Antimicrobial Resistance in

Developing Countries: Causes and Control Strategies

Sumanth Gandra MD, MPH

McGill University Global Health Talk

November 24, 2020

Disclaimer/Disclosures

• Research funded by US CDC and WHO

• Consultant to Global Hygiene Council

Outline of the Talk

• What are Antibiotics and their importance?

• What is Antibiotic Resistance?

• Why should we worry about Antibiotic Resistance?

• Causes of Antibiotic Resistance

• Antibiotic Resistance in resource limited settings (India)

• Influence of sociocultural and economic factors on Antibiotic Resistance

• Managing Antibiotic Resistance

What are Antibiotics?

• Antibiotics are molecules (drugs) that kill or inhibit the growth of bacteria

• Antibiotics fight infections caused by bacteria in humans and animals

Majority of antibiotics are natural products

Antibiotic Producer organism

Penicillin Penicillium chrysogenum

Cephalosporin Cephalosporium acremonium

Bacitracin Bacillus subtilis

Polymyxin B Bacillus polymyxa

Erythromycin Streptomyces erythreus

Streptomycin Streptomyces griseus

Tetracycline Streptomyces rimosus

Vancomycin Streptomyces orientalis

Gentamicin Micromonospora purpurea

Rifamycin Streptomyces mediterranei

Source: http://archive.bio.ed.ac.uk/jdeacon/microbes/penicill.htm

Death Rate for sepsis and Pneumonia in Sweden and Finland after introduction of

antibiotics

Source-Hemminki E et al. AJPH. 1976 Dec;66(12):1180-4

Leading causes of Death in the United States in 1900 and 1997

Source- MMWR, July 30, 1999 / 48(29);621-629

What is Antibiotic Resistance?

Normal Bacterium

Antibiotic Resistant Bacterium

Antibiotic resistance follows….

Profits drive drug innovation

Modern medicine depends on effective antibiotics

A 30% reduction in efficacy of antibiotic prophylaxis leads to 120,000 additional infections and 6,300 additional deaths in a year

Antimicrobial Resistance burden in 2050:

10 million deaths every year and mostly in Low-

and middle-income countries

AMR review- Jim O Neil

Why are Bacteria becoming increasingly Resistant to Antibiotics?

• Primary reason-

overuse andmisuse of Antibiotics

High Antibiotic Use = High Resistance

Bac

teri

al R

esi

stan

ce (

%)

Antibiotic consumptionSource- WHO

Antibiotic consumption trends by

income: 2000–2014

Source: Klein EY et al. PNAS, 2018

Antibiotic resistance prevalence and

national per-capita income

Gandra S et al. IJID, October 2016

Scoping Report on Antimicrobial Resistance in India

Identified drivers of antibiotic resistance and research gaps in India

Gandra S et al. Center for Disease Dynamics, Economics & Policy

Percentage of third generation cephalosporin

resistant Escherichia coli, by country (2011–2014)

State of the World’s Antibiotics Report, CDDEP 2015

Why India has high antibiotic resistance prevalence?

In 2015- India is the largest consumer of antibiotics, followed by China and the United States

Global Trends in Antibiotic Consumption

Per-capita antibiotic consumption: 2015

Source: Klein EY et al. PNAS, 2018

AntibioticsNarrow Spectrum• Act against limited group of

bacteria

• Less chance of resistance selection to other antibiotics

• Antibiotic choices available if resistance develops

• Examples- Penicillins, 1st

generation cephalosporins, Nitrofurantoin

Broad Spectrum

• Act against a larger group of bacteria

• Higher chance of resistance selection to other group of antibiotics

• Limited antibiotic choices if resistance develops

• Examples- 2nd and 3 generation cephalosporins, quinolones, macrolides

Narrow vs Broad spectrum antibiotic use in 75 countries

Source: Klein EY et al. LID, 2020

Lack of availability of narrow-spectrum agents

135

112102

89

6958

51

20

1 1 10

20

40

60

80

100

120

140

160

Number of formulation companies manufacturing various antibiotics for human use

Source: Gandra, S et al. AMR scoping report India

Fixed Dose Combination (FDC) Antibiotics

- India

• 118 (at least) FDC antibiotics are available in India– Cefixime + Azithromycin– Cefixime + Linezolid– Azithromycin + Levofloxacin– Cefixime + Levofloxacin ………

