Abstract
Healthcare-associated ventriculitis and meningitis (HCAVM) is a severe infection and is associated with high morbidity, mortality, and poor functional prognosis, and the associated microorganisms can be skin flora or nosocomial pathogens, most commonly Gram-negative bacteria. Enterococci-related HCAVM have rarely been discussed systemically, the related drug resistance and outcomes have been poorly researched. In this multicenter retrospective case series, we analyzed patients with Enterococci-related HCAVM from three tertiary hospitals. Our study assessed bacterial resistance patterns, antimicrobial treatment strategies, and clinical outcomes in this patient cohort. A total of 94 strains of Enterococci causing HCAVM were identified, including 58 strains of Enterococcus faecalis and 34 strains of Enterococcus faecium. Vancomycin resistance rate was 7.4%(7/94), which only occurred in E. faecium. The linezolid resistance rate was 1.1%(1/94). Ten tested antimicrobial agents showed higher resistance rates against E. faecium than against E. faecalis. Vancomycin was used in 88 patients as empirical treatment, which was changed to linezolid in 12 patients, including those with vancomycin-resistant E. faecium. Four (4.3%) patients experienced ineffective treatments, eight (8.5%) had poor outcomes, and the treatment course was 15.3 ± 10.9 days. In conclusion, our findings reveal the different resistance rates of Enterococcus faecalis and Enterococcus faecium to vancomycin and linezolid, reveal the clinical epidemiological characteristics of Enterococci-related HCAVM, and provide an important reference for the selection of antimicrobial agents.
Keywords: Enterococci, Healthcare-associated ventriculitis and meningitis, Antimicrobial susceptibility test, Vancomycin, Linezolid
Introduction
Enterococci-related healthcare-associated ventriculitis and meningitis (HCAVM) is a serious clinical threat. On one hand, Enterococci are relatively common pathogens causing HCAVM, and several studies have shown that 3.2–6.0% of HCAVM are caused by Enterococci [1–4]. However, vancomycin resistance is occasionally reported in Enterococci [5, 6]. As vancomycin is the most commonly used antimicrobial agent in gram-positive bacteria-related HCAVM [7], its resistance can lead to disastrous outcomes.
In recent years, Enterococci-related HCAVM has mostly been reported in case series [8–12]. Vancomycin is the most common antimicrobial agent [12], whereas linezolid, gentamicin, and rifampicin are the replacements for vancomycin-resistant Enterococci (VRE) [8–11]. The patient outcomes following treatment reflected great heterogeneity.
Several questions remain unanswered. First, the vancomycin resistance rate in Enterococci causing HCAVM remains unknown. Second, the appropriate antimicrobial agent to be used following vancomycin resistance is unknown. Although several antimicrobial agents have been reported to treat VRE [8–11], the evidence based on antimicrobial susceptibility tests is insufficient. Third, the treatment effect of HCAVM, clinical outcomes, and treatment course are unknown.
To understand Enterococci-related HCAVM, this study reported on the antimicrobial resistance of the pathogens along with their treatments and outcomes, with the aim of analysing clinical practices based on antimicrobial resistance.
Materials and methods
Study design and participants
In this multicenter retrospective case series, we recruited patients with Enterococci-related HCAVM based on the Electronic Record System from three tertiary teaching hospitals, including the Affiliated Hospital of Guizhou Medical University (Guiyang, China), Beijing Tiantan Hospital, Capital Medical University (Beijing, China), and the Affiliated Jinyang Hospital of Guizhou Medical University (Guiyang, China). At the beginning, we wanted to recruit the data from 2011 to 2020. However, the Electronic Record System in the corresponding hospitals is only available to 2014, 2012, and 2015. The HCAVM was diagnosed according to the guidelines [7].
Ethics
An informed consent from the study patients was not required because of the retrospective nature of the observational study and no interventions. The study was approved by the Ethics Committee of the Second People’s Hospital of Guiyang, and also applied for an exemption of informed consent of the subjects, and the number is JYYY-2024-WZ-10.
