Antimicrobial Chemotherapy PDF

Chapter 9 Antimicrobial Chemotherapy 1 Chemotherapeutic Agents are chemical agents used to treat disease destroy pathogenic microbes or inhibit their growth within host most are antibiotics – microbial products or their derivatives that kill susceptible microbes or inhibit their growth 2 Development...

Chapter 9 Antimicrobial Chemotherapy 1 Chemotherapeutic Agents are chemical agents used to treat disease destroy pathogenic microbes or inhibit their growth within host most are antibiotics – microbial products or their derivatives that kill susceptible microbes or inhibit their growth 2 Development of Chemotherapy Paul Ehrlich (1904) – developed concept of selective toxicity – identified dyes that effectively treated African sleeping sickness Sahachiro Hato (1910) – working with Ehrlich, identified arsenic compounds --- Salvarsan or syphilis Gerhard Domagk, and Jacques and Therese Trefouel (1935) – discovered sulfonamides and sulfa drugs 3 Copyright © The McGraw-Hill Companies. Permission required for reproduction or display. 4 Penicillin first discovered by Ernest Duchesne (1896), but discovery lost accidentally discovered by Alexander Fleming (1928) – observed penicillin activity on contaminated plate – did not think could be developed further effectiveness demonstrated by Florey, Chain, and Heatley (1939) Fleming, Florey, and Chain received Nobel Prize in 1945 for discovery and production of penicillin 5 Figure 9.1 6 Later Discoveries Streptomycin, an antibiotic active against tuberculosis, was discovered by Selman Waksman (1944) – Nobel Prize was awarded to Waksman in 1952 for this discovery by 1953 chloramphenicol, terramycin, neomycin, and tetracycline isolated 7 General Characterisitics of Antimicrobial Drugs selective toxicity – ability of drug to kill or inhibit pathogen while damaging host as little as possible therapeutic dose – drug level required for clinical treatment toxic dose – drug level at which drug becomes too toxic for patient (i.e., produces side effects) therapeutic index – ratio of toxic dose to therapeutic dose 8 General Characteristics of Antimicrobial Drugs… side effects – undesirable effects of drugs on host cells narrow-spectrum drugs – attack only a few different pathogens broad-spectrum drugs – attack many different pathogens cidal agent - kills microbes static agent - inhibits growth of microbes 9 Table 9.1 10 Table 9.1 11 General Characteristics of Antimicrobial Drugs… effect of an agent may vary – with concentration, microbe, host effectiveness expressed in two ways – minimal inhibitory concentration (MIC) lowest concentration of drug that inhibits growth of pathogen – minimal lethal concentration (MLC) lowest concentration of drug that kills pathogen 12 Determining the Level of Antimicrobial Activity dilution susceptibility tests for MIC disk diffusion tests – Kirby Bauer the E-test MIC and diffusion 13 Dilution Susceptibility Tests involves inoculating media containing different concentrations of drug – broth or agar with lowest concentration showing no growth is MIC – if broth used, tubes showing no growth can be subcultured into drug-free medium broth from which microbe can’t be recovered is MLC 14 Disk Diffusion Tests disks impregnated with specific drugs are placed on agar plates inoculated with test microbe drug diffuses from disk into agar, establishing concentration gradient observe clear zones (no growth) around disks 15 Table 9.2 16 Kirby-Bauer Method standardized method for carrying out disk diffusion test sensitivity and resistance determined using tables that relate zone diameter to degree of microbial resistance table values plotted and used to determine if concentration of drug reached in body will be effective 17 Figure 9.2 18 Figure 9.3 19 The E Test convenient for use with anaerobic pathogens similar to disk diffusion method, but uses strip rather than disk E-test strips contain a gradient of an antibiotic intersection of elliptical zone of inhibition with strip indicates MIC 20 Figure 9.4 21 Copyright © The McGraw-Hill Companies. 