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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
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