Principles of Antimicrobial Therapy

what is the primary goal of antimicrobial therapy

slow or stop the growth of microorganisms specifically in the treatment of infections

define selective toxicity

the drug only targets the bacteria and doesn’t affect the patient (minimizes side effects on the patient); dose that is toxic to bacteria and not to the host

define therapeutic index

indication of safety; the larger the ratio, the safer the drug (TI = TD50/ED50)

define spectrum of activity

range of microorganisms the antimicrobial can kill or inhibit

define bactericidal

disrupts the bacterial cell and cause bacterial death (acts on the cell wall, membrane or DNA synthesis)

define bacteriostatic

inhibits bacterial replication and proliferation; acts thru inhibition and works with the host’s defenses to clear infectious organisms

when is bactericidal preferred

serious infections and when immune system is depressed

define post-antibiotic effect

continued antimicrobial effects after drug levels in body have fallen below MIC

explain the mechanism of post-antibiotic effect

causes slow recovery of bacteria after non-lethal damage to cell structures → microorganism is more susceptible to the host’s immune system due to persistence of drug at target

define MIC

lowest concentration of drug required to inhibit visible growth;p specific for each drug and bacteria

methods in which MIC can be determined

• dilution method

• disc diffusion (kirby-bauer method)

• epsilometer method

define breakpoint concentration

based on microbiological, pharmacokinetic, pharmacodynamic, and clinical data

susceptible

MIC < breakpoint (at typical dose, high probability of being effective)

intermediate

MIC close to or at breakpoint (drug may be effective at higher doses but still safe at specific infection sites based on PD/PK)

resistant

MIC > breakpoint (drug is unlikely to achieve therapeutic success at safe doses)

serial dilutions

progressively dilute the antibiotic used to kill the bacteria and the lowest concentration that exhibits growth = MIC

disc diffusion

uses discs filled with different antibiotics and depending on zone of inhibition determines the effectiveness of the antibiotic

E test

non-porous plastic strip immobilized with predefined continuous and stable gradient of antibiotic concentrations on one side and MIC scale on the other → based on zone of inhibition measures the MIC of antibiotic

concentration dependent

rate and extent of killing increases with increasing concentration of antibiotic; peak plasma concentration to MIC ratio is important (higher doses with extended dosing intervals)

time dependent

maximum killing depends on how long the concentration is maintained above the MIC (achieved by continuous infusion or frequent dosing; increasing concentration does not increase killing)

list consequences of antibiotic use

• allergies/hypersensitivity

• adverse reactions/toxicities

• alterations in normal microbial populations

• antibacterial resistance

• patient harm

• emergence of MDR organisms

• increased healthcare costs

empiric antimicrobial therapy

educated guess

definitive antimicrobial therapy

confirmed identification

prophylaxis antimicrobial therapy

prevention

pharmacodynamic factors that can influence success of therapy

• drug target

• static vs cidal

• time vs concentration dependent

• PAE

pharmacokinetic factors that can influence success of therapy

• can it access infection site

• does it reach >MIC

• administration route

• metabolism

• dosage adjustment requirements

• adverse effect profile

microorganism factors that can influence therapy success

• organism type (gram stain, serology, cultures, etc)

• bacteriologic stats

• what is the organism sensitive to

• local resistance patterns

patient factors that can influence therapy success

• previous use of abx

• age (renal/hepatic function, drug related ADRs)

• pregnancy/lactation

• travel

• allergy/hypersensitivity

• concomitant disease states

• genetics

• other considerations (i.e. cost)
  

list reasons why a patient may not respond to antimicrobial therapy

• wrong drug, dose, admin route, inadequate penetration

• immunosuppression

• presence of abscess/necrotic tissue, biofilm

• lack of info related to organism

• patient is not adherent

intrinsic mechanisms for antimicrobial resistance

naturally occurring that evades the effects of microbial agents

acquired mechanisms for antimicrobial resistance

genetic changes after exposure to drug or received from another organism

target modification/mutation example

penicillin binding proteins changing to decrease affinity for beta lactams

example of permeability reduction

some gram + bacteria have extra thick cell wall → vanco resistance

gram - bacteria can modify or eliminate porins so abx can’t enter

efflux pumps

modification on bacteria that pumps abx out of cell

examples of inactivating enzymes

beta lactamases in bacteria breaks down lactams → ineffective

examples of target protective enzymes

tetracycline resistance by using proteins to act as decoy to bind the abx instead of bacterial ribosome

what organisms are classified as urgent health threats

• candida auris (fungus)

• carbapenem-resistant enterobacterales (CRE)

• carbapenem resistant acinetobacter

• ESBL-produing enterobacterales

• C. diff

• MRSA

• VRE

• MDR-pseudomonas aeruginosa