Introduction

Meningitis is an inflammation of the meninges surrounding the brain and the spinal cord while ventriculitis is an inflammation of the ventricles in the brain. Healthcare-associated meningitis and ventriculitis may result from invasive procedures (e.g., craniotomy, lumbar puncture, placement of external or internal ventricular catheters, intrathecal (IT) infusions of medications, or spinal anesthesia), complicated traumatic brain injury, or sometimes, metastatic infection in patients with hospital-acquired bacteremia [1]. These cases of meningitis and ventriculitis are caused by a different spectrum of pathogens (e.g., carbapenem-resistant Gram-negative bacilli and staphylococci) compared with cases acquired in the community [1]. Carbapenem-resistant Acinetobacter baumannii is found in 10% of healthcare-associated meningitis, with mortality ranging from 15 to 71% [2].

Meropenem is currently recommended for treatment of meningitis and ventriculitis caused by Acinetobacter species, while colistin or polymyxin B is recommended for carbapenem-resistant strains [2]. Intraventricular (IVT) or IT administration of polymyxin (colistin or polymyxin B) should be considered for patients with healthcare-associated A. baumannii meningitis and ventriculitis that are difficult to eradicate with IV colistin or polymyxin B [1, 3, 4]. However, even with the use of IVT/IT colistin or polymyxin B, some cases failed to respond [5], and many cases were infected with colistin-resistant A. baumannii [6, 7].

Despite its poor penetration to the cerebrospinal fluid (CSF) [8, 9], many clinical cases have reported the successful use of IV tigecycline, alone or in combination with colistin and other antibiotics, in the treatment of healthcare-associated A. baumannii meningitis and ventriculitis [10, 11]. Also, some clinical cases have reported the use of IVT tigecycline in combination IV antibiotics in the treatment of these diseases [6, 12]. The purpose of this review is to evaluate and provide a comprehensive summary of the clinical data on the safety and effectiveness of IV and IVT tigecycline in the treatment of these diseases.

Methods

A literature search was performed in PubMed (from 2005 to December 2018) using the following search terms: “tigecycline” and “meningitis” or “ventriculitis”. Publications in languages other than English were excluded. The bibliographies of the retrieved articles were searched for additional relevant studies. Articles were included if they described the use of tigecycline (IV and/or IVT) in patients with healthcare-associated A. baumannii meningitis or ventriculitis. Clinical studies as well as case series and case reports were included, while animal and in vitro studies were excluded. Articles that described the use of tigecycline (IV and/or IVT) in patients with healthcare-associated meningitis or ventriculitis caused by pathogen other than A. baumannii were excluded. Also, articles that described the use of tigecycline in infections other than meningitis or ventriculitis were excluded.

Results

The search strategy retrieved 44 citations (43 citations from PubMed and one from the bibliographies of the retrieved articles); only 14 citations met the inclusion criteria. Among the identified articles, 12 were case reports, one was case series, and one was a retrospective multicenter study that evaluated 23 carbapenem-resistant A. baumannii healthcare-associated meningitis cases treated with IV tigecycline including regimens. The search did not reveal any randomized controlled trials evaluating the use of tigecycline in patients with healthcare-associated A. baumannii meningitis or ventriculitis. Table 1 gives data regarding the demographic characteristics, underlying condition, presence of foreign bodies, susceptibilities to antimicrobial agents, antimicrobial and therapeutic schedules, dosages, CSF sterilization, and survival of the patients included in this review.

Table 1 Summary of cases received tigecycline (intravenous and/or intraventricular) for healthcare-associated Acinetobacter baumannii meningitis or ventriculitis
Full size table

Use of tigecycline for A. baumannii control

Wadi and Al Rub [11] described the first use of tigecycline in a patient with multidrug-resistant (MDR) Acinetobacter healthcare-associated meningitis (secondary to head trauma after a motor vehicle accident). Once the patient had meningeal signs, CSF culture was sent and showed MDR Acinetobacter (sensitivity to antibiotics was not reported). The patient was started on IV tigecycline monotherapy (50 mg q12 h). He showed significant improvement with subsidence of fever, headache, and confusion. Tigecycline was continued for 21 days until a week after the last sterile CSF culture.

