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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
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