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Polymyxins RevistedNew indications for old antibiotics Dr Ashok Rattan,Chairman: Laboratory Medicine

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Polymyxins Polypeptide antibiotics first isolated from Bacillus polymyxa5 chemically different compounds (Polymyxin A E)Polymyxin B Polymyxin E (Colistin)Polymyxin A, C and D too toxic for human use

#ColistinCationic cyclic deca peptideLinked to a fatty acid chainThrough an amide linkageAmino acid are: D leucine, L threonine, L diamino butyric acidFatty 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

#Formulations:Colistin sulphateOral, Tropical, inhalation useActive 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 7.21 million IU = 80 mg of CMSColistimethate sodium (CMS)Parental, inhalation useInactive prodrug, less toxic, hydrolysed in aqueous solution to active colistinTwo formulations:colomycin: 500 k, 1 M, 2 M international unitsColy mycin: 150 mg colistin active base/vial = 360 mg of CMS

#Available formulationsColomycin injectionColy-Mycin M ParenteralManufacturerDumex-Alpharma A/S,Copenhagen, DenmarkParkedale Pharmaceuticals, Rochester, MN, USALabelled content per vial500 000, 1 000 000 or 2 000 000 IU; about 12 500 units/mg150 mg colistin base activityMass of colistimethatesodium dry powder per vial40 mg, 80 mg, or 160 mgAbout 400 mgAppearanceCreamy-white powderWhite to slightly yellow lyophilised cakeRecommended dose*60 kg bodyweight: 50 K IU 75 K IU/kg per day in three divided doses, =46 mg/kg per day colistimethate sodium2.5 5mg/kg per day colistin base activity in two to four doses, = about 6.6713.3 mg/kg per daycolistimethate sodium

#Dose240 to 720 mg per day (3 to 9 million IU/day)In 2 4 divided dosesCMSInactive prodrug

Colistin SulphateActive drugInternational 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

#Fell into disrepute in early 1970sRyan KJ et al. Colistimethate toxicity: report of a fatal case in a previously healthy child. JAMA 1969; 207 : 2099 - 101Brown JM et al. Acute renal failure due to overdosage of colistin. Med J Aust 1970; 2: 923 4Koch 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.

#Aminoglycosides, FQs & Penems became the antibiotic work horse in 1970s - 2000

Gentamicin

CiprofloxacinMeropenem

Amikacin

#Emergence of MDR, XDR & PDR Gram Negative Bacterial Infections

Data courtesy Dr Chand Wattal

#Bad bugs, no drugs: No ESKAPECID 2009; 48: 1 - 12E SKAPEnterococcus faeciumtaphylococcus aureuslebseilla pneumoniaecinetobacter baumaniiseudomonas aeruginosanterobacter species

Clostridium difficile & E. coli

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We have a basic problem

Resistance in important pathogens

New and novel antibiotics We must make the best use of what we have

#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/mlBurkholderia cepacia (12)> 128> 1280Stenotrophomonas maltophilia (23)< 13273.9Morganella morganii (2)64> 1280Proteus mirabilis (2)64> 1280Acinetobacter baumannii (60)< 1296.7Pseudomonas aeruginosa (80)< 1< 1100Klebseilla pneumoniae (9)< 1< 1100Enterobacter spp. (5)< 12100

Tested MDR bacteria against: 12 antibiotics: Polymyxin B, Colistin, Ceftazidime, Cefepime, Imipenem, Meropenem, Ciprofloxacin, Levofloxacin, Amikacin, Tobramycin, Doxycycline, TMP-SMXColistin

#Anti Endotoxin ActivityInfection Immun 1996; 64: 4922 - 7

#Colistin: Revival of Polymyxins for the management of MDR GNB InfectionsFalagas & Kasiakou CID 2005; 40: 1333 - 41Treatment of infections caused by MDRAcinetobacter baumanniiPseudomonas aeruginosa Klebsiella pneumoniaeCystic FibrosisVAPNosocomial pneumoniaBacteriemiaUTIMeningitis

#Use of Colistin as salvage therapyColistin active against P. aeruginosa , Acinetobacter spp & Klebseilla spp.Can be used for Pneumonia, Bacteremia or UTI caused by these infectionsAcceptable toxicity & effectiveness

#NephrotoxicityCMS at 160 mg x 3 has satisfactory safetyCMS maybe safer than aminoglycosidesCMS + AG have increased renal toxicityRIFLE (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

#NeurotoxicityParasthesia, visual alteration, ataxia, neuromuscular blockadeReversible on stopping CMSCases are mild & infrequent (0 7%)

#Spectrum of activityPs aeruginosaAcinetobacter sppKlebsiella sppEsch coliEnterobacter sppSalmonella sppShigella sppHaemophilus influenzaeBordetella pertusisAnaerobic GNBSusceptibleResistant Gram Positive : All Gram Negative CocciNeisseria gonorrhoeaeN. meningitidis Gram Negative BacilliProteus groupSerratia sppBurkholderia sppBrucella spp.

#Variable activityStenotrophomonas maltophiliaAeromonas sppVibrio spp.

