Polymyxin olymyxin Use Use in in Clinical linical Practice ractice in Asia in Asia Visanu Thamlikitku Visanu Thamlikitkul, MD l, MD iii f f i i & i l di i iii f f i i & i l di i Division of Infectious Diseases & Tropical Medicine Division of Infectious Diseases & Tropical Medicine Faculty of Medicine Siriraj Hospital, Faculty of Medicine Siriraj Hospital, hid l i i kk h il d hid l i i kk h il d Mahidol University, Bangkok, Thailand Mahidol University, Bangkok, Thailand Not to be copied and distributed to others without the permission of the author
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PPolymyxin olymyxin UseUse in in CClinical linical PPractice ractice in Asiain Asia
Visanu ThamlikitkuVisanu Thamlikitkul, MDl, MD i i i f f i i & i l di i i i i f f i i & i l di i Division of Infectious Diseases & Tropical Medicine Division of Infectious Diseases & Tropical Medicine
Faculty of Medicine Siriraj Hospital, Faculty of Medicine Siriraj Hospital, hid l i i k k h il dhid l i i k k h il dMahidol University, Bangkok, ThailandMahidol University, Bangkok, ThailandNot
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(Am J Respir Crit Care Med (Am J Respir Crit Care Med 20112011;;184184::14091409))(Am J Respir Crit Care Med (Am J Respir Crit Care Med 20112011;;184184::14091409))
•• ANSORP = ANSORP = AAsian sian NNetwork for etwork for SSurveillance urveillance oof f RResistant esistant PP ththPPathogensathogens•• Multinational study of nosocomial pneumonia in Multinational study of nosocomial pneumonia in 22 554 554 adults in adults in 10 10 Asian countries (Asian countries (73 73 centers)centers) 2008 2008 2009200922,,554 554 adults in adults in 10 10 Asian countries (Asian countries (73 73 centers)centers), , 2008 2008 –– 20092009•• Overall Distribution of Common Bacterial Isolates Overall Distribution of Common Bacterial Isolates AcinetobacterAcinetobacter spp spp 2323%% 4343%% AcinetobacterAcinetobacter spp. spp. 2323%% P. aeruginosa P. aeruginosa 2020%% S. aureusS. aureus 1414%%
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K. pneumoniaeK. pneumoniae 1414%%Not to
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Distribution of Bacteria in NP in Asian CountriesDistribution of Bacteria in NP in Asian Countries
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* *Am J Respir Crit Care Med Am J Respir Crit Care Med 20112011;;184184::14091409
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Burden of XDR NonBurden of XDR Non--fermenter Infections in Asiafermenter Infections in AsiaANSORP St d N i l P iANSORP St d N i l P iANSORP Study on Nosocomial PneumoniaANSORP Study on Nosocomial Pneumonia•• CarbapenemCarbapenem--resistanceresistance AcinetobacterAcinetobacter spp. spp. 6767% (% (2222% to % to 8787%)%) P. aeruginosa P. aeruginosa 3030% (% (1010% to % to 5757%)%)gg % (% ( %% %)%) K. pneumoniaeK. pneumoniae 22% (% (00% to % to 44%)%)•• C li tiC li ti i t t i t t A i t b tA i t b t •• ColistinColistin--resistant resistant AcinetobacterAcinetobacter spp. spp. 8 8 Asian countriesAsian countries nonenone Taiwan Taiwan 99..55%% China China 11..44%%%%
