Cell+Wall+Agents+MOAs+2024.docx

**Pharmacodynamics** A. **Drug's effect on organism!** 1. **Bacteriostatic** -- **Inhibits growth at all concentrations above MIC** 2. **Bactericidal -- Inhibits growth above MIC, Kills above MBC** a. **Dose Dependent Killing (Peak to MIC) Concentration De...

**Pharmacodynamics** A. **Drug's effect on organism!** 1. **Bacteriostatic** -- **Inhibits growth at all concentrations above MIC** 2. **Bactericidal -- Inhibits growth above MIC, Kills above MBC** a. **Dose Dependent Killing (Peak to MIC) Concentration Dependent** b. **Exposure (Time) Dependent Killing (Time Above MIC)** B. **Bactericidal agents** 3. **Dose Dependent (Peak : MIC ratio)** c. **Aminoglycosides** d. **Quinolones** 4. **Exposure Dependent (Time \> MIC)** e. **Beta-Lactams** 5. **Composite (AUIC)** f. **Most bacteriocidal agents -- uses drug area under the curve and organism MIC** g. **For example: Vancomycin: AUIC \> 400 associated with better outcomes** Cover II. **Site of Infection** C. **Concentration of drug over time at site of infection relative to the MIC determines clinical success.** D. **Blood is major route of distribution for antibiotics throughout the body, regardless of route of administration.** E. **Blood levels can be measured with relative ease, but not other sites.** 6. **Vancomycin** h. Area Under the Inhibitory Concentration (AUIC): 400-600 i. **Trough (serious infections): 15-20 mcg/mL** j. **Trough (mild infections): 10-15 mcg/mL** 7. Aminoglycosides (traditional dosing) k. Peak: 3-13 mcg/mL depending upon site of infection l. Trough \< 2 mcg/mL to reduce nephrotoxicity risk F. **Penetration into other sites may be \> or \< blood** G. **CSF - protected by the BBB** - **In virtually all cases must give higher doses +/- IT** H. **Lungs -** 8. **quinolones & macrolides concentrate** 9. **Aminoglycosides and vancomycin penetrate poorly (Daptomycin)** I. **Bone, Heart Valve are difficult to penetrate** J. **Urine** 10. **Renally eliminated drugs concentrate** 11. **Quinolone, Fluconazole levels 100 x blood** III\. Historical A. 1929 -- Alexander Fleming 1\. Culture of *Penicillium notatum* 2\. Inhibition of *Staphylococcus aureus* B. 1941 -- Howard W Florey 1\. First patients received penicillin 2\. Treatment of streptococcal and gonococcal infections C. Emergence of penicillinase-producing staphylococci 1\. Addition of acyl side chain -- penicillinase resistant 2\. Further side chain changes -- activity against gram-negative aerobes a\. Aminopenicillins b\. Carboxypenicillins c\. Ureidopenicillins d\. β-lactamase inhibitors IV\. Structure and Mechanism of action  1. Bacterial cell wall structures  2. [Action of beta-lactam cell wall agents **(Bactericidal / Time-Dependent Killing)**] 3\. [Factors determining activity] b\. [Affinity] to penicillin-binding proteins c\. [Type] of penicillin-binding protein d\. [Concentration] of penicillin-binding protein e\. Activation of [endogenous autolytic system] (autolysins) Involved in normal remodeling of cell wall V. General Pharmacologic properties of beta-lactam antibiotics A. Absorption B. Distribution 1\. Excellent penetration 2\. Poor -- prostate, eye, bone 3\. [CNS -- inflamed meninges only] 4\. Placenta, breast milk 5\. Protein binding -- Antistaphylococcal penicillins (90+%) C. Metabolism / Excretion 3\. [Biliary excretion -- Nafcillin, Oxacillin], Piperacillin (and renal), [Ceftriaxone] D. Resistance 1\. [Inactivation by β-lactamases] a\. [Outside cell wall for gram-positives] b\. [In periplasmic space for gram-negatives] c\. [Hydrolysis of β-lactam ring] d\. ESBL - Extended-spectrum β-lactamases (*K. pneumoniae, E. coli*) 2\. Decreased permeability of cell wall 3\. Development of [new penicillin-binding proteins] a\. *[Streptococcus pneumoniae]* b\. *[Staphylococcus aureus MRSA]* E. Side Effects 1\. Nausea, vomiting, diarrhea 2\. [Pseudomembranous colitis -- precaution for all antibiotic classes CDAD] 3\. [Hemolytic anemia (positive direct Coomb's test)] 4\. Allergic Reaction a\. [PCN binds to human proteins (form hapten) -- recognized as non-self] c\. Anaphylaxis, urticaria, drug fever, delayed hypersensitivity, rashes d\. [Interstitial nephritis (esp. Nafcillin/Oxacillin)] VI. Mechanism of glycopeptide and lipoglycopeptide action **(Vancomycin -- Bactericidal / Time-Dependent Killing)**  **(Others -- Bactericidal / Concentration-Dependent Killing)** A. Mechanism of action (Inhibits cell wall synthesis) 1\. [Bind to D-Ala-D-Ala terminus] of the murein monomer 4\. [Weakens cell wall and damages underlying cell membrane] -- [esp. lipoglycopeptides, Daptomycin] B. Mechanisms of Resistance 1\. [Use of D-lactate in place of D-Ala (VanH and VanA resistance)] VII\. Agents A. Vancomycin (Vancocin^®^) MOA 1,2 IV, PO [Glycopeptide] B. Telavancin (Vibativ^®^) MOA 1,2,4 IV [Lipoglycopeptide] C. Oritavancin (Orbactiv^®^) compatible in [D5W only] MOA 1,2,3,4 IV [Lipoglycopeptide] D. Dalbavancin (Dalvance^®^) compatible in [D5W only] MOA 1,2,4 IV [Lipoglycopeptide] VIII\. General Pharmacologic Properties A. Absorption 1\. Poor oral absorption ([Vancomycin use PO and PR for C. diff colitis]) B. Distribution 1\. Vancomycin - [Poor CNS] (intrathecal dosing data) and [Lung penetration] (↑ trough (AUC) targeted) C. Metabolism / Excretion 1\. Vancomycin / Telavancin - Half-life 6 -- 10 hours (vancomycin up to 200 hours in renal failure) 2\. Oritavancin / Dalbavancin -- Half-life 14-16 days -- [once weekly dosing] 3\. Renal excretion -- [renally adjust]