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PHAR2210 Foundations of Pharmacology Lecture 17 Introduction to antimicrobial chemotherapy Dr Ricky Chen Chapter 51, Rang & Dale's Pharmacology (Tenth Edition, 2023)  Learning outcomes After completing this lecture, you should be able to list the mecha...

PHAR2210 Foundations of Pharmacology Lecture 17 Introduction to antimicrobial chemotherapy Dr Ricky Chen Chapter 51, Rang & Dale's Pharmacology (Tenth Edition, 2023)  Learning outcomes After completing this lecture, you should be able to list the mechanisms of action of antibacterial, antifungal, and anti-HIV drugs explain the difference in action between -cidal and -static antimicrobial drugs explain the difference in action between broad-spectrum and narrow-spectrum antimicrobial drugs explain the principle of broth microdilution to determine the minimum inhibitory concentration and the minimum bactericidal/fungicidal concentration of antimicrobial drugs explain the principle and interpretation of three phenotypic antimicrobial susceptibility tests outline the use of antibacterial, antifungal, and anti-HIV drugs in the context of treating and preventing infection Core concepts of pharmacology pharmacodynamics pharmacokinetics Drug-target Drug target Steady-state Drug absorption Drug bioavailability interaction concentration Mechanism of Structure-activity Drug distribution Volume of distribution drug action relationship Zero- and first- order kinetics Drug metabolism Drug clearance Affinity Drug selectivity Drug elimination Drug elimination half-life Potency Efficacy DRUG Dose/concentration- Drug tolerance response relationship Therapeutic index Adverse drug reaction Individual variation Adapted from Guilding et al. (2023) Defining and Drug interaction in drug response unpacking the core concepts of pharmacology: A global initiative. British Journal of Pharmacology, 1-18. Patient outcomes https://doi.org/10.1111/bph.16222  Antimicrobial chemotherapy Chemotherapy the use of drugs that are selectively toxic to pathogens but innocuous to the host Paul Ehrlich used Salvarsan (arsphenamine) to treat syphilis chemotherapy target-host specificity​ toxicity to the host​ +++ + antimicrobial chemotherapy antibacterial drugs antifungal drugs antiparasitic drugs Paul Ehrlich (1854–1915) antiviral drugs anticancer chemotherapy + +++ Discovery and development of antibiotics 2 aminoglycosides tetracyclines 1 amphenicols penicillins antibacterials 1 3 2 macrolides cephalosporins 3 azoles echinocandins antifungals polyenes allylamines Hutchings et al. (2019) Antibiotics and leading causes of deaths  Mechanisms of action of antibacterial drugs Mechanism of drug action refers to the process by which a drug produces a biological effect inhibit cell wall synthesis o penicillins* o cephalosporins* inhibit protein synthesis L18 antibacterial drugs o aminoglycosides* o tetracyclines* o amphenicols* o macrolides​* inhibit DNA replication​ inhibit metabolism Lewis (2013)  Mechanisms of action of antifungal drugs inhibit cell wall synthesis o echinocandins* alter cell membrane integrity or permeability L19 antifungal drugs o polyenes* o allylamines* o azoles* inhibit mitosis inhibit DNA synthesis Rang & Dale's Pharmacology (Chapter 54, 10th edition, 2020)  Mechanisms of action of anti-HIV drugs entry inhibitors reverse transcriptase inhibitors integrase inhibitors L20 anti-HIV drugs o -tegravir* protease inhibitors o -navir* Barré-Sinoussi et al. (2013)  Mode of action of anti-bacterial/fungal drugs A drug can be -cidal or -static depending on the species -cidal - lethal to organism and kills microbes -static - slow down microbial growth by blocking replication CFU: colony-forming unit Baquero and Levin (2020)  Spectrum of action of anti-bacterial/fungal drugs broad spectrum - drugs are effective against a wide range of species narrow spectrum - drugs are effective against specific species Lewis (2011)  Minimum inhibitory concentration minimum inhibitory concentration (MIC) the lowest concentration of a drug required to inhibit the visible growth of a microorganism minimum bactericidal / fungicidal concentration the lowest concentration of a drug required to kill a microorganism broth microdilution https://emerypharma.com/biology/minimum-inhibitory-concentration/  Antimicrobial drugs - PK/PD considerations time- and concentration-dependent - AUC:MIC concentration-dependent - Cmax:MIC time-dependent - Time > MIC comorbidities o e.g., HIV - drug-drug interactions o e.g., obesity dose optimisation optimal treatment avoid toxicity suppress drug resistance Rawson et al. (2021)  Antimicrobial resistance - a global issue one of the top 10 global public health threats (WHO) antimicrobial misuse and overuse (human health, agriculture) spread of drug-resistant microbes, e.g., poor infection prevention economic cost, e.g., prolonged hospital stays, disability and death Average proportion of infections caused by antimicrobial- https://www.amr.gov.au/resources/one-health-master-action- resistant bacteria (Stemming the Superbug Tide, OECD) plan-australias-national-antimicrobial-resistance-strategy-2020  Antimicrobial resistance spread of drug resistance person → person (by bacteria) bacterium → bacterium (by plasmids) plasmid → plasmid by transposons many strains carry multiple resistance genes HIV - mutations and (multi)drug resistance reverse transcriptase protease integrase gp41 Lewis (2013) Wensing et al. (2019)  Antimicrobial susceptibility testing (AST) phenotypic or genotypic identification of microbe(s) susceptibility and resistance of microbe isolates towards drugs standards and interpretation: EUCAST (European Committee on Antimicrobial Susceptibility Testing) / CLSI (the Clinical and Laboratory Standards Institute) phenotypic identification (I) - disk diffusion collect samples (e.g., body fluids) for culture → select colonies to prepare a large zone ​of inhibition suspension → inoculate onto an agar = sensitive organism plate → incubation agar plate measurement and interpretation (S / I / R) no zone of inhibition drug disk = resistant organism  Antimicrobial susceptibility testing (AST) phenotypic identification (II) - gradient diffusion Etest® strips - indicate MIC phenotypic identification (III) - broth microdilution determine MIC genotypic identification e.g., PCR technologies automated systems mass spectrometry microfluidics-based diagnostics Antifungal susceptibility testing (AFST) Sensititre YeastOne - colorimetric detection B. ATB Fungus 3 - 32-well drug-containing strip Durand et al. (2021)  Treatment and prevention antibacterial drugs spectrum of action o broad spectrum drugs affect both harmful and beneficial species in the GI tract ▪ reduce competition between species / increase levels of resistance genes / reduce diversity preoperative prophylaxis - ↓ risks of surgical site infection toxicity antifungal drugs spectrum of action route of administration, e.g., oral / topical / intravenous toxicity anti-HIV drugs combination therapy - single-pill, fixed-dose (e.g., Stribild) potential drug-drug interactions HIV prevention - PrEP (pre-exposure prophylaxis) / PEP (post-exposure prophylaxis)