Empirical cefepime+vancomycin versus ceftazidime+vancomycin versus meropenem+vancomycin in the treatment of healthcare-associated meningitis: results of the multicenter Ephesus study

Despite advances in medicine, neurosurgery, antimicrobial therapy, and critical care, meningitis, specifically nosocomial or healthcare-associated meningitis (HCAM), still poses a significant risk of mortality and morbidity [1‐3]. Prompt and appropriate treatment is essential in managing HCAM, as inappropriate treatment may lead to undesirable outcomes. In contrast to community-acquired meningitis (CAM), which is mainly caused by pneumococci and meningococci [4], healthcare-associated meningitis (HCAM) is typically caused by Gram-negative bacilli, such as Pseudomonas aeruginosa, Acinetobacter spp., or Enterobacteriaceae, and Gram-positive cocci, such as staphylococci or enterococci [1‐3, 5‐9]. This difference also results in a discrepancy in empirical antibiotic therapy. While the third-generation cephalosporin ± ampicillin and vancomycin or rifampin is recommended for empirical CAM therapy, HCAM empirical treatment is recommended to be a combination of vancomycin with ceftazidime or cefepime or meropenem [1, 2, 5, 7]. However, to our knowledge, there are no published clinical data comparing these empirical treatment regimens in terms of efficacy in HCAM. In this multicenter multinational retrospective cohort study, our main objective was to compare the microbiological and clinical efficacy of the main empirical antibiotic regimens used for HCAM.

This study was conducted in 15 tertiary-care educational hospitals across nine cities in Turkey, including Izmir, Ankara, İstanbul, Adana, Denizli, Antalya, Diyarbakir, Trabzon, and Mersin, as well as three centers in India, Egypt, and Romania. We extracted data and outcomes from all adult patients (aged 18 or older) with post-neurosurgical meningitis who met the inclusion criteria and were treated with one of the three empirical therapy options. The study period was between December 2006 and September 2018. Demographic, clinical, and laboratory findings (white blood cells, CRP and other findings were on the day empirical antibiotic was started), predisposing factors, as well as information on treatment response and outcomes were obtained retrospectively.

A total of 170 postneurological meningitis cases were included in the study, with 20 patients in the cefepime + vancomycin (CV) group, 31 in the ceftazidime + vancomycin (CFV) group, and 119 in the meropenem + vancomycin (MV) group. Of these patients, 28 (16.5%) had shunt infections, 20 (11.8%) were on lumbar drainage, and 36 (21.2%) were on external ventricular drainage at the time of diagnosis of nosocomial meningitis. Table 1 shows the underlying diseases, age, and other characteristics of the cases. There were no significant differences between the three therapy cohorts in terms of underlying diseases, shunt, lumbar or extraventricular drainage, treatment duration, gender, and age. However, admission to the intensive care unit (ICU) and any antibiotic therapy during the one-month prior to the meningitis episode were significantly more common in the MV subgroup.

HCAM is a very serious type of healthcare-associated infection that poses significant patient risks. The HCAM guidelines recommend ceftazidime, cefepime, or meropenem + vancomycin as empirical therapy options [5]. Although these combinations are the most commonly suggested regimens [1, 2, 4, 5], there has been no controlled or uncontrolled comparative analysis to determine the efficacy of these options. Cefepime has an advantage over ceftazidime in that it is resistant to inducible Ampc type beta-lactamases, while ceftazidime and cefepime both have the disadvantage of being susceptible to most ESBLs compared to meropenem. However, all three options are sensitive to carbapenemases [13, 14]. Using only one option for continuous antibiotic pressure may contribute to resistance; therefore, increasing the number of available empirical therapy options could increase the effective consumption periods of the available antibiotic options [13]. This study was conducted to determine whether these three options may be alternative to each other.

HCAM is a relatively rare nosocomial infection. However, in centers with overloaded neurosurgery clinics, it may comprise a more significant part of overall nosocomial infections. While HCAM is rare, it can lead to a mortality rate of 16–40.8% [15‐21] and significant morbidity. In our cohort, overall mortality at EOT (CV-CFV-MV) was 18,8%. The lowest mortality was observed in CV cohort (10%) and highest in CFV cohort (22.5%) (p = 0.489) all of which are compatible with the results published in the literature [15‐21]. It is worth noting that some patients experienced a relapse or developed other nosocomial infections, leading to additional mortality during the follow-up period. Hence, in our study, after 18.8% EOT mortality an additional 13 (7.6%) patients died until day 30 follow up. However, there was no significant difference in terms of mortality analysis between the three treatment groups.