The use of IV and/or IVT tigecycline was described in 39 patients infected with healthcare-associated A. baumannii meningitis or ventriculitis in 14 reports [6, 7, 10,11,12,13, 14••, 15•, 16,17,18,19,20,21]. Thirty-seven patients were adults (mean age, 49.14 years; ± 16.40 SD), while the remaining 2 were infants (2 and 4 months old). Most patients were male (27 of 39, 69%). In most cases, meningitis or ventriculitis was developed post-neurosurgical procedures for the management of different central nervous system diseases. The presence of a foreign body was reported in 34 cases; 19 cases had external ventricular drain, 10 cases had lumbar drain, and 2 cases had ventriculoperitoneal shunt. The sensitivity of A. baumannii was reported in 38 cases; 37 cases were sensitive to tigecycline while one case was resistant (MIC = 16 mg/L). Sensitivity to colistin or polymyxin B was reported in 27 cases; 24 cases were sensitive while 3 were resistant. No MIC breakpoints exist for tigecycline to A. baumannii. The common practice is to use the same Food and Drug Administration (FDA) breakpoints that were set for Enterobacteriaceae for A. baumannii as well (an isolate with an MIC of ≥ 4 mg/L was considered non-susceptible).

IV administration of tigecycline

IV tigecycline monotherapy was used in 7 patients [11, 14••]. Six of 7 patients were cured and survived. The duration of IV tigecycline monotherapy ranged from 5 to 21 days (mean, 14.14 days; ± 5.72 SD), while CSF sterilization was achieved in 3–5 days up to 14 days of tigecycline therapy. All seven patients received a regular dose of tigecycline (50 mg q12 h). High-dose IV tigecycline (100 mg q12 h) was used in four patients only [6, 12, 15•, 21]. In these cases, it was used in combination with other antibiotics and all patients were cured. Thirty-two patients received IV tigecycline in combination with other antibiotics (IV and/or IVT/IT) to treat healthcare-associated A. baumannii meningitis or ventriculitis [6, 7, 10, 12, 13, 14••, 15•, 16,17,18,19,20,21]. Other antibiotics used for the same diseases included IV colistin (18 cases), IVT/IT colistin (10 cases), IV polymyxin B (1 case), IVT polymyxin B (1 case), meropenem (8 cases), rifampicin (3 cases), IV netilmicin (5 cases), IT netilmicin (2 cases), IV amikacin (3 cases), IVT/IT amikacin (2 cases), and cefoperazone/sulbactam (3 cases). One patient received netilmicin as part of therapy but the route of administration was not reported [14••]. Patients who received IV tigecycline in combination with other antibiotics had a duration of IV tigecycline therapy ranging from 7 to 68 days (average, 26.12 days; ± 18.77 SD), while CSF sterilization was achieved in 3–5 days up to 68 days.

