Macrolides, Clindamycin, and Tetracyclines Flashcards
Macrolides
Mechanism of Action
binds reversibly to 50S ribosomal subunit
inhibits RNA-dependent protein synthesis
appears to compete for the same binding site as
clindamycin and chloramphenicol
erythromycin out of favor, clari, azithro more used
susceptibility reports might be for erythro but it can be used for the others too
how easy is it for macrolide resistance to occur?
placebo vs macrolides
early resistance compared to placebo
not used empircially for coverage of strep pneumoniae
macrolide Development of Resistance
1,2
moset clinically improtnat
*1) Active Efflux
(Staphylococci, S. pyogenes, S. pneumoniae)
results in M phenotype with cross-resistance between all 14 and 15 membered ring macrolides
The most frequent resistance phenotype
*2) Ribosomal Methylation
Gene responsible for methylation of the 50S ribosomal subunit (erm gene) is transmitted through a plasmid or transposon
methylation of 23S ribosomal RNA of the 50S ribosomal subunit (inducible)
(cross resistance with other macrolides (M), lincosamides (L), and Streptogramin B (SB), (MLSB phenotype)
most widespread mechanism of resistance to the macrolides
macrolide Development of Resistance
3,4,5
3) Alteration of 50S ribosomal subunit by chromosomal mutation (S. aureus, S. pyogenes, E.coli) → occasionally resistance to other macrolides and clindamycin
4) Enzyme inactivation (Enterobacterales)
5) ↓ Permeability of cell wall (
Usually cross-resistance to all macrolides.
macrolide spectrum of activity S. aureus s. pmneumoniae S. pyogenes Grp B strep
S. aureus
UAH 2017 MSSA 23%R (Dynalife not reported 2010 - 2018)
UAH stopped reporting in 2018
S. pneumoniae - increasing resistance – Edmonton Community
(15% 2006), 27% 2018 , 17% 2019
S. pyogenes
(2006 24%) UAH 2017 31% R, 2019 9% R
Grp B Streptococci (56% 2011), 48% R 2017
(poor activity against Enterococci)
(Listeria monocytogenes, Corynebacterium diptheriae –> unusal to use for this)
macrolide Spectrum of Activity
anaerobes
H. influenzae ranking?
Anaerobes
Many oral anaerobes
not active against B. fragilis, gut
Other
Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae
Moraxella catarrhalis
Bordetella pertussis
Campylobacter jejeuni
Ureaplasma urealyticum, some C. trachomatis,
Borreliella burgdorferi only if intolerant of 1st line treatment
only poor activity against H. influenzae
“Macrolides generally have poor / no activity against H. influenzae”
Azithromycin > Clarithromycin > Erythromycin (generally still quite poor)
Clarithromycin (Biaxin)
Spectrum
***Resistant staphylococci and streptococci resistant to erythromycin are also resistant to clarithromycin & azithromycin
Clarithromycin and azithromycin also active against
Mycobacterium avium (and other non-tuberculous
mycobacteria) (erythromycin not active against these organisms)
H. pylori in combination (clari 30x more potent than azi)
e.g., with PPI, amoxicillin, & metronidazole
Clarithromycin (Biaxin)
Pharmacokinetics
dosage form?
renal dose adjustment?
absorbed well, acid stable, may be taken with food
wide tissue distribution (including distribution into macrophages and polymorphs – “improved activity” against M. pneumoniae, C. pneumoniae)
predominantly metabolised by the liver (CYP 450 3A4)
14-hydroxy metabolite is active and synergistic with
clarithromycin
30 - 40% excreted renally
(decrease dose if CrCl < 30 ml/min)
t1/2 4.5 hr
BID dosing
Clarithromycin
Adverse Effects
GI - nausea (4%), diarrhea (3%), abdominal pain (2%), dyspepsia (2%), vomiting (1%), taste disturbance (1%)
Liquid tastes terrible and sand-like
transient hearing loss with high doses
many drug interactions
fetal abnormalities in animals (cardiovascular, cleft palate,
fetal growth retardation)
***(Category C in pregnancy)
tooth discoloration reported (may be removed by dental cleaning)
Increased QTc interval Eryth>Clarith>Azith
Azithromycin
dosage form
Tablets and Suspension may be given with food
Distributed extensively to the tissues
(tissue levels up to 50 X those of plasma)
Concentrated inside macrophages and PMNs
Blood levels low (caution when using for pneumococcal pneumonia which is associated with risk of bacteremia / septicemia)
??? Increased risk antibacterial resistance
Concern due to prolonged low concentrations
Azithromycin
renal dosage adjustment?
little metabolized by the liver, excreted in bile and faeces
only 6% eliminated in urine
Dosage adjustment not required in renal impairment
terminal t1/2 68 hours
Usually dosed once daily for 3-5 days
well tolerated - side effects similar to clarithromycin
Appears to be safe in pregnancy (Risk factor B)
Macrolides
Drug Interactions
Many, Many, Many with erythromycin and clarithromycin, but
not azithromycin
Metabolites of erythromycin and clarithromycin form inactive complexes with CYP 3A4 resulting in inhibition of CYP 3A4
May result in increased levels and toxicity with other drugs metabolized by CYP 3A4
Azithromycin does not have this effect
increased effects of statins -> temp stop statin until finish macrolide for primary prevention and distant secondary prevention
modify tx for DOAC’s?
Lincosamides
Clindamycin
clindamycin has much improved activitythan lincosamide
Clindamycin
Resistance
1) *Alteration of 50S ribosomal receptor site
(cross-resistance with macrolides)
2) *Alteration of 23S ribosomal RNA of 50S ribosomal subunit
(Plasmid mediated MLSB
- S. aureus, B. fragilis)
3) Enzyme inactivation (adenylation of lincosamide by
staphylococci (decreased activity of clindamycin)
4) Intrinsic resistance with Enterobacterales, Pseudomonas
Clindamycin
Spectrum of Activity
G+
Staphylococci ❑ S. aureus (All) 81% 2019, (79% 2014) ❑ MRSA 80% 2019, (62% 2011) ❑ CoNS 54% 2012, 67% 2011 Streptococci --? much better than macrolides against strep ❑ S. pyogenes 88% 2019, (93% 2011) ❑ S. pneumoniae 87% 2019, (79% 2011) ❑ (not Enterococci)
