6_Antibiotics_Principles of use PDF.pdf

PowerPoint® Lecture Presentations prepared by Mindy Miller-Kittrell, North Carolina State University...

PowerPoint® Lecture Presentations prepared by Mindy Miller-Kittrell, North Carolina State University CHAPTER 10 Controlling Microbial Growth in the Body: Antimicrobial Drugs © 2018 Pearson Education, Inc.  The History of Antimicrobial Agents Drugs Chemicals that affect physiology in any manner Chemotherapeutic agents Drugs that act against diseases Antimicrobial agents (antimicrobials) Drugs that treat infections © 2018 Pearson Education, Inc.  The History of Antimicrobial Agents Tell Me Why Why aren’t antibiotics effective against the common cold? © 2018 Pearson Education, Inc.  The History of Antimicrobial Agents Paul Ehrlich “Magic bullets” Arsenic compounds that killed microbes Alexander Fleming & previously Ernest Duchesne Penicillin released from Penicillium Florey, Chain, and Heatley (1939) Purified penicillin from culture and injected into mice. Fleming, Florey, and Chain received Nobel Prize in 1945 for discovery and production of penicillin. Gerhard Domagk Discovered sulfanilamide Selman Waksman Antimicrobial agents produced naturally by organisms (Streptomycin) © 2018 Pearson Education, Inc.  Figure 10.1 Alexander Fleming (1928). Antibiotic effect of Observed lack of growth on bacterial plate the mold Penicillium around mold. chrysogenum. Penicillium chrysogenum spores contaminated the Petri dish before inoculation with staphylococci. © 2018 Pearson Education, Inc.  The History of Antimicrobial Agents Semisynthetics Chemically altered antibiotics that are more effective, longer lasting, or easier to administer than naturally occurring ones Synthetics Antimicrobials that are completely synthesized in a lab © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Tell Me Why Some antimicrobial drugs are harmful to humans. Why can physicians safely prescribe such drugs despite the potential danger? © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Ideal Antimicrobial Agent Readily available Inexpensive Chemically stable Easily administered Nontoxic and nonallergenic Selectively toxic against wide range of pathogens © 2018 Pearson Education, Inc. 9 Clinical Considerations in Prescribing Antimicrobial Drugs Narrow-spectrum drugs—effective only against a limited variety of pathogens. Broad-spectrum drugs—target many different kinds of bacteria. May allow for secondary or superinfections to develop Bacteriostatic vs. Bactericidal activity Killing of normal flora reduces microbial antagonism Cidal agent—kills the target pathogen. Static agent— reversibly inhibits growth of microbes. © 2018 Pearson Education, Inc.  Figure 10.8 Spectrum of action for selected antimicrobial agents. © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Effectiveness Ascertained by Diffusion susceptibility test Minimum inhibitory concentration test (MIC) Minimum bactericidal/lethal concentration test (MBC or MLC) © 2018 Pearson Education, Inc.  Measuring Effectiveness of Antimicrobial Drugs Effectiveness of an agent may vary with concentration, microbe and host. Effectiveness expressed in two ways: Minimal inhibitory concentration (M IC)—lowest concentration of drug that prevents growth of the pathogen. Minimal lethal concentration (M LC)—lowest concentration of drug that kills the pathogen. © 2018 Pearson Education, Inc.  Figure 10.10 Minimum inhibitory concentration (MIC) test in wells. © 2018 Pearson Education, Inc. 14 Time dependent vs. Concentration dependent killing Conc dependent killing - GOAL: maximize concentration Time dependent killing - GOAL: maximize exposure © 2018 Pearson Education, Inc.  Figure 10.9 Zones of inhibition in a diffusion susceptibility (Kirby-Bauer) test. Often used to analyze rapidly growing bacteria. Disks impregnated with different antibiotics are placed on agar plates inoculated with a microbe. Antibiotic diffuses from disk into agar, establishing concentration gradient. High concentrations near the disk. Observe clear zones (no growth) around disks. Wide clear zones indicates a microbe is more susceptible to that antibiotic. © 2018 Pearson Education, Inc.  Figure 10.9 Zones of inhibition in a diffusion susceptibility (Kirby-Bauer) test. A B C E F D H I G Microbe resistant/sensitive to which ones? © 2018 Pearson Education, Inc.  Figure 10.9 Zones of inhibition in a diffusion susceptibility (Kirby-Bauer) test. A B C E F D H I G IF ALL OF THESE ANTIMICORBIAL AGENTS DIFFUSE AT THE SAME RATE AND ARE EQUALLY SAFE AND EASILY ADMINISTERED, WHICH ONE WOULD BE THE DRUG OF CHOICE FOR KILLING THIS PATHOGEN? © 2018 Pearson Education, Inc.  Figure 10.11 An Etest, which combines aspects of Kirby-Bauer and MIC tests. Often used in sensitivity testing. Bacteria inoculated on agar, then Etest® strips are placed on the surface. Etest® strips contain a gradient of an antibiotic. Intersection of elliptical zone of inhibition with strip indicates M I C. © 2018 Pearson Education, Inc.  Figure 10.12 A minimum bactericidal concentration (MBC) test. Minimal bactericidal/lethal concentration (MBC/MLC)—lowest concentration of drug that kills the pathogen. © 2018 Pearson Education, Inc.  