1. Vancomycin Class: Glycopeptide antibiotic MOA: Inhibition of bacterial cell wall synthesis by binding D- ala-D-ala Goodman & Gilman’s The Pharmacological Basis of Therapeutics – 11 th Ed. (2006)

2. “Penicillin binding protein” Peptidoglycan Synthesis

3. Vancomycin IV, PO Spectrum: Gram (+) Drug of Choice  MRSA Indications  IV: Serious methicillin-resistant Staphylococcal infections: pneumonia, endocarditis, osteomyelitis, SSSI  PO: pseudomembranous colitis (metronidazole preferred)  Staphylococcal infections in Penicillin allergic patients  NOTE: Do not use in non-Penicillin allergic patients. Vancomycin does not kill as rapidly as antistaphylococcal β-lactams, and may negatively impact clinical outcome Unique Qualities  Monitor trough serum concentrations  Poor oral absorption  Adjust dose for renal impairment ADRs  “Red Man” Syndrome  Ototoxicity  Nephrotoxicity w/ other nephrotoxic agents

4. Vancomycin Mechanism of action: Inhibits bacterial cell wall synthesis Spectrum of action: Gram positive organisms  Including: Listeria, Rhodococcus, Peptostreptococcus  Bacteriostatic against enterococcus Mechanism of resistance:  Enterococcus: Van A – E Peptidoglycan precursor has decreased affinity for vancomycin – D-ala-D-ala replaced by D-ala-D-lac  Staphylococcus aureus: VISA isolates: Increased amount of precursor with decreased affinity Thicker cell wall hVISA: heterogenous bacterial population

5. Vancomycin Dose:  Based on total body weight and renal function  15 – 20 mg/kg  Normal renal function: q 12 dosing Goal trough concentrations:  10 – 15 mcg/mL: bacteremia, skin and soft tissue infections  15 – 20 mcg/mL: osteomyelitis, meningitis, pneumonia

6. Linezolid Class: Oxazolidinedione MOA: Binds P site of 50s ribosomal subunit, preventing translation initiation Goodman & Gilman’s The Pharmacological Basis of Therapeutics – 11 th Ed. (2006) http://www.chm.bris.ac.uk/motm/linezolid/linezolid.htm

7. Linezolid IV, PO Gram (+) Indications  VRE (E. faecium)  Nosocomial pneumonia (S. aureus)  Community-acquired pneumonia (S. pneumoniae)  cSSSI (S. aureus) Unique Qualities  F~100%, IV=PO  Reserve use for treatment of multiple drug resistant strains  No CYP interaction ADRs  Generally well tolerated w/ minor SE in short term Rx  Myelosuppression: anemia, leukopenia, pancytopenia, thrombocytopenia  Peripheral and optic neuropathy

8. Linezolid Penetration:  Plasma  Pulmonary lining  Blister fluid Dose (IV or PO): 600 mg Q12H Drug-drug interactions:  Non-selective inhibitor of MAO  Possible serotonergic or adrenergic interaction with anti- depressant medications (incidence < 1%) > MIC 90 for Staphylococcus

9. Daptomycin Class: Cyclic lipopeptide MOA: In the presence of Ca 2+, binds bacterial membrane resulting in depolarization Goodman & Gilman’s The Pharmacological Basis of Therapeutics – 11 th Ed. (2006) http://cubicin.com/am_moa.htm

10. Daptomycin Indications:  Treatment of complicated SSTI’s caused by gram positive bacteria  Treatment of Staphylococcus bacteremia and right-sided endocarditis  Not used for treatment of pneumonia due to binding reaction with surfactant  inactivates daptomycin MOA:  Binds membrane  Rapid depolarization  Cell death

11. Daptomycin Pharmacokinetic profile:  Concentration-dependent killing  Post-antibiotic effect  Available for intravenous use only Penetration:  Good penetration into vascular tissues and plasma  Currently testing penetration into cerebral spinal fluid Dose:  SSTIs: 4 mg/kg IV daily  Bacteremia: 6 mg/kg IV daily  Adjust for decreased renal function – CrCl < 30, use qod  Interacts with assay for INR testing – results in falsely high INR  recommend point of care testing

12. Macrolide Mechanism of Action Bacteriostatic Inhibits protein synthesis  Bind reversibly to 50s unit of the ribosome  Blocks translocation of peptides from A-site to P-site. Goodman and Gilman’s The Pharmacological Basic of Therapeutics. 11ed. 2006

