Lecture 14 Antibiotic Resistance Overview PDF

ANTIMICROBIAL RESISTANCE by Dr. Daniel Czyż OVERVIEW Lecture 14 Today’s lecture will cover: Different types of antibiotic resistance Origins of antibiotic resistance Major mechanisms of antibiotic resistance WHO classification of antibiotics After complet...

ANTIMICROBIAL RESISTANCE by Dr. Daniel Czyż OVERVIEW Lecture 14 Today’s lecture will cover: Different types of antibiotic resistance Origins of antibiotic resistance Major mechanisms of antibiotic resistance WHO classification of antibiotics After completion of this lecture, students should be able to: Identify the difference between different types of antibiotic resistance Explain how antibiotic resistance arises Be familiar with major mechanisms of antibiotic resistance Explain why is it important to classify antibiotics What does it mean for a microbe to be resistant to antibiotics? Microbe 1 Microbe 2 MIC: 0.01 mg/L penicillin MIC: 64mg/L penicillin Non-toxic to humans Toxic to humans Achievable concentration & Non-achievable concentration: Elimination of bacteria Bacteria are deemed resistant What does it mean for a microbe to be resistant to antibiotics? KNOWLEDGE BOX Microbe 1 Microbe 2 MIC: 0.01 mg/L penicillin MIC: 64mg/L penicillin Clinical Resistance: multiple factors such as type of bacteria, infection site, antibiotic pharmacokinetics, and the immune response affecting clinical outcomes of antibiotic treatment Non-toxic to humans Toxic to humans Achievable concentration & Non-achievable concentration: Elimination of bacteria Bacteria are deemed resistant Clinical Resistance Antibiotic resistance is a term that is relative to antibiotic concentration that can kill bacteria in a Petri dish Susceptible Resistant non-toxic toxic non-toxic toxic Bacterial Survival Bacterial Survival Bacteria Bacteria MIC MIC Drug concentration Drug concentration Clinical Resistance Antibiotic resistance is a term that is relative to antibiotic concentration that can kill bacteria in a Petri dish KNOWLEDGE BOX Susceptible Resistant non-toxic toxic non-toxic toxic Minimum inhibitory concentration (MIC): Bacterial Survival Bacterial Survival Bacteria a minimum concentration of an antibiotic Bacteria required to completely inhibit bacterial growth MIC MIC Drug concentration Drug concentration Clinical Resistance Antibiotic resistance is a term that is relative to antibiotic concentration that can kill bacteria in a Petri dish Susceptible Resistant non-toxic toxic non-toxic toxic Bacterial Survival Bacterial Survival Bacteria The Bacteria infection is susceptible to treatment if the antibiotic MIC falls within a concentration that is non-toxic to humans MIC MIC Drug concentration Drug concentration Clinical Resistance Antibiotic resistance is a term that is relative to antibiotic concentration that can kill bacteria in a Petri dish Susceptible Resistant non-toxic toxic non-toxic toxic Bacterial Survival Bacterial Survival Bacteria Bacteria MIC MIC Drug concentration Drug concentration The infection manifests clinical resistance when the MIC of a specific antibiotic is toxic to humans and the infection can no longer be treated with that antibiotic  Clinical Resistance non-toxic toxic MIC Toxicity MIC Drug concentration Administration of toxic concentration of drugs into patients are made on individual basis and the benefits of the treatment must outweigh the risk The most effective treatment of bacterial infections is when the antibiotic MIC is non-toxic to humans What doesn’t kill you makes you stronger It does not take much to develop resistance to antibiotics Gullberg et al. 2011  Selection for antibiotic resistance Microbial Ecosystems: Adapted from Martinez (2009) Antibiotic Resistome exceeds 13,000 genes I Bioinformatic analysis of bacterial genomes predicts that there are over 13,000 antibiotic resistant genes Liu & Pop, 2009 Early indication of antibiotic resistance Edward Abraham Ernst Chain Anti-antibiotics are natural defense mechanisms Humans do not develop antibiotic resistance Bacteria naturally develop counter-attack mechanisms against other microbes that are trying to kill them High selective pressure accelerates bacteria to acquire resistance and Credit: David Jernigan lead to life-threatening infections  Two major types of resistance Intrinsic: Acquired: -Natural-occurring resistance to -Genetic mutations antibiotics -Acquisition of mobile elements carrying -The outer membrane of Gram-negative antibiotic resistant genes bacteria makes them more resistant to -It’s this type or resistance that poses the more antibiotics than Gram-positive highest risk bacteria -Bacteria that naturally produce antibiotics have an intrinsic ability to defend themselves What came first: antibiotic The chicken or the egg? Antibiotics or efflux pumps Major mechanism of antibiotic resistance Directly targeting antibiotic: Antibiotic inactivation: enzymatic inactivation of antibiotic to confer drug resistance (Lecture 15) Targeting antibiotic availability: Antibiotic efflux: transport of antibiotics outside of the cell (Lecture 16) Reduced permeability to antibiotics: generally through reduced production or modification of porins (Lecture 16) Resistance by absence: deletion of a gene (usually a porin) (Lecture 16) Target modification: Antibiotic target modification: mutational alteration or enzymatic modification of antibiotic target (Lecture 17) Antibiotic target replacement: replacement or substitution of antibiotic action target (Lecture 17) Antibiotic target protection: protection of antibiotic action target from antibiotic binding (Lecture 17) Card.mcmaster.ca/home  WHO antibiotic classification: Criterion Criterion 1 (C1): The antimicrobial class is the sole, or one of limited available therapies, to treat serious bacterial infections in people Criterion 2 (C2): The antimicrobial class is used to treat infections in people caused by either: (1) bacteria that may be transmitted to humans from nonhuman sources, or (2) bacteria that may acquire resistance genes from nonhuman sources Critically important: Antimicrobial classes which meet both C1 and C2 are termed critically important for human medicine. Highly important: Antimicrobial classes which meet either C1 or C2 are termed highly important for human medicine. Important: Antimicrobial classes used in humans which meet neither C1 nor C2 are termed important for human medicine.  WHO antibiotic prioritization: Prioritization Criterion Prioritization criterion 1 (P1): High absolute number of people, or high proportion of use in patients with serious infections in health care settings affected by bacterial diseases for which the antimicrobial class is the sole or one of few alternatives to treat serious infections in humans. Prioritization criterion 2 (P2): High frequency of use of the antimicrobial class for any indication in human medicine, or else high proportion of use in patients with serious infections in health care settings, since use may favor selection of resistance in both settings. Prioritization criterion 3 (P3): The antimicrobial class is used to treat infections in people for which there is evidence of transmission of resistant bacteria (e.g., non-typhoidal Salmonella and Campylobacter spp.) or resistance genes (high for E. coli and Enterococcus spp.) from non- human sources. Highest priority: Three out of three Prioritization Criteria (P1, P2, P3) High priority: Two out of three Prioritization Criteria Examples of Highest Priority Critically Important antimicrobials Question? Post to the Canvas Discussion Board