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A Tribute to - Fleming and Penicillin:

A Tribute to - Fleming and Penicillin Dr.T.V.Rao MD 2

Brief History of Antibiotics:

Brief History of Antibiotics 1928- Penicillin discovered by Fleming • 1932- Sulfonamide antimicrobial activity discovered ( Erlich) • 1935- First unsuccessful attempt to use Sulfonamide to treat • a case of meningitis • 1943- Drug companies begin mass production of penicillin • 1948- Cephalosporins precursor sent to Oxford for synthesis • 1952- Erythromycin derived from Streptomyces erythreus • 1956- Vancomycin introduced for penicillin resistant staphylococcus Dr.T.V.Rao MD 3

Recent Antibiotics in Use:

Recent Antibiotics in Use • 1962- Quinolone antibiotics first discovered • 1970s- Linezolid discovered but not pursued • 1980s- Fluorinated Quinolones introduced, making then clinically useful • 2000- Linezolid introduced into clinical practice Dr.T.V.Rao MD 4

The Magic Bullets:

The Magic B ullets Antibiotics revolutionised medicine The first antibiotic, penicillin, was discovered by Alexander Fleming in 1929 It was later isolated by Florey and Chain It was not extensively used until the 2nd World War when it was used to treat war wounds After 2nd World War many more antibiotics were developed Today about 150 types are used Most are inhibitors of the protein synthesis, blocking the 70S ribosome, which is characteristic of prokaryotes © 2008 Paul Billiet ODWS Dr.T.V.Rao MD 5

Survival of the Fittest. Darwin’s theory rules the Microbes:

Survival of the Fittest. Darwin’s theory rules the Microbes Various microorganisms have survived for thousands of years by their being able to adapt to antimicrobial agents. They do so via spontaneous mutation or by DNA transfer. These microorganisms employ several mechanisms in attaining multidrug resistance Dr.T.V.Rao MD 6


Resistance It took less than 20 years for, bacteria to show signs of resistance Staphylococcus aureus , which causes blood poisoning and pneumonia, started to show resistance in the 1950s Today there are different strains of S. aureus resistant to every form of antibiotic in use S Dr.T.V.Rao MD 7

Multiple drug resistance:

Multiple drug resistance Multiple drug resistance or Multidrug resistance is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety[1] of structure and function targeted at eradicating the organism. Organisms that display multidrug resistance can be pathologic cells, including bacterial . Dr.T.V.Rao MD 8

MDRO: Definition :

MDRO : Definition Multidrug-Resistant Organisms (MDROs) are defined as microorganisms that are resistant to one or more classes of antimicrobial agents. Three most common MDROs are: 1. Methicillin-Resistant Staph aureus (MRSA) 2. Vancomycin Resistant Enterococci : (VRE) 3. Extended Spectrum Beta-Lactamase producing Enterobacteriaceae. (ESBLs) CDC: Management of Multidrug-Resistant Organisms in Healthcare Settings, Healthcare Infection Control Advisory Committee, Jane D. Siegel et. al. pg 7-12 Dr.T.V.Rao MD 9

Antibiotic Pressure and Resistance in Bacteria What is it ? :

Antibiotic Pressure and Resistance in Bacteria What is it ? ” Selection pressure of antibiotics has led to the emergence of antibiotic-resistant bacteria.” Antibiotics can effect bacteria unrelated to the targeted infectious agent; these may be “normal” flora, leading to the emergence of resistant mutants inhabiting the same environment. Baquero et al., International Report 1996;23:819 Dr.T.V.Rao MD 10

Settings that Promote Drug Resistance:

Settings that Promote Drug Resistance Day-care centers Long term care facilities Homeless shelters Jails Dr.T.V.Rao MD 11


Intensive care units Oncology units Dialysis units Rehab units Transplant units Burn units Location contributing to Drug Resistance Dr.T.V.Rao MD 12

Transposons & Integrons:

Transposons & Integrons Resistance genes are often associated with transposons, genes that easily move from one bacterium to another Many bacteria also possess integrons, pieces of DNA that accumulate new genes Gradually a strain of a bacterium can build up a whole range of resistance genes This is multiple resistance These may then be passed on in a group to other strains or other species Dr.T.V.Rao MD 13

