
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

39237686
71660
10.1038/s41598-024-71660-4
Article
Factors influencing mortality in intracranial infections caused by carbapenem-resistant Klebsiella Pneumoniae
Lai Chengcheng 1
Ma Zijun 1
Luo Yonggang Luoyg_514@126.com

2
Gao Yuan 3
Wu Zhuanghao 2
Zhang Jun 4
Xu Weiwei 5
1 https://ror.org/056swr059 grid.412633.1 Department of General Practice, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
2 https://ror.org/056swr059 grid.412633.1 Department of Neurosurgical Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
3 grid.16821.3c 0000 0004 0368 8293 Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
4 https://ror.org/056swr059 grid.412633.1 Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450002 China
5 https://ror.org/056swr059 grid.412633.1 Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
5 9 2024
5 9 2024
2024
14 2067029 5 2024
29 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
It remains that intracranial infection has an alarming mortality and morbidity. Klebsiella pneumoniae (KP) have increasingly been isolated in ventriculitis and meningitis episodes. Intracranial infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) account for high mortality. To understand its clinical impact and related risk factors accurately are crucial in the management of bacterial intracranial infection. The retrospective study aimed to delineate the clinical risk of death from intracranial infection and analyze the risk factors. A total of 176 Klebsiella pneumoniae intracranial infectious patients were available to divide into CRKP group and carbapenem-susceptive Klebsiella Pneumoniae (CSKP) group. We performed survival analysis and estimate the time-varying effects of CRKP and CSKP infection on 30-day mortality. Infectious patients caused by CSKP was associated with lower mortality than CRKP group. The risk factors associated with death from intracranial infection caused by Klebsiella pneumoniae included SOFA scores, ventilator therapy, CRKP, and heart failure. Longer hospital stays are independently associated with lower mortality rates. Intracranial infection caused by CRKP was associated with excess mortality. Complex comorbidities mean higher mortality. Active supportive treatment is required for complicated patients with intracranial infections caused by carbapenem-resistant Klebsiella pneumoniae.

Keywords

Intracranial infection
Carbapenem-resistant Klebsiella Pneumoniae
Carbapenem-susceptive Klebsiella Pneumoniae
Subject terms

Diseases
Medical research
Neurology
Risk factors
Young and Middle-aged Scientific Technological Innovation Jie-Qing Talent ProjectYXKC2021042 Luo Yonggang Henan Province Key Medical Science and Technology Research Project Co-established by Provincial and Ministerial Authorities (CN)SBGJ202102081 Luo Yonggang Henan Province Science and Technology Research Project (CN)242102311040 Luo Yonggang Henan Province Natural Science Foundation Project (CN)242300420384 Luo Yonggang issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Intracranial infections are a significant concern within neurology, associated with high mortality rates and poor prognostic outcomes. These infections not only extend hospital stays and increase financial burdens for patients but also cause considerable psychological distress. In particular, infections caused by Klebsiella pneumoniae (K. pneumoniae) have emerged as a major clinical challenge1. Historically, K. pneumoniae was a rare cause of meningitis; a 1948 review of 3,377 meningitis cases identified only seven instances of K. pneumoniae meningitis2. However, with advances in microbiological understanding, K. pneumoniae has become a well-recognized pathogen, especially in post-neurosurgical contexts. However, with advances in microbiological understanding, K. pneumoniae has become a well-recognized pathogen, especially in post-neurosurgical contexts3. Mortality attributable to intracranial infection ranges between 48.5 and 66.0%4–6. Klebsiella pneumoniae became the main multidrug-resistant and extensively drug-resistant Gram-negative bacteria in intracranial infections, ranking second after Acinetobacter baumannii7. WHO has placed multidrug-resistant K. pneumoniae at one of the top three its ‘2017 Antibiotic-resistant Priority Pathogens List’. There are few reports in the literature on intracranial infections caused by K. pneumoniae8. Most studies on Klebsiella pneumoniae intracranial infection are still limited to case series reports9,10. To improve the cure rate and reduce the mortality of intracranial infections caused by K. pneumoniae, it is urgent to understand the epidemiological distribution of intracranial infections in hospitals and to evaluate the risk factors for all-cause mortality in patients with intracranial infections caused by K. pneumoniae.

