Drug Therapy and AMR - Spring 2024 - Dr. Gutierrez PDF

Antimicrobials Principle of Infectious Diseases Drug therapy & antimicrobial resistance (AMR) Dr. Ricardo Gutiérrez, Microbl., MSc, Ph.D. Assistant Professor [email protected] Spring semester, 2024 DRUG THERAPY Principles of drug therapy DRUG THERAPY (PHARMACOTHERAPY): Any medical treatment...

Antimicrobials Principle of Infectious Diseases Drug therapy & antimicrobial resistance (AMR) Dr. Ricardo Gutiérrez, Microbl., MSc, Ph.D. Assistant Professor [email protected] Spring semester, 2024 DRUG THERAPY Principles of drug therapy DRUG THERAPY (PHARMACOTHERAPY): Any medical treatment that utilizes one or more drugs to provide symptomatic relief, treat the underlying condition (metabolic, infectious) or act as a prevention for (other) diseases i ncludes therapy treating drug symptomatically aswellaspropmiaticannotfororowt.at supportivelyas wellascuratively promotion fifth KEY PROPERTIES OF A DRUG: Selectivity (target vs non-desired targets)wantt Yaffa.ua Concentrations (sufficient at the site of action vs toxicity) acknostcens mustbemaintaineduntiiitcompietesirsaesiredetien Time (maintenance vs depletion) inotaeneteanetor.name ffffifffifman tiff.fi n resistance DRUG THERAPY Drug therapy for infectious diseases ANTIMICROBIAL AGENT: t.int 1 iiiiiii Any substance of natural, semisynthetic or synthetic origin that either kills microbes (bacteria, fungi, virus) or prevents their multiplication, reducing their pathogenic effect DRUG THERAPY Antibiotics / Antibacterials destroys membrane plasma preventeenwan synthesis ftp 9iriiebinsopra u'ction cannot multiply divide metabolic disrupt pathways disrupt prevent DNAoranasanthesis E To interfere with bacterial cell life or growth, antibacterials must interact with a vital structure or block a metabolic pathway (i.e., without causing direct toxicity for hosts receiving treatment) problemw cancer treatment O DRUG THERAPY Administration routes Principles of drug therapy Routes Systemic Enteral Oral Sublingual Local Parenteral Inhalation Injection C Topical Transdermal Intramammary Intravenous moverapiarespons mostcommonaaministrano rontesarearaea.nrea Rectal Intramuscular Subcutaneous Others DRUG THERAPY DRUG THERAPY ABDC ME Principles of drug therapy ADME principle: 1. Absorption (concentration in the blood) 0080 2. Distribution (concentration in the tissues) 7541714 determinedistribution identifying.ae 3. Metabolism (determination of metabolites) determined by metabolites 4. Excretion (concentration in the feces/urine/others) cresianesstnatnavenenmoaitieaintneiiveror.name measureanarusioncentration intinianatisangrenased PHARMACOKINETICS (PK) is the study of what the body does to the drug… drug absorption, distribution, metabolism, and excretion iiii iii ii.ii iiii iiiiiiiiiiiiiii.it.in PHARMACODYNAMICS (PD) is the study of what the drug does to the body and the target… intensity of therapeutic (microbial death) and adverse effects PK/PD together can be thought of as an exposure/response relationship DRUG THERAPY Maximum efficacy Principles of drug therapy spnEion c ompletely Potency ftp.fnffffffsconcentraiionane Dose-Response Relationships if Drug effect is a function of dose and time Response to concentration may be complex and is often nonlinear Potency is y the concentration at which 50% of the maximum effect is achieved 0 atonongenoughtorittocompleteitsettect mostpotent Example If iiiii f fiI.im hiqm.aepoient DRUG THERAPY DRUG THERAPY Principles of drug therapy: in vitro evidence invitrointueras Minimum inhibitory concentration (MIC) The MIC is defined as the lowest concentration of antibiotic that completely inhibits growth of the specific organism being tested. Hideki sL'm Minimum bactericidal concentration (MBC) no int The MBC is defined as the lowest concentration tested of an antibiotic at which bacteria are killed. 0Diameters of inhibition zones (Disk diffusion test) Reference susceptibility test that provides for the evaluation of the diameters of the inhibition zones around the disks containing the antibiotic tested measurezoneotinnisition surrounding antibiotic.is the measureainminimeters correlatessusceptibilityresistance MBC DRUG THERAPY Principles of drug therapy: in vitro evidence Bacteriostatic versus bactericidal antibiotics KILL  BacteriCIDAL agents = kill bacteria and reduce the total number of viable organisms. Usually requires active growth. inamoran  BacterioSTATIC agents = inhibit growth and replication of bacteria, thus allowing the host immune system to complete pathogen elimination in iia mini's iearea nimman IEi i iitiiin m DRUG THERAPY Principles of drug therapy: in vitro evidence Spectrum of activity 00 Narrow-spectrum antimicrobials act against a limited group of bacteria Broad-spectrum antimicrobials act against a large group of bacteria (e.g. G+ & G- groups) 0 infection cause ifyouknow of s pectrum narrow youusea antimicrobial because don't bacteria want beneficial avoid p romoting emergence antimicrobial resistance to kill and of the Note 1: the spectrum is based on the susceptibility of the wild-type population of bacterial species… Note 2: the spectrum may not include all group-related species… DRUG THERAPY DRUG THERAPY Principles of drug therapy Killing of the pathogen within the host Antibiotic vs pathogen in vivo: 1. Binding to the target site in the bacterium 2. Sufficient concentration within the bacterium to adhere to enough targets 3. Sufficient time to cause effect Thus: killing effect => concentration & time DRUG THERAPY Principles of drug therapy if m L in erns microsiaipan Time-dependent vs. concentration-depending