Public health issues in AMR including antimicrobial resistance

surveillance in humans and animals

Dr Kamini Walia Indian Council of Medical Research

Antimicrobial resistance

Understanding challenges and identifying future approaches

Resistance in microbes is a natural phenomenon

Resistance is unresponsiveness to antimicrobial agents in standard doses

A natural biological unstoppable phenomenon

Resistance is generally slow to reverse or irreversible

All antimicrobial agents have the potential to select drug-resistant subpopulations of microorganisms

Resistance is fallout of inappropriate use of antimicrobials in different settings In animals and plants: Therapeutic and non-therapeutic (e.g. as growth

promoters) In community acquired infections In hospital-associated infections Irrational use of antibiotics is the greatest driver of

resistance

50% of antibiotics are prescribed inappropriately

50% of patients have poor compliance

50% of populations do not have access to essential antibiotics

Resistance is accelerated through inappropriate use of antimicrobials Standard treatment guidelines not provided to

physicians or provided but not adhered to Drugs available without prescription Accessible but poor quality Inadequate monitoring Irrational self-administration or prescription

Antimicrobial resistance

India: case scenario

Huge burden of infectious diseases Malaria, TB, HIV/AIDS, vector borne diseases, Influenza, other

outbreaks Diarrhea, pneumonia

Sanitation conditions, malnutrition Large number of vertical programs Treatment and prevention Weak surveillance systems Infection control practices in hospitals 70% of health care is dispensed through private sector

India: case scenario

$12.4 billion pharmaceutical industry Regulations over sale of antibiotics Guidelines for use of antibiotics in diarrhea and

pneumonia(IMNCI), not for other diseases of public health importance

Over the counter availability of antibiotics Use of antibiotics in livestock, poultry and agriculture Medical tourism Movement across borders

Health Care in India India has 48 doctors per 100,000 persons

Practitioners of alternate systems

Wide urban-rural gap in the availability of medical services:

Inequity

Poor facilities even in large Government institutions compared

to corporate hospitals

Infectious disease specialists missing link

Antimicrobial resistance surveillance Previous attempts by ICMR did not sustainve Invasive Bacterial Infection Surveillance: could not be

established as a permanent system Most of available data from small studies in labs or

medical institutes Methodology, uniformity issues

Antimicrobial Resistance in India • Precise extent of the problem is not known

• Majority of the published reports derive from individual units

or hospitals

• Very few multi center studies have been reported

• No local or national surveillance programs exist

• The best estimate of the resistance problem in selected common pathogens in India

GLOBAL TB PROGRAMME

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border

lines for which there may not yet be full agreement. WHO 2012. All rights reserved

Estimated number of MDR-TB Cases, 2011 >60% of all cases are in 6 countries

Russian Federation 44,000

(14% of global MDR burden)

India 99,000

(21% of global MDR burden)

China 61,000

(20% of global MDR burden)

Philippines 11,000

(4% of global MDR burden)

Pakistan 10,000

(3% of global MDR burden)

South Africa 8,100

Based on old survey data

MDR-TB in the SEA Region

Country Source of estimates

% MDR among new TB cases (95% CI)

% MDR among previously treated TB cases (95% CI)

Number of MDR-TB among incident total TB cases (95% CI)

Bangladesh model 2.2 (0.0–5.6) 14.7 (0.0–39.6) 9 800 (1 000–19 000)

Bhutan model 2.2 (0.0–5.6) 14.7 (0.0–39.6) 33 (4–61)

DPR Korea model 2.2 (0.0–5.6) 14.7 (0.0–39.6) 3900 (658–7 200)

India DRS, 2005 2.3 (1.8–2.8) 17.2 (14.9–19.5) 99 000 (79 000–120 000)

Indonesia DRS, 2004 1.9 (0.5–6.9) 16.7 (0.0–39.6) 9 300 (0–21 000)

Maldives model 2.2 (0.0–5.6) 14.7 (0.0–39.6) 3 (0–6)

