Shiva

Antibiotic resistance
Audience-Senior Medical Officers Venue- Pune Date- 9th May 2011

Dr.J.Nuchin. MD,MBA

World Health Day 2011

Antimicrobial drug
An anti-microbial is a substance that kills (microbiocidal) or inhibits (microbiostatic) the growth of microorganisms such as bacteria, viruses, fungi, or protozoans. Antibiotics are the sub-group of antimicrobial drugs that act against bacteria. Like that antiviral, chemotherapeutic agents,antifungal and antiparasites are named. Antiseptics are antimicrobial substances that are applied to living tissue/skin to reduce the possibility of infection, sepsis, or putrefaction. Disinfectants are antimicrobial substances used on nonliving objects or outside the body.

 Technically, antibiotics are only those substances that are produced by one microorganism that kill, or prevent the growth, of another microorganism. Of course, in today's common usage, the term antibiotic is used to refer to almost any drug that attempts to rid your body of a bacterial infection. Thus, antimicrobials include not just antibiotics, but synthetically formed compounds as well. The discovery of antimicrobials is one of the most important advances in health in human history alleviating suffering from disease and saving billions of lives over the past 70 years.

History of Antimicrobials
The history of antimicrobials begins with the observations of Pasteur and Joubert, who discovered that one type of bacteria could prevent the growth of another. They did not know at that time that the reason one bacterium failed to grow was that the other bacterium was producing an antibiotic. Alexander Fleming (1928) was the first to suggest that the Penicillium mould secrete an antibacterial substance, and the first to isolate the active substance which he named penicillin, but he was not the first to use its properties in man.

Howard Walter Florey, Baron Florey, an Australian pharmacologist and pathologist extracted the penicillin and used on humans. He shared the Nobel Prize in Medicine in 1945 with Sir Ernst Boris Chain and Sir Alexander Fleming for his role in the extraction of penicillin. In 1940, he treated his first patient, Albert Alexander, who had been scratched by a rose thorn. His whole face, eyes, scalp were swollen, and he had an eye removed to relieve some of the pain. Within a day of being given penicillin, he started recovering. However they did not have enough penicillin to help him to full recovery, he relapsed, and died.

Penicillin

Fleming 1928
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Florey & Chain 1940

Albert Alexander
First Patient who received Penicillin

 The discovery of antimicrobials like penicillin(1927) and tetracycline (1948 produced by the Streptomyces genus of Actinobacteria ) paved the way for better health for millions around the world. Before penicillin became a viable medical treatment in the early 1940s, no true cure for gonorrhea, strep throat, or pneumonia existed. Patients with infected wounds often had to have a wounded limb removed, or face death from infection. Now, most of these infections can be cured easily with a short course of antimicrobials.

Antimicrobial Resistance (AMR)

However, with the development of antimicrobials, microorganisms have adapted and become resistant to previous antimicrobial agents. Antimicrobial resistance also known as drug resistance occurs when microorganisms such as bacteria, viruses, fungi and parasites change in ways that render the medications used to cure the infections they cause ineffective.(WHO) Thus AMR is a condition when infectious microbes resist the destructive effects of antimicrobials. When the microorganisms become resistant to most antimicrobials they are often referred to as superbugs. (WHO) This is a major concern because a resistant infection may kill, can spread to others, and imposes huge costs to individuals and society.

History of resistance

1941 Penicillin 1943 Streptomycin 1945 Cephalosporins 1950 Tetracyclines 1952 Eryrthromycin 1956 Vancomycin

1960 1962 1962 1970 1980 2010

Methicillin Lincomycin Quinolones Penems Monobactams The end of the antibiotic era?

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 The emergence of resistance to such drugs is a natural biological phenomenon. Microbes are living organisms that evolve over time. Their primary function is to reproduce, thrive, and spread, quickly and efficiently. Therefore, microbes adapt to their environment and change in ways that ensure their survival. If something stops their ability to spread, such as an antimicrobial, genetic changes can occur that enable the microbe to survive. There are several ways this happens.

 Although the natural phenomenon by which resistance emerges can be accelerated and amplified by a variety of factors, the most important cause is the inappropriate and injudicious use of antimicrobials in humans, animals, and agriculture.

In veterinary use
Discuss in detail

How does animal use of antibiotics contribute to resistance?

Animals consume and excrete antibiotics (approximately 2
trillion lbs of manure generated in USA annually)

Animals can transmit resistant bacteria in food

Food of animal origin most common cause of food-borne infections due to:
Salmonella Campylobacter Yersinia E Coli 0157,H7

Genetic transfer to human specific organisms (avoparcin in pigs and chickens). This can also occur with plant bacteria.

