1. IMPORTANT ANTIBIOTICS AND ANTIMICROBIAL RESISTANCE A Presentation By Ms R.Venkatajothi, MSc., MPhil, PhD Senior Lecturer Department of Microbiology Faculty of Medicine AIMST UNIVERSITY

2. The objectives of this lecture are to The objectives of this lecture are to  Stress the global problem regarding anti-microbial resistance.  Reinforce the knowledge gained in the lecture on bacterial genetics regarding mechanisms of drug resistance and transfer.  Discuss the available measures to reduce incidence of drug resistance.  Discuss issues affecting the development of new anti- microbial agents. OBJECTIVES

3. INTRODUCTION   Antibiotic resistance is a serious problem. When antibiotics are used incorrectly and too frequently, bacteria can change and became resistance.   Once these bacteria change, the antibiotic is no longer useful. For example, the usefulness of penicillin, which was effective 50 years ago, is limited because of antibiotic resistance.   Not taking an antibiotic exactly as prescribed for a bacterial infection, can allow the bacteria to develop resistance.

4. Introduction continued…..  Abbreviation :- MRSA - Methicillin-resistant Staphylococcus aureus. MRSA - Methicillin-resistant Staphylococcus aureus. PRSP - Penicillin-resistant Streptococcus pneumoniae. PRSP - Penicillin-resistant Streptococcus pneumoniae. MDROs - Multidrug-resistant organisms. MDROs - Multidrug-resistant organisms. MDR- GNB - Multidrug resistant-Gram-negative bacteria. MDR- GNB - Multidrug resistant-Gram-negative bacteria. VRE - Vancomycin-resistant enterococci. VRE - Vancomycin-resistant enterococci. MDR-TB - Multidrug-Resistant Tuberculosis. MDR-TB - Multidrug-Resistant Tuberculosis. ESBLs - Extended-spectrum β-lactamases. ESBLs - Extended-spectrum β-lactamases.

5. GLOBAL PROBLEM IN ANTI-MICROBIAL RESISTANCE GLOBAL PROBLEM IN ANTI-MICROBIAL RESISTANCE  Antibiotic resistance is a global problem, because of international travel often results in rapid spread of resistant microorganisms around the world.  Infections with resistant microorganisms can occur in hospitals and in the community.  In the community, resistance can result from MRSA, PRSP, Penicillin and quinolone resistant Neisseria gonorrhoeae, or resistant pathogens as a result of travel eg: Shigella causes dysentery. dysentery

6. Global problem in anti-microbial resistance continued….. Global problem in anti-microbial resistance continued…..  Antibiotic resistance in hospitals most often results from the overuse of antibiotics and has been an important problem with MRSA, VRE and MDR – GNB.  The potential for the emergence of vancomycin resistant has long been recognized and recent reports from Japan and the United States of low-level vancomycin resistance in clinical isolates of S. aureus reported.

7. Global problem in anti-microbial resistance continued….. Global problem in anti-microbial resistance continued…..  A few outbreaks of MDR-TB have occurred in hospitals and result of delayed diagnosis and inadequate therapy, frequently in HIV-infected patients.  The family members or who are contact with the patient can be exposing of resistant bacteria. Then these people might also develop resistant bacterial infections.  Because antibiotics are used a lot (and sometimes are used inappropriately) antibiotic resistance is becoming a common problem in many parts of the world especially Malaysia, China, India, Africa and United States etc.

8. MECHANISM OF ANTIBIOTIC RESISTANCE NONGENETIC ORIGIN OF DRUG RESISTANCE NONGENETIC ORIGIN OF DRUG RESISTANCE  There are many different mechanisms by which microorganisms might exhibit resistance to drugs.  (1) Microorganisms produce enzymes which destroy the active drug.  Example: Staphylococci resistant to Penicillin. Because this bacteria producing enzyme known as β - lactamase which destroys the drug.

9. Mechanism of antibiotic resistance continued….  (2) Microorganisms change their cell wall permeability to the drug, possibly by alteration in the chemical nature of outer membrane.  Examples: Tetracycline resistance to pseudomonas aeruginosa.

10. Mechanism of antibiotic resistance continued…..  (3) Microorganisms develop an altered structural target for the drug.  Example: Penicillin resistance to Streptococcus pneumoniae and enterococci is due to altered penicillin-binding proteins (PBPs).  (4) Microorganisms develop an altered metabolic pathway that bypasses the reaction inhibited by the drug.

11. Mechanism of antibiotic resistance continued…..  (5) Microorganisms may lose the specific target structure for a drug for several generations and thus be resistant. Example: Cephalosporins. Example: Cephalosporins.  (6) Microorganisms may infect the host at sites where antimicrobials are excluded or are not active. Examples: Gentamicin are not effective in treating salmonella enteric fever. Examples: Gentamicin are not effective in treating salmonella enteric fever.