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Dr.T.V.Rao MD 14

Antibiotics promote resistance:

Antibiotics promote resistance If a patient taking a course of antibiotic treatment does not complete it Or forgets to take the doses regularly, Then resistant strains get a chance to build up The antibiotics also kill innocent bystanders bacteria which are non-pathogens This reduces the competition for the resistant pathogens The use of antibiotics also promotes antibiotic resistance in non-pathogens too These non-pathogens may later pass their resistance genes on to pathogens ODWS Dr.T.V.Rao MD 15

Multi-resistance :

Multi-resistance Multi-resistance Multi-resistance to different antibiotics generally results from a combination of different independent mechanisms of resistance . - P aeruginosa is a type of multi-resistant bacteria. It is resistant to β-lactams, including third-generation cephalosporins, quinolones, chloramphenicol, and Tetracycline's. (natural resistance) -Methicillin-resistant strains have become resistant to most antibiotics and with a high frequency of high resistance. (acquired) Cross-resistance Cross-resistance Occurs generally in antibiotics of the same family. -Cross-resistance between penicillin's, more widely between all the β-lactams Dr.T.V.Rao MD 16

Consequences of Antimicrobial Resistance:

Consequences of Antimicrobial R esistance Compromised therapy of human infections • Serious complications for elderly and children • Increased length of therapy and more doctor visits • Prolonged hospital stay and significant increase of treatment cost “Bacterial resistance is a major threat to public health” Dr.T.V.Rao MD 17

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Folic acid synthesis ß -lactams & Glycopeptides ( Vancomycin) 50 50 50 30 30 30 DNA mRNA Ribosomes PABA DHFA THFA Cell wall synthesis DNA gyrase Quinolones Protein synthesis inhibition Protein synthesis inhibition Tetracyclines Protein synthesis mistranslation Macrolides & Lincomycins Cohen. Science 1992; 257:1064 DNA-directed RNA polymerase Rifampin Aminoglycosides Sulfonamides Trimethoprim Dr.T.V.Rao MD 18

Causes of Resistance in MDROs:

Causes of Resistance in MDROs Enzymatic degradation Mutation at binding site Down regulation of outer membrane proteins Efflux pumps Transduction of genes Dr.T.V.Rao MD 19

Mechanisms of Resistance: Efflux:

Mechanisms of Resistance: Efflux Active, energy dependent pumps cause efflux of drugs Bacterial Cytosol PG layer Outer membrane drug Efflux pump Dr.T.V.Rao MD 20

Antibiotic Pressure and Resistance in Bacteria Why is it important? :

Antibiotic Pressure and Resistance in Bacteria Why is it important ? Antibiotic resistance has developed in almost all classes of bacteria of pathogenic potential. Resistance in organisms of low virulence can emerge as important pathogens. The development of resistant bacteria has driven pharmaceutical research to develop more potent, broad-spectrum antibiotics. Use of these in turn, has fueled the appearance of bacteria with newer modes of resistance. Dr.T.V.Rao MD 21


INCREASING PREVALENCE OF ANTIMICROBIAL RESISTANT MICROBES Hospital-acquired infections Methicillin-resistant staphylococci Vancomycin-resistant staphylococci Vancomycin-resistant enterococci ESC-resistant Gram-negative bacteria Azole-resistant Candida Dr.T.V.Rao MD 22

1.Methicillin-Resistant Staph aureus (MRSA):

1.Methicillin-Resistant Staph aureus (MRSA) These are organisms that are not sensitive to common penicillin based drugs such as methicillin, amoxicillin, penicillin, oxacillin 1 Normal flora- lives on human skin, noses, vaginal tract May cause infections if enters the body Contagious- through person to person contact Treatment - Vancomycin Dr.T.V.Rao MD 23

Vancomycin Resistant Enterococci (VRE):

Vancomycin Resistant Enterococci (VRE) Enterococci resistant to Vancomycin Present in human body such as urinary tract and GI tract. Contagious Hospital patients can get it from contact via health care providers. Normal flora that may cause disease especially in vulnerable populations: Eg elderly, children and immunocompromised patients. Dr.T.V.Rao MD 24

Vancomycin Resistant Enterococci (VRE):