Myanmar DRS, 2007 4.2 (3.2–5.6) 10.0 (7.1–14.0) 9 300 (6 400–12 000)

Nepal DRS, 2007 2.9 (1.9–4.3) 11.7 (7.6–17.6) 1 700 (990–2 300)

Sri Lanka DRS, 2006 0.2 (0.0–1.0) 18-21% 63 (0–130)

Thailand DRS, 2006 1.7 (1.1–2.6) 34.5 (28.2–41.5) 2 900 (2 100–3 800)

Timor-Leste model 2.2 (0.0–5.6) 14.7 (0.0–39.6) 130 (6–260)

SEA region 2.1 (1.7-2.5) 17 (17-18) 105,000

HIV and STIs – Data on HIV

resistance being generated

– Gonorrhoea widely resistant to penicillin & fluoroquinolones – 78% ciprofloxacin

resistant, – 51% tetracycline resistant, – 47% penicillin resistant, – 22% β-lactamase

producers Source: Sethi et al 2006

Kala-azar

– 60% resistance in pentavalent antimony and 25% in pentamidine

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30 3229 28

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Mohanasoundaram, K. M., et al. 2008. Indian J Med Res 127:78-84. Tiwari, H. K., et al. 2006. BMC Infect Dis 6:156. Mehta, A., et al. 2007. J Hosp Infect 67:168-74. Song, J. H., et al. 2004. Antimicrob Agents Chemother 48:4926-8.

MRSA resistance rates from various Indian studies vary but appear to increase over time

Staphylococcus aureus

Prevalence of MRSA range widely from 30 - 85%

Among the MRSA > 95% resistant to gentamicin

CAMRSA: Susceptible to majority of the non β lactam antibiotic classes such as chloremphenicol, tetracycline, sxt and macrolides

HAMRSA: a study conducted in seven cities reported MRSA as high as 87.5%.

Mohanasoundaram, K. M., et al. 2008. Indian J Med Res 127:78-84. Tiwari, H. K., et al. 2006. BMC Infect Dis 6:156. Mehta, A., et al. 2007. J Hosp Infect 67:168-74. Song, J. H., et al. 2004. Antimicrob Agents Chemother 48:4926-8.

Streptococcus pneumoniae Intermediate-level resistance to penicillin has increased

steadily over the last decade Currently, up to 11.3% intermediate and < 1 % complete

resistant to penicillin 11% to erythromycin and 85-90% resistance to co

trimoxazole is observed The neighbor island of Sri Lanka reports around 90%

penicillin resistance while Nepal profile was similar to India

Enterococcus spp VRE have been documented from Chandigarh, Lucknow, Mumbai

and Vellore

High-level aminoglycoside resistance (HLAR) appears relatively less frequent in the South as compared to North India where up to 84% have been reported.

Currently up to 23% of VRE as been reported

Almost all isolates are susceptible to linezolide and daptomycin

VRE isolation in different specimens

Enterobacteriaceae ESBLs - prevalence of 30-65% (IQR) in Enterobacteriaceae Carbapenamase resistance : ~ 5 % predominantly due to

NDM-1 In certain ICU, isolation rates reached 80% Amongst ESBL producers, resistance rates to

fluroquinolones are highest followed by co trimoxazole Wide difference is seen in percent susceptible to

aminoglycoside class of drugs Decrease susceptibility to Pip/tazo

Community VS Hospital acquired

What drives the use of carbapenems ? • Typically 3rd / 4th line agents in critically ill

• Fears of ESBLs

30- 70 % In India

What is the cut off for empirical use ?

