WAR AGAINST BACTERIAL RESISTANCE

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The enormous world of microorganism source antibiotics to mankind in the war against pathogenic microbes. These microbes in turn tilt the balance to their favor by acquiring resistance against antibiotics, through borrowed genes from a pool widely distributed in the microbial world itself. This collateral damage of misuse of antibiotics on one patient is not limited to that patient, but affects whole society, through expansion of environmental resistome. Both antibiotics and resistance are secondary metabolites involved in varied process, with existence history of million years. Therefore, any antibiotic that would be discovered in future, resistance against it would already be existing in microbial world, which will be acquired by the target bacteria sooner or later. The fight against infection cannot not be won with antibiotics, but truce may be attained through infection control and antibiotic stewardship.

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WAR AGAINST BACTERIAL RESISTANCE VICTORY VS TRUCE:

WAR AGAINST BACTERIAL RESISTANCE VICTORY VS TRUCE Dr. Ubaidur Rahaman MD (Internal Medicine), EDIC Internist and Critical Care Specialist

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Here is a hypothetical illustration. Mr X has a sore throat. He buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin. He then infects his wife. Mrs X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails. Mrs. X dies. Who is primarily responsible for Mrs. X’s death?” “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.

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1940 Penicillinase E. coli Penicillin 1943 Streptomycin 1944 1947 Penicillinase R Staph 1945 Streptomycin R Chloramphenicol and Polymyxin 1947 Erythromycin 1953 Bacitracin 1945 Tetracycline 1950 RESISTANCE AND ANTIBIOTIC DISCOVERY WALKED TOGETHER Methicillin 1960 Ampicillin

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Jon Clardy, Michael Fischbach, and Cameron Currie. The natural history of antibiotics. Curr Biol. 2009 June 9; 19(11): R437–R441. Nearly all the antibiotics discoveries, with few exception (trimethoprim, monobactams, fosfomycin and cabapenems ), were serendipitous by empirical screening not innovative.

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Erythromycin 1953 Tetracycline 1950 RESISTANCE IS A EMERGING PROBLEM 1959 Tetracycline R Shigella Methicillin 1960 Gentamycin 1967 Vancomycin 1972 Imipenem and Ceftazidime 1985 Levofloxacin 1996 Linezolid 2000 Ceftaroline 2010 1962 Methicillin R Staph 1968 Erythromycin R Streptococcus 1979 Gentamycin R Enterococcus 1987 Ceftazidime R Enterobacteriaceae 1988 Vancomycin R Enterococcus 1996 Levofloxacin R Pneumococcus 1998 Imipenem R Enterobacteria 2001 Linezolid R Staphylococcus 2002 Vancomycin R Staphylococcus 2004/5 PDR Acinetobacter and Pseudomonas 2009 PDR Enterobacteriaceae 2011 Ceftaroline R Staphylococcus

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DISCOVERY VOID OF ANTIBIOTICS (dates are reported initial discovery or patent) 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 PENICILLIN SULFONAMIDE SREPTOMYCIN BACITRACIN NITROFURAN CHLORAMPHENICOL POLYMYXIN CHLOROTETRACYCLIN CEPHALOSPRORIN ERYTHROMYCIN ISONIAZID VANCOMYCIN CYCLOSERINE NOVOBIOCIN RIFAMPICIN METRONIDAZOLE LINCOMYCIN TRIMETHOPRIM NALIDIXIC ACID FUSIDIC ACID MUPIROCIN CARBAPENEM MONOBACTUM OXAZOLIDINONE FOSFOMYCIN DAPTOMYCIN DISCOVERY VOID Lynn L. Silver. Challenges of Antibacterial Discovery. CLINICAL MICROBIOLOGY REVIEWS, Jan. 2011, p. 71–109

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1940 1950 1960 1970 1980 1990 2000 PENICILLINASE DISCOVERY ANTIBIOTIC RESISTANCE PLASMID TRANSMISSIBLE FLOUROQUINOLONE RESISTNCE INCREASING ANTIBIOTIC RESISTANCE THE DARK AGE (SEMMELWEIS) DISENCHANTMENT (SEMMELWEIS) (AGAIN) PHARMACOLOGIC BIOCHEMICAL TARGET GENOMIC HTS PRIMORDIAL GOLDEN FDA OFFICE OF NEW DRUG Julian Davies* and Dorothy Davies . Origins and Evolution of Antibiotic Resistance. MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS, Sept. 2010, p. 417–433 COMPLETING A FULL CIRCLE

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WHO REALLY DISCOVERED ANTIBIOTICS? WHO IS THE FIRST FARMER?

