Extended sequential intravenous and oral antimicrobial therapy improves cure rate in postoperative intracranial neurosurgical infections. A Spanish multicenter retrospective study

doi:10.21203/rs.3.rs-4946614/v1

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Research Article

Extended sequential intravenous and oral antimicrobial therapy improves cure rate in postoperative intracranial neurosurgical infections. A Spanish multicenter retrospective study

https://doi.org/10.21203/rs.3.rs-4946614/v1

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Background

Postoperative intracranial neurosurgical infections (PINI) complicate < 5% neurosurgeries. Scarce attention was dedicated to the extension and characteristics of its antimicrobial management considering their high morbidity, not negligible mortality, delayed hospital stay and increased healthcare costs.

Methods

We analyzed retrospectively (2014–2023) 162 PINI from eight Spanish third-level academic hospitals.

Results

Elective clean craniotomies after tumor or vascular causes were the leading procedures. Epidural abscess (24.7%), scalp infections (19.8%), postsurgical meningitis (16.7%) and cranioplasty infections (16.7%) were the most frequent PINI. Staphylococcus spp (43.9%) and Gram negative bacteria (38.6%) were the predominant isolates. Overall 85.2% patients underwent pus drainage, mostly by craniotomy (40.3%). Interestingly 34% were already receiving antibiotics for extracranial infections before developing PINI while 16.8% did not receive pre-operative antibiotic prophylaxis. In total 77.2% patients started a combined intravenous (IV) antimicrobial therapy, of which 85.2% switched after 5 days to a second-line IV antibiotic regimen, in 41.3% cases combined, after pus culture results, for a median of 21 days. Overall 61.1% patients continued on oral antimicrobials after hospital discharge, 30.3% as a combined regimen, for a median of 42 days. Complete cure was obtained in 81.5% cases, while 11.1% relapsed, 7.4% failed to cure and 6.8% died after PINI complications. In the multivariate analysis oral antimicrobial therapy after hospital discharge (p = 0.001) was significantly associated with PINI cure with a marginal positive effect on survival (p = 0.066) .

Conclusions

We conclude that an extended 6 weeks sequential IV and oral antimicrobial therapy in addition to neurosurgical correction increases PINI cure rate and might improve survival

Clinical Trial Number: not applicable

neurosurgery

intracranial infections

antimicrobial therapy

cure

mortality

Postoperative intracranial neurosurgical infections (PINI) complicate < 5% of all neurosurgeries [1–14]., with lower infection rates reported in American series [5]. Extensive consideration has been paid so far to infections of other neurosurgical procedures such as external and internal cerebrospinal fluid (CSF) shunts and other implantable neural devices, mostly to CSF shunts ventriculitis [13–14]. However scarce attention has been dedicated to PINI, with efforts mainly focused on PINI risk factors but not on their treatment. This is especially surprising considering that PINI have a high morbidity, not negligible mortality, generate delayed hospital stays and increase greatly healthcare costs. PINI treatment necessitates in most of the cases a second neurosurgical intervention or even more to achieve cure. In addition, PINI therapy requires specific antimicrobials, used in high doses, able to cross the blood-brain barrier, with activity again methicillin-resistant staphylococci in many cases, and not exempt of side effects. Furthermore, PINI antimicrobials need to be administer intravenously (IV) several times a day for several weeks through a central catheter complicating nursing work. Frequently used antimicrobial guidelines are not explicit for PINI regarding the type of antibiotic to be used, alone or in combination, its administration route, switching time from IV to oral, and total duration of therapy [13–15]. For all these reasons we underwent this retrospective study on PINI focusing especially on the characteristics and duration of their antimicrobial management and their influence on cure and mortality outcomes.

Inclusion criteria

Patients with 18 years or older diagnosed with PINI admitted to the Neurosurgery wards of Hospital Universitario Central de Asturias (HUCA), Oviedo, Hospital Universitario Fundación Jiménez Diaz, Madrid, Hospital 12 de Octubre, Madrid, Complejo Universitario de León, Hospital Universitario de Toledo, Hospital Universitario Germans Trias i Pujol, Badalona, Hospital Clínico Universitario de Valladolid and Hospital Vall d´Hebron; Barcelona, all in Spain, between May 1st 2014 and May 15th 2023 were included in the study. The diagnosis of PINI was primarily based on history, physical examination, microbiological, neuroimaging diagnostic procedures (head CT and/or MRI), and surgical findings at the operation room. The patients were followed a median of 9 months after hospital discharge by both a neurosurgeon and an Infectious Diseases (ID) consultant at each of the participant hospitals. The response to treatment was evaluated by the neurosurgeon in charge of the patient, based on clinical and neuroimaging findings and confirmed by the ID consultant PINI. cure implied absence of physical and neuroimaging signs of infection and lack of relapses or hospital re-admissions for neurosurgical infectious reasons during the follow-up. PINI relapse implied failure to cure, or initial response but relapse within 9 months of hospital discharge.