To enhance treatment outcomes and reduce mortality associated with K. pneumoniae intracranial infections, it is imperative to thoroughly investigate the epidemiological patterns and identify mortality risk factors in these patients. Advances in cerebrospinal fluid (CSF) biochemistry have greatly refined the diagnostic process for intracranial infections. Since 1978, lactate levels in the CSF have been recognized as indicators of intracranial infection11. Current research confirms that the glucose content ratio between CSF and blood provides valuable diagnostic insights. However, studies examining how biochemical ratios between CSF and blood might predict clinical outcomes are lacking. There has been no related research on the biochemical ratios between CSF and blood guiding prognosis. No studies have shown whether high lactate (Lac), glucose, and albumin ratios between cerebrospinal fluid and blood are associated with increased all-cause mortality in patients with Klebsiella pneumoniae intracranial infection. This study aims to explore the impact of CRKP on mortality and to identify risk factors for intracranial infections caused by Klebsiella pneumoniae.

Materials and methods

Study design and participants

We conducted a retrospective analysis of all patients diagnosed with intracranial infections at the First Affiliated Hospital of Zhengzhou University, a tertiary care center in Henan, China.

All patients aged 16 years and older who were admitted to the hospital between January 1, 2018, and June 30, 2023, and had at least two CSF culture results positive for the same bacterial strain were included in this study. Bacterial culture results were collaboratively determined by experts in pathology laboratories, pharmacology, and neurosurgery, based on clinical features and laboratory test outcomes. These patients with intracranial infections displayed common characteristics, including symptoms and signs of central nervous system infection such as fever, headache, altered consciousness, neck stiffness, signs of meningeal irritation, and mental state changes. All underwent either lumbar puncture or cerebrospinal fluid sampling via a ventricular drain during hospitalization. Criteria for inclusion required that CSF cultures or smears demonstrate bacterial presence, excluding contaminations and duplicates; repeated tests and multiple samples from the same patient were excluded. Patients who died within 48 h of admission or had a history of hospitalization and intracranial infection within two weeks prior to the onset were also excluded. The ‘time of diagnosis’ was defined as the time from admission to the first positive CSF culture. The proportion of the time of diagnosis to the total length of hospital stay was defined as the ‘time proportion’.

Clinical data collection

Standardized forms were pre-designed, and data that met the inclusion criteria were systematically collected from the electronic system. The data included, but were not limited to, general information such as gender, age, neck stiffness, length of hospital stay, and ventilator use; complications like hypertension, diabetes, bloodstream infections, and heart failure; blood biochemistry parameters including white blood cell count, hemoglobin, platelets, serum procalcitonin, venous glucose, serum lactate (Lac), total bilirubin, albumin, and glomerular filtration rate; and CSF biochemistry indicators such as white blood cell count, Lac, lactate dehydrogenase (LDH), glucose, protein, and albumin. CSF culture data encompassed the time of the first positive specimen sent for testing. Both blood and CSF biochemical indicators were obtained from the day the positive CSF culture was identified. The primary outcome variable was the 30-day all-cause mortality rate. The screening process is illustrated in Fig. 1.Fig. 1 Study flow diagram.

Antimicrobial susceptibility test

Klebsiella pneumoniae was identified using the Vitek 2 system (Biomerieux, Marcy-l'Etoile, France). The identification and antimicrobial susceptibility testing were conducted with the Vitek Compact system. Clinical tests for antimicrobial sensitivity were performed using either disc diffusion or broth or agar dilution MIC tests. The evaluation of sensitivity for tigecycline and polymyxins adhered to the standards and recommendations set forth by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)12. Antimicrobial susceptibility tests were conducted and interpreted in accordance with guidelines from the Clinical and Laboratory Standards Institute (CLSI)13. Resistance to carbapenems was defined as non-susceptibility to any carbapenem antibiotics, including ertapenem, meropenem, imipenem, and doripenem.

Statistical analysis

The primary outcome was the 30-day all-cause mortality, measured from the onset of intracranial infection, as indicated by a positive CSF culture. The occurrence of CRKP intracranial infection was assessed as a secondary outcome. Clinical features were compared between CRKP and CSKP infections, and risk factors for these outcomes were analyzed.

Statistical analyses were performed using IBM SPSS version 26.0. Depending on the data distribution, either the Chi-square (χ2) test or Fisher’s exact test was used for categorical variables, and the t-test or Mann–Whitney U test was employed for continuous variables. To assess the impact of intracranial infection with CRKP on 30-day all-cause mortality, survival analysis was initially conducted to generate Kaplan–Meier curves for both CRKP and CSKP. Subsequently, a Cox proportional hazards model was utilized to evaluate the influence of various factors on carbapenem resistance. This model included all potential predictors of CRKP as independent variables.

