Antimicrobial Agents and Antibiotic Treatment
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Kwame Nkrumah University of Science and Technology
Dr Francis O. Agyapong
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Summary
This document provides an overview of antimicrobial agents, including definitions of key terms like 'antimicrobial agent,' 'antibiotics,' and 'chemotherapy.' It also traces the history of antibiotics through notable figures like Louis Pasteur and Robert Koch, and the discovery of penicillin. The document then explores the general characteristics of antimicrobial agents, such as selective toxicity, range of effectiveness, and levels of activity. This includes various tests for understanding susceptibility to antibiotics. The document also delves into antimicrobial resistance and its mechanisms, including factors that promote resistance, and inappropriate antibiotic use.
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ANTIMICROBIAL AGENTS AND ANTI-BIOTIC TREATMENT Dr Francis O. Agyapong OUTLINE Introduction and History Classification of anti-microbial agents Mechanism of action of anti-biotics Anti-biotic resistance Introduction- Definitions Antimicrobial age...
ANTIMICROBIAL AGENTS AND ANTI-BIOTIC TREATMENT Dr Francis O. Agyapong OUTLINE Introduction and History Classification of anti-microbial agents Mechanism of action of anti-biotics Anti-biotic resistance Introduction- Definitions Antimicrobial agent = any agent that kills or inhibits growth of a susceptible organism. It could be anti-viral, anti-protozoal Anti-biotics – a product produced by a microorganism, or a similar substance produced wholly or partially by chemical synthesis, which in low concentrations, inhibits the growth of other microorganisms Chemotherapy = treatment of a disease by a chemical compound selectively directed against invading microbes or abnormal cells History History History History General Characteristics of Antimicrobial agents A. Selective toxicity – agent must kill or inhibit microbe while damaging the host as little as possible 1.Balance between the a) therapeutic dose – drug level required for therapeutic treatment of an infection b) toxic dose – drug level that is toxic to host 2. therapeutic index – ratio of toxic dose to therapeutic dose (larger the number = the better) (the lowest dose toxic to the patient divided by the dose typically used for therapy) General Characteristics of Antimicrobial agents B. Range of effectiveness 1. Narrow-spectrum 2. Broad-spectrum C. Classes based on target organisms that it affects D. Bactericidal vs. Bacteriostatic E. Levels of activity; ✓ measured by 1. MIC (minimal inhibitory concentration) - lowest concentration of drug that prevents growth 2. MLC (minimal lethal concentration) - lowest concentration of drug that kills microbe ✓ Tested in the lab by Susceptibility tests 1. Dilution susceptibility test - dilute antibiotic in 2-fold intervals and test for MIC 2. Disk diffusion test 3. Drug concentration in blood/body – via a variety of tests; important for verifying agent has reached blood or other bodily areas in therapeutic concentrations Factors that influence effectiveness of anti-microbial agents 1. route of administration a) oral – must survive acid b) topical c) parenteral – non-oral administration (i.e. injection) 2. access of site of infection 3. stability in body 4. susceptibility of pathogen 5. MIC – levels of drug at infection site must exceed MIC Susceptibility Tests 1. Broth dilution - MIC test 2. Agar dilution - MIC test Susceptibility Tests (cont’d) 3. Agar diffusion ✓ Kirby-Bauer Disk Diffusion Test Susceptibility Tests (cont’d) “Kirby-Bauer Disk-plate test” Diffusion depends upon: 1. Concentration 2. Molecular weight 3. Water solubility 4. pH and ionization 5. Binding to agar Susceptibility Tests “Kirby-Bauer Disk-plate test” (cont’d) Zones of Inhibition (~ antimicrobial activity) depend upon: 1. pH of environment 2. Media components – Agar depth, nutrients 3. Stability of drug 4. Size of inoculum 5. Length of incubation 6. Metabolic activity of organisms Antibacterial spectrum—Range of activity Antibiotic combinations—Combinations of of an antimicrobial against bacteria. A antibiotics that may be used (1) to broaden broad-spectrum antibacterial drug can the antibacterial spectrum for empiric inhibit a wide variety of gram-positive and therapy or the treatment of polymicrobial gram-negative bacteria, whereas a infections, (2) to prevent the emergence of narrow-spectrum drug is active only resistant organisms during therapy, and (3) against a limited variety of bacteria. to achieve a synergistic killing effect. Bacteriostatic activity—-The level of Antibiotic synergism—Combinations of antimicro-bial activity that inhibits the two antibiotics that have enhanced growth of an organism. This is determined bactericidal activity when tested together in vitro by testing a standardized compared with the activity of each concentration of organisms against a antibiotic. series of antimicrobial dilutions. The lowest concentration that inhibits the Antibiotic antagonism—Combination of growth of the organism is referred to as antibiotics in which the activity of one the minimum inhibitory concentration antibiotic interferes With the activity of the (MIC). other (e.g., the sum of the activity is less than the activity of the individual drugs). Bactericidal activity—The level of antimicrobial activity that kills the test Beta-lactamase—An enzyme that organism. This is determined in vitro by hydrolyzes the beta-lactam ring in the exposing a standardized concentration of beta-lactam class of antibiotics, thus organisms to a series of antimicrobial inactivating the antibiotic. The enzymes dilutions. The lowest concentration that specific for penicillins and cephalosporins kills 99.9% of the population is referred to aret he penicillinases and as the minimum bactericidal cephalosporinases, respectively. concentration (MBC). Categorization of anti-microbial agents Classification of antimicrobial agents 1.Based on therapeutic use/ organisms affected 2.Based on mechanism of action 3.Based on spectrum of activity 4.Based on type of action 5.Antimycobacterial agents 6.Based on source 7.Based on Chemical structure Categorization of anti-microbial agents Based on therapeutic use/ organisms affected Antibacterial - Penicillin, Chloramphenicol, Tetracyclines, Aminoglycosides Antifungal - Amphotericin B, Griseofulvin, ketoconazole Antivirals-Acyclovir, Tenofovir, Zidovudine, Ribavirin Antiprotozoal-Metronidazole, Quinapyramine, Diminazine Anti-helmintics-Albendazole, Levamisole, Niclosamide, praziquantel, Ivermectin Ectoparasiticides-permethrin, Lindane, Principles of Anti-biotic Treatment Mechanism of action of Anti-biotics Mechanism of Action 1. ANTIMETABOLITE ACTION ▪ Sulfonamides ✓ an analog of PABA, works by competitive inhibition ▪ Trimethoprim-sulfamethoxazole ✓ a synergistic combination; useful against UTIs Mechanism of Action ANTIMETABOLITE ACTION Sulfonamides, which resemble p- aminobenzoic acid and dapsone (leprosy and pneumocytis) competitively inhibit dihydropterate synthase. Trimethoprim inhibits the enzymatic action of dihydrofolate reductase. Both of these actions cause interference with the synthesis of folic acid, which is required by bacteria. Mechanism of Action 2. ALTERATION OF CELL MEMBRANES ▪ Polymyxins and colistin ✓ destroys membranes ✓ active against gram negative bacilli ✓ serious side effects ✓ used mostly for skin & eye infections ✓ Now not used systemically because they affect host cell membranes ✓ Toxicity due to the effect that it has on human cell membranes as well. Mechanism of Action ALTERATION OF CELL MEMBRANES (cont’d) Mechanism of Action (cont’d) 3. INHIBITION OF PROTEIN SYNTHESIS: Steps in synthesis: 1. Initiation 2. Elongation 3. Translocation 4. Termination Prokaryotes and eukaryotes (80S) have a different structure to ribosomes so can use antibiotics for selective toxicity against ribosomes of prokaryotes (70S) 80S vs. 70 S But similar to mitochondrial ribosomes which may account for some toxicity Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d) Aminoglycosides – bind to bacterial ribosome on 30S subunit; and blocks formation of initiation complex. Both actions lead to mis-incorporation of amino acids – Examples: Gentamicin Tobramycin Amikacin Streptomycin Kanamycin Spectinomycin Neomycin Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d) Aminoglycosides – broad spectrum Gram negative rods P. aeruginosa Drug-resistant gram negative rods Plague, Tularemia, Gonorrhea Pre-op (bowel) External (skin) – toxic at some level to eighth cranial nerve Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d) Macrolides: Azithromycin, Clarithromycin, erythromycin – bind to 50S subunit and blocks the translocation step Anaerobes Typhoid ✓ Chloramphenicol: Also binds to 50S Meningitis broad spectrum Mycoplasma ✓ Erythromycin: Legionella S. pyogenes Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d) Clindamycin – binds to 50S subunit and interferes with binding of the amino acid – acyl-tRNA complex and so inhibits peptidyl transferase – works best against Staphylococcus Bacteroides & anaerobic gram neg rods – Penicillin allergic people Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d) Tetracyclines – bind to 30S subunit and interferes with the attachment of the tRNA carrying amino acids to the ribosome – effective against: Chlamydia Rickettsia Mycoplasma Brucella Mechanism of Action (cont’d) 4. INHIBITION OF DNA/RNA SYNTHESIS ▪ Rifampin ✓ binds to RNA polymerase ✓ active against gram positive cocci ✓ bactericidal for Mycobacterium ✓ used for treatment and prevention of meningococcus Mechanism of Action INHIBITION OF DNA SYNTHESIS (cont’d) ▪ Metronidazole ✓ breaks down into intermediate that causes breakage of DNA ✓ active against: – protozoan infections – anaerobic gram negative infections ▪ Quinolones and fluoroquinolones ✓ affect DNA gyrase ✓ broad spectrum Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS (cont’d) Mechanism of Action (cont’d) 5. CELL WALL SYNTHESIS INHIBITORS β-Lactam Antibiotics – Penicillins – Cephalosporins – Carbapenems – Monobactams Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d) β-Lactam ring structure Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d) Action of β-Lactam antibiotics 1. Bactericidal; growing cells only 2. Drug links covalently to regulatory enzymes called PBPs (penicillin-binding proteins) 3. Blocks cross-linkage of peptidoglycan Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d) Action of β-Lactam antibiotics > MIC wall damage autolysins spheroplasting cell lysis Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d) Resistance to β-Lactams – Gram neg. Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d) Non - β-Lactams ▪ Vancomycin ✓active against gram positive cocci, but not gram negative because too large to pass through outer membrane ✓ interferes with PG elongation ▪ Cycloserine, ethionamide and isoniazid ✓inhibits enzymes that catalyze cell wall synthesis ✓for Mycobacterial infections Mechanism of Action of Anti-fungal Agents Mechanism of Action of Anti-viral Agents Overview of Antimicrobial Resistance; Epidemiology and Causes Major issues What is resistance Causes of resistance Factors affecting resistance Relevance of AMR Local Epidemiology Conclusion and way forward AMR alarm was sounded long ago In his 1945 nobel prize lecture, Fleming warned of the dangers of antimicrobial resistance: “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 underdose himself and by exposing his microbes to non-lethal quantities of the drug making them resistant.” What is antibiotic resistance? Antibiotic resistance occurs when an antibiotic has lost its ability to effectively control or kill bacterial growth; => the bacteria are "resistant" and continue to multiply in the presence of therapeutic levels of an antibiotic. Methods for Determining Susceptibility E-test® Kirby-Bauer Disk Diffusion Agar dilution Resistance Mechanisms Several mechanisms have evolved in bacteria which confer them with antibiotic resistance. These mechanisms include: 1. Inactivation of the drug eg beta-lactamases 2. Physical removal from the cell(drug efflux) eg energy dependent transporter system for tetracyclines 3. Altered target site eg. penicillin binding proteins 4. Decreased permeability (outer or inner membrane) Origins of resistance 1. Inheritance from mother cell 2. Spontaneous mutation 3. Acquisition of plasmid (R plasmid) or transposon, integrons or phage with drug resistance gene a) Via conjugation or transformation (plasmid) b) Via transduction (phage) Plasmids independent replicons – circular DNA dispensable several genes – drug resistance – metabolic enzymes – virulence factors host range – restricted or broad Mechanisms Of Antibiotic Resistance Bacteria are capable of becoming resistant through several mechanisms Decreased One or many mechanisms Permeability may exist in an organism Multidrug-resistant bacteria often have multiple mechanisms Genes encoding resistance may exist on plasmid or chromosome Alteration in Target Molecule Selection Antibiotics that are used correctly overwhelm the harmful bacteria Overuse of antibiotics or unnecessary use creates a selective environment Resistant strains survive and multiply After reproducing, the resistant bacteria may spread to another host Factors that promote resistance Exposure to sub-optimal levels of antimicrobials Exposure to broad-spectrum antibiotics Exposure to microbes carrying resistant genes Lack of hygiene in clinical environments Use of antibiotics in foods/agriculture What is Inappropriate antibiotic use? Use of broad spectrum