Pogue: Antimicrobials IIa Flashcards
AMINOGLYCOSIDES
MOA:
What does it require?
Effective against anaerobes?
Bacteriostatic or Bacteriocidal?
MOA: bind 30S subunit of the ribosome to cause a decrease in protein synthesis
Requires active transport into the bacterial cell to exert its action (oxygen dependent)
No activity against anaerobes
Bacteriocidal: except against enterococcus
AMINOGLYCOSIDES
Spectrum of Activity:
G+:
Activity against:
Only used when?
G-:
Active against:
Pseudomonas:
Anaerobes
Spectrum of activity
Gram (+)
–Activity against staph, strep
–Only used in this aspect for synergy (1 + 1 = 8) for serious infections
Gram (-)
–Active against many Gram-negative bacilli (including Pseudomonas)
–Pseudomonas: amikacin > tobramycin > gentamicin
Anaerobes
–No activity (remember the mechanism!)
AMINOGLYCOSIDES
Agents:
IV: gentamicin, tobramycin, amikacin, streptomycin (all used in hospital)
PO/topical: neomycin (topical creams, ointments etc.)
AMINOGLYCOSIDES
Synergy:
G+ Usually combined with: What allows more entry into the cell? Expands spectrum to include: Use:
G-
Synergy
Gram (+)
–Usually combined with ß-lactam for synergistic effect
–Cell wall disruption allows more entry into the cell
–Expands spectrum to include enterococcus
–Only used in serious infections
Gram (-)
–In vitro a similar effect is seen
–This has never translated to improved clinical outcomes
Gentamicin
Most common use:
AMINOGLYCOSIDE
Mostly used for synergy for staphylococcal or enterococcal infections
Eye ointments (as well as tobramycin)
Tobramycin/ amikacin
Use:
Amikacin:
AMINOGLYCOSIDE
Used for empiric coverage of nosocomial infections (double coverage)
Sometimes continued for definitive therapy
Amikacin has a role in some mycobacterial infections
Neomycin
Oral
Topical
AMINOGLYCOSIDE
Orally to decontaminate the GI tract prior to surgery
Often in topical creams (NEOsporin)
Streptomycin
Use (2)
AMINOGLYCOSIDE
Enterococcal infection when gentamicin resistance (for synergy)
Mycobacterial infections
Aminoglycoside monotherapy:
Should be avoided (for the most part) for definitive monotherapy for Gram (-) infections
Literature does not support outside of urinary tract infections
Aminoglycoside
Pharmacokinetics:
Oral absorption:
Lipophilic?
Affects?
Highly concentrates where?
Therapeutic drug monitoring:
Poor oral absorption (PO not used for systemic infections)
Concentration dependent killing
–Optimize PK
Hydrophilic (poor tissue concentration)
Highly concentrated in the urine
–Renal dosing
–Good for UTI
Therapeutic Drug Monitoring
–Cmax/MIC 8-12 mcg/mL
–Cmin< 1 mcg/mL
Aminoglycoside
Mechanisms of Resistance (3):
What does transferase enzyme do?
Mutation in what prevents binding?
What decreases porin production?
Enzyme modification
–Transferase enzyme adds an additional side chain to the drugs which prevent appropriate binding
Target-site modification
–Mutation in the 30S subunit, prevents binding
Decreased concentrations in the cell
–Decreased porin production
–Efflux pumps
Aminoglycoside Adverse events (3)
Most common?
Strategies to minimize:
What is associated with total drug exposure?
Nephrotoxicity
–Most common, and most serious adverse event
–Strategies to minimize
•Shorter durations
•Minimize trough levels (level at the end of the dosing interval)
Vestibular/ototoxicity
–Associated with total drug exposure (optimize PK)
Neuromuscular blockade
–Additive with other drugs; disease states (myasthenia)
Fluoroquinolones
MOA:
MOA: inhibit bacterial DNA replication (unique)
Fluoroquinolones
Agents of clinical relevance (5):
–Moxifloxacin –Gemifloxacin (not available) –Ciprofloxacin –Levofloxacin –Norfloxacin (different)
Fluoroquinolones
Bacteriostatic or Bactericidal
Bioavailability:
exception
Bactericidal, concentration-dependent killing
Excellent bioavailability
–80% ciprofloxacin; ~100% levofloxacin, moxifloxacin
–NOT norfloxacin (as we will see)
Fluoroquinolones
Spectrum of activity
G+:
Comparison of 3
Why shouldn’t levofloxacin be relied on to treat staph and enterococcus?
What has excellent strep coverage?