#Colistin Susceptibility Break PointsOrganizationBacteriaMICS I RDisk DiffusionS I RCLSIAcinetobacter spp< 2> 4No Break PointsPseudomonas aeruginosa< 24> 8< 10> 11EnterobacteriaceaeNo Break PointsNo Break PointsEUCASTAcinetobacter spp< 2> 4Pseudomonas aeruginosa< 2> 4Enterobacteriaceae* Only E.coli, Klebsiella spp & Enterobacter spp.< 2> 4

#PK PD correlationConcentration dependent killing

#Excretion of Colistin

#Recent Recommendations for Dose CalculationAnti Agents Chemother 2011: 55: 3284 - 3294Loading dose: 6 M IUdesired 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 CBAUseful to add Melatonin or Vit C as nephroprotectantsNot likely to attain AUC/MIC values likely to be effective for MIC >0.5; Donot use as monotherapy

#Mechanism of actionPolymyxin have strong positive charge & a hydrophobic aryl chainInitial target is LPS component of Outer membraneDisplaces divalent cations: Ca & MgCauses disruption of cell membraneIncreased permeability & leakage of cell contents & subsequent cell deathPolymyxin binds to Lipid A portion of LPS exhibit anti endotoxin activity

#Routes of administration of colistinColistin Methane Sulphonate (CMS)IV(IM)InhalationIntrathecalIntraventricularColistin SulphateLocal applicationOral (for Gut decontamination)

#Colistin by aerosolised routeNaesens R et al. BMS Infect Dis 2011; 11: 31720 ICU pts with Ps aeruginosa pneumonia6 received colistin by inhalation only 5 only by IV; 9 combinedAll received concomitent lactamClinical response & no deaths in 6/63/9 of combined & 5/5 of IV group diedDose: 2 M IU/by aerosole TID

#Clinical use of colistin in childrenFalagas ME et al: Int J Anti Agents 2009; 33: 503 e1 - 13326 children for treatment & 44 for prophylaxis271 of 311 children were available for evaluation235 (86.7%) cured; 10 (3.7%) improved6 (2.2%) deteriorated; 20 (7.4%) diedNo infection in 44 children who received prophylaxisNephrotoxicity in 10 childrenSystemic Colistin is an effective & acceptable option for MDR infectionsDose: 25 k IU/kg TID

#Mechanism of resistanceHetroresistance: Presence of colistin resistant subpopulation within a microbial population that is susceptible based on MIC.LPS change or lossEfflux pump/potassium systemColistinase is produced by B. polymyxa that produces colistin, but has not yet been detected in clinical isolates

#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

#Efflux Pump mediated Resistance to Colistin

#Phenotype of resistance by two compartment systemRegulatory SystemGeneContributing FactorsMechanism or Site of ActionEffectPmrA-PmrBPmrE PmrHFIJKLM PhoP-PhoQ activationMildly acidic pHHigh iron concentrationsLow magnesium concentrationsReduces negative charge of the bacteria's lipid A and LPSReduced binding affinity

PhoP-PhoQOprHExogenous polyaminesLow magnesium concentrationsOprH proteins occupy membrane magnesium sites reduce the binding site for colistin

#Resistance in Clinical isolates: Acinetobacter baumannii

LocationFindings Australia93.8% of 16 clinical isolates were heteroresistant to colistin. Spain19.1% of 115 clinical isolates were resistant to colistin. Korea27.9% 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 colistin heteroresistant. 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 colistin resistance developed (MIC > 1024 mg/L) Argentina46.4% 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.

#Resistance in Clinical isolates : Pseudomonas aeruginosa PlaceFindingsAustralia47.8% of 23 clinical isolates from patients with cystic fibrosis were resistant to colistin.

Germany34.9% 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.

#Resistance in Clinical isolates : Klebsiella pneumoniaeLocationFindingsGreece18 colistin-resistant isolates were identified in a tertiary hospital over a 16-mo period.Australia27.27% of 22 isolates were colistin resistant; colistin heteroresistance was seen in 93.8% of the 16 colistin-susceptible isolatesSouth Korea 6.8% of 221 isolates were colistin resistant

#Combination: FIC evaluationSynergyAdditiveAntagonismDoripenem9/123/120Amikacin7/114/110Teicoplanin10/111/110Cwfwpime9/123/120Rifampicin9/123/120

#Combination by Kill Kinetics & Population analysisPs aeruginosa: Imipenem or RifampicinAcinetobacter spp.: Doripenem or CefepimeKleb pneumoniae: Meropenem or Amikacin

Sulbactam was not tested.

#Colistin + Teichoplanin against Acinetobacter

#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

#Take home messagesColistin has emerged as effective treatment for carbapenem resistant Gram Negative infectionsColistin is associated with lower mortality than no effective treatment in these infections.Colistin is associated with higher mortality than beta lactam antibiotics in sensitive bacterial infections.Nephrotoxicity rates are not higher with colistin, colistin induced nephrotoxicity is reversibleEmergence of colistin resistance has been described in high use settingsSynergy with carbapenem, rifampicin & sulbactam has been reported

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Thank you for your attention

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