Le Infezioni in Medicina, n. 1, 103-107, 2023

doi: 10.53854/liim-3101-14

CASE REPORTS

Successful treatment of pan-drug resistant Acinetobacter baumannii nosocomial meningitis/ventriculitis by combined intravenous and intrathecal colistin-tigecycline administration: a case series

Andreas Theofanopoulos1, Dionysia Fermeli1, Dionysios Vekios2, Aristeidis Bizos2, Markos Marangos2, Constantine Constantoyannis1, Vasileios Panagiotopoulos1, Stelios F. Assimakopoulos2

1University Hospital of Patras, Department of Neurosurgery, Patras, Greece;

2University Hospital of Patras, Department of Internal Medicine, Division of Infectious Diseases, Patras, Greece

Article received 12 December 2022, accepted 25 January 2023

Corresponding author

Andreas Theofanopoulos

E-mail: andreastheofano@gmail.com

SummaRY

Background: This study aims to evaluate the efficacy of combined intraventricular and intravenous co-administration of colistin and tigecycline in the management of pan-drug resistant Acinetobacter baumannii meningitis/ventriculitis.

Methods: In this case series we report 3 patients with healthcare-associated ventriculitis/meningitis caused by pan-drug resistant Acinetobacter baumannii that were treated with combined colistin and tigecycline administration through both intraventricular and intravenous routes.

Results: All patients were administered colistin intraventricularly at a dose of 250.000 IU q.d. and intravenously at 9 million IU loading dose, followed after 12 hours by maintenance dose of 4.5 million IU every 12 hours and tigecycline intraventricularly at a dose of 10 mg b.i.d. and intravenously at 200 mg loading dose followed after 12 hours by 100 mg every 12 hours. In patients with a calculated creatinine clearance of less than 60 ml/min, according to the Cockcroft-Gault formula, the maintenance dose of colistin was reduced based on a modified formula. All patients had a favourable clinical and microbiological response with evidence of CSF sterilization.

Conclusions: Taking advantage of the synergistic action of combined colistin and tigecycline through administration both intraventricularly and intravenously may be a promising salvage option for critically ill patients with pan-drug resistant A. baumannii CNS infection.

Keywords: Ventriculitis, meningitis, A. baumannii, colistin, intraventricular administration.

INTRODUCTION

Hospital-acquired central nervous system (CNS) infections (ventriculitis and meningitis, VM) constitute serious complications of critically-ill neurosurgical patients, especially when attributed to resistant pathogens. The incidence of VM among neurosurgical patients is estimated between 5-7%, whereas it ranges between 1-20% after external ventricular drain (EVD) placement [1, 2]. Acinetobacter baumannii (A. baumannii) is found in 3.6-11% of CSF cultures [3].

Since VM is a nosocomial infection, multidrug-resistant (MDR) pathogens are usually implicated in its microbial etiology. Resistant A. baumannii is a difficult-to-treat nosocomial pathogen susceptible to limited therapeutic options, while extended- (XDR) and pan-drug resistant (PDR) A. baumannii isolates have emerged because of its constantly evolving resistance mechanisms [3, 4]. Treatment of PDR A. baumannii strains is a matter of growing concern associated with high mortality rates, while there are no established therapeutic regimens [5]. To overcome non-susceptibility to all antibiotics, diverse synergistic combinations have been previously tested including high-dose ampicillin/sulbactam with meropenem and colistin, high-dose ampicillin/sulbactam with high-dose tigecycline and colistin or colistin with fosfomycin [5, 6].

We present three patients with healthcare-associated ventriculitis/meningitis by pan-drug resistant A. baumannii treated with combined colistin and tigecycline administration through both intraventricular and intravenous routes with favourable clinical and microbiological outcome (Table 1).

CASES PRESENTATION

Definition of A. baumannii PDR phenotype

A. baumannii strains isolated from CSF were identified using Vitek 2 Advanced Expert System (bioMérieux, Marcy L’Étoile, France). Antibiotic susceptibility was performed by the Vitek 2 Advanced Expert System, while MIC to tigecycline was determined by Etest (AB Biodisk) and MIC to colistin by broth microdilution method. Results were interpreted according to EUCAST guidelines (EUCAST, 2022).

A. baumannii’s PDR phenotype was defined according to the international expert proposal for Interim standards guidelines [7]. Accordingly, PDR A. baumannii isolates were non-susceptible to all agents in all antimicrobial categories, with tigecycline MIC >2 μg/ml. In the latest EUCAST clinical breakpoints (v. 12.0, January 1, 2022) no clinical breakpoint is set for tigecycline due to insufficient evidence [8]. However, previous clinical studies with XDR A. baumannii infections, have shown that when tigecycline MIC is >2 μg/ml, significantly higher therapeutic failures and mortality were observed either when tigecycline was used as monotherapy or as part of combination therapy with colistin [9, 10]. The present study included patients with nosocomial ventriculitis/meningitis caused by carbapenem- and colistin-resistant A. baumannii with MIC to tigecycline 4 μg/ml (PDR A. baumannii strains).