Gram (+)
–Levofloxacin > moxifloxacin > ciprofloxacin
–Levofloxacin has some activity against staph and enterococcus, but should NOT be relied on to treat clinically (simple one step mutation for resistance)
–Levofloxacin and moxifloxacin have excellent streptococcus coverage (including s.pneumoniae)
The “respiratory fluoroquinolones”:
Excellent activity against:
Why isn’t cipro a respiratory FQ?
–Levofloxacin and moxifloxacin (and gemifloxacin)
–Excellent activity against all CAP organisms (S.pneumo, H.influenzae, M.cat, atypicals)
Not effective against most common pathogens
The Gram (-) fluoroquinolones: Coverage against:
Anaerobic FQ:
Ciprofloxacin and levofloxacin
Coverage against enteric Gram (-) as well as pseudomonas
Anaerobic FQ
–Moxifloxacin
FQ PK
Bioavailability?
What is notable about norfloxacin?
Hydrophilic or lipophilic?
Excellent bioavailability
–NOT norfloxacin –> clinically used for Selective Gut Decontamination (SGD), UTI
Highly lipophilic, allows to be used for infections in many body sites
-CSF, lungs, skin, tissue, bone, joint, blood
FQ
G-:
Comparison of 3
What has anti-pseudomonal activity?
Gram (-)
–Ciprofloxacin > Levofloxacin > Moxifloxacin
–Ciprofloxacin and levofloxacin have anti-pseudomonal activity (C > L)
–Resistance increasing in Gram (-) organisms likely secondary to overuse
FQ
Anaerobic:
What has activity?
Reliable against B. fragilis?
Only moxifloxacin has activity (not reliable against b. Fragilis)
Fluoroquinolones
Elimination:
Exceptions:
Renally eliminated (dose adjustment needed) –Exception is moxifloxacin
Fluoroquinolones Side Effects (5):
Central nervous system toxicity
Damage to growing cartilage
Tendon rupture
Dysglycemia
Cardiac arrhythmias and possible torsades
Fluoroquinolones
Side Effects
CNS:
Cartilage:
Tendon Rupture:
Central nervous system toxicity
–Headaches, dizziness, insomnia, seizures
–More common in elderly, h/oseizures, etc.
Damage to growing cartilage
–Only seen in animals so far
–Reason for soft contraindication in pediatrics
Tendon rupture (rare)
Fluoroquinolones
Side Effects
Dysglycemia:
Cardiac arrhythmias:
Dysglycemia
–Remember the story of gatifloxacin!
Cardiac arrhythmias and possible torsades
–Moxifloxacin is considered higher risk
–Minimal risk unless prone to arrhythmias or on other QT prolonging drugs
Fluoroquinolones
Drug Interactions:
Reduced oral absorption when taken with divalent cations
–Ca, Mg, Fe
–Due to chelation
Fluoroquinolones
Mech of resistance:
How does this affect unrelated antibiotics?
Efflux pumps
–Known inducers of efflux pumps which are able to carry many structurally unrelated antibiotics out of the cell as well (e.g. b-lactams, carbapenems, tetracyclines)
Target site modification
–Decrease binding at the site of action
Vancomycin
Class:
Overseas equivalent:
G+/-?
Aerobic vs anaerobic
Until recently, only commercially available antibiotic from the glycopeptide class in the USA –Overseas: Teicoplanin
Gram (+) organisms only
Aerobic coverage > anaerobic coverage
Vancomycin
Mechanism of Action
Binds to D-ala D-ala terminal portion of peptidoglycan precursors and prevents further cross-linking (slowly cidal)
Vancomycin
IV vs. PO
IV and PO formulations available
–IV for systemic infections
–PO formulation not absorbed; only used clinically to treat c. difficile colitis
Vancomycin
Type of elimination:
Trough levels:
Renally eliminated
–Dose adjustments needed in renal insufficiency
Trough levels monitored for efficacy
–15-20 mcg/mL goal for more serious infections
Vancomycin
Used empirically to cover:
Inferior to β-lactams for:
Use in pts with allergy to:
Used empirically to cover for MRSA
–Inferior to β-lactams for MSSA
Patients with β-lactam allergy
Vancomycin
Activity against streptococcus and enterococcus:
Compare to β-lactam:
Vancomycin has activity against streptococcus and enterococcus as well but inferior to β-lactam based therapy
Broader-spectrum, but weaker killing
What is MRSA?
Effect of β-lactams:
Penicillin-blinding protein alteration (addition of PBP2A)
β-lactams will not bind to PBP2A, thus β-lactams have no activity against MRSA
Continual problem in hospitals
~70% of staph in DMC is MRSA
Growing problem in community as well
Vancomycin and MRSA
Empiric regimens for hospital-acquired infections almost always include vancomycin to cover for MRSA
Vancomycin has been the standard of care for MRSA for many years
Elevation in vancomycin MIC’s have recently occurred in MRSA
–Much debate about the current optimal therapy
Vancomycin Side Effects (4):
Nephrotoxicity
–Historical incidence is smaller than most people believe
•Usually in combinations with other nephrotoxic agents
–Controversial newer data showing an increased incidence with higher doses
Ototoxicity
–Extremely rare. Associated with very high peaks
Rash
“Red-Man’s Syndrome”
“Red-Man’s Syndrome”
Definition
How do you overcome it?
