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

doi:10.21203/rs.3.rs-3017355/v1

Purpose

To examine the clinical characteristics of adult patients with community-acquired spontaneous bacterial meningitis (CASBM) with a fulminant clinical course.

Material 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.

bacterial meningitis

community-acquired

spontaneous

end-stage renal disease

high mortality

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]. 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 [1–4]. 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]. 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], however the 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) with culture-proven bacterial meningitis admitted to Chang Gung Memorial Hospital (CGMH) – Kaohsiung, a 2680-bed acute-care teaching hospital providing both primary and tertiary care, over a period of 23 years (January 2000 to December 2022). During the study period, 447 culture-proven 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. The clinical and laboratory data of these 127 patients were enrolled in this study for analysis. 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]. 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 hr of the hospitalization [4]. Bacteremia was defined as multiple blood cultures growing the same bacterial pathogen. Immunocompromised state was defined as primary immunodeficiency disorders [6] 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 [7]. During the study period, 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.

Statistical analysis

For prognostic analysis, mortality and modified Rankin Scale (mRS) [8] 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 x²-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 end-stage 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. 1.

Table 1

The clinical and laboratory features of the 127 community-acquired spontaneous adult bacterial meningitis patients with or without a fulminant clinical course
Characteristic	With fulminant course N = 69 (%)	With non-fulminant course N = 58 (%)	OR^a	95% CI^a	p-value	OR^b	95% CI^b	Adjusted p-value
Age	58.36 ± 15.36	56.47 ± 15.03			0.485
Gender
Male	47 (68.1)	41 (70.7)	1.129	0.529–2.411	0.754
Female	22 (31.9)	17 (29.3)	1.129	0.529–2.411	0.754
Outcome
In-hospital mortality
<72 hours	8 (21.6)	0 (0.0)	1.276	1.078–1.511	0.038*	-	-	0.999
>72 hours	13 (35.1)	0 (0.0)	1.541	1.217–1.953	0.005*	-	-	0.999
Discharge mRS
At discharge	4.57 ± 1.90	2.97 ± 2.39			< 0.001*	-	-	0.999
Three months later	4.30 ± 2.24	2.74 ± 2.57			< 0.001*	-	-	0.999
Mortality	35 (50.7)	16 (27.6)	1.839	1.141–2.964	0.008*	-	-	0.583
Underlying condition
Diabetes mellitus	34 (49.3)	22 (37.9)	1.299	0.865–1.952	0.200
Liver cirrhosis	16 (23.2)	7 (12.1)	1.921	0.849–4.348	0.105
Alcoholism	15 (21.7)	6 (10.3)	2.101	0.872–5.066	0.085
Systemic malignancy	9 (13.0)	13 (22.4)	0.582	0.268–1.263	0.165
Intracranial hemorrhage	7 (10.1)	11 (19.0)	0.535	0.222–1.291	0.156
End-stage renal disease	10 (14.5)	1 (1.7)	8.406	1.109–63.732	0.011*	12.474	0.740–210.300	0.080
Substance abuser	3 (4.3)	2 (3.4)	1.261	0.218–7.291	0.795
Brain tumor	1 (1.4)	3 (5.2)	0.280	0.030–2.622	0.231
Immunocompromised state	41 (59.4)	26 (44.8)	1.326	0.938–1.873	0.101
Clinical manifestations
Fever	59 (85.5)	51 (87.9)	0.972	0.849–1.114	0.689
Initial altered consciousness	63 (91.3)	37 (63.8)	1.431	1.164–1.761	< 0.001*	8.068	0.392-166.198	0.176
Seizure	32 (46.4)	9 (15.5)	2.989	1.557–5.736	< 0.001*	2.879	0.294–28.165	0.363
Septic shock	28 (40.6)	3 (5.2)	7.845	2.513–24.490	< 0.001*	10.337	1.020-104.759	0.048*
Hydrocephalus	15 (21.7)	16 (27.6)	0.788	0.427–1.453	0.445
Hyponatremia	16 (23.2)	5 (8.6)	2.690	1.049–6.897	0.028*	0.823	0.077–8.824	0.872
DKA/HHS	14 (20.3)	5 (8.6)	2.354	0.902–1.006	0.066
Brain abscess	11 (15.9)	6 (10.3)	1.541	0.607–3.911	0.356
Ischemic infarct	11 (15.9)	4 (6.9)	2.312	0.777–6.874	0.116
Liver abscess	6 (8.7)	5 (8.6)	1.009	0.324–3.136	0.988
Vasculitis	7 (10.1)	3 (5.2)	1.961	0.531–7.245	0.300
Subdural empyema	3 (4.3)	1 (1.7)	2.522	0.270-23.595	0.399
Spinal abscess	1 (1.4)	3 (5.2)	0.280	0.030–2.622	0.231
Infective endocarditis	2 (2.9)	2 (3.4)	0.841	0.122–5.783	0.860
Bacteremia	37 (53.6)	20 (34.5)	1.555	1.025–2.360	0.031*	0.373	0.051–2.716	0.330
Cerebrospinal fluid
Median (IQR) Glucose level (mmol/L)	1.67 (0.28, 4.58)	1.39 (0.28, 3.69)			0.181
Median (IQR) Total protein level (g/L)	5.07 (2.36, 7.85)	2.71 (1.44, 4.23)			< 0.001*		0.994–1.001	0.110
Median (IQR) Lactate level (mmol/L)	13.97 (8.55, 18.43)	11.54 (6.72, 19.09)			0.890
Median (IQR) WBC counts (10⁹/L)	1.07 (0.25, 5.38)	0.72 (0.09, 1.96)			0.827
OR = odds ratio; CI = confidence interval; mRS: modified Rankin Scale; DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state; ^* = p < 0.05; IQR: interquartile range a: The ORs and 95% CIs were calculated using univariate logistic regression b: The ORs and p values were calculated using multiple logistic regression

