Antibacterial Agents I

Question 1

Define and/or give examples for selective toxicity

Answer 1

Fundamental feature of antibiotic therapy as the effects of antimicrobial agents should be exerted selectively on microbe and not the host. No “perfect” antibiotics exist.
• Biochemical differences between the pathogen target and the host must be discovered and appropriately exploited.
• Folate metabolism: Bacteria must synthesize folate intracellularly, while mammalian cells can take up folate from the environment
• Protein synthesis: Bacterial ribosome consists of 30S and 50S ribosome, while mammalian ribosome subunits are 40S and 60S
• Nucleic acid synthesis: DNA gyrase (bacteria) vs topoisomerase (humans); RNA polymerase is structurally distinct in bacteria
• Cell wall synthesis: Peptidoglycan component does not occur in eukaryotes
• Fungal cell membrane: Ergosterol is the major constituent of fungal membranes vs cholesterol in mammalian membranes

Question 2

Define and/or give examples for antibiotic spectrum

Answer 2

COCCI:
Gram positive [Streptococci (pneumoniae, pyogenes, viridans), Staphylococci (aureus: MSSA vs MRSA), Enterococci (faecium, faecalis)]
Gram negative [Neisseria (gonorrheae)]
RODS:
Gram positive
Gram negative [H. influenzae, E. coli, Klebsiella, Pseudomonas aeruginosa]
ANAEROBES:
Gram positive rod [Clostridia (difficile, tetani, botulinum, perfingens)]
Gram negative rod [Bacteroides fragilis]
ATYPICAL:
[Chlamydia, Mycoplasma]

Question 3

Define and/or give examples natural resistance (i.e., natural vs. escape vs. acquired).

Answer 3

Natural (intrinsic) Resistance: Microbes lack a susceptible target for drug action. E.g., fungal cell walls do not contain peptidoglycans and mycoplasma do not have cell walls at all, thus they are naturally resistant to penicillins. Pseudomonas aeruginosa is intrinsically resistant to many antibiotics because they cannot cross its outer membrane.

Question 4

Define and/or give examples escape resistance

Answer 4

Escape: 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 5

Define and/or give examples acquired resistance

Answer 5

• Acquired Resistance. Selective pressure (i.e., antibiotic administration) produces successive generations of organisms with biochemical traits that minimize drug action. Two modes:

• Mutational (chromosomal) resistance [rate: 1 in 107-1012]: Chromosomal effect varies in degree with respect to location, type, and biological consequence of mutation. Multiple steps (generations) must occur for appreciable resistance as each succeeding generation becomes slightly more resistant if allowed to survive, thus proper dosing and duration of antibiotic therapy prevents survival of slightly resistant strains.
• Plasmid mediated resistance

Question 6

Plasmid mediated resistance:

Answer 6

• Plasmids are extrachromosomal pieces of circular DNA carrying genetic information that can confer antibiotic resistance to the organism [R in figure below]
• This is a clinically important source of multiple drug resistance that can emerge during a single course of treatment
• Nonpathogenic coliform bacteria (gram negative) are a large reservoir for plasmid-mediated transfer of antibiotic resistance to pathogenic organisms; can code for resistance to multiple drugs (MDR gene) via protein that transports antibiotic out of cell

Question 7

Mechanisms of resistance to antibiotics and implications for therapy:

Answer 7

A) Altered targets or receptors to which the abx cannot bind
B) enzymatic destruction or inactivation of abx
C) Alternate resistant metabolic pathway
D) Decreased entry (natural resistance)
E) Increased efflux (multi-drug resistance may be encoded by single gene)

Question 8

Altered targets or receptors to which the antibiotic cannot bind:

Answer 8

Penicillin-binding proteins [MRSA, S. pneumoniae, Enterococci) -> β-lactam antibiotics
DNA gyrase [S. aureus, Pseudomonas species] -> Fluoroquinolones
Peptidoglycan side chain [Enterococci (VRE), Staphylococci (VRSA)] -> Vancomycin
50S ribosome methylation [Strep-, Staph-, Enterococci] -> Macrolides, Clindamycin

Question 9

Enzymatic destruction or inactivation of antibiotic

Answer 9

β-lactamase [S. aureus, P. aeruginosa, Bacteroides, Enterococci] -> β-lactam antibiotics
Acetyl-/phospho-/adenylyltransferases [Enterococci] -> Aminoglycosides
Acetyltransferase [Staphylococci, Streptococci, Neisseria] -> Chloramphenicol

Question 10

Alternative resistant metabolic pathway

Answer 10

Overproduction of PABA or thymidine nucleotides [Streptococci] -> Sulfonamides

Question 11

Decreased entry (natural resistance)

Answer 11

β-lactam antibiotics [Pseudomonas aeruginosa]
Fluoroquinolones [Pseudomonas species]
Aminoglycosides [E. coli, Pseudomonas]

Question 12

Increased efflux (multi-drug resistance may be encoded by single gene)

Answer 12

Tetracyclines [Streptococci, Staphylococci, Enterococci]
Fluoroquinolones [Pseudomonas species]
Macrolides

Question 13

Resistance can be minimized by:

Answer 13

• –Only using antibiotic when need is established
• –Selecting antibiotic on basis of susceptibility tests
• –Using adequate concentration and duration to prevent emergence of first and second step mutants