The clinical characteristics and therapeutic outcomes of adult patients with community-acquired spontaneous bacterial meningitis with a fulminant clinical course in Taiwan

Purpose To examine the clinical characteristics of adult patients with community-acquired spontaneous bacterial meningitis (CASBM) with a fulminant clinical course. Materials and methods The clinical features and therapeutic outcomes of 127 adult CASBM patients were analyzed. The patients were divided into two groups as those with and without a fulminant clinical course. Fulminant clinical course was defined as meningitis presenting initially with marked consciousness disturbance (Glasgow Coma Scale score < 8) or a rapid deterioration in consciousness level within 48 h of hospitalization. Results Among the 127 enrolled patients, 69 had a fulminant clinical course (47 men and 22 women) and 58 did not. The patients with a fulminant clinical course had a significantly higher incidence of end-stage renal disease (ESRD), severe clinical manifestations and higher mortality rate, and the survivors had significantly worse therapeutic outcomes. Klebsiella (K.) pneumoniae (50 strains) was the most important pathogen for the development of a fulminant clinical course, and all strains were susceptible to ceftriaxone and ceftazidime. With treatment, 50.7% (35/69) of the patients with a fulminant clinical course died, and the presence of K. pneumoniae infection was significant prognostic factor. Conclusions The presence of ESRD, initial presentation of altered consciousness, septic shock, seizures and CSF total protein level and K. pneumoniae infection were significantly associated with a fulminant clinical course of adult CASBM, and patients with this specific infectious syndrome had high mortality and morbidity rates. The presence of K. pneumoniae infection is a significant prognostic factor.


Introduction
In recent decades, the epidemiologic trend of adult bacterial meningitis (ABM), a serious infectious disease of the central nervous system (CNS), has changed gradually [1], and the main changes included an increasing incidence of post-neurosurgical meningitis and a decreasing incidence of Streptococcus pnemoniae meningitis.The clinical course of bacterial meningitis is usually acute, but if the evolution of consciousness level is taken into consideration, its clinical course may range from hyper-acute to chronic [1][2][3][4].In recent years, through the introduction of advanced management, the mortality rate of ABM in Taiwan has decreased to 25.5% [1,5], however this figure of mortality and the rate of morbidity are still high [1].K. pneumoniae is the most important pathogen of spontaneous bacterial meningitis, and we have reported this specific finding in serial published studies [6][7][8][9], and most of the patients with K. pneumoniae infection have severe medical comorbidity including diabetes mellitus and severe liver disease.Clinically, a group of adult patients with community-acquired spontaneous bacterial meningitis (CASBM) with a rapid evolution of clinical course from symptom onset to marked consciousness disturbance has been reported [1,4].In the study of R. Muralidharan et al. [4], they defined the fulminant bacterial meningitis as the meningitis presenting initially with marked consciousness disturbance [Glasgow Coma Scale score < 8] or a rapid deterioration in consciousness level within 48 h of the hospitalization.However, the detailed clinical characteristics of this specific group of patients have not previously been investigated thoroughly.Therefore, in this study, we analyzed the clinical characteristics and therapeutic outcomes of 69 adult CASBM patients with a fulminant course in order to better delineate this specific group ABM patients.

Subjects
We retrospectively reviewed the medical records of including microbiological records of cerebrospinal fluid (CSF), blood cultures, laboratory data, medical records and outcomes of adult patients (≥ 18 years) diagnosed with ABM and we enrolled patients with culture-proven bacterial meningitis admitted to Chang Gung Memorial Hospital (CGMH) -Kaohsiung, a 2680-bed acutecare teaching hospital providing both primary and tertiary care, over a period of 23 years (January 2000 to December 2022).During the study period, 447 cultureproven patients with ABM were identified, of whom 139 belonged to spontaneous infections and the other 308, post-neurosurgical form.Among these 139 patients, 12 had nosocomial infections and the other 127 belonged to CASBM.We excluded patients with nosocomial infection and post-neurosurgical infection and only the clinical and laboratory data of the 127 CASBM patients were enrolled in this study for analysis (Fig. 1).This study was approved by the hospital's Ethics Committee (IRB No: 202101827B0).

