The State of the World’s Antibiotics

Ramanan Laxminarayan 2016 John Ring LaMontagne Memorial Lecture

I. Drugresistanceisrisingworldwideandthreatensgainsmadeinreducingtheburdenofinfec7ousdiseases

Percentage of Staphylococcus aureus isolates that are methicillin resistant (MRSA) in selected countries, 1999–2014

Source: CDDEP 2015 Depending on the country, resistance to one or more of the following drugs may have been used to test for MRSA: Oxacillin, cefoxitin, flucloxacillin, cloxacillin, dicloxacillin, and methicillin. Intermediate-resistant isolates are included as resistant

CREratesinchildrengrewbetween2000and2012

Loganetal,EID,2015

15

Clonal spread of S. pneumoniae 23F

Tennessee

Cleveland

Mexico

Colombia

Brazil

Argen7naUruguay

Chile SouthAfrica

SingaporeMalaysia

ThailandPhilippines

HongKongTaiwan

SouthKoreaSpain

FranceBM42001978?

Finland

Slidecourtesy:KeithKlugman

Numbers of unique β-lactamase enzymes identified since introduction of first β-lactam antibiotics

Clostridium difficile rates and oral vancomycin prescriptions

Polgreen,Yang,Kuntz,Laxminarayan,ICHE2011

Mortality outcomes are worse in neonates with resistant infections

KayangeM,KamugishaE,MwizamholyaDL,JeremiahS,MshanaSE.2010.Predictorsofposi7vebloodcultureanddeathsamongneonateswithsuspectedneonatalsepsisinater7aryhospital,Mwanza-Tanzania.BMCPediatrics10:39.

149

58

369

151

91

55

23

0

10

20

30

40

50

60

Culture GramReac7on ESBL MRSA

Death(%

)

Parameter

Posi7ve

Nega7ve

LaxminarayanetalLancet,2015

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

Teillantetal,LancetInfectDis,2015

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

Teillantetal,LancetInfectDis,2015

II. Risingincomesandincreasingaccesstoan7bio7csaresavinglives(althoughlackofaccesss7llkillsmorepeoplethanan7bio7cresistance)butarenotagoodsubs7tuteforpublichealth

Bacterial diseases are still major killers in developing countries because of lack of access to antibiotics

O’Brienetal,Lancet2009

Pneumococcal pneumonia deaths avertable with improved antibiotic access

Laxminarayanetal,Lancet,2015

What are we asking of antibiotics?

Substitute for immunization, infection control and water/sanitation

South Asia

Substitute for immunization, infection control and water/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.

Vaccines can be effective Invasive disease caused by Pneumococci in children under two declined in the US post pneumo vaccination

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

Invasive disease caused by non-susceptible Pneumococci, US

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 consumption has increased by 154% since it was approved for use in India in 2010

Gandraetal,ClinInfDis,2016

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

ESAC-Net 2015

Non-prescription use of antimicrobials is common

Morganetal,LancetID,2011

Van Boeckel et al, Lancet Inf Dis, 2014

The flu season is a key driver of antibiotic consumption

Influenza in the United States is nearly perfectly predicted by antibiotic sales data

PolgreenetalInfContHospEpi,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.

Global availability of colistin

Wertheim et al, JGAR 2013

Make better use of existing antibiotics

ImageCourtesyofShu^erstock

Find new antibiotics

ImageCourtesyofShu^erstock

III. Driversofan7bio7cuserelatetoincen7vesandbehaviorofpa7ents,physicians,pharma,payersandhealthcareins7tu7ons.

Incentives for Physicians

•  Sa7sfyingpa7entexpecta7ons

Dosh,JFamPr1999

Decision fatigue increases inappropriate prescribing

Linderetal,JAMAIM,2014

Rela7vetothefirsthourofasession,theadjustedoddsra7osofan7bio7cprescribinginthefourthhourwas1.26(95%CI,1.13–1.41)

Health insurance increases prescribing

What happens when antibiotics are provided free?

Overallincreaseinan7bio7cprescrip7onsaswellassubs7tu7onstocoveredan7bio7csfromnot-coveredan7bio7cs.

LiandLaxminarayan,HealthEconomics,2013

What happens when antibiotics are provided free?

Overallincreaseinan7bio7cprescrip7onsaswellassubs7tu7onstocoveredan7bio7csfromnot-coveredan7bio7cs.

LiandLaxminarayan,HealthEconomics,2013

Hospital Incentives

• An7bio7csareasubs7tuteforinfec7oncontrol

• Infec7oncontrolisodennotcompensated

Comparedwithabsenceofcomplica7ons,complica7onswereassociatedwitha$39017highercontribu7onmarginperpa7entwithprivateinsurance($55953vs$16936)anda$1749highercontribu7onmarginperpa7entwithMedicare($3629vs$1880).

