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CHEMOTHERAPY Antimicrobial Antiviral chemotherapy Antiparasitic Cancer chemotherapy Drugs Chemotherapy CHEMOTHERAPY Concepts Many easy to understand. distinct diseases so less prototype drugs. ANTIBIOTICS General Principles Mechanism of Action Pharmacokinetics/Therapeutic Adverse effects Uses STUDY AIDS Objectives Summary tables STUDY AIDS Review questions on web: http://info.unmc.edu/scholarchemo1/ AntiBio/AntibioTestframe.htm STUDY AIDS http://dev1.unmc.edu/JeopardyGame/A ntibiotics.htm http://dev1.unmc.edu/JeopardyGame/A ntibioticsDouble.htm ANTIMICROBIAL CHEMOTHERAPY Selective Toxicity CHEMOTHERAPY Allows the normal hostdefense mechanisms to gain control. CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS Control Number of bacteria Bacteriostatic agent Bactericidal agent Time BACTERIOSTATIC DRUGS Sulfonamides Erythromycin Tetracyclines BACTERICIDAL DRUGS Trimethoprim +Sulfamethoxazole Aminoglycosides β-lactams Inhibit Protein Synthesis Nucleic acid synthesis Cell membrane Permeability T XXXX Cell Wall Synthesis Antimetabolites CHOICE OF THE ANTIBIOTIC First determine etiology of the infection. CHOICE OF THE ANTIBIOTIC Sensitivity pattern of the infecting organism must be determined. Consider pharmacokinetics and host factors. PHARMACOKINETIC FACTORS Location Route of Infection. of Administration. Pattern of excretion, metabolism, and degree of protein binding. HOST FACTORS Host defense (Immunocompetence). Local factors. Age. Genetic Drug factors. Allergy. HOST FACTORS Renal disease and liver disease. AIDS Pregnancy. USES OF ANTIBIOTICS Empirical antimicrobial therapybefore the pathogen is known. Infections with known etiology. MISUSES OF ANTIBIOTICS Treatment of nonresponsive infections. Therapy of fever of unknown origin Fever of short duration Fever persisting for 2 or more weeks. MISUSES OF ANTIBIOTICS Dosing errors Wrong frequency Excessive or subtherapeutic doses MISUSES OF ANTIBIOTICS Inappropriate reliance on chemotherapy alone (e.g. abscesses). MISUSES OF ANTIBIOTICS Lack of adequate bacteriological information. • Absence of supporting data • Agents selected by habit • Doses are routine, rather than individualized COMBINATION CHEMOTHERAPY Separate but simultaneous administration. Combination ChemotherapyAdvantages Treatment of polymicrobial infections. Prevent or delay resistance. Synergy. Combination ChemotherapyAdvantages Severe infections of unknown etiology-empirical therapy. DISADVANTAGES Increased risk of toxicity. Increased likelihood of superinfections. Increased cost. Antagonism of an antibacterial effect. FIXED DOSE COMBINATIONS Ratio and dose of antibiotics are determined based on in vitro studies. Encourages inadequate treatment. PROPHYLAXIS OF INFECTION This should be used only in circumstances in which efficacy has been demonstrated and the benefits outweigh the risks. PROPHYLAXIS OF INFECTION Effective when a single drug is used to prevent infection from a specific microorganism. In patients undergoing organ transplantation or receiving cancer chemotherapy. PROPHYLAXIS OF INFECTION Primary and 2ndary prevention of opportunistic infections in AIDS patients when CD4 counts are below certain threshholds. PROPHYLAXIS OF INFECTION To prevent wound infections after various surgical procedures. Complications of Antimicrobial Therapy Drug Resistance Superinfections Toxicity DRUG RESISTANCE Involves a stable genetic change in the bacteria. DRUG RESISTANCE Mutation and selection with passage vertically. Horizontal transfer from a donor cell by transduction, transformation or conjugation. MUTATION-SELECTION Occurs in many different genes. Random events that confer a survival advantage when a drug is present. CHROMOSOMAL MUTATIONS Antibiotics agents. are acting as selecting + Antibiotic Resistant Population HORIZONTAL GENE TRANSFER Mobile genetic elements (plasmids, transposable elements, integrons, gene cassettes). Transduction Transformation CONJUGATION Direct cell to cell contact through a sex pilus or bridge Very important for the spread of resistance because multiple resistance genes can be transferred simultaneously. Enzyme Inactivation Altered Permeability Mod. of target site and reduced affinity CROSS-RESISTANCE e.g. sulfonamides, penicillins PREVENTION OR DELAY OF RESISTANCE Judicious (appropriate) or careful use of antibiotics Adequate Dosage Combination Chemotherapy SUPERINFECTIONS A new infection appearing during the chemotherapy of a primary one. Caused by removing inhibitory influence of the normal flora. + Antibiotic (Broad spectrum) Resistant pathogen Secondary infection from resistant organisms TREATMENT OF THE SUPERINFECTION Stop present therapy. Culture Treat infected area. against the offending microorganism. TOXICITY Hypersensitivity Direct Toxicity- GI BACTERICIDAL AGENTS Drugs whose killing action is time dependent don’t show increased killing above MBC; bactericidal activity continues as long as the serum concns. exceed MBC. Gram Gram _ + Rickettsia Gram Gram + _ Amoeba Drug Concentration on microbial killing AUC:MIC (area under the serum concentration time curve: minimal inhibitory concentration). Peak serum concentration:MIC Appropriate Dose of Antimicrobial Agent Principles of pharmacokinetics and pharmacodynamics are used to determine this. Appropriate Dose of Antimicrobial Agent Pharmacodynamic factors include cidal vs static activity and postantibiotic effects. CIDAL VS STATIC For primarily static agents inhibitory drug concn’s are much lower than cidal concn’s. Usually cell wall active drugs are cidal and protein synthesis inhibitors are static. CIDAL VS STATIC Some agents that are considered to be static may be cidal vs selected organisms. CIDAL VS STATIC Static and cidal agents are equivalent for immunocompetent hosts. Cidal agents should be used when host defenses are impaired. CIDAL VS STATIC Bactericidal agents can be divided into 2 groups (1) concentration dependent e.g. aminoglycosides and quinolones and (2)time dependent killing e.g. beta lactams and vancomycin. POSTANTIBIOTIC EFFECT Persistent suppression of bacterial regrowth after brief exposure. Mechanism is likely multifactorial and may vary with the specific antimicrobial drug and organism combination. No. of Viable bacteria/ml. Postantibiotic effect 0 Drug added 4 8 Hours Drug removed POSTANTIBIOTIC EFFECT With aminoglycosides it has allowed once daily dosing and less monitoring.