European Journal of Clinical Microbiology & Infectious Diseases

https://doi.org/10.1007/s10096-024-04794-y

ORIGINAL ARTICLE

Intraventricular or intrathecal polymyxin B for treatment

of post‑neurosurgical intracranial infection caused
by carbapenem‑resistant gram‑negative bacteria: a 8‑year
retrospective study
Yangmin Hu1 · Danyang Li2 · Gensheng Zhang2 · Yunjian Dai1 · Meng Chen1 · Huifang Jiang1 · Wei Cui2

Received: 20 September 2023 / Accepted: 26 February 2024

© The Author(s) 2024

Abstract
Purpose Post-neurosurgical intracranial infection caused by carbapenem-resistant gram-negative bacteria (CRGNB) is a
life-threatening complication. This study aimed to assess the current practices and clinical outcomes of intravenous (IV)
combined with intraventricular (IVT)/intrathecal (ITH) polymyxin B in treating CRGNB intracranial infection.
Methods A retrospective study was conducted on patients with post-neurosurgical intracranial infection due to CRGNB from
January 2013 to December 2020. Clinical characteristics and treatment outcomes were collected and described. Kaplan–Meier
survival and multivariate logistic regression analyses were performed.
Results The study included 114 patients, of which 72 received systemic antimicrobial therapy combined with IVT/ITH
polymyxin B, and 42 received IV administration alone. Most infections were caused by carbapenem-resistant Acinetobacter
baumannii (CRAB, 63.2%), followed by carbapenem-resistant Klebsiella pneumoniae (CRKP, 31.6%). Compared with the
IV group, the IVT/ITH group had a higher cerebrospinal fluid (CSF) sterilization rate in 7 days (p < 0.001) and lower 30-day
mortality (p = 0.032). In the IVT/ITH group, patients with CRKP infection had a higher initial fever (p = 0.014), higher
incidence of bloodstream infection (p = 0.040), lower CSF sterilization in 7 days (p < 0.001), and higher 30-day mortality
(p = 0.005) than those with CRAB infection. Multivariate logistic regression analysis revealed that the duration of IVT/ITH
polymyxin B (p = 0.021) was independently associated with 30-day mortality.
Conclusions Intravenous combined with IVT/ITH polymyxin B increased CSF microbiological eradication and improved
clinical outcomes. CRKP intracranial infections may lead to more difficult treatment and thus warrant attention and further
optimized treatment.

Keywords Central nervous system infection · Intraventricular · Polymyxin B · Gram-negative bacteria · Multidrug
resistance

Introduction

Post-neurosurgical central nervous system (CNS) infection,

a serious complication of neurosurgical procedures, is asso-
* Yangmin Hu ciated with high mortality, morbidity, and poor functional
zrhym@zju.edu.cn
outcomes [1, 2]. In recent years, gram-negative pathogen-
* Wei Cui related ventriculitis/meningitis have been reported more
zricu@zju.edu.cn
frequently and have had worse clinical characteristics and
1
Department of Pharmacy, Second Affiliated Hospital, prognostic outcomes than gram-positives [3–5]. To make
Zhejiang University School of Medicine, Hangzhou 310003, things worse, the incidence of carbapenem-resistant gram-
China negative bacteria (CRGNB) is increasing worldwide [6,
2
Department of Critical Care Medicine, Second Affiliated 7]. Clinically related CRGNB mainly include Acinetobac-
Hospital, Zhejiang University School of Medicine, ter baumannii, Pseudomonas aeruginosa, and Klebsiella
Hangzhou 310003, China