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DESPITE UTILIZING ANTIBIOTICS OVER MILLIONS OF YEARS, ANTIBIOTIC RESISTANCE DID NOT DEVELOP IN WILD ENVIRONMENT OF ATTINI ANTS [9] , WHILE HUMANS COULD NOT PREVENT THIS CATASTROPHE IN JUST 80 YEARS OF USE

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ANTIBIOTICS is ANCIENT

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RESISTANCE IS ANCIENT Soldier died in WW1 (March 1915) Shigella flexneri R to Penicillin and Erythromycin Penicillin discovered in 1929 Erythromycin discovered in 1953 Soil from beringian permafrost, place near bering strait in Alaska genes encoding resistance to beta lactam, tetracycline and glycopeptide antibiotics ESBL enzymes originated more than two billion years ago Beta lactamase is evolving for more than 100 million years

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Abraham, E. P., and E. Chain. 1940. An enzyme from bacteria able to destroy penicillin. Rev. Infect. Dis. 10:677–678. ANTIBIOTICS AND RESISTANCE ARE PRESENT IN MICROBIAL WORLD FOR MILLENNIA, WE ONLY ACKNOWLEDGED ITS EXISTENCE RECENTLY. ANTIBIOTICS AND RESISTANCE ARE ANCIENT

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WHAT IS THE ROLE OF SO CALLED ANTIBIOTICS AND RESISTANCE IN NATURE? ANTIBIOTICS ARE MESSENGER RESISTANCE ARE BLOCKERS Grace Yim , Helena Huimi Wang, Julian Davies . The truth about antibiotics. International Journal of Medical Microbiology 296 (2006) 163–170

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WHAT IS THE ROLE OF SO CALLED ANTIBIOTICS AND RESISTANCE IN NATURE? Diego Romero ,  Matthew F. Traxler ,  Daniel López ,  Roberto Kolter . Antibiotics as Signal Molecules. Chem Rev. 2011 Sep 14; 111(9): 5492–5505. SO CALLED ANTIBIOTICS ARE NOT MEANT FOR ANTIBIOSIS IN NATURE, IT EXERTS THIS EFFECT ONLY IN CONCENTRATION MUCH ABOVE THAN PRESENT IN NATURE

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ANTIBIOTICS POLLUTION

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Gerald B. Pier. On the Greatly Exaggerated Reports of the Death of Infectious Diseases.  Clin Infect Dis  2008;47(8):1113-4 Rustam I. Aminov . The role of antibiotics and antibiotic resistance in nature. Environ Microbiol 2009;11(12), 2970-88. BUT….. COMPLACENCY PREVAILED

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BUT….. COMPLACENCY PREVAILED It was presumed initially, that antibiotic resistance would largely be result of target modification through MUTATION which will remain limited to bacterial clone by VERTICAL INHERITANCE .

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C ell-to-cell contact was required for resistance-gene transfer, indicating that bacterial conjugation was involved. This was subsequently confirmed by experiments that showed that blending (agitation) interfered with transfer. Multiple antibiotic resistance of Shigella dysenteriae strains could be transferred to other Enterobacteriaceae, simply by mixing liquid cultures of resistant and sensitive bacteria and plating on solid medium containing the appropriate antibiotics as selective agents WAR TORN JAPAN 1959 Epidemic multidrug resistant Shigella dysenteriae (Streptomycin, Chloramphenicol, Tetracycline, Sulfonamide) HGT

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Naomi Dutta UNITED KINGDOM 1959 multidrug resistant Salmonella typhimurium G. LEBEK obtained evidence for transferable, multiple antibiotic resistance in Salmonella typhimurium and E. coli isolated from children in 1960. The presentation of his results was met with “harsh and unpleasant” criticism (his words) in Munich and LEBEK was dismissed. He was unemployed for several months and then accepted a position in Bern, Switzerland. A report of his work was eventually published in 1963 Lebek G. Uber die Enstehung mehrfachresistanter Salmonellen- Ein experimenteller Beitrag. Zbl . Bact., Dept. I, Orig. 1963;188: 494-499. HGT

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BORROWER BACTERIA RESISTANCE GENE DONOR BACTERIA CARBAPENEM R ENTEROBAC, ACINATOBACTER, PSEUDOMONAS blaCTX -M KLUYVERA CARBAPENEM R ENTEROBAC, ACINATOBACTER, PSEUDOMONAS blaNDM ERYTHROBACTER LITORALIS VRSA VanA VRE

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HGT Plasmid carry considerable variety of genes determining resistance to multiple antibiotics as well as genes conferring virulence to bacterium.

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MILLION YEARS OF MACRO EVOLUTION BY MAINLY VERTICAL GENE TRANSFER (MUTATION) 80 YEARS OF MICRO EVOLUTION MAINLY BY HGT EVOLUTION OF ANTIBIOTIC RESISTANCE AND SELECTION PRESSURE

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PAN MICROBIOME, PANGENOME AND RESISTOME PANGENOME

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GLOBAL MICROBIOME PANGENOME PANPROTEOME MOBILOZOME RESISTOME PARVOME CLINICALLY IMPORTANT RESISTANCE GENES CLINICALLY IMPORTANT ANTIBIOTIC MOLECULES HUMAN ANTIBIOTIC PRODUCTION Gillings MR. Evolutionary consequences of antibiotic use for the resistome, mobilome and microbial pangenome. Front Microbiol . 2013 Jan 22;4:4. CONCEPTUAL REPRESENTATION OF THE BIOLOGICAL MOLECULES OF RELEVANCE TO ANTIBIOTIC RESISTANCE.

