Clinical Features of Post-Operative Nosocomial Meningitis in Adults and Evaluation of Efficiency of Intrathecal Treatment

Abstract

Background:

Post-operative nosocomial meningitis is a critical complication that develops in patients after neurosurgical interventions and operations.

Patients and Methods:

Data were collected for 65 patients who were diagnosed as having nosocomial meningitis after neurosurgery. The agent profile, clinical and biochemical differences in gram-negative and gram-positive meningitis, and the effectiveness of intrathecal antibiotic administration in cases with carbapenem-resistant gram-negative agents were evaluated.

Results:

Gram-negative bacteria were isolated in 52.3% of patients. In gram-negative cases of post-operative nosocomial meningitis, white blood cell count (p = 0.015), C-reactive protein (p = 0.001), cerebrospinal fluid leukocyte count (p = 0.0001), and protein (p = 0.0001) were higher, and glucose (p = 0.002) was lower. Concurrent bacteremia (p = 0.041), 14-day mortality (p = 0.022), and 30-day mortality (p = 0.023) were higher in gram-negative cases. Empirical treatment was appropriate in 78.5% of the patients. Seventeen patients (26.2%) received intrathecal antibiotic agents in addition to intravenous antibiotic treatment because of carbapenem-resistant gram-negative bacteria. Nine (53%) of the patients receiving intrathecal therapy had Acinetobacter baumannii as the agent, six had Klebsiella pneumoniae (35.4%), one had Pseudomonas aeruginosa (5.8%), and one had Providencia rettgeri (5.8%). The mean intravenous treatment duration was 21.4 ± 10.6 (4–60) days, and the mean intrathecal treatment duration was 17.6 ± 14.0 (1–51) days. Eleven patients received colistimethate sodium intrathecally (1 × 10 mg/d), three patients received amikacin intrathecally (1 × 10 mg/d), and three patients received gentamicin intrathecally (1 × 10 mg/d). Clinical and microbiologic treatment success was achieved in nine patients (53%).

Conclusions:

In cases of meningitis caused by carbapenem-resistant agents, intrathecal administration of antibiotic agents such as gentamicin, amikacin, and colistin with limited blood-brain barrier transition in intravenous administration will increase survival. Therefore, intrathecal antibiotic administration should be considered as a part of routine of nosocomial meningitis.

Post-operative nosocomial meningitis (PNM) is a critical complication that develops in 0.34%–3.1% of patients after neurosurgical interventions and operations (craniotomy, internal or external catheter insertion, lumbar puncture, and spinal anesthesia), complicated head trauma, or rarely, nosocomial bacteremia and causes severe morbidity and mortality [1 –9].

Although a wide range of bacteria causes cases of PMN, gram-negative bacteria have been isolated more frequently in recent years [10,11]. Increased resistance rates reported in gram-negative bacteria also lead to problems in treatment [12]. Moreover, in cases caused by third- and fourth-generation cephalosporins and carbapenem-resistant (CR) bacteria such as Acinetobacter species, parenterally administered antimicrobial drugs do not reach sufficient concentration in cerebrospinal fluid, which makes treatment difficult [13]. Some studies report that intraventricular or intrathecal administration of aminoglycoside or colistin is beneficial in cases caused by multi-drug–resistant gram-negative bacteria [12,14,15].

In this study, we aimed to reveal the agent profile of cases of PNM, investigate the clinical and biochemical differences in gram-negative and gram-positive meningitis, and discuss the effectiveness of intrathecal antibiotic administration in cases with CR gram-negative agents.

Patients and Methods

This retrospective study included 65 patients older than 16 years of age who were followed up and treated for invasive intervention or PNM at the University of Health Sciences Antalya Training and Research Hospital between January 1, 2014 and December 31, 2018.

The demographic, clinical, and treatment information for the patients was obtained from the follow-up forms filled out by the infectious disease specialist. We evaluated the duration of pre-operative hospitalization, the time between the operation and the diagnosis of meningitis, the reason and type of the operation (urgent or elective), the presence of an extra-ventricular drainage (EVD) catheter, blood and cerebrospinal fluid (CSF) biochemical values, presence of concurrent bacteremia, CSF culture results, antibiotic agents given in empirical therapy, intravenous and intrathecal treatment duration, and survival status.

