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ANTIMICROBIAL

RESISTANCE
CURRENT SCENARIO AND
CHALLANGES
Dr A K Praharaj
M.D, Ph.D
Professor, Microbiology
KIMS
RESISTANCE WAS FORESEEN EARLY

Alexander Fleming, Nobel Lecture, December 1945

“The time may come when penicillin


can be bought by anyone in the shops.
Then there is the danger that the
ignorant man may easily under dose
himself and by exposing his microbes
to non-lethal quantities of the drug
make them resistant”
A GLOBAL PROBLEM!
Worldwide spread of the 23F clone of penicillin-resistant
pneumococci:

U. K
France
USA Korea

Japan
Thailand
Taiwan
Mexico
Colombia Singapore

Argentina Brazil S. Africa

By courtesy of Dr. Liselotte Diaz Högberg


Antimicrobial resistance (AMR) is the ability
What is AMR?that cause disease to
of microorganisms
withstand attack by antimicrobial
medicines.
AMR is rapidly becoming a major public
health risk and is threatening to undo
decades of advances in treating disease.

Source: WHO
MECHANISM OF AMR
 Genetic mutation
 Production of antibiotic destroying enzymes
 Efflux pump mechanism
 Cell wall remodelling
 Constitutional
 Why is antimicrobial resistance a global concern?
 New resistance mechanisms are emerging and spreading globally,
threatening our ability to treat common infectious diseases, resulting
in prolonged illness, disability, and death.
 Without effective antimicrobials for prevention and treatment of
infections, medical procedures such as organ transplantation, cancer
chemotherapy, diabetes management and major surgery (for example,
GI surgery or hip replacements) become very high risk.
 Antimicrobial resistance increases the cost of health care with
lengthier stays in hospitals and more intensive care required.
 Antimicrobial resistance is putting the gains of the Millennium
Development Goals at risk and endangers achievement of the
Sustainable Development Goals.
Introduction of antibiotics in clinical practice and emergence of antimicrobial resistance.

Bhabatosh Das et al. BMJ 2017;358:bmj.j3535

©2017 by British Medical Journal Publishing Group


ANTIBIOTIC RESISTANT INFECTIONS
Diseases Agent Resistances
Pneumonia S pneumoniae Penicillin
Dysentery S dysenteriae Multiple resistances
Typhoid S typhi Multiple resistances
Gonorrhea N gonorrhoeae Penicillin and tetracycline
Tuberculosis M tuberculosis Rifampicine and INH
Nosocomial infections S aureus Methicillin, vancomycin
Enterococci Vancomycin
Klebsiella, Pseudomonas Multiple resistances
LEADING GLOBAL INFECTIOUS DISEASES
S. pneumonia: Up to 55% resistance to
penicillin in some regions S. dyentariae: 90% resistance to cotrimoxazole S.Typhi:
Outbreaks of multi-resistant strains in 11 countries

HIV: Report of resistance


to all marketed agents M. tuberculosis:
Multi-drug resistant
tuberculosis

P. falciparum:
Chloroquine resistance in 81/92 countries
  WHO’s first release of surveillance data on antibiotic resistance
reveals high levels of resistance to a number of serious bacterial
infections in both high- and low-income countries.
 WHO’s new Global Antimicrobial Surveillance System (GLASS)
reveals widespread occurrence of antibiotic resistance among
500 000 people with suspected bacterial infections across 22
countries.
 The most commonly reported resistant bacteria
were Escherichia coli, Klebsiella pneumoniae, Staphylococcus
aureus, and Streptococcus pneumoniae, followed
by Salmonella spp.
WHAT ACCELERATES THE EMERGENCE AND SPREAD OF ANTIMICROBIAL
RESISTANCE?
 Antimicrobial resistance occurs naturally over time, usually through
genetic changes.
 Misuse and overuse of antimicrobials in people and animals accelerating
this process.
 Antibiotics used in viral infection, growth promotion in animals and in
fishery
 Antimicrobial resistant-microbes are found in people, animals, food, and
the environment (in water, soil and air).
 They can spread between people and animals, including from food of
animal origin, and from person to person.
 Poor infection control, inadequate sanitary conditions and inappropriate
food-handling
 Using Antibiotics for Growth Promotion
 When animals are given antibiotics for growth promotion or
increased feed efficiency, bacteria are exposed to low doses
of these drugs over a long period of time. This inappropriate
antibiotic use and can lead to the development of resistant
bacteria.
 As of 2017, medically important drugs–those that are
important to human health–are no longer allowed to be used
for growth promotion or feed efficiency in the U.S.
Import and spread of extended-spectrum β-lactamaseproducing Enterobacteriaceae by international travellers
(COMBAT study): a prospective, multicentre cohort study