Cultures and antimicrobial susceptibility tests
Cerebrospinal fluid (CSF) specimens were collected from patients with suspected HCAVM and incubated until they tested positive or for five days. The positive CSF cultures were Gram-stained and sub‐cultured onto a solid medium using standard protocols. The antimicrobial agents were tested for activity against bacteria using broth microdilution methods according to the guidelines of the Clinical and Laboratory Standards Institute. Techniques from the latest editions were employed at the corresponding times. Not all that antimicrobial agents were tested against every strain of bacteria, the main reason was the antimicrobial agents were packaged and sold to the hospitals, and the packages were different at different times to different institutes.
Interpretive categories were defined according to the Clinical and Laboratory Standards Institute M100 guidelines, 31 st edition [13].
Treatment and definition
During the study period, antimicrobial management of HCAVM adhered to established IDSA guidance [7]. Empirical regimens mandated agents with demonstrated central nervous system penetration capable of achieving therapeutic cerebrospinal fluid concentrations and exhibiting bactericidal activity against suspected pathogens. Following microbial isolation (Enterococcus species) and availability of in vitro susceptibility results, targeted therapeutic modifications were implemented. Dosing regimens include: vancomycin (15–20 mg/kg every 8–12 h, target trough > 15 µg/mL), linezolid (600 mg every 12 h), ampicillin (3 g every 4 h), gentamicin (5 mg/kg total daily dose administered in 8-hourly infusions), and ceftriaxone (2 g every 12 h with 2–3 h extended infusions). Definitions of treatment-related terms in the study of HCAVM were shown in Table 1.
Table 1.
Definitions of treatment-related terms in the study of HCAVM
| Term | Definition |
|---|---|
| Empirical treatment | Initial antimicrobial therapy administered before pathogen identification and susceptibility results became available. |
| Adjusted treatment |
Modified antimicrobial regimen based on: 1) Culture and susceptibility test results. 2) Clinical requirement for therapeutic modification. |
| Active antimicrobial agent |
An antimicrobial demonstrating: 1) Complete susceptibility. 2) Intermediate susceptibility (dose-dependent). 3) For untested agents: traditional anti-enterococcal agents with established clinical efficacy. |
| Treatment course | Total duration of active antimicrobial administration specifically targeting HCAVM. |
Patient outcomes
The treatment effect was classified into effective and ineffective treatments according to the guidelines [7]. The treatment was considered effective when HCAVM-related parameters, including CSF parameters, CSF culture, and clinical parameters, in order of descending importance, gradually returned to normal levels. Treatment was considered ineffective when HCAVM-related parameters, particularly CSF parameters, did not return to normal levels.
Clinical outcomes were classified into poor (Glasgow Outcome Scale [14] 1–3) and acceptable outcomes (Glasgow Outcome Scale 4–5).
The treatment effect and clinical outcomes were determined on the day of discharge from the hospital. Unplanned readmission within a month was considered a continuation of the previous hospitalisation.
Data collection and statistical analysis
In addition to the aforementioned data, demographic characteristics, basic health information, surgical history, infection-related information, and intensive care unit admission data were collected.
Categorical variables were presented as frequencies and percentages. Continuous variables were described using means and standard deviations. Statistical analyses were performed using R Programming Language software, version 4.0.2. The group characteristics were compared using contingency table analysis for categorical variables and the Kruskal–Wallis rank-sum test for continuous variables. Statistical significance was set at p < 0.05.
Results
Participants
Overall, 94 patients with Enterococci-related HCAVM were included. The mean age of the patients was 41.1 ± 16.6 years (2–77 years). Of the 94 patients, 42 (44.7%) were female, and 77 (81.9%) had solid tumours as the main diagnosis (Table 2). There were differences in craniotomy and transsphenoidal surgery between the two groups of patients (P < 0.05).
Table 2.