What antibiotics are used in food production?

Cattle, Swine, Sheep, Poultry
Amoxicillin Bambermycins Efrotomycin Maduramycin Oxytetracycline Tetracycline Sulfaethoxypyridazi ne

Ampicillin

Buquinolate

Erythromycin

Monensin

Penicillin

Tiamulin

Sulfamethazine

Amprolium

Carbadox

Fluoroquinilon es

Narasin

Penecillin/Streptomyc in

Tilmicosin

Sulfamethoxine

Apramycin

Ceftiofur

Furamazone

Neomycin

Robenidine

Tylosin

Sulfamyxin

Arsanilate

Chlortetracycline

Gentamycin

Nequinate

Roxarsone

Sulfabromomethazi ne

Sulfanitran

Arsanilate Sodium

Clopindal

Lacalocid

Nicarbazin

Salinomycin

Sulfachloropyrazine

Sulfaquinoxaline

Arsanilic Acid

Dequinate

Lasalocid

Novobiocin

Spectinomycin

Sulfachloropyridazin e

Sulfathiazone

Bacitracin

Dihydrostreptomyc in

Lincomycin

Oleandomyci n

Streptomycin

Sulfachlorpyidazine

Virginiamycin

Sulfadimethoxine

Zoalene

Mechanisms of resistance
The four most important antibiotic resistance mechanisms are 1. Alteration of the target site of the antibiotic 2. Enzyme inactivation of the antibiotic 3. Active transport of the antibiotic out of the bacterial cell, and 4. Decreased permeability of the bacterial cell wall to the antibiotic

Alteration of the target site of the antibiotic

By altering the target site to which an antibiotic must bind, an organism may decrease or eliminate the activity of the antibiotic. Alteration of the target site is the mechanism for one of the most problematic antibiotic resistances worldwide, methicillin resistance among Staphylococcus aureus.

Enzyme inactivation of the antibiotic

The most common mechanism by which bacteria are resistant to antibiotics is by producing enzymes that inactivate the drugs. For example, -lactam antibiotics (penicillins and cephalosporins) can be inactivated by enzymes known as -lactamases.

Active transport of the antibiotic out of the bacterial cell Active transport systems (efflux pumps) have been described for the removal of some antibiotics (such as tetracyclines, macrolides, and quinolones) from bacterial cells. In these situations, even though the drug can enter the bacterial cell, active efflux of the agent prevents it from accumulating and interfering with bacterial metabolism or replication.

Decreased permeability of the bacterial cell wall to the antibiotic

Bacteria are intrinsically resistant to many drugs based solely on the fact that the drugs cannot penetrate the bacterial cell wall or cell membrane. In addition, bacteria can acquire resistance to a drug by an alteration in the porin proteins (Porins are beta barrel proteins that cross a cellular membrane and act as a pore through which molecules can diffuse) that form channels in the cell membrane. The resistance that Pseudomonas aeruginosa exhibits to a variety of penicillins and cephalosporins is mediated by an alteration in porin proteins. Active transport of the antibiotic out of the bacterial cell

 About 80% patients in rural areas are dependent on quacks ," said Ajay Kumar, secretary, Bihar State Health Services Association, at the seminar, adding, "indiscriminate and inadequate use of antibiotics by them is a major concern, and probably this is the major cause of developing antimicrobial resistance in the state."

 In the late 1990s and 2000, WHO convened a series of consultative groups, expert workshops, and consensus meetings to assess the growing public health threat of antimicrobial resistance, to evaluate the impact of containment interventions, and to develop a series of recommendations for action. The culmination of this work was the publication in 2001 of the WHO Global Strategy for Containment of Antimicrobial Resistance and a series of supportive background materials and technical guidelines.

Conclusions
Increasing antibiotic resistance is a major threat to global public health National (and international surveillance) of resistance patterns is crucial to guide therapy; it also focuses the minds of clinicians, administrators and governments on the problem Excessive and inappropriate use of antibiotics occurs in all countries; this must be remedied at the national and local level Best-practice antibiotic guidelines coupled with drug audits, and other strategies can improve antibiotic use. The Internet and information technology holds promise for further improving prescribing in the future.