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 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.

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
Gram-negative
Klebsiella pneumoniae	33	17	0.040*
Pseudomonas aeruginosa	1	2	0.492
Other Pseudomonas species	2	2	0.906
Escherichia coli	3	4	0.325
Neisseria meningitidis	1	1	0.934
Proteus mirabilis	0	1	0.287
Salmonella enterica serogroup B	0	1	0.287
Salmonella enterica serogroup D	0	1	0.287
Chryseobacterium meningosepticum	1	0	0.343
Sphingomonas paucimobilis	1	0	0.343
Roseomonas mucosa	1	0	0.343
Fusobacterium nucleatum	0	1	0.287
Gram-positive
Staphylococcus aureus	6	5	0.638
Coagulase-negative staphylococci	1	2	0.492
Streptococcus pneumoniae	6	5	0.908
Viridans streptococci	5	8	0.153
β-streptococcus group B	1	1	0.934
Listeria monocytogenes	4	4	0.865
Enterococcus faecalis	3	0	0.343
Mixed infection	0	3	0.063
The statistical analysis was conducted using univariate analysis; ^*: p < 0.05

Analysis of prognostic factors

The clinical and laboratory features between the survivors of the fulminant and non-fulminant groups are listed in 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 Table 4. 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 hours after symptom onset, and the other 22 (62.9%) died > 72 hours after symptom onset. A comparison of the clinical and laboratory features of these two groups of patient is listed in Table 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.

