Combined Strategy for Post-Operative Patients with Central Nervous System Infections Caused by Extensively Drug-Resistant/Pan-Drug–Resistant Acinetobacter baumannii : A Retrospective Study

Abstract

Background:

Post-operative central nervous system infections (PCNSIs) caused by extensively drug-resistant (XDR) or pan-drug–resistant (PDR) Acinetobacter baumannii are rare but intractable problems. To investigate a potential combined strategy to treat Acinetobacter baumannii organisms that are resistant to not only meropenem but also colistin.

Methods:

We retrospectively reviewed cerebrospinal fluid positive culture isolates of Acinetobacter baumannii in patients who underwent neurosurgery. Medical records were collected by standard forms and analyzed.

Results:

Sixteen patients met the criteria and most patients were middle-aged males who had undergone craniotomy or endonasal trans-sphenoidal surgery. A total of 68.8% Acinetobacter baumannii isolates were XDR bacteria, and 18.8% of isolates were PDR bacteria. Twelve patients were treated by meropenem-based regimen strategy. Another four patients were administered tetracycline-based regimens. A total of 93.8% patients were treated with therapeutic drainage and strict hygiene rules were followed. Finally, 12 patients survived their infections, and the average Glasgow Outcome Scale score was 2.9 ± 1.4 at discharge. The mortality rates of carbapenem-resistant Acinetobacter baumannii (CRAB) were 8.3%.

Conclusions:

Post-operative central nervous system infections caused by XDR/PDR Acinetobacter baumannii are a rare and serious complication. Combined therapy based on the individual situation, including appropriate antimicrobial agents, surgical management, and strict hygiene management might be an effective therapeutic strategy.

Post-operative central nervous system infections (PCNSIs) are an uncommon but serious complication in neurosurgery, with an infection rate ranging from 4.5% to 7.4% [1,2]. As a result of the advent of the sterile field and prudent antibiotic use during the perioperative period, the overall mortality rate of PCNSIs has decreased substantially in the past several years, from 34% in 2005 [3] to 1.8% in a recent study; however, this mortality rate is still 3.78 times that of non-PCNSI patients [2]. Although most PCNSIs are caused by gram-positive bacteria, there has been a trend toward gram-negative organisms. The incidence of Acinetobacter baumannii is considered to vary, accounting for 15.7% to 24.2% of the gram-negative organisms [4,5].

The emergence of MDR Acinetobacter baumannii has become a serious medical problem worldwide, and the probable multi-drug–resistant (MDR) rate ranges from 50% to 70% [6]. More seriously, the decreasing sensitivity for various commonly used antibiotic agents, especially carbapenem-resistant Acinetobacter baumannii (CRAB), has increased from 31% to 66.7% in China, even reaching 80% in some reports [7]. The mortality rate of CRAB is higher than the sensitivity rate, usually exceeding 30% and even reaching 72.7% [8].

The primary treatment for Acinetobacter baumannii is antimicrobial agents in central nervous system (CNS) infections, which is complicated by both susceptibility and the existence of the blood-brain barrier (BBB) [9]. Meropenem is recommended as an initial therapy for meningitis [10]. Polymyxins, tigecycline, and sulbactam are the most commonly used therapies in CRAB and extensively drug-resistant (XDR) Acinetobacter baumannii infections [11]. Colistimethate sodium or polymyxin B is recommended for CNS infections that are resistant to carbapenems. However, the colistin resistance in XDR Acinetobacter baumannii has increased rapidly, from less than 10% to approximately 50% [12], and the use of colistin for human beings is still not approved in China because of its substantial toxicity [13]. How to treat XDR Acinetobacter baumannii that is resistant not only to meropenem but also to colistin is an intractable problem.

