-
Antibiotic
- Product of metabolism
- synthetic product produced as a structural analog of a naturally occurring compound
- antagonizes growth of microorganisms
- effective in low concentrations
- selective toxicity
- sufficient chemical stability
- elimination of the antibiotic must be slow to allow a convenient dosing schedule
-
Antibiotics in feed
increase meat production in many animals
-
Commercial production of antibiotics (6)
- isolation of pure culture of antibiotic producing organism
- fermentation
- isolation of the antibiotic from culture medium
- purification
- assay for potency, sterility...
- formulation into acceptable and stable dosage form
-
Mechanisms of Action
- Interfere with cell wall biosynthesis
- Interfere with microbial protein synthesis
- Interfere with Nucleic Acid synthesis
-
Cell Wall Biosynthesis Inhibitors
Bacteriocidal
-
Protein Biosynthesis Inhibitors
Bacteriostatic except aminoglycosides
-
Nosocomial
hospital acquired
-
B-Lactam Antibiotics
- Gram + Bacteria
- -Cidal Action with low toxicity
-
MoA of B-Lactams
- inhibition of bacterial cell wall synthesis
- Acylate active site serine in Penicillin binding proteins
-
1 Oxford Unit
amount of PCN that will inhibit the growth of a strain of staph in 50mL of culture medium
-
1 Unit Pure PCN
0.6 mcg PCN G
-
-
Chemical stability of B-Lactams
- lactam ring sensitive to acidic conditions
- Oxidizing agents inactivate PCN by oxidizing the S atom
- Prolonged heating will inactivate
- e- withdrawing group added = increased stability
-
PCN Allergy
- caused by formation of antigenic penicilloyl proteins formed in vivo by the reaction of nucleophillic groups on specific proteins with B-lactam carbonyl group
- #1 problem with PCNs
- between 1-10% of population
-
PCN Resistance (4)
- B-Lactamase
- decreased permeability (esp. in G-)
- Intrinsic Resistance (affinity of PBP for PCN)
- Tolerance (bacteria sense B-Lactam and stop growth to prevent lysis)
-
- Methicillin
- steric hinderance
-
Increase activity against gram negative bacilli
- ionized or polar group into a-position
- Increased hydrophilicity to pass through pores in cell membrane
- also more oral bioavailability
-
-
Carbenicillin***(3)
- pseudomonas
- klebsielia
- Non-toxic, ionized at phys pH
-

-
PCN and Aminoglycosides
- incompatible, both will inactivate
- good combo therapy
-
-
-
- Piperacillin
- acyl urido substituent
-
Class I B-Lactamase inhibitors
- clavulanic acid
- sulbactam
- tazobactam
- suicide substrates
-
Class II B-lactamase inhibitors
- "slow" Substrates
- carbapenemsm (imipenem)
-
-
- Imipenam
- destroyed in kidney if administered alone
- cilastatin inhibits DHP1
-
Cephalosporins
- similar to PCN but have a 6 membered ring rather than 5 attached to B-Lactam
- slightly more stable than PCNs
-
Oral Cephalosporins
- increased acid stability of lactam ring resulting from presence of protonated amino group on 7-acylamino portion of molecule
- absence of leaving group in 3 position
-
Cephalosporin spectrum
- broad spectrum
- more resistant to B-lactamase (esp. G+)
-
Cephalosporin B-Latamase Resistance
- Increased by 7-methoxyl substituent
- Increased by alkoximino in aminoacyl group
-
Adverse reactions and Drug Interactions of Cephalosporins
- #1: Allergic Reaction (3-7% allergic to both Cephs and PCNs)
- Cephalosporins with N-methyl 5-thiotetrazole (MTT) at 3 position increase incidence of hypoprothrombinemia due to inhibition of Vit. K requiring enzymes
- Treat with Vit. K
- MTT group also causes intolerance to alcohol
-
Cephalexin***
 - Homolog of Ampicillin
-
- Cefadroxil
- Homolog of amoxicillin
-
Monobactams
- Single ring system
- Aztreonam
-
-
Aminoglycosides (4)
- Oto- and nephrotoxicity
- not distributed to CNS, Bone, fatty or connective tissues
- aerobic gram-negative bacilli
- act on bacterial ribosome to inhibit protein synthesis and interfere with fidelity of translation
-
Aminoglycoside Resistance Mechanisms (3)
- acetylating
- phosphorylating
- adenylylating
-
Tetracylines (5)
- broad spectrum
- amphoteric compounds
- Strong acids and bases will inactivate
- di-tri-valent metals will form a complex and inhibit absorption
- bacteriostatic
-
Three biochemically distinct mechanisms of resistance to tetracyclines
- 1. Efflux
- 2. Ribosomal protection
- 3. Enzymatic oxidation
-
Macrolides
- Inhibitors of protein biosynthesis
- Bacteriostatic
- 1. large lactone ring
- 2. ketone group
- 3. glycosidically linked amino sugar
-
Macrolide Spectrum of Activity
- generally effective agains most G+
- some G- cocci (neisseria)
- mycoplasma
- chlamydia
- campylobacter
- legionella
-
-
Lincomycins
- Sulfur containing antibiotics
- resemble macrolides in spectrum
- static or cidal
- clindamycin
-
-
Polypeptides
- Renal toxicity
- Vancomycin
- 1. several strucurally similar entities
- 2. most are cyclic
- 3. frequently contain D-amino acids
- 4. many contain non-amino acid moities
-
Bacitracin and Vancomycin
- Interfere with cell wall synthesis
- effective only against Gram +
-
Gramicidins and polymyxins
interfere with cell membrane functions
-
- Vancomycin
- Binds to D-Ala, D-Ala terminus
- Resistance if D-Ala, D-Lac
-
- Chloramphenicol
- First broad spectrum antibiotic
- inhibits protein synthesis
- synthetic
-
Novobiocin
inhibitor of DNA gyrase
|
|