• Initiatives to improve the treatment of sepsis

Highly active antimicrobial therapy saves lives1

• Generic carbapenems are affordable

1Kumar et al Crit Care Med 2006,

Carbapenem resistance in Enterobacteriaceae

Until 2005, resistance to carbapenem in Enterobacteriaceae

had not been observed

2012: it is estimated that 5 % of E coli and up to 40 % of Klebsiella spp resistant to carbapenem

A higher percent of susceptibility to colistin (>90%), tigecycline (up to 59%) followed by aztreonam and amikacin

Salmonella spp S.typhi multidrug resistance (MDR) : ampicillin, chloramphenicol

and trimethoprim –sulfamethoxazole - downward trend

Isolation of highly FQ-resistant S. typhi is increasingly reported EUCAST has received the MIC break points 0.068 µg/Ml

Recently more number of cephalosporins resistance to S typhi is

being reported in the Indian literature

Interestingly, the incidence of S paratyphi is increasing country wide though the numbers of MDR, FQ and cephalosporins are very less

Shigella spp

S. flexneri most prevalent Shigella species, followed by S. sonnei, S. dysenteriae and S. boydii.

Shigella spp are virtually resistant to tetracycline

Resistance to ampicillin ranges from 39-88%; trimethoprim -sulfamethoxazole 81-92%; nalidixic acid 60-87%; ciprofloxacin 20-67% and ceftriaxone/cefixime upto 12% have been reported in India

S. dysenteriae type 1 and S. flexneri are the common species resistant to cephalosporins

Cholera V cholerae O1 strains were resistant to multiple antibiotics (Ampicillin,

Cotrimoxazole, Furazolidione, Nalidixic acid and Streptomycin) Reduced susceptibility to Ciprofloxacin. Increased isolation of Tetracycline resistant strains (27.2%) for Ogawa and

15% for Inaba

Non fermenting Gram Negative Bacilli (NFGNB) P. aeruginosa 25-31% to ciprofloxacin, aztreonam, amikacin, gentamicin,

tobramycin pipeacillin/tazobactum, cefaperazone/sulbactum and imipenem

15-22% is observed with ceftazidime and meropenem Acinetobacter spp 55-65% resistant to gentamicin, netilimycin, amikacin, aztreonam

and ciprofloxacin 32 – 43% to imipenem; 25-32% to meropenem; 21 – 26% to ceftazidime, ampicilin/sulbactum,

cefaperazone/sulbactum and piperacillin/tazo

Why resistance rates are high ?

Over the counter dispensing of antimicrobials

Between 2005 -2009- 40% increased antibiotic sale

Spurious drugs, Generic drugs

Lack of culture and susceptibility testing

No National or regional surveillance network

No Infectious disease speciality

Lack of good diagnostic support

Poverty: Non affordability and incomplete therapy

Haphazard sanitary infrastructure, malnutrition

Lacking : Public health, public spending, political will

Prescribing determinants of antibiotics

Source: Radyowijati and Haak, 2003

Dispensing determinants

Source: Radyowijati and Haak, 2003

Ecological model

Appropriate & inappropriate use of Antimicrobial agents

Antimicrobial Resistance

Prolonged morbidity Increased risk of mortality Increased risk of complications Transference

Cost of treatment

risk of mortality

cost of laboratory investigations

loss productivity & visit costs

USE Resistance Health Impact Economic Impact

Health system cost

Millenium Development Goals

1. Eradicating extreme poverty and hunger 2. Achieving universal primary education 3. Promoting gender equality and empowering women women 4. Reducing child mortality rates 5. Improving maternal health 6. Combating HIV/AIDS, malaria and other diseases 7. Ensuring environmental suatainability 8. Developing a global partnership for development Target 8E: In co-operation with pharmaceutical companies, provide access

to affordable, essential drugs in developing countries Proportion of population with access to affordable essential drugs on a sustainable basis

Target 8F: In co-operation with the private sector, make available the benefits of new technologies

Universal strategy for containment of AMR

reducing the disease burden and spread of infection; strengthening health systems and their surveillance

capabilities; improving access to appropriate antimicrobials; improving the use of antimicrobials; enforcing regulation and legislation; encouraging the development of appropriate new drugs and

vaccines.

