Module 9.10 Part A

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Antibiotic susceptibility and resistance :

Antibiotic susceptibility and resistance Module 9.10 Part A

Antimicrobial drug susceptibility testing :

Antimicrobial drug susceptibility testing

Susceptibility and resistance of bacteria to antimicrobials:

Susceptibility and resistance of bacteria to antimicrobials Sometimes highly predictable susceptibility (obligate intracellular, pyogenic streptococci) Sometimes highly predictable resistance – e.g., P. aeruginosa, Mycoplasma, enterics to penicillin G

What is susceptibility? :

What is susceptibility? Inhibition (bactericidal, bacteriostasis) by achievable tissue concentration of an antimicrobial drug Usually related to blood levels (since blood concentrations easier to measure than “generic tissue”) Determined in vitro

In vitro susceptibility measured::

In vitro susceptibility measured: Quantitatively, MIC Qualitatively, susceptible, resistant

Antimicrobial susceptibility:

Antimicrobial susceptibility Determined in vitro quantitatively, doubling dilutions Minimum inhibitory concentration Expressed as micrograms per ml MIC Last well in which no growth

Quantitative (MIC) susceptibility:

Quantitative (MIC) susceptibility Advantage: Allows drug dosage adjustment For “ concentration dependent antimicrobials ”: Aminoglycosides, fluoroquinolones only Killing a function of peak antimicrobial concentration Reduces emergence of resistance as well

Time-dependent antimicrobials:

Time-dependent antimicrobials The majority (beta-lactams, macrolides, TMS, tetracyclines) Antimicrobial has to exceed MIC for the majority of the dosing interval (ie time above MIC) Qualitative susceptibility is adequate, don’t need quantitative susceptibility

Qualitative susceptibility:

Qualitative susceptibility “Yes”, “no” (semi-quantitative); based on MIC extrapolation Advantage of testing of large number of drugs at same time, inexpensive

Susceptibility testing: “Breakpoints”:

Susceptibility testing: “Breakpoints” Interprets MIC or zone diameter as “susceptible” (“intermediate”) or “resistant” Usually related to serum drug concentrations with standard dosing May not be applicable eg local drug administration, urinary tract infections

Susceptibility testing:

Susceptibility testing Labs could be more helpful in providing dosage recommendations based on in vitro data Data on resistance coming from labs is “biased” to resistance No agreement yet on whether susceptibility testing should be done before certain AMs are used (eg 2 nd line, 3 rd line)

Acquired resistance to antimicrobial drugs:

Acquired resistance to antimicrobial drugs

Acquired resistance to antimicrobial drugs:

Acquired resistance to antimicrobial drugs Major problem accompanying antimicrobial drug use Multiple mechanisms, many of which synergize and include rapid movement of resistance genes through populations Complex issue, with important infection control and human health issues

Development of resistance:

Development of resistance

Antibiotic resistance is:

Antibiotic resistance is Increasing dramatically Associated with bad outcomes Result of (inappropriate) use Caught everyone “off guard” A crisis in medicine Emerging issue in veterinary medicine

PowerPoint Presentation:

Dancer, S. J. J. Antimicrob. Chemother. 2008 61:246-253; doi:10.1093/jac/dkm465 Mortality rates of staphylococcal bacteraemia over time

Problem:

Problem In past, dealt with resistance by developing another antibiotic New antibiotics are very expensive to develop Most antibiotics are variants of drug classes discovered in the 1940s Resistance is developing rapidly Complex process, not inevitable, varies with the bacterial host

Genetic change can occur in bacteria very rapidly:

Genetic change can occur in bacteria very rapidly Not inevitable; bacteria are better at becoming resistant?

Evolution of resistance:

Evolution of resistance Complex process of assembly of increasingly “fit” bacteria and resistance genes Combination of chromosomal mutation and horizontal gene transfer Multiple, additive and synergistic events Horizontal gene transfer is very rapid Then clonal expansion of these fit strains

Concept of “infectious resistance”:

Concept of “infectious resistance”

PowerPoint Presentation:

MULTIPLE ANTIBIOTIC RESISTANCE PLASMID

PowerPoint Presentation:

Davies, J. et al. 2010. Microbiol. Mol. Biol. Rev. 74(3):417-433 Numbers of unique beta-lactamase enzymes identified since the introduction of the first beta-lactam antibiotics

Antimicrobial resistance: Public health implications:

Antimicrobial resistance: Public health implications Movement of resistant bacteria and of resistant genes

PowerPoint Presentation:

Animal Feeds Meat Direct Contact EXTENDED CARE FACILITIES HOSPITALIZED HUMAN Commercial Abattoirs / Processing Plants Rendering FOOD ANIMALS SHEEP CATTLE SWINE POULTRY VEAL CALVES Offal COMPANION ANIMALS Vegetation, Seed Crops, Fruit Sewage Drinking water Drinking Water Sea / Lakes Swimming AQUACULTURE Rivers and Streams EPIDEMIOLOGY OF ANTIMICROBIAL RESISTANCE Industrial & Household Antibacterial Chemicals OTHER FARMED LIVESTOCK COMMUNITY - URBAN -RURAL WILDLIFE SOIL Handling Preparation Consumption after Linton AH (1977), modified by Irwin RJ Dead stock Farm Effluents and Manure Spreading

What is contribution of animal (agricultural) use of antibiotics to resistance in human pathogens?:

What is contribution of animal (agricultural) use of antibiotics to resistance in human pathogens? 1% 5%? 10%? 20% 50%?

PowerPoint Presentation:

Bywater, R. J. et al. J. Antimicrob. Chemother. 2000 46:643-645; doi:10.1093/jac/46.4.643 Perceived contribution (%) of individual bacterial species (square), and of possible animal sources (black square), to antibiotic resistance in humans

Decline in human fecal VRE after the ban:

Decline in human fecal VRE after the ban ( Wegener, 2003)

We don’t know the contribution of animal use of antibiotics to resistance in human pathogens:

We don’t know the contribution of animal use of antibiotics to resistance in human pathogens But it’s a real part of the resistance story

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