Clinical characteristics of the patients
| Variables | Overall (n = 94) |
E. faecalis
a (n = 58) |
E. faecium
b (n = 34) |
P-value |
|---|---|---|---|---|
| Age (y), mean ± SD | 41.1 ± 16.6 | 41.0 ± 15.2 | 39.9 ± 18.6 | 0.955 |
| Female, n (%) | 42 (44.7) | 27 (46.6) | 13 (38.2) | 0.576 |
| Main diagnosis, n (%) | ||||
| Solid tumour | 77 (81.9) | 51 (87.9) | 24 (70.6) | 0.073 |
| Vascular malformation | 11 (11.7) | 4 (6.9) | 7 (20.6) | 0.105 |
| Other diseases c | 6 (6.4) | 3 (5.2) | 3 (8.8) | 0.805 |
| Admission GCS d, n (%) | ||||
| 13–15 | 89 (94.7) | 57 (98.3) | 30 (88.2) | 0.116 |
| 9–12 | 2 (2.1) | 1 (1.7) | 1 (2.9) | 1.000 |
| 3–8 | 3 (3.2) | - | 3 (8.8) | 0.091 |
| Surgery, n (%) | ||||
| Craniotomy | 67 (71.3) | 37 (63.8) | 29 (85.3) | 0.049 |
| Transsphenoidal surgery | 24 (25.5) | 20 (34.5) | 3 (8.8) | 0.013 |
| Other | 3 (3.2) | 1 (1.7) | 2 (5.9) | 0.634 |
| Chronic diseases e, n (%) | 19 (20.2) | 11 (19.0) | 8 (23.5) | 0.799 |
| Other bacteria f, n (%) | 24 (25.5) | 13 (22.4) | 9 (26.5) | 0.852 |
| Abscess, n (%) | 1 (1.1) | - | 1 (2.9) | 0.786 |
| CSF g leak, n (%) | 16 (17.0) | 11 (19.0) | 4 (11.8) | 0.542 |
| ICU admission h, n (%) | 10 (10.6) | 4 (6.9) | 6 (17.6) | 0.211 |
| Incision site infection, n (%) | 5 (5.3) | 3 (5.2) | 2 (5.9) | 1.000 |
| Course (day) i, mean ± SD | 15.3 ± 10.9 | 16.7 ± 12.3 | 12.9 ± 7.7 | 0.140 |
| Ineffective treatment, n (%) | 4 (4.3) | 3 (5.2) | 1 (2.9) | 1.000 |
| Poor outcome, n (%) | 8 (8.5) | 3 (5.2) | 5 (14.7) | 0.237 |
aPatients with E. faecalis infection.
bPatients with E. faecium infection.
cTraumatic brain injury in two patients, intracerebral haemorrhage in two patients, and Chiari malformation and epilepsy in one patient each.
dGlasgow outcome scale.
eHypertension in five patients, type 2 diabetes mellitus in four patients, and other diseases, including coronary heart disease, atrioventricular block, arrhythmia, nephrotic syndrome, chronic gastritis, and renal insufficiency. Three patients had two chronic diseases and one patient had three chronic diseases.
fOther bacteria-related healthcare-associated ventriculitis and meningitis. fluid.
gCerebrospinal
hIntensive care unit admission for > 24 h.
iThe course of active antimicrobial agents targeting Enterococci-related healthcare-associated ventriculitis and meningitis.
Bacteria
Ninety-four bacterial strains, including Enterococcus faecalis (n = 58), Enterococcus faecium (n = 34), Enterococcus avium (n = 1), and Enterococcus durans (n = 1) were identified.
Vancomycin resistance
As the most common antimicrobial agent used for treating gram-positive bacteria-related HCAVM, vancomycin was tested against all strains, and seven (7.4%) strains were resistant (Table 3).
Table 3.