U.S. Centers for Disease Control and Prevention (CDC) criteria were applied in the definition of nosocomial meningitis [16]. Patients diagnosed with nosocomial meningitis were included in the study providing that proliferation was observed in the CSF culture or at least one of the signs of meningeal irritation was present such as headache, neck stiffness, cranial nerve involvement for no other reason, and that the patients displayed at least one of these criteria (increased neutrophil count, increased protein and/or decreased glucose level in the CSF; micro-organism in CSF gram stain; a proliferation in blood culture; positive antigen test in blood, CSF, or urine; increased antibody titer against the pathogenic micro-organism). Cases with brain abscess, peritoneal shunt infection, those with incomplete demographic and clinical information, and those who died within the first 72 hours after the initiation of treatment were excluded from the study. One patient who had a CSF culture in which multiple bacteria proliferated (coagulase-negative staphylococci and diphtheroid bacillus) and who died within two days of the treatment was also not included in the study.

Cerebrospinal fluid samples were taken via EVD catheters with suspected PNM or by lumbar puncture in patients without a catheter. Cell count, glucose, and protein were studied from the CSF sample, and inoculation was performed in a blood culture vial. Blood culture was taken simultaneously. Bacteria isolated in CSF and blood culture were identified through the VITEK 2 identification system (bioMerieux, France). Antibiotic susceptibility patterns of the isolated bacteria were identified by the VITEK 2 system and reported to the Clinical Laboratory Standards Institute (CLSI).

A cure was defined as the improvement of meningitis findings, no proliferation in control CSF culture, and no relapse within three months after antibiotic treatment was completed clinically and laboratory [17]. Mortality was considered to be attributable to meningitis if all the following criteria were met: no negative CSF culture result, non-resolving inflammatory parameters, no resolution of clinical signs of meningitis, and no agent other than meningitis was found to be more probable according to the physician [17 –19].

Empiric intravenous antibiotic agents were administered to all patients. Treatment was modified based on the CSF culture result. It was defined as appropriate treatment, providing that the bacteria proliferated in CSF culture were susceptible to empirical therapy. In cases in which CR gram-negative bacteria proliferated in CSF culture, intrathecal antibiotic treatment was added to the intravenous treatment.

The data obtained in the study were analyzed by SPSS Statistics, version 21 (IBM Corp, Armonk, NY) software. Continuous variables were shown as mean ± standard deviation, median (minimum-maximum), and categorical variables as n (%). Chi-square and Mann-Whitney U test were used for comparison of the groups. A p value <0.05 value was considered statistically significant.

This study was approved by the Ethics Committee of University of Health Sciences Antalya Training and Research Hospital with the date of June 20, 2019 and the number 15/14.

Results

The mean age of the 65 patients included in the study was 47.4 ± 13.3 (16.0–76.0). Thirty-eight patients (58.5%) were male. The most common cause of operation was hemorrhage (34/65; 52.3%). The mean time between hospitalization and operation was 4.6 ± 8.6 (1–55) days, and the mean post-operative meningitis development time was 14.1 ± 9.4 (4–47) days. Twenty-ine patients (32.3%) had concurrent bacteremia with meningitis. Table 1 summarizes the demographic characteristics of the patients.

Table 1.

Demographic and Clinical Features of Patients with Post-Operative Nosocomial Meningitis

Age (y, mean ± SD)	47.4 ± 13.3
Time between operation and meningitis (d, mean ± SD)	14.1 ± 9.4
Gender (n, %)
Male	38 (58.5)
Female	27 (41.5)
Reason for operation (n, %)
Hemorrhage	34 (52.3)
Hydrocephalia	15 (23.0)
Tumor	12 (18.5)
Trauma	4 (6.2)
Operation type (n, %)
Urgent	34 (52.3)
Elective	31 (47.7)
Extra-ventricular drainage catheter (n, %)	24 (36.9)
Concurrent bacteremia (n, %)	20 (30.8)
Intrathecal therapy (n, %)	17 (26.2)

SD = standard deviation.

