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(oral and parenteral)
- Azithromycin (Zithromax)
- Clarithromycin (Biaxin, Biaxin XL)
- Fidaxomicin (Dificid)- used for C. diff
which macrolide is unstable in gastric acid and must be administered with esters or salts or via enteric coated tablets?
dosing and indication for azithromycin (Zithromax):
- Infections, bacterial [500 mg PO x1 on day 1, then 250 mg PO q24h x4 days] ·
- Pneumonia (same dosing as bacterial infections)
- Notes: azithromycin used for many other indications, including PID, Chlamydial infections
- Azithromycin comes in numerous liquid formulations for a variety of pediatric indications
- azithromycin is also available as an opthalmic preparation (AzaSite for bacterial conjunctivitis)
- Macrolides inhibit protein synthesis.
- They bind the 23SrRNA molecule of the 50S ribosomal unit to inhibit protein synthesis. When the macrolid binds, it inhibits peptidyl transferase. This blocks the the addition of AA to the growing chain.
- Macrophages phagocytose macrolides and deliver them to the site of infection.
macrolide resistance mechanism:
- they are pumped out of some resistant bacteria.
- Some bacteria methylate the portion of the 50S ribosome where the macrolide normally binds. When methylated, the macrolide cannot bind.
- mutation of the portion of the ribosome bound by the macrolide
- Bacteria may produce enzymes that break down the macrolide.
- If a bacterium is resistant to one macrolide, it will be resistant to the others.·
- Do not pick another macrolid if your pt is resistant to one of them
macrolide antimicrobial spectrum.
Gram + bacteria:
- Some streptococcus pyogenes
- Some viridans streptococci
- Some streptococcus pneumoniae
- Some staphylococcus aureus
which antibx's good for staphlococcoxyl but not for MRSA?
narrow spectrums (dicloxicillin)
what does erythromycin lack specificity against?
what is it also used for?
- Haemophilus influenza, so less useful for tx of respiratory infeections
- also used for gastroparesis
which macrolide has somewhat better activity against aerobic Gram+bacteria and H. influenza (gram -) than erythromycin?
and is a semi-synthetic derivative of erythromycin
structure modification allows better:
taken up by:
not distributed into:
- Allows better penetration of some aerobic Gram- bacteria.
- Useful for treatment of H. Influenzae
- Taken up by tissues & slowly released over days( 5 day oral treatment results in 10 days of therapeutic drug levels)
- Not distributed into the CNS
- Has a long half life (68 hours)
- GI (particularly, erythromycin)
- QT prolongation
- Liver impairment
- Erythromycin & Clarithromycin CYP3A4 inhibitors; thus lots of interactions
- Azithromycin dose not inhibit CYP 450.
inhibits bacterial ribosomes, completely synthetic compounds, bacteriostatic
- Linezolid (Zyvox)·
- Limit tyramine food content <100 mg/meal
- Linezolid is bacteriostatic
- Linezolid binds to the 23S rRNA of the 50S ribosomal subunit, preventing binding of the 50S to the 30S subunit.
- It also inhibits protein synthesis by preventing formation of the first peptide bond.
- Mutation of the 23S binding site is a possible mechanism of resistance.
- some Gram negative bacteria such as E. Coli are intrinsically resistant since they possess an efflux pump that pumps out linezolid.
- Weak MAOI--- can cause serotonin syndrome
- High serum levels achieved via either oral or IV route
- GI: N&V, diarrhea
- Thrombocytopenia, anemia and leukopenia
- Serotonin syndrome
- Hyperlactatemia & metabolic acidosis
- Optic neuropathy
spectrum of activity.
used for what type of bacteria:
- Gram +
- Streptococcus pyogenes
- Viridans group streptococci
- Streptococcus pneumoniae
how do you know which antibx to choose?
- Choose treatments based on the infection site, patient's age, antibiotic sensitivities, patient tolerance, cost, etc
Sulfonamides & other folate synthesis inhibitors drugs:
- Sulfadiazine, sulfanilamide; sulfacytine; sulfamethizole
- Topical: silver sulfadiazine; sulfacetamide
- Non-sulfas: trimethoprim; pyrimethamine
- Trimethoprim-Sulfamethoxazole TMP/SMX (Bactrim, Septra, Sulfatrim)
- Sulfisoxazole with erythromycin
- UTI tx/prophylaxis
- Travelers diarrhea (off-label)
- Otitis media in kids but some bacteria resistant
- Humans absorb folate, a precursor to THF from their diet.
- Bacteria cannot do this and must synthesize THF. This bacterial synthetic pathway is a good target for antibiotics
- Sulfonamides are inhibitors of folate synthesis.
- Sulfonamides are competitive inhibitors of PABA, the first reaction in the folate synthesis pathway.
- Trimethoprim blocks the last step in the folate synthesis pathway.
- Inhibiting THF results in reduced DNA synthesis which stops bacterial growth.
- Replication occurs when bacterial enzymes use the chromosome as a template.
- A supply of deoxynucleotides is required.
- Bacteria use a number of pathways to manufacture the deoxynucleotides.
- Tetrahydofolate (THF) is an essential cofactor in several pathways.
Sulfa mech of resistance:
- Metabolized in liver
- Renal excretion§ Oral and parenteral formulations available
- Well absorbed orally
- Precipitation in urine (like crystals)
- Stevens-Johnson syndrome- life threatening, severe burning, blistering
- Kernicterus (contraindicated in patients <2 months)
sulfa anti-microbial activity:
- Gram +:
- Some streptococcus pneumoniae
- Some staphylococci
- Listeria monocytogenes
- works for some gram - too
metronidazole spectrum of activity:
- Anaerobic bacteria and protozoa.
- Bacteroides fragilis·
- Clostridium sp·
- Most other anaerobes
- Small molecule; passively diffuses into bacteria
- Has a nitro group that extends from the core 5-membered ring. This group must be reduced.
- The reduction reaction occurs due to an enzyme called ferredoxin
- As part of their machinery, anaerobic bacteria have electron transport proteins which donate electrons to the nitro group.
- Once reduced, the nitro group is postulated to lead to toxic products that result in DNA breakage and subsequent cell death
metronidazole resistance mechs:
- Some bacteria can live in the presence of very little oxygen (Microaerophiles)
- Others can live with or without oxygen (facultatively anaerobic)
- In these types of bacteria, the genes to produce ferredoxin can be switched off
- If ferredoxin is not produced, metronidazole will not be reduced and will remain inactive
- Formulations include oral, parenteral, topical and vaginal
- Oral metronidazole is extremely well absorbed & results in comparable levels to IV administration
- Dosing adjustment are required for hepatic impairment
- Metallic taste
- Furring of the tongue
- Peripheral neuropathy -- rare
- CNS toxicity, including seizures – rare
- Ethanol: Avoid combination during and for 72 hours after treatment.
- Aldehyde dehydrogenase is inhibited. Causes ace to build up and causes N/V
why should you try not to use the macrolides?
they can have worsen weakness