Antibacterials I _General Principles (1).pptx

HOAD GENERAL PRINCIPLES OF ANTIBACTERIAL DRUGS Wandikayi C. Matowe, BSc, BA, BSc(Pharm), RPEBC, PhD Email: [email protected] Office: Room 125 Building #1 1 ...

HOAD GENERAL PRINCIPLES OF ANTIBACTERIAL DRUGS Wandikayi C. Matowe, BSc, BA, BSc(Pharm), RPEBC, PhD Email: [email protected] Office: Room 125 Building #1 1  Reading and Practice Questions Chapter 51: Clinical Use of Antimicrobial Agents https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=3461&sectionid= 285599491 Practice Questions End of Chapter https://tmedweb.tulane.edu/pharmwiki/quizzes/ abx1.htm https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/ book.aspx?bookid=3461 Reserved for captions  Learning Objectives After this lecture, the student should know and be able to: Explain the importance of normal flora especially in the GIT Explain the differences between bactericidal and bacteriostatic drugs Describe the pharmacokinetics of antimicrobial agents for dose schedule Explain the mechanism of action of antibacterial drugs Discuss the mechanisms of resistance to antibacterial drugs List the prophylactic uses of antibacterial therapy Define superinfection and ways to reduce it  High-Yield Terms Antimicrobial Use of antimicrobial drugs to decrease the risk of prophylaxis infection Combination Two or more drugs used together to increase efficacy antimicrobial drug more than can be accomplished with use of a single therapy agent; synergism possible Empiric (presumptive) Initiation of drug treatment before identification of a antimicrobial therapy specific pathogen Minimum inhibitory An estimate of the drug sensitivity of pathogens for concentration (MIC) comparison with anticipated levels in blood or tissues Antibacterial effect that persists after drug Postantibiotic effect concentration falls below the minimum inhibitory (PAE) concentration Susceptibility testing Laboratory methods to determine the sensitivity of the isolated pathogen to antimicrobial drugs  Importance of Normal Flora (Micorbiome) Normal flora (microbiome) contributes to health:  Maintaining pH especially of gut flora Inhibiting colonization by pathogenic organisms  Synthesizing certain vitamins (e.g. B and K) Normal flora contributes to infection  If misplaced (fecal flora to urinary tract)  If patient is immunocompromised (overgrowth)  If suppressed (e.g., Antibiotic associated diarrhea – Clostridiodes difficile)  Bacteriostatic & Bactericidal Bacteriostatic drugs: arrest bacterial growth and replication  limit the spread of infection until the immune system attacks and eliminates the pathogen.  E.g., Azithromycin, sulfonamides  Generally, protein synthesis inhibitors are bacteriostatic  Not preferred in immunocompromised patients, and not preferred in life threatening infections  Bacteriostatic & Bactericidal Bactericidal drugs: kill the bacteria  reduce the total number of viable organisms Bacteriostatic  E.g., Rifampin, penicillins, Bacterici cephalosporins, vancomycin dal  All cell wall synthesis https://o.quizlet.com/4W7XZfMyXiu9O-amXv8j8Q.png inhibitors are bactericidal  Antibiotic Pharmacokinetics Basis for selection of dose and schedule Minimum inhibitory concentration (MIC)  lowest antimicrobial concentration that prevents visible growth of an organism after 24 hours of incubation Three indices important to the microbial kill  C max / MIC (Maximum concentration)  T > MIC (Time over MIC) Cmax – Concentration maximum; T-time; AUC-area under the curve  AUC (Area under the curve)   certain dose schedules maximize antimicrobial effect  Killing kinetics Time–dependent killing  β-lactams (penicillins, cephalosporins and carbepenems) and vancomycin exhibit time dependent killing  Clinical efficacy is best predicted by the percentage of time that blood concentrations of a drug remain above the MIC.  Multiple daily doses are preferred over a single large dose. Concentration-dependent killing  Aminoglycosides (streptomycin and gentamicin) and fluoroquinolones show a significant increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64- fold the MIC of the drug.  