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)
Clindamycin
Spectrum of Activity
anaerobes
pretty good for Most anaerobes including
► B. fragilis (some resistance)
► Clostridia
► (not C. difficile)
► Actinomyces
other agents such as the penicillin and beta-lactam inhibitor combinationsnas well as the carbopenems
and metronidazole all have more reliable activity for B. fragilis
Other
► Gardnerella vaginosa, Toxoplasma, Pneumocystis jirovecii,
Plasmodia (Malaria)
► All enterococci & Gram negative aerobic bacteria resistant
Clindamycin is particularly noted for its activity in reducing
toxin production by toxin-producing stains of:
S. aureus
S. pyogenes
Useful in the treatment of necrotizing facsciitis due to this effect.
Clindamycin
Pharmacokinetics
dosage form
renal adj?
► palmitate ester orally (rapidly hydrolyzed to active base)
► excellent absorption orally (90%)
► slightly delayed but not reduced with food
► excellent for switch IV/PO therapy (step-down), might be less tolerable orally above 450mg
► phosphate for parenteral use
► well absorbed from IM site (little pain)
good penetration into most tissues (good levels brain, not CSF) (good levels in bone & abscesses) most metabolized in liver (85%) some active metabolites some excreted in urine t1/2 2.4 hr (6 hr in renal failure) *Dosage adjustment not necessary in renal impairment
Clindamycin
Adverse Effects
Nausea
► may limit oral dose
► 450 mg q6h better tolerated than 600 mg q8h
Diarrhea
► up to 20%
► more common with oral
Pseudomembranous Colitis (C. diff infections) ► 0.01-10% (not dose related) ► may occur more commonly after oral or parenteral therapy than other antibacterials
Allergic Reactions
Rashes (10% may develop maculopapular rash, fever)
rarely anaphylaxis
Hepatotoxicity
↑ transaminases - reversible
hepatocellular damage – rare
Neutropenia, Thrombocytopenia, & Agranulocytosis
reversible, rare, ? unrelated
Clindamycin
Drug Interactions
► may be antagonism between macrolides and clindamycin
► may enhance the effects of neuromuscular blocking agents
► may decrease effect of cyclosporine
Tetracyclines
4 cyclic rings
shorti acting vs long acting ones
MOA read
short aciting: tetracycline
long acting: doxycylcine, minocycline
Tetracyclines Resistance
- decrease influx or has efflux pump
- raely inactivated or chem altered by bac
- resistance to 1 = all
problem widely in animal feed for growth promo
Tetracyclines Spectrum of Activity
S. aureus (all) 96% 2019 (97% 2016)
MRSA 95% 2019
S. pneumoniae 82% 2019 (77% 2016)
H. influenzae, M. catarrhalis
No longer reliable against Enterobacterales
Not reliable against anaerobes (doxycycline best)
Active against Stenotrophomonas maltophilia
Intracellular organisms and atypical organisms
Chlamydiae, Mycoplasma, Legionella
Rickettsiae (Rocky Mountain Spotted Fever)
Helicobacter pylori
Spirochetes - Borreliella burgdorferi, Treponema pallidum
Vibrio cholera, Protozoa (e.g., Plasmodium (malaria))
Actinomycetes, Brucella
tetracycline Absorption
longer acting = more lipophilic better abs
dec absorbtion with multivalent cations or food
reduced 30-50% with food, 50-60% milk
mino, doxy can be taken with food (20% reduction with dairy pdts)
space with antacids, supplements as tetra can bind and prevent absorption
tetracycline
Distribution / Excretion
readily cross fetal tissue and breast milk
time-dependent illing
tetra AE
photosensitivity - red rash to exposed areas (toxic effect)
-pigmentation of skin, nail,gums, thyroid (Rare prodlonged use)
- hypersenstitivity, urticaria, periorbital edema, rashes - not common
oncycholysis - separtion of fingernal from skin underneath
tetra AE
teeth and bones
if taken during preg
fetal fx: yellow-brown discolouration, hypoplasia of tooth enamel, depression of skeletal growth in infants (irreversible?)
avoid in preg women and children up to 8 yrs
- rocky mt spotted fever (only tx avail
- doxy is safest and binds less to calc
❑ Found no difference in tooth shade or weakening of
tooth enamel between children who had received a
short course of doxycycline and those not
Best evidence to date – short courses doxycyline do
not cause dental staining in children < 8 yrs of age
tetra hepatotox
renal tox
all tetra given IV, largele with logn term use of minocycline
use in renal failure/preg, fine droplet fattty metamorphhosis
renal tox:
- increase azotemia in pt w/ renal failure
- fanconi-like syndrome w/ old out-dated tetra pdts - unlikely now
- nephro diabetes insipids wih demeclocyline (used to treat SIADH)
tetra GI fx
immune-mediated AE
esophageal ulceration (take /w/ glass of water in upright position not just before bed - important that bedridden pt propped up diarrhea - alteration in bowel flora
immune mediated
2 form of liver injury:
acute hepatitis like syndrome
chronic hep like synd (serum enzyme elevations0
Immune-Mediated
Adverse Events - Minocycline
❑ Chronic liver disease with or without jaundice typically
occurs after long-term use
❑ Automimmune chronic hepatitis syndrome is the most
common presentation
❑ Can be severe and fatal if not stopped promptly
❑ Usually present acutely ~ 6 months – after many
years of therapy, with jaundice, fatigue, joint aches
❑ Autoantibodies usually present, ANA titres > 1:160
❑ May respond with drug withdrawal ± corticosteroids
❑ Some require transplant, some fatalities
other tetra AE
superinfection: oral or vaginal candidiasis, staph, diarrhea
black hariy tongue
mino - vertigo mroe common in women
Glycylcyclines (Tigecycline)
5 fold greater binding to ribosome
active against resistant strains carrying efflux pump and ribosomal protection proteins
no resistance currently
Tigecycline
spectrum
MSSA, MRSA, MSSE, MRSE
strep including PRSP
entercocci both including *VRE
G- : H. influ, E. coli, Klebsiella, enterobacter, acinetobacter
B. fragilis - one of few drugs against NDM-1
producing organisms
poor against P. aerug
Tigecycline – Original Indications
pt >18 yes complicated skin and soft tissue inf complicated intra-abdominal inf CAP only IV
FDA Drug Safety Communication
Increased Risk of Death
Tigecycline
ISSUE: higher risk of death among patients receiving
Tygacil compared to other antibacterial drugs:
❑ 2.5% (66/2640) vs. 1.8% (48/2628), respectively
❑ adjusted risk difference for death 0.6% (95% CI (0.0% - 1.2%).
❑ deaths resulted from
❑ worsening infections
❑ complications of infection, or
❑ other underlying medical conditions.
Health care professionals should reserve Tygacil
for use in situations when alternative treatments
are not suitable.