Vancomycin Resistant Enterococci (VRE ) VRE include: Enterococcus faecalis Enterococcus faecium Treated with Synercid (quinupristin and dalfopristin) VRE can live on surfaces for up to 7 days!!! Haemophilus influenzae lives about 2 days Dr.T.V.Rao MD 25

VRE prevention:

VRE prevention Standard precautions Hand hygiene Personal Protective Equipment (PPE) Needle stick and sharps injury prevention. Cleaning & disinfection Respiratory hygiene (Cough Etiquette) Waste disposal Safe injection practices Center for Disease Control and Prevention: Accessed June 17 th 2009 Dr.T.V.Rao MD 26

Extended Spectrum Beta-Lactamase producing Enterobacteriaceae. (ESBL) :

Extended Spectrum Beta-Lactamase producing Enterobacteriaceae. (ESBL) ESBLs are plasmid-mediated beta lactamases described in gram negative bacilli 2 Eg. Klebsiella, Acinetobacter MOA – hydrolysis of beta- lactam ring in Penicillin's Narrow spectrum cephalosporins Beta-lactamase inhibitors inhibit ESBL producing strains Clavulanic acid Sulbactam Tazobactam . Dr.T.V.Rao MD 27

Enzymatic degradation of ESBLs: Mechanisms of b-lactamase:

Enzymatic degradation of ESBLs: Mechanisms of b -lactamase N O N O OH S CH 3 CH 3 O R H b -lactamase CH 2 OH b -lactamase CH 2 OH N O N O OH S CH 3 CH 3 O R H b -lactamase CH 2 O H H 2 O N O N O OH S CH 3 CH 3 O R H H OH b -lactamase CH 2 OH + Hydrolysis of Oxyimino group Penicillin drug Inactivated drug Dr.T.V.Rao MD 28

Other Drug Resistant Diseases:

Other Drug Resistant Diseases Extensively-Drug Resistant Tuberculosis (XDR-TB) This is a TB causing organism that is resistant to almost all drugs that are used to treat TB. Isoniazid Rifampin Fluoroquinolones At least one of: Amikacin, kanamycin, capreomycin The main cuasitive organism is M ycobacterium tuberculosis 3 Contagious through droplets but slower than viral infection such as flu Dr.T.V.Rao MD 29

CDC Reports:

CDC Reports Three Enterobacteriaceae isolates carrying a newly described resistance mechanism, the New Delhi metallo-beta-lactamase (NDM-1) , were identified from three U.S. states at the CDC antimicrobial susceptibility laboratory. This is the first report of NDM-1 in the United States, and the first report of metallo-beta-lactamase carriage among Enterobacteriaceae in the United States Dr.T.V.Rao MD 30

CDC reports the new genetic mechanisms:

CDC reports the new genetic mechanisms The isolate, Klebseilla pneumoniae 05-506, was shown to possess a metallo-beta-lactamase (MBL) but was negative for previously known MBL genes. Gene libraries and amplification of class 1 integrons revealed three resistance-conferring regions; the first contained bla(CMY-4) flanked by ISEcP1 and blc . The second region of 4.8 kb contained a complex class 1 integron with the gene cassettes arr-2, a new erythromycin esterase gene; ereC; aadA1; and cmlA7 Dr.T.V.Rao MD 31

Genetic origin of the NDM-1:

Genetic origin of the NDM-1 An intact ISCR1 element was shown to be downstream from the qac/sul genes. The third region consisted of a new MBL gene, designated bla(NDM-1), flanked on one side by K. pneumoniae DNA and a truncated IS26 element on its other side. The last two regions lie adjacent to one another, and all three regions are found on a 180-kb region that is easily transferable to recipient strains and that confers resistance to all antibiotics except fluoroquinolones and colistin. NDM-1 shares very little identity with other MBLs, with the most similar MBLs being VIM-1/VIM-2, with which it has only 32.4% identity. Dr.T.V.Rao MD 32

Molecular configuration of NDM-1:

Molecular configuration of NDM-1 NDM-1 also has an additional insert between positions 162 and 166 not present in other MBLs. NDM-1 has a molecular mass of 28 kDa, is monomeric, and can hydrolyze all beta-lactams except aztreonam. Compared to VIM-2, NDM-1 displays tighter binding to most Cephalosporins. Dr.T.V.Rao MD 33

