1. General Principles of Antimicrobial Therapies Flashcards
Definition of antibiotic stewardship
Has been defined as the optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance
Important determinants for successful antimicrobial therapy
- Selection of antimicrobial therapy based on microbiology results and susceptibility testing
- Understanding the pharmacokinetics of the drug
- Knowledge of the pharmacodynamics of the drugs and how it can be optimised to improve the dosing schedule
Susceptibility testing can be performed to…
- Narrow down the list of antimicrobials that can be used and establish the MIC
- Test if the bacteria isolated is resistant to known antibiotics (establish the IC50)
- Test if the maximal response effect (Emax) can be achieved
Definition of bactericidal drugs
Bacteria are killed at blood (or urine) concentrations with therapeutic dosing regimens
Definition of bacteriostatic drugs
They arrest the growth and replication of the bacteria at the achievable and therapeutic blood (or urine) concentration
Do anti-microbials eradicate microbes?
No! It is the patient’s immune response that eliminates the pathogens
What can affect the antimicrobials’ pharmacokinetics?
- Drug penetration
- Host factors
- Drug-drug interactions
Drug penetration can be modulated by
- Solubility of the drug (e.g lipophilicity) → polar molecules can penetrate the BBB poorly compared to lipophilic molecules
- Molecular weight → lower → easier to move across barriers
- Presence of specialised membrane transporters (e.g. P-glycoprotein) → can export a wide variety of drugs
- Specialized compartment → BBB guards the CNS via tight junctions at the endothelial cells of cerebral micro vessels and prevents paracellular transport
- Protein binding in plasma → free unbound drugs can achieve higher conc. in compartments like CNS
Host factors that can affect pharmacokinetics of antimicrobials
- Age and weight
- Renal function
- Hepatic function
- History of drug allergy
- History of recent antimicrobial use
- Immune system
- Dietary history
- Pregnancy and lactation
Drug-Drug interactions in the usage of antimicrobials
- Drugs that synergise → penicillins and streptomycin → penicillin acts to weaken cell walls → easier for streptomycin to penetrate the cells and inhibit the ribosomes
- Drugs that antagonise → penicillin and tetracyclines →
tetracycline is bacteriostatic → stops cells from growing
penicillin → only effective against actively growing cells
combination → reduces bactericidal effects of penicillin
Pharmacodynamics of antimicrobials
Antimicrobial drugs can modulate microbial clearance in a:
- Time-dependent manner
- Concentration-dependent manner
- Persistent post-antibiotic effect
Time-dependent killing
- The rate and extent of microbe killing remain unchanged regardless of how high the conc. is, provided that it is above the MIC
- T > MIC → administered regularly so that antibiotic is above MIC for as long as possible
Concentration-dependent killing
- The rate and extent of microorganism killing are dependent on the antimicrobial concentration
- Cmax / MIC → high doses at less frequent intervals
Both time-dependent and concentration-dependent killing
AUC/MIC
Post antibiotic effects
PAE is the suppression of microbial growth that persists after levels of antibiotics have fallen below the MIC
Advantage of broad spectrum antimicrobials
Covers a broad spectra of microbes → less need to wait to identify pathogen with real certainty before commencing treatment
Disadvantages of broad spectrum antimicrobials
Killing or suppressing “good” bacteria → broad spectrum antimicrobials may promote the development of super-infection caused by pathogenic drug-resistant microbes
Advantages of narrow spectrum antimicrobials
- Less potential to cause super-infection as only the particular pathogenic microbes are targeted
- Normal bacterial flora is preserved
- Discourage the proliferation of pathogenic drug-resistant bacteria
Disadvantages of narrow spectrum antimicrobials
The antibiotics have limited use due to their high specificity
Which is preferred? Monotherapy or combination
Monotherapy. Decrease the risk of antimicrobial toxicity and selection of antimicrobial-resistant pathogens
Principles of combination therapy
- Preventing resistance to monotherapy
- Accelerating the rapidity of microbial kill
- Enhancing therapeutic efficacy by use of synergistic interactions
- Paradoxically, reducing toxicity by administering lower doses
Causes of antimicrobial resistance
- Enhanced export of antibiotics by efflux pumps
- Release of microbial enzymes that destroy the antibiotics
- Alteration of microbial proteins that transform pro-drug to the effective moieties
- Alteration of target proteins
- Development of alternative pathways to those inhibited by the antibiotics
