Antimicrobial Drugs Flashcards
Antibiotics Definition
Agents produced by one organism that have some toxic or inhibitory effect on another organism or cell
Used to treat bacteria, fungi and cancer cells
NO impact on viruses
Selective toxicity
The idea that you can use toxic drugs, which as long as they are more toxic to your target than to normal tissues, can be useful
Bacteriocidal Antibiotics
Drugs that cause the death of the bacteria
Required if the patient is immunosuppressed
Bacteriostatic Antibiotics
Drugs that inhibit the growth of the bacteria
Growth resumes when the drug is removed
Success depends on there being an effective immune response
6 general features of bacterial cells we can attack
- A completely unique structure (ex: peptidoglycan)
- Pathways that are absent in mammalian cells (folic acid synthesis)
- Structures that differ between human and bacterial cells (ribosomal subunits)
- Enzymes that differ (ex: DNA gyrase)
- Cellular constituents that are different (certain lipids)
- Cellular constituents that are enriched (other lipids)
Transpeptidation
Forming the cross bridge between the 2 NAMs
Terminal Ala is removed, then first Ala can join to Gly
3 groups of beta lactam drugs that inhibit transpeptidation
- Penicillins
- Cephalosporins
- Cabapenems
Why is penicillin V better than G?
Penicillin G breaks down in acid
Narrow Spectrum vs Extended-Spectrum
Narrow (penicillin V): against Gram + bacteria
Extended (amoxicillin): against Gram + and some Gram - (they are better drugs - wider spectrum, better absorbed, longer half life)
What can we do about the beta lactamases?
- Use a beta-lactamase-resistant antibiotic (Nafcillin)
2. Combine with a beta lactamase inhibitor (Clavulanate)
What properties have changed from first to 4th generations cephalosporins?
- Better activity against gram negative bacteria
- Better ability to cross into tissue spaces
- Generally more resistant to beta lactamases
Carbapenems
Ex: Imipenem
Penicillin-like antibiotics in which the sulfur atom of the penicillin structure is replaced with a carbon
Altered spectrum
Resistant to beta-lactamases
Vancomycin
Cell Wall synthesis inhibitor
Binds to the growing peptide chain
Prevents subsequent ability to cross link
Bacitracin
Cell wall synthesis inhibitor
Mixture of cyclic peptides
Works inside the cell to block cell wall synthesis (stops lipid recycling - no dephosphorylation)
4 drugs that effect the function of ribosomes and how they work
- Erythromycin and other macrolides (binds to 50S subunit, prevents translocation-movement of ribosome along mRNA)
- Tetracyclines (like tetracycline) - interferes with attachment of tRNA to mRNA-ribosome complex
- Aminoglycosides such as gentamicin or streptomycin (changes shape of 30S subunit, causes code on mRNA to be read incorrectly)
- Chloramphenicol (Binds to 50S portion and inhibits formation of peptide bonds)
Chloramphenicol
Broad spectrum, active against many different bacteria
Bacteriostatic
Binds to 50S portion and inhibits formation of peptide bonds
Problems: bone marrow disturbances, common interactions with other drugs, gray baby syndrome
Macrolides
Work best against gram positive microorganisms
Bacteriostatic
Include: erythromycin, clarithromycin, azithromycin
Erythromycin
Macrolide
Base is somewhat unstable in acid conditions
Food reduces absorption
Works well against gram positive organisms
Poor against gram negatives
Useful in penicillin-resistant infections
Clarithromycin
Macrolide Chemically modified from erythromycin Additional methyl group Improved acid stability Improved oral absorption Most active against gram positives
Azithromycin
Macrolide Further modified from clarithromycin Additional lactone ring Excellent tissue penetration Released from tissue slowly Longer half-life Best activity against gram negative anaerobes Acts against spirochetes Less likely to become involved in drug interactions
Aminoglycosides
examples, targets, route of administration, toxic to what
Ex: Streptomycin, gentamicin
Used mostly against gram negative enteric bacteria
Oral doses are very poorly absorbed
Usually given intramuscularly or intravenously
Toxic to ears and kidneys
3 functions of aminoglycosides
- Block formation of the initiation complex
- Miscoding in the polypeptide chain
- Block of translocation
Tetracyclines
Broad-spectrum
Active against bacteria, mycoplasma, some protozoa
bacteriostatic
Resistance is common
Chelate divalent metal ions
Adverse effects: GI irritation, accumulate in bone and teeth, teratogenic
If macrolides, tetracyclines and aminoglycosides all block protein synthesis in bacteria, why are they different in use?