Standard univariate and multivariable logistic regression analyses were performed to calculate odds ratios (ORs), 95% confidence intervals (CIs), and p-values. Variables demonstrating a p-value less than 0.01 in the univariate analysis were subsequently included in the multivariate logistic regression analysis. This analysis aimed to identify factors associated with clinical outcomes in patients with intracranial infections, utilizing a stepwise logistic regression method. Statistical significance was established at a p-value of less than 0.05. The dependent variables, CRKP occurrence and 30-day mortality, were analyzed separately.

Result

From January 1, 2018, to June 30, 2023, a total of 1,164 patients were included in the study, of which 201 culture-proven K. Pneumoniae intracranial infectious patients. Of these, 176 cases had confirmed CSF culture results for Klebsiella pneumoniae and met the inclusion criteria for the study. The screening process is depicted in Fig. 1.

Characteristics of the CRKP and CSKP group

Among the 176 patients included in the final analysis, the median age was 52.5 years, ranging from 17 to 74 years. A total of 112 patients (63.6%) were male, and 64 (36.4%) were female. Additionally, 75.6% of the patients had been previously admitted to the intensive care unit, with an average hospital stay of 27.5 days. Of the 176 cases of Klebsiella pneumoniae intracranial infection, 90 cases (51.1%) involved samples obtained via ventricular drainage, which was more frequent than those obtained via lumbar puncture, although the difference was not pronounced. KPCs (Klebsiella pneumoniae carbapenemases) was the most prevalent carbapenemase, found in 62 isolates (60%). Additionally, the presence of ESBLs (extended-spectrum beta-lactamases) and AmpC beta-lactamases further contributes to drug resistance. Clinical characteristics of the patients are detailed in Table 1.Table 1 Clinical characteristics of intracranial infection caused by K. Pneumoniae.