Exclusion criteria

Patients younger than 18 years, those with CNS infections due to external and internal (ventriculoperitoneal and ventroculoatrial) CSF shunts and to neurostimulators and those with spinal infections were excluded .

Data collecting

Many demographic, epidemiological, topographic, microbiological, clinical, laboratory, imaging, prognostic, hospitalization, and therapeutic (both surgical and antibiotic) data were collected and analyzed according to the PINI response to surgical and antimicrobial therapy. Regarding the diverse PINI, positive cultures obtained from blood, CSF, operation room drained pus collections and infected neurosurgical wounds exudates were considered.

Statistical analysis

Descriptive statistics was reported as median with interquartile range (IQR) for continuous variables and absolute numbers with percentages for categorical variables. Univariable and multivariable logistic regression and Cox proportional hazard models were employed to assess the effect of the variables of interest on PINI cure and mortality, respectively. The referring hospital was included in each model as a cluster to take into account that patients coming from the same hospital are more similar to each other. To avoid overfitting, variables included in the multivariable models were identified by performing a backward selection based on the Akaike Information Criterion (BIC). Results of logistic regression models were reported as Odds Ratio (OR) with its 95% confidence interval (95%CI) and p-value, while results of Cox regression models were reported as Hazard Ratio (HR) with its 95% confidence interval (CI) and p-value.

The analyses were performed using R software (version 4.3.2). R Core Team (2023). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria.

Demographic characteristics of patients with PINI and predisposing factors leading to these infections

The characteristics of the patients regarding gender, age and predisposing factors for PINI are presented in Table 1

Table 1

Demography, and predisposing factors to postoperative intracranial neurosurgical infections (PINI)
		Patients (n = 162)
Demography
- Gender	Male	86 (53.1%)
- Gender	Female	76 (46.9%)
- Age	years	57.4 (47.2–69.0)
Predisposing factors
- Diabetes	Yes	23 (14.2%)
- Diabetes	No	139 (85.8%)
- Past or present smoking	Yes	42 (25,9%)
- Past or present smoking	No	120 (74.1%)
- Alcohol abuse	Yes	15 (9.3%)
- Alcohol abuse	No	147 (90.7%)
-Previous extracranial infection	Yes	31 (19.1%)
-Previous extracranial infection	No	131 (80.9%)
- Immunodepression	Yes	30 (18.5%)
- Immunodepression	No	132 (81.5%)
		n = 30
- Cancer	Yes	4(13.3%)
- Cancer	No	26 (86.7%)
…….Steroids therapy	Yes	1 (3.3%)
	No	29 (96.7)
Other immunosuppressive therapy	Yes	2 (7.1%)
	No	28 (93.3%)
Other immunosuppression causes	Yes	23 (76.7%)
	No	7 (23.3%)
Comorbidities	Yes	40 (24.7%)
Comorbidities	No	122 (75.3%)
ICU stay before neurosurgery	Yes	39 (24.1%)
ICU stay before neurosurgery	No	123 (75.9%)
ICU stay before neurosurgery	days	0 (0-0.3)

Values are expressed as median (IQ range) or absolute number (%).

. Interestingly, one fifth had a previous extracranial infection when the PINI was diagnosed. Overall 18.5% had an immunodepression and one quarter carried other comorbidities that could facilitate PINI. Although one quarter of the patients were admitted to the ICU before neurosurgery their ICU stay was so short that did not contribute to PINI.

Neurosurgery-related parameters of PINI

The characteristics of neurosurgical procedures leading to PINI are presented in Table 2.

