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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
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)

slide2

“Penicillin binding protein”

Peptidoglycan Synthesis

vancomycin3
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
vancomycin4
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
vancomycin5
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
linezolid
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

linezolid7
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
linezolid8
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

daptomycin
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

daptomycin10
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
daptomycin11
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
macrolide mechanism of action
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

macrolides
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
clarithromycin
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

clarithromycin15
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
azithromycin
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

azithromycin17
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
macrolide resistance
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
clindamycin
Clindamycin
  • Class: Lincosamide
  • Mechanism of Action: Binds exclusively to the 50S subunit of bacterial ribosomes and suppress protein synthesis
clindamycin20
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
clindamycin21
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
clindamycin22
Precautions:

Renal impairment/liver disease

Elderly

Meningitis

GI disease

Superinfections

Pregnancy Category B

Drug Interactions:

Erythromycin

Neuromuscular blocking agents

ADRs:

Dermatologic, GI, Hypersenstivity

Clindamycin
aminoglycosides
Aminoglycosides
  • Bactericidal inhibitors of protein synthesis
  • Concentration dependent bacteria killing
  • Postantibiotic effect
  • Major limitation of use is toxicity
    • Nephrotoxicity
    • Ototoxicity
aminoglycosides indications
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
penetrating the cell
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

mechanism of action
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

aminoglycosides resistance
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
structure
Structure

Goodman and Gilman’s

aminoglycosides29
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
aminoglycosides30
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
aminoglycosides31
Aminoglycosides
  • Toxicity:
    • Nephrotoxicity:
      • Incidence 5% to 25%
      • Risk factors:
    • Ototoxicity (cochlear, vestibular)
    • Neuromuscular blockade (very rare)
toxicity
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
aminoglycosides33
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.
gentamicin once daily dosing
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
tobramycin
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
amikacin
Amikacin
  • Broadest spectrum of activity
    • Resistant to aminoglycoside-inactivating enzymes
    • Less active against enterococci
  • Similar dosing interval and monitoring
  • Peak
    • Life-threatening infection 25-30 mcg/ml
    • Serious infection 20-25 mcg/ml
  • Trough
    • Life threatening infection 4-8 mcg/ml
    • Most infections 1-4 mcg/ml