Treating bacterial infections

Question 1

4 basic mechanisms of resistance

Answer 1

Prevent entry of drug
Pump drug out of the bacteria
Inactivate drug (modification/degradation)
Change target site for the drug

Question 2

intrinsic antimicrobial resistance

Answer 2

Bacteria’s “natural” ability to resist effects
Innate insensitivity ex:
* lack of affinity of the drug for the bacterial target
* inaccessibility of the drug into the bacterial cell
* extrusion of the drug by chromosomally encoded active exporters
* innate production of enzymes that inactivate the drug

All bacteria of a certain type possess this ability:
* Aminoglycosides for anaerobes
* Metronidazole for aerobes
* Sulfonamides, trimethoprim, tetracyclines, chloramphenicol for Pseudomonas aeuruginosa
A normal P. aeruginosa will look “multi-drug resistant”

Question 3

acquired antibiotic resistance

Answer 3

The bacteria gains the ability to resist a drug, where it was previously susceptible
Tends to be found in some strains/subtypes of a bacterial species
Multiple mechanisms by which bacteria can acquire resistance:
* Mutation
* Acquisition of resistance genes

when exposed to selection pressure

Question 4

Mechanisms of Acquired Resistance

Answer 4

Mutations of genes that code for physiological processes
* Mycobacterium tuberculosis & rifampin - rpoB

Acquisition of foreign genes that encode resistance
* Horizontal gene exchange which are then passed on vertically
* MRSA – mecA

Question 5

When are susceptibility tests indicated?

Answer 5

Young (neonates) or critically ill patients
* Decreased immune defences

Site of infection that are normally sterile
* especially if they are difficult to treat (e.g., osteomyelitis)
* have a significant impact on the health of a patient (e.g., septicemia)

Bacterial pathogens whose susceptibility cannot be reliably predicted or if rapid development of resistance is anticipated
* e.g., E. coli, Staphylococcus aureus, Klebsiella spp., and Enterobacter spp

Failure of presumptive or confirmed bacterial infection to respond to therapy

Question 6

When are susceptibility not tests indicated?

Answer 6

If bacteria are predictably susceptible
* e.g., β-hemolytic Streptococcus spp. (penicillin)

High level of efficacy of empiric therapy
* e.g. treatment of uncomplicated cystitis in dogs

If have multiple bacteria isolated from abscesses or wounds

Testing of non-pathogenic normal flora is meaningless
* If they are isolated, it is because there was suboptimal sample collection!

Testing the susceptibility of (many) strict anaerobes
* Technically difficult and most anaerobes are predictably sensitive to a range of antimicrobials, including penicillin (except those that produce beta-lactamases), metronidazole, and clindamycin

Question 7

Agar Disc Diffusion susceptibility test

Answer 7

1. Bacteria are spread over specific agar plates (Mueller-Hinton) in a lawn
2. Paper disks impregnated with antimicrobial drugs are placed on bacterial lawn, permitting diffusion of the drug through the agar
3. Plates are incubated overnight
4. The zone of inhibition around the disk is measured, and the susceptibility of the bacteria to the drug is correlated through a breakpoint value

limitation: Interpretive criteria to establish susceptibility breakpoints are available for only a small number of antimicrobial drugs IN ANIMALS!

aka Kirby Bauer disk diffusion

Question 8

broth microdilution susceptibility test

Answer 8

These tests directly measure the minimum inhibitory concentration (MIC) of an organism
Two-fold dilutions of antimicrobials are inoculated in a 96 well plate
* the concentrations represent serum concentrations of the antimicrobial in the patient when the drug is administered at recommended dosages

Advantage: can get MIC to optimize dosing (need a pharmacologists help)

limitation: Interpretive criteria to establish susceptibility breakpoints are available for only a small number of antimicrobial drugs IN ANIMALS!

Question 9

Susceptible vs intermediate vs resistant

Answer 9

Susceptible
* Treatment with this drug using standard label or recommended doses has a high probability of a cure

Intermediate
* Uncertain therapeutic effect of the drug unless dosing modifications or site-specific drug concentration occurs
* Give higher concentrations of the antibiotic or a higher total daily dose/shorter dosing intervals
* If the drug reaches higher concentrations at the site of infection
* e.g., urinary tract infections

Resistant
* Treatment with this drug is associated with treatment failure regardless of the dose administered or location of the infection
* Function of either: A specific resistance mechanisms of the bacterial strain or Low concentrations of drug in a host species

Question 10

antibiotic concentration in tissues

Answer 10

Breakpoints are based on the average blood concentrations of antimicrobials that can be achieved with standard, fixed dose regimens

Breakpoints used in veterinary medicine are often extrapolated from human data
Relatively few breakpoints have been derived for antibiotics given to animals