JAC Advance Access originally published online on August 17, 2006
Journal of Antimicrobial Chemotherapy 2006 58(5):1078-1081; doi:10.1093/jac/dkl347
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Cure of multiresistant Acinetobacter baumannii central nervous system infections with intraventricular or intrathecal colistin: case series and literature review
1 Department of Microbiology and Infectious Diseases, South Western Area Pathology Service Liverpool, Sydney, New South Wales, Australia 2 Department of Pathology, School of Medical Sciences, Faculty of Medicine, University of New South Wales Sydney, New South Wales, Australia 3 Clinical Immunology & Infectious Diseases Unit, John Hunter Hospital New Lambton, Newcastle, New South Wales, Australia
*Corresponding author. Tel: +61-2-9828-5128; Fax: +61-2-9828-5129; E-mail: Iain.Gosbell{at}sswahs.nsw.gov.au
Received 11 April 2006; returned 10 May 2006; revised 20 July 2006; accepted 2 August 2006
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Abstract |
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Objectives: CNS infections due to multiresistant Acinetobacter baumannii (MRAB) are an emerging problem in neurosurgical patients. Colistin remains one of the few remaining treatment options for MRAB but has poor CNS penetration. We describe our experience with intraventricular or intrathecal colistin for this infection.
Methods: Cases known to have received intraventricular or intrathecal colistin for CNS infections due to MRAB were retrospectively reviewed regarding colistin treatment, colistin efficacy and adverse events.
Results: Five patients were identified. All were admissions to the neurosurgical ICU and all were cured of their CNS infections. Three cases were complicated by drug-induced aseptic meningitis or ventriculitis.
Conclusions: This largest case series to date shows that direct instillation of colistin into the CNS may cause chemical meningitis or ventriculitis but it is an effective treatment option for MRAB CNS infection. Further study of dosing regimens is needed.
Keywords: A. baumannii , CNS infections , polymyxin E , injections , ventriculitis , meningitis
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Introduction |
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Multidrug-resistant Acinetobacter baumannii (MRAB) is increasingly common,1 and CNS MRAB infections are now seen.2–9 MRAB isolates at our hospitals are resistant to all available parenteral antibiotics other than amikacin, severely limiting therapeutics. Amikacin has poor CNS penetration and when formulated with the preservative sodium metabisulphite is not recommended for intraventricular or intrathecal use. The new glycylcycline tigecycline, active in vitro against MRAB, is bacteriostatic and its role in CNS infection is undefined. Colistin (polymyxin E) has good activity against Gram-negative bacilli including
98% of MRAB isolates in recent studies.1 CNS penetration of colistin is poor, but recent case reports suggesting efficacy of this drug administered directly into the CNS for MRAB ventriculitis/meningitis prompted its use in our cases. |
Materials and methods |
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Cases were identified from the authors' personal experience and were defined as having (i) clinical evidence of CNS infection, (ii) isolation of MRAB from CSF and (iii) receiving colistin via intraventricular or intrathecal routes.
Retrospective chart review was performed. Risk factors for MRAB infection (prior colonization, admission to ICU and preceding use of broad-spectrum antibiotics) were recorded. Survival or death, response to treatment and adverse drug reactions were recorded. Cure was defined as absence of clinical and laboratory evidence for ongoing infection at the last day of original admission.
Colistimethate sodium (colistin methane sulphonate; colistin methylsulphonate) [‘Coly-Mycin M Parenteral (Injection)’, Parke-Davis, supplied by Link Medical Products Pty Ltd, Sydney, Australia] was used for all cases and all administration routes. Intravenous dosing was 5 mg/kg/day (maximum 300 mg) in divided doses. Intraventricular or intrathecal dosing was 5–10 mg in 1–2 mL of sterile normal saline, given after removal of a greater or equal volume of CSF. The intraventricular colistin was given via an external ventricular drain (EVD), which was then clamped for 1 h and released. Intrathecal colistin was given via lumbar puncture.
Clinical isolates of A. baumannii were identified by morphology, Gram stain and reactions with the Vitek 2 GNI card (bioMérieux-Vitek, Australia, Pty Ltd). Susceptibility to colistin was determined by disc diffusion (10 µg disc, Oxoid Australia Pty Ltd) at John Hunter Hospital and Etest (AB Biodisk, Solna, Sweden) at South Western Area Pathology Service.
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Results |
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Five patients were identified, as summarized in Table 1. Two were male and three female, aged 4–74 years. Three infections were associated with an EVD and one with a CSF leak. One patient had prior MRAB colonization, four patients received broad-spectrum antibiotics prior to their MRAB infections, and all were resident in the ICU before infection developed. Three received intraventricular colistin and two received intrathecal colistin. All five were cured of their infections.
