Antibacterial Agents 1 - Overview

Question 1

Targets of Antibacterials (5)

Answer 1

• Inhibition of synthesis or damage to cell wall
• Inhibition of synthesis or damage to cell membrane
• Modification of synthesis or metabolism of nucleic acids
• Inhibition or modification of protein synthesis
• Modification of intermediary metabolism (folate metabolism)

Question 2

Selective Toxicity: Differences in Folate metabolism

Answer 2

Inhibition of a metabolic pathway found in bacteria but not in humans: Bacteria must synthesize folate intracellularly, while mammalian cells can take up folate from the environment

Question 3

Selective Toxicity: Differences in Protein synthesis

Answer 3

Pathway exists in both bacteria and humans, but differences in enzyme structure: Bacterial ribosome consists of 30S and 50S ribosome, while mammalian ribosome subunits are 40S and 60S

Question 4

Selective Toxicity: Differences in Nucleic acid synthesis

Answer 4

Pathway exists in both bacteria and humans, but differences in enzyme structure: DNA gyrase (bacteria) vs topoisomerase (humans); RNA
polymerase is structurally distinct in bacteria

Question 5

Selective Toxicity: Differences in Cell wall synthesis

Answer 5

Macromolecular structure does not exist in humans: Peptidoglycan component does not occur in eukaryotes

Question 6

Selective Toxicity: Differences in Fungal cell membrane

Answer 6

Macromolecular structure differs between microbes and humans: Ergosterol is the major constituent of fungal membranes vs cholesterol in mammalian membranes

Question 7

Resistance: What is Natural (intrinsic) Resistance?

Answer 7

Microbes lack a susceptible target for drug action

• fungal cell wall: no peptidoglycan
• mycoplasma: no cell wall

Question 8

Resistance: What is Escape?

Answer 8

Microbes are sensitive and antibiotic reaches target BUT organism “escapes” the consequences due to availability of purines, thymidine, serine, methionine released from purulent infections (sulfonamide resistance) or failure to “lyse” due to lack of osmotic pressure difference (penicillin resistance). Emphasizes important role for surgical drainage procedures if practical.

Question 9

Resistance: What are the two types of acquired resistance?

Answer 9

• Mutational: Multiple generations must occur for appreciable resistance: each generation slightly more resistant if allowed to survive > proper dosing and duration of antibiotic therapy prevents survival of slightly resistant strains
• Plasmid mediated resistance: extrachromosomal pieces of circular DNA > resistance that can emerge during single course of treatment
• Conjugation between two physically attached bacteria with exchange of plasmid DNA containing resistant determinant
• Transduction with virus (bacteriophage) carrying resistance determinant R to bacteria
• Transformation - pick up free DNA from the environment

Question 10

Resistance: What are the 5 major mechanisms of bacterial resistance to antibiotics?

Answer 10

1) Altered targets or receptors to which the antibiotic cannot bind
2) Enzymatic destruction or inactivation of antibiotic
3) Alternative resistant metabolic pathway
4) Decreased entry (natural resistance)
5) Increased efflux (multi-drug resistance may be encoded by single gene)

Question 11

Bactericidal vs Bacteriostatic

Answer 11

organisms are killed vs organisms are prevented from growing

Question 12

Bactericidal Mechanisms (3)

Answer 12

• Inhibition of cell wall synthesis
• Disruption of cell membrane function
• Interference with DNA function or synthesis

Question 13

Bacteriostatic Mechanisms (2)

Answer 13

• Inhibition of protein synthesis (exception: aminoglycosides, which are -cidal)
• Inhibition of intermediary metabolic pathways

Question 14

Characteristics of Bactericidal Agents

Answer 14

• Preferred in severe infections
• Act more quickly and their action is often irreversible
• Can compensate for patients with an impaired host defense
• Required for treatment of infections in locations that are not accessible to host immune system responses

Question 15

Beneficial Accumulation vs Selective Accumulation That Is Harmful

Answer 15

*Beneficial: clindamycin into bone, macrolides into pulmonary cells, tetracyclines into gingival crevicular fluid and sebum, rapid excretion of nitrofurantoin into
urine
* Increased potential for toxicity: aminoglycoside
binding to cells of the inner ear and renal brush border resulting in an increased tendency for
ototoxicity and nephrotoxicity, tetracyclines binding to Ca
2+ in developing bone and teeth resulting abnormal bone growth and brownish tooth discoloration in the fetus or young children

Question 16

1) Duration of Antimicrobial Activity
2) What is post-antibiotic effect?
3) What is concentration-dependent killing?

Answer 16

• If duration too short OR dose too low > resistance can develop as well as, recurrence of infection
• If duration too long > superinfection more likely
• If dose too high > dose-related toxicities more likely to occur

*post-antibiotic effect: continue to kill or inhibit
growth of bacteria for several hours after the concentration of the drug falls below the MIC

*Some antibiotics kill bacteria faster when given in doses that result in higher plasma concentrations

Question 17

Spectrum of Antibacterial Activity

Answer 17

*Narrow spectrum: effective against either gram positive or gram negative; often most effective on susceptible organism; less disturbance of host flora
*Extended spectrum: effective against gram
positive and gram negative
*Broad spectrum: effective against gram positive, gram negative, and atypical organisms; sacrifice efficacy for greater scope of activity for initial empiric coverage; more likely to cause superinfections