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
Characteristic	With fulminant course N = 34 (%)	With non-fulminant course N = 42 (%)	OR^a	95% CI^a	p-value	OR^b	95% CI^b	Adjusted p-value
Age	56.32 ± 16.95	55.29 ± 15.73			0.783
Gender
Male	24 (70.6)	30 (71.4)	1.042	0.385–2.821	0.936
Female	10 (29.4)	12 (28.6)	1.042	0.385–2.821	0.936
Initial consciousness level (Glasgow coma scale)	6.21 ± 1.43	13.07 ± 2.51			< 0.001*	-	-	0.984
Outcome (mRS)
At discharge	3.09 ± 1.73	1.81 ± 1.73			0.002*	-	-	0.991
Three months later	2.56 ± 2.03	1.50 ± 1.85			0.020*	-	-	0.988
Underlying condition
Diabetes mellitus	20 (58.8)	17 (40.5)	1.453	0.915–2.307	0.112
Systemic malignancy	5 (14.7)	7 (16.7)	0.882	0.307–2.534	0.816
Liver cirrhosis	7 (20.6)	3 (7.1)	2.882	0.806–10.312	0.085
Intracranial hemorrhage	3 (8.8)	10 (23.8)	0.371	0.111–1.241	0.085
Alcoholism	5 (14.7)	4 (9.5)	1.544	0.449–5.307	0.487
End-stage renal disease	4 (11.8)	0 (0.0)	1.134	1.002–1.282	0.022*	-	-	0.998
Substance abuser	1 (2.9)	2 (4.8)	0.618	0.058–6.525	0.685
Brain tumor	1 (2.9)	1 (2.4)	1.235	0.080-19.029	0.879
Immunocompromised state	18 (52.9)	12 (28.6)	1.853	1.044–3.289	0.031*	-	-	0.999
Clinical manifestations
Fever	30 (88.2)	37 (88.1)	1.002	0.849–1.182	0.985
Seizure	17 (50.0)	5 (11.9)	4.200	1.727–10.214	< 0.001*	-	-	1.000
Hydrocephalus	7 (20.6)	10 (23.8)	0.865	0.368–2.030	0.738
DKA/HHS	9 (26.5)	4 (9.5)	2.779	0.937–8.246	0.051
Hyponatremia	10 (29.4)	1 (2.4)	12.353	1.663–91.760	0.001*	-	-	0.999
Brain abscess	7 (20.6)	4 (9.5)	2.162	0.690–6.774	0.173
Septic shock	10 (29.4)	0 (0.0)	1.416	1.140–1.761	< 0.001*	-	-	1.000
Ischemic infarct	7 (20.6)	3 (7.1)	2.882	0.802–10.312	0.085
Liver abscess	3 (8.8)	3 (7.1)	1.235	0.266–5.7341	0.787
Vasculitis	4 (11.8)	3 (7.1)	1.647	0.395–6.862	0.488
Subdural empyema	3 (8.8)	1 (2.4)	3.706	0.403–34.038	0.211
Spinal abscess	0 (0.0)	2 (4.8)	0.952	0.890–1.019	0.197
Infective endocarditis	1 (2.9)	1 (2.4)	1.235	0.080-19.029	0.879
Bacteremia	17 (50.0)	12 (28.6)	1.750	0.975–3.140	0.056
Cerebrospinal fluid
Median (IQR) Glucose level (mmol/L)	1.67 (0.28, 6.60)	1.94 (0.28, 3.97)			0.180
Median (IQR) Total protein level (g/L)	6.15 (2.01, 7.69)	2.66 (1.36, 4.65)			0.012*	-	-	0.992
Median (IQR) Lactate level (mmol/L)	13.54 (8.66, 17.76)	10.55 (6.74, 21.84)			0.796
Median (IQR) WBC counts (10⁹/L)	1.25 (0.20, 6.67)	0.73 (0.08, 1.84)			0.911
OR = odds ratio; CI = confidence interval; mRS: modified Rankin Scale; DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state; ^* = p < 0.05; IQR: interquartile range a: The ORs and 95% CIs were calculated using univariate logistic regression b: The ORs and p values were calculated using multiple logistic regression