Vol.:(0123456789)

pneumoniae, which are resistant to piperacillin, third-gen-
eration cephalosporins, carbapenems, and fluoroquinolones
[8]. For the treatment of CRGNB infection, clinicians often
resort to combination therapy based on polymyxins (colistin
or polymyxin B), aminoglycosides, and tigecycline [9, 10].
However, these antibiotics were found to have inadequate
penetration from the blood–brain barrier, making it difficult
to achieve adequate cerebrospinal fluid (CSF) concentra-
tions using systemic therapy [11]. Therefore, the choice of
antibiotics for CRGNB ventriculitis/meningitis is extremely
limited, greatly increasing the difficulty of treatment.
The presence of CRGNB has forced the use of topical
therapies to achieve an effective therapeutic concentration of
antibiotics at the site of infection [12]. Intraventricular (IVT)
and intrathecal (ITH) therapies are widely recognized treat-
ments for ventriculitis and meningitis, especially when the
pathogen is carbapenem-resistant bacteria [13]. Such thera-
pies bypass the blood–brain and blood–CSF barriers and
overcome the limited penetration of antibiotics into the CSF,
raise the respective drug concentrations, and minimize sys-
temic toxicities [11, 14]. The current guideline recommends
that the adjunct IVT/ITH antimicrobial therapy should be
reserved for patients with infections caused by multidrug-
resistant (MDR) gram-negative bacteria or for those who
poorly respond to the standard intravenous agents [15]. Sev-
eral studies have chosen IVT/ITH administration to achieve
an adequate level of drugs in the CSF to combat these resist-
ant organisms [16–19].
Because of its potent activity against CRGNB, polymyxin
B is used as the last therapy after all other treatment schemes
fail [20]. However, most previous studies have focused on
the treatment of MDR A. baumannii infections with small
samples, whereas the treatment of intracranial infections
caused by other MDR gram-negative bacteria is extremely
limited. In addition, there is a dearth of concrete evidence to
determine the optimal dose and duration of IVT/ITH poly-
myxin B for patients with intracranial infection caused by
CRGNB. To further confirm the efficacy and safety of the
IVT/ITH strategy, we retrospectively analyzed the clinical
features and eventual outcomes of 114 patients with post-
neurosurgical intracranial infection caused by CRGNB.
Methods
Patients and definition
This retrospective study was conducted from January 2013
to December 2020 at the Second Affiliated Hospital of Zhe-
jiang University, School of Medicine, which is a tertiary
care hospital. All adult patients with a positive CSF culture
for CRGNB after neurosurgery were enrolled. Patients with
any of the following conditions were excluded: (i) less than
European Journal of Clinical Microbiology & Infectious Diseases
18 years of age; (ii) a polymicrobial result from CSF cul-
ture; (iii) possible contamination; (iv) IVT/ITH polymyxin
B only once after the diagnosis of intracranial infection; or
(v) incomplete clinical data. Each patient was included in
the study only once at the time of the first positive CSF
culture. The diagnosis and treatment management of intrac-
ranial infections and evaluation of the final outcomes were
determined by physicians. After inclusion, patients were
classified into two groups: patients receiving intravenous
(IV) plus IVT/ITH polymyxin B (IVT/ITH group) and those
who received only IV treatment (IV group). In the IVT/ITH
group, the process of local injection of polymyxin B was
that the clinician removed 5 mL of CSF via the ventricular
drainage tube or lumbar cistern drainage tube and discarded
it, then injected 5 mg/day of polymyxin B and finally closed
the tube for 2 h. The clinician determined whether or not to
change the dosing interval based on CSF results. Approval
for this study was granted with waiver of individual con-
sent by the Ethics Committee of the 2nd Affiliated Hospital,
School of Medicine, Zhejiang University (No. 2023 − 0193).
CRGNB intracranial infection was defined in such a way
that a positive culture of CRGNB from CSF cultures was
found at least once, with increased white cells, decreased
