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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
19 18
30 3229 28
3236
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53
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2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
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