Treatment regimen

Colistin was administered intraventricularly at a dose of 250.000 IU q.d. and intravenously at 9 million IU loading dose, followed after 12 h by maintenance dose of 4.5 million IU every 12 hours and tigecycline was administered intraventricularly at a dose of 10 mg b.i.d. and intravenously at 200 mg loading dose followed after 12 hours by 100 mg every 12 hours. In patients with a calculated creatinine clearance of less than 60 mL/min, according to the Cockcroft-Gault formula, the maintenance dose of colistin was reduced based on a modified formula from Garonzik et al. (daily maintenance colistin dose [IU] = CLCR/10+2) [11]. The ventricular drainage device was closed for 1 hour after the injection of the antibiotics.

All three patients were admitted and treated in the ICU of our hospital.

The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Due to the study’s retrospective nature, ethics committee approval was not required.

Case 1

A 60-year-old woman with aneurysmal subarachnoid hemorrhage and acute hydrocephalus was treated with external ventricular drain upon admission; the aneurysm was successfully embolized. Neurological deterioration due to vasospasm led to intubation and ICU admission. During hospitalization a ventriculoperitoneal shunt was placed. On the 33rd post-operative day she developed fever and progressed to septic shock. CSF analysis performed the same day revealed infection by carbapenem and colistin-resistant A. baumannii with tigecycline MIC 4 μg/mL (PDR strain). The patient was started on combined colistin and tigecycline intravenously and intrathecally via the VP shunt, as described in the treatment regimen section. The septic shock was reversed within two days, but the patient became afebrile with normal inflammatory markers and negative CSF cultures at 35 days after treatment initiation, whereupon IVT infusions were terminated on the 37th day after treatment initiation. She survived for 82 days in a severe clinical state owing to the subarachnoid hemorrhage and died by sepsis due to carbapenem-resistant Pseudomonas aeruginosa bacteremia.

Case 2

A 33-year-old male patient was admitted intubated due to severe traumatic brain injury (TBI) with acute subdural hematoma and brain edema. He was treated with craniectomy, drainage of the hematoma and insertion of EVDs bilaterally due to post-traumatic hydrocephalus. On the 42nd post-operative day the patient developed fever; CSF analysis performed the same day indicated infection by PDR A. baumannii. The patient was started on colistin and tigecycline intravenously and intrathecally via the EVD drain. CSF cultures became negative at 5 days from treatment initiation with fever resolution and normalization of inflammatory markers, with termination of IVT infusions on the 7th day after treatment initiation. The patient was eventually discharged to continue physiotherapy at the rehabilitation center.

Case 3

A 56-year-old male presented with aneurysmal subarachnoid hemorrhage. He was successfully embolized; on the 1st post-operative day he developed acute hydrocephalus which required an EVD, which was replaced thrice due to malfunction caused by the hemorrhage. On the 11th post-operative day he became septic; CSF samples drawn the same day showed PDR A. baumannii. The patient was treated with the described regimen of combined intravenous and intrathecal colistin and tigecycline. CSF was sterilized at 17 days after treatment initiation with gradual clinical and laboratory response. The IVT drug infusions were terminated on the 19th day after treatment initiation. The patient died 32 days later by massive pulmonary embolism.

DISCUSSION

Emergence of colistin resistance in A. baumannii has limited our therapeutic armamentarium. MDR A. baumannii infections show mortality rates over 60% [5]. Therefore, in severe XDR and PDR infections, it is reasonable to use combination regimens to exploit antibiotic synergism. Different combinations of antibiotics have demonstrated synergistic action against XDR A. baumannii, such as colistin combined with rifampicin, tigecycline, sulbactam, vancomycin, and carbapenems combined with colistin, sulbactam, aminoglycosides or rifampicin [6, 12, 13]. The tigecycline-colistin combination was shown to be more synergistic than the tigecycline-rifampicin and colistin–rifampicin combination [14]. However, synergy is not universal and not applicable to every A. baumannii strain. Clinically relevant synergy may be less likely for strains with very high MICs [12]. In a recent study from our hospital, 10 patients with PDR A. baumannii ventilator-associated pneumonia were administered a triple combination regimen of high-dose ampicillin sulbactam (6/3 g every 8 hours), high-dose tigecycline (200 mg loading dose followed after 12 hours by 100 mg every 12 hours) and combined intravenous and inhaled colistin; resulting in clinical success in nine patients, and microbiological eradication in seven [6].