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Burden of XDR NonBurden of XDR Non--fermenter Infections in Asiafermenter Infections in AsiaANSORP St d N i l P iANSORP St d N i l P iANSORP Study on Nosocomial PneumoniaANSORP Study on Nosocomial Pneumonia•• Colistin was used for empiric treatment in Colistin was used for empiric treatment in 33% to % to 1414%%•• Initial empiric antibiotics were discordant in Initial empiric antibiotics were discordant in 4040%%•• MortalityMortality AllAll--cause Pneumoniacause Pneumonia--related related yy AcinetobacterAcinetobacter spp. spp. 4949% % 3535%% K iK i 3838% % 2323%% K. pneumoniaeK. pneumoniae 3838% % 2323%% P. aeruginosaP. aeruginosa 3131% % 2222%%•• Mortality of patients receiving discordant empiric Mortality of patients receiving discordant empiric antibiotic treatment was higher than those receiving antibiotic treatment was higher than those receiving g gg gconcordant treatment (concordant treatment (3232%%--4444% vs. % vs. 2121%%--3535%; p=%; p=00..002002) )
Polymyxins are really needed in Asian Countries !Polymyxins are really needed in Asian Countries !Not to
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Polymyxin Availability among ANSORP MembersPolymyxin Availability among ANSORP MembersCountryCountry ColistinColistin Polymyxin BPolymyxin BCountryCountry ColistinColistin Polymyxin BPolymyxin B•• Singapore Singapore Yes YesYes Yes•• Malaysia Malaysia Yes YesYes YesMalaysia Malaysia Yes YesYes Yes•• Thailand Thailand YesYes No No •• Korea Korea YesYes NoNo•• VietnamVietnam YesYes NoNo•• TaiwanTaiwan YesYes NoNo•• Hong Kong Hong Kong YesYes NoNo•• IndonesiaIndonesia YesYes NoNo
I diI di Y NY N•• IndiaIndia Yes NoYes No•• PhilippinesPhilippines Yes*Yes* NoNo•• Sri LankaSri Lanka No NoNo No•• Sri LankaSri Lanka No NoNo No•• China China No NoNo No•• Japan Japan No NoNo No•• Japan Japan No NoNo No
**compassionate use in several private hospitals & tertiary care centerscompassionate use in several private hospitals & tertiary care centers
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Polymyxin Use in ThailandPolymyxin Use in Thailand•• Mortality of XDR nonMortality of XDR non fermenter infections treated with fermenter infections treated with •• Mortality of XDR nonMortality of XDR non--fermenter infections treated with fermenter infections treated with nonnon--susceptible antibiotics was susceptible antibiotics was 8080% prior to availability % prior to availability
f C li if C li iof Colistinof Colistin•• In vitro activity of Colistin against XDR nonIn vitro activity of Colistin against XDR non--fermenters fermenters isolated from hospitalized patients at Siriraj Hospital in isolated from hospitalized patients at Siriraj Hospital in 2003 2003 was was 100100%%•• Colistin has been available since Colistin has been available since 20042004
**Cockcroft & Gaulf equationCockcroft & Gaulf equationE i i ThE i i Th 3030%%•• Empiric TherapyEmpiric Therapy 3030%%
•• Combination TherapyCombination Therapy 7070%%M di D ti C li ti M di D ti C li ti 10 10 dd•• Median Duration Colistin Median Duration Colistin 10 10 daysdaysNot
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Polymyxin Use in ThailandPolymyxin Use in Thailand• Mortality of XDR nonMortality of XDR non fermenter infections treated with fermenter infections treated with • Mortality of XDR nonMortality of XDR non--fermenter infections treated with fermenter infections treated with Colistin in Thailand is still Colistin in Thailand is still 4040% to % to 5050% (decrease from % (decrease from 8080%)%)8080%)%)•• Contributing factors for a modest response to ColistinContributing factors for a modest response to Colistin Severe underlying diseasesSevere underlying diseases Severe & serious infectionsSevere & serious infections Delay Colistin initiationDelay Colistin initiation Inappropriate Colistin dosing*Inappropriate Colistin dosing*Inappropriate Colistin dosingInappropriate Colistin dosing OthersOthers