Table 2

Neurosurgery-related parameters of postoperative intracranial neurosurgical infections (PINI)
		Patients (n = 162)
Surgery timing
	Urgent	50 (30.9%)
	Elective	112 (69.1%)
-
Surgery type
	Clean	124 (76.5%)
	Clean-contaminated	25 (15.4%)
	Contaminated	8 (4.9%)
	Dirty	5 (3.1%)
Neurosurgery category
	Craniotomy	114 (70.4%)
	Craniectomy	15 (9.3%)
	Cranioplasty	29 (17.9%)
	Other	4 (2.5%)
Surgery cause
	Vascular	35 (21.6%)
	Tumor	74 (45.7%)
	Trauma	25 (15.4%)
	Infection	8 (4.9%)
	Other	20 (12.3%)
Surgery duration	hours	3.0 (2.0–5.0)
GCS at surgery		15.0 (15.0–15.0)
Postsurgical CSF leakage	Yes	33 (20.4%)
Postsurgical CSF leakage	No	129 (79.6%)

Values are expressed as median (IQ range) or absolute number (%).

GCS = Glasgow Coma Scale ; CSF = cerebrospinal fluid

Two-thirds of the patients underwent elective, mostly clean, neurosurgery. Craniotomy was the predominant surgical procedure. The cause of neurosurgery was tumor in almost half of the patients followed by a vascular reason. Patients had a full Glasgow Coma Scale (GCS) score when entering the operating room. Surgery lasted a median of 3 hours .The main post-surgical complication was a cerebrospinal fluid (CSF) leakage in one fifth of the cases, enhancing post-surgical meningitis.

PINI type, location and microbiology

PINI type, location and microbiology of the drained pus, blood and CSF samples are shown in Table 3

Table 3

Type, location and microbiology of postoperative intracranial neurosurgical infections (PINI)
		Patients (n = 162)
Infection type ^a
	Scalp Infection	32 (19.8%)
	Cranioplasty infection	27 (16.7%)
	Skull osteomyelitis	15 (9.3%)
	Epidural abscess	40 (24.7%)
	Subdural abscess	17 (10.5%)
	Intraparenchymal brain abscess	5 (3.1%)
	Meningitis	27 (16.7%)
	Other infections	11 (6.8%)
Infection location ^a
	Frontal	47 (29.0%)
	Right parieto-temporal	44 (27.2%)
	Left parieto-temporal	32 (19.8%)
	Occipital	13 (8.0%)
	Not focalized	30 (18.5%)
Cultured pus samples
	Yes	159 (98.1%)
	No	3 (1.9%)
Culture positive pus samples
	Yes	132 (83.0%)
	No	27 (17.0%)
Pus identified pathogens^b
Single pathogens
Staphylococcus spp		58 (43.9%)
Streptococcus spp		2 (1.5%)
Gram negative bacteria		51 (38.6%)
Other aerobic bacteria		4 (3.0%)
Polimicrobial aerobes		19 (14.4%)
Anaerobes^c		20 (15.2%)
Blood cultures
	Not drawn	91 (56.2%)
	Positive	11 (6.8%)
	Negative	60 (37.0%)
Blood identified pathogens^c
Staphylococus spp		7 (43.8%)
Streptoccocus spp		1 (6.3%)
Gram negative bacteria		7 (43.8%)
Other		1 (6.3%)
Spinal tap
	Not performed	121 (74.7%)
	Positive CSF culture	31 (19.1%)
	Negative CSF culture	10 (6.2%)
CSF identified pathogens
Staphylococus spp		13 (41.9%)
Streptococcus spp		1 (3.2%)
Gram negative bacteria		14 (45.2%)
Other bacteria		3 (9.7%)

Values are expressed as absolute number (%).; ^a sum is > 162 because several patients had more than one postoperative neurosurgical infection; ^b sum is > 132 because several patients had mixed aerobic and anaerobic infections; ^c sum is > 11 because several patients had > 1 microorganism in blood cultures

.One quarter of the patients had an epidural abscess, one fifth a scalp infection, followed by postsurgical meningitis and cranioplasty infections. Staphyloccoccus spp and Gram negative bacteria were the microorganisms most frequently from the drained pus. Same microorganisms were isolated from blood and CSF.

Laboratory studies at diagnosis of PINI

Laboratory data from blood and CSF are presented in Table 4.