Tigecycline is a broad-spectrum glycylcycline antimicrobial agent with in vitro activity against MDR gram-negative bacteria such as MDR Acinetobacter baumannii [14]. Although previous reviews do not recommend tigecycline for meningitis because of poor penetration of the BBB [10,15], there have been some successful cases [16,17]. Sulbactam is of potential use in serious Acinetobacter baumannii infections given its in vitro activity against the organism, including some carbapenem-resistant strains [18]. The synergistic effect of sulbactam with meropenem, colistin, or tigecycline was observed in vitro [19]. Sulfamethoxazole-trimethoprim (SMZ-TMP) was considered an alternative therapy against some gram-negative bacteria [10] because of its high concentration in cerebrospinal fluid (CSF) and the hope of obtaining a possible synergistic effect.

In addition to antimicrobial agents, combined therapeutic strategies in CNS infection should not be ignored; these strategies include complete removal of an infected CSF shunt, replacement with an external ventricular drain (EVD) [10], hand hygiene, contact precautions, and standard dressing changes [9].

Patients and Methods

We performed a retrospective clinical study of PCNSIs caused by Acinetobacter baumannii during the period between January 2010 and December 2018. Our hospital is a university general hospital and tertiary referral center in northern China, where the incidence and death rate of PCNSIs were 0.9% and 8%, respectively [7].

The patients were identified by reviewing CSF Acinetobacter baumannii- positive culture isolates from neurosurgery department via a computerized log containing records, as our team previous reported [7]. The cultures were analyzed by the microbiology laboratory of the hospital using the API^® or VITEK^® system (bioMérieux, Marcy l'Etoile, France). Culture contamination was determined by specialists from the clinical laboratory and neurosurgery, which was based on the identity of the micro-organism itself and its clinical features [10]. A disk diffusion method was used to determine antibiotic susceptibility according to the standards established by the Clinical and Laboratory Standards Institute [20]. The resistance of Acinetobacter baumannii was described as MDR, XDR, and pan-drug–resistant (PDR), defined by Magiorakos et al. [21], on the basis of the susceptibility to certain antimicrobial categories. Specifically, there are nine categories with 22 antimicrobial agents for Acinetobacter spp. Multi-drug–resistant was defined as non-susceptible to one or more agent in three or more antimicrobial categories. Extensively-drug–resistant was defined as non-susceptible to one or more agent in all but two or less categories, and PDR was non-susceptible to all antimicrobial agents listed.

Patients with Acinetobacter baumannii isolates from CSF were collected from medical records using previously designed standardized evaluation forms that included demographic characteristics, types of neurosurgery, laboratory data, antimicrobial susceptibility testing, therapy information, and outcome information. Glasgow Outcome Scale (GOS) scores were recorded at hospital discharge. Patients who met the diagnostic criteria of PCNSIs were included in the analysis; these criteria included a history of surgery, clinical signs of meningitis (fever, meningeal signs, low consciousness level), a low glucose level (2.3 mmol/L) and an elevated protein level (0.45 g/L) in the CSF, and infection acquired more than 48 hours after admission to the hospital. The results of analyses of continuous variables are expressed herein as the median, interquartile range (IQR), or mean ± standard deviation (SD).

Results

During 2010–2018, there were approximately 9,000 in-hospital patients treated with approximately 10,000 operations in the department of neurosurgery. There were 16 patients with PCNSIs caused by Acinetobacter baumannii over the past nine years, with an incidence of approximately 0.17%. Most patients were middle-aged males (nine cases), and the primary diseases were different, including pituitary lesions, hemorrhage, and cerebral. Four patients were comatose, with a GCS of less than seven on admission. Most patients underwent craniotomy (7 cases) or endonasal trans-sphenoidal surgery (six cases) and were in the hospital for 19 days (IQR = 15.75) before the onset of CNS infections caused by Acinetobacter baumannii. Four patients with PCNSIs transferred from other hospitals.

