Polymyxins revisited
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Transcript of Polymyxins revisited
Polymyxins RevistedNew indications for old antibiotics
Dr Ashok Rattan,
Chairman: Laboratory Medicine
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Polymyxins
Polypeptide antibiotics first isolated from Bacillus polymyxa
5 chemically different compounds
(Polymyxin A – E)
Polymyxin B
Polymyxin E (Colistin)
Polymyxin A, C and D too toxic for human use
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Colistin
Cationic cyclic deca peptide
Linked to a fatty acid chain
Through an α amide linkage
Amino acid are:
D leucine,
L threonine,
L α γ diamino butyric acid
Fatty acid could be
6 methyl octon oic acid (colistin A)
6 methyl eptanoic acid (colistin B)
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Polymyxin E (Colistin)
Colistin Methane Sulphonate, pentasodium colistimethanesulphate, colistin sulfonyl methate, CMS
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Formulations:
Colistin sulphate
Oral, Tropical, inhalation use
Active drug, not absorbed orally
International Unit is defined as minimal conc that inhibits growth of E.coli 95 ISM in 1 ml broth at pH 7.2
1 million IU = 80 mg of CMS
Colistimethate sodium (CMS)
Parental, inhalation use
Inactive prodrug, less toxic, hydrolysed in aqueous solution to active colistin
Two formulations:
A. colomycin: 500 k, 1 M, 2 M international units
B. Coly mycin: 150 mg colistin active base/vial = 360 mg of CMS
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Available formulationsColomycin injection Coly-Mycin M Parenteral
Manufacturer Dumex-Alpharma A/S,Copenhagen, Denmark
Parkedale Pharmaceuticals, Rochester, MN, USA
Labelled content per vial 500 000, 1 000 000 or 2 000 000 IU; about 12 500 units/mg
150 mg colistin base activity
Mass of colistimethatesodium dry powder per vial
40 mg, 80 mg, or 160 mg About 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 colistimethate sodium
2.5– 5mg/kg per day colistin base activity in two to four doses, = about 6.67–13.3 mg/kg per daycolistimethate sodium
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Dose
240 to 720 mg per day (3 to 9 million IU/day)
In 2 – 4 divided doses
CMSInactive prodrug
Colistin SulphateActive drug
International Unit is defined as minimal conc that inhibits growth of E.coli 95 ISM in 1 ml broth at pH 7.2
12 500 IU = 1 mg of CMS
2.67 mg of CMS = 1 mg colistin base activity
2 M IU of CMS = 160 mg of drug = 60 mg colistin base activity
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Fell into disrepute in early 1970s
Ryan KJ et al.
Colistimethate toxicity: report of a fatal case in a previously healthy child. JAMA 1969; 207 : 2099 - 101
Brown JM et al.
Acute renal failure due to overdosage of 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 & Penems became the antibiotic work horse in 1970s - 2000
Gentamicin Ciprofloxacin
Meropenem
Amikacin
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Emergence of MDR, XDR & PDR Gram Negative Bacterial Infections
Data courtesy Dr Chand Wattal
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Bad bugs, no drugs: No ESKAPECID 2009; 48: 1 - 12
E
S
K
A
P
E
nterococcus faecium
taphylococcus aureus
lebseilla pneumoniae
cinetobacter baumanii
seudomonas aeruginosa
nterobacter species
Clostridium difficile & E. coli
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We have a basic problem
Resistance in im
portant p
athogens
New and novel antibiotics
We must make the best use of what we have
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In vitro susceptibility of MDR bacteriaAna Gales et al: JCM 2001; 39 (1): 183 - 190
Organisms (number) MIC50 (ug/ml)
MIC90 (ug/ml)
% Susceptible < 2 ug/ml
Burkholderia cepacia (12) > 128 > 128 0
Stenotrophomonas maltophilia (23) < 1 32 73.9
Morganella morganii (2) 64 > 128 0
Proteus mirabilis (2) 64 > 128 0
Acinetobacter baumannii (60) < 1 2 96.7
Pseudomonas aeruginosa (80) < 1 < 1 100
Klebseilla pneumoniae (9) < 1 < 1 100
Enterobacter spp. (5) < 1 2 100
Tested MDR bacteria against: 12 antibiotics: Polymyxin B, Colistin, Ceftazidime, Cefepime, Imipenem, Meropenem, Ciprofloxacin, Levofloxacin, Amikacin, Tobramycin, Doxycycline, TMP-SMX
Colistin
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Anti Endotoxin ActivityInfection Immun 1996; 64: 4922 - 7
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Colistin: Revival of Polymyxins for the management of MDR GNB Infections
Falagas & Kasiakou CID 2005; 40: 1333 - 41
Treatment of infections caused by MDR
Acinetobacter baumannii
Pseudomonas aeruginosa
Klebsiella pneumoniae
Cystic Fibrosis
VAP
Nosocomial pneumonia
Bacteriemia
UTI
Meningitis
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Use of Colistin as salvage therapy
Colistin active against P. aeruginosa , Acinetobacter spp & Klebseilla spp.
Can be used for Pneumonia, Bacteremia or 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,end stage)
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
Acinetobacter spp
Klebsiella spp
Esch coli
Enterobacter spp
Salmonella spp
Shigella spp
Haemophilus influenzae
Bordetella pertusis
Anaerobic GNB
Susceptible Resistant Gram Positive : All
Gram Negative Cocci
Neisseria gonorrhoeae
N. meningitidis
Gram Negative Bacilli
Proteus group
Serratia spp
Burkholderia spp
Brucella spp.