Antimicrobial agents tested in antimicrobial susceptibility tests and n (%) of resistant, intermediate, or dose-dependent susceptible isolates and susceptibleisolates
| Drugs | Isolates tested, n | Resistant, n (%) | Intermediate a, n (%) | Susceptible, n (%) |
|---|---|---|---|---|
| Penicillin | 94 | 20 (21.3) | - | 74 (78.7) |
| Vancomycin | 94 | 7 (7.4) | - | 87 (92.6) |
| Linezolid | 91 | 1 (1.1) | 14 (15.4) | 76 (83.5) |
| Erythromycin | 80 | 40 (50.0) | 22 (27.5) | 18 (22.5) |
| Tetracycline | 64 | 43 (67.2) | - | 21 (32.8) |
| Nitrofurantoin | 64 | 8 (12.5) | 12 (18.8) | 44 (68.8) |
| Levofloxacin | 58 | 20 (34.5) | - | 38 (65.5) |
| Ampicillin | 50 | 11 (22.0) | - | 39 (78.0) |
| Ciprofloxacin | 46 | 29 (63.0) | 3 (6.5) | 14 (30.4) |
| Rifampicin | 43 | 37 (86.0) | 3 (7.0) | 3 (7.0) |
| Teicoplanin | 37 | 2 (5.4) | - | 35 (94.6) |
| Daptomycin | 6 | 1 (16.7) | 3 (50.0) | 2 (33.3) |
| Quinupristin-dalfopristin | 1 | - | 1 (100.0) | - |
aOr dose-dependent susceptible
Resistance to other antimicrobial agents
In addition to vancomycin, 12 antimicrobial agents were included in the antimicrobial susceptibility tests. Three antimicrobial agents were tested in > 80% of Enterococci, and the range of resistance rate was 1.1–50.0%. The erythromycin resistance rate was the highest, whereas the linezolid resistance rate was the lowest. Among all tested antimicrobial agents, the resistance rates to nitrofurantoin (12.5%) and teicoplanin (5.4%) were relatively low (Table 3).
Antimicrobial resistance of VRE
The seven strains of VRE were pan-resistant to levofloxacin, erythromycin, ciprofloxacin, ampicillin, rifampicin, and teicoplanin; partially resistant to penicillin, tetracycline, and nitrofurantoin; and non-resistant to linezolid.
The comparison of antimicrobial resistance of E. faecalis and E. faecium
Of the antimicrobial agents tested in antimicrobial susceptibility tests, ten showed higher resistance rates in E. faecium, with statistically significant results for six antimicrobial agents. Linezolid and tetracycline had higher resistance rates in E. faecalis, with a statistically significant result for tetracycline. Vancomycin resistance was observed only in E. faecium (Table 4).
Table 4.
Antimicrobial agents tested in antimicrobial susceptibility tests and n (%) of resistant isolates of E. faecalis and E. faecium
| Antimicrobial agents | E. faecalis | E. faecium | P-value |
|---|---|---|---|
| Penicillin | 58 | 34 | |
| Resistant, n (%) | 3 (5.2) | 16 (47.1) | < 0.001 |
| Vancomycin | 58 | 34 | |
| Resistant, n (%) | - | 7 (20.6) | 0.001 |
| Linezolid | 55 | 34 | |
| Resistant, n (%) | 1 (1.8) | - | 1.000 |
| Erythromycin | 52 | 26 | |
| Resistant, n (%) | 21 (40.4) | 19 (73.1) | 0.013 |
| Tetracycline | 37 | 25 | |
| Resistant, n (%) | 31 (83.8) | 10 (40.0) | < 0.001 |
| Nitrofurantoin | 37 | 25 | |
| Resistant, n (%) | - | 8 (32.0) | < 0.001 |
| Levofloxacin | 32 | 24 | |
| Resistant, n (%) | 4 (12.5) | 16 (66.7) | < 0.001 |
| Ampicillin | 34 | 16 | |
| Resistant, n (%) | 1 (2.9) | 10 (62.5) | < 0.001 |
| Ciprofloxacin | 28 | 16 | |
| Resistant, n (%) | 15 (53.6) | 12 (75.0) | 0.279 |
| Rifampicin | 29 | 14 | |
| Resistant, n (%) | 24 (82.8) | 13 (92.9) | 0.670 |
| Teicoplanin | 27 | 10 | |
| Resistant, n (%) | 1 (3.7) | 1 (10.0) | 1.000 |
| Daptomycin | 2 | 4 | |
| Resistant, n (%) | - | 1 (25.0) | 1.000 |
Treatment
As empirical treatment, vancomycin was used in eighty-eight patients, linezolid and gentamicin in two patients each, and tigecycline and ceftriaxone in one patient each. As adjusted treatment, vancomycin was changed to linezolid in twelve patients, including seven patients with VRE. Additionally, gentamicin was switched to vancomycin in two patients, linezolid to vancomycin in one patient, and vancomycin to ampicillin in another patient.
