Lecture 5 - Macrolides, Tetracycline, & Tigecycline Flashcards
Drugs that are considered Macrolides
Erythromycin
Clarithromycin
Azithromycin
Fidaxomicin
Erythromycin MOA
Protein synthesis inhib, bacteriostatic
Inhibits RNA-depended protein synthesis at the step of chain elongation
Which part of ribosome does Erythromycin bind?
Binds to 23S ribosomal RNA component of 50S subunit of bacterial ribosome at the peptide exit tunnel
Erythromycin Gram + activity
Limited staph coverage due to resistance
some activity against strep, but growing resistance for S.pnemoniae
No activity against enterococci
Erythromycin Gram - activity
- campylobacter jejuni
- Coxiella burnetti (Q fever)
- Bordetella pertussis (whooping cough)
- Moraxella catarrhalis
- No activity agent Enterobacteriaceae or non-fermenters
Erythromycin Anaerobic activity
(-): moderate, including Prevotella
(+): better activity, including Actinomyces, P/C acnes, Lactobacilli, Clostridium spp, and Peptostreptococci
Bacteroides Fragilis & Clostridiodes difficile are resistant
Erythromycin Atypical Bacteria uses
Usually used as an add on
active against most Atypical except Mycoplasma genitalium***
Myco. Tuberculosis is resistant
Erythromycin GI issue
- In low pH enivocnoment (stomach), erythromycin is degraded to an inactive intermediate that is associated with GI adverse effects associated with its use
Has DDI due to ABCB1
Erythromycin metabolism & excretion
- All macrolide are lipophilic and widely distributed in blood and tissues
- Conc in tissues is 50X those found in plasma
3, substrate of SLCO1B1 and SLCO1B3 for uptake into hepatocytes
Erythromycin DI
Inhibits CYP3A4
Inhibits P-gp & ABCB1
QTc prolongation
Erythromycin ADR
- *** Ototoxicity in large doses
- **QT prolongation (whole macrolide class)
GI, allergic reactions
Clinical uses of Erythromycin
Most frequently used for its motility effects = due to its GI effects
other macrolides are better with less SE/DI
Clarithromycin vs Erythromycin
It has similar coverage but better tolerance and SE
Clarithromycin Gram + Activity
2-4 fold more active than Erythromycin against most strep, including S.penumoniae (growing resistance) , S.pyogenes, MSSA(but not drug of choice).
Most staph resistent to macrolides
No activity against Enterococci
Clarithromycin Gram - activity
- campylobacter jejuni
- Coxiella burnetti (Q fever)
- Bordetella pertussis (whooping cough)
- Moraxella catarrhalis (slightly more than Erythromycin)
- No activity agent Enterobacteriaceae or non-fermenters
Clarithromycin Anaerobic bacteria
Not as active against Actinomyces
(+):P/C acnes, Lactobacilli, Clostridium spp, and Peptostreptococci
Bacteroides Fragilis & Clostridiodes difficile are resistant
Clarithryomycin Atypical Bacteria activity
Active against most Atypical except Mycobacterium Genitalium
useful against CAP
1 of main drugs against Mycobacterium
Drugs that work against M.abscessus
Azithromycin and Clarithromycin
Clarithromycin PK properties
More acid-stable than erythromycin and is not degraded as extensively in the stomach
Also affects ABCB1 = DI
Clarithromycin Metabolism & Excretion
- Lipophilic and widely distributed in blood tissues
2. thought to undergo metabolism by CYP3A4 in liver & inhibits CYP3A4, leading to similar DI as erythromycin
Clarithromycin ADR
Rare: Mania, Ototoxicity = large dose, QT prolongation
Clarithromycin DI
Inhibits CYP3A4
Inhibits P-gp, ABCB1, OATP1B1/B3
QTc prolongation
Clarithromycin Clinical uses
combo with amoxicillin or metronidazole and a PPI for H.pylori (1st line)
Mycobacterial infections
Bartonella spp.