As shown in Table 1, all patients had fever (>38.5°C) with neck stiffness or meningeal signs, and 10 patients had leukocytosis (>10*10⁹/L) with a polymorphonuclear predominance. The CSF changes showed a high leukocyte count, low glucose level, and elevated protein level. Eleven (68.8%) Acinetobacter baumannii isolates from CSF were XDR bacteria and three (18.8%) were PDR bacteria. Only one isolate was MDR, and one isolate was resistant to fewer than three antimicrobial categories. The details of antimicrobial susceptibility are shown in Supplementary Table S1. Ten patients had a pulmonary infection, and in seven of these patients, Acinetobacter baumannii was isolated from samples other than the CSF, such as blood and sputum.

Table 1.

Demographic and Clinical Characteristics of Sixteen Patients with PCNSIs Caused by Acinetobacter baumannii

Characteristic	Value (N = 16)
Demographic parameters
Mean age (y)	41.7
Gender, male:female	11:5
GCS	12.5 ± 4.4
Interval between infection and the initial neurosurgery (median)	19 (IQR = 15.75)
In hospital days(median)	48 (IQR = 60)
Death case	4 (25%)
GOS	2.9 ± 1.4
Operation types
Endonasal trans-sphenoidal approach	6 (37.5%)
Craniotomy	7 (43.8%)
Burr hole drilling	2 (12.5%)
Others	1 (6.2%)
CSF data
Leukocyte count (10⁶/L)	Median = 1,600 (IQR = 4763)
Glucose level (mmol/L)	Median = 1.8 (IQR = 1 .55)
Protein level (g/L)	Median = 1.3 (IQR = 5.3)
Resistance
PDR	3 (18.8%)
XDR	11 (68.8%)
MDR	1 (6.3%)
Acinetobacter isolates from other source	7 (43.8%)

CSF = cerebrospinal fluid; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; IQR = interquartile range; MDR = multi-drug–resistant PCMSIs, post-operative central nervous system infections; PDR = pan-drug–resistant; XDR = extensively drug-resistant.

As shown in Table 2, although most isolates (75%) were resistant to meropenem, meropenem was still used as a basic treatment in 12 patients (75%), which was combined with sulbactam in four patients, minocycline in five patients and SMZ-TMP in four patients. Four patients (25%) were only treated by tetracyclines combined with SMZ-TMP without meropenem; three patients, with tigecycline; and one patient, with minocycline. SMZ-TMP was used in eight patients (50%), and sulbactam was used in five patients (31%). All antibiotic agents were administered via intravenous infusion, and no antibiotic agents were administered via intrathecal injection. Most patients underwent external drainage. In total, 93.8% of patients underwent therapeutic drainage and four patients were treated with a ventriculoperitoneal (VP) shunt immediately after recovery from the infection. Hygiene management rules, such as avoiding routine CSF samples, not changing drainage bags routinely, and performing routine catheter changes, were followed. The therapy details of each patient are shown in Supplementary Table S2.

Table 2.

Intervention Strategy

Interventions	Value (N = 16)
Antibiotic
Meropenem	2
Meropenem + sulbactam	4
Meropenem + SMZ-TMP/tetracyclines	6
Meropenem + third-generation cephalosporins	3
Tetracyclines-based combination	4
Drainage
LD	12
EVD	3
VP shunt	4

EVD = external ventricular drainage; LD, lumbar drainage; SMZ-TMP = Sulfamethoxazole-trimethoprim; VP, ventriculoperitoneal.

Of the 16 patients analyzed, cure of the PCNSIs were achieved in 12 cases, but the remaining four patients (25%) died as a direct consequence of the infection, three of whom underwent an endonasal transsphenoidal approach and were sensitive to meropenem. The mortality rates of PCNSIs caused by CRAB were 8.3% (1/12). The median number of hospitalization days was 48 (IQR = 60) days. The GOS score in approximately half of the patients (7 cases) was above four points, and the average score was 2.9 ± 1.4 at discharge.

Discussion

Post-operative central nervous system infections caused by Acinetobacter baumannii are still a serious but rare condition. In the present research, the morbidity and mortality were approximately 0.17% and 25% [7], which was similar to the findings of previous studies [22]. The mortality was reported to be more than 30% in some previous studies and even more than 70% when the isolates were resistant to carbapenems [8], which are higher rates than that found in our study (25%). The meningitis-related nerve defects in these patients were also catastrophic consequences. The average GCS score was 12.5 before the surgery, and the GOS score was only 2.9 after PCNSIs caused by Acinetobacter baumannii, which means that most patients experienced severe injury with a permanent need for help with daily living.