Principles / Definitions Prophylaxis - antimicrobial agents are administered to prevent infection Treatment - antimicrobial agents are administered to cure existing or suspected infection © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Routes of Administration Topical (TOP) application of drug for external infections Oral (PO) route requires no needles and is self-administered Intramuscular (IM) administration delivers drug via needle into muscle Intravenous (IV) administration delivers drug directly to bloodstream Must know how antimicrobial agent will be distributed to infected tissues Figure 10.13 The effect of route of administration on blood levels of a chemotherapeutic agent. © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Safety and Side Effects Toxicity Cause of many adverse reactions poorly understood Drugs may be toxic to kidneys, liver, or nerves Consideration needed when prescribing drugs to pregnant women Therapeutic index is the ratio of the dose of a drug that can be tolerated to the drug's effective dose Figure 10.14 Some side effects resulting from toxicity of antimicrobial agents. © 2018 Pearson Education, Inc.  therapeutic window Toxicity of Antimicrobial Drugs no effect Harm the host Kill the pathogen 0 Concentration of drug Selective toxicity Ability of drug to kill or inhibit pathogen while damaging host as little as possible. Degree of selective toxicity expressed via: Therapeutic dose—drug level required for treatment of an infection. Toxic dose—drug level at which the agent is too toxic for host. Therapeutic index Ratio of toxic dose to therapeutic dose. The larger the index, the better the chemotherapeutic agent in general. © 2018 Pearson Education, Inc. 23  Clinical Considerations in Prescribing Antimicrobial Drugs Safety and Side Effects Allergies Allergic reactions are rare but may be life threatening Anaphylactic shock Disruption of normal microbiota May result in secondary infections Overgrowth of normal flora causing superinfections Of greatest concern for hospitalized patients © 2018 Pearson Education, Inc.  Antimicrobial resistance Resistance: the inability to kill or inhibit the organism with clinically achievable drug concentrations Resistance may be innate (naturally resistant) - vancomycin and gram negative bacteria Resistance may be acquired Mutation / acquisition of DNA - expanded spectrum of enzymatic activity - target-site modification - up / down regulation © 2018 Pearson Education, Inc.  Antimicrobial Selection of Resistance Spontaneous mutations during replication and division Bacterial Population Exposure to selecting antibiotic Susceptible population killed, mutants survive & proliferate Wild type Resistant Dead © 2018 Pearson Education, Inc.  Resistance to Antimicrobial Drugs The Development of Resistance in Populations Some pathogens are naturally resistant Resistance by bacteria acquired in two ways: New mutations of chromosomal genes Acquisition of R plasmids via transformation, transduction, and conjugation conjugation © 2018 Pearson Education, Inc. Figure 10.15 The development of a resistant strain of bacteria.  Antimicrobial Production (USA) ~50 Kg > 107 Tons 1950’s Present Day Selective Pressure >> © 2018 Pearson Education, Inc.  Antimicrobial resistance Factors which may accelerate the development of resistance - inadequate levels of antibiotics at the site of infection - duration of treatment too short / long - overwhelming numbers of organisms - overuse / misuse of antibiotics - poor quality counterfeits - animal husbandry - no prescription requirement (over the counter (OTC)) - frequent exposure – same class © 2018 Pearson Education, Inc.  “Not All Bugs Need Drugs” Stott, BMJ 1976 Problem: Lack rapid, accurate point of care (POC) tests Solution: Understanding the epidemiology / natural course © 2018 Pearson Education, Inc. © 2018 Pearson Education, Inc.  A Changing Landscape for Numbers of Approved Antibacterial Agents Number of agents approved 18 16 14 12 Resistance 10 8 6 4 2 1 0 1983-87 1988-92 1993-97 1998-02 2003-07 2008 Bars represent number of new antimicrobial agents approved by the FDA during the period listed. Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286; New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912 © 2018 Pearson Education, Inc.  The Drug Discovery Pipeline for Antibiotics Is Slowing to a Trickle.… … We Need to Conserve What We Have Through Judicious Use $1.4 BILLION US Drug: Avibactam Relebactam © 2018 Pearson Education, Inc.  Implications Of Resistance Treatment failure - increased morbidity / mortality Forced to use more expensive and/or toxic alternatives Longer hospital stays - increased health care costs Possibility of no alternate agents © 2018 Pearson Education, Inc.  Antimicrobial Resistance Health care advocates MUST recognize the impact of antimicrobial resistance on patients and future patients! Too often, antibiotics have not been given the respect they deserve and have, at times, been regarded as drugs of convenience. Given the dearth of new drug development, we MUST, do a better job of prescribing these agents in order to preserve the integrity of the existing antibiotic classes! 35 © 2018 Pearson Education, Inc.  Antimicrobial Stewardship Limit use of antimicrobials to those patients that absolutely require them: Fluoroquinolones Piperacillin-tazobactam Carbapenems (meropenem) © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Successful chemotherapy requires selective toxicity Antibacterial drugs constitute largest number and diversity of antimicrobial agents Fewer drugs to treat eukaryotic infections Antiviral drugs limited © 2018 Pearson Education, Inc.  Figure 10.2 Mechanisms of action of microbial drugs. © 2018 Pearson Education, Inc.  General Mechanisms of Resistance Mechanisms of Resistance Multiple mechanisms of microbial resistance - Pump antimicrobial drug out of the cell before it can act - Slow or prevent entry of drug into the cell - Bacteria in biofilms can resist antimicrobials - Over production of the target - Alter their own metabolic chemistry (metabolic bypass) - Produce enzyme that destroys or deactivates drug © 2018 Pearson Education, Inc. - Alter target of drug so it binds less effectively