As our study was a retrospective cohort study, it was not possible to balance the cohorts in all parameters including patient numbers or culture-negative cases in the three cohorts. MV combination was used more commonly than CV or CFV combination in the study centers, which created an imbalance in disfavor of CV and CFV cohorts. Additionally, the GCS at the start of empirical antibiotic therapy, the number of patients managed in the ICU, and the number of cases that received antibiotics in the previous month of the HCAM episode were significantly disfavored in the MV arm. It is possible that all these disadvantages, which are risk factors for ESBL, might have caused selection of meropenem rather than cefepime or ceftazidime. Furthermore, sequalae were more common in the MV arm, which may be due to the significantly lower GCS score and significantly higher ICU need in that cohort [1, 4]. However, the EOT clinical success, day-30 mortality, and overall clinical success at the end of the one-month follow-up did not differ significantly between the three cohorts.

Nosocomial Acinetobacter infections, including meningitis, are becoming increasingly common in ICUs. According to a recent systematic review of HCAM in Turkey [3], Acinetobacter spp. caused 30.7% of 899 CSF culture positive nosocomial meningitis episodes. The pooled carbapenem-resistance rate was 37.5%. In addition, carbapenem-resistant Enterobacteriales are increasingly being reported as a cause of HCAM [22, 23]. However, carbapenems, ceftazidime, and cefepime have the disadvantage of not covering carbapenem-resistant strains. As a result, all three treatment arms evaluated in our cohorts failed in the carbapenem-resistant subgroup.

Herein, we detected the overall clinical success rate with vancomycin as 60.6% in the ampicillin-resistant enterococci and methicillin-resistant staphylococci subgroup. As glycopeptides are relatively large molecules, their ability to penetrate the central nervous system is limited. Strains with a low MIC (< 1mg/l) are expected to have a higher likelihood of clinical success. Hence, we found that clinical success at EOT was lower in patients with a vancomycin MIC > 1mg/l compared to those with a MIC ≤ 1mg/l (p = 0.001) [9, 24, 25].

The reported penetration rates of the included antimicrobial agents into inflamed CSF are as follows: 20–40% for ceftazidime [26], 10.3% for cefepime [27], 39% for meropenem [27], and 30% for vancomycin [27]. However, the drug levels were not measured in any of the study centers.

Our study has several limitations i) its retrospective design ii) with a relatively small number of cases in the ceftazidime and cefepime groups, it was underpowered to demonstrate the efficacy of the three empirical treatment regimens in well-balanced cohorts and also unable to show the outcome differences in methicillin-resistant versus sensitive cases, as well as 3^rd generation and carbapenem resistant bacterial strains iii)the absence of antibiotic levels, pharmacokinetic and pharmacodynamic data including vancomycin, which were not measured in any of the cases iv) repeated lumbar puncture was not repeated In all cases vi) we did not analyse the neutrophil rates of CSF samples v) all the included cases fulfilled the inclusion criteria but we did not further examine the excluded cases) vi) Though we could include the meningitis episodes developping after 90 days we wanted to stay within the 90 days period in implant cases [28]. Herein, our primary objective was to compare the efficacies of empirical therapy and assess EOT clinical success and EOT mortality as the most critical outcomes. However, due to the fact that EOT not having a fixed time point, we conducted further analysis of day-30 ACM, which could have been impacted by revisions to intravenous/intrathecal antibiotic therapy after the etiology was elucidated. Nevertheless, needing such modifications was considered an unsuccessful outcome, and analysis of these modifications was kept outside the scope of this study. Additionally, infection related mortality was considered as per the treating physician. Due to the inability to perform autopsies, definitive reasons for mortality could not be determined. Our analysis indicated considerable mortality, relapse, and reinfection after the EOT, suggesting potential problems in infection control or reaching the best available therapy (especially in carbapenem-resistant Gram-negative cohort) at the study centers. Despite these limitations, to our knowledge, this is the first and the largest dataset evaluating the microbiological and clinical efficacy of empirical therapy regimens in HCAM, providing valuable insights into this area of study.

In conclusion this retrospective cohort study revealed no significant difference in EOT clinical success, EOT mortality, overall clinical success, and day-30 ACM among the three treatment arms. Our study was the first to compare three empirical therapy regimens in HCAM. While all three options had basicdisadvantages against carbapenem-resistant strains, vancomycin was found to have average efficacy against methicillin-resistant staphylococci. We suggest a randomized controlled trial to further analyze these three regimens. In addition, we suggest evaluating empirical therapy regimens that may be effective against carbapenem-resistant Gram-negative bacteria. We strongly recommend developing speedy diagnostic systems for HCAM, similar to those used in community-acquired meningitis or other infections [29, 30]. Finally the medical community should seek more effective measures for infection control in HCAM.