Polymyxins revisted

clinical use of colistin

1. PolymyxinsRevisted
New indications for old antibiotics
Dr Ashok Rattan,
Chairman: Laboratory Medicine

2. 2
Polymyxins
Polypeptide antibiotics first isolated from Bacillus
polymyxa
5 chemically different compounds
(PolymyxinA –E)
PolymyxinB
PolymyxinE (Colistin)
PolymyxinA, C and D too toxic for human use

3. 3
Colistin
Cationic cyclic decapeptide
Linked to a fatty acid chain
Through an α amide linkage
Amino acid are:
D leucine,
L threonine,
L αγdiaminobutyric acid
Fatty acid could be
6 methyl octonoicacid (colistinA)
6 methyl eptanoicacid (colistinB)

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PolymyxinE (Colistin)
ColistinMethane Sulphonate, pentasodiumcolistimethanesulphate, colistinsulfonylmethate, CMS

5. 5
Formulations:
Colistinsulphate
Oral, Tropical, inhalation use
Active drug, not absorbed
orally
International Unit is defined as
minimal concthat inhibits
growth of E.coli95 ISM in 1
ml broth at pH 7.2
1 million IU = 80 mg of CMS
Colistimethatesodium (CMS)
Parental, inhalation use
Inactive prodrug, less toxic,
hydrolysedin aqueous
solution to active colistin
Two formulations:
A.colomycin: 500 k, 1 M, 2 M
international units
B.Colymycin: 150 mg colistin
active base/vial = 360 mg
of CMS

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Available formulations
Colomycininjection Coly-MycinM Parenteral
Manufacturer Dumex-AlpharmaA/S,
Copenhagen, Denmark
ParkedalePharmaceuticals,
Rochester, MN, USA
Labelledcontent per vial500 000, 1 000 000 or
2 000 000 IU;
about 12 500 units/mg
150 mg colistinbase activity
Mass of colistimethate
sodium dry powder per vial
40 mg, 80 mg, or 160 mgAbout 400 mg
Appearance Creamy-white powder White to slightly yellow lyophilised
cake
Recommended dose* ≤60 kg bodyweight: 50 K
IU–75 K IU/kg per day in
three divided doses, =
4–6 mg/kg per day
colistimethatesodium
2.5–5mg/kg per day colistinbase
activity in two to four doses, =
about 6.67–13.3 mg/kg per day
colistimethatesodium

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Dose
240 to 720 mg per day (3 to 9 million IU/day)
In 2 –4 divided doses
CMS
Inactive prodrug
ColistinSulphate
Active drug
International Unit is defined as minimal concthat inhibits growth of
E.coli95 ISM in 1 ml broth at pH 7.2
12 500 IU = 1 mg of CMS
2.67 mg of CMS = 1 mg colistinbase activity
2 M IU of CMS = 160 mg of drug = 60 mg colistinbase activity

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Fell into disrepute in early 1970s
Ryan KJ et al.
Colistimethatetoxicity: report of a fatal case in a previously
healthy child. JAMA 1969; 207 : 2099 -101
Brown JM et al.
Acute renal failure due to overdosageof colistin. Med J Aust
1970; 2: 923 –4
Koch Weser J et al.
Adverse effects of sodium colistimethate: manifestations and
specific reaction rates during 317 courses of therapy.
Ann Intern Med 1970; 72: 857 –68.

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Aminoglycosides, FQs & Penemsbecame the
antibiotic work horse in 1970s -2000
Gentamicin Ciprofloxacin
Meropenem
Amikacin

10. 10
Emergence of MDR, XDR & PDR
Gram Negative Bacterial Infections
Data courtesy Dr ChandWattal

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Bad bugs, no drugs: No ESKAPE
CID 2009; 48: 1 -12
E
S
K
A
P
E
nterococcusfaecium
taphylococcusaureus
lebseillapneumoniae
cinetobacterbaumanii
seudomonasaeruginosa
nterobacterspecies
Clostridium difficile&E. coli

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We have a basicproblem
We must make the best use of what we have

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In vitro susceptibility of MDR bacteria
Ana Gales et al: JCM 2001; 39 (1): 183 -190
Organisms (number) MIC50
(ug/ml)
MIC90
(ug/ml)
% Susceptible
<2 ug/ml
Burkholderiacepacia(12) >128 >128 0
Stenotrophomonasmaltophilia(23)<1 32 73.9
Morganellamorganii(2) 64 >128 0
Proteus mirabilis (2) 64 >128 0
Acinetobacterbaumannii(60) <1 2 96.7
Pseudomonas aeruginosa(80) <1 <1 100
Klebseillapneumoniae(9) <1 <1 100
Enterobacterspp. (5) <1 2 100
Tested MDR bacteria against: 12 antibiotics: PolymyxinB, Colistin,
Ceftazidime, Cefepime, Imipenem, Meropenem, Ciprofloxacin, Levofloxacin,
Amikacin, Tobramycin, Doxycycline, TMP-SMX
Colistin