effect (killing of the pathogen) Antibiotics can be classified according to their pattern of antimicrobial activity: concentration-dependent killing, timedependent killing, or a hybrid pattern Concentration-dependent killing pattern: as more drug more antimicrobial effect marugconcentrationgreaterantimicromette grief Time-dependent killing pattern: no matter how much we increase the concentration of the drug, the duration of pathogen exposure to an antibiotic is what matters. I.fi concentrationindependent norarionninoreasea p fi otieaatoagreater winn The area under the serum concentration curve (AUC) after a dose of antibiotic measures how high (concentration) and how long (time) the antibiotic levels remain above the target MIC during any dosing interval. DRUG THERAPY Principles of drug therapy Time-dependent vs. concentration-depending effect (killing of the pathogen) timearugconcentrationisabovemi f.m.nmn.name I DRUG THERAPY Principles of drug therapy ECOFF: epidemiological cut-off I Defining susceptibility breakpoints in researon Breakpoints are set according to several parameters: Microbiological (in vitro testing) Pharmacological (PK/PD indexes and response to treatment) Clinical (best evidence from literature) They are ultimately derived from clinical studies comparing outcomes with the MICs for the infecting pathogen susceptible intermediate resistant Strains are then categorized as: Susceptible (when bacterial strain growth is inhibited in vitro by a concentration of the antibiotic that is associated with a high likelihood of therapeutic success) Intermediate (uncertain probability of successful treatment) Resistant (high likelihood of therapeutic failure) DRUG THERAPY Principles of drug therapy in food-producing animals Acceptable Daily Intake (ADI) Defined as the daily intake of a substance which, over the entire lifetime of a human, appears to be without adverse effects or harm to the health of that human Maximum residue limits (MRLs) Defined as the maximum concentration of a drug residue in the animal consumable product that is legally tolerated Withdrawal period The time that must elapse between the last administration of a veterinary medicine and the slaughter or production of food from that animal, to ensure that the food does not contain levels of the medicine that exceed the maximum residue limit. DRUG THERAPY Principles of drug therapy in food-producing animals Withdrawal period The time that must elapse between the last administration of a veterinary medicine and the slaughter or production of food from that animal, to ensure that the food does not contain levels of the medicine that exceed the maximum residue limit. Tissue concentration of antibiotic and metabolites Concentration (ug/kg) Liver Muscle Kidney Fat fissure I Time in days in fmriMRL DRUG THERAPY Principles of drug therapy Factors affecting drug choice DRUG THERAPY Principles of drug therapy Factors affecting drug choice sina.se.se ii.fi i iiiiiiiiii ii i iiiiiii DRUG THERAPY Principles of drug therapy Factors affecting drug choice antibiotic spectrum given broad received results lab until 0 AMR Antimicrobial Resistance (AMR) mirror pandemic silent Predicted mortality from AMR compared to common causes of death today (O’Neill 2016; Murray et al. 2022) AMR Antimicrobial Resistance (AMR) 0 AMR Antibiotics Resistance mechanisms  Innate (natural) resistance: preexisting genomic property (mutation or gene)eximpermeability drugs toantibiotic  Acquired resistance: acquired by mutation or horizontal gene transfer (conjugation, transduction and transformation) AMR AMR generation & dissemination bacteria kinda tooof agent never can say anantibioticorantimicrobial Bacteria that have acquired resistance keep passing it to other bacteria. At the same time, antimicrobials keep killing bacteria that have no resistance, increasing the share of resistant bacteria. DRUG THERAPY d evelop AMR can even during treatment AMR slide last oftestablematerial Mutagenesis due to stress Antibiotic Stress response (SOS) stress activates mutagenesis responsemass stress a ctivating by is wn.cn activates error prone results mistakes and in that may result resistant ma not mutation polymerases ina Error-prone Polymerases Increased Mutation Rates Resistant mutation Fitzgerald et al., 2017; Annu Rev Cancer Biol AMR The “Mega-Plate” (Kishony ‘s Lab – WIS & Harvard) AMR 5 days 10 days Rifampicin antibiotic MIC original= 0.023 ug/ml >>> MIC new = 512 ug/ml Supra-MIC conditions 1000X Mutation rates increased Activation of all HGT mechanisms Gutierrez et al., 2021;Mol. Biol. Evol. AMR Antibiotic source Gradient of concentration Tolerance +++ RpoE ++ DNA repair - - -/+ Prophages ++++ DNA breaks (?) 99.99998% susceptible 0.0002% heteroresistant 0% resistant SUB-MIC SUPRA-MIC Gutierrez et al., 2021;Mol. Biol. Evol. AMR AMR generation & dissemination The environment and various components (water sources, soil, biodiversity) act as a depository for the accumulation, formation, and spread of antibiotic resistance. ARG’s = antimicrobial resistance genes can be spread via horizontal gene transfer (conjugation, transduction) between bacteria, through mobile genetic elements ANTIMICROBIALS AMR timeline ANTIMICROBIALS Become a responsible vet! Prevention is better than cure Rational antimicrobial use: actions that prevent or minimize development of AMR Antimicrobial Stewardship: coordinated programs design to implement appropriate use of antimicrobials Use narrow-spectrum drugs when possible Culture and AST De-escalate antimicrobials when possible Follow treatment regimes and guidelines Search for alternatives!