.098 • Alcoholism 11 (7.2) 55 (9) 0.210 Charlson comorbidity index ≥3 42 (39.6) 90 (14.8) < 0.001 Distant focus of infection 41 (38.7) 200 (32.8) 0.266 Route of acquisition • Hospital-acquired (vs. community-acquired) 4 (3.8) 28 (4.6) 1.000 Symptoms on presentation • Fever 100 (94.3) 579 (95.1) 0.849 • Altered mental status 83 (78.3) 383 (62.9) 0.009 • Neck stiffness 59 (55.7) 458 (75.2) < 0.001 • Triad of fever, neck stiffness, and change in mental status 44 (41.5) 282 (46.3) 0.577 • Headache 44 (41.5) 473 (77.7) < 0.001 • Nausea and/or vomiting 34 (32.1) 340 (55.8) < 0.001 • Focal neurological deficits 25 (23.6) 100 (16.4) 0.095 • Coma 21 (19.8) 94 (15.4) 0.254 • Seizures 10 (9.4) 49 (8) 0.819 • Rash 13 (12.3) 160 (26.3) 0.007 • Systolic blood pressure – mm Hg (SD) 140 (32) 128 (30) < 0.001 • Diastolic blood pressure – mm Hg (SD) 80 (19) 75 (20) 0.004 Interval symptoms-admission, hours (IQR) 25 (51.7) 24 (28) 0.184 Interval admission-therapy, hours (IQR) 4 (9) 3 (8) 0.821 Prior antimicrobial therapy 28 (26.4) 185 (30.4) 0.647 Cerebral computed tomography 45 (42.5) 192 (31.5) 0.039 White blood cell count, median (IQR) 15,025 (8525) 15,300 (10650) 0.704 Platelet count/mm3, median (IQR) 206,000 (252275) 189,500 (120750) 0.715 a b Patients may have more than one co-morbid condition. Includes: chronic bronchitis, asthma, idiopathic pulmonary fibrosis, other pneumopathies. CI confidence interval. IQR interquartile range, SD standard deviation Values are reported as no. / no. evaluated (%), unless otherwise noted DM were older and have a Charlson comorbidity score A distant focus of infection was present in 41 of the of ≥3 more often than non-diabetics. When the Charlson 106 episodes (39%), with otitis or sinusitis (12 episodes, score was recalculated excluding DM without and with 11%), upper respiratory tract infection (7 episodes, 7%) end-organ failure, the comorbidity score for the two and pneumonia (6 episodes, 6%) being the most fre- groups was similar (Charlson comorbidity index ≥3 was quently diagnosed distant foci. 18/106 [17%] in diabetic patients versus 89/609 [15%], Altered mental status was more frequent among pa- p = 0.555). tients with DM than among non-diabetics, whereas neck Hypertension and cancer were the most common stiffness, headache, nausea, and rash were less frequent. underlying conditions in these patients. The median blood glucose level in people with DM Diagnosis and microbiology was 12.4 mmol/l (IQR 7.6), statistically higher than in Lumbar puncture was performed in all episodes, and the non-diabetics: 7.4 mmol/l (IQR 2.9), p < 0.001. CSF showed at least one CSF finding suggestive of acute Pomar et al. BMC Infectious Diseases (2020) 20:292 Page 5 of 9 bacterial meningitis: increased protein levels in 103 cases statistically different from the rest of the population (97%), a decreased CSF glucose/blood glucose ratio in 83 (Table 1). cases (78%), and pleocytosis with an elevated neutrophil Initial empirical antibiotic treatment was appropriate count in 100 cases (94%). CSF cyto-biochemical findings in 93 patients with diabetes (88%), being less frequent, did not differ significantly between the two groups of although not statistically significant, than for non- patients (Table 2). On the contrary, blood cultures were diabetic patients (93%, p = 0.109) (Table 3). There was more frequently positive in diabetic patients (63% vs. no difference between the 2 periods (37 [40%] vs. 56 45%, p < 0.001) (Table 2). [60%], p = 0.230). The most organisms not adequately The most common organisms were S. pneumoniae covered by initial empiric therapy were L.monocytogenes, (24% in people with DM vs. 25% in non-diabetic Pseudomonas aeruginosa, and Staphylococcus aureus. patients, p = 0.632) followed by L. monocytogenes (18% The median duration of antibiotic treatment was 15 vs. 10%, respectively, p < 0.033). There were only 11 days (IQR 11). (10%) cases of meningococcal meningitis, which was There was no difference between the two groups in significantly more common in non-diabetic patients (194 the administration of adjunctive steroids before or to- episodes, 32%, p < 0.001). S. agalactiae was detected in 9 gether with the first dose of antibiotic treatment (37% diabetic patients (8.5%) and in 6 non-diabetic patients vs. 36%, p = 0.910). (0.98%), with OR = 9.32 (2.88–32.42), p < 0.001. (Table 2). The etiologic spectrum of BM did not vary significantly Outcome between the two periods of the study except for listerial Neurological complications were not different between meningitis, which was more frequent in the second period: patients with and without DM. However, the presence of 3 (7%) vs. 16 (26%) cases (p = 0.01). focal neurological deficits after discharge (between survi- vors) was more frequent in diabetics (7.5% vs. 3.1%, p = Treatment 0.046) (Table 3). There was a high number of patients with DM having Systemic complications were also more frequent in received out-of-hospital antibiotic therapy, although not diabetics (45% vs. 30%, p = 0.024). Table 2 CSF findings, microbiologic features and etiology of bacterial meningitis in diabetic patients Characteristics Diabetic Patients Other Patients P value (n = 106) (n = 609) CSF examination • White blood cell count, median (IQR) 960 (2672) 1008 (2670) 0.723 • Protein, g/l, median (IQR) 3.2 (6.4) 3.4 (4.75) 0.445 • CSF/plasma glucose ratio, median (IQR) 0.31 (0.36) 0.21 (0.36) 0.079 Positive CSF gram-stained smear 37 (34.9) 255 (41.9) 0.57 Positive CSF culture 81 (76.4) 429 (70.4) 0.39 Positive blood culture 67 (63.2) 273 (44.8) < 0.001 Etiology • Meningococcal 11 (10.4) 194 (31.9) < 0.001 • Pneumococcal 26 (24.5) 154 (25.3) 0.632 • Listeria and gram-positive bacillia 19 (17.9) 64 (10.5) 0.033 • Gram-negative bacillib 10 (9.4) 32 (5.3) 0.114 • Haemophilus influenza 3 (2.8) 16 (2.6) 0.753 • Otherc 17 (16) 30 (4.9) < 0.001 • Mixedd 0 (0) 4 (0.7) 1.000 • Unknown origin 16 (15.1) 115 (18.9) 0.415 Gram-positive bacillia: Listeria monocytogenes (79) and Bacillus spp. (4). Gram-negative bacillib: Escherichia coli (17), Pseudomonas aeruginosa (9), Pseudomonas spp (3), Klebsiella spp (2), Proteus mirabilis (2), Serratia marcescens (1), Serratia spp (2), Enterobacter cloacae (1), Citrobacter freundii (1), Bacteroides melaninogenicus (1), Acinetobacter baumannii (1), Fusobacterium (1). Otherc: S. agalactiae (9), Staphylococcus aureus (8), Enterococcus faecalis (3), S. pyogenes (3), S. viridans (3), Brucella spp (2), Neisseria subflava (1), Staphylococcus anginosus (1), Staphylococcus lugdunensis (1), Staphylococcus spp. (19, Group G Streptococcus (1). Mixed meningitisd: Bacteroides intermedius + Streptococcus viridans (1), E.cloacae + S.viridans (1), Peptostreptococcus spp + anaerobic unidentified gram negative bacilli (1), and Peptostreptococcus spp + Bacteroides spp (1) CI confidence interval, IQR interquartile range, SD standard deviation, CSF cerebrospinal fluid Values are reported as no./no. evaluated (%), unless otherwise noted Pomar et al. BMC Infectious Diseases (2020) 20:292 Page 6 of 9 Table 3 Evolving features and outcome of bacterial meningitis in diabetic patients Characteristics Diabetic Patients Other Patients P value (n = 106) (n = 609) Neurological complications 31 (29.2) 123 (20.2) 0.210 • Coma 21 (19.8) 94 (15.4) 0.254 • Seizures 18 (17) 70 (11.5) 0.148 • Focal neurological deficits 8 (7.5) 19 (3.1) 0.046 • Cranial palsies 7 (6.6) 28 (4.6) 0.337 Systemic complications 48 (45.3) 184 (30.2) 0.024 • Acute respiratory failure 28 (26.4) 103 (16.9) 0.029 • Acute kidney failure 27 (25.5) 72 (11.8) < 0.001 • Septic shock 19 (17.9) 88 (14.4) 0.376 • Disseminated intravascular coagulation 11 (10.4) 47 (7.7) 0.677 • Rhabdomyolysis 6 (5.7) 22 (3.6) 0.286 Therapeutics • Adequate empiric antibiotic therapy 93 (87.7) 568 (93.3) 0.109 • Dexamethasone therapy 39 (36.8) 220 (36.1) 0.910 • Vasoactive drugs 17 (16) 77 (12.6) 0.350 • Mechanical ventilation 17 (16) 88 (14.4) 0.839 • Dialysis 3 (2.8) 15 (2.5) 0.895 Outcome • Neurological sequelae 8 (7.5) 19 (3.1) 0.046 • In-hospital mortality 27 (25.5) 97 (15.9) 0.025 CI confidence interval, IQR interquartile range, SD standard deviation Values are reported as no./no. evaluated (%), unless otherwise noted The overall mortality rate was significantly higher in meningitis were present less often than in non-diabetics. patients with DM (25% vs. 16%, p = 0.025) (Table 3), The reason could be the immunosuppression, but also being higher in the first study period (18 between 1982 to the fact that this group is older and with other under- and 1999 (66.7%) vs. 9 between 2000 and 2017 (33.3%), lying diseases, both factors being associated with atypical p = 