Scope/limits Colistin on ICU

18/03/2014
How to use colistin?
Joost Wauters, UZ Leuven
BAPCOC National Study Day 22 03 2014
Scope/limits
• Colistin in ICU
• No data presented on:
– Cystic fibrosis
– Children
Colistin on ICU
• Dose-outcome
• Nephrotoxicity
• Clinical use:
– Colistin for VAP
– Colistin for sepsis
– Combination therapy
• Emerging resistance
1
18/03/2014
•
•
•
•
•
•
76 pt (79% ICU), retrospective (2005-2010)
APACHE II ??
45% catheter-related, 25% abdominal, 20% respiratory
Coli >= 72h, dosing decided by clinician
Microbiological success = eradication blood cultures d7 therapy
Microbiological failure = persistence blood cultures d7 or death by
d7 (7% no BC)
• No difference in baseline characteristics
• Combination therapy: 70% in both groups (p=0,79)
Vicari, CID 2013
Outcome-dose
CMS (MIU)
Microbiological
success day 7
(n=52, 68%)
Microbiological
failure day 7
(n=24, 32%)
p
7 (4-8,5)
3,5 (2,5-4,5)
0,01
• Survival day 7 (?? %):
6 vs 3,5 MIU CMS (p=0,007)
•
No correlation dose – 28d
survival
• AKI day 7 (36%):
8,5 vs 4 MIU CMS (p=0,007)
• Tigecycline
31% vs 54% in failure group
(p=0,051)
Vicari, CID 2013
•
•
•
•
•
258 pt (86% ICU), retrospective (2000-2007)
APACHE II 17 (2-39), hospital-mortality: 35%
60% pneumonie (infection/colonization??), 13% bacteremia
Coli >= 72h, dosing decided by clinician
Combination therapy (86%):
– 14% coli mono
– 63% coli/mero
– 23% coli/other
Falagas, Int J Antimicrob Agents 2010
2
18/03/2014
Outcome-dose
• Clinical cure:
– Coli (mono/+mero): 83%
– Coli+other: 61-75%
• Hospital mortality:
–
–
–
–
3 MIU CMS/day: 39%
6 MIU CMS/day: 28%
9 MIU CMS/day: 22%
Multivariate: daily colistin dose OR 1,22 (1,05-1,42), p=0,009
Falagas, Int J Antimicrob Agents 2010
Colistin on ICU
• Dose-outcome
• Nephrotoxicity
• Clinical use:
– Colistin for VAP
– Colistin for sepsis
– Combination therapy
• Emerging resistance
Mechanism nefrotoxicity
• Charge/hydrophobicity
Activation caspase pathway
Mitochondrial morfology/m
Apoptosis tubular cells
• Time/concentration
dependent
• Develop new-generation
polymyxins
3
18/03/2014
Nephrotoxicity
• Old studies: AKI up to 50%
• Newer studies: 10-30% AKI
• Disparity between old/new studies:
–
–
–
–
More purified colistin
Use of CMS instead of colistin
More adequate dose adjustment
Improvement ICU care
• Newest studies use RIFLE criteria:
– very sensitive
higher incidences AKI
N
AKI
(RIFLE)
Pogue, CID 2011
126
43%
Hartzell, CID 2009
66
45%
Sorli, BMC Inf 2013
102
26-49%
• Dose dependent
• Time dependent
• Partially reversible
Adverse effects of colistin
Neurotoxicity
• Rate: 0-7%, reversible
• Dose dependent, in the first few days of therapy
• Dizziness, weakness, facial and peripheral paresthesia,
vertigo, confusion, ataxia-neuromuscular blockade, acute
respiratory failure and apnea
CMS: 3*3 MIU/d
Creat 1,2 mg/dL
Coli: 8,1 mg/L
CMS onmeetbaar hoog
Miscellaneous
• Hypersensitivity reactions (rash, urticaria, itching): 2% of
patients
• pseudomembranous colitis
Falagas, CCM 2006
Spaepen, J Infection 2011
4
18/03/2014
Colistin on ICU
• Dose-outcome
• Nephrotoxicity
• Clinical use:
– Colistin for VAP
– Colistin for sepsis
– Combination therapy
• Emerging resistance
Colistin: clinical use
– Directed therapy:
• Coli + carbapenem (tigecycline?)