Table 4

Laboratory studies at diagnosis of postoperative intracranial Neurosurgical infections (PINI)
		Patients (n = 162)
Blood determinations
Total leukocyte counts	cells/µL (n = 162)	9750 (7170.0-13600.0)
Absolute neutrophil counts	cells/µL (n = 162)	7480.0 (5200.0-11600.0)
C-reactive protein	mg/L (n = 110)	6.6 (1.9–20.5)
Erythrocyte sedimentation rate	mm/h (n = 16)	45.0 (31.0-64.8)
Creatinine	mg/dl (n = 162)	0.7 (0.5–0.8)
Glucose	mg/dl (n = 162)	108.0 (95.0-136.0)
CSF
Total leukocyte counts	cells/µL (n = 41)	440 (74.0-5000.0)
Absolute neutrophil counts	cells/µL (n = 41)	711 (41.5–4470.0)
Glucose	mg/dl (n = 41)	43.0 (33.5–71.5)
Proteins	mg/dl (n = 41)	31.0 (2.75–113.0)

Values are expressed as median (IQ range)

Leukocytosis with neutrophilia and increased values of C-reactive protein (C-RP) and erythrocyte sedimentation rate (ESR) were the dominant findings in blood parameters .Similar increase of leukocytes and neutrophils was observed in CSF:

Surgical corrective treatment of PINI

Most of the patients underwent a surgical corrective procedure detailed in Table 5.

Table 5

Surgical corrective treatment of postoperative intracranial neurosurgical infections (PINI)
		Patients (n = 162)
Surgical procedure^a	Yes	138 (85.2%)
	No	24 (14.8%)
Surgical corrective procedure type ^a
	Pus drainage by craniotomy	56 (40.3%)
	Pus drainage by burr hole and aspiration	5 (3.6%)
	Cranioplasty change	9 (6.5%)
	CSF leakage closure	12 (8.6%)
	Other surgery	57 (41.0%)
Number of surgical procedures
	0	24 (15.5%)
	1	95 (61.3%)
	2	20 (12.9%)
	3	7(4.5%)
	4	9 (5.8%)

Values are expressed as absolute number (%).

^a Sum is > 138 because several patients underwent more than one surgical correction procedure

Pus drainage by craniotomy was the most frequent corrective surgery and 8.6% underwent a CSF leakage closure. One fourth needed more than one corrective surgery.

Antimicrobial therapy of PINI

These results are shown in Table 6.

Table 6

Antimicrobial therapy of postoperative intracranial neurosurgical infections (PINI)
		Patients (n = 162)
Antimicrobial therapy before surgery	Yes	55 (34.0%)
	No	107 (66.0)%
Pre-operative prophylaxis	Cefazolin	104 (64.9%)
∗	Vancomycin	7 (4.2%)
	Other antimicrobial	13 (8.4%)
	No	28 (16.8%)
	Unknown	10 (24.6%)
Antimicrobial therapy after infection diagnosis
	Amoxicillin/clavulanate	12 (7.4%)
	Cefazolin	2 (1.2%)
	Carbapenems	3 (1.9%)
	Piperacillin-tazobactam	1 (0.6%)
	Other β-lactams	2 (1.2%)
	Vancomycin	3 (1.9%)
	Linezolid	2 (1.2%)
	Quinolones	9 (5.6%)
	Other single antimicrobial	3 (1.9%)
	Combined antimicrobial regimen	125 (77.2%)
Switch of the initial antimicrobial regimen	Yes	138 (85.2%)
	No	24 (14.8%)
		n = 138
Reason for antimicrobial regimen switch	Culture result	106 (76.8%)
	Poor evolution	10 (7.2%)
	Antimicrobial side effects	4 (2.9%)
	Other reason	18 (13.0%)
		n = 138
Antimicrobial therapy after the switch	Amoxicillin/Clavulanate	6 (4.3%)
	Cefazolin	4 (2.9%)
	Carbapenems	10 (7.2%)
	Piperacillin/tazobactam	1 (0.7%)
	Other β-lactams	22 (15.9%)
	Clindamycin	3 (2.2%)
	Vancomycin	7 (5.1%)
	Linezolid	10 (7.2%)
	Aminoglycosides	1 (0.7%)
	Other single antimicrobial	17 (12.3%)
	Combined antimicrobial regimen	57 (41.3%)
Median duration antimicrobial therapy before the switch	days	5.0 (3.0–7.0)
Total number of antimicrobials used during hospital stay		3.0 (2.0–4.0)
Median duration of antimicrobial used during hospital stay	days	21.0 (12.5–31.5)
Antimicrobial therapy after hospital discharge	Yes	99 (61.1%)
	No	63 (38.9%)
		n = 99
Antimicrobials used after hospital discharge	Amoxicillin/clavulanate	7 (7.1%)
	Cefuroxime	1 (1.0%)
	Clindamycin	2 (2.0%)
	Quinolones	31 (31.3%)
	Cotrimoxazole	5 (5.1%)
	Other antimicrobial	23 (23.2%)
	Combined antimicrobial regimen	30 (30.3%)
Total number of antimicrobials used after hospital discharge		4.0 (3.0.0–4.0)
Mean duration of antimicrobial therapy after hospital discharge	days	42.0 (25.0–60.0)

Values are expressed as median (IQ range) or absolute number (%).