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Types of Antimicrobial Drugs 22 Antimicrobial Drugs 23 inhibitors of cell wall synthesis protein synthesis inhibitors metabolic antagonists nucleic acid synthesis inhibition Inhibitors of Cell Wall Synthesis penicillins – most are 6-aminopenicillanic acid derivatives and differ in side chain attached to amino group – most crucial feature of molecule is the lactam ring essential for bioactivity many penicillin resistant organisms produce lactamase (penicillinase) which hydrolyzes a bond in this ring 24 Figure 9.5 25 Penicillins… mode of action – blocks the enzyme that catalyzes transpeptidation (formation of crosslinks in peptidoglycan) – prevents the synthesis of complete cell walls leading to lysis of cell – acts only on growing bacteria that are synthesizing new peptidoglycan 26 Other Actions of Penicillins binds to periplasmic proteins (penicillin-binding proteins, PBPs) may activate bacterial autolysins and murein hydrolases stimulate bacterial holins to form holes or lesions in the plasma membrane 27 Penicillins… naturally occurring penicillins – penicillin V and G are narrow spectrum semisynthetic penicillins have a broader spectrum than naturally occurring ones resistance to penicillins, including the semisynthetic analogs, continues to be a problem ~1–5% of adults in U.S. are allergic to penicillin – allergy can lead to a violent allergic response and death 28 Cephalosporins structurally and functionally similar to penicillins broad-spectrum antibiotics that can be used by most patients that are allergic to penicillin grouped into four categories based on their spectrum of activity 29 Figure 9.6 30 Vancomycin and Teicoplanin glycopeptide antibiotics inhibit cell wall synthesis vancomycin has been important for treatment of antibiotic-resistant staphylococcal and enterococcal infections – previously considered “drug of last resort” so rise in resistance to vancomycin is of great concern 31 Protein Synthesis Inhibitors many antibiotics bind specifically to the bacterial ribosome – binding can be to 30S (small) or 50S (large) ribosomal subunit other antibiotics inhibit a step in protein synthesis – – – – 32 aminoacyl-tRNA binding peptide bond formation mRNA reading translocation Aminoglycoside Antibiotics large family which all contain a cyclohexane ring and amino sugars bind to 30S ribosomal subunit and interfere with protein synthesis by directly inhibiting the process and by causing misreading of the messenger RNA resistance and toxicity 33 Figure 9.8 34 Tetracyclines all have a four-ring structure to which a variety of side chains are attached are broad spectrum, bacteriostatic combine with 30S ribosomal subunit – inhibits bind of aminoacyl-tRNA molecules to the A site of the ribosome sometimes used to treat acne 35 Figure 9.9 36 Macrolides contain 12- to 22-carbon lactone rings linked to one or more sugars e.g., erythromycin, Clindamycin, Zithromax.. – broad spectrum, usually bacteriostatic – binds to 23S rRNA of 50S ribosomal subunit inhibits peptide chain elongation used for patients allergic to penicillin 37 Chloramphenicol S. venezuelae now is chemically synthesized binds to 23s rRNA on 50S ribosomal subunit and inhibits peptidyl transferase reaction toxic with numerous side effects so only used in life-threatening situations 38 Metabolic Antagonists act as antimetabolites – antagonize or block functioning of metabolic pathways by competitively inhibiting the use of metabolites by key enzymes are structural analogs – molecules that are structurally similar to, and compete with, naturally occurring metabolic intermediates block normal cellular metabolism 39 Sulfonamides or Sulfa Drugs structurally related to sulfanilamide, a paminobenzoic acid (PABA) analog PABA used for the synthesis of folic acid and is made by many pathogens – sulfa drugs are selectively toxic for these pathogens because they compete with PABA for the active site of an enzyme involved in folic acid synthesis, resulting in a decline in folic acid concentration pathogen dies because folic acid is a precursor to purines and pyrimidines which are nucleic acid building blocks 40 Figure 9.11 41 Trimethoprim synthetic antibiotic that also interferes with folic acid production broad spectrum can be combined with sulfa drugs to increase efficacy of treatment – combination blocks two steps in folic acid pathway --- PABA & DHF acid ie DHFR (dihydrofolate reductase) has a variety of side effects including abdominal pain and photosensitivity reactions 42 Nucleic Acid Synthesis Inhibition a variety of mechanisms – block DNA replication