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Colistin

• Bactericidal drug; disruption of the outer cell membrane of Gram-negative bacteria.

• Primarily used for infections with P.A. and A.B.

• E coli, some Enterobacter spp, H. influenzae, • E coli, some Enterobacter spp, H. influenzae, Bordetella pertussis, L. pneumophila, Klebsiella spp, Salmonella spp, Shigella spp, and the majority of Stenotrophomonas maltophilia strains.

• For otherwise panresistant nosocomial infections, especially those due to Pseudomonas and Acinetobacter spp.

Introduction-1

• Post-neurosurgical nosocomial meningitis has arisen in bacterial meningitis in the hospital setting.

• Acinetobacter baumannii was the most frequent• Acinetobacter baumannii was the most frequentGram negative micro-organism in the neurosurgery setting.

• Therapeutic treatment is considered extremely challenging

– Develop resistance easily.

Introduction-2

• Colistin

– Great in vitro activity and excellent in vivo potency against A.B.

– Penetration of colistin into the CSF in poor.– Penetration of colistin into the CSF in poor.

– Intraventricular(IVT) administration of colistin appears to have a crucial role in the treatment of post-neurosurgical ventriculitis/meningitis caused by A.B. with multiple patterns of resistance.

Introduction-3

• 6 neurosurgical patients complicated with

XDR A.B. ventriculitis and meningitis, with

concomitant bacteraemia in 3 of them, who concomitant bacteraemia in 3 of them, who

were cured with IVT administration of

colistin.

Patients and methods

Subjects-1

• Intensive Care Unit (ICU) and the

Department of Neurosurgery and

Interventional Neuroradiology of Hygeia Interventional Neuroradiology of Hygeia

General Hospital (Athens, Greece)

• 2010-01-01~2012-12-01

Subjects-2

• Criteria

– (i)clinical evidence of CNS infection;

– (ii)microbiological evidence in CNS infection;– (ii)microbiological evidence in CNS infection;

– (iii)isolation of A.B. from CSF;

– (iv)necessity of colistin administration via the

IVT route.

Subjects-3

• Recorded

– age; sex; primary diagnosis; presence of foreign

bodies; antimicrobial regimens prescribed; bodies; antimicrobial regimens prescribed;

– days from admission to diagnosis of meningitis;

– days for sterilisation of CSF;

– duration of intravenous (IV) and

IVT/intrathecal (ITH) colistin treatment;

– toxicity; outcome; and follow-up

Colistin administration-1

• IVT route

– Loading dose of 500,000 IU (40 mg)

– Followed by a dose of 125,000–250,000 IU (10–20 mg) every 24–48 h (10–20 mg) every 24–48 h

– For a median period of 17 days.

• Continued through the ITH route (3), because of removal EVD

– 125,000–250,000 IU (10–20 mg) every 48 h


• IV colistin concomitantly

– 3,000,000 IU (240 mg) every 8 h or 4,500,000

IU (360 mg) every 12 h for a median duration IU (360 mg) every 12 h for a median duration

of 21 days.

– A loading dose of 6,000,000 IU (480 mg) was

administered in 3 patients.


• IVT colistin

– Diluted with 2 mL of sterile N/S given after

removal of an equal volume of CSF.removal of an equal volume of CSF.

– Clamped for 1h and released.

• ITH colistin was given through LBP.

Microbiology

– A.B. was identified using a VITEK®

– Susceptibility to colistin was defined as MIC ≤2

ug/mL.

Case reports

Case 1

• 60 y/o, male

• Past hx:nil

• ICU: SAH, right ant. communicating artery aneurysmaneurysm

• Tx:endovascular occlusion, EVD

• Fever, CSF(D12) :

– WBC(2030x106/L), PMN(85%), lymphocyte(2%), Glucose(45mg/dl), protein(198 mg/dL)

– Culture: A.B. sentive to tigecycline, colistin

• afebrile and culture(-), 2 days after IVT

• VP shunt(D32); discharged(D42); f/u 22months

Case 2

• 26 y/o, male

• Past hx:alcohol abuse, drug addiction

• ICU:vehicle accident head injury; right subdural haematoma, temporal bone and the base of the haematoma, temporal bone and the base of the skull fx otorrhoea complicated by CSF leakage; thoracic and lumbar vertebrate fx

• Tx: decompressive craniotomy, EVD,

• CSF(D11) :



Case 2-2

• After IVT of colistin

– Culture sterile(d5), afebrile(d8)

• VP shunt(D55); discharged(D70); f/u • VP shunt(D55); discharged(D70); f/u

20months

Case 3

• 53 y/o, male

• Past hx:hypertension on medication

• ICU: intra-parenchymal haemorrhage, anterior circulation aneurysm rupturecirculation aneurysm rupture

• Tx: endovascular coil placement, EVD (10days)

• Fever, AMS, CSF(D15) :



Case 3-2

• After colistin

– Afebrile(d3), Culture sterile(d3),

• Discharged(D85); f/u 18months• Discharged(D85); f/u 18months

Case 4

• 44 y/o, female

• Past hx:?