In the CSF cultures of cases of PNM, 52.3% (34/65) gram-negative bacteria were isolated (Table 2). The most common bacteria were CoNS (20/65; 30.7%), Klebsiella pneumoniae (11/65; 17.0%), and Acinetobacter baumannii (10/65; 15.3%). Gram-negative bacteria were the causative agents in 61.7% (21/34) of 34 cases who were operated on urgently (p = 0.08). Gram-positive bacteria in six of 24 cases with EVD catheter (6/24; 25%), and gram-negative bacteria in 14 (14/24; 75%) were isolated as causative agents (p = 0.001).

Table 2.

Causative Agents of Post-Operative Nosocomial Meningitis

		n (%)
Gram negative n = 34 (52.3%)	Klebsiella pneumoniae	11 (17.0)
	Acinetobacter baumannii	10 (15.3)
	Pseudomonas aeruginosa	5 (7.7)
	Enterobacter spp.	4 (6.1)
	Escherichia coli	2 (3.0)
	Providencia rettgeri	1 (1.6)
	Serratia	1 (1.6)
Gram positive n = 31 (47.7%)	Coagulase negative Staphylococcus	20 (30.7)
	Streptococcus spp.	4 (6.2)
	Streptococcus pneumoniae	3 (4.6)
	Staphylococcus aureus	3 (4.6)
	Enterococcus spp.	1 (1.6)

Demographic and biochemical parameters of gram-positive and gram-negative cases of PNM were compared (Table 3). In gram-negative cases of PNM, white blood cell count (WBC) (p = 0.015), C-reactive protein (CRP) (p = 0.001), CSF WBC (p = 0.0001), and CSF protein (p = 0.0001) were higher, and CSF glucose (p = 0.002) was lower (Table 3). Concurrent bacteremia (p = 0.041), 14-day mortality (p = 0.022), and 30-day mortality (p = 0.023) were higher in gram-negative cases of PNM (Table 3).

Table 3.

Comparison of the Demographic and Clinical Features of Gram-Negative and Gram-Positive Post-Operative Sosocomial Meningitis

	Gram positive n = 31	Gram negative n = 34	p
Age (y), mean ± SD	48.6 ± 13.7	46.4 ± 13.1	0.521
Duration between operation and meningitis (d), mean ± SD	14.0 ± 10.6	14.1 ± 8.4	0.603
Gender
Male	17 (54.8)	21 (61.8)
Female	14 (45.2)	13 (38.2)
Reason for operation
Hemorrhage	15 (48.4)	19 (55.9)
Tumor	6 (19.4)	6 (17.6)
Hydrocephalus	9 (29.0)	6 (17.6)
Trauma	1 (3.2)	3 (8.8)
Operation type
Urgent	13 (4.9)	21 (61.8)	0.177
Elective	18 (58.1)	13 (38.2)
Extra-ventricular drainage catheter	6 (19.4)	18 (52.9)	0.011
Leukocyte count (blood)	11,200 (6,100–263,00)	13,600 (8,600–32,500)	0.015
C-reactive protein	48 (2–105)	126.5 (21–410)	0.001
Leukocyte count (CSF) mean ± SD	100 (10–4,500)	715 (80–16,720)	0.0001
Glucose (CSF) mean ± SD	50 (0–143)	14 (0–80)	0.002
Protein (CSF) mean ± SD)	118 (50–6,605)	314.8 (34.9–6,605)	0.0001
Empirical treatment suitability	31 (100)	20 (58.8)	0.0001
Intravenous treatment duration	18.8 ± 4.5	23.7 ± 13.7	0.052
Concurrent bacteremia	6 (19.4)	14 (41.2)	0.041
Mortality (14 d)	2 (6.5)	11 (32.4)	0.022
Mortality (30 d_	4 (12.9)	14 (41.2)	0.023

SD = standard deviation; CSF = cerebrospinal fluid.