Diagnostic methods
In this study, the criteria for a definite diagnosis of bacterial meningitis were: (1) a positive CSF culture for bacterial pathogen(s); (2) clinical features of meningitis; and (3) purulent CSF features [1].Patients who had not been admitted to the hospital, demonstrated no clear distinctive disease characteristics, and had not undergone any invasive procedures were classified as having CASBM [1].Community-acquired meningitis was defined as positive bacterial infection presented when the patient was admitted to hospital or clinical evidence of an infection less than 48 h after the admission, or in out-hospital patients who developed the clinical evidence of meningitis in more than one month after prior hospitalization, especially those with a major surgical procedure including neurosurgical procedure or more than one month after the discharge from nursing home) [1,10].Patients were considered to have "mixed bacterial meningitis" if at least two bacterial organisms were isolated from the initial CSF culture [1].A fulminant clinical course of the CASBM patients was defined as meningitis presenting initially with marked consciousness disturbance [Glasgow Coma Scale score < 8] or a rapid deterioration in consciousness level within 48 h of the hospitalization [4].Bacteremia was defined as multiple blood cultures growing the same bacterial pathogen.Immunocompromised state was defined as primary immunodeficiency disorders [11] and secondary immunodeficiency state for patients with cancer, liver cirrhosis, end-stage renal disease (ESRD), long-term therapy with immunosuppressive agents for an overactive immune system or steroids for certain diseases, patients who had undergone organ transplantation and were receiving anti-rejection agent therapy, and patients with malnutrition [12].In our hospital and most hospitals in Taiwan, the intravenous administration of penicillin G or vancomycin combined with a 3rd generation cephalosporin (ceftriaxone, ceftazidime) were used as the initial empiric antibiotics for treating adult patients with clinical evidence of bacterial meningitis.Further antibiotic treatment was then adjusted according to the results of pathogen identification and antibiotic susceptibility tests.The appropriateness of antibiotics use was defined as (1) administration of right empirical regimens as soon as possible upon the patients' arrival of hospital, (2) adequate duration of antibiotics therapy as 3-4 weeks and adjustment of the therapy duration according to patients' clinical condition and image finding and (3) adjustment antibiotics as soon as possible according to the susceptibility result from once the CSF culture result available [1,4,13,14].

Statistical analysis
For prognostic analysis, mortality and mRS [15] were used to evaluate the therapeutic results, and the patients were divided into two groups: those with good outcomes (mRS score = 0-2) and those with poor outcomes (mRS score ≥ 3).Initially, we analyzed all data using univariate logistic regression.For categorical variables related to fulminant bacterial meningitis and prognosis analysis, data including sex, underlying conditions, clinical manifestations, and therapeutic outcomes were analyzed using the x 2 -test; while differences in continuous variables such as age between the two groups and CSF data were analyzed using the Student's t-test.Continuous data were expressed as the means ± standard deviations or medians (interquartile ranges), and the variables that were not normally distributed were logarithmically transformed to improve normality, and then compared using the independent t-test.Significant relationships among variables and the two patient groups were analyzed using stepwise multiple logistic regression analysis adjusted for other potential confounding factors.Variables with zero cell counts were eliminated from the logistic analysis, and only variables with statistical significance (p < 0.05) were included in the final model.All analyses were conducted using SSPS software version 22.0.

Demographic data and clinical comparisons
The demographic data, clinical features and therapeutic outcomes of the 127 enrolled CASBM patients are listed in Table 1.Among the 127 patients, 69 (47 men and 22 women, age range 19-83 years, median 59 years) had a fulminant clinical course (fulminant group), and 58 did not (non-fulminant group).The leading underlying conditions in the 69 patients in the fulminant group were immunocompromised state (41), diabetes mellitus (DM, 34), liver cirrhosis (16), alcoholism (15) and endstage renal disease (ESRD, 10).Of the initial manifestations of the fulminant group, altered consciousness (63), fever (59), seizures (32) and septic shock (28) were the leading clinical features.Bacteremia was found in 37 of the 69 patients in the fulminant group.Compared to the non-fulminant group (Table 1), the presence of ESRD and bacteremia, initial presentation of altered consciousness, seizures, septic shock, diabetic ketoacidosis/hyperosmolar hyperglycemic state (DKA/HHS), and CSF total protein level were potentially different.However, after multiple logistic regression analysis, only the presence of septic shock was significantly difference.Although it did not reach the significance of statistical analysis, Table 1 also shows that the fulminant group had a significantly higher mortality rate (50.7% vs. 27.6%),and the survivors also had a significantly worse prognosis at discharge and at 3 months after discharge.The distribution of the mRS scores of the survivors is shown in Fig. 2.

Implicated pathogens
Table 2 shows the implicated pathogens in the fulminant and non-fulminant groups.Klebsiella (K.) pneumoniae was the most common implicated pathogen in both groups, accounting for 47.8% (33/69) and 29.3% (17/58) of the patients, respectively, and the difference of its infectious rates between the two groups of patients was significant (p = 0.040).Of the 50 implicated K. pneumoniae strains, 39 strains were identified in the study period of 2000-2009 and the other 11 in the 2010-2022.The 11 K. pneumoniae strains isolated in the 2nd study period were found in the time period of 2010-2019 The statistical analysis was conducted using univariate analysis; * : p < 0.05 and none was found in the study period of 2020-2022.
The results of the antibiotic susceptibility test of the 50 implicated K. pneumoniae strains showed that they were all susceptible to both ceftazidime and ceftriaxone.The other implicated pathogens shown in the Table 2 did not show significant difference between the two groups of the enrolled patients.