glucose, and/or increased protein levels in the CSF, as well
as clinical symptoms suspicious for meningitis or ventricu-
litis [15]. If the patient did not exhibit clinical symptoms or
had normal levels of glucose, protein, and nucleated cells,
the positive CSF culture was regarded as contaminated. The
clinical outcomes were defined as follows: (i) the 30-day
mortality: death within 30 days after the first CSF bacterial
culture was positive; (ii) CSF sterilization: a positive CSF
culture, followed by at least one and all subsequent CSF
cultures being negative after treatment [21].
Data collection
Data of the patients were extracted from electronic medical
records, including demographics, primary disease, comor-
bidities, craniocerebral surgery, length of hospital stay,
intensive care unit (ICU) admission, acute physiology and
chronic health evaluation II (APACHE II) score, Glasgow
coma scale (GCS) on admission, sequential organ failure
assessment (SOFA) score using the worst physiological
parameters within 24 h before the CSF culture was posi-
tive. The data were also extracted from laboratory test data,
including CSF white blood cell count, CSF glucose, CSF
protein levels, CSF bacterial culture results, antimicrobial
use, and treatment efficacy.
Microbiology
Drug susceptibility tests were carried out using a VITEK
2 Compact automated microbiological analysis system
European Journal of Clinical Microbiology & Infectious Diseases
(bioMérieux, France) or the disk diffusion method accord-
ing to the Clinical and Laboratory Standards Institute (CLSI)
criteria in our microbiology laboratory. The results were
interpreted in accordance with the CLSI 2021 criteria, and
Enterobacteriaceae with minimum inhibitory concentration
(MIC) ≥ 4 mg/L and A. baumannii and P. aeruginosa with
MIC ≥ 8 mg/L were considered resistant to carbapenem [22].
Statistical analysis
Statistical analysis was performed using SPSS version 25.0.
Measurement data were expressed as median and interquar-
tile range (IQR) for continuous variables and percentages
(%) for categorical variables. Normally distributed con-
tinuous variables were analyzed by the t test, while non-
normally variables were analyzed by the Mann–Whitney
test. The chi-square test and Fisher’s exact test were used
to compare categorical variables. The 30-day survival was
compared with Kaplan–Meier analysis and log-rank test.
Variables with p-values < 0.1 were included in multivariate
logistic regression to estimate odds ratios (ORs) for 30-day
mortality. All p-values were two-tailed, and a p-value < 0.05
was considered statistically significant.
Fig. 1  Flowchart of patient
enrollment. CSF, cerebrospinal Patients with positive CSF culture (n=629)
fluid; CRGNB, carbapenem-
resistant gram-negative bacte-
ria; IVT/ITH, intraventricular/
intrathecal
Patients with CRGNB (n=261)
Patients included in the analysis (n=114)
Intravenous group (n=42)
Results
Clinical characteristics
A total of 629 patients with positive CSF cultures were
retrospectively reviewed, of which 515 were excluded,
and 114 were finally enrolled. There were 72 patients in
the IVT/ITH group, and 42 in the IV group (Fig. 1). The
most prevalent reason for admission was cerebrovascu-
lar disease (65/114, 57.0%), followed by craniocerebral
trauma (34/114, 29.8%) and intracranial tumors (15/114,
13.2%). A comparison of the clinical features of the two
patient groups is revealed in Table 1. Compared with
the IV group, patients in the IVT/ITH group were older
(p < 0.001), and fewer patients received intravenous car-
bapenems (p = 0.038). There was a higher CSF steriliza-
tion in 7 days (p < 0.001), and lower 30-day mortality was
observed (p = 0.032). In the IVT/ITH group, the median
duration of IVT/ITH polymyxin B was 10 days, with a
cumulative dose of 45 mg. Among them, one patient expe-
rienced tremors after ITH polymyxin B; the symptoms
were mild and completely resolved after withdrawal.
Exclusion of non-CRGNB (n=368)
Exclusion:
Age < 18 years old (n=8)
Polymicrobial from CSF culture (n=20)
Contamination (n=37)
incomplete clinical data (n=72)
IVT/ITH polymyxin B only once (n=10)
IVT/ITH polymyxin B group (n=72)
 European Journal of Clinical Microbiology & Infectious Diseases