Antimicrobial therapy characteristics administered to PINI patients are shown in Table 6. One third of the cases were on antimicrobials before PINI diagnosis. Over three-quarters had received pre-operative prophylaxis, mostly with cefazolin.

Over three-quarters of patients received an initial combined IV antimicrobial regimen that was mostly switched after a median of 5 days to a second IV antimicrobial regimen mainly after culture results. The most frequent initial antimicrobial IV combinations were meropenem + linezolid in 31 (19.1%) cases, meropenem + vancomycin in 24 (14.8%) and vancomycin + other antimicrobial in 10 (6.2%) cases. The second IV antibiotic regimen was a combined one in roughly half of the patients. The most frequently used antimicrobial combination after switch was meropenem + other antimicrobial in 13 (8.0%) cases. The complete IV antimicrobial therapy extended to a median of 21 days using a median of 3.0 antimicrobials of diverse classes.

Roughly two-thirds of PINI cases were discharged from the hospital on oral antibiotics. This oral regimen was based on quinolones in 47 (47.5%) cases, in 31 of them (31.3%) as monotherapy Overall the antimicrobial regimen IV plus oral lasted a median of 42. days.

Healthcare and outcome characteristics of PINI

These results are shown in Table 7.

Table 7

Hospital stay and outcome characteristics of patients with postoperative intracranial neurosurgical infections (PINI)
		Patients (n = 162)
Hospital stay time	days	34 (17.5–64.8)
Overall follow-up time	days	279 (78.0-918.5)
Cure	Complete cure	132 (81.5%)
	Relapse	18 (11.1%)
	No cure	12 (7.4%)
Overall death		41 (25.3%)
Death related to the infection		11 (6.8%)

Values are expressed as median (IQ range,) or absolute number (%).

The median length of hospital stay for PINI was slightly more than one month and they were followed at the outpatient’s clinic during a median of 9 months after hospital discharge. Regarding PINI outcome, over four-fifths reached a complete cure, 11.1% relapsed and 7.4% failed to cure. A 6.8% died for reasons related to the neurosurgical infection while 18.5% died for other reasons.

Univariate and multivariate analysis of independent factors associated with cure and mortality in PINI

Results of the univariate and multivariate analysis are shown in Tables 8 and 9.

Table 8

Univariate analysis of independent factors associated with cure and mortality outcomes in patients with postoperative intracranial neurosurgical infections
	OR	95% CI	P value
Cure
Other neurosurgery ^a	1.194	1.127–1.264	< 0.001
Scalp suture infection	1.122	1.015–1.242	0.025
Combined initial IV antimicrobial regimen with vancomycin + other antimicrobial ^b	1.350	1.190–1.531	< 0.001
Other initial combined antimicrobial regimen ^{b, c}	1.197	1.024-1.400	0.024
Switch of the initial IV antimicrobial regimen	0.833	0.802–0.866	< 0.001
Switch of the initial IV antimicrobial regimen to a combined antimicrobial regimen ^d	1.145	1.071–1.224	< 0.001
Switch to a combined IV antimicrobial regimen with quinolones + cotrimoxazole ^e	1.188	1.060–1.332	0.003
Switch to a combined IV antimicrobial regimen with amoxicillin/clavulanate + other antimicrobial ^e	1.188	1.06–1.332	0.003
Oral antimicrobial therapy after hospital discharge	1.168	1.063–1.284	0.001
Mortality	HR	95% CI	P value
Male gender	1.799	1.034–3.128	0.038
Age > 60 years	2.643	1.130–6.182	0.025
Diabetes	2.882	1.819–4.568	< 0.001
Immunodepression	2.608	1.333–5.101	0.005
Scalp suture infection	0.339	0.149–0.773	0.010
Cranioplasty infection	0.468	0.326–0.671	< 0.001
Post-neurosurgical meningitis	2.160	1.095–4.260	0.026
Other post neurosurgical infection ^f	2.229	1.148–4.328	0.018
Combined antimicrobial regimen	5.684	2.087–15.483	0.001
Other initial combined IV antimicrobial regimen ^{b, c}	0.409	0.197–0.846	0.016
Oral antimicrobial therapy after hospital discharge	0.462	0.203–1.053	0.066
^a other neurosurgery excluding craniectomy and cranioplasty compared to craniotomy
^bcompared to patients treated with IV carbapenems + aminoglycosides
^c other initial IV antimicrobial combinations excluding the combinations carbapenem + vancomycin and amoxicillin/clavulanate + vancomycin
^d compared to patients switched to an antimicrobial IV monotherapy regimen
^e compared to the patients treated with IV quinolones in monotherapy
^f other post-neurosurgical infections excluding scalp suture infection, bone flap osteomyelitis, epidural abscess, subdural abscess, brain abscess and meningitis
OR = Odds ratio; HR = Hazard ratio; 95% CI = confidence interval