antibiotics when not indicated (eg Ceftriaxone for furuncle) Use of antibiotics with no clinical indication (eg viral infections) Inappropriate choice of empiric antibiotics Inappropriate drug regimen Inappropriate dose Inappropriate route Inappropriate duration Current situation Clinical diagnosis of infectious diseases in Africa is associated with increased misdiagnosis and mortality but when laboratory testing is available it remains under-utilized. Barriers to utilization of laboratories may be: physicians perceptions, previous experience leading to mistrust, quality of laboratory testing, under valued test/test result, apparent or true high cost of test, inadequate laboratory capacity etc etc Practices contributing to misuse of antibiotics within hospitals Inappropriate specimen selection and collection Inappropriate handling/storage of sample Failure to use stains/smears Failure to use appropriate cultures and susceptibility tests Factors beyond the Healthworker antibiotics available OTC poor patient compliance (1-2 days) cost (take sub-therapeutic course) Low quality antibiotic – counterfeit – adulterated – poor quality (potency) Initiating antibiotics therapy Ideally, before beginning antibiotic therapy, the suspected areas of infection should be cultured to identify the causative organism and potential antibiotic susceptibilities Empiric therapy: treatment of an infection before specific culture information has been reported or obtained Prophylactic therapy: treatment with antibiotics to prevent an infection, eg peri-operatively The guidelines (if they exist) are not being followed. Decisions can be difficult to make But the sputum is green. But he is coughing really bad for a whole week But the temperature is 39.7 But I need to cover for any eventuality But what if its an infection I am missing? Sensitivity of Gram –ves in KATH 2015 E.Coli Klebsiella Pseudo. Enterobact S. typhi S. spp alcaligen spp aeruge. er spp es Septrin 10.4% 3.2% 10% 5.6% 23.1% 20% Ampicillin 8.5% 0% 40% 12.5% 10% 0% Chloramphenicol 14.6% 26.1% 22.2% 14.3% 33.3% 9.1% Gentamicin 50% 46.7% 87.9% 70% 100% 100% 60% Amikacin 84.6% - 86.2% 100% 100% 100% 100% Cefuroxime 19.2% 20.5% 45.5% 50% 57.7% 13.3% Ceftriaxone 46.3% 31.3% 50% 93.3% 78.6% 27.8% Ceftazidime 68.4% 74.1% 25% 100% 100% 100% Cefotaxime 34.9% 50% 73.9% 71.4% 30% Meropenem 100% 92.4% 85.7% 100% 100% 100% 83.3% Ciprofloxacin 69.6% 74.4% 83.3% 71.4% 89.5% 93.3% 84.6% Resistance pattern in Dept of Medicine Antibiotic E.coli Klebsiella Meronem 0% 0% Amikacin 0% 5.2% Ciprofloxacin 53.1% 43.2% Ceftriaxone 81.3% 78.5% Ceftazidime 58.3% 40% Cefuroxime 85.7% 84.2% Gentamicin 37.1% 70.7 Ampicillin 97.8% 94.5% The AMR complexity…… …..leads to a problem which cannot be tackled by one scientific domain or even by research alone but that needs a collaborative approach Resistance has huge negative impact on health Longer duration of illness Longer treatment Higher mortality Treatment with expensive drugs Increased burden on health system Negates technological advances in medical sector – Complex surgeries – Transplantations and other interventions Patient acts as reservoir of resistant organisms which are passed to community and health-care workers Huge economic impact Way forward - Strategies to delay widespread antibiotic resistance: Don’t use antibiotics to treat viruses or viral infections Avoid mild doses of antibiotics over a long period of time When treating a bacterial infection with antibiotics, take the full dose Where required, use a combination of drugs to treat bacterial infections Reduce/eliminate “preventive” use of antibiotics on livestock and crops Way forward - stewardship Use a multi-disciplinary team with the aim to reduce patient morbidity and mortality, and to prevent or slow the emergence and spread of antimicrobial resistance. This is a strategy that combines various approached including: Education/guidelines Formulary restriction Prospective audits with intervention and feedback “Antimicrobial stewardship” is the way to go. Antibiotics are a precious resource We need to preserve this resource by working together Combating antimicrobial resistance: No action today, no cure tomorrow Thank you very much Which of the following is recognized for hearing impairment as side effect A. Streptomycin B. Clindamycin C. Erythromycin D. Ceftriazone Which of the following affect the cell wall A. Ceftriazone B. Gentamycin C. Azithromycin D. chroramphenicol Which of the following affect the bacterial cell wall A. Aminoglycosides B. Macrolides C. Cephalosporins D. polymixins