1. General Principles of Antimicrobial Therapies

Question 1

Definition of antibiotic stewardship

Answer 1

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

Question 2

Important determinants for successful antimicrobial therapy

Answer 2

1. Selection of antimicrobial therapy based on microbiology results and susceptibility testing
2. Understanding the pharmacokinetics of the drug
3. Knowledge of the pharmacodynamics of the drugs and how it can be optimised to improve the dosing schedule

Question 3

Susceptibility testing can be performed to…

Answer 3

1. Narrow down the list of antimicrobials that can be used and establish the MIC
2. Test if the bacteria isolated is resistant to known antibiotics (establish the IC50)
3. Test if the maximal response effect (Emax) can be achieved

Question 4

Definition of bactericidal drugs

Answer 4

Bacteria are killed at blood (or urine) concentrations with therapeutic dosing regimens

Question 5

Definition of bacteriostatic drugs

Answer 5

They arrest the growth and replication of the bacteria at the achievable and therapeutic blood (or urine) concentration

Question 6

Do anti-microbials eradicate microbes?

Answer 6

No! It is the patient’s immune response that eliminates the pathogens

Question 7

What can affect the antimicrobials’ pharmacokinetics?

Answer 7

1. Drug penetration
2. Host factors
3. Drug-drug interactions

Question 8

Drug penetration can be modulated by

Answer 8

1. Solubility of the drug (e.g lipophilicity) → polar molecules can penetrate the BBB poorly compared to lipophilic molecules
2. Molecular weight → lower → easier to move across barriers
3. Presence of specialised membrane transporters (e.g. P-glycoprotein) → can export a wide variety of drugs
4. Specialized compartment → BBB guards the CNS via tight junctions at the endothelial cells of cerebral micro vessels and prevents paracellular transport
5. Protein binding in plasma → free unbound drugs can achieve higher conc. in compartments like CNS

Question 9

Host factors that can affect pharmacokinetics of antimicrobials

Answer 9

1. Age and weight
2. Renal function
3. Hepatic function
4. History of drug allergy
5. History of recent antimicrobial use
6. Immune system
7. Dietary history
8. Pregnancy and lactation

Question 10

Drug-Drug interactions in the usage of antimicrobials

Answer 10

1. Drugs that synergise → penicillins and streptomycin → penicillin acts to weaken cell walls → easier for streptomycin to penetrate the cells and inhibit the ribosomes
2. 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

Question 11

Pharmacodynamics of antimicrobials

Answer 11

Antimicrobial drugs can modulate microbial clearance in a:

1. Time-dependent manner
2. Concentration-dependent manner
3. Persistent post-antibiotic effect

Question 12

Time-dependent killing

Answer 12

1. The rate and extent of microbe killing remain unchanged regardless of how high the conc. is, provided that it is above the MIC
2. T > MIC → administered regularly so that antibiotic is above MIC for as long as possible

Question 13

Concentration-dependent killing

Answer 13

1. The rate and extent of microorganism killing are dependent on the antimicrobial concentration
2. Cmax / MIC → high doses at less frequent intervals

Question 14

Both time-dependent and concentration-dependent killing

Answer 14

AUC/MIC

Question 15

Post antibiotic effects

Answer 15

PAE is the suppression of microbial growth that persists after levels of antibiotics have fallen below the MIC

Question 16

Advantage of broad spectrum antimicrobials

Answer 16

Covers a broad spectra of microbes → less need to wait to identify pathogen with real certainty before commencing treatment

Question 17

Disadvantages of broad spectrum antimicrobials

Answer 17

Killing or suppressing “good” bacteria → broad spectrum antimicrobials may promote the development of super-infection caused by pathogenic drug-resistant microbes

Question 18

Advantages of narrow spectrum antimicrobials

Answer 18

1. Less potential to cause super-infection as only the particular pathogenic microbes are targeted
2. Normal bacterial flora is preserved
3. Discourage the proliferation of pathogenic drug-resistant bacteria

Question 19

Disadvantages of narrow spectrum antimicrobials

Answer 19

The antibiotics have limited use due to their high specificity

Question 20

Which is preferred? Monotherapy or combination

Answer 20

Monotherapy. Decrease the risk of antimicrobial toxicity and selection of antimicrobial-resistant pathogens

Question 21

Principles of combination therapy

Answer 21

1. Preventing resistance to monotherapy
2. Accelerating the rapidity of microbial kill
3. Enhancing therapeutic efficacy by use of synergistic interactions
4. Paradoxically, reducing toxicity by administering lower doses

Question 22

Causes of antimicrobial resistance

Answer 22

1. Enhanced export of antibiotics by efflux pumps
2. Release of microbial enzymes that destroy the antibiotics
3. Alteration of microbial proteins that transform pro-drug to the effective moieties
4. Alteration of target proteins
5. Development of alternative pathways to those inhibited by the antibiotics