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Variable activity
Stenotrophomonas maltophilia
Aeromonas spp
Vibrio spp.
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Colistin Susceptibility Break Points
Organization Bacteria MICS I R
Disk DiffusionS I R
CLSI Acinetobacter spp < 2 > 4 No Break Points
Pseudomonas aeruginosa
< 2 4 > 8 < 10 > 11
Enterobacteriaceae No Break Points
No Break PointsEUCAST Acinetobacter spp < 2 > 4
Pseudomonas aeruginosa
< 2 > 4
Enterobacteriaceae* Only E.coli, Klebsiella spp & Enterobacter spp.
< 2 > 4
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PK PD correlationConcentration dependent killing
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Excretion of Colistin
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Recent Recommendations for Dose CalculationAnti Agents Chemother 2011: 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 Vit C as nephroprotectants
Not likely to attain AUC/MIC values likely to be effective for MIC >0.5;
Donot use as monotherapy
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Mechanism of action
1. Polymyxin have 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. Polymyxin binds to Lipid A
portion of LPS exhibit anti
endotoxin activity
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Routes of administration of colistin
Colistin Methane Sulphonate (CMS)
IV
(IM)
Inhalation
Intrathecal
Intraventricular
Colistin Sulphate
Local application
Oral (for Gut decontamination)
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Colistin by aerosolised routeNaesens R et al. BMS Infect Dis 2011; 11: 317
20 ICU pts with Ps aeruginosa pneumonia
6 received colistin by inhalation only
5 only by IV; 9 combined
All received concomitent β lactam
Clinical response & no deaths in 6/6
3/9 of combined & 5/5 of IV group died
Dose: 2 M IU/by aerosole TID
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Clinical use of colistin in childrenFalagas ME et al: Int J 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
Nephrotoxicity in 10 children
Systemic Colistin is an effective & acceptable option for MDR infections
Dose: 25 k IU/kg TID
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Mechanism of resistance
Hetroresistance: Presence of colistin resistant subpopulation within a microbial population that is susceptible based on MIC.
1. LPS change or loss
2. Efflux pump/potassium system
3. Colistinase is produced by B. polymyxa that produces colistin, but has not yet been detected in clinical isolates
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Mechanism of resistanceMoffatt JH et al: Colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production . 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
FactorsMechanism or Site of Action Effect
PmrA-PmrB PmrE PmrHFIJKLM
PhoP-PhoQ activationMildly acidic pHHigh iron concentrationsLow magnesium concentrations
Reduces negative charge of the bacteria's lipid A and LPS
Reduced binding affinity
PhoP-PhoQ OprH Exogenous polyaminesLow magnesium concentrations
OprH proteins occupy membrane magnesium sites
reduce the binding site for colistin
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Resistance in Clinical isolates: Acinetobacter baumannii
Location Findings
Australia 93.8% of 16 clinical isolates were heteroresistant to 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 Pacific 3.3% of 30 isolates were resistant to colistin, 23% of the 30 isolates were colistin heteroresistant.
United States Ventilator-associated pneumonia in a 55-year-old woman was initially susceptible to colistin (MIC 0.5 mg/L); after i.v. therapy, high-level colistin resistance developed (MIC > 1024 mg/L)
Argentina 46.4% of 28 isolates from 28 different patients in an ICU showed colistin heteroresistance. A 22-year-old man initially susceptible to colistin developed resistance (MIC 32 mg/L) after receiving intrathecal colistin for 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 nonmucoid and 51.9% of mucoid strains were susceptible to colistin among 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 colistin for a mean duration of 3.1 yrs.
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Resistance in Clinical isolates : Klebsiella pneumoniae
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 colistin resistant; colistin heteroresistance was seen in 93.8% of the 16 colistin-susceptible isolates
South Korea 6.8% of 221 isolates were colistin resistant
Resistance in Clinical isolates
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Combination: FIC evaluationSynergy Additive Antagonism
Doripenem 9/12 3/12 0
Amikacin 7/11 4/11 0
Teicoplanin 10/11 1/11 0
Cwfwpime 9/12 3/12 0
Rifampicin 9/12 3/12 0
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Combination by Kill Kinetics & Population analysis
Ps aeruginosa: Imipenem or Rifampicin
Acinetobacter spp.: Doripenem or Cefepime
Kleb pneumoniae: Meropenem or Amikacin
Sulbactam was not tested.
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Colistin + Teichoplanin against Acinetobacter
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Synergistic activity of sulbactam combined with colistin against colistin-resistant Acinetobacter baumannii
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Zhai B et al. JAC 2010; 65: 931 - 938
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Take home messages
1. Colistin has emerged as effective treatment for carbapenem resistant Gram Negative infections
2. Colistin is associated with lower mortality than no effective treatment in these infections.
3. Colistin is associated with higher mortality than beta lactam antibiotics in sensitive bacterial infections.
4. Nephrotoxicity rates are not higher with colistin, colistin induced nephrotoxicity is reversible
5. Emergence of colistin resistance has been described in high use settings
6. Synergy with carbapenem, rifampicin & sulbactam has been reported
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