Not a true allergy
Histamine response related to rapid infusion
Can overcome by slowing down infusion (no greater rate than 1g over 1 hr) and premedication with diphenhydramine
What does MSSA have that makes it resistant to penicillin?
What does MRSA have that makes it resistant to Nafcillin?
Penicillinase
PBP alteration
Telavancin
MOA
Second generation glycopeptide (came to market 2010)
MOA: same as vancomycin, plus direct binding to the bacterial membrane disrupting barrier function
Telavancin
Comparative effect against G+:
Activity against MRSA:
Increased bactericidal activity against Gram positives
–Some activity against MRSA with elevated vancomycin MIC’s
Telavancin
Pharmacological issues (3)
–Nephrotoxicity (higher than vancomycin)
–Interference with coagulation tests (significant!)
–Teratogenicity in animal studies
DAPTOMYCIN
MOA:
Bactericidal?
Spectrum of action:
IV only
MOA: embeds in membrane and creates a K+ efflux channel, leading to depolarization of the membrane and cell death
Bactericidal: HIGHLY
Spectrum of Action: GRAM (+) ONLY; staphylococcus, streptococcus and enterococcus
DAPTOMYCIN
Clinical applications:
Major uses: MRSA and VRE bloodstream infections, endocarditis, and soft tissue infections
Daptomycin
Issues:
Cross resistance:
Some cross-resistance seen with strains of MRSA that have elevated vancomycin MICs
–Cell wall thickening (VISA)
Overall, still one of the safest drugs
What is the only available oxazolidinone?
Linezolid
Linezolid
MOA
Inhibits protein synthesis by binding to the 50S ribosomal subunit
Linezolid
Spectrum of activity
Gram (+) only (staph and enterococcus)
Linezolid
Pharmacokinetics
Elimination
Great absorption (~100%) IV and PO dose the same Not renally eliminated (no dosage adjustment)
Linezolid
Clinical application
Drug of choice for VRE infections
Some use for MRSA (particularly pneumonia +/- elevated vancomycin MIC)
DOC for VRE Infections
Linezolid
Linezolid
Side effects of concern (WILL BE ASKED!)
Thrombocytopenia –> Usually seen with long courses (~day 14 of therapy)
Rare peripheral/optic neuropathy
Linezolid
DDIs
Serotonin syndrome
Linezolid is a weak MAOI
Concern for serotonin syndrome with drugs which work on serotonergic receptors (e.g. SSRIs)
Serotonin syndrome: fever, agitation, mental status changes, etc.
Can also occur if tyramine is given (good pharmacologic jeopardy question!)
Daptomycin
Adverse event of concern:
Effect in lungs:
Avoid:
Adverse event of concern
–CPK elevations and rhabdomyolysis
–Infrequent; caution with statins
Irreversible binding to pulmonary surfactant
– Surfactant is like a G+ membrane
– Avoid in pneumonia
Vancomycin-resistant enterococcus
Common in what?
Common in e.faecium; occasionally occur in e.faecalis
–Detroit is oddly enough the capital of the vancomycin resistant e.faecalis
In e.faecium, ampicillin resistance also common
Treatment choices for VRE (4)
–Linezolid
–Daptomycin
–Quinupristin/dalfopristin (e.faecium only)
–Tigecycline (maybe other tetracyclines)
Vancomycin mechanism of action
Binds to D-ala D-ala terminal portion of peptidoglycan precursors and prevents further cross-linking (slowly cidal)
What happens to D-ala D-ala in VRE? How does this affect vancomycin?
In VRE: D-ala D-ala becomes D-ala D-lac (or d-ser) in which vancomycin cannot bind
–Same mechanism in VRSA, although rarely seen
•(again Detroit is the place to go for this bug as well!)
What was the first drug for treatment of VRE?
quinupristin/dalfopristin
Why has quinupristin/dalfopristin fallen out of favor?
High rates of infusion reactions, arthralgias, and myalgias, hepatotoxicity
Availability of other agents
No activity versus e.faecalis
Quinupristin/dalfopristin
Class:
MOA:
Brand name:
Streptogramin
Ribosomal as well (50S)
Brand name: Synercid
One more look at S. aureus
VISA-Cell wall thickening (vanco MIC 4-16 mcg/mL) ↑ MRSA ↓ VRSA-Transfer of VRE resistance gene (vanco MIC > 32 mcg/mL)