Table 9

Multivariate analysis of independent factors associated with cure and mortality outcomes in patients with postoperative intracranial neurosurgical infections
	OR	95% CI	P value
Cure
Other neurosurgery^a	1.240	1.184–1.298	< 0.001
Combined antimicrobial therapy	0.933	0.838–1.038	0.202
Oral antimicrobial therapy after hospital discharge	1.173	1.071–1.284	0.001
	HR	95% CI	P value
Mortality
Age > 60 years	3.880	1.009–14.917	0.048
Diabetes	2.300	1.202–4.403	0.012
Immunodepression	2.211	1.228–3.980	0.008
Post-neurosurgical meningitis	2.737	1.089–6.878	0.032
Other post neurosurgical infection^b	5.533	1.430-21.567	0.013
Combined initial IV antimicrobial regimen	6.279	2.061–19.127	0.001
OR = Odds ratio; HR = Hazard ratio; CI = confidence interval
^aOther neurosurgery excluding craniectomy and cranioplasty, compared to craniotomy
^b Other post-neurosurgical infections excluding scalp suture infection, bone flap osteomyelitis, epidural abscess, subdural abscess, brain abscess and meningitis
OR = Odds ratio; HR = Hazard ratio; 95%CI = confidence interval

Cure

Scalp suture and other neurosurgeries (excluding craniectomy and cranioplasty) compared to craniotomy were associated with cure in the univariate analysis (p < 0.03). Also the use of a combined initial IV antimicrobial therapy containing vancomycin + other antimicrobial compared to carbapenems + aminoglycosides and the switch of the initial IV antibiotic treatment to a combined IV regimen made of quinolones + cotrimoxazole, of amoxicillin/clavulanate + other antimicrobial or to other different antimicrobial combination compared to quinolones monotherapy were associated with cure (p < 0.03). Finally, the administration of oral antimicrobials after hospital discharge was also associated with cure in the univariate analysis (p = 0.001). The multivariate analysis showed that undergoing a neurosurgical procedure different from craniectomy and cranioplasty, compared to craniotomy, and receiving oral antimicrobial therapy after hospital discharge were significantly associated with cure (p < 0.001 and p = 0.001, respectively).

Mortality

Male gender, age > 60 years, diabetes, immunodepression, undergoing other neurosurgical procedures (different from scalp suture infection, bone flap osteomyelitis, epidural, subdural and brain abscesses) were associated with higher mortality (p < 0.04) in the univariate and multivariate analysis. Individually, cranioplasty infections were associated with higher survival (p < 0.001) while postsurgical meningitis were associated with higher mortality (p = 0.026) An initial combined IV antimicrobial therapy was associated with higher mortality ( p = 0.001) in the univariate and multivariate analysis except for a combined antimicrobial regimen different from carbapenems + vancomycin and amoxicillin/clavulanate + vancomycin, compared to carbapenems + aminoglycosides in the univariate analysis (p = 0.016). Oral antimicrobial therapy after hospital discharge showed a marginal effect on survival on survival (p = 0.066) in the multivariate analysis.

We observed that an extended sequential 6 weeks antimicrobial therapy in addition to neurosurgical correction was significantly associated with PINI cure and might increase patients´ survival in this study. Patients received a median of 3 weeks of IV antimicrobials, mainly as a combined regimen and other 3 weeks of oral antimicrobials after hospital discharge. In the multivariate analysis oral antimicrobial therapy after hospital discharge (p = 0.001) was significantly associated with PINI cure and had a marginal improving effect on survival (p = 0.066). These results were obtained after retrospectively analyze 162 PINI episodes from 8 Spanish third-level academic hospitals in the period 2014-23.

