Antimicrobial Resistance

Ramanan LaxminarayanSingapore International Infectious Disease Conference 2017

Inthebeginning…

Cyanobacteriareleaseoxygenintotheatmosphereviaphotosynthesispavingthewayformorecomplexlifeforms

Dinosaursappears265millionyearsago

Dinosaurs

Hominidsarrivedafewmillionyearsago

Earliest hominids

Lifedependsonmicrobes

• Microbesoutnumberallotherspeciesandmakeupmostlivingmatter(~60%oftheearthsbiomass).

• Lessthan0.5%oftheestimated2to3billionmicrobialspecieshavebeenidentified.

• Microbesgeneratehalftheoxygenthatwebreathe

MicrobeswerealsothecauseofdeathAll causes (United States, 1900) 1548.4

11- Tuberculosis2- Pneumonia and influenza3- Heart disease4- Diarrhea, enteritis, ulcers5-Intrachrania lesions – vascular6- Nephritis7- Accidents excluding automobile8- Cancer 9- Senility10- Bronchitis

174.2161.3145.4104.9103.990.672.566.345.239.4

CDC/NCHS – National Vital Statistics Mortality vol48

ButnolongerAll causes (United States, 2000)19

864.7

1- Heart Disease2 - Malignant neoplasm's (cancer)3 - Cerebrovascular diseases4- COPD5- Accidents Automobile/Others6- Pneumonia and influenza7- Diabetes mellitus8- Suicide 9 - Nephritis10- Chronic Liver Disease

268.2200.358.641.716.1/2034.024.011.39.7CDC/NCHS – National Vital Statistics Mortality vol48

DeathRatesforCommonInfectiousDiseasesintheUnitedStates(per100,000Population) 1900 1935 1970

Influenza and Pneumonia 202.2 104 31

Tuberculosis 194.4 55 3

Gastroenteritis 142.7 14 1

Diphtheria 40.3 3 0

Typhoid fever 31.3 3 0

Measles 13.3 3 0

Dysentery 12 2 0

Whooping Cough 12 4 0

Scarlet fever (including strep throat) 9.6 2 0

Meningococcal infections 6.8 2 0

Bassett et al, Science, 1980

Alexander Fleming1881-1955

When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionise all medicine by discovering the world's first antibiotic, or bacteria killer. But I suppose that was exactly what I did.

— Alexander Fleming

Alexander Fleming1881-1955

Giuseppe Brotzu1895-1976

Cephalosporium acremonium

Mortalityratesofpatientswithbacteremicpneumococcalpneumonia

Treatment No. % mortalitySymptomatic1 356 80Penicillin1 (1940s) 333 17

1M. Finland. Clinical Pharmacology and Therapeutics 13:469-511, 1972.

I. Drugresistanceisrisingworldwideandthreatensgainsmadeinreducingtheburdenofinfectiousdiseases

D’Costa,Nature,2011

Woerther,Clin Microbiol Rev.2013

ESBLcarriageratesareincreasingovertime

36

ClonalspreadofS.pneumoniae 23F

Tennessee

Cleveland

Mexico

Colombia

Brazil

ArgentinaUruguay

Chile SouthAfrica

SingaporeMalaysia

ThailandPhilippines

HongKongTaiwan

SouthKoreaSpain

FranceBM42001978?

Finland

Slidecourtesy:KeithKlugman

Numbersofuniqueβ-lactamaseenzymesidentifiedsinceintroductionoffirstβ-lactamantibiotics

DaviesandDavies,Microbiol.Mol.Biol.Rev.2010.

Mortalityoutcomesareworseinneonateswithresistantinfections

Kayange M,Kamugisha E,Mwizamholya DL,JeremiahS,Mshana SE.2010.Predictorsofpositivebloodcultureanddeathsamongneonateswithsuspectedneonatalsepsisinatertiaryhospital,Mwanza- Tanzania.BMCPediatrics10:39.