13. Macrolides Achieve higher tissue than plasma concentrations  Penetrate into respiratory, tonsillar, and prostate tissues  Also penetrate into PMN leukocytes Important for Atypicals like: Chlamydia and Legionella species PD: Time the bacteria is exposed to therapeutic concentrations above the MIC best predicts efficacy – time dependent killing

14. Clarithromycin 14-membered lactone ring Replace hydroxyl group at C-6 position with methoxyl group  Increase stability under acidic conditions Partially metabolized via CPYP3A4  converted to active metabolite 14-OH- clarithromycin Primarily excreted in urine Goodman and Gilman’s The Pharmacological Basic of Therapeutics. 11ed. 2006

15. Clarithromycin PO: Biaxin® 250-500 mg q 12 hours; Biaxin XL® 1000 mg qday Spectrum of Activity: Gram (+) and Gram (-) Indications: otitis media, CAP, pharyngitis/tonsillitis, sinusitis, uncomplicated skin infections, prevention of MAC, duodenal ulcer disease  S. aures, S. pyogenes, S. pneumoniae, Mycobacterium avium complex  C. pneumoniae, C. trachomatis, L. pneumoniae  H. influenzae, H.pylori Drug Interactions: Substrate of CYP 3A4 and Inhibits CPY 3A4(major) CYP 1A2 (weak)  Theophylline, statins, digoxin, warfarin, cyclosporine Renal Adjustments:  CrCl < 30 ml/min: ½ the normal dose or double the dosing interval ADR:  Prolongs the QT interval – use with caution in CAD  N/V, diarrhea, headache Counseling Points:  Take XL formulation with food; do not chew or crush

16. Azithromycin 15-membered lactone ring  N-methyl group inserted between C-9 and C-10  Ketone replaced with – CH2 Goodman and Gilman’s The Pharmacological Basic of Therapeutics. 11ed. 2006

17. Azithromycin PO, IV  Azithromyicn: 500 mg x day 1 then 250 mg x day 2-5  STDs: C. trachomatis: 1 g x 1; N. gonorrheae: 2 g x 1 Spectrum of Activity: Less Gram (+), increased Gram (-) Indications: otitis media, pharyngitis/tonsillitis, upper and lower respiratory tract infections, skin and skin structure, CAP, PID, STDs  S. aures, S. pneumoniae, H. influenzae, Mycobacterium avium complex  C. trachomatis, M. catarrhalis, M. pneumonia, N. gonorrheae, Chlamydia pneumoniae Drug Interactions: not as significant as other macrolides  Most documented with cyclosporine and tacrolimus Unique Characteristics:  T ½ of immediate release: 68-72 hours; extended release: 59 hours  Caution in patients with CrCl < 10 ml/min ADRs:  Generally well-tolerated, may cause GI upset

18. Macrolide Resistance Decrease of permeation of drug through the cell membrane, or drug efflux pumps Methylase modifies the ribosomal target Hydrolysis of macrolides by endogenous esterase

19. Telithromycin: Ketolide 1 st of ketolide class Designed to target macrolide-resistant respiratory tract pathogens Compared to macrolide- more highly concentrated in tissue Not currently recommended in guidelines due to hepatotoxicity Goodman and Gilman’s The Pharmacological Basic of Therapeutics. 11ed. 2006

20. Telithromycin (Ketek ®) PO: CAP-800 mg qday x 7-10 days Spectrum of activity: Gram (+) and Gram (-) Indications: acute exacerbations of chronic bronchitis, acute sinusitis, CAP  Staphylococci, S. pneumoniae (DRSP), H. influenzae, Moraxella catarrhalis, mycoplasma, chlamydia, Legionella Drug Interactions: Inhibits CYP2D69(weak) 3A4(strong):  Multiple Drug Interactions ADRs  Hepatotoxicity: Monitor LFTs, sxs of liver failure  QT prolongation  N/V: take with or without food  Dose adjust for renal insufficiency Goodman and Gilman’s The Pharmacological Basic of Therapeutics. 11ed. 2006

21. Clindamycin Class: Lincosamide Mechanism of Action: Binds exclusively to the 50S subunit of bacterial ribosomes and suppress protein synthesis

22. Clindamycin Trade names: Cleocin ®, Clindesse®, Clindagel ®, Delivery forms:  capsules: 75, 150, 300 mg;  granules for oral solution 75mg/5ml;  injection 150 mg/ml;  vaginal cream 2%;  vaginal suppositories 100 mg; Clindamax ®, Evoclin ®  topical gel 1%;  topical lotion 1%;  topical solution 1%;  foam 1%