Table 1  Clinical characteristics Variable IVT/ITH group (n = 72) IV group (n = 42) p value
and outcomes of patients
Age, years 58 [49, 66] 48 [36.5, 55] < 0.001
Male, n (%) 39 (54.2%) 26 (61.9%) 0.421
Primary disease, n (%)
Craniocerebral trauma 21 (29.2%) 13 (31.0%) 0.122
Intracranial tumour 13 (18.1%) 2 (4.8%)
Cerebrovascular disease 38 (52.8%) 27 (64.3%)
Comorbidities, n (%)
Hypertension 27 (37.5%) 13 (31.0%) 0.480
Diabetes 11 (15.3%) 1 (2.4%) 0.065
ICU admission, n (%) 65 (90.3%) 37 (88.1%) 0.960
SOFA score 4 [2, 5] 4 [3, 6] 0.605
GCS on admission 8 [5, 13] 8 [5, 10] 0.196
APACHE II score 18 [15, 23] 20 [17, 22] 0.921
Any surgeries before infection, n (%)
Craniotomy evacuation of hema- 30 (41.7%) 15 (35.7%) 0.531
toma + decompressive craniectomy
Lumbar cistern drainage 26 (36.1%) 10 (23.8%) 0.173
External ventricular drainage 19 (26.4%) 17 (40.5%) 0.119
Intracranial tumor resection 13 (18.1%) 2 (4.8%) 0.043
Craniotomy aneurysm clipping 12 (16.7%) 7 (16.7%) 1.000
Aneurysm embolization 7 (9.7%) 0 (0.0%) 0.093
Ventricle peritoneal shunt 3 (4.2%) 5 (11.9%) 0.238
Initial fever, mean, ℃ 38.8 ± 0.8 38.7 ± 0.8 0.364
Initial CSF WBC, cells/µL 3500 [1014,11150] 1886 [574, 4970] 0.066
Initial CSF Glucose, mmol/L 0.07 [0.02, 0.56] 0.49 [0.03, 1.31] 0.060
Initial CSF Protein, mg/dL 289.8 [180.1, 353.15] 248.6 [172.3, 356.9] 0.533
Gram-negative bacteria in CSF, n (%)
Acinetobacter baumannii 45 (62.5%) 27 (64.3%) 0.867
Klebsiella pneumoniae 24 (33.3%) 12 (28.6%)
Pseudomonas aeruginosa 2 (2.8%) 2 (4.8%)
Other CRE 1 (1.4%) 1 (2.4%)
Bloodstream infection 11 (15.3%) 8 (19.0%) 0.602
AKI 6 (8.3%) 1 (2.4%) 0.383
Surgical treatment after infection a, n (%) 61 (84.7%) 32 (76.2%) 0.257
Intravenous carbapenems 39 (54.2%) 31 (73.8%) 0.038
IVT/ITH administration of polymyxin B
Duration, days 10 [5, 17]
Cumulative dose, mg 45 [25,60]
ICU length of stay, days 27 [13,51] 17 [6, 46] 0.228
Hospital length of stay, days 42 [28,58] 34 [20, 59] 0.172
CSF sterilisation in 7 days, n (%) 46 (63.9%) 11 (26.2%) < 0.001
30-day mortality 20 (27.8%) 20 (47.6%) 0.032