Global action

Percentages of travellers that acquired β-lactamase-producing Enterobacteriaceae per subregion

Arcilla, LID 2016


PRESENT SITUATION
 Resistance in bacteria
 Antibiotic resistance is present in every country.
 Resistance in Klebsiella pneumoniae 
 Major cause of Hospital acquired infection
 Resistance to many antibiotics
 Carbapenem resistance varies from 17% to 67%
 Resistant to Colistin – 5%-21%
 Resistance in E. coli
 Common cause of UTI
 Resistant has increased to Fluroquinolones, Ampicillin, Co-
trimoxazole
 Carbapenem resistance in HAI – 7%- 52%
 Many centers have reported Colistin resistance
 Treatment failure in Gonorrhoea
 Resistance to penicillin and third generation cephalosporin
 Resistance to  Staphlylococcus aureus
 Common cause of severe infections in health facilities and the
community—is widespread.
 People with MRSA (methicillin-resistant Staphylococcus aureus) are
estimated to be 64% more likely to die than people with a non-
resistant form of the infection.
 Resistance to Vancomycin and Teicoplanin
 Resistant to 5th generation cephalosporin ceftaroline and
Cefbioprole
 Colistin resistance:
 Colistinis the last resort treatment for life-threatening infections
caused by Enterobacteriaceae which are resistant to carbapenems.
 Resistance to colistin has recently been detected in several
countries and regions, making infections caused by such bacteria
untreatable.
 Resistance in tuberculosis (TB)
 WHO estimates that, in 2014, there were about 480 000 new
cases of multidrug-resistant tuberculosis (MDR-TB), a form of
tuberculosis that is resistant to the 2 most powerful anti-TB
drugs Rifampicin and Isoniazid (3.3% to 20%).
 XDR -T.B
 9.7% of MDR TB have XDR TB

WHO report 2014


 Resistance in malaria
 Most Plasmodium falciparum are resistant to Chloroquin
 As of July 2016, resistance to the first-line treatment for P.
falciparum malaria (artemisinin-based combination therapies, also
known as ACTs) has been confirmed in 5 countries of the Greater
Mekong subregion (Cambodia, the Lao People’s Democratic
Republic, Myanmar, Thailand and Viet Nam).
 Along the Cambodia-Thailand border, P. falciparum has become
resistant to almost all available antimalarial medicines.
 The spread of resistant strains to other parts of the world could
pose a major public health challenge and jeopardize important
recent gains in malaria control.
 Resistance in HIV
 An estimated 7% of people starting antiretroviral therapy
(ART) in developing countries have drug-resistant HIV.
 In developed countries, the same figure was 10–20%. Some
countries have recently reported levels at or above 15%
amongst those starting HIV treatment, and up to 40% among
people re-starting treatment.
 Increasing levels of resistance have important economic
implications as second and third-line regimens are 3 times
and 18 times more expensive, respectively, than first-line
drugs.
 Resistance in influenza
 Antiviral drugs are important for treatment of epidemic and
pandemic influenza. So far, virtually all influenza A viruses
circulating in humans were resistant to one category of
antiviral drugs – M2 Inhibitors (amantadine and rimantadine).
 However, the frequency of resistance to the neuraminidase
inhibitor oseltamivir remains low (1-2%).
AMR DECADES OF CONCERN
 1959 WHO scientific group on antibiotics research recommends studies on
resistance (The Work of WHO, 1959, Official Records of WHO no. 98)
• 1981 WHO Scientific Working Group on Antimicrobial Resistance report
includes guidelines for the appropriate use of antibiotics)
(WHO/BVI/PHA/ANT/82.1)
• 2001 WHO Global Strategy for containment of antimicrobial resistance
(WHO/CDS/CSR/DRS/2001.2)
• 2011 World Health Day “Antimicrobial resistance: no action today, no cure
tomorrow” policy package
• 2012 The evolving threat of antimicrobial resistance Options for action
• 2015 Adoption by WHO of Global Action Plan for AMR • 2016 AMR
resolution at the UN General Assembly
 The Global Antimicrobial Resistance Surveillance System (GLASS)
 The WHO-supported system supports a standardized approach to the collection, analysis
and sharing of data related to antimicrobial resistance at a global level to inform decision-
making, drive local, national and regional action.
 Global Antibiotic Research and Development Partnership (GARDP)
A joint initiative of WHO and Drugs for Neglected Diseases initiative (DNDi), GARDP encourages
research and development through public-private partnerships. By 2023, the partnership aims to
develop and deliver up to four new treatments, through improvement of existing antibiotics and
acceleration of the entry of new antibiotic drugs.
 Inter- agency Coordination Group on Antimicrobial Resistance (IACG)
The United Nations Secretary-General has established IACG to improve coordination
between international organizations and to ensure effective global action against this
threat to health security. The IACG is co-chaired by the UN Deputy Secretary-General
and the Director General of WHO and comprises high level representatives of relevant
UN agencies, other international organizations, and individual experts across different
sectors.
 