• VAP (ventilator-associated pneumonia)
• HAP (hospital acquired pneumonia)
• Bacteremia
• Urinary/abdominal
– Empiric therapy:
• Surveillance cultures
• Endemic region/local microbiological flora
• combination
Petrosillo, CMI 2008
Nation, Curr Opin Inf Dis 2009
Colistin on ICU
• Dose-outcome
• Nephrotoxicity
• Clinical use:
– Colistin for VAP
– Colistin for sepsis
– Combination therapy
• Emerging resistance
5
18/03/2014
–
–
–
–
–
6 controlled studies (coli vs. comparator)
359 patients, APACHE II 18
Clinical response: OR 1,14 (0,74-1,77), p=0,56
Hospital mortality: OR 0,92 (0,50-1,67), p=0,78
Nefrotoxicity: no difference
Florescu, CID 2012
Colistin aerosol for VAP
– inhaled colistin versus placebo on top of iv antibiotics
• Rattanaupawan 2010 (RCT):
– No difference clinical outcome
– bacteriological outcome: colistin 61% (n=51) vs. placebo 38% (n=49),
p=0.03
– No difference in nefrotoxicity: 26% vs. 22% (p=0.82)
– iv colistin versus iv colistin + inhaled colistin:
• Korbila 2010 (retrospective):
– Clinical cure: 61% (n=43) iv colistin vs. 80% (n=78) iv + aerosol colistin
(p=0.025)
– No effect mortality
• Kofteridis 2010 (retrospective): n=43/43
– No difference clinical cure, mortality, bacteriological eradication
• Doshi 2013 (retrospective): n=51/44
– No difference clinical cure, mortality, bacteriological eradicationPetrosillo, CMI 2008
Nation, Curr Opin Inf Dis 2009
6
18/03/2014
Colistin: aerosol
Kofteridis, CID 2010
Colistin aerosol for VAP
– Remarks:
•
•
•
•
•
Colistin aerosol without iv: better for nephrotoxicity
Lung penetration: plugging, atelectasis, hepatisation???
Variety of nebulizers applied
Cost devices: +++
Interference with functioning mechanical ventilator
=> Conclusion:
• Evidence still debated, no recommendation for additional
benefit
• RCT = urgent !!
Petrosillo, CMI 2008
Nation, Curr Opin Inf Dis 2009
Colistin on ICU
• Dose-outcome
• Nephrotoxicity
• Clinical use:
– Colistin for VAP
– Colistin for sepsis
– Combination therapy
• Emerging resistance
7
18/03/2014
Colistin for sepsis
• Meta-analysis clinical studies
– Covering systemic colistin/polymyxin B vs.
comparator/s
– Patients with sepsis
– Outcome = mortality
• Regardless of type of infection,
bacteria, dosing
• Published in the last decade
Paul, Prato 2013
Description of studies I
Study
Location
Betrosian 2008
Greece
Durakovic 2010
Croatia
Garnacho‐Montero 2003
Spain
Gounden 2009
South Africa
Hachem 2007
US, Texas
Infection
Bacteria
VAP
Acinetobacter
P. aeruginosa infections / P. aeruginosa
hematology
VAP
A. baumannii
Kallel 2007
Tunisia
ICU infections
A. baumannii
P. aeruginosa infections/ P. aeruginosa
cancer
VAP
A. baumanii or P. aeruginosa
Ku 2012
US, Detroit
any nosocomial
Kvitko 2011
Brazil
P. aeruginosa bacteremia P. aeruginosa
Acinetobacter, Klebsiella
Oliveira 2008
Brazil
any nosocomial
Paul 2010
Israel
any nosocomial
Acinetobacter
Acinetobacter, Klebsiella
Reina 2005
Argentina
ICU infections
Rigatto 2013
Brazil
VAP or VAT
Rios 2007
Argentina
VAP
A. baumanii or P. aeruginosa
A. baumanii or P.
aeruginosa
A. baumanii or P. aeruginosa
Betrosian 2008
Greece
VAP
Acinetobacter
Description of studies II
Study
Coli/polymyx
Dose
Combi
Comparator
Betrosian 2008
Colistin
9 MU
No
Ampicillin/ sulbactam
Durakovic 2010
Colistin
9 MU
Yes
Beta‐lactams
Garnacho‐Monte 2003 Colistin
Gounden 2009
Colistin
2.5–5.0 mg/kg ?
Imipenem
4 MU
Tobramycin
?
Hachem 2007
Colistin
5 mg/kg
Yes
Antipseudomonal
Kallel 2007
Colistin
6 MU
?
Imipenem
Ku 2012
Colistin
NR
?
Tigecycline
Kvitko 2011
Polymyx
141+‐54 mg
?
Antipseudomonals
Oliveira 2008
C or Polymyx
NR
?
Paul 2010
Colistin
6 MU
?