Empiric antibiotic therapy was provided for patients with suspected PNM. In empirical treatment, 39 patients received meropenem plus linezolid. Empirical treatment was appropriate in 78.5% (51/65) of patients. In 14 patients (21.5%), treatment was changed on average of 4.2 ± 2.5 (2–10) days depending on the culture results. Seventeen patients (26.2%) received intrathecal antibiotic agents in addition to intravenous antibiotic treatment because of to CR gram-negative bacteria.

Nine (53%) patients receiving intrathecal therapy had Acinetobacter baumannii as the agent, six had Klebsiella pneumoniae (35.4%), one had Pseudomonas aeruginosa (5.8%), and one had Providencia rettgeri (5.8%). The mean intravenous treatment duration was 21.4 ± 10.6 (4–60) days, and the mean intrathecal treatment duration was 17.6 ± 14.0 (1–51) days. Eleven patients received colistimethate sodium intrathecally (1 × 10 mg/d), three patients received amikacin intrathecally (1 × 10 mg/d), and three patients received gentamicin intrathecally (1 × 10 mg/d). Clinical and microbiologic treatment success was achieved in nine patients (53%).

Discussion

Post-operative nosocomial meningitis is an infection with high morbidity and mortality [1,4,9]. One-third of the cases occur in the first week and one-third in the second week after surgery [1,4]. In our study, the mean duration of PNM after surgery was 14.1 ± 9.1 days.

As a result of the increase in operations and the use of broad-spectrum antibiotic agents in recent years, the agent profile of nosocomial meningitis has changed in favor of multi-drug–resistant bacteria as in other nosocomial infections [20]. The treatment of gram-negative nosocomial meningitis has become a major problem in recent years since multi-drug–resistant pathogens are often isolated as agents [21 –23].

Acinetobacter baumannii is an important nosocomial pathogen and causes high mortality and morbidity [24 –26]. In recent years, China, Iran, and Turkey have reported an increase in cases of meningitis caused by Acinetobacter baumannii [24,27 –29]. In our study, 52.3% (34/65) of gram-negative bacteria were isolated as agents, 17% (11/65) of which was classified as Klebsiella pneumoniae and 15.3% (10/65) as Acinetobacter baumannii.

The choice of empirical antimicrobial therapy in nosocomial bacterial meningitis depends on the pathogenesis of the infection [7]. A combination of cefepime, ceftazidime, or meropenem along with vancomycin is preferred for empirical treatment in nosocomial meningitis that develops in patients hospitalized for a long time after surgery or with penetrating head trauma or skull base fracture [7,30]. Linezolid is an antibiotic of the oxazolidinone group that has reached adequate therapeutic efficacy in CSF and is effective in staphylococcal meningitis. It can also be used instead of vancomycin [31,32].

The main treatment for nosocomial meningitis is parenteral antibiotic therapy. However, most antibiotic agents cannot cross the blood-brain barrier and reach adequate concentration in the CSF [33,34]. In cases in which parenteral antimicrobial treatment alone is not sufficient and especially when resistant bacteria are the agents, in addition to systemic antibiotic therapy, the effectiveness of intraventricular and intraspinal administration of the antibiotic directly to the CSF has been demonstrated [12,13,30,35 –38]. Also, the application of intraventricular therapy in nosocomial meningitis resistant to standard intravenous treatment is included in the guidelines [39]. Vancomycin (5–20 mg/d), gentamicin 4–8 mg/d, amikacin (5–50 mg/d), and colistimethate sodium (10 mg/d) were used in the treatment in this way [7]. In a meta-analysis comparing intravenous with intravenous plus intrathecal treatment in patients with gram-negative nosocomial meningitis, it was shown that the infection-related mortality was reduced in CR cases [40].

Conclusions

As in nosocomial infections, the agent profile changes in favor of resistant gram-negative bacteria in nosocomial meningitis. Antibiotic resistance, especially in gram-negative bacteria, causes difficulty in treatment. Another critical factor affecting the treatment success in meningitis is the transition rate of the antibiotics to CSF. In cases of meningitis caused by CR agents, intrathecal administration of antibiotic agents such as gentamicin, amikacin, and colistin with limited blood-brain barrier transition in intravenous administration will increase survival. Therefore, intrathecal antibiotic administration should be considered as a part of routine treatment in the treatment of nosocomial meningitis.