The observation of a significantly increased cure and lower mortality rates of PINI after minor neurosurgical procedures different from craniectomy and cranioplasty, compared to craniotomy in the multivariate analysis seems reasonable. Both neurosurgical procedures imply opening of the dura mater membrane or its physical contact with previously stored autologous or synthetic bone to restore the normal shape of the skull. Therefore both surgical procedures might enhance PINI. The overall rate of complications related to cranioplasty after craniectomy is not negligible. Chang et al reported 13% of infection in 212 patients that underwent cranial repair after craniectomy [16]. In addition neurosurgical procedures different from scalp suture infection, bone flap osteomyelitis, epidural, subdural and brain abscess and meningitis were significantly associated with higher mortality. The surgical correction of infected scalp wounds with simple wound cleaning, of infected cranioplasties with their removal, of intracranial abscesses with pus drainage procedures mainly by a small burr hole and of CSF leakages closure with stitches or graft patches are minor surgical procedures that lead to a shorter hospital stay and a higher survival rate than other more aggressive neurosurgical approaches.

We found an association of PINI mortality with age > 60 years, diabetes or immunodepression in the multivariate analysis. These variables are known to be associated with an increased risk of developing a neurosurgical infection after craniotomy [9, 11]. However we could not demonstrate an association of PINI cure or mortality with male gender, length of hospital stay before surgery, duration of operation (> 4 hours), number of operations (> 1), or nontraumatic reason of surgery that other authors found [1, 2, 4, 6–12]. Probably the relatively small size of our cohort limited the statistical analysis. In spite of the lack of association of CSF leakage with PINI mortality in our study, previously reported by others, an association of post-neurosurgical meningitis, favored by the CSF-leakage, with mortality was demonstrated in our work [1, 9].

Most of the microorganisms isolated from pus drainage, blood or CSF of our patients, mainly Staphyloccosus spp were similar to those identified in previous series [1, 4, 6, 8, 11]. Interestingly more than one third of isolates of our PINI cases were Gram negative bacilli in a number much higher than previous works. This fact might suggest that in those cases Gram negative bacilli from the hospital flora colonized the neurosurgical wounds enhancing PINI.

Overall 16.8% of our PINI patients did not receive pre-operative antimicrobial prophylaxis. One of the explanations for this fact might be that almost one third of the cases underwent urgent surgery due to vascular or trauma reasons. Buffet-Bataillon et al in a study of 883 patients recruited in the period 2008–2009 in France found that emergence neurosurgical procedures were associated with an increased risk of surgical site infections [17]. Antibiotic prophylaxis decreased infection rate from 97–5.8% in 4578 patients undergoing craniotomy [1]. Mollman and Haines performed a case-control analysis on 9,202 patients with neurosurgical wounds and found that antibiotic prophylaxis was associated with a decreased rate of surgical site infection [18]. However, we could not observe a worse evolution in those PINI patients that did not receive pre-operative antimicrobial prophylaxis. Furthermore an increased PINI cure rate or increased survival in our patients that were receiving antimicrobial therapy previously to neurosurgery was not found, either.

There are not standard antimicrobial guidelines for PINI treatment [13–15]. Therefore many antimicrobials in monotherapy and multiples antibiotic combinations were used to treat PINI in our series precluding the statistical analysis of these variables. Although we observed a significant association of some combined initial IV antimicrobial regimens, some of them containing vancomycin (carbapenem + vancomycin, amoxicillin/clavulanate + vancomycin) with PINI cure when compared to the combination of carbapenems + aminoglycoside in the univariate analysis, the instauration of a combined antimicrobial therapy was nor associated with cure in the multivariate analysis (p = 0.202). Surprisingly a combined initial IV antimicrobial regimen was significantly associated with higher mortality (p = 0.001). This unexpected finding could be explained by the fact that patients with more severe PINI were started on empiric combined IV antimicrobial regimens due to their serious clinical situation more frequently than those with minor PINI that were put initially on IV antimicrobial monotherapies.

Our results of a median of 3 weeks of IV antimicrobial therapy for PINI shorten to a half the guidelines made by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) that recommend 6–8 weeks of IV antimicrobials for aspirated or conservatively treated brain abscesses. However only 62 patients of our study (38.3%) had a CNS abscess and 19.8% had other had other infections such as scalp´s (19.8% ) that did not require long IV antimicrobial therapy. The same ESCMID guidelines do not recommend neither early transition to oral antimicrobials nor oral consolidation treatment after > 6 weeks of IV antimicrobials for brain abscess. Extended oral antimicrobial therapy after hospital discharge was significantly associated with cure in our PINI cases .This oral therapy was combined in one third of cases and was based on single or combined quinolones regimens. Quinolones cross easily the blood-brain barrier and through the bacterial-generated biofilm and are ideal antimicrobials to treat PINI especially with foreign body devices such as cranioplasty grafts. [13–15].