Poor drug blood-brain barrier permeability is another important obstacle. Combination of intravenous and intrathecal administration of colistin and other antibiotics to enhance drug concentrations at the infection site is often employed. Current choices for intrathecal administration include aminoglycosides, tigecycline and colistin [3, 15, 16]. The combination regimen of colistin and tigecycline used here was an off-label salvage option for our critically-ill patients; there is very limited experience with its application [16]. There were no side effects of this co-administration, including chemical meningitis, seizures or nephrotoxicity.

The most important limitations of our presented cases are:

a) the fact that synergy between colistin and tigecycline was not tested in vitro;

b) antibiotic levels were not determined in CSF to compare with respective in vitro MICs of A. baumannii and

c) the possibility of selection bias always exists in case series, therefore a prospective cohort or RCT is needed to more accurately determine the potential benefit of such treatment.

However, the positive clinical and microbiological response reported herein warrants further investigation, considering the limited therapeutic options and adverse outcomes that are usually encountered in nosocomial VM by PDR A. baumannii.

CONCLUSION

Successful CSF sterilization with concomitant clinical response in the above cases indicates that exploiting the synergistic action of combined colistin and tigecycline through administration both intraventricularly and intravenously may be a promising salvage option for critically-ill patients with pan-drug resistant A. baumannii CNS infection.

Conflicts of interest

All authors declare no conflict of interest.

Funding

No funds, grants, or other support were received.

REFERENCES

[1] McClelland S, Hall WA. Postoperative Central Nervous System Infection: Incidence and Associated Factors in 2111 Neurosurgical Procedures. Clin Infect Dis. 2007; 45, 55-59.

[2] Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis. 2017; 64, e34-65.

[3] Karaiskos I, Galani L, Baziaka F, Giamarellou H. Intraventricular and intrathecal colistin as the last therapeutic resort for the treatment of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii ventriculitis and meningitis: a literature review. Int J Antimicrob Agents. 2013; 41, 499-508.

[4] Fournier P-E, Vallenet D, Barbe V, et al. Comparative Genomics of Multidrug Resistance in Acinetobacter baumannii. PLoS Genet. 2006; 2, e7.

[5] Karakonstantis S, Kritsotakis EI, Gikas A. Pandrug-resistant Gram-negative bacteria: a systematic review of current epidemiology, prognosis and treatment options. J Antimicrob Chemother. 2020; 75 (2), 271-282.

[6] Assimakopoulos SF, Karamouzos V, Lefkaditi A, et al. Triple combination therapy with high-dose ampicillin/sulbactam, high-dose tigecycline and colistin in the treatment of ventilator-associated pneumonia caused by pan-drug resistant Acinetobacter baumannii: a case series study. Infez Med. 2019; 27, 11-16.

[7] Magiorakos A-P, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012; 18, 268-281.

[8] The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 12.0, 2022. 2022; Available at: https://www.eucast.org/. Accessed 26 May 2022.

[9] Cheng A, Chuang Y-C, Sun H-Y, et al. Excess mortality associated with colistin-tigecycline compared with colistin-carbapenem combination therapy for extensively drug-resistant Acinetobacter baumannii bacteremia. Crit Care Med. 2015; 43, 1194-1204.

[10] Chuang Y-C, Cheng C-Y, Sheng W-H, et al. Effectiveness of tigecycline-based versus colistin- based therapy for treatment of pneumonia caused by multidrug-resistant Acinetobacter baumannii in a critical setting: a matched cohort analysis. BMC Infect Dis. 2014; 14, 102.

[11] Garonzik SM, Li J, Thamlikitkul V, et al. population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011; 55, 3284-3294.

[12] Karakonstantis S, Ioannou P, Samonis G, Kofteridis DP. Systematic Review of Antimicrobial Combination Options for Pandrug-Resistant Acinetobacter baumannii. Antibiotics (Basel). 2021; 10, 1344.

[13] Poulikakos P, Tansarli GS, Falagas ME. Combination antibiotic treatment versus monotherapy for multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter infections: a systematic review. Eur J Clin Microbiol Infect Dis. 2014; 33, 1675-1685.

[14] Dizbay M, Tozlu DK, Cirak MY, Isik Y, Ozdemir K, Arman D. In vitro synergistic activity of tigecycline and colistin against XDR-Acinetobacter baumannii. J Antibiot. 2010; 63, 51-53.

[15] Hu Y, He W, Yao D, Dai H. Intrathecal or intraventricular antimicrobial therapy for post-neurosurgical intracranial infection due to multidrug-resistant and extensively drug-resistant Gram-negative bacteria: A systematic review and meta-analysis. Int J Antimicrob Agents. 2019; 54, 556-561.

[16] Tsolaki V, Karvouniaris M, Manoulakas E, et al. Intraventricular CNS treatment with Colistin-Tigecycline combination: A case series. J Crit Care. 2018; 47, 338-341.