IVT intraventricular, ITH intrathecal, IV intravenous, ICU intensive care unit, SOFA sequential organ fail-
ure assessment, GCS Glasgow coma scale, APACHE II acute physiology and chronic health evaluation II,
CSF cerebrospinal fluid, WBC white blood cell, CRE carbapenem-resistant Enterobacteriaceae, AKI Acute
Kidney Injury
a
including removal, replacement, or insertion of new intracranial devices, and debridement
European Journal of Clinical Microbiology & Infectious Diseases

Microbiology (p = 0.036), combined intravenous carbapenems (p = 0.015),

All CSF cultured demonstrated CRGNB, including 72 cases
(63.2%) of carbapenem-resistant A. baumannii (CRAB)
infection, 36 (31.6%) of carbapenem-resistant K. pneumo-
niae (CRKP) infection, 4 (3.5%) of carbapenem-resistant P.
aeruginosa (CRPA) infection, and 2 (1.8%) of other carbape-
nem-resistant Enterobacteriaceae (CRE) infection (Table 1).
All A. baumannii and K. pneumoniae isolates were resist-
ant to carbapenems and were susceptible to polymyxin B
(Table 2).
CRKP and CRAB infections
In the IVT/ITH group, patients with CRKP infection tended
to have a higher initial fever (p = 0.014), higher incidence of
bloodstream infection (p = 0.040), and lower CSF steriliza-
tion in 7 days (p < 0.001) than those with CRAB infection.
In addition, a significant difference was observed in males
and IVT/ITH administration (p = 0.035) between the two
groups. Patients with CRKP infection had a higher 30-day
mortality rate than those with CRAB infection (50.0% vs.
17.8%, p = 0.005; Table 3). Kaplan–Meier curves also dem-
onstrated a significant difference between the two groups
(p = 0.002; Fig. 2). However, no significant difference was
found between CRAB and CRKP infections in the IV group
(Table 3).
Factors related to 30‑day all‑cause mortality
in patients with IVT/ITH polymyxin B
The 30-day all-cause mortality rate in patients treated with
IVT/ITH polymyxin B was 27.8% (20/72). Univariate analy-
sis depicted that CRKP infection (p = 0.003), bloodstream
infection (p = 0.031), IVT or ITH administration (p = 0.027),
duration of IVT/ITH polymyxin B (p = 0.008), combined
intravenous carbapenems (p = 0.028), and CSF sterilization

Table 2  Antibiotic resistance of Antibiotics Acinetobacter Klebsiella Pseudomonas Other CRE

carbapenem-resistant gram- baumannii (n = 72) pneumoniae (n = 36) aeruginosa (n = 4) (n = 2)
negative bacteria (CRGNB)
isolates in cerebrospinal fluid Ceftazidime 97.2 (69/71) 100.0(35/35) 50.0 (2/4) 100.0 (2/2)
(CSF)
Cefepime 94.4 (68/72) 83.3 (30/36) 75.0 (3/4) 0.0 (0/2)
Carbapenem 100.0 (72/72) 100.0(36/36) 100.0 (4/4) 100.0 (2/2)
Cefoperazone/Sulbactam 64.3 (45/70) 100.0(36/36) 100.0 (4/4) 100.0 (2/2)
Levofloxacin 62.5 (45/72) 83.3 (30/36) 75.0 (3/4) 0.0 (0/2)
Tigecycline 3.1 (2/64) 13.3 (4/30) - 0.0 (0/1)
Amikacin 35.4 (23/65) 41.7 (15/36) 0.0 (0/4) 0.0 (0/2)
Polymyxin B 0.0 (0/60) 0.0 (0/27) 0.0 (0/4) 0.0 (0/1)
CRE carbapenem-resistant Enterobacteriaceae

Fig. 2  Kaplan-Meier curves of

30-day mortality after the first
CSF bacteria culture positive in
IVT/ITH group
 European Journal of Clinical Microbiology & Infectious Diseases

Table 3  Clinical characteristics and outcomes of patients with CRAB and CRKP infection
IVT/ITH group IV group