149

58

369

151

91

5523

0

10

20

30

40

50

60

Culture GramReaction ESBL MRSA

Death(%

)

Parameter

Positive

Negative

DeNIS Study,LancetID,2016

LaxminarayanetalLancet,2015

Absolute risk reduction (ARR) of infection with antibiotic prophylaxis in common surgical procedures and blood cancer chemotherapy in the

USA

Teillant etal,LancetInfectDis,2015

Number of additional infections per year in the USA under a 30% decreased efficacy of antibiotic prophylaxis

Teillant etal,LancetInfectDis,2015

Surgicalsiteinfections

• Thereare92millionsurgeriesinlow-incomecountrieseachyear• 5.5millionsurgicalsiteinfectionsorSSIs(6per100procedures)–aboutathirdofallhealthcareassociatedinfections

• SSIsaretheleadingcauseofinfectioninsettingswithlimitedresources

• MortalityratefromSSIRatesofmortalityfromsurgicalsiteinfectionsare3%intheUSandbetween8and20%inlow-incomecountries

• Between400,000andamilliondeathsfromSSIseachyearwithanincreasingnumbercausedbyresistantpathogens.

Lahra etal,MicrobiologyAustralia,Nov2016

II. Risingincomesandincreasingaccesstoantibioticsaresavinglives(althoughlackofaccessstillkillsmorepeoplethanantibioticresistance)butarenotagoodsubstituteforpublichealth

Bacterialdiseasesarestillmajorkillersindevelopingcountriesbecauseoflackofaccesstoantibiotics

O’Brienetal,Lancet2009

Pneumococcalpneumoniadeathsavertablewithimprovedantibioticaccess

Laxminarayanetal,Lancet,2015

Whatareweaskingofantibiotics?

Substituteforimmunization,infectioncontrolandwater/sanitation

South Asia

Substituteforimmunization,infectioncontrolandwater/sanitation

Sub-Saharan Africa

Population without access to improved sanitation, by MDG region 2012

Source: WHO/UNICEF 2014

Kyaw MH et al. N Engl J Med 2006;354:1455-1463.

VaccinescanbeeffectiveInvasivediseasecausedbyPneumococciinchildrenundertwodeclinedintheUSpostpneumovaccination

EffectofPCV7introductionin2000onantibioticprescriptionsandambulatorycarevisits

Zhou et al, Pediatrics 2008

EffectofPCV7introductionin2000onantibioticprescriptionsandambulatorycarevisits

Zhou et al, Pediatrics 2008

Antibiotic prescriptions attributable to acute otitis media decreased from 1244 to 722 prescriptions per 1000 person-years – a 41.9% reduction.

LaxminarayanetalLancet,2015

Antibiotic consumption is increasing in developing countries...

Source: Based on data obtained under license from IMS Health MIDAS ™ (January 2005-December 2010); IMS Health Incorporated. All Rights Reserved.

0

5000

10000

15000

20000

25000

BRAZIL, RETAIL INDIA, RETAIL VIETNAM, RETAIL NORWAY, RETAIL USA, RETAIL

Stan

dard

Uni

ts pe

r 100

0 po

pula

tion

Per capita total antibiotic use, retail sector, 2005-2010

2005

2006

2007

2008

2009

2010

-50 – -30 -29 – -20 -19 – -10 -9 – 0 1 – 10 11 – 20 21 – 40 41 – 80 >80 No data

Percentage change in antibiotic consumption per capita 2000–2010*, by country

Source: Van Boeckel et al. 2015 (adapted; based on IMS MIDAS)

*Data for Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua and Panama were available only as a group classified as Central America. Similarly, data for Benin, Burkina Faso, Cameroon, Côte d’Ivoire, Gabon, Guinea, Mali, Republic of the Congo, Senegal, and Togo were grouped and classified as French West Africa. The data for these countries represent the estimates for the corresponding regional groupings they belong to. For countries that did not have data available for 2000, the values for the earliest years for which data were available after 2000 were used to calculate the percentage changes. These countries and initial years are Algeria (2002), Bangladesh (2007), Croatia (2005), Netherlands (2005), and Vietnam (2005).