Footnotes

Funding Information

The authors received no specific funding for this work.

Author Disclosure Statement

No competing financial interests exist.

References

Kurtaran

, Kuscu

, Ulu

, et al. The causes of postoperative meningitis: The comparison of gram-negative and gram-positive pathogens. Turk Neurosurg, 2018; 28:589–596.

Dettenkofer

, Ebner

, Els

, et al. Surveillance of nosocomial infections in a neurology intensive care unit. J Neurol, 2001; 248:959–964.

Federico

, Tumbarello

, Spanu

, et al. Risk factors and prognostic indicators of bacterial meningitis in a cohort of 3580 postneurosurgical patients. Scand J Infect Dis, 2001; 33:533–537.

Korinek

, Baugnon

, Golmard

, et al. Risk factors for adult nosocomial meningitis after craniotomy: Role of antibiotic prophylaxis. Neurosurgery, 2006; 59:126–133.

Palabiyikoglu

, Tekeli

, Cokca

, et al. Nosocomial meningitis in a university hospital between 1993 and 2002. J Hosp Infect, 2006; 62:94–97.

Van Aken

, de Marie

, van den Lely

, et al. Risk factors for meningitis after transsphenoidal surgery. Clin Infect Dis, 1997; 25:852–856.

Van de Beek

, Drake

, Tunkel

. Nosocomial Bacterial Meningitis. N Engl J Med, 2010; 362:146–154.

Reichert

, Medeiros

, Ferraz

. Hospital-acquired meningitis in patients undergoing craniotomy: Incidence, evolution and risk factors. Am J Infect Control, 2002; 30:158–164.

Mc Clelland

, Hall

. Postoperative central nervous system infection: Incidence and associated factors in 2111 neurosurgical procedures. Clin Infect Dis, 2009; 45:55–59.

10.

Logigan

, Mihalache

, Turcu

. Clinical study of 57 Cases of nosocomial meningitis. J Prevent Med, 2008; 16:59–68.

11.

Mancebo

, Domingo

, Blanch

, et al. Post-neurosurgical and spontaneous gram-negative bacillary meningitis in adults. Scand J Infect Dis, 1986; 18:533–538.

12.

Falagas

, Biliziotis

, Tam

. Intraventricular or intrathecal use of polymyxins in patients with gram-negative meningitis: A systematic review of the available evidence. Int J Antimicrob Agents, 2007; 29:9–25.

13.

Kim

, Peleg

, Lodise

, et al. Management of meningitis due to antibiotic-resistant Acinetobacter species. Lancet Infect Dis, 2009; 9:245–255.

14.

Katragkou

, Roilides

. Successful treatment of multidrug-resistant Acinetobacter baumannii central nervous system infections with Colistin. J Clin Microbiol, 2005; 43:4916–4917.

15.

Rodriguez Guardado

, Blanco

, Asensi

, et al. Multidrug-resistant Acinetobacter meningitis in neurosurgical patients with intraventricular catheters: Assessment of different treatments. J Antimicrob Chemother, 2008; 61:908–913.

16.

Leverstein-Van Hall

, Hopmans

TEM

, Van Der Sprenkel

JWB

, et al. A bundle approach to reduce the incidence of external ventricular and lumbar drain-related infections. J Neurosurg, 2010; 112:345–353.

17.

Tangden

, Enblad

, Ullberg

, Sjölin

. Neurosurgical gram-negative bacillary ventriculitis and meningitis: A retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases. Clin Infect Dis, 2011; 52:1310–1316.

18.

Wang

, Lin

, Chou

, et al. Intraventricular antimicrobial therapy in postneurosurgical gram-negative bacillary meningitis or ventriculitis: A hospital-based retrospective study. J Microbiol Immunol Infect, 2014; 47:204–210.

19.

Durand

, Calderwood

, Weber

, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med, 1993; 328:21–28.

20.

