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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). “Penicillin binding protein”. Peptidoglycan Synthesis. Vancomycin. IV, PO

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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 – 11th Ed. (2006)


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“Penicillin binding protein”

Peptidoglycan Synthesis


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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


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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


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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


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Linezolid

  • Class: Oxazolidinedione

  • MOA: Binds P site of 50s ribosomal subunit, preventing translation initiation

Goodman & Gilman’s The Pharmacological Basis of Therapeutics – 11th Ed. (2006)

http://www.chm.bris.ac.uk/motm/linezolid/linezolid.htm


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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


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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%)

> MIC90 for Staphylococcus


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Daptomycin

  • Class: Cyclic lipopeptide

  • MOA: In the presence of Ca2+, binds bacterial membrane resulting in depolarization

Goodman & Gilman’s The Pharmacological Basis of Therapeutics – 11th Ed. (2006)

http://cubicin.com/am_moa.htm


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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


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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

  • Can Interact with certain assays for INR testing – results in falsely high INR  recommend point of care testing


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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


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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


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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


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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. aureus, 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


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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


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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. aureus, 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 60-70 hours

    • Caution in patients with CrCl < 10 ml/min

  • ADRs:

    • Generally well-tolerated, may cause GI upset


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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


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Clindamycin

  • Class: Lincosamide

  • Mechanism of Action: Binds exclusively to the 50S subunit of bacterial ribosomes and suppress protein synthesis


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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%

Clindamycin


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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

Clindamycin


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Precautions:

Renal impairment/liver disease

Elderly

Meningitis

GI disease

Superinfections

Pregnancy Category B

Drug Interactions:

Erythromycin

Neuromuscular blocking agents

ADRs:

Dermatologic, GI, Hypersenstivity

Clindamycin


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Aminoglycosides

  • Bactericidal inhibitors of protein synthesis

  • Concentration dependent bacteria killing

  • Postantibiotic effect

  • Major limitation of use is toxicity

    • Nephrotoxicity

    • Ototoxicity


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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


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Penetrating the Cell

Gram Negative Bacteria

  • 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


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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


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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


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Structure

Goodman and Gilman’s


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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


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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


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Aminoglycosides

  • Toxicity:

    • Nephrotoxicity:

      • Incidence 5% to 25%

      • Risk factors:

    • Ototoxicity (cochlear, vestibular)

    • Neuromuscular blockade (very rare)


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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 1st symptom


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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.


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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


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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


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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


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