Total antibiotic consumption in selected countries, 2000 and 2010

Van Boeckel et al. 2014 (based on IMS MIDAS)

Antibiotic use per capita by income in selected countries, 2010

Source: Van Boeckel et al. 2014 (based on IMS MIDAS) and World Bank 2015

Carbapenem retail sales in selected countries, 2005–2010 (per 1,000 population)

Source: Laxminarayan et al. 2013 (based on IMS MIDAS)

*An IMS grouping of Benin, Burkina Faso, Cameroon, Côte d’Ivoire, Gabon, Guinea, Mali, Republic of the Congo, Senegal, and Togo

Faropenem consumptionhasincreasedby154%sinceitwasapprovedforuseinIndiain2010

Gandra etal,Clin Inf Dis,2016

Carbapenem consumption in the hospital sector in selected European countries, 1997–2013

ESAC-Net 2015

Non-prescriptionuseofantimicrobialsiscommon

Morganetal,LancetID,2011

Van Boeckel et al, Lancet Inf Dis, 2014

Thefluseasonisakeydriverofantibioticconsumption

InfluenzaintheUnitedStatesisnearlyperfectlypredictedbyantibioticsalesdata

Polgreen etalInf Cont Hosp Epi,2011

Hospital use of carbapenems is rapidly growing

0

10

20

30

40

50

60

70

VIETNAM, HOSPITAL CHINA, HOSPITAL NORWAY, HOSPITAL USA, HOSPITAL

Stand

ard

Units

per

100

0 po

pula

tion

Per capita total carbapenem use, hospital sector, 2005-2010

2005

2006

2007

2008

2009

2010

Source: Based on data obtained under license from IMS Health MIDAS ™ (January 1999-December 2010); IMS Health Incorporated. All Rights Reserved.

Globalavailabilityofcolistin

Wertheim et al, JGAR 2013

III. Driversofantibioticuserelatetoincentivesandbehaviorofpatients,physicians,pharma,payersandhealthcareinstitutions.

IncentivesforPhysicians

• Satisfyingpatientexpectations

Dosh,JFamPr1999

Decisionfatigueincreasesinappropriateprescribing

Linderetal,JAMAIM,2014

Relativetothefirsthourofasession,theadjustedoddsratiosofantibioticprescribinginthefourthhourwas1.26(95%CI,1.13–1.41)

HospitalIncentives

•Antibioticsareasubstituteforinfectioncontrol

• Infectioncontrolisoftennotcompensated

WhatproportionofhospitalizedpatientsintheUnitedStatesareadministeredanantimicrobial?

A. 25%B. 40%C. 55%D. 70%

WhatproportionofhospitalizedpatientsintheUnitedStatesareadministeredanantimicrobial?

A. 25%B. 40%C. 55%D. 70%

Comparedwithabsenceofcomplications,complicationswereassociatedwitha$39017 highercontributionmarginperpatientwithprivateinsurance($55953vs $16936)anda$1749highercontributionmarginperpatientwithMedicare($3629vs $1880).

• At the start of therapy, 220 (30%) patients were afebrile and had normal white blood cell counts.

• Appropriate cultures were collected from 432 (59%) patients, and 250 (58%) were negative.

• By the 5th day of therapy, 12.5% of empirical antimicrobials were escalated, 21.5% were narrowed or discontinued, and 66.4% were unchanged.

• Narrowing or discontinuation was more likely when cultures were collected at the start of therapy and no infection was noted on an initial radiological study.

IV. Antibioticuseinanimalsectorisincreasinggloballyinresponsetothetremendousgrowthindemandforanimalprotein.

Meanwhileantibioticmanufacturingisexpeditingtheaccumulationofresistancegenesintheenvironment.

Antibioticuseforgrowthpromotionanddiseaseprevention

2/3rds ofthetonnageofantibioticssoldworldwideareusedinagriculture

DemandforpoultryinIndiaandChinaissettoincreasetwotosevenfoldbetween2000and2030

FAO, 2011

Growthindemandforpoultrymeatfrom2000to2030inAsia

GilbertM,ConcheddaG,VanBoeckelTP,CinardiG,LinardC,etal.(2015)IncomeDisparitiesandtheGlobalDistributionofIntensivelyFarmedChickenandPigs.PLOSONE10(7):e0133381.https://doi.org/10.1371/journal.pone.0133381http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133381

Productivity(kgofmeatperanimalperyear)asafunctionofGDPpercapita

• TotalconsumptioninChina- 92700tonsin2013,

• 54000tonsofantibioticsexcretedbyhumanandanimals- muchofthisenteredintothereceivingenvironmentfollowingvariouswastewatertreatmentsinto58riverbasinsofChina

Zhangetal,Env Sci Tech,2015

High-capacityquantitativePCRarraysdetected149uniqueresistancegenesamongallofthefarmsamples,thetop63ARGsbeingenriched192-fold(median)upto28,000-fold(maximum)comparedwiththeirrespectiveantibiotic-freemanureorsoilcontrols.

