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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
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Antibiotics in feed
increase meat production in many animals
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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
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Mechanisms of Action
- Interfere with cell wall biosynthesis
- Interfere with microbial protein synthesis
- Interfere with Nucleic Acid synthesis
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Cell Wall Biosynthesis Inhibitors
Bacteriocidal
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Protein Biosynthesis Inhibitors
Bacteriostatic except aminoglycosides
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Nosocomial
hospital acquired
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B-Lactam Antibiotics
- Gram + Bacteria
- -Cidal Action with low toxicity
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MoA of B-Lactams
- inhibition of bacterial cell wall synthesis
- Acylate active site serine in Penicillin binding proteins
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1 Oxford Unit
amount of PCN that will inhibit the growth of a strain of staph in 50mL of culture medium
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1 Unit Pure PCN
0.6 mcg PCN G
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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
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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
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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)
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- Methicillin
- steric hinderance
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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
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Carbenicillin***(3)
- pseudomonas
- klebsielia
- Non-toxic, ionized at phys pH
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PCN and Aminoglycosides
- incompatible, both will inactivate
- good combo therapy
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- Piperacillin
- acyl urido substituent
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Class I B-Lactamase inhibitors
- clavulanic acid
- sulbactam
- tazobactam
- suicide substrates
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Class II B-lactamase inhibitors
- "slow" Substrates
- carbapenemsm (imipenem)
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- Imipenam
- destroyed in kidney if administered alone
- cilastatin inhibits DHP1
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Cephalosporins
- similar to PCN but have a 6 membered ring rather than 5 attached to B-Lactam
- slightly more stable than PCNs
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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
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Cephalosporin spectrum
- broad spectrum
- more resistant to B-lactamase (esp. G+)
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Cephalosporin B-Latamase Resistance
- Increased by 7-methoxyl substituent
- Increased by alkoximino in aminoacyl group
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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
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Cephalexin***
- Homolog of Ampicillin
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- Cefadroxil
- Homolog of amoxicillin
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Monobactams
- Single ring system
- Aztreonam
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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
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Aminoglycoside Resistance Mechanisms (3)
- acetylating
- phosphorylating
- adenylylating
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Tetracylines (5)
- broad spectrum
- amphoteric compounds
- Strong acids and bases will inactivate
- di-tri-valent metals will form a complex and inhibit absorption
- bacteriostatic
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Three biochemically distinct mechanisms of resistance to tetracyclines
- 1. Efflux
- 2. Ribosomal protection
- 3. Enzymatic oxidation
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Macrolides
- Inhibitors of protein biosynthesis
- Bacteriostatic
- 1. large lactone ring
- 2. ketone group
- 3. glycosidically linked amino sugar
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Macrolide Spectrum of Activity
- generally effective agains most G+
- some G- cocci (neisseria)
- mycoplasma
- chlamydia
- campylobacter
- legionella
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Lincomycins
- Sulfur containing antibiotics
- resemble macrolides in spectrum
- static or cidal
- clindamycin
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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
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Bacitracin and Vancomycin
- Interfere with cell wall synthesis
- effective only against Gram +
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Gramicidins and polymyxins
interfere with cell membrane functions
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- Vancomycin
- Binds to D-Ala, D-Ala terminus
- Resistance if D-Ala, D-Lac
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- Chloramphenicol
- First broad spectrum antibiotic
- inhibits protein synthesis
- synthetic
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Novobiocin
inhibitor of DNA gyrase
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