Table 4

The prognostic factors of the community-acquired spontaneous adult bacterial meningitis patients with a fulminant clinical course
Characteristic	Mortality N = 35 (%)	Survival N = 34 (%)	OR^a	95% CI^a	p-value
Age	60.34 ± 13.58	56.32 ± 16.95			0.280
Gender
Male	23 (65.7)	24 (70.6)	1.252	0.454–3.457	0.664
Female	12 (34.3)	10 (29.4)	1.252	0.454–3.457	0.664
Initial consciousness level (Glasgow coma scale)	5.71 ± 1.93	6.21 ± 1.43			0.234
Underlying condition
Diabetes mellitus	14 (40.0)	20 (58.8)	0.680	0.415–1.114	0.118
Liver cirrhosis	9 (25.7)	7 (20.6)	1.249	0.524–2.974	0.614
Alcoholism	10 (28.6)	5 (14.7)	1.943	0.741–5.096	0.163
End-stage renal disease	6 (17.1)	4 (11.8)	1.457	0.451–4.713	0.526
Systemic malignancy	4 (11.4)	5 (14.7)	0.777	0.228–2.651	0.686
Intracranial hemorrhage	4 (11.4)	3 (8.8)	1.295	0.313–5.362	0.720
Substance abuser	2 (5.7)	1 (2.9)	1.943	0.185–20.446	0.572
Brain tumor	0 (0.0)	1 (2.9)	0.971	0.916–1.029	0.307
Immunocompromised state	23 (65.7)	18 (52.9)	1.241	0.834–1.846	0.280
Clinical manifestations
Initial altered consciousness	32 (91.4)	31 (91.2)	1.003	0.867–1.160	0.970
Fever	29 (82.9)	30 (88.2)	0.939	0.773–1.140	0.526
Seizure	15 (42.9)	17 (50.0)	0.857	0.515–1.426	0.552
Septic shock	18 (51.4)	10 (29.4)	1.749	0.948–3.2251	0.063
Hyponatremia	6 (17.1)	10 (29.4)	0.583	0.238–1.427	0.227
Hydrocephalus	8 (22.9)	7 (20.6)	1.110	0.452–2.725	0.819
DKA/HHS	5 (14.3)	9 (26.5)	0.540	0.201–1.447	0.208
Brain abscess	4 (11.4)	7 (20.6)	0.555	0.179–1.726	0.299
Ischemic infarct	4 (11.4)	7 (20.6)	0.555	0.179–1.726	0.299
Vasculitis	3 (8.6)	4 (11.8)	0.729	0.176–3.016	0.660
Liver abscess	3 (8.6)	3 (8.8)	0.971	0.211–4.482	0.970
Infective endocarditis	1 (2.9)	1 (2.9)	0.971	0.063-14.9151	0.983
Bacteremia	20 (57.1)	17 (50.0)	1.143	0.735–1.778	0.552
K. pneumoniae infection	22 (62.9)	11 (32.4)	1.943	1.122–3.363	0.011*
Cerebrospinal fluid
Median (IQR) Glucose level (mmol/L)	1.64 (0.28, 3.97)	1.67 (0.28, 6.60)			0.211
Median (IQR) Total protein level (g/L)	4.95 (2.71, 8.32)	6.15 (2.01, 7.69)			0.893
Median (IQR) Lactate level (mmol/L)	14.65 (7.22, 18.87)	13.54 (8.66, 17.76)			0.673
Median (IQR) WBC counts (10⁹/L)	0.60 (0.28, 4.26)	1.25 (0.20, 6.67)			0.287
OR = odds ratio; CI = confidence interval; DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state; K. pneumoniae: Klebsiella pneumoniae; ^* = p < 0.05; IQR: interquartile range a: The ORs and 95% CIs were calculated using univariate logistic regression

Table 5

The affecting factors of the time of mortality in the community-acquired spontaneous adult bacterial meningitis patients with a fulminant clinical course
Characteristic	≤ 72 hours N = 13 (%)	> 72 hours N = 22 (%)	OR^a	95% CI^a	p-value	OR^b	95% CI^b	Adjusted p-value
Age	62.31 ± 14.55	59.18 ± 13.19			0.519
Gender
Male	10 (76.9)	13 (59.1)	0.433	0.092–2.031	0.283
Female	3 (23.1)	9 (40.9)	0.433	0.092–2.031	0.283
Initial consciousness level (Glasgow coma scale)	5.69 ± 2.10	5.73 ± 1.88			0.960
Underlying condition
Diabetes mellitus	6 (46.2)	8 (36.4)	1.269	0.567–2.843	0.568
Alcoholism	4 (30.8)	6 (27.3)	1.128	0.390–3.267	0.825
Liver cirrhosis	2 (15.4)	7 (31.8)	0.484	0.118–1.988	0.282
Systemic malignancy	2 (15.4)	2 (9.1)	1.692	0.270-10.614	0.572
Intracranial hemorrhage	1 (7.7)	3 (13.6)	0.564	0.065–4.876	0.593
End-stage renal disease	0 (0.0)	6 (27.3)	0.729	0.563–0.939	0.039*	-	-	0.999
Substance abuser	0 (0.0)	2 (9.1)	0.909	0.797–1.037	0.263
Immunocompromised state	8 (61.5)	15 (68.2)	0.903	0.539–1.512	0.689
Clinical manifestations
Fever	10 (76.9)	19 (86.4)	0.891	0.633–1.253	0.474
Septic shock	7 (53.8)	11 (50.0)	1.077	0.560–2.071	0.8261
Seizure	6 (46.2)	9 (40.9)	1.128	0.521–2.4432	0.762
Hydrocephalus	2 (15.4)	6 (27.3)	0.564	0.133–2.395	0.418
DKA/HHS	4 (30.1)	1 (4.5)	6.769	1.845–54.253	0.032*	-	-	0.112
Hyponatremia	3 (23.1)	3 (13.6)	1.692	0.399–7.186	0.474
Brain abscess	1 (7.7)	3 (13.6)	0.564	0.065–4.876	0.593
Ischemic infarct	2 (15.4)	2 (9.1)	1.692	0.270-10.614	0.572
Liver abscess	1 (7.7)	2 (9.1)	0.846	0.085–8.444	0.886
Vasculitis	1 (7.7)	2 (9.1)	0.846	0.085–8.444	0.886
Bacteremia	9 (69.2)	11 (50.0)	1.385	0.796–2.407	0.267
K. pneumoniae infection	11 (84.6)	11 (50.0)	5.000	0.884–28.288	0.056
Cerebrospinal fluid
Median (IQR) Glucose level (mmol/L)	2.69 (0.76, 5.67)	0.44 (0.28, 3.89)			0.114
Median (IQR) Total protein level (g/L)	7.13 (2.60, 1.17)	4.64 (2.04, 7.72)			0.146
Median (IQR) Lactate level (mmol/L)	17.76 (11.29, 22.76)	12.32 (5.86, 17.59)			0.089
Median (IQR) WBC counts (10⁹/L)	0.60 (0.33, 4.41)	1.47 (0.27, 5.37)			0.332
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