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Anti EndotoxinActivity
Infection Immun1996; 64: 4922 -7

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Colistin: Revival of Polymyxinsfor the management of
MDR GNB Infections
Falagas& KasiakouCID 2005; 40: 1333 -41
Treatment of infections caused by MDR
Acinetobacterbaumannii
Pseudomonas aeruginosa
Klebsiellapneumoniae
Cystic Fibrosis
VAP
Nosocomialpneumonia
Bacteriemia
UTI
Meningitis

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Use of Colistinas salvage therapy
Colistinactive against P. aeruginosa,
Acinetobacterspp& Klebseillaspp.
Can be used for Pneumonia, Bacteremiaor UTI
caused by these infections
Acceptable toxicity & effectiveness

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Nephrotoxicity
CMS at 160 mg x 3 has satisfactory safety
CMS maybe safer than aminoglycosides
CMS + AG have increased renal toxicity
RIFLE (Risk, injury, failure,loss,endstage)
66 pt, 45% met criteria for nephrotoxicity
21% stopped CMS, reversible,
toxicity 3.7 x > if dosed for more than 14 days

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Neurotoxicity
Parasthesia, visual alteration, ataxia,
neuromuscular blockade
Reversible on stopping CMS
Cases are mild & infrequent (0 –7%)

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Spectrum of activity
Ps aeruginosa
Acinetobacterspp
Klebsiellaspp
Eschcoli
Enterobacterspp
Salmonella spp
Shigellaspp
Haemophilusinfluenzae
Bordetellapertusis
Anaerobic GNB
Susceptible Resistant
Gram Positive : All
Gram Negative Cocci
Neisseriagonorrhoeae
N. meningitidis
Gram Negative Bacilli
Proteus group
Serratiaspp
Burkholderiaspp
Brucellaspp.

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Variable activity
Stenotrophomonasmaltophilia
Aeromonasspp
Vibriospp.

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ColistinSusceptibility
Break Points
OrganizationBacteria MIC
S I R
Disk Diffusion
S I R
CLSI Acinetobacterspp <2 >4 No Break Points
Pseudomonas
aeruginosa
<2 4 >8 <10 >11
Enterobacteriaceae No Break Points
No Break Points
EUCAST Acinetobacterspp <2 >4
Pseudomonas
aeruginosa
<2 >4
Enterobacteriaceae*
Only
E.coli, Klebsiellaspp
& Enterobacterspp.
<2 >4

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PK PD correlation
Concentration dependent killing

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Excretion of Colistin

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Recent Recommendations for Dose Calculation
Anti Agents Chemother2011: 55: 3284 -3294
Loading dose: 6 M IU
desired target conc. X 2 X body wt
= 300 mg CBA ( 1 mg CBA = 12 500 IU)
Maintenance dose:
desired target conc. X (1.5 X Cr Cl+ 30) mg CBA
Useful to add Melatonin or VitC as nephroprotectants
Not likely to attain AUC/MIC values likely to be
effective for MIC >0.5;
Donotuse as monotherapy

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Mechanism of action
1.Polymyxinhave strong positive charge & a hydrophobic aryl chain
2.Initial target is LPS component of Outer membrane
3.Displaces divalent cations: Ca & Mg
4.Causes disruption of cell membrane
5.Increased permeability & leakage of cell contents & subsequent cell
death
6.Polymyxinbinds to Lipid A
portion of LPS exhibit anti
endotoxinactivity

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Routes of administration of colistin
ColistinMethane Sulphonate(CMS)
IV
(IM)
Inhalation
Intrathecal
Intraventricular
ColistinSulphate
Local application
Oral (for Gut decontamination)

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Colistinby aerosolisedroute
NaesensR et al. BMS Infect Dis2011; 11: 317
20 ICU pts with Ps aeruginosapneumonia
6 received colistinby inhalation only
5 only by IV; 9 combined
All received concomitentβlactam
Clinical response & no deaths in 6/6
3/9 of combined & 5/5 of IV group died
Dose: 2 M IU/by aerosoleTID