Variables	Total (n = 176)	CSKP (n = 73)	CRKP (n = 103)	p values	
Age, years	52.5 [43, 60]	54.00 [47.00, 64.00]	50.00 [41.00, 57.00]	0.034*	
Male, n (%)	112 (63.6)	41 (56.2)	71 (68.9)	0.083	
LOS, days	27.5 [13, 41]	30.00 [17.00, 41.00]	23.00 [11.50, 41.00]	0.152	
CSF	
 WBC count (*106/L)	3001 [283.75, 11,320.25]	2317.00 [513.00, 10,763.00]	3781.00 [262.50, 11,472.00]	0.949	
 Glu (mmol/L)	1.165 [0.11, 2.90]	0.90 [0.11, 2.36]	1.31 [0.11, 3.26]	0.32	
 LDH (U/L)	457.5 [164.75, 1169.75]	357.00 [83.00, 942.00]	565.00 [222.00, 1600.50]	0.002*	
 Lac (mmol/L)	11.76 (34.57)	12.24 (5.63)	11.41 (6.06)	0.357	
 Protein (mg/L)	3603 [1372.25, 7847.75]	3618.00 [1735.00, 7648.00]	3297.00 [1204.50, 7822.50]	0.764	
 Albumin (mg/L)	2080.1 [736.1, 4137.4]	2304.00 [852.00, 3960.00]	2005.00 [675.00, 4162.50]	0.894	
Blood	
 WBC (*109/L)	12.11 [9.64, 15.64]	11.68 [9.17, 14.45]	12.49 [9.84, 17.22]	0.039*	
 HB (g/L)	104.5 [89, 118]	108.00 [92.00, 121.00]	101.00 [88.00, 114.00]	0.02*	
 PLT (*109/L)	225.5 [131.75, 290.75]	204.00 [131.00, 283.00]	241.00 [141.00, 297.00]	0.429	
 Lac (mmol/L)	1.3 [1, 1.8]	1.30 [1.00, 1.80]	1.30 [1.00, 1.70]	0.637	
 PCT (ng/mL)	0.96 [0.4225, 3.33]	0.90 [0.42, 1.45]	1.14 [0.45, 4.30]	0.034*	
 Glu (mmol/L)	8.5 [6.92, 11.08]	8.50 [7.00, 10.80]	8.50 [6.94, 11.20]	0.626	
 Bilirubin (μmol/L)	11.1 [7.125, 17.275]	10.80 [7.40, 16.60]	11.40 [6.85, 17.25]	0.883	
 ALB (g/L)	33.42 (40.54)	32.99 (6.02)	33.73 (6.61)	0.451	
 GFR (ml/min/1.73m2)	113.30 [101.93, 127.08]	111.24 [102.33, 123.30]	117.06 [102.18, 131.30]	0.138	
 SOFA (score)	6 [4, 8]	5.00 [3.00, 8.00]	7.00 [5.00, 8.50]	0.01*	
The ratio of CSF to arterial blood	
 Lac ratio	7.89 [5.61, 12.15]	8.11 [6.10, 10.48]	7.71 [5.28, 12.39]	0.629	
 Glu ratio	0.13 [0.013, 0.329]	0.11 [0.01, 0.25]	0.14 [0.01, 0.41]	0.387	
 Alb ratio (*10–3)	66.86 [21.35, 132.32]	77.21 [23.44, 122.89]	57.70 [19.64, 138.92]	0.875	
 Time of diagnoses (days)	6 [1, 14.75]	5.00 [1.00, 14.00]	6.00 [1.00, 15.50]	0.474	
 Time proportion	0.295 [0.13, 0.61]	0.30 [0.14, 0.59]	0.28 [0.10, 0.60]	0.45	
Access to cerebrospinal fluid	
 Sampling via a ventricular drain (%)	90 (51.1)	36 (49.3)	54 (52.4)	0.684	
Comorbidity	
 Cerebral hemorrhage (%)	115 (65.3)	41 (56.2)	74 (71.8)	0.031*	
 Acute cerebral infarction (%)	17 (0.1)	8 (11.0)	9 (8.7)	0.623	
 Traumatic brain injury (%)	41 (23.3)	18 (24.7)	23 (22.3)	0.719	
 Intracranial tumor (%)	34 (19.3)	21 (28.8)	13 (12.6)	0.008*	
 Admission to ICU setting (%)	133 (75.6)	44 (60.3)	89 (86.4)	< 0.001*	
 Stiff neck (%)	118 (67.0)	41 (56.2)	77 (74.8)	0.01*	
 Ventilator therapy (%)	95 (80.5)	32 (43.8)	63 (61.2)	0.023*	
 Hypertension (%)	56 (31.8)	22 (30.1)	34 (33.0)	0.687	
 DM (%)	30 (17.0)	7 (9.6)	23 (22.3)	0.027*	
 BSI (%)	54 (30.7)	16 (21.9)	38 (36.9)	0.034*	
 HF (%)	19 (10.8)	7 (9.6)	12 (11.7)	0.664	
Antibiotic resistance	
 Tigecycline (n = 176)	16 (9.0)	0	16 (16.0)	< 0.001*	
 Polymyxins (n = 136)	16 (11.8)	0	16 (21.1)	< 0.001*	
 Fluoroquinolones (n = 172)	138 (80.2)	57 (79.2)	81 (81.0)	0.766	
 Piperacillin-tazobactam (n = 176)	130 (73.9)	49 (67.1)	81 (78.6)	0.087	
 Cefoperazone-sulbactam (n = 148)	95 (84.1)	33 (52.4)	62 (72.9)	0.01*	
 Non-MDR	60	60 (82)	0		
 MDR	33	13 (18)	20 (19.4)		
 XDR	78	0	78 (75.7)		
 PDR	5	0	5 (4.8)		
Resistance mechanisms in CRKP isolates (n = 103)	
 KPCs			62 (60)		
 AmpCs or/and ESBLs			54 (52.4)		
 MBLs			14 (13.3)		
*p < 0.05. Data are presented as mean (SD), median [IQR], or %, except where otherwise specified. CRKP, carbapenem-resistant K. pneumoniae; CSKP, carbapenem-susceptive K. Pneumoniae; LOS, length of stay; CSF, cerebrospinal fluid; WBC, White blood cell; Glu, glucose; LDH, lactate dehydrogenase; PCT, procalcitonin; Lac, lactate; ALB, albumin; GFR, glomerular filtration rate; SOFA, Sequential Organ Failure Assessment; ICU, intensive care unit; DM, diabetes; BSI, bloodstream infection; HF, heart failure; KPCs, Klebsiella pneumoniae carbapenemases; ESBLs, Extended-spectrum beta-lactamases; AmpCs, AmpC beta-lactamases; MBLs, metallo-beta-lactamases, mainly contains NDM (New Delhi metallo-beta-lactamase), VIM (Verona integron-encoded metallo-beta-lactamase), and IMP (Imipenemase metallo-beta-lactamase).

Outcome after CRKP versus CSKP

The 30-day mortality rate for patients with CRKP was 57.3% (59 of 103 patients), compared to 31.5% for those with CSKP (23 of 73 patients). Survival analysis conducted using the Kaplan–Meier method revealed that the CSKP group exhibited a higher survival rate and longer survival time compared to the CRKP group (p < 0.001, log-rank test). Furthermore, the hazard ratio for mortality in the CRKP group was 2.224 times higher than that in the CSKP group (95% CI 1.372–3.605, p < 0.001). After adjustments, the mortality hazard ratio increased to 2.380 (95% CI 1.436–3.944, p < 0.001). These results, including hazard ratios (HRs) and p-values, are summarized in Table 2 and illustrated in Fig. 2.Table 2 Hazard ratios for death (73 CSKP, 103 CRKP).