Analysis of prognostic factors
The clinical and laboratory features between the survivors of the fulminant and non-fulminant groups are listed in  5.The results showed that the presence of ESRD and DKA/HHS were potential factors, however they were all not significant in multiple logistic regression analysis and we found the appropriateness use of antibiotics had no influence of mortality in fulminant CASBM.

Discussion
Many factors including age, underlying medical/surgical conditions, vaccination status and bacterial pathogens may influence the clinical manifestations, course and therapeutic outcomes of adult bacterial meningitis [1][2][3][4][5]16].Clinically, we defined fulminant bacterial meningitis as a syndrome consisted of the following pictures: a sudden onset of symptomatic meningitis, a rapid deterioration of neurological signs with or without shock, abrupt cerebral edema, or intractable intracranial hypertension [17].The pathophysiology and pathogenesis of bacterial meningitis involved complicated interaction between pathogen factors and host immune response.Meningeal pathogens also increase the permeability of the bloodbrain barrier (BBB), allowing pathogens and cytokines and neutrophils move into the subarachnoid space and the intense subarachnoid inflammatory response leads to consequences of bacterial meningitis including cerebral edema and increased intracranial pressure [18] 1, the CASBM patients with ESRD as the preceding event had a significantly higher rate of developing a fulminant clinical course, and those with a fulminant clinical course also had significantly more severe clinical presentations including initial presentation of altered consciousness, septic shock, seizures, and a higher CSF total protein level.In addition, compared to those without a fulminant clinical course, those with a fulminant clinical course had a higher mortality rate (50.7%, 35/69) (Table 1), and this figure of mortality rate was much higher than that of the overall group of patients with ABM (25.5%) [1].It is well known that ESRD is associated with an increased risk of infection and infection-related mortality [19,20].In Taiwan, the number of patients receiving maintenance dialysis is increasing rapidly, and Taiwan now has the highest incidence of ESRD globally [21].The higher incidence of ESRD and severe neurologic manifestations of the CASBM patients with a fulminant clinical course (Table 1) are known to be important prognostic factors of ABM [22][23][24][25].In addition, those who had a fulminant course and survived had significantly worse therapeutic outcomes at discharge and at 3 months after discharge.The significant factors associated with the poor therapeutic outcomes included initial consciousness level and seizures (Table 3); both of which are known to be important prognostic factors of bacterial meningitis [1,26].
In contrast to the epidemiologic trend of bacterial meningitis in Western countries, in which Streptococcus (S.) pneumoniae is the most common and important bacterial pathogen of community-acquired bacterial meningitis [27,28], K. pneumoniae is the most implicated pathogen of meningitis in Taiwan [1,5,25].Because of the vaccination program in Taiwan, the incidence of S. pneumoniae infection in adult bacterial meningitis has decreased gradually [1].The annual incidence of overall S. pneumoniae infection decreased from 41.2 per 1000 to 15.2 per 1000 in children and from 5.0 per 1000 to 1.5 per 1000 in adult from a 12-year-period study review and in this study, the meningitis caused by S. pneumoniae The ORs and 95% CIs were calculated using univariate logistic regression b: The ORs and p values were calculated using multiple logistic regression accounted for 1.3% of all adult patient with S. pneumoniae infection [29].From studies published between 2010 and 2019, the annual incidence of S. pneumoniae meningitis was around 24.3% in India, 6.4% in Singapore, 3.1% in Korea and 0.2-0.26 per 100,000 population in Japan [30][31][32][33].The above data were comparable with the result of higher incidence was published in India and lower in Taiwan and Japan [34].Although a post-neurosurgical state is the preceding event in some patients with adult K. pneumoniae meningitis, K. pneumoniae meningitis is usually acquired spontaneously in the community.
Therefore, it is not surprising that K. pneumoniae was the most common pathogen in the 127 enrolled CASBM patients, accounting for 40.3% (50/124) of those with a monomicrobial infection (Table 2).Other than K. pneumonia, several other implicated bacterial pathogens were found in the 127 patients (Table 2), however only the presence of K. pneumoniae infection was a significant factor for the development of a fulminant clinical course.Even though K. pneumoniae strains have been reported to have a high level of carbapenem resistance and broad resistance to many beta-lactam antibiotics in Taiwan [35,36], none of the 50 enrolled K. pneumoniae strains showed resistance to either ceftriaxone or ceftazidime.Both of these cephalosporins are commonly used as empiric antibiotics for the treatment of adult bacterial meningitis in Taiwan.In this study, more than half of the CASBM patients with a fulminant clinical course died (Tables 1 and 4).As shown in Table 4, the presence of K. pneumoniae infection was the most important factor for mortality in this specific group of patients.K. pneumoniae infection including meningitis is a very distinctive infectious syndrome in Taiwan [37][38][39][40].Many factors may influence the therapeutic results of K. pneumoniae meningitis, however the timing of appropriate antimicrobial therapy is currently the major determinant of survival and neurological outcomes for this group [41,42].The high mortality rate of the CASBM patients with a fulminant clinical course may be related to the rapid deterioration in consciousness before the use of appropriate antimicrobial agents.Besides those with K. pneumoniae infection, the case numbers of the other implicated pathogens in the patients with this specific infectious syndrome were too small to allow for adequate analysis.Both DKA/HHS and ESRD are severe medical conditions which may make the patients vulnerable to infectious diseases and poor therapeutic outcomes [12,[15][16][17].However, although both factors were potentially associated with the development of early mortality (≤ 72 h) in the 35 patients with CASBM and a fulminant course who died, neither factor was significant in multiple logistic regression analysis (Table 5).
As shown in our previous study [43], we found higher mortality in ESRD patients with CASBM and the most implicated pathogen was S. aureus, through the catheter for dialysis and higher resistant rate to penicillin and oxacillin were noticed in S. aureus.Therefore, the physicians should choose vancomycin rather than oxacillin as the empirical antibiotics for CASBM patients under dialysis.
From the result of this study, we found high mortality rate of this group of CASBM patients; therefore, aggressive medical support and timely using appropriate antibiotics were crucial for the clinicians in treating this specific group of infectious disease.However, it needs time for the culture result available, so the more rapid test for pathogen detection is necessary.In addition to the above-mentioned appropriate antibiotics use, early detection of pathogens and the susceptibility of antibiotics by using polymerase chain reaction (PCR) test [44,45] may be also important for a successful treatment of fulminant CASBM.

