Antimicrobials Flashcards
Selective Toxicity
- using toxic drugs as long as they are more toxic to your target than to normal tissues
1. antimicrobial drugs
2. anticancer drugs
Bactericidal vs Bacteriostatic Drugs
- growth is arrested (e.g.. sulfonamides), success depends on an effective immune response
- bacteria is killed (e.g. penicillins), use if the patient is immunosuppressed
- explain in terms of eggs vs milk
Draw the structure of gram negative and gram positive cells, highlighting important features
-see antimicrobial lecture
Penicillin binding proteins catalyze which step of cell wall formation?
-transpeptidation-the creation of links between glycine and alanine
Transpeptidation inhibitors include… (3)
- penicillins
- carbapanems
- cephalosporins
- all beta lactams
What is the ‘attack strategy’ of penicillins?
- bacteria have a rigid cell wall
- they need this to survive and grow
- its made up of a fibrous scaffold
- the scaffold is assembled using enzymes
- block the enzymes so the cell wall cannot be made properly (binds to the PBPs)
- bacteria will not survive
What are the 2 potential problems of penicillin use?
- getting across the outer lipid membrane in gram neg bacteria –>porins
- interference by beta lactamases, cleave the beta lactam ring
There are different penicillins which differ in their…
-sensitivity to beta lactamases ‘
-pharmacokinetics
-spectrum of action
narrow spectrum-penicillin V
extended spectrum-amoxicillin
What can we do about beta lactamases?
- use a beta lactamase resistant antibiotic (eg. Nafcillin, penicillinase resistant)
- combine with a beta lactamase inhibitor (e.g. clavulanate, clavulin-amoxicillin and clavulanate)
Why are 4th gen cephalosporins better than 1st gen?
- better activity against gram neg bacteria
- better ability to cross into tissue spaces
- generally more resistance to beta lactamases
Carbapanems
- eg. Imipenem
- penicillin like antibiotics in which the S atom is replaced with C
- altered spectrum
- resistant to beta lactamases
What are the 2 other major cell wall inhibitors besides penicillin?
Vancomycin-binds to the growing peptide chain, prevents subsequent ability to cross link
Bacitracin-a mixture of cyclic peptides, works inside the cell to block cell wall synthesis
What are the 4 different classes of drugs that block protein synthesis?
- chloramphenicol
- macrolides (erythromycin)
- aminoglycosides (gentamicin)
- tetracyclines (tetracycline)
Chloramphenicol
-binds to the 50s subunit and inhibits formation of peptide bond
-broad spectrum, active against many types of bacteria
-bacteriostatic
Problems:
-bone marrow disturbances
-common interactions with other drugs
-gray baby syndrome
Macrolides (‘omycin’)
- work best against gram positive bacteria
- bacteriostatic
Erythromycin
- binds to 50s portion
- prevents translocation-movement of ribosome along mRNA
- unstable in acid conditions
- food reduces absorption
- useful in penicillin resistant infections
Clarithromycin
- has an additional methyl group compared to erythromycin
- improved acid stability
- improved oral absorption
Azithromycin
- has an additional lactone ring compared to erythromycin
- excellent tissue penetration
- longer half life
- best activity against gram neg anaerobes
- also acts against spirochetes
- less likely to be involved in drug interactions
Aminoglycosides (streptomycin and gentamicin)
- changes shape of 30s
- used against gram negative enteric bacteria
- oral doses poorly absorbed (given intramuscularly, by IV)
- ototoxic and nephrotoxic
- have a hexose ring
Aminoglycosides cause (3)…
- block formation of initiation complex
- miscoding
- block of translocation
Tetracyclines
- broad spectrum
- bacteriostatic
- resistance is common
- chelate divalent cations (Ca)
- cause GI irritation
What is the MOA of tetracyclines?
-interfere with attachment of tRNA to mRNA ribosome complex
If macrolides, tetracyclines and aminoglycosides all block protein synthesis in bacteria, why are they different in use? (2)
- Different chemically -affects stability and absorption
2. Interfere at different sites on the ribosome-different therapeutic actions
Draw the folic acid synthesis pathway with the drugs that effects the pathway
-antimicrobial drugs
Fluoroquinolones
eg ciproflaxin
-inhibition of DNA gyrase (topo II), needed for uncoiling DNA
Polymyxins
- molecule has detergent like properties
- binds to PE in cell membrane
- causes disruption of the bacterial cell membrane
What are the advantages and disadvantages of polymyxins?
Disadvantages-human cells have PE, toxic if given systemically
-used topically
Advantages-resistance rarely develops, hypersensitivity is rare
What are the advantages of using antimicrobial drugs in combinations? (3)
- wider spectrum
- reduced dose
- synergism
What are the disadvantages of using antimicrobial drugs in combinations?
- increased possibility of adverse reactions
- antagonism between antibiotics
- greater risk of antibiotic resistance
Septra
- sulfamethoxazole=bacteriostatic
- trimethoprim-bacteriostatic
- synergistic
- septra=bactericidal
What are 4 mechanisms of antibiotic resistance?
- altered site
- enzymatic degradation
- bypass pathway
- decreased entry
- efflux pump
Sulfonamide resistance
- decreased permeability of the cell membrane
- the bacteria produce a form of dihydropteroate synthetase that binds the sulfonamide poorly
- increased production of PABA by the bacteria (increase the amnt of substrate)
Trimethoprim resistance
- deceased permeability of the cell membrane
- the bacteria produce a form of DHFR that binds trimethoprim poorly
- the bacteria produces more DHFR
How do antifungals work?
- mostly target ergosterol
- form pores
- inhibit enzymes important in making ergosterol
Amphotericin B
- polyene macrolide antibiotics
- lipophillic on one side
- hydrophillic on the other side
- aggregates and forms pores in lipid membranes
- may be some toxicity (nephrotoxicity) due to cholesterol binding
Fluconazole
- an azole anti fungal drug
- inhibits fungal cyto P450
- lower affinity for human P450
- works through ergosterol