23. Clindamycin Indications: Serious infections caused by susceptible anaerobic bacteria Off-label indications: CNS toxoplasmosis in AIDS patients in addition to pyrimethamine; chlamydia infections in women; bacterial vaginosis due to Gardnerella vaginalis Dosing:  Adults:150-450 mg Q 6 hrs  Children:8-20 mg/kg/day divided TID-QID Instructions:  Take with full glass of water Warning:  Pseudomembranous colitis

24. Clindamycin Precautions:  Renal impairment/liver disease  Elderly  Meningitis  GI disease  Superinfections  Pregnancy Category B Drug Interactions:  Erythromycin  Neuromuscular blocking agents ADRs:  Dermatologic, GI, Hypersenstivity

25. Aminoglycosides Bactericidal inhibitors of protein synthesis Concentration dependent bacteria killing Postantibiotic effect Major limitation of use is the serious toxicity Nephrotoxicity Ototoxicity

26. Aminoglycosides: Indications Primarily against aerobic, gram negative bacilli Activity against gram positive bacteria limited Synergistic effect against “sensitive” (high- level) streptococci and enterococci when used with a cell wall active agent

27. Penetrating the Cell Diffuse through porin proteins on the outer membrane of gram negative cell wall Transport across inner membrane depends on electron transport Membrane potential drives permeation Transport can be blocked by reduction in pH and anaerobic environment Adapted from: http://web.indstate.edu/thcme/micro/respiratory/sld006.htm Gram Negative Bacteria

28. Mechanism of Action Bactericidal Inhibit protein synthesis Bind to bacterial 30S ribosomal subunit Blocks initiation of protein synthesis Cause misreading of mRNA template Cause premature termination of translocation Goodman and Gilman’s

29. Aminoglycosides: Resistance Modes of resistance Decreased permeation of aminoglycosides Low affinity for bacterial ribosome Drug inactivation by microbial enzymes Important clinically Amikacin is less vulnerable

30. Structure Goodman and Gilman’s

31. Aminoglycosides Resistance: Intrinsic vs. Acquired  Intrinsic: Anaerobes: lack active electron transport chain to cross membrane Mutation at 16s rRNA (ie TB)  Acquired: Efflux: seen in Pseudomonas Decreased transmembrane potential: seen in Enterococcus

32. Aminoglycosides Distribution:  Freely into the vascular space  Interstitial spaces of most tissues  Volume of distribution increases in edematous states and decreases in obese patients (on L/kg basis) Decreased concentrations:  Bronchial secretions, CSF, biliary tract, synovial fluid, and in the eye Excreted by the kidneys Half-life: 1.5 to 3.5 hours

33. Aminoglycosides Toxicity:  Nephrotoxicity: Incidence 5% to 25% Risk factors:  Ototoxicity (cochlear, vestibular)  Neuromuscular blockade (very rare)  Renal Disease  Hypotension  Hepatic dysfunction  Frequent dosing interval  Larger doses  Other nephrotoxic medications  Increased Age  Treatment > 3 days

34. Toxicity Dependent on: Total amount of drug AND duration of therapy Nephrotoxicity Most often reversible Accumulation of drug in proximal tubular cells Mild rise in Scr (0.5-1 mg/dl) Reduced excretion of drug = increased risk of ototoxicity Ototoxicity Largely irreversible if not caught early Destruction of vestibular and cochlear sensory cells High-pitched tinnitus is often 1 st symptom

35. Aminoglycosides Site of infection: determines goal levels and dose  Peak concentrations: Gram + Synergy: 3 – 5 mcg/mL UTI: 3 – 4 mcg/mL Bacteremia: 6 – 8 mcg/mL Pneumonia: 8 – 10 mcg/mL Weight based dosing: use IBW or ABW Interval: once-daily dosing for gram-negative infection (normal renal function, 7 mg/kg/day). Gram + synergy 1mg/kg q 8-12h.

36. Gentamicin: Once Daily Dosing 5-7mg/kg/24hrs (ABW) Target peak 14-20 mcg/ml Allows low troughs Avoid in patients with: Burns, CF, pregnancy, children, endocarditis or CrCl < 20ml/min

37. Tobramycin Antimicrobial activity and PK properties very similar to gentamicin Superior activity against P. aeruginosa Less active than gentamicin against enterococci Can be given IV or IM Dosage and serum levels are same as gentamicin

38. Amikacin Broadest spectrum of activity Resistant to aminoglycoside-inactivating enzymes Less active against enterococci Similar dosing interval and monitoring Peak Life-threatening infection25-30 mcg/ml Serious infection20-25 mcg/ml Trough Life threatening infection4-8 mcg/ml Most infections1-4 mcg/ml