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 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 – 11 th 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

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

Class: Cyclic lipopeptide

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

Goodman & Gilman’s The Pharmacological Basis of Therapeutics – 11 th 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-OH-clarithromycin

Primarily excreted in urineGoodman 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 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

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 ®,

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

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

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” (high-level) streptococci and enterococci when used with a cell wall active agent

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

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:

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

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/mLUTI: 3 – 4 mcg/mLBacteremia: 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 25-30 mcg/ml• Serious infection 20-25

mcg/ml

• Trough• Life threatening infection 4-8 mcg/ml• Most infections 1-4 mcg/ml