	Outcome	
	Death (with 30 days after intracranial infection)	
Exposure	Unadjusted hazard ratio
(95%CI)	Adjusted hazard ratio
(95%CI)	
CSKP	1(Ref.)	1(Ref.)	
CRKP	2.224

(1.372–3.605)

p = 0.001

	2.380

(1.436–3.944)

p = 0.001

	
Hazard ratios are adjusted for age (10-year groups), gender and SOFA score (3 groups). CI, confidence intervals; CRKP, carbapenem-resistant K. pneumoniae; CSKP, carbapenem-susceptive K. Pneumoniae. SOFA, Sequential Organ Failure Assessment.

Fig. 2 Survival curve for 30-day all-cause mortality on intracranial infection caused by CRKP and CSKP.

Hazard ratios for patients with CRKP versus CSKP intracranial infection by time since admission

In the primary inverse unadjusted COX model, high SOFA score (HR = 1.050, 95%CI 1.003–1.099, p = 0.038) and low time proportion (HR = 0.475, 95%CI 0.247–0.914, p = 0.026) and intracranial tumor (HR = 0.502, 95%CI 0.280–0.898, p = 0.020), was associated with CRKP intracranial infection. The higher rate of admission to ICU setting(HR = 2.575, 95%CI 1.464–4.528, p = 0.001), stiff nick(HR = 1.747, 95%CI 1.119–2.727, p = 0.014), ventilator therapy(HR = 1.592, 95%CI 1.070–2.367, p = 0.022), diabetes(DM) (HR = 1.781, 95%CI 1.119–2.836, p = 0.015), BSI (HR = 1.578, 95%CI 1.057–2.357, p = 0.026), and increased CSF LDH(HR = 1.287, 95%CI 1.115–1.484, p = 0.001), Blood WBC(HR = 1.056, 95%CI 1.019–1.095, p = 0.003), Serum PCT(HR = 1.174, 95%CI 1.083–1.273, p < 0.001) are associated with the occurrence of drug-resistant Klebsiella pneumoniae intracranial infections(eTable 1). Significant risk factors for CPKP in the adjusted Cox model included Blood WBC (HR = 1.047, 95%CI 1.010–1.085, p = 0.012), serum PCT (HR = 1.134, 95%CI 1.039–1.238, p = 0.005), DM (HR = 1.699, 95%CI 1.056–2.735, p = 0.029) and time proportion (HR = 0.521, 95%CI 0.275–0.986, p = 0.045) (Table 3).Table 3 Adjusted Hazard ratios for patients with CRKP versus CSKP intracranial infection by time since admission.

Variables	hazard ratio (95%CI)	p value	
CSF LDH(U/L)†	1.159(0.996, 1.348)	0.056	
Blood WBC	1.047(1.010, 1.085)	0.012*	
Serum PCT	1.134(1.039, 1.238)	0.005*	
SOFA score	0.996(0.938, 1.058)	0.895	
Time proportion	0.521(0.275, 0.986)	0.045*	
intracranial tumor	0.713(0.373, 1.364)	0.307	
admission to ICU setting	1.346(0.687, 2.638)	0.387	
Stiff neck	1.414(0.845, 2.365)	0.187	
ventilator therapy (more than 24 h)	1.075(0.663, 1.743)	0.771	
DM	1.699(1.056, 2.735)	0.029*	
BSI	1.229(0.780, 1.934)	0.374	
*p < 0.05. †After semi-logarithmic conversion, the data participated in the establishment of the model. CI, confidence intervals.

CRKP, carbapenem-resistant K. pneumoniae. CSF, cerebrospinal fluid; LDH, lactate dehydrogenase; PCT, procalcitonin; SOFA, Sequential Organ Failure Assessment; ICU, intensive care unit; DM, diabetes; BSI, bloodstream infection.

Risk factor for intracranial infection caused by Klebsiella pneumoniae

Univariate logistic regression analysis was performed and results presented in eTable 2. The multivariate logistic regression analysis revealed that length of stay(OR = 0.923, 95%CI 0.891–0.951, p < 0.001), SOFA score(OR = 1.178, 95%CI 1.015–1.388, p = 0.037), the ratio of cerebrospinal fluid to blood Lac(OR = 1.105, 95%CI 1.014–1.211, p = 0.025), the rate of mechanical ventilation usage(OR = 3.608, 95%CI 1.37–9.868, p = 0.01), infection with carbapenem-resistant Klebsiella pneumoniae(OR = 3.253, 95%CI 1.297–8.566, p = 0.014), and heart failure(OR = 6.652, 95%CI 1.477–40.278, p = 0.022), are independent risk factors for 30-day all-cause mortality (Table 4).Table 4 30-day mortality of multivariate analysis for intracranial infection caused by K. pneumoniae.

