Transcript Antibacterials II: Vancomycin, Linezolid, Daptomycin, Macrolides

Vancomycin
 Class: Glycopeptide
antibiotic
 MOA: Inhibition of
bacterial cell wall
synthesis by binding Dala-D-ala
Goodman & Gilman’s The Pharmacological Basis of Therapeutics – 11th Ed. (2006)
Peptidoglycan Synthesis
“Penicillin binding
protein”
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
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
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
 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
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
Linezolid
 Penetration:
Plasma
Pulmonary lining
Blister fluid
> MIC90 for Staphylococcus
 Dose (IV or PO): 600 mg Q12H
 Drug-drug interactions:
Non-selective inhibitor of MAO
Possible serotonergic or adrenergic interaction with antidepressant medications (incidence < 1%)
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
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
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
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
 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
 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-OHclarithromycin
 Primarily excreted in urine
Goodman and Gilman’s The Pharmacological Basic of Therapeutics. 11ed. 2006
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
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
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
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
Telithromycin: Ketolide
 1st of ketolide class
 Designed to target
macrolide-resistant
respiratory tract
pathogens
 Compared to macrolidemore highly concentrated
in tissue
 Not currently
recommended in
guidelines due to
hepatotoxicity
Goodman and Gilman’s The Pharmacological Basic of Therapeutics. 11ed. 2006
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
Clindamycin
 Class: Lincosamide
 Mechanism of Action: Binds exclusively to the
50S subunit of bacterial ribosomes and
suppress protein synthesis
Clindamycin
 Trade names: Cleocin ®,
Clindesse®, Clindagel ®,
Clindamax ®, Evoclin ®
 Delivery forms:
 capsules: 75, 150, 300
mg;
 granules for oral solution
75mg/5ml;
 injection 150 mg/ml;
 vaginal cream 2%;
 vaginal suppositories 100
mg;
 topical gel 1%;
 topical lotion 1%;
 topical solution 1%;
 foam 1%
Clindamycin
 Indications: Serious infections
caused by susceptible
anaerobic bacteria
 Dosing:
 Adults:150-450 mg Q 6
hrs
 Children:8-20 mg/kg/day
divided TID-QID
 Off-label indications: CNS
toxoplasmosis in AIDS patients
in addition to pyrimethamine;
chlamydia infections in
women; bacterial vaginosis
due to Gardnerella vaginalis
 Instructions:
 Take with full glass of
water
 Warning:
 Pseudomembranous
colitis
Clindamycin
 Precautions:
Renal impairment/liver
disease
Elderly
Meningitis
GI disease
Superinfections
Pregnancy Category B
 Drug Interactions:
Erythromycin
Neuromuscular
blocking agents
 ADRs:
Dermatologic, GI,
Hypersenstivity
Aminoglycosides
• Bactericidal inhibitors of protein synthesis
• Concentration dependent bacteria killing
• Postantibiotic effect
• Major limitation of use is the serious
toxicity
• Nephrotoxicity
• Ototoxicity
Aminoglycosides: Indications
• Primarily against aerobic, gram negative bacilli
• Activity against gram positive bacteria limited
• Synergistic effect against “sensitive” (highlevel) streptococci and enterococci when used
with a cell wall active agent
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
• 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
Modes of resistance
• Decreased permeation of aminoglycosides
• Low affinity for bacterial ribosome
• Drug inactivation by microbial enzymes
• Important clinically
• Amikacin is less vulnerable
Structure
Goodman and Gilman’s
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
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
Aminoglycosides
 Toxicity:
Nephrotoxicity:
Incidence 5% to 25%
Risk factors:
 Renal Disease
 Hypotension
 Hepatic dysfunction
 Frequent dosing interval
 Larger doses
 Other nephrotoxic medications
 Increased Age
 Treatment > 3 days
Ototoxicity (cochlear, vestibular)
Neuromuscular blockade (very rare)
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
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
• 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
• 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
• Broadest spectrum of activity
• Resistant to aminoglycoside-inactivating enzymes
• Less active against enterococci
• Similar dosing interval and monitoring
• Peak
• Life-threatening infection
• Serious infection
25-30 mcg/ml
20-25 mcg/ml
• Trough
• Life threatening infection
• Most infections
4-8 mcg/ml
1-4 mcg/ml