The State of the World’s Antibiotics Ramanan Laxminarayan 2016 John Ring LaMontagne Memorial Lecture
I. Drug resistance is rising worldwide and threatens gains made in reducing the burden of infec7ous diseases
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
CRE rates in children grew between 2000 and 2012
Logan et al, EID, 2015
Clonal spread of S. pneumoniae 23F Finland France BM4200 1978 ? Spain
Cleveland
South Korea
Tennessee Taiwan Hong Kong Philippines Thailand
Mexico
Colombia
Malaysia Singapore
Brazil
Chile
Uruguay
South Africa
Argen7na Slide courtesy: Keith Klugman
15
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, ICHE 2011
Mortality outcomes are worse in neonates with resistant infections 60
9 36
50
Death (%)
40
30
91 149 23
58
20
10
Posi7ve
55
151
0 Culture
Gram Reac7on
ESBL
MRSA
Parameter
Kayange M, Kamugisha E, Mwizamholya DL, Jeremiah S, Mshana SE. 2010. Predictors of posi7ve blood culture and deaths among neonates with suspected neonatal sepsis in a ter7ary hospital, Mwanza- Tanzania. BMC Pediatrics 10: 39.
Nega7ve
Laxminarayan et al Lancet, 2015
Absolute risk reduction (ARR) of infection with antibiotic prophylaxis in common surgical procedures and blood cancer chemotherapy in the USA
Teillant et al, Lancet Infect Dis, 2015
Number of additional infections per year in the USA under a 30% decreased efficacy of antibiotic prophylaxis
Teillant et al, Lancet Infect Dis, 2015
II. Rising incomes and increasing access to an7bio7cs are saving lives (although lack of access s7ll kills more people than an7bio7c resistance) but are not a good subs7tute for public health
Bacterial diseases are still major killers in developing countries because of lack of access to antibiotics
O’Brien et al, Lancet 2009
Pneumococcal pneumonia deaths avertable with improved antibiotic access
Laxminarayan et al, 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
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
Kyaw MH et al. N Engl J Med 2006;354:1455-1463.
Laxminarayan et al Lancet, 2015
Antibiotic consumption is increasing in developing countries... Per capita total antibiotic use, retail sector, 2005-2010 25000
Standard Units per 1000 population
20000
2005 15000
2006 2007 2008
10000
2009 2010
5000
0 BRAZIL, RETAIL
INDIA, RETAIL
VIETNAM, RETAIL
NORWAY, RETAIL
USA, RETAIL
Source: Based on data obtained under license from IMS Health MIDAS ™ (January 2005-December 2010); IMS Health Incorporated. All Rights Reserved.
Percentage change in antibiotic consumption per capita 2000–2010*, by country
-50 – -30
-29 – -20
-19 – -10
-9 – 0
1 – 10
11 – 20
21 – 40
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).
41 – 80
>80
No data
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
Gandra et al, Clin Inf Dis, 2016
Carbapenem consumption in the hospital sector in selected European countries, 1997–2013
ESAC-Net 2015
Non-prescription use of antimicrobials is common
Morgan et al, Lancet ID, 2011
The flu season is a key driver of antibiotic consumption
Van Boeckel et al, Lancet Inf Dis, 2014
Influenza in the United States is nearly perfectly predicted by antibiotic sales data
Polgreen et al Inf Cont Hosp Epi, 2011
Hospital use of carbapenems is rapidly growing Per capita total carbapenem use, hospital sector, 2005-2010
Standard Units per 1000 population
70 60 50
2005 2006
40
2007 2008
30
2009 20
2010
10 0 VIETNAM, HOSPITAL
CHINA, HOSPITAL
NORWAY, HOSPITAL
USA, HOSPITAL
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 Image Courtesy of Shu^erstock
Find new antibiotics
Image Courtesy of Shu^erstock
III. Drivers of an7bio7c use relate to incen7ves and behavior of pa7ents, physicians, pharma, payers and healthcare ins7tu7ons.
Incentives for Physicians • Sa7sfying pa7ent expecta7ons
Dosh, J Fam Pr 1999
Decision fatigue increases inappropriate prescribing Rela7ve to the ďŹ rst hour of a session, the adjusted odds ra7os of an7bio7c prescribing in the fourth hour was 1.26 (95% CI, 1.13–1.41)
Linder et al, JAMA IM, 2014
Health insurance increases prescribing
What happens when antibiotics are provided free?
Overall increase in an7bio7c prescrip7ons as well as subs7tu7ons to covered an7bio7cs from not-covered an7bio7cs. Li and Laxminarayan, Health Economics, 2013
What happens when antibiotics are provided free?