NDM genetic coding differs from other recent isolates:

NDM genetic coding differs from other recent isolates Compared to VIM-2, NDM-1 displays tighter binding to most cephalosporins, in particular, cefuroxime, cefotaxime, and cephalothin (cefalotin), and also to the penicillins. NDM-1 does not bind to the carbapenems as tightly as IMP-1 or VIM-2 and turns over the carbapenems at a rate similar to that of VIM-2. In addition to K. pneumoniae 05-506, bla(NDM-1) was found on a 140-kb plasmid in an Escherichia coli strain isolated from the patient's feces, inferring the possibility of in vivo conjugation Dr.T.V.Rao MD 34

Antibiotic use and Major abuse:

Antibiotic use and Major abuse Viral infections are not stopped by antibiotics Yet doctors still prescribe (or are coerced into prescribing) antibiotics to treat them Dr.T.V.Rao MD 35


INCREASING PREVALENCE OF ANTIMICROBIAL RESISTANT MICROBES Community-acquired infections Multidrug resistant pneumococci Drug-resistant H. influenzae FQ- and ESC-resistant Salmonella Multidrug resistant Shigella FQ-resistant gonococci Multidrug-resistant M. tuberculosis Drug-resistant malaria Drug-resistant HIV Dr.T.V.Rao MD 36

Nosocomial infections – Attains Higher Resistance.:

Nosocomial infections – Attains Higher Resistance. Major nosocomial pathogens increasingly resistant to antimicrobial drugs include Escherichia coli, Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus species, and Pseudomonas aeruginosa . Infections from methicillin- resistant staphylococci, vancomycin-resistant enterococci (VRE), and aminoglycoside-resistant Pseudomonas spp. are becoming common. Dr.T.V.Rao MD 37

Antibiotic Misuse – Consequences.:

Antibiotic Misuse – Consequences . Large amounts of antibiotics used for human therapy, as well as for farm animals and even for fish in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. Multidrug resistance in bacteria may be generated by one of two mechanisms. First, these bacteria may accumulate multiple genes, each coding for resistance to a single drug, within a single cell. This accumulation occurs typically on resistance (R) plasmids. Second, multidrug resistance may also occur by the increased expression of genes that code for multidrug efflux pumps, extruding a wide range of drugs. Dr.T.V.Rao MD 38

Bacteria attains Resistance by Complex Mechanisms :

Bacteria attains Resistance by Complex Mechanisms # No longer relying on a glycoprotein cell wall # Enzymatic deactivation of antibiotics # Decreased cell wall permeability to antibiotics # Altered target sites of antibiotic # Efflux mechanisms to remove antibiotics[3] # Increased mutation rate as a stress response[4 Dr.T.V.Rao MD 39

Gene Transfers play a Major rule in Antibiotic Resistance:

Gene Transfers play a Major rule in Antibiotic Resistance Many different bacteria now exhibit multidrug resistance, including staphylococci, enterococci, gonococci, streptococci, salmonella, Mycobacterium tuberculosis and others. In addition, some resistant bacteria are able to transfer copies of DNA that codes for a mechanism of resistance to other bacteria, thereby conferring resistance to their neighbors, which then are also able to pass on the resistant gene. This process is called horizontal gene transfer. Dr.T.V.Rao MD 40

Role of clinical Microbiology Laboratories :

Role of clinical Microbiology L aboratories The clinical laboratory has several critical roles in controlling hospital-acquired infections: accurately identifying nosocomial pathogens, detecting unexpected antimicrobial-drug resistance, and epidemiologic typi ng Dr.T.V.Rao MD 41

Antibiotic Pressure and Resistance in Bacteria What factors promote their development and spread ?:

Antibiotic Pressure and Resistance in Bacteria What factors promote their development and spread ? Alteration of normal flora Practices contributing to misuse of antibiotics Settings that foster drug resistance Failure to follow infection control principles Dr.T.V.Rao MD 42

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Inappropriate specimen selection and collection Inappropriate clinical tests Failure to use stains/smears Failure to use cultures and susceptibility tests Practices Contributing to Misuse of Antibiotics Dr.T.V.Rao MD 43