- They’re different chemically, which affects things like their stability and absorption.
- They interfere at different sites on the bacterial ribosomes, which means they have different therapeutic actions.
Where can we attack bacteria?
- Interfere with their ability to synthesize materials needed for DNA (folic acid)
- Cell wall syntheis
- Protein synthesis
- DNA gyrase
- RNA elongation
- PM structure
- DNA-directed RNA polymerase
Sulfamethoxazole/trimethoprim
Septra - blocks the folic acid pathway (bacteriocidal)
More effective than either drug alone
Still works if resistance develops to one drug
Used at a dose ration of 1:5, which gives a plasma concentration ratio of 1:20 (optimal)
DNA gyrase (topoisomerase type 2)
Untangles the DNA in a cell (cuts it)
Fluoroquinolones block it (ex: ciprofloxacin)
Fluoroquinolones
Inhibit DNA gyrase
Useful against systemic infections
Stop the bacterium form using its DNA
Overuse has lead to widespread resistance (especially respiratory pathogens)
Polymyxins
Cause disruption of the bacterial membrane
Molecule has detergent like properties
Binds to phosphatidylethanolamine in PM
Problems: humans have PE too, so toxic if given systemically
Advantages: resistance and allergy is rare
3 advantages and 3 risks of using antimicrobial drugs in combination
Advantages: 1. Wider spectrum for mixed infections 2. Reduced dose for individual agents 3. Synergism between antibiotics Disadvantages: 1. Increased possibility of adverse reactions 2. Antagonism between antibiotics 3. Greater risk of antibiotic resistance
Example of an antagonistic combination
Chloramphenicol and aminoglycoside
4 examples of synergistic combinations
- Cell wall synthesis inhibitors and amino glycosides
- Beta lactam drugs and beta lactamase inhibitors
- Beta lactams that act on different PBPs
- Sulfonamides and trimethoprim
5 mechanisms of antibiotic resistance
- Decreased entry
- Efflux pump
- Altered target site
- Bypass pathway
- Enzymatic degradation
Sulfonamide resistance may be due to (3 things)
- Decreased permeability of the cell membrane
- The bacteria produce a form of dihydropteroate synthetase that binds teh sulfonamide poorly
- Increased production of PABA by the bacteria
Trimethoprim resistance may be due to (3 things)
- Decreased permeability of the cell membrane
- The bacteria produce a form of dihydrofolate reductase that binds trimethoprim poorly
- The bacteria produce more dihydrofolate reductase
3 antifungals to treat candidiasis
- Ketoconazole (potentially hepatotoxic)
- Fluconazole (alternative to ketoconazole and less toxic)
- Amphotericin B (for extreme cases given IV, significantly toxic and may case renal damage)
2 general ways antifungals work
- Bind ergosterol and form pores that leak out cell contents
- Inhibit enzymes that are important in making ergosterol
Amphotericin B
Antifungal
Polyene macrolide antibiotic
Large molecule that is lipophilic on one side and hydrophilic on the other (so can form pores in the membrane by binding to ergosterol)
Some binding to human cell membranes so it has nephrotoxicity
Fluconazole
Azole antifungal drug Acts by inhibiting fungal cytochrome P450 enzymes Stops synthesis of ergosterol Lower affinity for human P450 enzymes Less toxic than polyene antifungals
Therapeutic Window
From the minimal beneficial effects to minimal toxic effects
Therapeutic index
Toxic dose 50/ Effective dose 50