Overall increase in an7bio7c prescrip7ons as well as subs7tu7ons to covered an7bio7cs from not-covered an7bio7cs. Li and Laxminarayan, Health Economics, 2013
Hospital Incentives • An7bio7cs are a subs7tute for infec7on control • Infec7on control is oden not compensated
Compared with absence of complica7ons, complica7ons were associated with a $39 017 higher contribu7on margin per pa7ent with private insurance ($55 953 vs $16 936) and a $1749 higher contribu7on margin per pa7ent with Medicare ($3629 vs $1880).
Documented Diagnosis for Star7ng Index An7bio7c
Number of Pa7ents
1200
89.2%
1000 800 600 400 200
10.8%
0
No
Yes Braykov et al, Lancet Inf Dis, 2015
Presence of Fever and High WBC among Pa7ents with Empiric An7bio7c Therapy 600 69.9%
Number of Pa7ents (N=730)
500
Breakdown of Infec7on Site for "No" Pa7ents
400
Bloodstream (8%)
300
Other (6%)
Gastro-Intes7nal (8%)
Respiratory (43%)
30.1% 200 Sod 7ssue (18%)
100
Urinary tract (18%)
0
No
Yes
Braykov et al, Lancet Inf Dis, 2015
Pa7ents Receiving An7bio7cs on Index Day 700
51.7% 600
15.5%
500
Number of Pa7ents
48.3%
Jus7fica7ons For Different Indica7ons
11.1%
400
No Apparent Reason
300 73.4%
200
To Increase Spectrum of Coverage for Single Indica7on
100 0 One An7bio7c
Two or More An7bio7cs Braykov et al, Lancet Inf Dis, 2015
IV. An7bio7c use in animal sector is increasing globally in response to the tremendous growth in demand for animal protein
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
• Total consump7on in China - 92700 tons in 2013, • 54000 tons of an7bio7cs excreted by human and animals - much of this entered into the receiving environment following various wastewater treatments into 58 river basins of China
Zhang et al, Env Sci Tech, 2015
High-capacity quan7ta7ve PCR arrays detected 149 unique resistance genes among all of the farm samples, the top 63 ARGs being enriched 192-fold (median) up to 28,000-fold (maximum) compared with their respec7ve an7bio7c-free manure or soil controls.
Increase of antibiotic resistance genes among soils collected at five sites in The Netherlands from 1940 to 2008. Knapp et al Env Sci Tech, 2010
Temporal associa7on between contamina7on of retail chicken with cediofur-resistant Salmonella Heidelberg strains and incidence of cediofur resistant Salmonella Heidelberg infec7on in humans
Du7l et al, 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 Š 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
Log10 [(mg/pixel) + 1] 0-1
4-5
Van Boeckel et al., PNAS, 2015
5-6
6-7
7-8
8-9
9 - 10
10 - 11
No data
Global antibiotic consumption in livestock (mg per 10 km2 pixels) 2010
Global consump7on of an7microbials in food animal produc7on • es7mated at 63,151 (±1,560) tonnes in 2010 • projected to rise by 67%, to 105,596 (±3,605) tonnes by 2030 • hotspots like India where areas of high consump7on (30 kg per km2) for industrial poultry produc7on are expected to grow 312% by 2030 Log10 [(mg/pixel) + 1] 0-1
4-5
Van Boeckel et al., PNAS, 2015
5-6
6-7
7-8
8-9
9 - 10
10 - 11
No data
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’s the role of innova7on?
Loss of first line drugs increases drug costs
Source: WHO Policy Perspec7ve 2005, adapted from WHO Model Formulary, WHO Clinical Guidelines and Management Sciences for Health’s 2004 Interna7onal Drug Price Indicator Guide (slide courtesy: David Heymann)
Laxminarayan, Science, 2015
Laxminarayan, Science, 2015
The rich pay with their wallets, the poor with their lives Developed world cost per course of therapy
Supplier $1,480
Pfizer Eli Lilly
Developed world
$666.80
Oscient
$223.30
GSK
$145 $144.8
Roche
$121
Ortho-McNeill Bayer
$103
Pfizer
Developing world
$39
$16
Branded product only
Roche GSK
Generic product available
$11
IDA
$5*
various $3.60
$1,500
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.
Is the rate of new drug development declining?
Trends in development of new antibiotics
Trends in development of new antibiotics Of the 61 new an7bio7cs approved between 1980 and 2009, 26 (43%) were withdrawn either because of toxicity or lack of market, compared with a 13% withdrawal rate for other therapeu7c categories (Ou^erson et al 2013)
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
Incen7ves for new an7bio7cs, as proposed by BARDA and EU may encourage new drug development but don’t impact incen7ves for using drugs appropriately
Laxminarayan, Science, 2014
• Diagnos7cs • Vaccines for Staph and Gram-nega7ve infec7on • Bacteriophages • Probio7cs • Quorum sensing
Image Courtesy of Shu^erstock
Image Courtesy of Shu^erstock
Resistancemap.org
Slides are downloadable @ www.cddep.org
Thank you