Reina 2005
Colistin
5 mg/kg
No
ampicillin/sulb
Imipenem, meropenem or ampicillin/ sulbactam
Any
Rigatto 2013
Polymyx
med 150 mg
?
Beta‐lactams
Rios 2007
Colistin
5 mg/kg
?
Imipenem or meropenem
Betrosian 2008
Colistin
9 MU
No
Ampicillin/ sulbactam
8
18/03/2014
IV colistin
vs.
comparator
antibiotics
for sepsis
all-cause
mortality
OR 1.90
(95% CI 1.53-2.33)
Paul, Prato 2013
Colistin probably somewhat
less effective than betalactams and more toxic
Colistin on ICU
• Dose-outcome
• Nephrotoxicity
• Clinical use:
– Colistin for VAP
– Colistin for sepsis
– Combination therapy
• Emerging resistance
9
18/03/2014
• 39 publications, 1054 bacterial isolates (A. baumanii, Ps.
Aeruginosa, K. pneumoniae)
• Synergy rates: 44-77%, no antagonism
• Clinical translation?
– Beta-lactam + aminoglycoside in gram-:
• in vitro synergy
• no evidence of survival benefit or less resistance
AAC online, 2013
CPE: combination therapy for BSI
Study
Organism
Combi
Therapy
Mono
Therapy
Mortality
Combi vs mono
Qureshi,
AAC 2012,
n=34
KPC Klebsiella BSI
single center
retrospective
Carbapenem +
coli of tige
(44%)
Carbapenem
or coli
or tige
(56%)
13% vs 58% (p=0,01)*
Tumbarello,
CID 2012,
n=125
KPC Klebsiella BSI
multicenter (3)
retrospective
Carbapenem + coli +
tige (of 2 vd 3)
(63%)
Carbapenem or
coli or tige
(37%)
34% vs 54% (p=0,02)*
Zarkotou, CMI
2011,
n=35
KPC Klebsiella BSI
single center
retrospective
Carbapenem + coli +
tige + genta
(57%)
Carbapenem or
coli or tige or genta
(43%)
0% vs 47% (p=0,001)*
Tam,
JAC 2010,
n=55
multiple foci
review 15 studies
28-day
30-day
Hospital mortality (7d)
71-75% vs 14-40%
Clinical success rate
*confirmed in multivariate analysis
47% colistin
10
18/03/2014
Colistin probably somewhat
less effective than betalactams and more toxic
Prevent
carbapenemresistant infection
Dosing/
schedule
Improve efficacy Compare colistin
and safety profile with
of colistin
aminoglycoside
Combination
therapy
Prevention of
nephrotoxicity
Combinatie therapie
• Data studies:
– in vitro synergism
– mortality↓ in patients with BSI
• Treat subpopulations (not cultured)
• Prevent development resistence
• Prevent nefrotoxicity: high dose for normal
clearance/ARC
The Future in Prato: RCTs
Colistin efficacy
• Colistin vs. carbapenem/ conventional treatment – 2
trials
Colistin combination therapy
• Colistin - imipenem/ meropenem (2 trials, AIDA, NIH)
• Colistin - fosfomycin (1 trial)
• Colistin –rifampin (2 trials)
Inhalation colistin
• IV vs. nebulized+IV colistin for VAP/ HAP (2 trials)
Prevention of nephrotoxicity
• Colistin - ascorbic acid (1 trial)
11
18/03/2014
Colistin on ICU
• Dose-outcome
• Nephrotoxicity
• Clinical use:
– Colistin for VAP
– Colistin for sepsis
– Combination therapy
• Emerging resistance
Resistance to polymyxins
• Acquired resistance
– Mutations on prmA/prmB with modifications of lipid
A (=component LPS)
– Mutations on lpxA, lpxC and lpxI with complete loss
of lipid A (A. baumannii)
• Heteroresistance (resistance manifested by a
fraction of a microbial population that is
considered susceptible) seems a frequent event
• Colistin monotherapy in-vitro <=24h
• Difference with in vivo: immune system, …
MIC and susceptibility categorization results to 15 antimicrobials of 13 CPE isolates
Ctr
Nr
Org
Bacterial
species
Carbapenem.
enzyme
TMO
C03
Uri
K.
pneumoniae
OXA-48
C10
Uri
K.
pneumoniae
OXA-48
C10
Uri
K.
pneumoniae
OXA-48
C12
Res
p
K. oxytoca
KPC
C12
Pus
K.
pneumoniae
NDM
C12
Res
p
K.
pneumoniae
KPC
C13
Res
p
E. coli
OXA-48
768
>64
2
C15
Uri
K.
pneumoniae
OXA-48
1024
>64
16
C17
Scre
K.