IVT administration of tigecycline

IVT tigecycline was never used alone and it was always used in combination with IV antibiotics or IV antibiotics plus IVT polymixin. Six adult patients received IVT tigecycline as part of treatment for healthcare-associated A. baumannii meningitis or ventriculitis [6, 12, 15•, 18, 21]. One patient received initially high-dose IV tigecycline (100 mg q12 h) plus meropenem (2 g q8 h) and vancomycin (1 g q12 h). Because CSF cultures remained positive for A. baumannii (only sensitive to tigecycline), IVT tigecycline at a dose of 2 mg/day (after 10 days, the dose was escalated to 2 mg q12 h) was added. Also, IVT colistin (60,000 IU q12 h for 2 days, then escalated to 120,000 IU q12 h) was added for this patient [6]. The second patient received initially IV colistin (4.5 MIU q12 h) plus IVT colistin (250,000 IU q24 h); the A. baumannii strain in the CSF was sensitive only for colistin and tigecycline. However, after 15 days of IVT colistin infusions, fever persisted, and the CSF analysis remained abnormal. Therefore, IVT tigecycline (4 mg q24 h) was added to IVT colistin [12]. The third patient received high-dose IV tigecycline (100 mg q12 h) plus rifampicin (600 mg) and IV colistin (4.5 MIU q12 h) and IVT colistin (250,000 MIU q24 h); the A. baumannii strain in the CSF was sensitive only for tigecycline (MIC = 2 mg/L). Because the patient did not improve, IVT tigecycline (4 mg q24 h) was added to IVT colistin [12]. The fourth patient had an extensively drug-resistant (XDR) A. baumannii (tigecycline MIC = 16 mg/L). He was administered high-dose IV tigecycline (100 mg q12 h), IV cefoperazone/sulbactam (2 g q8 h), and continuous ventricular irrigation of tigecycline (10 mg/500 mL saline twice daily, in from the right occipital horn and out from the left horn). After 12 days, IV tigecycline was reduced to 50 mg q12 h, while continuous ventricular irrigation of tigecycline was modified to IVT tigecycline (2 mg q12 h) [15•]. The fifth patient received IV tigecycline (100-mg loading then 50 mg q12 h) plus IV cefoperazone/sulbactam (3 g q8 h). After 6 days, the same A. baumannii strain sensitive only to tigecycline (polymyxin sensitivity was not tested) was still isolated from the CSF, so IVT tigecycline (2 mg q12 h) was started [18]. The last patient received initially IV tigecycline (50 mg q12 h) for 10 days. Then, his body temperature raised to 40 °C and his CSF culture was abnormal showing A. baumannii. Thus, IVT tigecycline (3 mg q24 h) and cefoperazone/sulbactam (3 g q12 h) were added with an increase of IV tigecycline dose (100 mg q12 h). His fever improved 6 days later but the CSF culture was still positive, and an IVT tigecycline dose was increased to 4 mg q12 h [21]. The duration of IVT tigecycline ranged from 10 to 75 days. None of the patients experienced any side effect from IVT tigecycline, and all patients were cured.

Concerning the technical aspects of IVT tigecycline administration, Lauretti et al. [6] closed the CSF drain temporarily for 2 h after every injection to prevent untimely washout of the drug. While Tsolaki et al. [12] withheld the CSF diversion for 4 h, this additional time might enhance IVT tigecycline effect by leaving it to equilibrate better throughout the CSF compartment. Long et al. [15•] described a treatment that involved continuous ventricular irrigation (CVI) of 10 mg of tigecycline in 500-mL saline twice daily, in from the right occipital horn and out from the left horn. After 12 days of CVI of tigecycline, ventriculitis signs resolved, and the load of Acinetobacter in the CSF decreased until CSF sterilization. At that moment, CVI of tigecycline was adjusted to IVT tigecycline (2 mg twice daily). Lastly, Fang et al. [21] administered tigecycline in the ventricular system, closing the drainage tube for almost 1 h.

Regarding outcome after treatment with IV and/or IVT tigecycline, treatment failed in two patients; the CSF of one of them was cleared from A. baumannii but it showed positive growth of Pseudomonas at the end of treatment [14••]. The outcome was not reported in 5 patients while 32 patients were cured. Survival was reported in 34 cases [6, 10, 11, 13, 14••, 15•, 16,17,18,19, 21] and only 5 patients died (mortality rate = 14.71%). Only two patients developed side effects from receiving IV tigecycline, resulting in an elevation of liver enzymes but tigecycline was continued for them on top of this side effect [14••].

Discussion

A. baumannii is a strict aerobic Gram-negative bacillus that has been increasingly involved as an important cause of healthcare-associated infections and resulted in high mortality rate reaching up to 35% depending on type of infection and Acinetobacter strain [22]. The incidence of MDR and pandrug-resistant A. baumannii has recently increased because of the abuse of antibiotics and the development of various mechanisms of antibiotic resistance [23]. Post-neurosurgical A. baumannii infection is common in healthcare settings [24]. Treatment of such infections is challenging because of the presence of antibiotic resistance and poor penetration of antibiotics through the blood-brain barrier.