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 [1–5, 9]. In the 23-year study period, spontaneous adult bacterial meningitis accounted for 31.1% (139/447) of the overall adult bacterial meningitis cases, and the other 68.9% (308/447) were caused by postneurosurgical infections. This relative relatively lower rate of spontaneous infections and higher rate of postneurosurgical infections is consistent with our previous epidemiologic studies of adult bacterial meningitis in Taiwan [1, 5, 10]. Of the enrolled 139 patients with adult bacterial meningitis with spontaneous infections, 91.4% (127/139) had community-acquired infections. Of these 127 patients, 54.3% (69/127) had a fulminant clinical course and the other 45.7% (58/127) had a non-fulminant clinical course.

As shown in Table 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 [10, 11]. In Taiwan, the number of patients receiving maintenance dialysis is increasing rapidly, and Taiwan now has the highest incidence of ESRD globally [12]. 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 [13–16]. 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, 17].

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 [18, 19], K. pneumoniae is the most commonly implicated pathogen of meningitis in Taiwan [1, 5, 16]. Because of a vaccination program in Taiwan, the incidence of Streptococcus (S.) pneumonia infection in adult bacterial meningitis has decreased gradually [1]. In Taiwan, K. pneumoniae infection is usually seen in patients with DM and/or liver diseases, especially cirrhosis, as the underlying conditions [20–22]. Although a postneurosurgical state is the preceding event in some patients with adult K. pneumoniae meningitis, K. pneumoniae meningitis is usually acquired spontaneously in the community [21]. 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 [23, 24], 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 [25–27]. Many factors may influence the therapeutic results of K. pneumoniae meningitis, however the timing of appropriate antimicrobial therapy, as defined by consciousness level, is currently the major determinant of survival and neurological outcomes for this group [28, 29]. 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 [9–12]. However, although both factors were potentially associated with the development of early mortality (≤ 72 hours) in the 35 patients with CASBM and a fulminant course who died, neither factor was significant in multiple logistic regression analysis (Table 5).

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.

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 patient 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 hours 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.

CASBM community-acquired spontaneous bacterial meningitis

CNS central nervous system

CSF cerebrospinal fluid

DKA diabetic ketoacidosis

ESRD end-stage renal disease

HHS hyperosmolar hyperglycemic state

mRS modified Rankin scale

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Kaohsiung Chang Gung Memorial Hospital (IRB No: 202101827B0).

Informed consent: From the institutional Review Board (IRB) of Chang Gung Medical Foundation, the informed consents were waived for retrospective medical records review study.

Consent of publications

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study available from the first author and the corresponding author on reasonable request.

Conflict of interests

The authors declare that they have no competing interests.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author’s contribution

Chia-Yi Lien wrote the main manuscript and analyzed the preliminary data

Chun-Chih Chien collected the preliminary data and review the medical charts

Cheng-Hsien Lu analyzed the preliminary data

Wen-Neng Chang corrected the main article of manuscript

All authors reviewed the manuscript

Acknowledgements

Not applicable

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No competing interests reported.

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

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Demographic data and clinical comparisons

Implicated pathogens

Analysis of prognostic factors

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