inhibition of DNA polymerase inhibition of DNA helicase – block transcription inhibition of RNA polymerase drugs not as selectively toxic as other antibiotics because bacteria and eukaryotes do not differ greatly in the way they synthesize nucleic acids 43 Figure 9.13 44 Quinolones broad-spectrum, synthetic drugs containing the 4-quinolone ring nalidixic acid was first quinolone to be synthesized (1962) generations of fluoroquinolones produced now act by inhibiting bacterial DNA-gyrase and topoisomerase II broad spectrum, bactericidal, wide range of infections 45 Copyright © The McGraw-Hill Companies. Permission required for reproduction or display. 46 Antifungal Drugs fewer effective agents because of similarity of eukaryotic fungal cells and human cells – many have low therapeutic index and are toxic easier to treat superficial mycoses than systemic infections – combinations of drugs may be used 47 Treating Mycoses superficial mycoses – e.g., Candida – topical and oral – disrupt membrane permeability and inhibit sterol synthesis – disrupts mitotic spindle; may inhibit protein and DNA synthesis 48 Treating Systemic Mycoses difficult to control and can be fatal three common drugs – amphotericin B - binds sterols in membranes – 5-flucytosine – disrupts RNA function – fluconazole low side effects, used prophylactically 49 Copyright © The McGraw-Hill Companies. Permission required for reproduction or display. Antiviral Drugs These interfere with – critical stages in the virus life cycle Amantadine, rimantadine and ritonavir – Inhibit synthesis of virus-specific nucleic acid Acyclovir, zidovudine etc Drug combinations are mor effective 50 Copyright © The McGraw-Hill Companies. Permission required for reproduction or display. Antiprotozoan Drugs Block steps in NA synthesis, ETC, protein synthesis, folic acid synthesis……. 51 Factors Influencing Antimicrobial Drugs ability of drug to reach site of infection susceptibility of pathogen to drug ability of drug to reach concentrations in body that exceed MIC of pathogen 52 Ability of Drug to Reach Site of Infection depends in part on mode of administration – oral some drugs destroyed by stomach acid – topical – parenteral routes nonoral routes of administration drug can be excluded by blood clots or necrotic tissue 53 Factors Influencing Ability of Drug to Reach Concentrations Exceeding MIC 54 amount administered route of administration speed of uptake rate of clearance (elimination) from body Drug Resistance an increasing problem – once resistance originates in a population it can be transmitted to other bacteria – a particular type of resistance mechanism is not confirmed to a single class of drugs microbes in abscesses or biofilms may be growing slowly and not be susceptible resistance mutants arise spontaneously and are then selected 55 Mechanisms of Drug Resistance prevent entrance of drug – drug can’t bind to or penetrate pathogen drug efflux (pump drug out of cell) inactivation of drug – chemical modification of drug by pathogen modification of target enzyme or organelle use of alternative pathways or increased production of target metabolite 56 Figure 9.19 57 The Origin and Transmission of Drug Resistance immunity genes – resistance genes that exist in nature to protect antibiotic producing microbes from their own antibiotics horizontal gene transfer – transferred immunity genes from antibiotic producers to non-producing microbes 58 The Origin and Transmission of Drug Resistance resistance genes can be found on – bacterial chromosomes – plasmids – transposons – integrons when found on mobile genetic elements they can be freely exchanged between bacteria 59 Origin and Transmission… chromosomal genes – resistance results from (rare) spontaneous mutations which usually result in a change in the drug target R plasmids – resistance plasmids – can be transferred to other cells by conjugation, transduction, and transformation – can carry multiple resistance genes 60 Figure 9.20 61 Overcoming Drug Resistance give drug in appropriate concentrations to destroy susceptible give two or more drugs at same time use drugs only when necessary possible future solutions – continued development of new drugs – use of bacteriophages to treat bacterial disease? 62 Copyright © The McGraw-Hill Companies. 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