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CLINICAL ECOSYSTEM HIGH SELECTION PRESSURE NON-CLINICAL ECOSYSTEM MODERATE SELECTION PRESSURE ENVIRONMENTAL ECOSYSTEM RESISTOME Eileen R. Choffnes , David A. Relman , Alison Mack. Antibiotic resistance: implications for global health and novel intervention strategies: workshop summary rapporteurs; Forum on Microbial Threats, Board on Global Health, Institute of Medicine of the National Academies. United States: Washington D.C. National Academies Press; 2010. EXPANSION OF RESISTOME

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ANTIBIOTIC EXPLOITATION

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WATER TREATMENT PLANT/ SEWER RIVER/ SOIL EXPANSION OF ENVIRONMENT RESISTOME ANTIBIOTIC RESISTANCE AND WASTE DISPOSAL

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CLINICAL ECOSYSTEM HIGH SELECTION PRESSURE NON-CLINICAL ECOSYSTEM MODERATE SELECTION PRESSURE ENVIRONMENTAL ECOSYSTEM RESISTOME Eileen R. Choffnes , David A. Relman , Alison Mack. Antibiotic resistance: implications for global health and novel intervention strategies: workshop summary rapporteurs; Forum on Microbial Threats, Board on Global Health, Institute of Medicine of the National Academies. United States: Washington D.C. National Academies Press; 2010. EXPANSION OF RESISTOME

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PATIENT ADMITTED TO HOSPITAL

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Help us from antibiotic pollution These humans polluted our environment with our secondary metabolites Not to worry mates. Borrow these variety of resistance genes How come man forget, We produce antibiotics as well as resistance. they are unleashing havoc on our siblings with weapon provided by us. We will enrich our colleagues with counter weapons They call it antibiotics Our genes will prevail over humans wits ESBL AMP C MBL MRSA ESBL MBL AMP C BACTERIAL SOCIAL SECURITY SYSTEM 06/01/2018

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“Long term harm to self, others and environment, when unrestrained individual behavior to maximize personal short-term gain, results in depletion or devastation of resources”

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ANTIBIOTICS ARE SOCIETAL DRUGS The collateral damage of misuse of antibiotics on one patient is not limited to that patient, but affects whole society, through expansion of environmental resistome .

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EVOLUTION OF NEW PATHOGENS HOW BENIGN COMMENSALS/ ENVIRONMENTAL BACTERIA TURN INTO DREADED PATHOGENS Bacteria can evolve rapidly to adapt to environmental change. When the "environment" is the immune response of an infected host, this evolution can turn harmless bacteria into life-threatening pathogens Miskinyte M, Sousa A, Ramiro RS, de Sousa JAM, Kotlinowski J, Caramalho I, Magalhães S, Soares MP and Gordo I.  The Genetic Basis of Escherichia coli Pathoadaptation to Macrophages .  PLoS Pathog , 9(12): e1003802

VIRULENCE VS RESISTANCE:

VIRULENCE VS RESISTANCE RESISTANCE COMES AT EVOLUTIONARY COST OF VIRULENCE Beceiro A, Tomás M, Bou G. Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world?.  Clin Microbiol Rev. 2013;26(2):185-230. HGT

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WHO WILL WIN THE WAR? OUR WITS VERSUS THEIR GENES “FUTURE OF HUMANITY AND MICROBES LIKELY WILL UNFOLD AS EPISODES OF A SUSPENSE THRILLER THAT COULD BE TITLED  ‘OUR WITS VERSUS THEIR GENES’” “As the climax is arriving, it is becoming more evident that our wits of discovering secondary metabolites of bacteria, and tinkering, producing and using it as antibiotic in exuberant amount, cannot not keep pace with bacterial ability to manipulate its genetic pool of resistance”

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WE CAN NEVER WIN THE WAR WITH ANTIBIOTICS ALONE 06/01/2018

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SOLUTION- VICTORY VERSUS TRUCE ANY ANTIBIOTIC THAT WOULD BE DISCOVERED IN FUTURE, RESISTANCE AGAINST IT WOULD ALREADY BE EXISTING IN MICROBIAL WORLD, WHICH WILL BE ACQUIRED BY THE TARGET BACTERIA SOONER OR LATER.

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SOLUTION- VICTORY VERSUS TRUCE

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MILLION YEARS OF MACRO EVOLUTION BY MAINLY VERTICAL GENE TRANSFER (MUTATION) 80 YEARS OF MICRO EVOLUTION MAINLY BY HGT TRUCE

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must be reflected in clinical examination, nursing care and invasive procedure Maximize clinical outcome and minimize collateral damage

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Yong, Ed. I Contain Multitudes: The Microbes Within Us and a Grander View of Life (Kindle Location 1). Random House. Kindle Edition.

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