Variable CRAB (n = 45) CRKP (n = 24) p value CRAB (n = 27) CRKP (n = 12) p value
Age, years 58 [52, 65] 59 [46, 67] 0.982 48 [37, 55] 51 [36, 59] 0.778
Male, n% 20 (44.4%) 17 (70.8%) 0.036 14 (51.9%) 9 (75.0%) 0.291
Primary disease, n%
Craniocerebral 13 (28.9%) 6 (25.0%) 0.476 7 (25.9%) 4 (33.3%) 0.802
trauma
Intracranial tumour 6 (13.3%) 6 (25.0%) 1 (3.7%) 0 (0.0%)
Cerebrovascular 26 (57.8%) 12 (50.0%) 19 (70.4%) 8 (66.7%)
disease
Comorbidities, n%
Hypertension 19 (42.2%) 8 (33.3%) 0.471 10 (37.0%) 3 (25.0%) 0.714
Diabetes 8 (17.8%) 3 (12.5%) 0.736 1 (3.7%) 0 (0.0%) 1.000
ICU admission, n% 43 (95.6%) 21 (87.5%) 0.333 25 (92.6%) 11 (91.7%) 1.000
SOFA score 4 [2, 5] 4 [3, 5] 0.861 5 [3, 6] 4 [3, 6] 0.944
GCS on admission 7 [5, 11] 8.5 [5, 14.5] 0.419 8 [5, 9] 7 [4, 9] 0.593
APACHE II score 18.5 [15, 22] 18 [14, 24] 0.641 20 [17, 21] 19 [16, 23] 0.681
Initial fever, mean, ℃ 38.7 ± 0.8 39.2 ± 0.6 0.014 38.5 ± 0.8 38.6 ± 0.6 0.994
Initial CSF WBC, 3200 [1225,8460] 5180 [1010.5,23840] 0.153 2080 [520, 6880] 2251 [677, 5400] 0.975
cells/µL
Initial CSF Glucose, 0.065 [0.02,0.30] 0.11 [0.015,1.00] 0.586 0.55 [0.03, 1.70] 0.05 [0.01, 0.68] 0.179
mmol/L
Initial CSF Protein, 278.65 [176.80,340.67] 322.45 [180.45,369.32] 0.215 278.55 [165.13, 280.90 [191.80, 0.574
mg/dL 361.35] 437.00]
Bloodstream infec- 4 (8.9%) 7 (29.2%) 0.040 5 (18.5%) 3 (25.0%) 0.682
tion, n (%)
AKI, n (%) 5 (11.1%) 1 (4.2%) 0.657 1 (3.7%) 0 (0.0%) 1.000
Surgical treatment 39 (86.7%) 19 (79.2%) 0.496 19 (70.4%) 8 (29.6%) 0.228
after infection a, n
(%)
Intravenous carbap- 20 (44.4%) 18 (75.0%) 0.015 17 (63.0%) 11 (91.7%) 0.122
enems, n (%)
IVT/ITH administration of polymyxin B
IVT injection, n (%) 9 (20.0%) 9 (37.5%) 0.035
ITH injection, n (%) 34 (75.6%) 11 (45.8%)
IVT + ITH injection, 2 (4.4%) 4 (16.7%)
n (%)
Duration, days 10 [5.5, 16] 9.5 [6, 19] 0.545
Cumulative dose, mg 45 [25,60] 40 [26.25,65] 0.432
IVT/ITH administra- 23 (51.1%) 10 (41.7%) 0.454
tion within 48 h
after the CSF culture
results, n (%)
ICU length of stay, 27 [13,52.5] 23 [11,49.5] 0.203 18 [6, 45] 21 [10, 71] 0.353
days
Hospital length of 43 [28,63.5] 36.5 [24, 55] 0.132 32 [15, 60] 38 [27, 71] 0.344
stay, days
CSF sterilisation in 7 37 (82.2%) 6 (25.0%) < 0.001 6 (22.2%) 4 (33.3%) 0.693
days, n (%)
30-day mortality, n 8 (17.8%) 12 (50%) 0.005 15 (55.6%) 5 (41.7%) 0.423
(%)