Given the currently increasing threat of XDR and PDR Acinetobacter baumannii, the appropriate combined strategy needs to be explored. Most isolates in our study were XDR (68.8%) or PDR (18.8%), of which 75% were resistant to carbapenems. Similar trends were also observed in blood stream infections, with a CRAB of approximately 90% [4]. Despite the recent trend toward polymyxins, there is some hesitancy regarding their use because of their toxicity profile [11] and they are still not available in China. How to choose appropriate antimicrobial agents is crucial for the survival and favorable outcome of patients. Additionally, surgical management and hygiene management should not be ignored.

Carbapenem-based combination therapy was used in our case series even in infections resistant to carbapenems. Twelve of 16 cases involved carbapenem-resistant isolates, and eight cases were treated with meropenem. Finally, seven patients were cured of CNS infections caused by CRAB. The possible reasons were as follows. First, full-dose meropenem (2 g every 8 hours) was applied in most patients to maintain an effective concentration in the CSF. Second, four of eight patients were treated with sulbactam-meropenem combination therapy. The sulbactam itself possesses direct bactericidal activity and showed synergistic effects in vitro combined with meropenem. Although clinical experience with sulbactam combined with ampicillin or cefoperazone in the treatment of Acinetobacter baumannii meningitis has been mixed [9]. However, the combination of sulbactam-meropenem was limited. From the results of our study, sulbactam, as a single agent combined with meropenem, showed good effects in CRAB meningitis. Third, three of eight patients were treated with a minocycline combination.

Tetracyclines, such as tigecycline and minocycline, are another potential choice. In the present study, 10 of 16 patients underwent susceptibility testing for minocycline and tigecycline, and four and six isolates, respectively, were sensitive. Except for meningitis, tigecycline is regarded as the first agent in the glycylcycline class, which is less prone to efflux-mediated resistance and ribosomal protection resistance [11]. However, there are many concerns in CNS infections. First, the penetration of tigecycline into the CSF is minimal, even in patients with meningeal inflammation [23]. Second, a previous systematic review reported that there was no difference in mortality compared with that in control groups (24). However, since Wadi et al. [25] in 2007 reported a patient with meningitis who was treated successfully by tigecycline, many researchers have tried to use tigecycline as a combination therapeutic strategy by intravenous administration [26], and two cases have been treated by intraventricular injection [16,17]. In the present study, three patients with CRAB were treated successfully with tigecycline through intravenous injections of minocycline combined with SMZ-TMP. Tigecycline could be considered a valuable therapy in managing life-threatening CRAB CNS infections. Minocycline is recommended as an alternative therapy against MDR Acinetobacter baumannii [11,27], even for minocycline-resistant Acinetobacter baumannii [28]. Additionally, minocycline allows greater penetration of the BBB [29]. In the present study, nine of 16 patients were treated with minocycline as the context of combination therapy or as step-down therapy through intravenous or oral formulations.

Sulfamethoxazole-trimethoprim is recommended by the Infectious Disease Society of America (IDSA) as an alternative therapy to treat infections caused by gram-negative bacilli that hyperproduce β–lactamase [10]. Furthermore, considering the activity of SMZ-TMP against MDR Acinetobacter baumannii in vitro, Garnacho et al. [27] have suggested SMZ-TMP as an alternative therapy for CRAB infection. In the present study, three of 16 isolates were sensitive to SMZ-TMP, and eight of 16 patients were treated with a combination. Clinical experience is lacking, however, some in vitro studies have shown a synergistic effect in combination with imipenem (62%) and colistin [30].