10.8%

89.2%

0

200

400

600

800

1000

1200

No Yes

Num

berofPa7

ents

DocumentedDiagnosisforStar7ngIndexAn7bio7c

Braykovetal,LancetInfDis,2015

30.1%

69.9%

0

100

200

300

400

500

600

No Yes

Num

berofPa7

ents(N

=730

)PresenceofFeverandHighWBCamongPa7entswith

EmpiricAn7bio7cTherapy

Respiratory(43%)

Urinarytract(18%)

Sod7ssue(18%)

Gastro-Intes7nal(8%)

Bloodstream(8%)

Other(6%)

BreakdownofInfec7onSitefor"No"Pa7ents

Braykovetal,LancetInfDis,2015

Jus7fica7ons

73.4%

51.7%

11.1%

48.3%

15.5%

0

100

200

300

400

500

600

700

OneAn7bio7c TwoorMoreAn7bio7cs

Num

berofPa7

ents

Pa7entsReceivingAn7bio7csonIndexDay

ForDifferentIndica7ons

NoApparentReason

ToIncreaseSpectrumofCoverageforSingleIndica7on

Braykovetal,LancetInfDis,2015

IV. An7bio7cuseinanimalsectorisincreasinggloballyinresponsetothetremendousgrowthindemandforanimalprotein

Increase in demand for poultry in India and China between 2000 and 2030

FAO, 2011

Antibiotic use for growth promotion and disease prevention

2/3rds of the tonnage of antibiotics sold worldwide are used in agriculture

•  Totalconsump7oninChina-92700tonsin2013,

•  54000tonsofan7bio7csexcretedbyhumanandanimals-muchofthisenteredintothereceivingenvironmentfollowingvariouswastewatertreatmentsinto58riverbasinsofChina

Zhangetal,EnvSciTech,2015

High-capacityquan7ta7vePCRarraysdetected149uniqueresistancegenesamongallofthefarmsamples,thetop63ARGsbeingenriched192-fold(median)upto28,000-fold(maximum)comparedwiththeirrespec7vean7bio7c-freemanureorsoilcontrols.

Increase of antibiotic resistance genes among soils collected at five sites in The Netherlands from 1940 to 2008.

KnappetalEnvSciTech,2010

Temporalassocia7onbetweencontamina7onofretailchickenwithcediofur-resistantSalmonellaHeidelbergstrainsandincidenceofcediofurresistantSalmonellaHeidelberginfec7oninhumans

Du7letal,EID,2010

Amounts, in mg, of veterinary antibacterial agents sold in 2007 per kg biomass of pig meat, poultry meat and cattle meat produced plus estimated live weight of dairy cattle. *2005 data. **The substances included vary from country to country.

Grave K et al. J. Antimicrob. Chemother. 2010;65:2037-2040

© The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Meat production and sales of antibiotic feed additives, United States, 1951-1970

Source:Cromwell(2002)

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

Globalconsump7onofan7microbialsinfoodanimalproduc7on•  es7matedat63,151(±1,560)tonnesin2010•  projectedtoriseby67%,to105,596(±3,605)tonnesby2030•  hotspotslikeIndiawhereareasofhighconsump7on(30kgperkm2)for

industrialpoultryproduc7onareexpectedtogrow312%by2030

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

Van Boeckel et al., PNAS, 2015

Sales of active ingredients of antibiotics for food-producing animals in Denmark

DANMAP 2013 (adapted)

Laxminarayan et al, OECD Report, 2015

Productivity reductions and costs per produced pig incurred by removing AGPs

Laxminarayan et al, OECD Report, 2015

V. What’stheroleofinnova7on?

Loss of first line drugs increases drug costs

Source:WHOPolicyPerspec7ve2005,adaptedfromWHOModelFormulary,WHOClinicalGuidelinesandManagementSciencesforHealth’s2004Interna7onalDrugPriceIndicatorGuide(slidecourtesy:DavidHeymann)

Laxminarayan,Science,2015

Laxminarayan,Science,2015

The rich pay with their wallets, the poor with their lives

Developed world cost per course of therapy D

eve

lop

ed

wo

rld

De

velo

pin

g w

orld

Supplier

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

Is the rate of new drug development declining?

Trends in development of new antibiotics

Trends in development of new antibiotics

Ofthe61newan7bio7csapprovedbetween1980and2009,26(43%)werewithdrawneitherbecauseoftoxicityorlackofmarket,comparedwitha13%withdrawalrateforothertherapeu7ccategories(Ou^ersonetal2013)

Systemic new molecular entity (NME) antibiotics still marketed in the US by period of introduction, 1980–2015*

Source: Outterson et al. 2013 *As of August 21, 2015; additional market discontinuations since 2009 are not calculated. Bedaquiline, approved for multidrug-resistant tuberculosis in 2012, is included.

Laxminarayan, Science, 2014

Laxminarayan, Science, 2014

Incen7vesfornewan7bio7cs,asproposedbyBARDAandEUmayencouragenewdrugdevelopmentbutdon’timpactincen7vesforusingdrugsappropriately

ImageCourtesyofShu^erstock

• Diagnos7cs• VaccinesforStaphandGram-nega7veinfec7on

• Bacteriophages• Probio7cs• Quorumsensing

ImageCourtesyofShu^erstock

Resistancemap.org

Slides are downloadable @ www.cddep.org

Thank you