Kim

, Kim

, Park

, et al. The causes and treatment outcomes of 91 patients with adult nosocomial meningitis. Korean J Intern Med, 2012; 27:171–179.

21.

Camacho

, Boszczowski

, Basso

, et al. Infection rate and risk factors associated with infections related to external ventricular drain. Infection, 2011; 39:47–51.

22.

Chi

, Chang

, et al. Infections associated with indwelling ventriculostomy catheters in a teaching hospital. Int J Infect Dis, 2010; 14:e216–219.

23.

Bargiacchi

, Rossati

, Car

, et al. Intrathecal/intraventricular colistin in external ventricular device-related infections by multi-drug resistant gram-negative bacteria: Case reports and review. Infection, 2014; 42:801–809.

24.

Metan

, Alp

, Aygen

, et al. Carbapenem-resistant Acinetobacter baumannii: An emerging threat for patients with post-neurosurgical meningitis. Int J Antimicrob Agents, 2007; 29:112–113.

25.

Gulati

, Kapil

, Das

, et al. Nosocomial infections due to Acinetobacter baumannii in a neurosurgery ICU. Neurol India, 2001; 49:134–137.

26.

Wroblewska

, Dijkshoorn

, Marchel

, et al. Outbreak of nosocomial meningitis caused by Acinetobacter baumannii in neurosurgical patients. J Hosp Infect, 2004; 57:300–307.

27.

Chen

, Zhang

, Yu

, et al. The incidence and risk factors of meningitis after major craniotomy in China: A retrospective cohort study. PloS One, 2014; 9:e101961.

28.

Yadegarynia

, Gachkar

, Fatemi

, et al. Changing pattern of infectious agents in postneurosurgical meningitis. Caspian J Intern Med, 2014; 5:170–175.

29.

Kourbeti

, Vakis

, Ziakas

, et al. Infections in patients undergoing craniotomy: Risk factors associated with post-craniotomy meningitis. J Neurosurg, 2015; 122:1113–1119.

30.

Tunkel

, Hartman

, Kaplan

, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis, 2004; 39:1267–1284.

31.

Kessler

, Kourtis

. Treatment of meningitis caused by methicillin-resistant Staphylococcus aureus with linezolid. Infection, 2007; 35:271–274.

32.

Lee

, Palermo

, Chowdhury

. Successful treatment of methicillin-resistant Staphyloccus aureus meningitis with daptomycin. Clin Infect Dis, 2008; 47:588–590.

33.

Nau

, Sörgel

, Eiffert

. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev, 2010; 23:858–883.

34.

Ziaka

, Markantonis

, Fousteri

, et al. Combined intravenous and intraventricular administration of colistin methanesulfonate in critically ill patients with central nervous system infection. Antimicrob Agents Chemother, 2013; 57:1938–1940.

35.

Pfausler

, Spiss

, Beer

, et al. Treatment of Staphylococcal ventriculitis associated with external cerebrospinal fluid drains: A prospective randomized trial of intravenous compared with intraventricular vancomycin therapy. J Neurosurg, 2003; 98:1040–1044.

36.

Wen

, Bottini

, Hall

, Haines

. The intraventricular use of antibiotics. Neurosurg Clin N Am, 1992; 3:343–354.

37.

Ziai

, Lewin JJ

III

. Improving the role of intraventricular antimicrobial agents in the management of meningitis. Curr Opin Neurol, 2009; 22:277–282.

38.

Kim

, Peleg

, Lodise

TP et al

. Management of meningitis due to antibiotic-resistant Acinetobacter species. Lancet Infect Dis, 2009; 9:245–255.

39.

Tunkel

, Hasbun

, Bhimraj

, et al. 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for healthcare-associated ventriculitis and meningitis. Clin Infect Dis, 2017; 64:e34–e65.

40.

Karvouniaris

, Brotis

, Tsiamalou

, Fountas

. The role of intraventricular antibiotics in the treatment of nosocomial ventriculitis/meningitis from gram-negative pathogens: A systematic review and meta-analysis. World Neurosurg, 2018; 120:e637–e650.