Variables	odds ratio (95%CI)	p value	
LOS (days)	0.923(0.891, 0.951)	< 0.001*	
CSF Glucose (mmol/L)	0.842(0.663, 1.057)	0.144	
SOFA score	1.178(1.015, 1.388)	0.037*	
Lac ratio	1.105(1.014, 1.211)	0.025*	
Male	2.238(0.867, 5.961)	0.099	
Ventilator therapy	3.608(1.37, 9.868)	0.01*	
CRKP	3.253(1.297, 8.566)	0.014*	
HF	6.652(1.477, 40.278)	0.022*	
*p < 0.05, CI, confidence intervals.

LOS, length of stay; CSF, cerebrospinal fluid; Lac, lactate; SOFA, Sequential Organ Failure Assessment; CRKP, carbapenem-resistant K. pneumoniae; HF, heart failure.

Discussion

It was observed that the predominant pathogenic bacteria in this study were gram-negative, with Klebsiella pneumoniae being the most prevalent (Fig. 1). This finding contrasts with previous studies where Acinetobacter baumannii or Escherichia coli were identified as the primary pathogens14,15. This variation in predominant pathogens may be attributed to the differences in patient populations and case types included in previous studies compared to our research. Earlier studies on adult intracranial infections often focused on specific pathogens such as pneumococcal meningitis or Acinetobacter baumannii infections following neurosurgery. In contrast, our study encompassed a broader range of intracranial infections resulting from various central nervous system diseases, including strokes, hemorrhages, and traumas, predominantly among critically ill patients in the intensive care unit. The microbiological profile of intracranial infections observed in our hospital aligns with findings reported in the existing literature, primarily indicating bacterial infections with an increasing dominance of gram-negative bacterial1. The data presented in this paper further corroborate the widespread prevalence of Klebsiella pneumoniae.

In this study, patients with confirmed Klebsiella pneumoniae meningitis, evidenced by two or more consecutive positive cerebrospinal fluid (CSF) smears or cultures, experienced a 30-day all-cause mortality rate of 46.6%. According to various research reports, the mortality rate for similar conditions ranges from 48.5 to 66.0%4–6.These figures are consistent with the rates reported in previous studies.

The high mortality rate observed in this study can be attributed to several factors: (1) A significant proportion of patients (75.6%, or 133 out of 176) were admitted to the intensive care unit with unstable vital signs, multiple complications, and comorbid conditions, contributing to an elevated overall mortality rate. (2) The emergence and increasing prevalence of multidrug-resistant strains have led to a rise in antibiotic-resistant infections, for which treatment options are severely limited. (3) Variability in the incidence, culture positivity, and mortality rates of meningitis across different studies can be attributed to variations in inclusion criteria and endpoints, complicating direct comparisons. (4) Certain strains of Pneumococcus exhibit highly adhesive and virulent characteristics, making the bacteria more difficult to eradicate from the body. Additionally, the study's methodology, which included only patients with positive cerebrospinal fluid (CSF) cultures confirmed by lumbar puncture, inherently excludes cases with false-positive intracranial infections. However, the exclusion of some patients with negative CSF cultures, despite previous studies indicating a positive culture rate of approximately 50%16,17, may lead to an underestimation of the mortality rates. This suggests that the actual all-cause mortality rate might be higher than reported.

In this study, laboratory indices indicated poorer health outcomes in the CRKP group compared to the CSKP group. LDH, a fermentative enzyme widely present in many tissues and body fluids including CSF, has been previously noted to increase in conditions such as tuberculous and bacterial meningitis. Studies have shown that total CSF LDH activity is higher in bacterial meningitis compared to aseptic meningitis18, and it is particularly elevated in the bacterial meningitis group when compared to non-meningitis groups. It has been suggested that LDH isoenzyme levels may have clinical diagnostic value in meningitis18. Our research supports the notion that CSF LDH levels could serve as a biomarker to differentiate between CSKP and CRKP intracranial infections. Moreover, the findings suggest that the longer the duration until a definitive diagnosis of CSF intracranial infection is made, the greater the likelihood of encountering CRKP.

