Macrolides and Tetracyclines Flashcards
Describe the MOA of macrolides?
Bind to 50S ribosomal subunit, inhibiting protein synthesis (via blocking of transpeptidation/translocation reactions). They may be bacteriostatic or bactericidal, depending on such factors as drug concentration.
What are the 3 resistance mechanisms for macrolides?
- reduced permeability of the cell membrane or active efflux;
- Production (by Enterobacteriaceae) of esterases that hydrolyze macrolides;
- Methylation of the target site (the ribosome) that prevents the binding to the ribosome.
Efflux and methylase are the most commone reason for resistances in GRAM +VE organisms.
If erythromycin has resistance, do the others?
Cross-resistance is complete between erythromycin and the other macrolides.
Constitutive methylase production also confers resistance to structurally unrelated but mechanistically similar compounds such as clindamycin and streptogramin B (so-called macrolide-lincosamide-streptogramin, or MLStype B, resistance), which share the same ribosomal binding site.
Describe the spectrum of activity of macrolides?
Clarithromycin, azithromycin have extended spectrum against gram –ve and gram +ve when compared to erythromycin
What are common toxicities (SE) of macrolides?
Stimulate GI motility, resulting in abdominal cramps, nausea and diarrhea o More common with erythromycin due to metabolites that bind to motilin receptors
* Allergic reactions are uncommon; usually manifest as rash
* Cholestatic hepatitis has been associated with estolate preparations of erythromycin; rare
* QT prolongation
* Reversible sensorineural hearing loss with azithromycin. More likely seen on those on it on a continuous basis.
Which macrolide can cause reversible sensorineural hearing loss?
Azithromycin - More likely seen on those on it on a continuous basis
How are macrolides metabolised?
Hepatically
What are the significant drug interactions with clarithromycin and erythromycin?
erythromycin and clarithromycin are inhibitors of cytochrome P450;
o just check every time
* concomitant use of other QT prolonging agents o just check every time
What is the spectrum of activity of Macrolides?
Gram +ve * gram positive bacteria including Strep species and methicillin-sensitive Staph aureus (erythromycin is perhaps less active against Staph) o This may vary according to local susceptibilities
Gram –ve
* Moraxella catarrhalis and H. influenzae are susceptible
o (NOTE: erythromycin is NOT reliable against H. influenzae)
* Enterobacteriaceae (e.g. E. coli, Klebsiella, etc.) *are resistant to macrolides *
* Legionella species Anaerobes
* Some anaerobic activity, but not Bacteroides fragilis
Atypical Pathogens:
* Mycoplasma pneumoniae
* Chlamydia pneumoniae and Chlamydia trachomatis
Others:
* Clarithromycin is active against H. pylori
- Clarithromycin and azithromycin are active against Mycobacterium avium- intracellular complex (MAC) and other NTMs
Describe the UNIQUE macrolide
FIDAMOXICIN
It has minimal GI absorption and is used for the treatment of C. difficile mediated toxin-diarrhea only. Does not disrupt normal GI flora
- Hypersensitivity reactions have been known to occur.
- May be considered as efficacious as oral vancomycin.
What is the MOA of Tetracyclines?
Bind to the 30S ribosomal subunit, inhibiting protein synthesis (Macrolides are 50S)
What are the three mechanisms of resistance to tetracycline:
- decreased intracellular accumulation due to either impaired influx or increased efflux by an active transport protein pump
- ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; and
- enzymatic inactivation of tetracyclines.
The MOST important of these is the EFFLUX PUMP.
The pump protein is encoded on a plasmid and may be transmitted by transduction or by conjugation.
- Because these plasmids commonly encode resistance genes for other drugs, e.g., aminoglycosides, sulfonamides, and chloramphenicol, tetracycline resistance is a marker for resistance to multiple drugs.
What are some common toxicities of tetracyclines
- photosensitivity
- Teeth and bone - causes depression of bone growth, permanent gray-brown discoloration of teeth and enamel hypolasia when administered during tooth developement
- Mild GI effects - ESOPHAGEAL ulceration has been reported with doxycylcine - take with lots of fluids
- may exacerbate pre-existing renal dysfunction
- ## Vestibular effects including dizziness, ataxia, and vertigo have been reported with minocycline
Describe the PK of tetracyclines?
usually administered orally
* absorption is incomplete; all should be administered on empty stomach o food or milk decreases absorption by about 20%
- absorption is impaired if coadministered with milk, antacids or iron preps
- doxycycline and minocycline have longer half-lives which permit twice daily dosing
What is the spectrum of activity of tetracyclines?
Gram +ve
* gram positive bacteria including Staph aureus (both MSSA and MRSAdoxycycline and minocycline only). Strep coverage is more unreliable o Again check susceptibilities
Gram –ve
* limited coverage
* Moraxella catarrhalis and H. influenzae are susceptible
* Legionella species
* Brucella spp.
* Vibrio vulnificus (when used synergistically with cell-wall inhibitors)
Anaerobes * some anaerobic activity, but not Bacteroides fragilis
Atypical Pathogens: * Mycoplasma pneumoniae * Chlamydia pneumoniae and Chlamydia trachomatis * Rickettsia spp. (Spotted Fever and Typhus) Others: * parasites (malaria)