Regarding PINI outcome four fifths of our PINI patients cured, 11.8% relapsed and one fourth died but only 6.8% due to PINI. Bodilsen et al in a recent meta-analysis found a relapse or recurrence rate of 3.4% in children and adults with brain abscesses treated with IV antimicrobials for > 6 weeks and surgical pus drainage [16]. However 26% of our PINI patients had cranioplasty infections or skull osteomyelitis with a very high relapse rate, higher than CNS abscess The mortality rate due to PINI in our cases, in whom one fifth was immunodepressed and one fourth had comorbiditites was slightly higher than the 4.7% reported by Korinek et al in France in a large prospective cohort of 383 PINI patients after 6243 consecutive craniotomies. However when these authors considered only those patients with postsurgical meningitis the mortality raised to 13.7% [3]. A fatality rate of 4.4% was observed in 45 Indian patients with subdural empyema treated with pus drainage and broad-spectrum antibiotics [20]. Bodilsen et al in a recent meta-analysis found a fatality rate of 9% in children and adults with brain abscess treated with aspiration or excision [19].

The main strength of this work relies on its focus on PINI antimicrobial therapy, a point neglected by most of the previous studies on this topic, the relatively large sample size and the elevated number of parameters assessed, which allowed to adjust for and minimize the effect of confounders in the uni and multivariate analysis. Limitations include those common to retrospective studies, the long time needed, 9 years, for closing the study due to the interfering COVID-19 pandemia, the absence of a unified antimicrobial treatment protocol for PINI, which would allow the evaluation of the responses to the same treatment, and the variability characteristic of multicenter studies, particularly regarding procedural and management aspects. However, as we have mentioned before, currently no single or widely accepted treatment protocol exists considering the great diversity of clinical and microbiological issues related to PINI, and the multicenter character of the study allows the evaluation of the real clinical practice across our country, minimizing potential biases from a single institution.

We conclude that an extended 6 weeks sequential IV for 3 weeks and oral antimicrobial therapy for other 3 weeks in addition to neurosurgical correction increases PINI cure rate and might improve patients´ survival .

CI :confidence interval; CNS: Central Nervous System; C-RP: C-reactive protein; CSF: Cerebrospinal fluid; CT:computerized tomography; ESR: erythrocyte sedimentation rate; GCS: Glasgow Coma Scale; HR: hazard rate; ICU: Intensive Care Unit; IV: intravenous; ID: Infectious Diseases; MRI: magnetic resonance imaging; OR :Odds ratio; PINI : Postoperative intracranial neurosurgical infections

Acknowledgements

The authors thank the Infectious Diseases Working Group of the Spanish Society of Internal Medicine (SEMI) for help promoting and funding this study. This organization had no role in the study design, collection,

Ethics approval and consent to participate

:This was an observational study, using anonymized data, in which the patients underwent routine clinical care for PINI, without any change in its management or specific determinations or procedures. Therefore, no formal written informed consent was obtained from the patients. The Research Ethics Committee of the Principality of Asturias granted a formal waiver of ethical approval for this study.

Consent for publication

Not applicable

Availability of data and materials

Not applicable

Competing interest

The authors declare that they have no competing interest .

Funding

The Infectious Diseases Working Group of the Spanish Society of Internal Medicine (SEMI) supported and funded this study

Authors’ contributions

C.V., H.G., S.S.-D., E.A.-D.;N.C.-A., A.G.-R.,M.V.M., J.M.G., J.A., M.A.S., X.G.-C., C.D., and M.B. recruited patients and collected the data, JC designed the study data file, VC did the statistical analysis of the data and VA designed the study, recruited patients, collected data and wrote the manuscript. All authors have read and approved the final version manuscript.

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No competing interests reported.

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Extended sequential intravenous and oral antimicrobial therapy improves cure rate in postoperative intracranial neurosurgical infections. A Spanish multicenter retrospective study

Status:

Version 1

Abstract

Background

Patients and Methods

Inclusion criteria

Exclusion criteria

Data collecting

Statistical analysis

Results

Demographic characteristics of patients with PINI and predisposing factors leading to these infections

Neurosurgery-related parameters of PINI

PINI type, location and microbiology

Laboratory studies at diagnosis of PINI

Surgical corrective treatment of PINI

Antimicrobial therapy of PINI

Univariate and multivariate analysis of independent factors associated with cure and mortality in PINI

Cure

Mortality

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1