Intraventricular antibiotics for severe central nervous system infections: a case series

Informed consent was obtained from all patients or their legal guardians. The study was approved by the local ethics committee (Kantonale Ethikkommission Zürich, BASEC- Nr2021-00,631) and was conducted in accordance with the ethical standards laid down in the 2013 Declaration of Helsinki for research involving human study participants.

Study population, inclusion and exclusion criteria

This retrospective study included patients who received IVT for CA-CNSI and HAVM between January 2011 and July 2023 at the Neurocritical Care Unit (NCCU) of the University Hospital of Zurich, Switzerland. Inclusion criteria were: 1) adults (≥ 18 years old), 2) admission to the NCCU; 3) administration of IVT. Exclusion criteria was patient’s written or documented oral refusal to have his or her data analyzed for research projects.

Data collection

All data were collected from the hospital’s electronic health records (KISIM-TM Cistec® Zurich, Switzerland).

CA-CNSI includes infectious meningitis, meningoencephalitis, encephalitis, and suppurative intracranial infections (e.g. brain abscess, subdural empyema, and epidural abscess), as previously defined^4,14. HAVM was defined based on the guidelines of the Infectious Diseases Society of America⁶, adapted for patients with hemorrhagic stroke¹⁵. CNSI was considered “severe”, if the patient required NCCU admission due to hemodynamic instability and/or respiratory or neurological failure requiring intubation, and/or need of an EVD^16,17.

Demographics and baseline characteristics were collected, including: sex, age, presence of comorbidities, as assessed with the Charlson Comorbidity Index (CCI)¹⁸, estimated mortality at admission based on the Simplified Acute Physiology Score (SAPS) II¹⁹, first available Glasgow Coma Scale (GCS), and GCS at NCCU-admission. Presence of seizures and/or status epilepticus at any time during the ICU-stay was noted.

In case of CA-CNSI, specific underlying conditions such as otitis, sinusitis or endocarditis were assessed. In case of HAVM, data were collected on previous surgery (neurosurgery versus others) and primary reason for the hospitalization (hemorrhagic stroke, traumatic brain injury, ischemic stroke, brain tumor, other).

The duration and dosages of IVT and ST for CA-CNSI and HAVM were listed. Data on possible toxicity associated with IVT during the NCCU stay was sought in medical reports. (e.g. hearing loss, painful radiculitis, red man syndrome, nausea, eosinophilia, intraventricular hemorrhage, epileptic seizure).

Relapse after IVT withdrawal was defined as a new positive CSF sample (culture or broad range eubacterial polymerase chain reaction (ePCR)) after CSF sterilization and the time to relapse was noted.

Regarding outcome, data on NCCU- and hospital length of stay (NCCU-LOS and H-LOS), as well as functional outcome were collected. Functional outcome was assessed with the modified Rankin Scale (mRS) at different time points (at hospital discharge, at six, twelve and 24 months) and dichotomized in favourable (mRS ≤ 3) and unfavorable(mRS ≥ 4)^20,21. Missing data were considered in the analysis.

Intravenous antibiotics

In case of suspected CNS infection, ST is started as soon as possible empirically, based on the most recent guidelines for management of patients with HAVM and CA-CNSI^4,6,7,14. In case of suspected CA-CNSI, ceftriaxone and-depending on the risk factors-ampicillin are empirically initiated, together with acyclovir, where appropriate. In case of suspected brain abscess, metronidazole is added.

In case of suspected HAVM, meropenem and vancomycin are started empirically. As soon as CSF microbiology is available, ST is adapted.

IVT antibiotics

IVT is administrated through the EVD following a standardized protocol based on available data⁷. EVDs (Bactiseal, INTEGRA LIFESCIENCES USA) are inserted by the neurosurgical team in the operating room, the emergency room or at the NCCU under sterile conditions. Silver impregnated lines (Silverline®, Spiegelberg, Germany) are used. A single shot cefuroxime (or clindamycin in case of allergies) is given intravenously if the patient is not yet under antibiotic treatment. The inserting route involves an 8 cm tunneling between the skin insertion and the borehole.

IVT antibiotics of choice are gentamicin, vancomycin, colistin, alone or in combination, based on the possible causative microorganisms and successively on the available microbiological findings. Frequency of administration and dosage of IVT is based on the daily amount of drained CSF (Table 1, supplementary 1). The duration of treatment is highly individualized, depending on the clinical condition (e.g., HAVM versus CA-CNSI) and the pathogen (e.g., a shorter course of antibiotics is often sufficient after the removal of a foreign body infected with coagulase-negative staphylococci)¹⁰.

Laboratory findings and CSF diagnostics

At our institution, CSF sampling in patients with an EVD is performed routinely twice a week and whenever clinically indicated, under sterile conditions. Routinely collected parameters are CSF-WBC (available within 2 h) and microbiological culture with Gram staining (available within 24 h). In case of negative Gram staining but clinical suspicion of CSF infections, ePCR is performed. CSF glucose, lactate and protein are not routinely measured in case of HAVM, condition often associated with intraventricular blood (i.e., ventricular extension of the hemorrhage), making the values less specific/suggestive for/of infection. If necessary, CSF- WBC is corrected for the number of erythrocytes (red blood cell count [RBC]) in the same specimen, using the following formula: corrected WBC = [total WBC – (1.5 × RBC)] / 1000).

Statistical analysis

Statistical analysis was performed using R, version 4.3 and MATLAB R2023a (The MathWorks Inc., Natick, Massachusetts). Significance was defined as the probability of a two-sided type 1 error being < 5% (p-value < 0.05). Descriptive statistics are reported as counts/percentages, mean ± standard deviation (SD), or as median including the interquartile range as appropriate. All continuous data were tested for normality using Shapiro–Wilk’s test. Categorical variables were compared with Pearson’s χ2 or Fisher’s exact test, continuous/ordinal variables using Student’s t-tests or Mann–Whitney U tests for parametric and non-parametric data, respectively, where appropriate. Binary variables were tested using the Chi-Square-Test.

Survival analysis was performed using the logrank test and illustrated by Kaplan–Meier plots using MatSurv (Creed et al., (2020). MatSurv: Survival analysis and visualization in MATLAB. Journal of Open Source Software, 5(46), 1830, To assess between-groups differences in CSF-WBC dynamics, linear mixed-effects models were applied to logarithmized CSF-WBC values as a function of time, assuming fixed effects of time and group (including an interaction term between the two) with random intercepts and slopes. In Wilkinson notation, the models can be expressed as log(CSF-WBC) ~ time*group + (1 + time|ID). Thus, the models explore the association between CSF-WBC and time from IVT initiation while accounting for variation introduced by the group (i.e. CA-CNSI vs. HAVM, and favorable outcome vs. unfavorable outcome, respectively) and controlling for non-independence of repeated CSF-WBC measures.