Outcomes
Overall, 4 (4.3%) patients experienced ineffective treatments, 8 (8.5%) patients had poor outcomes, and the treatment course was 15.3 ± 10.9 days (3–69 days) (Table 2).
Outcomes related to E. faecalis and E. faecium
Among patients with E. faecalis and E. faecium-related HCAVM, there were no significant differences in the ineffective treatment rate [(5.2% (3/58) vs. 2.9% (1/34), P = 1.000], poor outcome rate [(5.2% (3/58) vs. 14.7% (5/34), P = 0.237], and treatment course (16.7 ± 12.3 vs. 12.9 ± 7.7, P = 0.140) (Table 2).
Discussion
Enterococci-related HCAVM is a relatively rare infection. Our study found that E. faecalis was the most common pathogen, followed by E. faecium. These results were similar to those of previous studies regarding pathogens causing healthcare-associated infections [15–18]. Among the tested antimicrobial agents, linezolid showed the lowest resistance rate (1.1%). Therefore, linezolid could be considered the first-line treatment for Enterococci-related HCAVM, similar to previous studies on VRE-related HCAVM [8–11].
Our study found that VRE was not rare (7.4%). We found only vancomycin resistance in E. faecium, indicating that the vancomycin resistance rate in E. faecium was 20.6% (7/34). Therefore, vancomycin may be inefficient in treating E. faecium-related HCAVM. This result was consistent with that of previous studies, which reported a high vancomycin resistance rate in E. faecium [15, 16, 19–21].According to antimicrobial susceptibility tests, linezolid may be effective against all vancomycin-resistant E. faecium strains, whereas other antimicrobial agents have limited effects. Similarly, Pintado et al. performed a multicenter cohort study assessing linezolid’s efficacy and safety in Staphylococcus aureus meningitis, their findings suggest that linezolid is a viable alternative for Staphylococcal meningitis treatment, demonstrating comparable safety and effectiveness to standard therapies [22].
Considering that E. faecium has a higher vancomycin resistance rate than E. faecalis, we compared the antimicrobial resistance between E. faecium and E. faecalis. Among the tested antimicrobial agents, the antimicrobial resistance in E. faecium was higher than that in the other strains. The resistance mechanisms could explain some differences [23–25]. While ampicillin remains first-line for susceptible E. faecalis bacteremia [26], its role in HCAVM requires nuanced evaluation. We observed 62.5% ampicillin resistance in E. faecium and clinicians’ preferential use of linezolid/vancomycin (93.8% of adjustments) suggest that de-escalation opportunities may be limited to E. faecalis-dominant cohorts with confirmed susceptibility. Even then, pharmacokinetic concerns and device-associated biofilm infections might justify maintaining broader-spectrum therapy until hardware removal. Our study found that there were differences in craniotomy and transsphenoidal surgery between the two groups of patients (P < 0.05). Among them, the proportion of patients infected with E. faecalis who underwent transsphenoidal surgery was higher, while the proportion of patients infected with E. faecium who underwent craniotomy was higher. The specific reasons for this phenomenon remain to be further explored. And also, E. faecium has inherent resistance to ampicillin owing to the presence of a low-affinity penicillin-binding protein [23]. Hence, antimicrobial resistance should be carefully distinguished between E. faecium and E. faecalis, and our results were similar to those of previous studies.