12. Mechanism of antibiotic resistance continued….. EXTENDED-SPECTRUM BETA- LACTAMASES (ESBLs) EXTENDED-SPECTRUM BETA- LACTAMASES (ESBLs)  There is one group of β -lactamases that is occasionally found in certain species of gram- negative bacilli, usually Klebsiella pneumoniae and Escherichia coli.  These enzymes are termed extended-spectrum β-lactamases (ESBLs) because they confer upon the bacteria the additional ability to hydrolyze the β-lactam rings of cefotaxime, ceftazidime etc.

13. GENETIC ORIGIN OF DRUG RESISTANCE GENETIC ORIGIN OF DRUG RESISTANCE CHROMOSOMAL RESISTANCE CHROMOSOMAL RESISTANCE  Bacteria can continue to develop resistance to currently available antibacterial drugs by either new mutations or the exchange of genetic information, that is, putting old resistance genes into new host.  The antimicrobial drugs selectively suppress susceptible organisms and favour the growth of resistant mutants.  This is very commonly found in the case of Mycobacterium tuberculosis.

14. Genetic origin of drug resistance continued….. Genetic origin of drug resistance continued….. EXTRACHROMOSOMAL RESISTANCE  Bacteria often contain extra chromosomal genetic elements called Plasmids.  Extra chromosomal resistance occurs by transfer of genetic material.  ‘R factors’ (resistance transfer factor) are a class of plasmids that contain genes which code for drug resistance against one and often several antimicrobial drugs.

15. Genetic origin of drug resistance continued….. Genetic origin of drug resistance continued….. EXTRACHROMOSOMAL RESISTANCE  Genetic material and plasmids can be transferred by transduction, transformation and conjugation.  Many antibiotic resistance genes reside on plasmids, facilitating their transfer. superbug superbug  If a bacterium carries several resistance genes, it is called multidrug resistant (MDR) or, informally, a superbug or super bacterium. For example MDR- GNB, MDR - TB etc.

16. MEASURES TO REDUCE INCIDENCE OF DRUG RESISTANCE  Although managing antibiotic resistance is a major challenge, physicians have an important role to play in their own communities.  Even though the problem of antibiotic resistance is global, physicians gain better knowledge of antibiotics in their own practices, thereby protecting the health of their patients in the community.  Health care workers can advice people about washing hands with soap and water before eat and after use the bathroom. This can prevent the infections in the community.

17. Measures to reduce incidence of drug resistance continued……  Before using antibiotics, make use of diagnostic methods, when appropriate, to identify the causative pathogen so that a drug targeted at the microbe can be chosen.  By avoiding exposure of microorganisms to a particularly valuable drug by limiting its use, especially in hospitals.   Barrier isolation precautions may help reduce transmission of resistant bacteria among hospitalized patients and control outbreaks but such approaches are not generally applicable to the community.

18. Measures to reduce incidence of drug resistance continued……  The other vital aspect of controlling the spread of multidrug-resistant organisms is providing sufficient personnel and resources for infection control in all healthcare facilities.  New antibacterial agents with different mechanisms of action are also needed.

19. COMPLICATING THE DEVELOPMENT OF NEW ANTI-MICROBIAL AGENTS  The resistance problem demands that a renewed effort be made to seek antibacterial agents effective against pathogenic bacteria resistant to current antibiotics.  Newer antimicrobial agents can be developed to deal with resistance microorganisms.  However, development of new antimicrobial agents has slowed considerably and often, when available, such agents are far more expensive.

20. Complicating the development of new anti-microbial agents continued….  Furthermore, given time, the microorganisms would eventually develop resistance to these newer agents.  Traditional healers long have used plants to prevent or cure infectious disease.  Many of these plants have been investigated scientifically for antimicrobial activity, and a large number of plant products have been shown to inhibit the growth of pathogenic microorganisms.

21. Complicating the development of new anti-microbial agents continued….  A number of these agents appear to have structures and modes of action that are distinct from those of the antibiotics in current use, suggesting that cross - resistance with agents already in use may be minimal.  So, it is worthwhile to study plants and plant products for activity against resistant bacteria.

22. LEARNING OUTCOMES  Evaluate the global problem of rising anti-microbial resistance data.  Describe the mechanisms by which organisms develop drug resistance.  Judge the effects of the various methods used to prevent the problem of anti-microbial resistance.  Discuss the issues complicating the development of new anti-microbial agents.

23. BOOKS FOR REFERENCE  Text book of Microbiology by Ananthanarayan and Paniker’s.  A Text book of Microbiology by P.Chakraborty.  Medical Microbiology by Jawetz, Melnick, & Adelberg's.  Medical Microbiology by Murray.