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Factors that influence the choice of
antimicrobials
Efficacy / sensitivity / pharmacokinetics & pharmacodynamics ToxicityCost TERM 2
Antimicrobial Susceptibility Testing - sensitive
or resistant?
DEFINITION 2 depends on microbe, achievable serum level, and ultimately clinical response TERM 3
Determination of Minimal Inhibitory
Concentration (MIC)
DEFINITION 3
- Broth Dilution Technique Also can be done with solid media Agar Dilution Technique MIC concentration = 32 ug/mL the lowest concentration of antimicrobial agent needed to inhabit growthCan be followed up with test to determineMinimal Bactericidal Concentration (MBC)MBC = 64 ug/ml lowest concentration that kills 99.9% of microbe TERM 4
Determination of Minimal Inhibitory
Concentration (MIC) -continued
DEFINITION 4 2. Kirby-Bauer Disk Diffusion Technique Measure diameter of zone of inhibitionCompare with chart to determineCLINCAL SUSCEPTIBILITYResult reported are qualitaitivesensitive, intermediate, or resistant TERM 5
Determination of Minimal Inhibitory
Concentration (MIC) -continued again
DEFINITION 5
- ETEST (Epsilometer)Gradient concentration of antimicrobial onstrip marked with MIC valuesMIC is read on strip at junction of microbe growth and strip
Common Mechanisms of Antimicrobial
Resistance
- Degradation or modification of antimicrobial2. Modification of target of antimicrobial3. Denial of antimicrobial entry4. Efflux pump TERM 7
Antimicrobials: Mechanisms of Resistance -
General Types of Resistance
DEFINITION 7 Intrinsic - innate or naturally-occurring resistance Ex. Pseudomonas aeruginosa has always been resistant to penicillin dueto the restricted (small) size of its porin channels in the outer membrane Acquired - once susceptible microbes develop resistance Ex. prior to 1945 practically all strains of Staphylococcus aureus were susceptible to penicillin G, today practically all hospital-acquired isolates are resistant to penicillin G TERM 8
Mechanisms of Acquired Antimicrobial
Resistance
DEFINITION 8 Mutational Resistance (random mutation & selection) Acquisition of New DNA (new genes provide mechanisms of antimicrobial resistance) Transformation Transduction - bacteriophage Conjugation - plasmids & transposons TERM 9
Genetic Variability of Microbes
DEFINITION 9 Microbes have the ability to rapidly change their genomes and thus express altered or different proteins that may: increase their pathogenicty aid in avoiding the immue system mediate resistant to antimicrobial drugs TERM 10
Microbial Mechansims of Genetic Variation
DEFINITION 10 Spontaneous Mutation replication errors Movement of DNA segments (rearrangements) (1) movement of DNA segments within a genome (intracellular) inversion translocation (2) movement of DNA segments between genomes (intercellular) transformation conjugation / plasmids transposition / transposons transduction / bacteriophages
Movement of DNA Segments
large DNA sequence rearrangements result from movement of blocks of DNA from one position to anotherrequires genetic recombination genetic recombination mediates a wide variety of other fundamental processes (a) exchange between homologous chromosomes during meiosis(b) the repair of damaged DNA (c) the assembly of active genes during differentiation (d) chromosomal integration of extrachromosomal elements TERM 17
Genetic Recombination may occur
DEFINITION 17 (a) within a single DNA molecule ex. translocation & inversion(b) between DNA molecules ex. transformation & transposition TERM 18
Genetic Recombination -translocation
DEFINITION 18 DNA rearrangements within a single DNA molecule (1) translocation a segment of DNA moves from one location to anotheri.e. from silent storage sites to active expression sites (analogy - CD or cassette player) ex. Neisseria gonorrhoeae & trypanasomes used by several microbes to vary the expression of their surface proteins (antigens) and thus evade the immune response TERM 19
Genetic Recombination -inversion
DEFINITION 19 DNA rearrangements within a single DNA molecule (2) inversion a segment of DNA changes orientation by 180E (only 1 vinyl record in your collection) Salmonella typhimurium alternates its expression of two differentflagellar antigens by inversion of a segment that contains a promoter TERM 20
Genetic Recombination -Transformation
DEFINITION 20 DNA rearrangement between DNA molecule &/or between bacterial cells (1) Transformation uptake & incorporation of naked DNA from the environment recombination between incoming DNA & recipient genomeincorporation of exogenous DNA sequence information
Genetic Recombination -conjugation
DNA rearrangement between DNA molecules &/or between bacterial cells (2) Conjugation many plasmids carry genes which enable them to transfer copies of themselves from donor bacterium to a recipient bacterium specialized pilus which mediates plasmid transfer and DNA mobilizing enzymes required for DNA transfer TERM 22
R factors
DEFINITION 22 conjugative plasmids that carry multiple drug resistance genessome conjugative plasmids have a broad host rangethey can replicate in many different bacterial species &become widely distributed TERM 23
Hfr plasmids
DEFINITION 23 high frequency of recombination movement of chromosomal genes by conjugation TERM 24
Transposons (jumping genes)
DEFINITION 24 self-mobilizable segments of DNAmay be present on plasmids or on chromosomecan move (transpose) from one position to a different positionwithin a single DNA molecule or between two DNA moleculescomposite transposons often carry genes that encode antibiotic resistance and toxin productionplasmids & transposons responsible for rapid spread of resistance to antimicrobials TERM 25
Transduction
DEFINITION 25 genetic variation mediated by bacteriophages bacteriophages can contribute to genetic variation by(1) transducing (moving) chromosomal genes between bacterial cells &/or(2) expression of viral genes during lysogenic infection