Limitations
There are several limitations to this study: (1) patients with culture negative ABM were not included in the study, and (2) the choice of GSC score < 8 to define the fulminant clinical course may have led to bias influencing patient group classification and the analysis of the prognostic factors.

Conclusions
In the present study, 54.3% of the CASBM patients had a fulminant clinical course, and the presence of ESRD was an important factor for its development.This specific group of patients had severe neurologic manifestations and also a high mortality rate (50.7%).In Taiwan, K. pneumoniae is an important implicated pathogen of adult bacterial meningitis, especially the community-acquired spontaneous form.It was also an important factor for the development of CASBM with a fulminant clinical course and the high mortality rate of the patients in this study.In addition, of the patients with CASBM and a fulminant clinical course who died, 18.8% died ≤ 72 h after symptom onset.In addition, the CASBM patients with a fulminant clinical course who survived had poor therapeutic outcomes at discharge and at 3 months after discharge.

Fig. 2
Fig. 2 Distribution of the modified Rankin Scale scores of the survivor.mRS = modified Rankin scales

Table 2 The
implicated pathogens of the 127 community-acquired spontaneous adult bacterial meningitis patients with a fulminant and non-fulminant clinical course Pathogen With fulminant course (N = 69) With non-fulminant course (N = 58) p value

Table 3 .
The potential different factors were initial consciousness level, outcomes at discharge, ESRD, immunocompromised state, seizures, DKA/HHS, hyponatremia, septic shock and CSF total protein level.But after multiple logistic regression analysis, none of them were significant.Analysis of the prognostic factors in the 35 patients who died and the other 34 who survived in the fulminant group is shown in Table4.The results showed that the presence of K. pneumoniae infection was a significant factor.Of the 35 patients who died, 13 (37.1%)died ≤ 72 h after symptom onset, and the other 22 (62.9%)died > 72 h after symptom onset.A comparison of the clinical and laboratory features of these two groups of patient is listed in Table

Table 3
The clinical and therapeutic outcome comparison between the survivors of the community-acquired spontaneous adult bacterial meningitis patients with and without a fulminant clinical course

Table 4
The prognostic factors of the community-acquired spontaneous adult bacterial meningitis patients with a fulminant clinical course

Table 5
The affecting factors of the time of mortality in the community-acquired spontaneous adult bacterial meningitis patients with a fulminant clinical course OR = odds ratio; CI = confidence interval; DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state; * = p < 0.05; IQR: interquartile range a: The ORs and 95% CIs were calculated by using univariate logistic regression b: The ORs and p values were calculated by using multiple logistic regression