Possible solutions

Determine the extent of the problem

Rationalize the use of available antimicrobial agents

Prevent emergence of resistance by reducing selection pressure by appropriate control measures

Promote discovery, development and dissemination of new antimicrobial agents

ICMR’s Antimicrobial Surveillance Network Six nodal centers, 25 regional centers Enterobacteriaceae causing sepsis: PGIMER, Chandigarh. Fungal pathogens :PGIMER, Chandigarh Gram negative nonfermenters: Christian Medical College,

Vellore. Enteric fever organisms AIIMS, New Delhi Diarrhoeagenic organisms: CMC, Vellore Grampositives including MRSA: JIPMER, Pondicherry

Surveillance of infectious diseases

Nodal centers

Regional centers

Data management Center

Diagnostics under recognized underexploited tool for resistance containment

influence 60–70% of health decisions and in developing countries, spending on diagnostics ranges from negligible to 6% Need to fund research around point of care diagnostics Create regulatory systems for uptake of existing tools Good diagnostics to win confidence of doctors Especially useful for rural health settings where labs are not

available

Source:Lewin, 2005; Peeling and Mabey, 2010

Tracking antimicrobial use Ability to undertake extensive surveillance is lacking A reproducible and sustainable surveillance methodology

needed for quantifying antibiotic use and resistance in the community Investigating the reasons and factors underlying Identify the barriers to behaviour change Implementing and evaluating interventions

National policy for containment of antimicrobial resistance

Front-page news of NDM-1in 2010 Task force of MoH, GOI prepared the national policy for

containment of antimicrobial resistance, 2011 with objective to monitor AMR, steps to decrease the AMR & misuse of ABs in the country

National policy available on National Centre for Disease Control website which is an institute under MoH

Highlights of policy Monitor use and misuse of antibiotics: Introducing schedule

H1, exclusively for sale of antibiotics.

Color coding system and restricting access for third generation antibiotics and all newer antibiotics to tertiary care hospitals

Hospital based sentinel surveillance system for monitoring antibiotic resistance: Identifying one or more Central Institute at the national level as coordinating centers

Documenting prescription patterns and establishing a monitoring system for antibiotic use

Highlights of policy Enforcement and enhancement of regulatory provisions

for use of antibiotics in human, veterinary and industrial use

Promoting rational use of drugs

Strengthening diagnostic for antimicrobial resistance monitoring

Priority initiatives • Strengthen surveillance: Implement and stregnthen national AR

surveillance plan.

• Strengthen monitoring: Develop and implement procedures for monitoring antimicrobial use in human medicine, agriculture, veterinary medicine and consumer products.

• Educate: Develop and facilitate the implementation of educational and behavioral interventions that will assist clinicians in appropriate antimicrobial prescribing

• Educate: Educational and behavioral interventions for communities to encourage adherence to recommended regimens and discourage self-prescription

Priority initiatives

Improve availability of quality diagnostics : focus to early screening and accurate diagnosis to guide/inform medicines prescription

Rationalise drug use: Support demonstration projects to evaluate comprehensive strategies that use multiple interventions to promote appropriate drug use and reduce infection rates.

Develop Standard treatment guidelines: in consultation with academia and the private sector

Infection control: Evaluate the effectiveness (including cost) of current and novel infection control practices for health care and in the community.

Superbugs* are visible manifestations of our prolonged failure to preserve antibiotics

** Methicillin resistant Staph aureus, MDR-and XDR Mycobacteria, ESBL producing Gram negative bacteria and NDM-1 producing enterobacteriaceae bacteria are few examples of superbugs because these fail to respond to large number of commonly used

Known but neglected. Need immediate action

Known but inevitable

Requirements for Strategic Success Awareness and understanding

Commitment to Action Plan

Multiple participants, public and private

Multifaceted collaborative approach

Comprehensive funding

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We need to preserve this resource by working

together

Antibiotics are a precious resource