Intro To AntiMicrobials PDF

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. B A S I C P R I N C I P L E S O F A N T I M I C R O B I A L A N T T H E R A P Y ANTIBIOTICS  BASIC PRINCIPLES OF ANTIMICROBIAL THERAPY Chemotherapy Use of chemicals against invading organisms An...

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. B A S I C P R I N C I P L E S O F A N T I M I C R O B I A L A N T T H E R A P Y ANTIBIOTICS  BASIC PRINCIPLES OF ANTIMICROBIAL THERAPY Chemotherapy Use of chemicals against invading organisms Antibiotic Strictly speaking—a chemical that is produced by one microbe and has the ability to harm other microbes Antimicrobial agent Any agent that has the ability to kill or suppress microorganisms Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 2  SELECTIVE TOXICITY Toxic to microbes—harmless to host Disruption of bacterial cell wall Inhibition of an enzyme unique to bacteria Disruption of bacterial protein synthesis Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 3  CLASSIFICATION OF ANTIMICROBIAL DRUGS Various themes used to classify The two used for this textbook: Classification by susceptible organism Classification by mechanism of action Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 4  CLASSIFICATION OF ANTIBIOTICS Drugs work on: Cell wall synthesis Cell membrane permeability Protein synthesis (lethal) Nonlethal inhibitors of protein synthesis Synthesis of nucleic acids Antimetabolites Viral enzyme inhibitors Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 5 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 6  ACQUIRED RESISTANCE TO ANTIMICROBIAL DRUGS Over time, organisms develop resistance May have been highly responsive and then became less susceptible to one or more drugs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 7  ORGANISMS WITH MICROBIAL DRUG RESISTANCE Enterococcus faecium, Staphylococcus aureus, Enterobacter species, Klebsiella species, Pseudomonas aeruginosa, Acinetobacter baumannii, Clostridium difficile Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 8  MICROBIAL MECHANISMS OF DRUG RESISTANCE Four basic actions Decrease the concentration of a drug at its site of action Inactivate a drug Alter the structure of drug target molecules Produce a drug antagonist Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 9  MECHANISMS FOR ACQUIRED RESISTANCE Spontaneous mutation Conjugation Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 10  CONJUGATION Spontaneous mutation Conjugation Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 11  DELAYING EMERGENCE OF DRUG RESISTANCE Vaccinate Get the catheters out Target the pathogen Nosocomial infections Superinfection Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 12  DELAYING EMERGENCE OF DRUG RESISTANCE Treat infection, not contamination Treat infection, not colonization Know when to say “No to vanco” Stop treatment when infection is cured or unlikely Isolate the pathogen Break the chain of contagion Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 13  SELECTION OF ANTIBIOTICS Identify organism Drug sensitivity of organism Drug selection based on Clinical evaluation Knowledge of microbes most likely to have caused infection Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 14  HOST FACTORS Host defenses Site of infection Age Pregnancy and lactation Previous allergic reactions Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 15  DOSAGE SIZE AND DURATION Antibiotic must be present: At the site of infection For a sufficient length of time Antibiotics must not be discontinued prematurely Teach patients to complete full prescription Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 16  PROPHYLACTIC USE OF ANTIMICROBIALS Agents given to prevent infection rather than to treat an established infection Surgery Bacterial endocarditis Neutropenia Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 17  PENICILLINS Active against a variety of bacteria Direct toxicity: Low Principal adverse effect: Allergic reaction Structure includes a beta-lactam ring Beta-lactam family: Includes cephalosporins, aztreonam, imipenem, meropenem, and ertapenem 18 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 18  PENICILLINS Mechanism of action Weaken the cell wall, causing bacteria to take up excessive water and rupture Active only against bacteria undergoing growth and division Bactericidal Bacterial resistance Inability of penicillins to reach their target Inactivation of penicillins by bacterial enzymes 19 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 19  MECHANISMS OF BACTERIAL RESISTANCE Three factors Inability of penicillins to reach their targets Inactivation of penicillins by bacterial enzymes Production of penicillin-binding proteins (PBPs) that have a low affinity for penicillins 20 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 20  STAPHYLOCOCCUS AUREUS 1940s: Penicillin introduced All strains of S. aureus were sensitive 1960: 80% of S. aureus isolates in hospitals displayed penicillin resistance Penicillin derivative (methicillin) developed; resistant to actions of beta-lactamases Methicillin-resistant Staphylococcus aureus (MRSA) has a unique mechanism of resistance ‒ it produces PBPs with a low affinity for penicillins and all other beta-lactam antibiotics MRSA developed this ability by acquiring genes that code for low-affinity PBPs from other bacteria 21 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 21  PENICILLINASES Beta-lactamases Enzymes that render penicillin inactive Bacteria can produce a large variety of these enzymes specific for penicillins (and other beta- lactam antibiotics) 22 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 22  CLASSIFICATION OF PENICILLINS Narrow-spectrum penicillins Penicillinase sensitive Narrow-spectrum penicillins Penicillinase resistant Broad-spectrum penicillins Extended-spectrum penicillins 23 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 23  CELL ENVELOPE Gram-negative cell envelope Three layers Thin cell wall and an additional outer membrane that is hard to penetrate Gram-positive cell envelope Only two layers Relatively thick cell wall that is easily penetrated Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 24 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 25  PENICILLINASE-RESISTANT PENICILLINS Available in the United States Nafcillin Oxacillin Dicloxacillin MRSA: methicillin-resistant Staphylococcus aureus Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 26  BROAD-SPECTRUM PENICILLINS Broad-spectrum penicillins (aminopenicillins) Ampicillin (Principen) Amoxicillin (Amoxil, DisperMox, Moxatag, Trimox) Adverse effects Rash Diarrhea Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 27 EXTENDED-SPECTRUM PENICILLINS Extended-spectrum penicillins (antipseudomonal penicillins) Piperacillin Broad-spectrum, but penicillinase-sensitive Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 28 DRUGS THAT WEAKEN BACTERIAL CELL WALL C EP HA LO SPO RI N S , C AR B A PE NE MS , E TC. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.  CEPHALOSPORINS Most widely used group of antibiotics Beta-lactam antibiotics Similar to penicillin structure Bactericidal Usually given parenterally Low toxicity 30 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 30  CEPHALOSPORINS Mechanism of action Bind to penicillin-binding proteins (PBPs), disrupt cell wall synthesis, and cause cell lysis Most effective against cells undergoing active growth and division Resistance Beta-lactamases (cephalosporinases) First-generation destroyed Second-generation less sensitive Third-, fourth-, and fifth-generation agents more resistant than first- and second-generation agents 31 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 31 CLASSIFICATION OF CEPHALOSPORINS First generation Cephalexin Second generation Cefoxitin Third generation Cefotaxime Fourth generation Cefepime Fifth generation Ceftaroline 32 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 32  CEPHALOSPORINS Therapeutic uses First generation: Widely used for prophylaxis against infection in surgical patients; rarely used for active infections Second generation: Rarely used for active infection Third generation Preferred therapy for several infections Highly active against gram-negative organisms Able to penetrate to cerebrospinal fluid (CSF) 33 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 33  CEPHALOSPORINS Therapeutic uses (Cont.) Fourth generation Commonly used to treat health care‒ and hospital-associated pneumonias, including those caused by the resistant organism Pseudomonas Fifth generation Infections associated with methicillin-resistant Staphylococcus aureus (MRSA) 34 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 34  CARBAPENEMS Beta-lactam antibiotics have an extremely broad antimicrobial spectrum with low toxicity Not active against MRSA Imipenem Meropenem Ertapenem Doripenem 35 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 35  CARBAPENEMS Imipenem [Primaxin] Active against most bacterial pathogens, including organisms resistant to other antibiotics Highly active against gram-positive cocci and most gram-negative cocci and bacilli Most effective beta-lactam antibiotic for use against anaerobic bacteria Intravenous administration Adverse effects and interactions 36 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 36  VANCOMYCIN Action Inhibits cell wall synthesis Uses Severe infections only MRSA, Staphylococcus epidermidis, Clostridium difficile Intravenous administration Interactions 37 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 37 VANCOMYCIN [VANCOCIN, VANCOLED] Adverse effects Ototoxicity (reversible or permanent) “Red man” syndrome Thrombophlebitis (common) Thrombocytopenia (rare) Allergy 38 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 38  TETRACYCLINES Tetracyclines Broad-spectrum antibiotics Inhibit protein synthesis Increasing bacterial resistance has emerged Uses Rickettsial disease Chlamydia trachomatis Brucellosis Cholera Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 39  TETRACYCLINES Four members of the tetracycline family available for systemic therapy Tetracycline Demeclocycline Doxycycline Minocycline Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 40  TETRACYCLINES Uses (cont’d) Mycoplasma pneumoniae Lyme disease Anthrax Helicobacter pylori Acne Peptic ulcer disease Periodontal disease Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 41  MACROLIDES (ERYTHROMYCIN) Broad-spectrum antibiotic Mechanism of action (MOA): inhibition of protein synthesis Usually bacteriostatic but can be bactericidal Use if allergic to penicillin Active against most gram-positive and some gram- negative bacteria Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 42  MACROLIDES (ERYTHROMYCIN) Therapeutic uses Whooping cough, acute diphtheria, Corynebacterium diphtheriae, chlamydial infections, M. pneumoniae, group A Streptococcus pyogenes Drug interactions Adverse effects Gastrointestinal QT prolongation and sudden cardiac death Superinfection Other Macrolides Clarithromycin (Biaxin) Azithromycin (Zithromax) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 43  AMINOGLYCOSIDES Most commonly employed agents Gentamicin, tobramycin, amikacin Narrow-spectrum antibiotics Bactericidal Use: aerobic gram-negative bacilli Can cause serious injury to inner ear and kidney Not absorbed from the GI tract Microbial resistance Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 44  AMINOGLYCOSIDES Adverse effects Nephrotoxicity Ototoxicity (total cumulative and trough levels) Hypersensitivity reactions Neuromuscular blockade Blood dyscrasias Other Drug interactions Beneficial Adverse Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 45  SERUM LEVELS Dosing Single large dose each day or 2–3 smaller doses Monitoring of serum levels is common; the same aminoglycoside dose can produce very different plasma levels in different patients Peak levels must be high enough to kill bacteria; trough levels must be low enough to minimize toxicity Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 46  SULFONAMIDES AND TRIMETHOPRIM Broad-spectrum antibiotics Have closely related mechanisms Suppress bacterial growth by inhibiting tetrahydrofolic acid, a derivative of folic acid or folate 47 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 47  SULFONAMIDES First drugs available for systemic treatment of bacterial infection More effective and less toxic drugs are now available Inhibit the synthesis of folic acid (folate) Mammalian cells do not manufacture their own folate (not affected as bacteria are affected) Primary use now: Urinary tract infection (UTI) Other uses: Nocardiosis, Chlamydia trachomatis, conjugation therapy for toxoplasmosis/malaria, ulcerative colitis 48 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 48  SULFONAMIDES Microbial resistance Many bacterial species have developed resistance to sulfonamides Especially high among gonococci, meningococci, streptococci, and shigellae Resistance may be acquired by spontaneous mutation or by transfer of plasmids that code for antibiotic resistance (R factors) 49 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 49