Pertussis
Azithromycin Gram + activity
Less active against S.pneumoniae & S.pyogenes than erythromycin
no activity against Enterococci
some activity against strep, but growing resistance
Azithromycin Gram - activity
Most common macrolide used
more active, especially in H.influenzae & M. catarrhalis
- campylobacter jejuni
- Coxiella burnetti (Q fever)
- Bordetella pertussis (whooping cough)
- Moraxella catarrhalis
- N.gonorrhoeae
Questionable activity in Enterobacteriaceae
No activity in non-fermenters
Azithromycin Anaerobic bacteria
Not as active against Actinomyces
(+):P/C acnes, Lactobacilli, Clostridium spp, and Peptostreptococci
Bacteroides Fragilis & Clostridiodes difficile are resistant
Drugs for Mycobacteria
Azithromycin & Clarithromycin have activity against M. avian complex, but Clarithromycin is 4X more active
Azith usually used for prophylaxis
Both have activity against M.abscessus
Azithromycin Atypical Bacteria Activity
greater activity than Erythromycin against Ureaplasma urealyticum & Chlamydia Trachomatis
more active against Legionella pneumophilia and M. pneumoniae
Azithromycin PK properties
more acid-stable than Erythromycin, resulting in longer serum 1/2 life and increased conc in tissue
absorption limited in intestine by P-gp transporters
Azithromycin Metabolism & excretion
lipophilic and widely distributed in blood and tissues
doesn’t interact with SLCO1B1/B3 and doesn’t inhibit CYP3A4 activity
Most excreted unchanged in bile = hepatic
Azithromycin ADE
GI > 10%
Rare: Elevated LFTs, ototoxicity = high dose, QTc prolongation
Azithromycin Clinical uses
CAP (L.pneumophila, C.pneumoniae, M. pneumoniae
Infectious Diarrhea : Campylobacter jejune
STI: Chalmydia trachomatis
Mycobacterial infections
Pertussis
Bartonella spp.
Fidaxomicin MOA
Baactericidal
Bacterial RNA polymerase inhibition at transcription initiation
Fidaxomicin Spectrum of activity
Only clinically used for C.difficile
Fidaxomicin Metabolism & Excretion
excreted almost entirely through the feces
oral form minimally absorbed via GI
Does Fidaxomicin have DI
nah
Fidaxomicin ADR
GI = nausea, abdominal pain, vomiting, GI hemorrhage
some hypersensitivity - rare
Fidaxomicin clinical uses
used for C.difficile
Vancomycin is used 1st, and then consider this drug
Tetracyclines
Tetracycline Doxycycline minocycline Omadacycline Eravacycine
Tigecycline
Tetracycline MOA
Protein synthesis inhibitor
Bacteriostatic
Where are the Tetracycline binding sites
Binding sites on the 30S subunit of the 70S ribosome (primary = Tet1) and secondary (Tet2)
1st gene Tetracycline
Tetracycline
Tetracycline Gram + activity
Worst activity out of all Tetracyclines
some against MSSA
Limited against Streptococci, including Group A/B
Limited activity against Enterococci
Tetracycline Gram - activity
Vibrio Cholerae = cholera
1st line H.pylori (w/ bismuth, PPI, Metronidazole)
Tetracycline Anaerobic bacteria activity
has some against Gram +/-
B.Fragilis has resistance
None against C.diff
Tetracycline Activity Atypical Bacteria
good activity against most that cause urogenital infections and those that cause CAP
reduced activity against M.genitalium
Tetracycline Metabolism & Excretion
eliminated primarily in the kidneys, about 30-60% of oral dose is excreted in urine and 20-60% in feces
Tetracycline adverse effects
GI = most common
Teeth & bone deposits = reasons why avoided in meds
Photosensitivity and Hyperpigmentation