IVT intraventricular, ITH intrathecal, IV intravenous, CRAB carbapenem-resistant Acinetobacter baumannii, CRKP carbapenem-resistant Kleb-
siella pneumoniae, ICU intensive care unit, SOFA sequential organ failure assessment, GCS Glasgow coma scale, APACHE II acute physiology
and chronic health evaluation II, CSF cerebrospinal fluid, WBC white blood cell, AKI Acute Kidney Injury
a
including removal, replacement, or insertion of new intracranial devices, and debridement
European Journal of Clinical Microbiology & Infectious Diseases
Table 4  Univariate and multivariate logistic regression analysis for 30-day mortality in patients with IVT/ITH administration
Variable Survivors(n = 52)
Initial fever, mean, ℃ 38.7 ± 0.8
CRKP infection, n (%) 12 (23.1%)
Bloodstream infection, n (%) 5 (9.6%)
IVT or ITH administration
IVT injection, n (%) 11 (21.2%)
ITH injection, n (%) 38 (73.1%)
IVT + ITH injection, n (%) 3 (5.8%)
Duration of IVT/ITH polymyxin B, days 11 [6, 20]
Combined intravenous carbapenems, n (%) 24 (46.2%)
CSF sterilisation in 7 days, n (%) 38 (73.1%)
CRKP carbapenem-resistant Klebsiella pneumoniae, IVT intraventricular, ITH intrathecal, CSF cerebrospinal fluid
in 7 days (p = 0.009) were associated with 30-day mortal-
ity. Multivariate logistic regression analysis revealed that
the duration of IVT/ITH polymyxin B (p = 0.021) was an
independent risk factor associated with 30-day mortality
(Table 4).
Discussion
This study retrospectively evaluated patients with post-
neurosurgical intracranial infection caused by CRGNB and
observed that patients receiving IVT/ITH polymyxin B had
increased CSF microbiological eradication and reduced mor-
tality. In addition, for patients receiving IVT/ITH admin-
istration, the mortality of patients with CRKP infection
was significantly higher than that of patients with CRAB
infection.
CRGNB is associated with increased mortality [23].
CRAB has become the most common pathogen for noso-
comial intracranial infection neurosurgery wards [5, 24].
A retrospective study showed that the 30-day mortality of
postoperative CNS infection caused by MDR/XDR A. bau-
mannii was 28.6%, even after IVT/ITH administration [25].
Notably, the pathogenicity and toxicity of CRKP are higher
than those of CRAB, resulting in high mortality [26]. A ret-
rospective study displayed that ICU admission, bacteremia,
and hospital-acquired pneumonia were risk factors for CRE
meningitis, and the overall mortality of CRE meningitis/
encephalitis was as high as 69.2% [27]. To date, few stud-
ies or cases have reported IVT/ITH administration in treat-
ing intracranial infections caused by CRKP, most of which
were retrospective studies [28–31]. In our study, the mortal-
ity of patients with intracranial infections caused by CRKP
remained high even with IVT/ITH polymyxin B, but we also
found that patients with CRKP infection had more combined
bloodstream infections than those with CRAB infection.
Mortality in patients with CRGNB infection was linked to
Non-survivors(n = 20) p value OR (95% CI) p value
39.1 ± 0.7 0.064
12 (60.0%) 0.003
6 (30.0%) 0.031
9 (45.0%) 0.027
8 (40.0%)
3 (15.0%)
7.5 [5, 10] 0.008 0.87 (0.77–0.98) 0.021
15 (75.0%) 0.028
8 (40.0%) 0.009
various factors, including age, SOFA score, Charlson Index
and bacteremia [23, 32]. Consequently, large-scale clinical
studies of CRKP intracranial infection are still needed.
Although the preferred approach for the treatment of
CRGNB intracranial infections remains unclear, a combina-
tion of intravenous and IVT/ITH therapy may be necessary
for optimal clinical outcomes [33]. Combining IVT with
intravenous administration is likely to achieve higher antibi-
otic levels in CSF and more effective sterilization than IVT
therapy alone [21, 34], This combination may help prevent
compartments with subinhibitory antibiotic concentrations,
thereby reducing the probability of the selection of resistant
bacteria and relapse [35]. In a setting of high prevalence
of nosocomial infections caused by CRGNB, polymyxins
should be considered in combination with other drugs. Sev-
eral in vitro and clinical studies have suggested the clinical
benefits of adopting polymyxin–drug combination therapy,
especially polymyxin plus meropenem, with synergistic
killing against MDR/XDR gram-negative bacteria [36–39].
Although meropenem is recommended as the main empiri-
cal treatment for healthcare-associated ventriculitis and
meningitis against gram-negative bacteria [40], resistance
may lead to delayed treatment effectiveness and adverse out-
comes. This study found no beneficial results for the com-
bination of polymyxin B and carbapenems, even when car-
bapenem therapy was optimized, such as increasing the dose
and extending the infusion. This indicates that optimizing
the combination treatment regimen for intracranial infection
caused by CRGNB is extremely challenging.
The current guideline suggests CSF antimicrobial concen-
trations of 10–20 times the MIC of the isolate and a daily IVT
dose of 5 mg polymyxin B for gram-negative ventriculitis and
meningitis [15]. The CSF antimicrobial concentrations are
affected by the ventricular size and daily drain output, and
drain clamping should be performed after each administration
(15–60 min). IVT administration ensures distribution through-
out CSF compartment, whereas ITH dosing often fails to attain

