Antibacterial Agents & Resistance Flashcards
Discuss the origin of antimicrobials
- Salvarsan documented 1st antimicrobial = antisyphilitic
- Sulfonamide is first sulfa drug - competitive inhibitor to para-aminobenzoic acid (folate metabolism)
- Alexander Fleming notified no staph colonies around penicillin in culture - Chain and Florey isolated compound
- Prontosil Drug
- Waksman isolated streptomycin from soil bacteria (Streptomyces griseus)
Explain the concept of selective toxicity and its relationship to antimicrobial agents
- antibiotics cause greater harm to microorganisms than human host
- expressed as a therapeutic index
- lowest dose toxic to patient divided by dose typically used for treatment –> lower therapeutic index = less toxic to patient
Discuss the desired antimicrobial properties and pharmacologic activities of antimicrobial agents
- inhibit growth or kill bacterium
- narrow or broad spectrum
- con of broad-spectrum = kill off normal flora - Negatives
- antimicrobial resistance
- suppresion of normal flora
- allergic reactions
- toxic effects
Explain the roles of bacterial chromosomal mutations, plasmids, transposons and integrons in the generation of antibiotic resistance mechanisms
Mutations: spontaneous, not very effective with drugs that have multiple targets
Plasmids: provides stability, transmissibility; carry multiple resistance cassettes
Transposons:
Integrons:
Describe the major mechanisms of bacterial resistance to antibiotics
- Mycoplasma has no cell wall
- Mycobacterium has impermeable waxy coat
- chlamydia, rickettsia, brucella, legionella - live in host cells
What is a bacteriostatic drug? And why use them?
- inhibits growth
- relies on host immunity to eliminate pathogen
What is a bactericidal drug?
kills the bacteria
Semisynthetic drugs
- alteration of drug structure to give new properties
- Penicillin G altered to make ampicillin
- broadened spectrum of antimicrobial effect
What is a synergistic drug interaction?
one drug enhances another
What is an antagonsistic drug interaction?
one drug interferes with another
What is a vertical evolution?
spontaneous gene mutation (antibiotic resistance)
-low rate
How is mycoplasma resistant to antibiotics?
no cell wall
How is mycobacterium resistant to antibiotics?
impermeable wax coating
What bacteria live in host cells and therefore are resistant to antibiotics?
Chlamydia, Rickettsia, Brucella, Legionella
Mechanisms to resist antibiotics?
- drug inactivation
- alteration of drug molecule (Penicillin Binding Protein)
- decreased uptake of the drug
- increased elimination of the drug
Describe beta-lactams regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms
- all bind PBP (responsible for cross-linking petides in proteoglycan synthesis)
- all types have B-lactam rings (square, 3Cs, 1 N)
- low oral bioavailability, cannot pass thru BBB due to polarity
- ineffective against intracellular organisms
- excreted in urine
- carbapenam has broadest spectrum
- chephalosporins is more potent against gram (-)s than penicillin
Describe beta-lactamase inhibitors regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms
-named after the substrate
-
Describe glycopeptides regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms
- large peptides w/ few monosaccharides
- gram-(+) only; can’t penetrate cell wall of gram (-)
- binds peptide ends
- main indication is B-lactam resistant Gram (+) bacteria (MRSA)
- poorly absorbed in GI tract
- lactobacilli resist because of unique peptide ends: D-alanyl-D-lactate – VanA, VanB, VanD enables
- plasmid associated resistance
What type of drug target has a high therapeutic index?
cell wall synthesis –> we don’t have cell walls
Describe cephalosporins
- beta-lactase
- chemical structure makes them resistant to beta-lactamases
- low affinity for gram-(+) bacteria
Describe carbapenems
- very resistant to B-lactamases
- effective against a wide range of gram (+) and (-)organisms
- can be given to patients with penicillin allergy
Describe monobactams
- very resistant to beta-lactamases
- primarily effective against enterobaccteriaceae
- can be given to patients with penicillin allergy
Describe monobactams
- very resistant to beta-lactamases
- primarily effective against enterobaccteriaceae
- can be given to patients with penicillin allergy
Explain the advantages and clinical use of semisynthetic penicillins (oxacillin, cloxacillin, ampicillin, and amoxicillin)
- you can change the side group to make the drug more bioavailable and have a broader spectrum
- 3 goals: acid stability, B-lactamase resistance, extended spectrum
Discuss the mechanism of action, clinical use, and spectrum of activity of polypeptide antibiotics
Bacitracin
-inhibit dephosphorylation & recycling of bactoprenol
-damage cytoplasmic membrane & inhibit transcription
-low therapeutic index – only use topicaly
Polymyxins
-cyclic polypeptides
-insert into membranes to increase cell permeability
-most effective against gram (-)s
-nephrotoxicity – topical application only
Compare and contrast antibacterial agents that interfere with protein synthesis regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms
Aminoglycosides
-irreversibly bind 30S subunit –> distortion & malfunction, blocks transcription
-not effective against anaerobes, enterococci, and streptococci
-in combo with B-lactam drugs – more permeability
-low oral bioavailability
-use for severe life-threatening gram (-) infections
-side effects: nephrotoxicity & ototoxicity
-resistance through modifying proteins and alteration of ribosomal target
Tetracyclines
-reversibly bind 30S subunit –> block attachment of tRNA, prevents protein elongation
-effective against gram-(+) and (-)
-resistance due to decreased penetration into cell, active efflux out of cell (transposon mediated), alteration of ribosomal target, enzymatic modification of drug
Macrolides
-reversibly bind to 50S subunit –> prevents continuation of protein synthesis
-good GI absorption, wide distribution
-effective against gram (+), some gram (-) coccobacilli and intracellular bacteria
-for patients allergic to penicillin
-resistance due to methylation of 50S subunit, enzymatic modification of drug, efflux of antibiotic
Discuss cross-resistance between macrolides, lincosamides, and streptogramins
-due to methylated 50S ribosome
Discuss antibacterial agents that interfere with nucleic acid synthesis regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms
Quinolones
- inhibit action of topoisomerase DNA gyrase
- effective against gram (+) and gram (-)
- resistance due to alteration of DNA gyrase, altered uptake, and efflux (all due to a mutation)
Explain the mechanisms of synergism between sulfonamides and trimethoprim
-metabolic pathway inhibitors
-inhibit prooduction of folic acid
Sulfonamides
-sulfa drug family
-inhibit growth of gram-(+) and (-)s – competitive inhibition
-structurally similar to para-aminobenzoic acid in folate pathway (humans don’t have this enzyme)
-resistance due to plasmid
Trimethoprim
-inihibits dihydrofolate reductase
-resistance due to plasma encoded alternative enzyme
Discuss antibacterial agents for treating M. tuberculosis infection regarding regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms
Rifampin
Streptomycin
Isoniazid –> inihibits synthesis of mycolic acid
Ethambutol –> inihibits arabinogalactan synthesis in cell wall
Pyrazinamide –> disrupts proton motive force; inhibits FAS1
-resistance due to chromosomal gene mutations
-these first line drugs have low toxicity