In addition to the antibiotic strategy, as a nosocomial infection, surgical management and hygiene management should be considered in PCNSIs. Once the patients were diagnosed with PCNSIs, we not only completely removed any surgical implements, as the IDSA recommends [10], but also performed therapeutic CSF drainage in 93.8% patients, which could eliminate viable bacteria and reduce excitotoxic elements in the infected CSF as well as control intracranial pressure (ICP) [31]. Ren et al. [32] also reported that adjuvant closed continuous lumbar drainage can lead to lower mortality and an improved GOS score, which was found in a retrospective series including 1,062 patients with meningitis after neurosurgery. Regarding surgical management, concerns about the complications of therapeutic CSF drainage, especially the recurrence of infection, are another important issue.

Hygiene management is a crucial rule throughout the treatment of PCNSIs, especially for patients with therapeutic CSF drainage. Twelve patients in this study were treated with lumbar drainage and three patients were treated with an EVD. All the procedures followed the guidelines suggested by the Neurocritical Care Society, using an EVD management bundle that includes aseptic insertion, limited manipulation of the closed system, and standardized dressings and weaning. On the basis of these principles, all the EVDs in the present study were inserted in the operating room and lumbar drainage was conducted outside the operating room, with all procedures performed by trained neurosurgeons following a normal protocol. We tried to avoid routine CSF samples, especially those from the collection-device drainage bags. The duration of the EVD or lumbar drainage catheter implementation was not more than seven to 14 days, and the changes were routine. For less manipulation, no antibiotic agents were administered by intrathecal injection.

Four patients did not survive the infection, however, three were sensitive to meropenem and were administered the proper antibiotic strategy. Unfortunately, these three patients were diagnosed with a mass in the sellar area and treated by endonasal trans-sphenoidal surgery. These findings may be related to the following three points. First, approximately half of the neurosurgery operations at our hospital involved the endonasal trans-sphenoidal approach, and the percentage involving PCNSIs was also nearly 50%, as previously reported [7]. Second, CSF rhinorrhea, a complication of the surgery, is an important risk factor in PCNSIs [10]. It was difficult to avoid recurrent infection during persistent CSF leakages, especially those that were not able to be repaired. Third, both the surgery in the sellar area and the primary localization of the infection could lead to hypopituitarism or hypothalamic–pituitary dysfunction [33], which resulted in water-electrolyte imbalance, euthyroid sick syndrome, hypocortisolemia, and so forth.

Our study has the following limitations. First, it was a retrospective study including a small number of patients with inherent weaknesses. However, the PCNSIs caused by drug-resistant Acinetobacter baumannii is a rare condition that is difficult to handle. To the best of our knowledge, this is the largest study to date on PCNSIs caused by XDR/PDR Acinetobacter baumannii. Second, although the antibiotic regimens used were all appropriate, they were not standardized, which limited the summary of the potential guidelines. The antibiotic choice made by the multidisciplinary team was based on the individual patient situation. Third, there were three isolates judged as XDR Acinetobacter baumannii because of the lack of susceptibility test results for the tetracycline categories, which underestimated the incidence of PDR. Fourth, because polymyxins are not available in China, the clinical bacteriology laboratories in our hospital did not test the colistin or polymyxin B susceptibility in Acinetobacter baumannii. We regarded these isolates resistant to the polymyxin category.

Conclusions

Post-operative central nervous system infections caused by XDR/PDR Acinetobacter baumannii are a rare and serious complication. A combination therapy based on the individual situation might be an effective therapeutic strategy, which includes appropriate antimicrobial agents, surgical management, and strict hygiene management.

Funding Information

This research received a grant from National Key R&D Program of China (2018YFA0108600), which support the design of the study and collection, analysis, and interpretation of data. There was no other grant from funding agencies in the public, commercial, or not-for-profit sectors.

Footnotes

Author Disclosure Statement

The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. All authors declare no competing interests.

This study was approved by the Ethics Committee of Peking Union Medical College Hospital (PUMCH) and written informed consents were obtained from all patients. CJB and CYH contributed equally to the manuscript. WJJ and WRZ were co-corresponding authors.

Supplementary Material

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