Erdman - Macrolides Flashcards
CHEMISTRY
- ___ is a natural macrolide derived from Streptomyces erythreus that contains a 14-membered macrocyclic lactone ring
- ___ is a semisynthetic macrolide structurally derived from erythromycin
- ___ is also a semisynthetic derivative of erythromycin in which an amino group is inserted into the ring at position 9a (15-membered ring) and is technically considered an azalide
- Erythromycin
- Clarithromycin
- Azithromycin
MECHANISM OF ACTION
- Macrolide antibiotics interfere with microbial protein synthesis (translocation steps) at the ribosomal level. The macrolides reversibly bind to the ___ ribosomal subunit to induce dissociation of peptidyl transfer RNA from the ribosome during the elongation phase so that ___ synthesis is suppressed and bacterial growth is inhibited
- Macrolides typically display ___ activity; however, they may display bactericidal activity when present at high concentrations against very susceptible organisms (Streptococcus pneumoniae, Streptococcus pyogenes).
- 50S
- protein
- bacteriostatic
MOR
- active ___ - ___ gene: confers low-level resistance to the macrolides (macrolide therapy may still be used in some cases)
- Alteration in the ___ site - ___ gene: confers high-level resistance to all macrolides AND other antibiotics that bind to the 50S ribosome
- ___ is usually observed among the macrolides
- efflux, mef
- binding, erm
- cross-resistance
SPECTRUM OF ACTIVITY
The macrolides are primarily ___
- ___ dependent activity
bacteriostatic
- time
SPECTRUM OF ACTIVITY
Gram-positive aerobes ( __ > __ > __ )
- Group and Viridans streptococci
- S. pneumoniae (overall covers ~65 to 70% of strains; primarily active against ___ ; poor activity against PISP and PRSP)
- Methicillin–susceptible S. aureus (MSSA – mild to moderate infections only)
- Bacillus spp, Corynebacterium spp.
Gram-negative aerobes ( __ > __ > __ ) – NOT the ___
- Haemophilus influenzae (not erythromycin)
- Moraxella catarrhalis
- Neisseria spp
- C > E > A
- PSSP
- A > C > E
- Enterobacteriaceae
SPECTRUM OF ACTIVITY
Other Organisms: (Azithro and Clarithro are better for ___ and ___ )
Anaerobes – activity against anaerobes ___ the diaphragm
- Legionella, Mycoplasma
- above
___ and ___ are available PO and IV
- erythromycin
- azithromycin
Absorption
Erythromycin
- base - needs ___ coating
- esters (stearate, estolate, ethyl
succinate) – are more acid stable and better absorbed
Clarithromycin
- acid stable and well absorbed from the GI tract (regardless of the presence of ___ )
Azithromycin
- acid stable; oral bioavailability approaches 37% with peak concentrations occurring at 2 to 3 hours; ___ does not affect the absorption of the tablets or suspension
- enteric
- food
- food
Distribution
- All 3 macrolides extensively distribute into tissues (except for the ___ ) and cells (including ___ and ___ )
- may be ineffective for ___
- CSF, macrophages, neutrophils
- bacteremia
Elimination
Erythromycin
- Excreted primarily in the bile with some demethylation in the liver by ___ enzymes
- Half-life = 1.4 hours, but may be prolonged up to 5 hours in patients
with renal failure (but ___ dosage adjustment is necessary)
Clarithromycin
- Extensively metabolized in the liver by the ___ enzymes
- Elimination half-life = 3 to 7 hours in normal renal function and is
markedly prolonged in the presence of renal insufficiency so that dosage adjustment is necessary in patients with a CrCl < ___
ml/min
Azithromycin
- Biliary excretion, predominantly as unchanged drug into the feces
- Elimination half-life = ___ hours due to extensive tissue sequestration and binding (tissue half-life estimated at 4 days
NONE of the macrolides are removed during hemodialysis or peritoneal dialysis
- CYP450
- NO
- CYP450
- 30
- 68
CLINICAL USES
Respiratory Tract Infections
- Pharyngitis, Tonsillitis, Otitis Media, Sinusitis – alternative in penicillin-allergic patients
- Acute Exacerbations of Chronic Bronchitis – azithromycin and clarithromycin are best if H. influenzae is suspected
- Community Acquired ___ - especially for ___ coverage;
monotherapy for outpatients or combined with a B-lactam (e.g., ceftriaxone) for inpatients
4. Other – Pertussis, C. diphtheriae
- Pneumonia
- atypical
Clinical Uses
Sexually Transmitted Diseases
- A single 1-gram dose of ___ is used for the treatment of nongonococcal urethritis or cervicitis due to ___
- azithromycin
- Chlamydia trachomatis
Clinical Uses
___ avium Complex Infections (MAC) – clarithromycin (500 to 1000 mg every 12 hours) as part of a combination regimen with ethambutol and/or rifabutin for treatment; azithromycin alone for prophylaxis (1200 mg weekly)
- Other: Campylobacter jejuni infections, Helicobacter pylori (in combination)
Macrolides are ___ antibiotics for the treatment of the following mild to moderate infections in penicillin-allergic patients:
- Group A streptococcal upper respiratory infections
- Prophylaxis of bacterial endocarditis
- Syphilis and gonorrhea
- Superficial minor staphylococci infection
- Rheumatic fever prophylaxis
- Mycobacterium
- alternative
ADVERSE REACTIONS
- Gastrointestinal - epigastric distress, abdominal pain, nausea, vomiting, and diarrhea – most common (in up to 33% of patients) with oral administration of ___ (may also occur with IV)
- Cholestatic hepatitis (rare) - most often seen in adult patients who receive > 1 to 2 weeks of erythromycin estolate therapy
- ___ and infusion site irritation (IV erythromycin and azithromycin)
- allergy
- ototoxicity
- ___ prologation
- Exacerbation/worsening of symptoms of myasthenia gravis
- erythromycin
- Thrombophlebitis
- QTc
DRUG INTERACTIONS
Both ___ and ___ are inhibitors of the cytochrome P450 3A4 and 2C9
Concomitant administration may increase the serum concentrations of the following drugs (and potentially lead to toxicity)
- Theophylline
- Carbamazepine
- Valproate
- Cyclosporine
- Digoxin
- Phenytoin
- ___
erythromycin, clarithromycin
- Warfarin
Azithromycin does NOT inhibit the cytochrome P450 enzyme system, and is
NOT thought to be associated with the drug-drug interactions listed above
However, ___ has been reported during post-marketing surveillance in patients stabilized on ___
- hypoprothrombinemia
- warfarin