Signs and symptoms may be more severe in the CRKP group than CSKP group. The CRKP group exhibited a higher incidence of stiff neck, a greater proportion of cerebral hemorrhage, higher rates of diabetes, bloodstream infections, and intracranial tumor complications. Moreover, patients in the CRKP group were more frequently admitted to the intensive care unit, had higher SOFA scores, and required greater use of mechanical ventilation.

In contrast, the incidence of stiff neck in meningitis was only 67%. In the community-acquired intracranial infections study by Diederik van de Beek, which included 696 cases, nearly all patients (95%) exhibited at least two of the four key symptoms: headache, fever, stiff neck, and altered mental status. Advanced age, positive blood cultures, and decreased platelet count were identified as poor prognostic factors19. However, this study did not find age and platelet count to influence prognosis significantly. In the univariate analysis, the mortality rate among male patients was significantly higher than that among female patients, though gender did not emerge as an independent risk factor for poor prognosis. Studies in Taiwan have indicated a correlation between pneumococcal infection and males, along with diabetes and cirrhosis4,20. Yet, a study of 621 cases of bacterial meningitis found no difference in treatment outcomes between genders21, suggesting that factors such as alcoholism and cirrhosis, which vary significantly between genders, may more directly impact outcomes than gender itself.

Furthermore, concomitant conditions such as traumatic brain injury, intracranial tumors, bloodstream infections, heart failure, increased SOFA scores, and the use of mechanical ventilation upon admission significantly heightened the 30-day all-cause mortality in patients with intracranial infections. Stepwise logistic regression analysis identified an extended hospital stay as a protective factor against poor prognosis, while heart failure and mechanical ventilation emerged as independent predictors of poor outcomes. Heart failure is a well-recognized prognostic marker, and the necessity for mechanical ventilation typically indicates respiratory failure, both of which substantially affect patient outcomes. This finding aligns with Li et al.'s retrospective study of 25 patients with pneumococcal meningitis, where the non-survivor group exhibited higher mechanical ventilation usage22.

For patients presenting with poor admission conditions and multiple-system damage, these factors pose significant challenges. An early comprehensive assessment of overall health status upon admission is crucial to guide subsequent clinical decision-making.

All-cause mortality rates at the 30th day after diagnosis of intracranial infection caused by CRKP were significantly higher compared to those in patients with carbapenem-susceptible infections. These differences remained significant after adjustments were made for age, sex, and SOFA scores. The rapid diagnosis of intracranial infections is a critical function of clinical laboratories, typically reliant on analyses of CSF parameters such as glucose, protein, white cell counts and differential, as well as Gram stain and culture. Previous studies have associated low CSF white cell counts with adverse outcomes23. However, our study found opposite significant correlation between CSF white cell count and all-cause mortality. Similar statistical outcomes were noted for CSF lactate dehydrogenase (LDH), protein, and albumin, where large fluctuations led to odds ratios and 95% confidence intervals approximating 1. After data processing with semi-logarithmic transformations, the hazard ratios reached canonical values. Our findings indicate that decreased CSF glucose levels, increased Lac levels, and elevated protein and albumin levels significantly elevated the 30-day all-cause mortality rate in patients with Klebsiella pneumoniae intracranial infections.

Previous research has highlighted that the ratio of CSF to blood glucose can meaningfully guide the diagnosis of intracranial infections. However, no existing studies have provided guidance on prognosis based on CSF to blood biochemical ratios. In this study, it was noted significant increases in all-cause mortality associated with the CSF to blood ratios of Lac, glucose, and albumin in patients with K. pneumoniae intracranial infections. Therefore, we recommend that for patients with suspected intracranial infections, CSF biochemical levels should be assessed alongside readily accessible blood biochemical markers, and the prognostic assessment should incorporate the CSF to blood biochemical ratios.

In unadjusted and adjusted Cox regression analyses, the time proportion showed an association with CRKP. However, this association weakened in multifactor Cox regression analyses. A limitation of this study was the inadequate representation of participants with intracranial infection caused by CRKP. The exclusion of some patients due to the reliance on a single diagnostic method, the low positive rate of bacterial cultures, and an even lower rate of cerebrospinal fluid specimens potentially skewed the findings.

After adjusting for confounders, factors such as the SOFA score, the CSF to blood Lac ratio, the use of mechanical ventilation, CRKP infection, and heart failure were identified as independent risk factors for 30-day all-cause mortality. While serum Lac levels were not predictive of prognosis, CSF Lac levels significantly impacted outcomes. After removing linear correlations among variables, the CSF to blood Lac ratio independently predicted mortality outcomes, underscoring that CSF Lac levels, unaffected by serum concentrations, are a significant determinant of CSF Lac.