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Use of antibiotics with no clinical indication (eg, for viral infections) Use of broad spectrum antibiotics when not indicated Inappropriate choice of empiric antibiotics Lack of quality control in manufacture or outdated antimicrobial Inadequate surveillance or defective susceptibility assays Poverty or war Use of antibiotics in foods Inappropriate Antibiotic Use Dr.T.V.Rao MD 44

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Inappropriate dose - ineffective concentration of antibiotics at site of infection Inappropriate route - ineffective concentration of antibiotics at site of infection Inappropriate duration Inappropriate Drug Regimen Dr.T.V.Rao MD 45

Newer methods too have limitations:

Newer methods too have limitations Most new rapid tests are not yet helpful for infection control purposes, and automated systems for bacterial identification and susceptibility testing are not as reliable as desired for detecting organisms with emerging drug resistance Dr.T.V.Rao MD 46

Microbiology Laboratories to Play Greater Role:

Microbiology Laboratories to Play Greater Role A microbiology laboratory fully equipped to cooperate in the management of nosocomial infections will also have the necessary infrastructure to act as a sentinel to detect new antimicrobial agent resistance Dr.T.V.Rao MD 47

Implication of MDROs:

Implication of MDROs Increase hospital stay Average 3-5 additional days Increase hospital costs Increase morbidity and mortality CDC: Management of Multidrug-Resistant Organisms in Healthcare Settings, Healthcare Infection Control Advisory Committee, Jane D. Siegel et. al. pg 7-12 Dr.T.V.Rao MD 48

MDROs prevention :

MDROs prevention Observe the universal standard precautions Practice 200% percent safety rule Good hygiene practice Frequent hand wash Cover cuts and scrapes Do not share personal items eg razors Do not pressure doctors for antibiotics Finish all antibiotic medications Health care providers to wash hands before touching patients Isolation for serious cases Dr.T.V.Rao MD 49

Proposals to Combat Antimicrobial Resistance:

Proposals to Combat Antimicrobial Resistance Speed development of new antibiotics Track resistance data nationwide Restrict antimicrobial use Direct observed dosing (TB) Dr.T.V.Rao MD 50

Proposals to Combat Antimicrobial Resistance:

Proposals to Combat Antimicrobial Resistance Use more narrow spectrum antibiotics Use antimicrobial cocktails Dr.T.V.Rao MD 51

Limiting Antibiotic Resistance:

Limiting Antibiotic Resistance Use antibiotics only for bacterial infections Identify the causative organism if possible Use the right antibiotic; do not rely on broad-range antibiotics Not stop antibiotics as soon as symptoms improve; finish the full course Not use antibiotics for most colds, coughs, bronchitis, sinus infections, and eye infections, which are caused by viruses . Dr.T.V.Rao MD 52

Physicians Can Impact:

Physicians Can Impact Other clinicians Patients Optimize patient evaluation Adopt judicious antibiotic prescribing practices Immunize patients Optimize consultations with other clinicians Use infection control measures Educate others about judicious use of antibiotics Dr.T.V.Rao MD 53

Future – Developing New Antibiotics:

Future – Developing New Antibiotics Antimicrobial peptides Broad spectrum antibiotics from plants and animals Squalamine (sharks) Protegrin (pigs) Magainin (frogs) Antisense agents Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription Dr.T.V.Rao MD 54

World Health Day 2011:

Dr.T.V.Rao MD 55 World Health Day 2011 For World Health Day 2011, WHO will launch a worldwide campaign to safeguard these medicines for future generations . Antimicrobial resistance - the theme of World Health Day 2011 - and its global spread, threatens the continued effectiveness of many medicines used today to treat the sick, while at the same time it risks jeopardizing important advances being made against major infectious killers.

Hand Washing is A Great Investment in Controlling Multi Drug Resistant Strains:

Dr.T.V.Rao MD 56 Hand Washing is A Great Investment in Controlling Multi Drug Resistant Strains

The Programme is dedicated to Ignaz PH Semmelweis:

The Programme is dedicated to Ignaz PH Semmelweis Dr.T.V.Rao MD 57

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The Programme is created by Dr.T.V.Rao MD for ‘ e ‘ learning resources on Awareness on Implications of Antibiotic Misuse and Consequces . Email Dr.T.V.Rao MD 58

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