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Polymyxin Use in ThailandPolymyxin Use in Thailand•• PK study in PK study in 103 103 Thai patients of project “Thai patients of project “Optimizing Optimizing •• PK study in PK study in 103 103 Thai patients of project Thai patients of project Optimizing Optimizing dosing of colistin for infections resistant to all other dosing of colistin for infections resistant to all other antibiotics” (NIAID/NIH Rantibiotics” (NIAID/NIH R0101--AIAI7089670896--0101) ) ( /( / ))MaleMale 5959%%Mean AgeMean Age 66 66 y y Mean AgeMean Age 66 66 y y Mean APACHE II ScoreMean APACHE II Score 2222 Pneumonia due to XDR nonPneumonia due to XDR non fermentersfermenters 9191%% Pneumonia due to XDR nonPneumonia due to XDR non--fermentersfermenters 9191%% Colistin Susceptible (MICColistin Susceptible (MIC<< 2 2 mg/l) mg/l) 9696%%
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CMS & Colistin Levels at Steady State in CMS & Colistin Levels at Steady State in 103 103 Thai patientsThai patientsPolymyxin Use in ThailandPolymyxin Use in Thailand
CMS & Colistin Levels at Steady State in CMS & Colistin Levels at Steady State in 103 103 Thai patientsThai patients
CMS (mg/L)CMS (mg/L) Formed Formed ColistinColistin (mg/L)(mg/L)
averageaverageaverageaverage
averageaverage
hours on PK sampling day (d hours on PK sampling day (d 3 3 –– 4 4 of CMS Rx)of CMS Rx)Not to
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Polymyxin Use in ThailandPolymyxin Use in Thailand•• PK study in PK study in 103 103 Thai patients Thai patients •• PK study in PK study in 103 103 Thai patients Thai patients •• Colistin dosing regimens were computed from PK dataColistin dosing regimens were computed from PK data Colistin MIC Distribution XDR nonColistin MIC Distribution XDR non--fermenters from fermenters from 103 103 Thai Patients : MICThai Patients : MIC5050 = = 00..55, MIC, MIC9090 = = 115050 9090
PK/PD Targets : Cmax ~ PK/PD Targets : Cmax ~ 22..5 5 and AUC/MIC ~ and AUC/MIC ~ 5050
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Suggested Colistin Dosing Regimens since March Suggested Colistin Dosing Regimens since March 20112011
> > 50 50 300300 150 150 q q 12 12 h or h or 100 100 q q 8 8 h h qq qq41 41 –– 50 50 300 300 150 150 q q 12 12 h or h or 7575--100 100 q q 8 8 hh31 31 –– 4040 300 75 300 75 -- 100 100 q q 12 12 hh31 31 4040 300 75 300 75 100 100 q q 12 12 hh21 21 –– 3030 300 300 75 75 q q 12 12 h or h or 150 150 q q 24 24 hh11 11 20 20 300 300 100 100 q q 24 24 hh11 11 –– 20 20 300 300 100 100 q q 24 24 hh
<< 1010 150 150 75 75 q q 24 24 hh**C k ft & G lf tiC k ft & G lf ti**Cockcroft & Gaulf equationCockcroft & Gaulf equation
Acute RRTAcute RRT 150 150 100 100 q q 24 24 hhqq
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Polymyxin Use in ThailandPolymyxin Use in ThailandEffectiveness of Suggested Dosing RegimensEffectiveness of Suggested Dosing RegimensEffectiveness of Suggested Dosing RegimensEffectiveness of Suggested Dosing Regimens
CFR C l ti F ti f RCFR C l ti F ti f RCFR = Cumulative Fraction of ResponseCFR = Cumulative Fraction of ResponseDD1 1 = Day = Day 11 SS = Steady StateSS = Steady StateSD = Suggested DosingSD = Suggested Dosing AD = Actual DosingAD = Actual DosingSD Suggested DosingSD Suggested Dosing AD Actual DosingAD Actual DosingMD = Manufacture Dosing GD = Sanford Guide DosingMD = Manufacture Dosing GD = Sanford Guide DosingNot