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 Hemant Shukla, regional team leader of the WHO, said on Thursday on the occasion of World Health Day "As a result of irrational use of antibiotic drugs in the last few decades, infections are no longer easily cured, leading to prolonged and expensive treatment and greater risk of death," .(TNN, Apr 7, 2011)

Overview
Trends in antimicrobial resistance Problems in developing drugs for resistant pathogens Focused development: one possible solution

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Selected resistant bacteria of public health concern: 2002

Nosocomial
Methicillin-resistant S. aureus (MRSA) Methicillin-resistant coagulase-negative staphylococci (MRCNS) Vancomycin-resistant enterococci (VRE) Multidrug-resistant Klebsiella, Pseudomonas

Community
Penicillin-resistant S. pneumoniae (PRSP) Multidrug-resistant Salmonella (non-typhi)
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Antibiotic resistance: Prevalence and incidence estimates

Microorganism Penicillin-nonsusceptible Streptococcus pneumoniae Vancomycin-resistant Enterococcus Methicillin-resistant Staphylococcus aureus Fluoroquinolone-resistant Neisseria gonorrhoaeae Multidrug-resistant Klebsiella Multidrug-resistant Salmonella
* Bloodstream infections

% resistant (US) 25% 15-25% 35-40%

Cases/yr (US) >490,000 4000* 12,000*

0.1% 10-15% 8%

500-1000 2000* 112,000

Mainous and Pomeroy (2001) 28 Extrapolation from Edmond et al. (1999) Clin Inf Dis 29:239-44

Gram-Positive Resistance - United States, 1980-1999

100

80

MRCNS Percentage of Pathogens 60 Resistant to Antibiotics 40

20 0 1975 1980 1985 1990 1995 1997

MRSA PRSP VRE GISA

2000

Paladino JA. Am J Health Syst Pharm 2000;57 Suppl 2:S10-2.

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 The search for new antibiotics Synthesis of new chemical entities Screening for new antibiotics Mammalian peptide antibiotics Peptide antibiotics from other organisms Revitalizing old antibiotics Altered peptide synthetases Alteration of peptide linkers Phenotypic conversion Carbohydrate-modified compounds Vaccines Genomic approaches Targeting virulence factors Other strategies to overcome antibiotic resistance Bacteriophage Non-antibiotics

Chlorhexidine
Application for more than one week can cause an increased resistance in S. mutans and S. sobrinus

Moral of the Story..

Avoid broad spectrum antibiotics if able Prescribe antibiotics judiciously

Prescribe for the appropriate amount and duration

Practical causes of antibiotic resistance

Development of resistance is often complicated and multi factorial Hypothesized causes in medicine and industry
Overuse and injudicious use of antimicrobials in human medicine (ample evidence and the primary cause) Overuse and injudicious use in animals (real effect is unknown) Overuse in other agricultural enterprises (?)

Other effects
Liberal availability of antibiotics to non-professionals (foreign pharmacies, feed stores) Increasing numbers of immunocompromised individuals and the elderly Patient demand to treat viral conditions with antibiotics Increase in institutional care environments (same phenomenon in concentrated animal husbandry) International travel (disseminates resistant organisms rapidly)

Antimicrobial resistance
Resistance occurs due to:
Intrinsic ability (penicillinase in E Coli) Random genetic mutation Transfer of resistance on a plasmid (extra-chromosomal DNA)

Antibiotic resistance does not always follow antibiotic use

Strept pyogenes and penicillin

Removal of antibiotic use does not always lead to reversal

Chloramphenicol reistant E Coli still present in Britain years after chloramphenicol use ceased

Illustration of plasmid transfer

Antibiotic resistance: A public health concern

Increased cost to healthcare ($3 billion/yr, range $100 million to $30 billion)
More expensive antibiotics required Longer hospital stays

Development of new antibiotics is slow and costly Prolonged illness and greater risk of death Greater risk of antibiotic resistant food borne illness (Salmonella DT-104, fluoroquinilone resistant Campylobacter)

Impact of Resistance on Antibiotic Use

Increased complexity of empiric antibiotic coverage Greater empiric use of antibiotics Increased use of broad spectrum antibiotics Perpetuates the cycle of resistance

References: on the Internet

WHO Report Overcoming Microbial Resistance: http://www.who.int/multimedia/antibiotic_res/index.html Australian Medicines Policy 2000: http://www.health.gov.au/haf/docs/nmp2000.htm Australian Quality Use of Medicines Site: http://www.qum.health.gov.au/ Australian Therapeutic Guidelines: http://www.tg.com.au/ Australian prescribing decision support project: http://wwwsph.health.latrobe.edu.au/telehealth/industry.htm#Electronic Australian and International Medicinal Drug Resources: http://wwwsph.health.latrobe.edu.au/Resources/druginfo.htm Australian HealthConnect Project: http://www.health.gov.au/healthonline/welcome.htm
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Questions?