pneumoniae
OXA-48
>1024
>64
>64
C17
Res
p
K.
pneumoniae
OXA-48
>1024
2
C17
Scre
K.
pneumoniae
OXA-48
>1024
C19
Uri
K.
pneumoniae
KPC
C23
Pus
K.
pneumoniae
KPC
susceptible
intermediat
CTX
CAZ
FEP
PTZ
>1024
4
512
>64
≤0,5
2
>128
16
16
>128
1024
>64
16
16
128
16
32
>64
32
48
>64
>64
48
>64
>64
MER
AZT
GEN
AMI
TOB
CIB
TIG
COL
2
1
≤0,5
≤1
≤4
≤1
≤0,25
0,25
0,5
0,5
0,5
31
≤1
≤4
8
>2
0,5
1
0,5
≤0,25
32
≤1
≤4
8
>2
0,25
1
>128
4
8
>64
2
16
>8
>2
1
0,5
>64
>128
4
2
>64
>8
≤4
8
>2
0,5
>8
32
>128
2
2
>64
>8
>32
>8
>2
1
0,5
4
128
4
8
8
>8
≤4
4
0,5
≤0,12
0,5
32
>128
2
0,5
32
>8
≤4
>8
>2
0,5
2
>64
>128
4
16
>64
>8
≤4
>8
>2
2
1
≤0,5
≤0,5
128
1
2
≤0,5
≤1
≤4
≤1
≤0,25
2
1
>64
32
>64
>128
8
16
64
>8
≤4
>8
>2
0,5
0,5
64
>64
>64
>64
>128
>32
>32
>64
8
16
>8
≤0,25
0,5
1
1024
>64
>64
>64
>128
32
>32
>64
4
32
>8
>2
0,5
0,5
resistant
IMI
Glupczynski, AAC 2012
12
18/03/2014
Antibiotic susceptibilities for New Delhi
metallo-β‐lactamase 1 positive
Enterobacteriaceae
UK (n = 37)
MIC50/MIC90
Meropenem
Pip-tazo
Cefotaxime
Cefepime
Ciprofloxacin
Amikacin
Tigecycline
Colistin
Chennai (n = 44)
%
susc.
MIC50/MIC90
3
0
0
0
8
0
64
89*
32/32
>64/>64
>256/>256
>64/>64
>8/>8
>64/>64
4/8
1/32
32/32
>64/>64
>256/>256
>64/>64
>8/>8
>64/>64
1/4
0.5/8
Haryana (n = 26)
%
susc.
MIC50/MIC9
3
0
0
0
8
0
56
94**
>32/>32
>64/>64
>256/>256
>64/>64
>8/>8
>64/>64
1/2
1/2
0
%
susc.
3
0
0
0
8
0
67
100
*M. morganii, Providencia spp., Enterobacter spp., Klebsiella spp.
**2x Proteus spp., 1x K. pneumoniae
Kumarasamy, Lancet Inf 2010
Antimicrobial sensitivities of 536 multi-drug-resistant Gramnegative bacilli isolated from patients treated on surgical wards
in Greece
All
(N=536)
P.
aeruginosa
(N= 118)
A. baumannii
(N = 115)
K.
pneumoniae
(N=50)
E. coli
(N=161)
Pip-tazobactam
37,1
19,5
6,1
66
64
ceftazidime
39,6
28,8
6,1
66
64,6
cefepime
40,7
28
3,5
72
68,3
meropenem
56,9
32,2
18,3
92
84,5
tobramycin
50,4
55,9
12,2
72
67,7
amikacin
55,8
55,1
20,9
76
74,2
ciprofloxacin
35,1
18,6
0,9
72
56,5
colistin
82,5
94,1
93,9
74
68,9
Maraki, Surg Inf 2012
De Smet, NEJM 2009
13
18/03/2014
• 1246 respiratory samples, 1840 rectal swabs
• Acquisition colistin-resistant GNB
– respiratory tract
• 1/1000 patient-days (very low)
• No difference SDD, SOD, standard care (SC)
– Gastro-intestinal tract:
• 3.3/1000 patient-days
• Conversion rates to colistin-resistance in colistin-sensible GNB
carriage:
– Respiratory tract: 1-4/1000 patient-days, no difference SDD-SC
– Gastro-intestinal tract: 3-16/1000 patient-days (!!if tobra-resistance)
Conclusions
• Dosing regimen:
– Loading/maintainance dose: 9MIU
– Higher dose => better outcome
• Directed therapy VAP/HAP/sepsis
• Combination therapy: colistin +
carbapenem
• Emerging resistance
14

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