Antibiotic Drug Information PDF

Chemotherapeutic Agents 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  The Development of Chemotherapy...

Chemotherapeutic Agents 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  The 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 that effectively treated syphilis Gerhard Domagk, and Jacques and Therese Trefouel (1935) – discovered sulfonamides and sulfa drugs  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)  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  General Characteristics 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 cidal - kills static – inhibits growth broad-spectrum drugs – attack many different pathogens narrow-spectrum drugs – attack only a few different pathogens  Determining the Level of Antimicrobial Activity 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 two techniques are routinely used to determine MIC and MLC  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  Dilution Susceptibility Tests Broth Tube Drug Concentration  Measuring Antimicrobial Sensitivity 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 Measuring Antimicrobial Sensitivity 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 Zone of Inhibition  Measuring Antimicrobial Sensitivity The E Test 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  Measurement of Drug Concentrations in the Blood concentration of drug at infection site must be > MIC to be effective microbiological, chemical, immunological, enzymatic, or chromatographic assays can be used to determine concentration of drug in blood  Mechanism of Action of Antimicrobial Agents can impact pathogen by targeting some function necessary for its reproduction or survival targeted function is very specific to pathogen → higher therapeutic index Modes of Antimicrobial Action  Competitive Inhibitors – Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Broad spectrum Figure 5.7  Factors Influencing the Effectiveness of 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  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  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  Penicillins… Mode of action – blocks the enzyme that catalyzes transpeptidation (formation of cross-links in peptidoglycan) – prevents the synthesis of complete cell walls leading to lysis of cell – acts only on growing bacteria that are synthesizing new peptidoglycan  Cephalosporins Structurally and functionally similar to penicillins Broad-spectrum antibiotics that can be used by most patients that are allergic to penicillin Four categories based on their spectrum of activity  Vancomycin and Teicoplanin Glycopeptide antibiotics Inhibit cell wall synthesis Vancomycin - 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  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 – aminoacyl-tRNA binding – peptide bond formation – mRNA reading – translocation Example: Streptomycin, Tetracycline, Chloramphenicol  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 Example: Rifampin  Mechanisms of Drug Resistance exclusion of drug – drug can’t bind to or penetrate pathogen pump drug out inactivation of drug – chemical modification of drug by pathogen alteration of target enzyme or organelle use of alternative pathways or increased production of target metabolite General Drag Resistance Mechanism 33 The Origin and Transmission of Drug Resistance resistance genes can be chromosomal or on plasmids – small DNA molecules that can exist separate from chromosome or integrated into it  Origin of resistance genes chromosomal genes – mutations, usually of drug target R plasmids – resistance plasmids – can be transferred to other cells by conjugation, transduction, and transformation – can carry multiple resistance genes 36  Name of Antifungal Nyastatin(mycostatin): Yeasts Griseofulvin (Grisactin): Dermatophyte fungi Amphotercin B (Fungizone): Systemic fungi  Antifungal Agents Not that successful as eukaryotic fungal cells are similar to human cells Many drugs that inhibit or kill fungi are quite toxic for humans. In addition most fungi have a detoxification system that modifies many antibiotics, probably by hydroxlation  Fungal infections usually subdivided into infections of superficial tissues or superficial mycoses and systemic mycoses. Most antifungal drugs binds to sterols in fungal membranes, disrupting membrane permeability and causing leakage of cell constituents  Superinfection development and spread of drug-resistant pathogens – caused by drug treatment, which destroys drug sensitive strains e.g., pseudomembranous enterocolitis – caused when treatment with certain antibiotics kills intestinal flora, leaving Clostridium difficile to flourish and produce a toxin  Preventing emergence of drug resistance When necessary give drug in high concentrations give two or more drugs at same time if needed use drugs only when necessary possible future solutions – continued development of new drugs – use of bacteriophages to treat bacterial disease  Antiviral Drugs Relatively few because difficult to specifically target viral replication  used to prevent influenza infections blocks penetration and uncoating of influenza virus inhibits herpes virus enzymes involved in DNA and RNA synthesis and function inhibits herpes virus and cytomegalovirus DNA polymerase inhibits herpes virus DNA polymerase Broad-spectrum anti-DNA virus drugs inhibits viral DNA polymerase papovaviruses, adenoviruses, herpesviruses iridoviruses, and poxviruses  Anti-HIV Drugs Reverse transcriptase (RT) inhibitors – nucleoside RT inhibitors – non-nucleoside RT inhibitors Protease inhibitors – mimic peptide bond that is normally attacked by the protease Fusion inhibitors – prevent HIV entry into cells Most successful are drug cocktails to curtail resistance Reverse transcriptase inhibitors Protease inhibitors