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No nephrotoxicity, neurotoxicity or neuromuscular blockade was noted with systemic colistin use. One patient died (case 1) but this was unrelated to the infection or treatment. Chemical meningitis or ventriculitis was noted in cases 3, 4 and 5.
All MRAB isolates were susceptible to colistin and amikacin but resistant to all other antimicrobials tested.
Case synopses
Case 1. A 74-year-old woman admitted for bowel perforation and myocardial infarction. Subarachnoid haemorrhage (SAH) with obstructive hydrocephalus occurred, and an EVD was inserted on day 3. On day 8, the EVD was removed; the tip and CSF grew Staphylococcus epidermidis and MRAB. Intravenous vancomycin and amikacin were commenced. Her condition worsened. Recurrent hydrocephalus was detected, another EVD was inserted on day 12, CSF grew MRAB, and intraventricular colistin was commenced, 5 mg then 10 mg daily for 18 days. CSF samples from day 15 to 31 were culture negative and clinically the infection resolved. On day 32 another myocardial infarction resulted in death.
Case 2. A 56-year-old woman presenting with SAH and obstructive hydrocephalus. An EVD was inserted and was replaced three times (days 4, 5 and 11). CSF and the EVD tip from day 11 grew MRAB. Intravenous amikacin and colistin 150 mg 12 hourly were commenced but the CSF remained culture positive for MRAB. On day 17, intraventricular colistin was commenced at 5 mg initially then 10 mg daily for 3 days. CSF cultures were negative from day 19 and sepsis resolved, but treatment was truncated due to poor neurological outcome. The patient survived and was transferred to a nursing home.
Case 3. A 38-year-old woman presented with a closed head injury. An EVD was inserted on day 1 and removed on day 10. Culture-negative ventriculitis was treated with intravenous vancomycin, meropenem and amikacin from days 21 to 41. CSF from a newly inserted EVD on day 40 yielded MRAB. Intraventricular colistin was administered from days 42 to 53, initially 5 mg then 10 mg daily. She also received intravenous colistin and amikacin from days 50 to 63. CSF became culture negative from day 46. On day 53 despite clinical improvement the CSF white cell count rose to 210 x 106/L, so colistin was ceased and the CSF leucocytosis resolved. Clinical recovery occurred and the patient underwent rehabilitation.
Case 4. A 26-year-old man presenting with lower limb injury and intracerebral haemorrhages requiring EVD insertion. The leg wound became infected with MRAB and intravenous amikacin was commenced on day 8. Blood, CVC tip, CSF and EVD tips submitted on days 13 and 14 grew MRAB. Intravenous and intrathecal colistin (initially 5 mg then 10 mg daily) were commenced on day 14. CSF cultures were negative on days 15 and 19. Despite clinical recovery, on day 19 the CSF white cell count rose to 588 x 106/L, falling when intrathecal colistin was ceased. Intravenous colistin and amikacin ceased on day 35. The patient was discharged to rehabilitation.
Case 5. A 4-year-old boy presenting with medulloblastoma requiring craniotomy. On day 10 focal seizures occurred, CT showed leptomeningeal enhancement, and MRAB was isolated from CSF and blood. Intravenous amikacin and colistin 2.5 mg/kg 12 hourly were commenced. CSF remained culture positive, so intrathecal colistin was administered, initially 1 mg, then two doses of 2 mg, then 4 mg daily for 13 days. A CSF leucocytosis of 165 x 106/L developed and the intrathecal colistin dose was reduced to 2 mg, with reduction in the leucocytosis. CSF cultures became negative on day 3 of intrathecal colistin. The meningitis resolved but functional recovery was poor despite rehabilitation.
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Discussion |
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Administration of colistin directly into the CNS appears to be successful and well tolerated apart from a high incidence of chemical ventriculitis. All 5 patients were cured, as were all 11 previously reported episodes of MRAB treated with intraventricular or intrathecal colistin (Table 2).2–9 This is superior to 70% (9/13 cases) survival from Acinetobacter spp. meningitis treated with intravenous ß-lactams and aminoglycosides.10
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In cases 2 and 5, the CSF remained culture positive despite intravenous colistin, with subsequent cure only after administering colistin directly into the CNS. Of the 10 reviewed cases (total 11 episodes) given intraventricular or intrathecal colistin for MRAB CNS infection,2–9 3 failed to respond to initial intravenous colistin.3,5,6
Cases 1, 2 and 5 failed to respond to treatment including amikacin and cases 3 and 4 developed infection while on amikacin, showing that this drug fails despite in vitro susceptibility.