Single large dose to reach higher concentrations is preferred over multiple daily doses  Post-antibiotic effect (PAE) PAE is a persistent suppression of microbial growth that occurs even after levels of antibiotic have fallen below the MIC. Aminoglycosides and fluoroquinolones exhibits a long PAE that often require only one dose per day, particularly against gram negative bacteria. Clinical Use & Antimicrobial Drug Selectivity Selective toxicity: Takes advantage of differences between microbes and hosts Many antimicrobial agents target features that are unique to the microbe  e.g. cell wall Less likely to cause adverse reactions Features that are similar in humans (e.g., protein synthesis / DNA synthesis / Folic acid metabolism) Higher risk of adverse drug reactions  Resistance to Antibiotics Resistance Examples Mechanism Natural or innate Mycoplasma resistant to penicillin resistance Obligate anaerobes resistant to aminoglycosides Acquired Resistance Penicillin resistance to S. pneumoniae (PRSP) Altered targets (mutation) Methicillin resistance to Staph aureus (MRSA) Gram-negative organisms limit penetration to β-lactam antibacterial Decreased entry drugs Increased efflux Tetracycline resistance to B. fragilis Penicillinases (beta-lactamases) inactivate β-lactams Enzymatic inactivation Acetyltransferases inactivate aminoglycosides and chloramphenicol Esterases hydrolyze macrolides in Gram-ve. Microorganisms irreversibly attach to and grow on a surface and Biofilm formation produce extracellular polymers that facilitate attachment and matrix formation. Reduce antibiotic penetration  Rationale for Combinations Enhance efficacy Provide broad spectrum coverage  Empirical therapy  Polymicrobial infection Abdominal abscess Penicillin with gentamicin for Enterococcal endocarditis Seriously ill (e.g. meningitis) Reducing dose-related toxicity  When synergistic drugs are combined, individual doses may be lower in the combination Preventing resistance to monotherapy  Tuberculosis and HIV  Combinations to Avoid Antagonism of antibacterial drugs Penicillin + tetracycline Penicillin is bactericidal – works better when cells are rapidly dividing Tetracycline is bacteriostatic – reduces the rate of cell division in the bacteria Exceptions to this rule may apply in certain clinical conditions Induction of enzymatic inactivation Beta-lactamases induced by ampicillin may antagonize piperacillin in Gram-ve bacteria  Types of Antibacterial Treatment Type of therapy Features Prophylactic Not infected yet but at high risk of infection Preemptive Asymptomatic and infected individuals Lab test positive for infection Empirical Symptomatic patients Based on site of infection Sample has been taken, microbiological diagnosis or sensitivity not yet known Empirical treatment can reduce mortality or morbidity Definitive Well established infection, lab diagnosis of the Treatment microorganism and its sensitivity known  Superinfections Infection occurring in a patient on an antibiotic treatment Occurs due to suppression of the normal flora allowing other bacterial to overgrow Broad spectrum antibiotics have a higher tendency to cause superinfections  Broad spectrum antibiotics are those that can kill multiple types of microorganisms (e.g. tetracyclines can kill G +ve, G –ve, and atypical organisms)  E.g., Clostridium difficile → pseudomembranous colitis (antibiotic associated diarrhea)  E.g., Candida infection of the vaginal tract  E.g., Resistant S. aureus (MRSA) colonization of the anterior nares Ways to reduce superinfections:  Reduce the use of broad-spectrum antibiotics when not needed  Reduce antibiotic overuse  Detect infections and treat early Summary: Drug Targets and Mechanisms  Summary 1. Reasons for susceptibility testing of isolates and determination of antibiotic blood levels in the treatment of many infections. 2. Explanation of antibiotics that require major modifications of dosage in renal or hepatic dysfunction 3. Rationale for the use of antimicrobial drugs in combination and the probable mechanisms involved in drug synergy 4. Principles underlying valid antimicrobial chemoprophylaxis Questions 19