ANTIMICROBIAL RESISTANCE RESEARCH AND INTERVENTIONS GLOBALLY

 In 2011, the Chinese Ministry of Health implemented a campaign for


rational use of antibiotics in healthcare, accompanied by supervision audits
and inspections. Over a year, superfluous prescription of antimicrobials
was reduced by 10-12% for patients in hospital and for outpatients, as were
drug sales for antimicrobials.
 The Swedish Strategic Programme against Antibiotic Resistance (STRAMA)
led to a decrease in antibiotic use for outpatients from 15.7 to 12.6 daily
doses per 1000 inhabitants . The decrease was most evident for macrolides
(65%)
 The effect of WHO essential medicines policies was studied in 55 countries.
These policies were linked to reductions in antibiotic use of ≥20% in upper
respiratory tract infections.
 A national strategy to contain antibiotic resistance was associated with a
30% reduction in the use of antibiotics in acute diarrheal illness.
CONTD…
 An antimicrobial stewardship programme (2009-2014) in 47
South African hospitals led to a reduction in mean antibiotic
defined daily doses per 100 patient days from 101.4 to 83.04
 In the US, infections with carbapenem resistant
Enterobacteriaceae declined after the Antimicrobial Resistance
Monitoring and Research Programme was started. In addition,
there were no further reports of outbreaks caused by colistin
resistant Acinetobacter spp
 In the Netherlands, a decrease of CTX-M-1-1-like ESBL genes
(from 44% to 25%) in livestock was seen during 2010-14, possibly
linked to considerable (>60%) reduction in antibiotic use in
livestock.
Trends in glycopeptide consumption and MRSA rate
Correlation between resistance rate and consumption

In the “red” country there is


an increasing usage of
antibiotics although rate of
resistance are significantly
decreasing

Tacconelli (under submission)


WHAT CAN BE DONE TO REDUCE AMR
 Promoting further research on the drivers of AMR with due
importance to components other than antimicrobial use for
human health alone.
 Framing of antibiotic stewardship plans for healthcare settings
to monitor and ensure judicious use of antimicrobials.
 Strict vigilance and control over sale of antimicrobial agents.
Prescription audit to bring down the over the counter (OTC)
sale
 Disciplinary control over the functioning of hospital effluent
plants with periodic assessment and reporting of antimicrobial
residue in the discharge
 Regulation of waste water discharges from pharmaceutical
companies with regular monitoring of antimicrobial residues in
them along with provision of legislative support to punish offenders
 Framing and implementing rules and regulations for the use of
antimicrobial agents in food animals including farmed seafood
 Improving agricultural practices by ensuring use of environment-
friendly manure and fertilizers
 Educating the masses at the community level regarding AMR and
formulating educational bodies/non-governmental organizations
for continued dissipation of information.
 Development of newer Antibiotics
DISCOVERING ANTIBIOTICS IN NEW WAYS
Teixobactin: iChip
A new class of antibiotics

In the Nature study, teixobactin was shown to kill Staphylococcus


aureus and Mycobacterium tuberculosis without the bacteria developing
a resistance to the antibiotic.

Binds to lipids that build the cell wall.


Thank you