Intraventricular colistin alone can be adequate therapy for MRAB CNS infection. Case 1 was effectively treated by intraventricular colistin without intravenous colistin and in case 3 the CSF was sterilized using intraventricular colistin before intravenous colistin was initiated. There is one other reported case cured using only intrathecal colistin,7 and two cases where CSF continued to grow MRAB despite intravenous colistin and cure was achieved with intraventricular colistin.5,6
Treating MRAB CNS infection with intraventricular or intrathecal colistin alone will avoid the significant renal toxicity associated with the intravenous route of administration. Although adverse reactions to intravenous colistin were not observed in our series, direct CNS instillation of colistin produced CSF inflammatory changes in cases 3, 4 and 5. In cases 3 and 4, the chemically induced CSF leucocytosis led to the discontinuation of colistin by this route, while in case 5 a dose reduction in intrathecal colistin allowed it to be continued. This has not been reported previously.2–9 One case of a seizure secondary to an intraventricular colistin dose of 8 mg was also reported.6
An intraventricular or intrathecal dose of 5 mg initially then 10 mg once daily was used for the adult patients in this series. Reported dosages range from 1.6 to 20 mg/day as single or divided doses.2–9 Notably, the lowest reported doses of 1.6–3.2 mg were combined with intrathecal amikacin.3 The twice daily regimens are only practical if an EVD or ventricular shunt is in situ, and a higher frequency of administration might increase the risk of inadvertently introducing another pathogen into the CNS.
The intrathecal or intraventricular colistin regimen used was selected based on dosages used in the literature and the fact it worked on the initial patients. CSF volumes of distribution of neurosurgical patients vary considerably thus varying the therapeutic dose. EVD drainage rates are widely variable—in those with excess drainage, intraventricular antibiotics will be diluted more, and conversely if drainage is minimal, higher levels and possibly greater toxicity may result. We clamped the EVDs for 1 h to deal with the problem of excessive drainage. Further study of these parameters is required.
Intraventricular or intrathecal colistin is effective and well tolerated apart from reversible chemical meningitis/ventriculitis and should be considered for MRAB CNS infection.
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None declared.
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Acknowledgements |
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This study was unfunded.
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References |
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1 Henwood CJ, Gatward T, Warner M, et al. (2002) Antibiotic resistance among clinical isolates of Acinetobacter in the UK, and in vitro evaluation of tigecycline (GAR-936). J Antimicrob Chemother 49:479–87.
2 Fernandez-Viladrich P, Corbella X, Corral L, et al. (1999) Successful treatment of ventriculitis due to carbapenem-resistant Acinetobacter baumannii with intraventricular colistin sulfomethate sodium. Clin Infect Dis 28:916–7.[Web of Science][Medline]
3 Kasiakou SK, Rafailidis PI, Liaropoulos K, et al. (2005) Cure of post-traumatic recurrent multiresistant gram-negative rod meningitis with intraventricular colistin. J Infect 50:348–52.[CrossRef][Web of Science][Medline]
4 Kaplan SL and Patrick CC. (1990) Cefotaxime and aminoglycoside treatment of meningitis caused by gram-negative enteric organisms. Pediatr Infect Dis J 9:810–4.[Web of Science][Medline]
5 Bukhary Z, Mahmood W, Al-Khani A, et al. (2005) Treatment of nosocomial meningitis due to a multi-drug resistant Acinetobacter baumannii with intraventricular colistin. Saudi Med J 26:656–8.[Web of Science][Medline]
6 Sueke H, Marsh H, Dhital A. (2005) Using intrathecal colistin for multidrug resistant shunt infection. Br J Neurosurg 19:51–2.[CrossRef][Web of Science][Medline]
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Vasen W, Desmery P, Ilutovich S, et al. (2000) Intrathecal use of colistin. J Clin Microbiol 38:3523.
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Berlana D, Llop JM, Fort E, et al. (2005) Use of colistin in the treatment of multiple-drug-resistant gram-negative infections. Am J Health Syst Pharm 62:39–47.
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Benifla M, Zucker G, Cohen A, et al. (2004) Successful treatment of Acinetobacter meningitis with intrathecal polymyxin E. J Antimicrob Chemother 54:290–2.
10 Chen SF, Chang WN, Lu CH, et al. (2005) Adult Acinetobacter meningitis and its comparison with non-Acinetobacter gram-negative bacterial meningitis. Acta Neurol Taiwan 14:131–7.[Medline]
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