Indian government banned 327 FDCs which includes several antibiotics in 2018

Source: Ahmad A et al. Lancet GH 2016Source: Shankar PR et al. Lancet GH 2016

Social FactorsAmong general public

• self-medication• access to antibiotics without prescription

Healthcare providers in private sector• perceived patient demand• fear of losing patients if asked for diagnostic investigations• economic incentives from pharmaceutical companies• lack of continuing medical education

Healthcare providers in public sector• heavy patient load • lack of diagnostic facilities • lack of continuing medical education

Source: Gandra, S et al. AMR scoping report India

Global Antimicrobial Consumption in Food Animals

Some Hot spots:Southeast coast ChinaSouth coast of India, Mumbai, Delhi

Source: Van Boeckel et al PNAS- 2015

Countries with Highest Antimicrobial

consumption in Food Animals

2010 2030

Source: Van Boeckel et al PNAS. 2015.

Shifting farming practices• To meet the increasing demand a shift towards

highly cost-efficient and vertically integrated intensive livestock production systems

Colistin sulphate for growth promotion in Food Animals- India

Source: Center for Science and Environment

Effluent Pollution From Antibiotic Manufacturing Units- India

Nordea Report, Feb 2016

Antibiotic manufacturing units hotspots

Cities/towns with 5 or more drug (antimicrobials and/or others) manufacturing units

Cities/towns with 4 or fewer drug (antimicrobials and/or others) manufacturing units

Source: Gandra, S et al. AMR scoping report India

Effluent Pollution From Antibiotics

Manufacturing Units

• ‘Good Manufacturing Practices’ (GMP), do not include environmental safeguards

• Unfortunately, environmental regulation are currently left up to national regulators

Ciprofloxacin concentration in Effluent from

drug manufacturers, Hyderabad, India- 2006

Larson JDG et al. J Hazardous Material, 2007

• Up to 31,000µg/L

• “Discharge load of 45 kg per day = amount consumed in Sweden(population nine million) over 5-days”

Poor Environmental Sanitation

World Bank 2016

Conditions suitable for rapid spread

of resistance genes in India

Risk of Extended Spectrum Beta-lactamase(ESBL)

Enterobacteriaceae colonization for a traveler

• South Asia: 55%

• Asia (except South Asia): 39%

Hassing RJ et al. Eurosurveillance 2015Kuenzli E et al. BMC ID 2014

0%

20%

40%

60%

80%

100%

India Nepal Bhutan Sri Lanka

87%79% 78%

35%

Cultural Activities

NDM-1 (antibiotic resistance gene) levels are 20 times greater in the Ganga river at the time of pilgrimage season when compared to non-pilgrimage season

Source: Ahammad ZS et al. Env. Science & Tech. 2014

Perfect conditions for emergence of Superbugs

HUMAN SECTOR ANIMAL SECTOR

PHARMA SECTOR

BREEDING GROUND

Global Antibiotic Resistance: Beyond Bugs and Drugs

World Bank data for 103 countries

• Governance– Rule of Law– Corruption index (from

Transparency International)– Political Stability

• Education– Literacy rate– secondary education rate– primary education rate– Female literacy rate

• Climate– Average temperature– Average precipitation

• GDP per-capita

• Health Expenditure– Total GDP on healthcare– Ratio of Public/Private

• Infrastructure– % with adequate sanitation– % with clean water source– % urbanized population– % access to electricity

• Antibiotic consumption data

Collignon P et al. Lancet Planetary Health 2018

Factors influencing Antibiotic Resistance

VariableMeasuredin

StandardDeviations

fromSampleMean

ImpactonAggregate

ResistanceofaOneStandard

DeviationIncreasein

ExplanatoryVariable(Logit)

P-value ImpactonE.coliResistance

ofaOneStandardDeviation

IncreaseinExplanatory

Variable(Logit)

P-value

Antibioticusage 2.36 0.07 -0.88 0.64

Governance -11.18 0.00 -7.89 0.02

HealthExpenditure -6.34 0.01 -5.54 0.09

GDPper-capita 3.36 0.11 6.62 0.03

Education 8.59 0.00 7.93 0.06

Infrastructure -13.24 0.01 -16.84 0.01

ClimateIndex -0.25 0.86 2.01 0.33

Collignon P et al. Lancet Planetary Health 2018

Aggregate resistance includes: E. coli and Klebsiellaspp. resistant to 3GC, FQs, carbapenems and MRSA

Strategies to MANAGE antimicrobial

resistance

State of the World’s Antibiotics Report, CDDEP 2015

Thank you