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Polymyxin Use in ThailandPolymyxin Use in ThailandEffectiveness of Suggested Dosing RegimensEffectiveness of Suggested Dosing RegimensEffectiveness of Suggested Dosing RegimensEffectiveness of Suggested Dosing Regimens
3% 48% 38% 4%8%8686%%3% 48% 38% 4%8%8686%%
CFR C l ti F ti f RCFR C l ti F ti f RCFR = Cumulative Fraction of ResponseCFR = Cumulative Fraction of ResponseDD1 1 = Day = Day 11 SS = Steady StateSS = Steady StateSD = Suggested DosingSD = Suggested Dosing AD = Actual DosingAD = Actual DosingSD Suggested DosingSD Suggested Dosing AD Actual DosingAD Actual DosingMD = Manufacture Dosing GD = Sanford Guide DosingMD = Manufacture Dosing GD = Sanford Guide DosingNot
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Polymyxin Use in ThailandPolymyxin Use in ThailandAdverse Effects of ColistinAdverse Effects of ColistinAdverse Effects of ColistinAdverse Effects of Colistin•• Nephrotoxicity (RIFLE Classification)Nephrotoxicity (RIFLE Classification) I idI id 5050% % IncidenceIncidence ~ ~ 5050% % RRisk isk ~ ~ 3232%% IInjury njury ~ ~ 3232%% IInjury njury ~ ~ 3232%% FFailure ailure ~ ~ 3535%% 22%% required temporary renal replacement therapyrequired temporary renal replacement therapy 22%% required temporary renal replacement therapyrequired temporary renal replacement therapyMajor Major RRisk factors isk factors (J Infect (J Infect 20112011;;6262::187187--9090))
C li i d & d iC li i d & d i Colistin dose & durationColistin dose & duration Concomitant use of VancomycinConcomitant use of Vancomycin•• NeurotoxicityNeurotoxicityMild and reversible paresthesia in up to Mild and reversible paresthesia in up to 1111%%p pp p
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Polymyxin Use in ThailandPolymyxin Use in ThailandSusceptibility Testing Methods (Broth microdilution Etest Susceptibility Testing Methods (Broth microdilution Etest Susceptibility Testing Methods (Broth microdilution, Etest, Susceptibility Testing Methods (Broth microdilution, Etest, Disk & VITEKDisk & VITEK22) for Colistin against ) for Colistin against 290 290 A. baumannii A. baumannii strainsstrains
[ MIC : S ≤[ MIC : S ≤2 2 & R ≥& R ≥4 4 mg/L] [ Disk : S ≥mg/L] [ Disk : S ≥11 11 and R ≤and R ≤10 10 mm]mm][[ g/ ] [g/ ] [ ]]
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Polymyxin Use in ThailandPolymyxin Use in ThailandMIC MIC (B(Broth roth MMicrodilutionicrodilution) vs Inhibition Z) vs Inhibition Zone one DDiameter iameter MIC MIC (B(Broth roth MMicrodilutionicrodilution) vs. Inhibition Z) vs. Inhibition Zone one DDiameter iameter
44..44% of isolates with % of isolates with
Colist
Colist
zone diameter >zone diameter >11 11 mm mm had MIC >had MIC >2 2 mg/lmg/l
tin MI
tin MI 100100%%IC
(mg/
IC (m
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00%% 9696%%
Inhibition Zone Diameter (mm)Inhibition Zone Diameter (mm)Not to
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PPolymyxin olymyxin UseUse in in CClinical linical PPractice ractice in Asiain Asia
Visanu ThamlikitkuVisanu Thamlikitkul, MDl, MD i i i f f i i & i l di i i i i f f i i & i l di i Division of Infectious Diseases & Tropical Medicine Division of Infectious Diseases & Tropical Medicine
Faculty of Medicine Siriraj Hospital, Faculty of Medicine Siriraj Hospital, hid l i i k k h il dhid l i i k k h il dMahidol University, Bangkok, ThailandMahidol University, Bangkok, ThailandNot
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