FicketalEnv Tox andChem,2009

IncreaseofantibioticresistancegenesamongsoilscollectedatfivesitesinTheNetherlandsfrom1940to2008.

KnappetalEnv Sci Tech,2010

Global antibiotic consumption in livestock (mg per 10 km2 pixels) 2010

Van Boeckel et al., PNAS, 2015

Log10 [(mg/pixel) + 1]

No data0 - 1 4 - 5 5 - 6 6 - 7 7 - 8 8 - 9 9 - 10 10 - 11

Global antibiotic consumption in livestock (mg per 10 km2 pixels) 2010

Van Boeckel et al., PNAS, 2015

Log10 [(mg/pixel) + 1]

No data0 - 1 4 - 5 5 - 6 6 - 7 7 - 8 8 - 9 9 - 10 10 - 11

Globalconsumptionofantimicrobialsinfoodanimalproduction• estimatedat63,151(±1,560)tonnes in2010• projectedtoriseby67%,to105,596(±3,605)tonnes by2030• hotspotslikeIndiawhereareasofhighconsumption(30kgperkm2)for

industrialpoultryproductionareexpectedtogrow312%by2030

Antibiotic consumption in livestock, top ten countries 2010–2030 (projected for 2030)

Van Boeckel et al., PNAS, 2015

V. Isfindingnewantibioticstheanswer?

Therichpaywiththeirwallets,thepoorwiththeirlives

Developed world cost per course of therapyDe

velo

ped

wor

ldDe

velo

ping

wor

ldSupplier

Pfizer

GSK

Ortho-McNeill

Bayer

Roche

Pfizer

Roche

GSK

IDA

Eli Lilly

Oscient

various

Branded product only

Generic product available

Price/full course of therapy

Notes: *Chloramphenicol is not available in developed world—price is therefore estimated. †Ceftriaxone and ciprofloxacin may be available in some tertiary settings in developing world.Source: The Medical Letter (2006), Disease control priorities in developing countries, Lancet (2006), Expert interviews.

$1,500

$1,480

$666.80

$223.30

$16

$11

$5*

$3.60

$103

$39

$121

$145

$144.8

Sulfonamides

Oxazolidinones

Trimethoprim

Streptogramins

Quinolones

Lincosamides

Chloramphenicol

Tetracyclines

Macrolides

Glycopeptides

Aminoglycosides

Penicillins

1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s

Discoveryofnewclassesofantibiotics

Pipelineofnewanti-microbialdrugsgrowingafteralonglagButpricesarelikelytobehigh

...Is being addressed by large recent reinvestment in novel mechanism development

**

#ofmoleculesinnon-standardanti-microbialclassesinallphasesofdevelopment

#ofmolecules

Year Class of drug

1935194119441945194919501952

19561957195919621968

2000200320052007

SulfonamidesPenicillinsAminoglycosidesCephalosporinsChloramphenicolTetracyclinesMacrolides / Lincosamides /StreptograminsGlycopeptidesRifamycinsNitroimidiazolesQuinolonesTrimethoprim

OxazolidinonesLipopeptidesGlycylcyclinesPleuromutilins

Significant gap in first introduction of new antimicrobial classes...

Source:“BadBugs,NoDrugs”whitepaper,Pharmaprojects,RodmanandRenshaw,NatureReviewsDrugDiscovery,BCGAnalysis

30yeardevelopmentgap

Trendsindevelopmentofnewantibiotics

Trendsindevelopmentofnewantibiotics

Ofthe61newantibioticsapprovedbetween1980and2009,26(43%)werewithdrawneitherbecauseoftoxicityorlackofmarket,comparedwitha13%withdrawalrateforothertherapeuticcategories(Outtersonetal2013)

Laxminarayan, Science, 2014

Laxminarayan, Science, 2014

Incentivesfornewantibiotics,asproposedbyBARDAandEUmayencouragenewdrugdevelopmentbutdon’timpactincentivesforusingdrugsappropriately

ImageCourtesyofShutterstock

• Diagnostics• VaccinesforStaphandGram-negativeinfection

• Bacteriophages• Probiotics• Quorumsensing

ImageCourtesyofShutterstock

Resistancemap.org

Slides are downloadable @ www.cddep.org