Tetracycline DI
Food: Reduces absorption by 50%, dec iron absorb, calc dec tetracycline con
CYP3A4 inducers = reduce conc of it
CYP3A4 inhibitors = inc conc of it
Interacts with Vit K
Tetracycline Clinical uses
1st line for H.pylori w/ metronidazole, bismuth, PPI
Treatment of cholera (Vibrio cholerae)
2nd Gen Tetracyclines
Doxycycline
Minocycline
Doxy & Mino Gram + activity
** improved activity against Staph, including MSSA/MRSA
Less active against Streptococci, including Group A/B
Limited activity against Enterococci
Doxy & Mono Gram - activity
Limited enterobacteriaceae coverage
mino has broader activity against MDR Gram - organisms (stenotrophomonas and acinetobacter)
Doxy is preferred agent for what infections
Borrelia burgdorgeri = Lyme disease
Yersinia pestis = Black Plague
Ehrlichia spp, Anaplasma spp. = tick borne disease
R.ricketsii = Rocky Mountain spotted fever
Doxy & Mino Anaerobic bacteria activity
Similar activity against Gram +/- anaerobes
C.diff = no activity
B.fragilis has resistance
Doxy & Mino Atypical Bacteria Activity
good activity against most that cause urogenital infections and those that cause CAP
reduced activity against M.genitalium
Doxy & Mino Metabolism & Excretion
Less than 30% of doxy is renally excreted
Mino extensively metabolized in liver, only 4-19% eliminated by kidneys
Mino specific rare Adverse effects
Neurotoxicity
Hypersensitivity reactions
Mino/Doxy common adverse effects
GI
Teeth & bone deposits
Photosensitivity & Hyperpigmentation
Doxy & Mino DI
Food: absorption reduced ~20% when w/ food or milk
Tetracycline dec absorption of iron
Ca dec conc of tetracyclines
Drug:
PPIs decrease bioavailability of doxy
other:
Vitamin K
Drugs that can decrease conc of doxy
Carbamazepine
Phenytoin
fosphenytoin
Doxy & Mino clinical uses
Doxy:
CAP, Travelers poop, Urogenital infections, tick borne disease, bioterrorism
Mino:
Acne, MDR Stenotrophomonas & Acinetobacter
3rd gen Tetracyclines
Tigecycline = IV Omadacycline = Oral Eravacycline = IV
3rd gen Tetracyclines Gram + activity
improved against all Gram +
Great S.aureus, MSSA,MRSA coverage
improved Streptococcal coverage
improved activity against Enterococci, including VRE
3rd gen Tetracyclines Gram - activity
sig improved coverage of Enterobacteriaceae
improved activity against MDR Acineto-, Stenotrop-
3rd gene Tetracyclines Anaerobic bacteria activity
less B.fragilis resistance
some activity against C.diff
no activity against actinomyces
3rd gene Tetracyclines Atypical bacteria
activity against Mycobacteria
Atypical bacteria similar for CAPs, reduced against C.trach, U.ureal, M.genit
Eravacycline M&E
1/2 life is 20hrs
~34% urine ~46% poop
Tigecycline M&E
1/2life ~27-67hrs
excreted 59% poop, 33% urine
Omadacycline M&E
1/2life ~16hrs
food decreases rate/extent of absorption
excretion mostly through poop
Tigecycline GI sideeffects
Diarrhea
vomiting
heartburn
Omadacycline GI sideeffects
Nausea
Heartburn
Omadcycline DI
Substate: P-gp, ABCB1
Food: serum lvls may dec if taken w/ high fat meal or dairy, separate by 4hrs and avoid food/drink for 2hrs after
Eravacycline DI
substrate: CYP3A4 minor
Tigecycline DI
none
Omadacycine uses
oral options for infections caused by MDR Gram -
M.abscessus infections
Eravacycline & Tigecycine Clinical uses
MDR Stenotroph/Acinetobac
if need gram +/- coverage (intra-abdominal infections)
Add on therapy in severe C.diff