Vancomycin is the main agent for empirical and targeted treatment, which is consistent with the guideline recommendations [7]. Linezolid is occasionally used for empirical treatment. Active antimicrobial agents are frequently used during targeted treatment, especially in patients with VRE. However, other antimicrobial agents, such as rifampicin, ampicillin, and gentamycin, are rarely used. Ineffective treatments were observed in 4.3% of patients and poor outcomes in 8.5%. The treatment course was 15.3 ± 10.9 days. The holistic outcomes of patients with Enterococci-related HCAVM were acceptable and better than those reported in previous studies [8–12]. Even in patients with VRE, a timely switch to linezolid was helpful. Therefore, active antimicrobial agents, such as vancomycin and linezolid, based on antimicrobial susceptibility tests are valuable for empirical and adjusted treatments. Our study’s retrospective design precluded standardized analysis of antimicrobial dosing schemes or CSF penetration metrics. However, institutional protocols during the study period aligned with IDSA guidelines for bacterial meningitis [7], recommending high-dose regimens, future prospective studies should incorporate therapeutic drug monitoring (TDM) and CSF concentration measurements to validate these empiric dosing strategies in Enterococci-related HCAVM.
The unique infection environment of ventriculitis and meningitis, characterized by the blood-brain barrier, significantly influences antibiotic cerebrospinal fluid concentrations and therapeutic efficacy. While IDSA meningitis dosing (ampicillin 3 g q4h) was empirically applied [7], the optimal dosing of β-lactam antibiotics for enterococcal infections requires further investigation [27, 28]. The pharmacokinetic properties of β-lactams - including hydrophilicity, low plasma protein binding, low molecular weight, small volume of distribution, and moderate ventricular penetration [29] - present challenges. Furthermore, susceptibility testing concentrations for β-lactamase inhibitors typically exceed achievable cerebrospinal fluid concentrations [30], introducing systematic errors. Regarding vancomycin, while the target AUC/MIC ratio serves as the validated efficacy metric for MRSA infections, trough concentrations commonly serve as practical surrogates in clinical settings. For MIC values of 0.5–1 µg/mL, trough concentrations of 10–20 µg/mL are recommended to achieve AUC/MIC ≥ 400 [31], though the precise therapeutic window requires further validation [32]. Clinically, two-thirds of treatment failures in our cohort occurred in patients receiving guideline doses without therapeutic drug monitoring, underscoring the need for individualized pharmacokinetic approaches.
Although it is useful in clinical practice, this study has several limitations. First, it was a retrospective case series that only included data from three hospitals, which may lead to selection bias. Secondly, not all antibacterial agents, such as linezolid, have been tested for every bacterial strain, and the drug resistance spectrum of the bacteria may not be detailed enough. Thirdly, although this study is the one with the largest sample size among all Enterococci-related HCAVM studies, the subsequent adjustment analysis is rather difficult. Finally, the absence of granular dosing data and therapeutic drug monitoring prevents direct correlation between antimicrobial exposure and clinical outcomes. This underscores the need for protocolized PK/PD studies in ventricular infections.
Conclusion
Linezolid, unlike vancomycin, is a reliable antimicrobial agent according to antimicrobial susceptibility tests and analysis of clinical practices. It provided acceptable outcomes, with no differences between E. faecium and E. faecalis, although vancomycin resistance was observed only in E. faecium.
Acknowledgements
We are very grateful to the reviewers for their professional review of the manuscript.
Authors’ contributions
GL and GW conceived the idea; YQ, YY, and GS designed the study; QY, JZ, XG, and YM collected the data; YQ, YY, QY, and JZ performed the statistical analysis; YQ and YY drafted the manuscript; GL and GW provided critical revisions. YQ and YY contributed equally to this work. GL and GW are corresponding authors, they contributed equally to this work. All authors contributed to review and revision and have seen and approved the final version of the manuscript.
Funding
This study was supported in part by grants from the Guiyang high level innovative youth health talent project fund [Grant No.2021-SWJJ-010]; the Natural Science Foundation of China [Grant No. 81971126, 82001380]; and the Guizhou Province Emergency Rescue and Critical Medicine Talent Base Funding.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
The study was retrospective and observational; hence, informed consent from the study participants was not required. The study was approved by the Ethics Committee of the Second People’s Hospital of Guiyang, and the number is JYYY-2024-WZ-10.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yuyang Qiu and Yi Ye are co-first authors.
Guiyun Li and Guofeng Wu contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.