0.006). The BM-attributable death in diabetic presentations [21]. Despite the complex immune system patients was 52%, and among non-diabetics was 63% dysfunction associated with diabetes, our patients (p = 0.72). The mean number of days until death did not displayed increased white cell blood counts. differ between diabetic and non-diabetic patients (14 vs. There are significant differences in the regional distri- 15, p = 0.857). Independent factors associated with an bution of the etiological agents of BM [43], and the unfavorable outcome by multivariate analysis included: available vaccines have led to further changes in the septic shock, coagulation disorder, age 65 or older, acute etiologic spectrum of bacterial meningitis. In our investi- renal failure, the periods of the study, and gram-negative gation, S. pneumoniae was the most frequent pathogen bacillary etiology. Diabetes was not associated with in patients with DM, while L. monocytogenes ranked higher mortality (Table 4). second, and it was much more frequent than in patients without diabetes. The main risk factors for listerial men- Discussion ingitis are age (newborns an elderly), pregnancy, cancers Diabetes mellitus is steadily increasing in western soci- and immunosupression [5, 21, 44, 45]. Given the eties, and its association with the development of several complex immunosuppression caused by DM, this finding types of infection is well-known [4, 8, 11, 16, 19–21]. On was expectable. Some other uncommon pathogens have the other hand, common infections in diabetic patients been described [18, 19]. In our study N.meningitidis is may be caused by unusual pathogens, and the presenta- uncommon in diabetic patients concerning other tion and course may be different from those without patients, so diabetes mellitus does not seem to be a DM, which may delay the correct diagnosis and the predisposing condition for meningococcal meningitis. adequate therapy [9–15, 17–19]. However, it is logical to see that diabetes can be present Previous studies, as well as our own, have shown an in older adults who have meningococcal meningitis, and increased frequency of BM in patients with DM over the most likely, this is a product of age together with the 36-year study period [16, 20], but in contrast to a study age-dependent trend in the incidence of meningococcal by van Veen KEB, et al. [20] the classic symptoms of disease. Pomar et al. BMC Infectious Diseases (2020) 20:292 Page 7 of 9 Table 4 Multivariate analysis for effect on unfavorable outcome Variable Odds Ratio 95% CI P value Septic shock 8.896 4.272–18.527 <0.001 Coagulation disorder 4.108 1.585–10.646 0.004 Age (≥65 years) 2.311 1.352–3.950 0.002 Acute renal failure 2.238 1.206–4.152 0.011 Impaired mental status 1.612 0.797–3.261 0.184 Charlson comorbidity index ≥3 1.594 0.902–2.818 0.109 Positive CSF culture 1.219 0.596–2.492 0.588 Positive blood culture 1.223 0.689–2.170 0.493 Triad of fever, neck stiffness, and change in mental status 0.801 0.443–1.450 0.464 Diabetes mellitus 0.762 0.398–1.460 0.413 White cell count in CSF > 1000/mm3 0.664 0.390–1.132 0.132 Period time 0.552 0.317–0.962 0.036 Adequate empiric antibiotic therapy 0.270 0.129–0.565 0.001 Etiology • Neisseria meningitidis 1.000 (reference) • Streptococcus pneumoniae 1.045 0.463–2.359 0.916 • Listeria monocytogenes 1.150 0.483–2.738 0.753 • Gram-negative bacilli 2.893 1.043–8.027 0.041 CI confidence interval. Nagelkerke’s R2 for the adjusted model = 0.446 On the other hand, S. agalactiae was detected more imaging before lumbar puncture: focal neurological defi- frequently in diabetic patients. The rate of S. agalactiae cits, new-onset seizures, severely altered mental status, infections in adults is thought to be increasing, with an and severely immunocompromised state [39]. Following estimated twofold to fourfold increase in its incidence in these guidelines, most of the cerebral computed tomog- non-pregnant adults reported in the past two decades raphy performed in our patients was unnecessary. [24]. Though infrequent, S. agalactiae has emerged as In diabetic patients, if the CSF Gram stain is negative, an outstanding etiologic agent of bacterial meningitis in or it not seems a pneumococcal meningitis, empiric anti- adults with severe co-morbid conditions [24]. biotic coverage should always be directed at