Background <p>Intracranial infections due to carbapenem-resistant organisms (CRO) pose substantial challenges in the neurosurgical intensive care unit (NICU). The increasing prevalence of infections caused by carbapenem-resistant Acinetobacter (CRAB) and carbapenem-resistant Klebsiella pneumoniae (CRKP) necessitates the development of novel treatment strategies. This prospective observational study aims to evaluate the efficacy and safety of intraventricular/intrathecal polymyxin B sulfate (PBS) in NICU patients after neurosurgery.</p> Methods <p>We enrolled patients diagnosed with hospital-acquired post-neurosurgical central nervous system (CNS) infections caused by CRO at Fudan University-affiliated Huashan Hospital between January 2021 and December 2023. Detailed information on demographic characteristics, course of CRO infection treatment and follow-up data was recorded for each patient collected in this study. Upon diagnosis, all external devices were immediately removed. The treatment regimen included local intraventricular/intrathecal PBS injections, systemic antibiotics, and cerebrospinal fluid (CSF) drainage. The Fisher exact test, theχ² test, and the Student t-test were used for statistical analysis as appropriate.</p> Results <p>Among the 27 patients included in this study, 13 were infected with CRAB and 14 with CRKP, with a mean age of 49.4 ± 16.54 years. 96.3% patients had undergone surgical procedures prior to diagnosis, of which 66.7% involved combined surgeries. At the onset of infection, the mean Glasgow Coma Scale (GCS) score was 6.0 ± 2.17, the average APACHE II score was 17.3 ± 3.80, and the mean SOFA score was 5.9 ± 2.20. The total bacterial clearance rate of CSF was 81.5% (22/27), with CRAB cases achieving a clearance rate of 92.3% and CRKP cases achieving 71.4% (<i>p</i> = 0.163). The clinical cure rates were 69.2% (9/13) for CRAB and 64.2% (9/14) for CRKP. Importantly, the mean duration from the onset of CNS infection to the initiation of intraventricular/intrathecal injection was 4.3 ± 5.01 days, while the mean duration of treatment was 9.9 ± 3.92 days. The time to achieve negative CSF cultures averaged 10.6 ± 7.02 days. No significant differences were found between the CRAB and CRKP groups, except for variations in sex ratio.</p> Conclusion <p>The findings of our study verified the efficacy and safety of intraventricular/intrathecal PBS in treating CRO-related intracranial infections in neurosurgical patients. The combination of local PBS administration and systemic antibiotic therapy offers a more efficient treatment approach for these complex infections.</p>