MB3057 Antimicrobial drug esistance a global threat 2 - Oggioni

Page 1

Antimicrobial Resistance Overview

  • Title: Antimicrobial Resistance: A Global Threat

  • Speaker: Marco R. Oggioni

  • Affiliation: Department of Genetics and Genome Biology, University of Leicester

Page 2

Antimicrobial Drug Resistance and Susceptibility Testing

  • Definitions:

    • Clinically Susceptible (S): Micro-organisms defined as susceptible by their likelihood of therapeutic success based on antimicrobial activity.

    • Clinically Resistant (R): Micro-organisms categorized as resistant based on likelihood of therapeutic failure.

  • Microbiological Resistance Terms:

    • Wild Type (WT): Absence of resistance mechanisms to the drug. Defined via phenotypic tests.

    • Non-Wild Type (NWT): Presence of resistance mechanisms. Defined via phenotypic tests.

Page 3

Susceptibility Testing: Microbroth Dilution Method

  • Minimal Inhibitory Concentration (MIC):

    • Involves incubating bacteria in two-fold dilutions of drugs for 24 hours.

    • Turbid wells indicate resistance; transparent wells indicate growth inhibition.

  • Minimal Bactericidal Concentration (MBC):

    • Involves plating on solid media to check for growth.

    • Absence of growth indicates bactericidal effect.

    • Bactericidal antibiotics (e.g., beta-lactams) have similar MIC and MBC. Bacteriostatic antibiotics may show low MIC but higher MBC.

Page 4

Disc Diffusion Susceptibility Testing

  • Method Overview:

    • Seed bacteria on agar plates and overlay discs with antibiotics.

    • Incubate for 24 hours, measure inhibition zone diameter.

    • Compare results with breakpoint tables to classify as susceptible (S) or resistant (R).

  • E-test Procedure:

    • Similar to disc diffusion but uses a gradient of antibiotic concentrations to determine MIC.

Page 5

MIC Distribution Examples for Staphylococcus aureus

  • Resistance Patterns:

    • Penicillin: Most strains are resistant.

    • Ampicillin: No breakpoint available.

    • Clarithromycin: Good distinction between S and R.

    • Daptomycin & Vancomycin: All strains are susceptible.

Page 6

Mechanisms of Antimicrobial Drug Resistance (AMR)

  • Streptococcus pneumoniae Resistance Examples:

    • Natural Resistance & Acquired Resistance:

      • Mutation of drug targets, new genes via horizontal gene transfer.

      • Mechanisms include target modification, drug inactivation, efflux, and alternative targets.

    • Consequences of Selective Agent Use: Any use can select for resistant strains.

Page 7

AMR in Staphylococcus aureus

  • Overview of resistance mechanisms to treatments like Oxacillin and Penicillin.

  • BlaZ Plasmid: Encodes beta-lactamase, contributing to high-level resistance.

Page 8

Key Genetic Mutations in AMR

  • Core Genome Genes in Streptococcus pneumoniae:

    • Mutations in genes encoding cell wall biosynthesis enzymes linked to decreased susceptibility to penicillin.

Page 9

High-Level Resistance Mechanisms

  • ErmC Methylase:

    • Methylates 23S rRNA at position 2058, leading to high-level macrolide resistance.

Page 10

Efflux Systems in AMR

  • MefA Efflux System:

    • Encoded by a phage-like element; confers low-level macrolide resistance.

Page 11

Resistance Encodings in Staphylococcus aureus

  • mecA Gene:

    • Located on SCCmec, encodes PBP2A enzyme, which is oxacillin-resistant.

Page 12

Learning Summary

Lecture 1: The Antibiotics

  • Antimicrobial drugs target essential bacterial functions; the drug discovery pipeline is facing threats due to decreased investment from big pharma.

  • Lecture 2: Antimicrobial Resistance

    • Antimicrobial susceptibility testing anticipates therapeutic efficacy.

    • AMR results from mutations or gene transfers and significantly influences clinical antimicrobial choices.

    • The impact of AMR is severe, with projections of 10 million deaths by 2050.

Page 13

Part 2: The Impact of AMR

Page 14

Historical Perspective on Infectious Disease Mortality

  • Comparison of historical mortality rates from infectious diseases and the impact of antibiotics over the years.

Page 15

WHO AMR Priority List (2017)

  • Groups and Resistance Patterns:

    • 1: Critical (e.g., Acinetobacter baumannii, Carbapenem resistance).

    • 2: High (e.g., Staphylococcus aureus, Vancomycin resistance).

    • 3: Medium (e.g., Streptococcus pneumoniae, Penicillin resistance).

Page 16

Surveillance Data on AMR

  • Examples of resistance patterns in Klebsiella pneumoniae and MRSA.

Page 17

The O’Neill Report on AMR

  • Projection: 10 million lives at risk annually by 2050 without new antibiotics.

  • Urgent Action Needed: Choosing to act is crucial to prevent severe outcomes.

Page 18

Media Coverage on AMR Threat

  • Concerns from medical professionals about the impact of antibiotic resistance, equating it to major global threats.

Page 19

Misconceptions about AMR

  • Critique of the notion that resistance will return us to a pre-antibiotic era; discusses advances in medicine and hygiene that lessen some impacts.

Page 20

STATISTICS ON AMR DEATH RATES

  • Annual Deaths Estimates:

    • 25,000 deaths/year in Europe from antibiotic resistance.

    • CDC estimates 23,000 deaths/year in the US due to antibiotic resistance.

Page 21

Population Vulnerability to AMR

  • At-risk populations include immuno-depressed patients, the elderly, and individuals in developing countries.

Page 22

Impact of Antibiotic Resistance on Infections

  • Expectations vs. Reality:

    • Comparison of mortality rates in patients with carbapenem-resistant infections to susceptible strains in detailed studies.

Page 23

Final Learning Summary

  • Recap of lectures emphasizing the selective activity of antibiotics, the urgency of drug discovery, the complications of AMR, and its dire impact predicted on global health.