Tigecycline, a glycylcycline antibiotic, has an excellent activity against species of MDR Gram-positive and Gram-negative bacteria including Acinetobacter species [25]. In 2005, the US FDA approved the clinical use of IV tigecycline for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community-acquired pneumonia. Its CNS penetration is low (around 11%) [8] and thus, it is not currently recommended for the treatment of Acinetobacter-caused meningitis [2]. Polymixin use as a therapy of healthcare-associated A. baumannii meningitis and ventriculitis was not successful in many cases [5], and because of antimicrobial resistance (mainly colistin and carbapenem resistance) [6, 7], IV and/or IVT tigecycline was considered as a salvage therapy in many cases of healthcare-associated A. baumannii meningitis and ventriculitis.

The use of tigecycline in the treatment of healthcare-associated A. baumannii meningitis and ventriculitis was successful in most cases as detailed in this study. Treatment failed in two patients and two patients died. Even using IV tigecycline monotherapy was successful in treating patients with healthcare-associated A. baumannii meningitis or ventriculitis [11, 14••], despite having low CNS penetration [8]. Regarding safety, only two cases experienced side effects from IV tigecycline [14••]; both cases had elevation in liver enzymes but tigecycline was not held for them. None of the cases that received IVT tigecycline had side effects.

Only four patients with healthcare-associated A. baumannii meningitis or ventriculitis received high-dose IV tigecycline [6, 12, 15•, 21]. It was used in combination with other antibiotics and all patients were cured. High-dose tigecycline is associated with better outcomes compared with conventional dose in non-approved indications like ventilator-associated pneumonia due to Gram-negative MDR bacteria including carbapenem-resistant A. baumannii [26]. In the literature, tigecycline (IV and/or IVT/IT) has been proven to be effective for treating healthcare-associated meningitis or ventriculitis caused by other Gram-negative and Gram-positive pathogens including Klebsiella pneumoniae, Elizabethkingia meningoseptica, and Enterococcus faecium [27,28,29,30].

Due to its excellent effectiveness against XDR bacteria, its preservative-free formulation, its safety profile, and limited CNS penetration, tigecycline is an ideal candidate for IVT use. In the six patients who received IVT tigecycline for healthcare-associated A. baumannii meningitis or ventriculitis, the dose of IVT tigecycline ranged from 2 to 8 mg/day [6, 12, 15•, 18, 21]. Wu et al. [27] evaluated the IVT administration of tigecycline for the treatment of MDR bacterial meningitis caused by MDR K. pneumoniae. They analyzed the pharmacokinetics of tigecycline and measured tigecycline trough concentrations for the three different dosages of IV and IVT tigecycline. The results of this study showed levels of 0.313, 1.290, and 2.886 mg/L for 49 mg IV plus 1 mg IVT q12 h, 45 mg IV plus 5 mg IVT q12 h, and 40 mg IV plus 10 mg IVT q12 h, respectively. The highest IVT tigecycline dosage achieved the optimal trough concentration, which was higher than the MIC for K. pneumoniae (2 mg/L). Although the level of tigecycline in the CSF was not measured for patients with healthcare-associated A. baumannii meningitis or ventriculitis who received IVT tigecycline, 4 mg/day of IVT tigecycline was sufficient in five cases. Only one patient required a high-dose IVT tigecycline (8 mg/day) [21].

Conclusion

Post-neurosurgical A. baumannii infection is common in healthcare settings. Treatment of such infections is challenging because of the presence of antibiotic resistance and poor penetration of antibiotics through the blood-brain barrier. IV and IVT tigecycline has been used successfully for the treatment of healthcare-associated A. baumannii meningitis and ventriculitis. IV and IVT tigecycline might be considered in cases with healthcare-associated A. baumannii meningitis and ventriculitis when initial therapy with polymyxin fails, when polymyxin resistance appears, and when patients develop side effects (mainly neurotoxicity) from IVT/IT polymixin. However, large randomized controlled trials are necessary to clearly evaluate the safety and effectiveness of IV and IVT tigecycline in healthcare-associated A. baumannii meningitis and ventriculitis.