L. monocy- Moreover, we found that diabetic patients had more togenes [3, 5]. In contrast with other studies [19], co-morbid conditions, and this may have had an impact diabetes patients were not less likely to be treated with on the etiology and prognosis of bacterial meningitis. adjunctive dexamethasone therapy. As other previous studies have shown [17, 46], the Furthermore, DM influences the outcome of specific CSF parameters were diagnostic for bacterial meningitis infections, such as bacteremia and mortality following and did not differ between the two groups; therefore, pneumococcal pneumonia [12, 22]. Compared to non- these parameters were still helpful for the diagnosis of diabetic patients with BM [19, 20], we found a higher meningitis. mortality rate among patients with diabetes, and 52% of Cerebral computed tomography (CT) was more fre- mortality was attributable to meningitis. The probable quently performed among diabetic patients in our study, reasons were age, the frequent presence of comorbidi- maybe due to the greater availability of such a tool in ties, altered mental status on admission, and the devel- the second half of the study. However, most probably, opment of complications such as renal failure. The the attending physicians tend to consider diabetic pa- mortality improved between the two study periods, most tients as immunocompromised. Fortunately, this was not likely due to the adjunctive dexamethasone therapy, as associated with an increased ATI, which carries a worse guidelines recommend [2, 40, 47, 48], and the higher prognosis [3, 4, 39, 40]. Nevertheless, this interval needs rate of adequate empiric antibiotic therapy. However, we to be reduced if we want to improve the outcome of our cannot exclude that improvements in the management patients. Current international guidelines have proposed of critical patients, and diabetes and its complications the “red flags” for identifying patients that need a cranial may have played a role. Pomar et al. BMC Infectious Diseases (2020) 20:292 Page 8 of 9 Given the fact that S. pneumoniae is the leading cause Ethics approval and consent to participate of BM in diabetics and that pneumococcal infections are The study and its subsequent amendments were approved by the ethics committee of the Hospital de la Santa Creu i Sant Pau. potentially vaccine-preventable, it is worth recommend- Verbal informed consent was obtained from all participants because of the ing such vaccination in people with DM. years and the kind of the study. For the minors’ consent was obtained from Our study has inherent limitations. It is based on a the parents or the guardians. Patients also signed a generic consent when admitted to the Hospital in which they agreed to anonymously yield the single hospital, and therefore the results may not apply data derived from its process. Our ethic committee accepts this situation. to other geographical areas or populations. Secondly, the number of diabetic patients was relatively small, Consent for publication Not applicable. although the present study is one of the largest to date. Thirdly, the long study period may integrate changes in Competing interests the medical procedures or in the antimicrobial resist- The authors declare that they have no competing interests. ance, changes in the modern comorbidities therapies, Author details and the introduction of vaccines in the population. 1 Infectious Diseases Unit (Department of Internal Medicine), Hospital de la Fourthly, although there can be an overlap in the cyto- Santa Creu i Sant Pau – Institut d’Investigació Biomèdica Sant Pau. biochemical profile between bacterial and mycobacterial Universitat Autònoma de Barcelona, Barcelona, Spain. 2Emergency Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. or viral meningitis and meningitis without proven patho- 3 Department of Clinical Microbiology, Hospital de la Santa Creu i Sant Pau. – gen, the increasing availability of diagnostic tools for Institut d’Investigació Biomèdica Sant Pau, Universitat Autònoma de these etiologies led to the refinement of the diagnosis of Barcelona, Barcelona, Spain. meningitis of unknown origin, and we honestly feel that Received: 22 January 2020 Accepted: 8 April 2020 the possibility of misdiagnosis is it is minimal. 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