adequate antibiotic concentrations in the ventricles [11]. How-
ever, this study did not find significant differences in clinical
outcomes between these two regimens.
Prompt diagnosis and intervention using appropriate antibi-
otics are considered imperative. A case series and systematic
review demonstrated that death was related to delayed ITH/
IVT therapy compared with survival (7 vs. 2 days, p = 0.01)
[41]. Furthermore, studies on the association between the
timing of ITH/IVT administration and clinical outcomes are
sparse. The results of this study showed that timely IVT/ITH
treatment within 48 h of a positive CSF culture had no signifi-
cant effect on clinical outcome.
The length of IVT delivery varied among the available
studies, while the total treatment duration has often not been
specified [13]. The current guideline recommends that ade-
quate antimicrobial therapy should continue for 21 days by
gram-negative bacilli and up to 10–14 days after the last posi-
tive culture in patients with repeatedly positive CSF cultures
[15]. The median/mean duration of treatment with IVT/ITH
polymyxins was 13–15 days in the current small retrospective
study [18, 42, 43], which is similar to the results of this study.
In a recent meta-analysis, the incidence of complications
in 229 patients with meningitis caused by gram-negative
pathogens who received intrathecal administration was as
high as 13%, and chemical meningitis and seizures repre-
sented the majority of the complications [44]. However, the
adverse effects of IVT/ITH administration reported in pre-
vious studies were mainly due to colistin rather than poly-
myxin B [20]. Since patients receiving IVT/ITH therapy are
usually in a coma or are sedated, adverse drug effects may
have gone unnoticed or been attributed to complications of
the underlying disease, and the true incidence of adverse
effects of IVT/ITH therapy may be underestimated.
There are some limitations to the current study. First, this
was a retrospective study with a small sample size in a single
center and relied on clinical culture results, which may intro-
duce bias in data interpretation. Second, as patients were
seriously ill and other confounding factors were common in
the ICU, we could not identify the impact of these factors
on mortality. Third, the modified Rankin scale or Glasgow
Outcome Scale were not used, as some patients may survive
and present in a vegetative state, which is also a devastating
outcome. Finally, the effect of ventricular size and daily CSF
drainage volume on the outcome of IVT/ITH administra-
tion was not analyzed, and further multicenter randomized
controlled studies are required.
Conclusions
Intravenous combined with IVT/ITH polymyxin B increased
CSF microbiological eradication and reduced mortality.
CRKP intracranial infection may lead to more difficult
European Journal of Clinical Microbiology & Infectious Diseases
treatment and worse outcome, requiring attention and fur-
ther optimized treatment.
Acknowledgements We would like to thank Prof. Hongwei Zhou,
the Department of Laboratory Medicine, Second Affiliated Hospital,
Zhejiang University School of Medicine, for the interpretation of the
microbiological results.
Author contributions Yangmin Hu contributed to design and drafting
of the article; Danyang Li and Gensheng Zhang contributed to the revi-
sion of the intellectual content; Yunjian Dai, Meng Chen and Huifang
Jiang contributed to data collection and analysis, Wei Cui supervised
the research and revised the manuscript. All authors read and approved
the final manuscript.
Funding This study was supported by the Zhejiang Provincial Natural
Science Foundation of China under Grant No. LYY22H310016.
Data availability The datasets generated during and/or analyzed during
the current study are not publicly available due to institutional ethics,
privacy, and confidentiality regulations, but are available from the cor-
responding author on reasonable request.
Declarations
Ethics approval and consent to participate The study was approved
with waived of informed consent by the Ethics Committee of the 2nd
Affiliated Hospital, School of Medicine, Zhejiang University (No.
2023 − 0193). As this was a noninterventional, retrospective study
with data management processed anonymously, informed consent was
waived.
Consent for publication Not applicable.
Conflict of interest The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri-
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copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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