Globally, the emergence of antibiotic resistance poses a serious challenge, affecting empirical treatment choices across many countries. CRKP has emerged as a major threat associated with high mortality rates, recognized as an independent risk factor for hospital mortality, with associated mortality rates exceeding 50%24. Our study, comparing carbapenem-susceptible and resistant groups, found a significant correlation between CRKP infections and increased all-cause mortality. After adjusting for multiple variables, the 30-day all-cause mortality rate for patients with CRKP was nearly three times that of those with carbapenem-susceptible strains. In contrast, research by Yuming Li et al., which included only 25 patients and lacked variable adjustments, did not find a significant difference in mortality rates between CSKP and CRKP groups22. The core of bacterial resistance to carbapenems is the emergence of carbapenemases and the widespread dissemination of their encoding genes among different pathogens, significantly compromising the efficacy of these drugs. KPCs, often plasmid-mediated, enables the spread of resistance genes among Enterobacteriaceae and can hydrolyze a wide range of antimicrobials, including penicillins, cephalosporins, carbapenems, and β-lactamase inhibitors. The prevalence of CRKP complicates antibiotic selection, making the timely and accurate prediction of resistance essential for effective treatment and the prevention of the spread of resistant bacteria25.

The strength of our study lies in its robust design, which ensured all included patients had positive CSF cultures, thereby eliminating false positives and enrollment biases. This approach addresses a gap in previous studies, which included fewer case reports on this specific subject. Additionally, our study uniquely investigated the impact of the CSF to blood biochemical ratio on prognosis, identifying the CSF to blood Lac ratio as an independent risk factor for 30-day all-cause mortality—a factor predominantly attributed to CSF Lac levels.

However, this study is not without limitations. First, while this study included more isolates than some previous studies, data from a single institution may not accurately represent the broader Chinese population. Future research could benefit from multicenter, large-sample studies to enhance the representativeness and reliability of findings. Second, the pathogenesis and resistance mechanisms of K. pneumoniae intracranial infections were not extensively explored at a basic scientific level; further detection of genotypes and molecular-level studies of resistance characteristics of each isolate were not conducted. During our study period, we did not concern isolates that exhibited the hypervirulent phenotype typically associated with hvKP (hypervirulent KPN) because our study only identified no more than 10 cases of hvKP. Finally, some laboratory tests, such as CRP testing in CSF—a simple, rapid, and accurate method for diagnosing bacterial meningitis—and CSF PCT, though less accurate than serum PCT, were not performed. Nevertheless, changes in these biomarkers could provide valuable insights for diagnosing suspected intracranial infections.

Conclusion

Patients with intracranial infection caused by CRKP have a higher mortality. A higher SOFA score, increased cerebrospinal fluid/blood Lac ratio, use of mechanical ventilation. Higher SOFA scores, higher Lac ratio in cerebrospinal fluid to blood, concomitant heart failure, and infection with carbapenem-resistant Klebsiella pneumoniae indicate a poor prognosis, while longer hospital stays in patients with intracranial infections are associated with lower mortality risks. Therefore, active supportive treatment is required for patients with intracranial infections and systemic complications due to carbapenem-resistant Klebsiella pneumoniae, preferably in a comprehensive medical facility with rescue capabilities.

Supplementary Information

Supplementary Information.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-71660-4.

Acknowledgements

Not applicable.

Author contributions

Yonggang Luo and Chengcheng Lai proposed ideas and specify implementation plans. Weiwei Xu and Zhuanghao Wu collected and organized clinical data. Chengcheng Lai and Zijun Ma wrote the entire manuscript, Jun Zhang finished data analysis. Yonggang Luo and YuanGao revised and reviewed the entire article. All authors read and approved the final manuscript.

Funding

This research was funded by Young and Middle-aged Scientific Technological Innovation Jie-Qing Talent Project (YXKC2021042), Henan Province Key Medical Science and Technology Research Project Co-established by Provincial and Ministerial Authorities (CN) (SBGJ202102081), Henan Province Science and Technology Research Project (CN) (242102311040), Henan Province Natural Science Foundation Project (CN) (242300420384).

Data availability

Data is provided within the manuscript or supplementary information files. Find some help on our Data availability statements page.

Competing interests

The authors declare no competing interests.

Ethics approval

This study protocol was approved by the institutional review board (IRB) of the First Affiliated Hospital of Zhengzhou University (No. 2023-KY-1485-001) and was performed in accordance with the principles of the Declaration of Helsinki. Since this was a retrospective medical chart review study, informed consent was not obtained from participants and the Ethics Review Committee of the First Affiliated Hospital of Zhengzhou University granted a waiver of informed consent.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Chengcheng Lai and Zijun Ma.
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