• ICU: SAH, AVM

• Tx: endovascular occlusion, EVD• Tx: endovascular occlusion, EVD



– Culture: A.B. sentive to gentamicin, colistin

– B/C(+): A.B.

Case 4-2

• After colistin

– Afebrile(d2), Culture sterile(d3),

• Fever again(D17)=>chemical meningitis • Fever again(D17)=>chemical meningitis

– Afebrile(d5), CSF srerile

• VP shunt (D50), Discharged(D50); f/u

14months

Case 5

• 60 y/o, male

• Past hx:HTN

• ICU: SAH, post. communicating artery aneurysm rupturerupture

• Tx: EVD

• Fever(D22), XDR A.B. no improvent of fever with IV colistin

• CSF(D27) :


– Culture: A.B. sentive to amikacin, colistin

Case 5-2

• After colistin

– Afebrile(d2), Culture sterile(d2), remove

hematoma(d14)hematoma(d14)

• Expired(D68)

– KPC-positive Klebsiella pneumoniae

bacteraemia resistant to colistin that originated

from the urinary tract.

Case 6

• 62 y/o, female

• Past hx:HTN

• ICU: SAH, post. communicating artery aneurysm rupturerupture

• Tx: endovascular occlusion, EVD(3 weeks)


– WBC(9300x106/L), PMN(95%), Glucose(<10mg/dl), protein(1920 mg/dL)

– Culture: A.B. sentive to tobramycin, colistin

Case 6-2

• After colistin

– Culture sterile(24hr), afebrile(d5)

• Fever again(D17)=>chemical meningitis • Fever again(D17)=>chemical meningitis

– Afebrile(d5), CSF srerile

• VP shunt (D120), f/u 5months

Discussion-1

• CNS infections either as ventriculitis or

meningitis caused by A.B. are challenging.

– High mortality rate > 15%.; MDR, XDR– High mortality rate > 15%.; MDR, XDR

• Carbapenems are considered reference

standard for empirical treatment of

Acinetobacter meningitis

– increasing resistance rate => limit therapeutic

option

Discussion-2

• Tigecycline, active in vitro against A.B.

– Poor blood-CSF barrier penetration => not

recommended

• Colistin, a revived antibiotic of the 1950s• Colistin, a revived antibiotic of the 1950s

– Has accumulated most experience against MDR and

XDR Gram-negative isolates, including Acinetobacter.

• Colistin concentration in the CSF is poor.

– Administration of IVT or ITH colistin.

Discussion-3

• There was no detailed data defining the

exact role and dosage.

• Infectious Diseases Society of America • Infectious Diseases Society of America

(IDSA) in 2004

– 125,000IU(10mg) for IVT colistin

administration.

– No FAD approved for IVT use.

Discussion 4

• Dosage

– Loading dose of 500,000IU (40mg)

– Then dosage around around the IDSA guidelines q24hr

until CSF culture(-), then q48hruntil CSF culture(-), then q48hr

– After CSF culture(-) 10~14 days => DC colistin

• Direct administration of colistin into the CSF was

effective and well tolerated in the treatment of

A.B. meningitis of our patient.

Discussion 5

• Microbiological eradication was at a median

time of 2.5days (range1~5days)

• Chemical ventriculitis (case 2); chemical • Chemical ventriculitis (case 2); chemical

meningitis (case 4).

– Postponed treamtment for 2 days

– Reduction dose, half(case 2); q24=>q48 (case 4)

Dicussion 6

• Chemical irritation

– Reverseable.

– Resembled bacterial meningitis in clinical and – Resembled bacterial meningitis in clinical and

CSF study.

– Only difference => sterile CSF cultures.

• No toxicity reported in IVT(median time of

17 days) and IV(median time of 21 days).

Discussion 7

• Relapse was not documented at follow-up of a median time of 18 months.

• Regarding neurological deficits, it was difficult to distinguish whether the episode of A.B. distinguish whether the episode of A.B. meningitis was the causal agent or whether the underlying CNS haemorrhage was the major contributing factor or both.

• Recovered completely => case 1,2,3

• Left hemiplegia and required an intensive rehabilitation programme => case 4

Discussion 8

• Moderate neurological disabilities with

deafness, and required tracheostomy and

gastrostomy as well as physiotherapy in a gastrostomy as well as physiotherapy in a

rehabilitation centre => case 6

Conclusion

• IVT administration of colistin

– Safe and efficacious therapeutic option for

XDR A.B. ventriculitis/meningitisXDR A.B. ventriculitis/meningitis

– Should be considered in the neurosurgery

setting.

Thanks for your attention~

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