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Clinical use of colistinin children
FalagasME et al: IntJ Anti Agents 2009; 33: 503 e1 -13
326 children for treatment & 44 for prophylaxis
271 of 311 children were available for evaluation
235 (86.7%) cured; 10 (3.7%) improved
6 (2.2%) deteriorated; 20 (7.4%) died
No infection in 44 children who received prophylaxis
Nephrotoxicityin 10 children
Systemic Colistinis an effective & acceptable option for
MDR infections
Dose: 25 k IU/kg TID

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Mechanism of resistance
Hetroresistance: Presence of colistinresistant
subpopulation within a microbial population
that is susceptible based on MIC.
1.LPS change or loss
2.Efflux pump/potassium system
3.Colistinaseis produced by B. polymyxathat
produces colistin, but has not yet been
detected in clinical isolates

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Mechanism of resistance
MoffattJH et al: ColistinResistance in AcinetobacterbaumanniiIs Mediated by Complete Loss of
LipopolysaccharideProduction . AAC 2010; 54: 4971 -7
LPS

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Efflux Pump mediated Resistance to Colistin

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Phenotype of resistance by two compartment system
Regulatory
System
Gene
Contributing
Factors
Mechanism or
Site of Action
Effect
PmrA-PmrB PmrE
PmrHFIJKLM
PhoP-PhoQ
activation
Mildly acidic pH
High iron
concentrations
Low magnesium
concentrations
Reduces negative
charge of the
bacteria's lipid A
and LPS
Reduced binding
affinity
PhoP-PhoQ OprH Exogenous
polyamines
Low magnesium
concentrations
OprHproteins
occupy
membrane
magnesium sites
reduce the
binding site for
colistin

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Resistance in Clinical isolates: Acinetobacterbaumannii
Location Findings
Australia 93.8% of 16 clinical isolates were heteroresistantto colistin.
Spain 19.1% of 115 clinical isolates were resistant to colistin.
Korea 27.9% of 214 isolates were resistant to colistin, with most of these
resistant strains susceptible to conventional antibiotics.
Western Pacific3.3% of 30 isolates were resistant to colistin, 23% of the 30 isolates
were colistinheteroresistant.
United StatesVentilator-associated pneumonia in a 55-year-old woman was
initially susceptible to colistin(MIC 0.5 mg/L); after i.v. therapy,
high-level colistinresistance developed (MIC > 1024 mg/L)
Argentina 46.4% of 28 isolates from 28 different patients in an ICU showed
colistinheteroresistance. A 22-year-old man initially susceptible to
colistindeveloped resistance (MIC 32 mg/L) after receiving
intrathecalcolistinfor 48 hrs.

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Resistance in Clinical isolates : Pseudomonas aeruginosa
Place Findings
Australia 47.8% of 23 clinical isolates from patients with cystic
fibrosis were resistant to colistin.
Germany 34.9% of nonmucoidand 51.9% of mucoidstrains were
susceptible to colistinamong 385 isolates obtained
from patients with cystic fibrosis.
United
Kingdom
Colistin-resistant isolates were obtained from 6
children with cystic fibrosis over a 5-yr period; the
children had previously received aerosolized colistinfor
a mean duration of 3.1 yrs.

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Resistance in Clinical isolates : Klebsiellapneumoniae
Location Findings
Greece 18 colistin-resistant isolates were identified in a
tertiary hospital over a 16-mo period.
Australia 27.27% of 22 isolates were colistinresistant;
colistinheteroresistancewas seen in 93.8% of the
16 colistin-susceptible isolates
South Korea 6.8% of 221 isolates were colistinresistant

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Combination: FIC evaluation
Synergy Additive Antagonism
Doripenem 9/12 3/12 0
Amikacin 7/11 4/11 0
Teicoplanin10/11 1/11 0
Cwfwpime 9/12 3/12 0
Rifampicin9/12 3/12 0

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Combination by Kill Kinetics & Population analysis
Ps aeruginosa: Imipenemor Rifampicin
Acinetobacterspp.: Doripenemor Cefepime
Klebpneumoniae: Meropenemor Amikacin
Sulbactamwas not tested.

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Colistin+ Teichoplaninagainst Acinetobacter

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Synergistic activity of sulbactamcombined with colistin
against colistin-resistant Acinetobacterbaumannii

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ZhaiB et al. JAC 2010; 65: 931 -938

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Take home messages
1.Colistinhas emerged as effective treatment for carbapenem
resistant Gram Negative infections
2.Colistinis associated with lower mortality than no effective
treatment in these infections.
3.Colistinis associated with higher mortality than beta lactam
antibiotics in sensitive bacterial infections.
4.Nephrotoxicityrates are not higher with colistin, colistin
induced nephrotoxicityis reversible
5.Emergence of colistinresistance has been described in high
use settings
6.Synergy with carbapenem, rifampicin& sulbactamhas been
reported

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