Post on 21-May-2020
Macrolides
• erythromycin
• clarithromycin (Klacid, Karin, Klaridex)
• roxithromycin (Rulid, Roxo)
• azithromycin (Azenil, Zeto) [an Azalide]
1
Macrolides
reversible binding to 50S ribosomal subunit
Mode of action
protein-synthesis inhibition
(chain elongation phase)
release of RNA-building
enzyme from ribosome
reduction of 50S
subunit synthesis
ribosomal
channel blockade
erythromycin in red
2
roxithro clarithro azithro erythro
50% 50% 38% 18-45% absorption
85-96% 76% 7-50% 75-90% protein
binding
(hepatic) hepatic hepatic (35%) hepatic metabolism
12hr 5-7hr 68hr 2hr T1/2
7-12% 20-40% 5-12% 2-15% renal
excretion
53% fecal
13% pulmonary 19% fecal 50% fecal
Fecal
(major) other
excretion
Macrolides
PK parameters
3
Macrolides
practical macrolides sub-classifications
clarithro
roxithro
azithro
erythro ADEs
roxithro
azithro
erythro
clarithro DDIs
clarithro
azithro
erythro
roxithro Spectrum
4
• GI
Macrolides
• cholestatic hepatotoxicity
• hearing loss (reversible)
• ventricular arrhythmia
ADEs - erythromycin
• as for erythro, milder, less frequent
ADEs - newer macrolides
5
• CYP450-3A4 inhibition - ↑ levels of:
Others: theophylline, cyclosporin, carbamazepine,
valproate, triazolam, pimozide, clozapine, warfarin,
colchicine, sildenafil, bromocriptine
Macrolides
Calcium-Channel Blockers (diltiazem, verapamil)
Statins (simvastatin, lovastatin, atorvastatin - ↑40%)
DDIs - erythro+clarithro
6
• CYP450-3A4 substrates - ↑ levels by:
Others: nefazodone, cimetidine
Macrolides
Calcium-Channel Blockers (diltiazem, verapamil)
Nitro-imidazoles (keto-/flu-/itra-conazole)
DDIs - erythro+clarithro
7
anti-arrhythmics:
• Additive pro-arrhythmic effect
Macrolides
other drugs with pro-arrhythmic potential:
- thioridazine, some quinolones, …
- [H-1 blockers (astemizole, terfenadine)]
DDIs - erythro+clarithro
8
Ray WA et al; NEJM 2004; 351(11):1089-1096
Oral erythromycin and the risk of sudden death
from cardiac causes
• retrospective evaluation of 1476 cases of
sudden cardiac death
Macrolides
concomitant erythro+CYP-3A4 inhibitors: OR~5
DDIs - erythro+clarithro
erythro use: OR~2
9
• digoxin: ↑ levels (40-110%)
Macrolides
alteration of GI flora
inhibition of P-glycoprotein
DDIs - erythro+clarithro
10
• Al/Mg antacids ? [azithro] (stagger)
Macrolides
• avoid thioridazine
• no clinically significant CYP450 effects
DDIs - azithro+roxithro
11
Macrolides
Anaerobic: weak (B. fragilis usually resistant)
Atypical: Mycoplasma, Chlamydia, Legionella
Gram positive: susceptible Strep., [MSSA]
Gram-negative: Neisseria, H. influenza, M. catarrhalis
Enterobacteriaceae - generally resistant
Antimicrobial spectrum - azithromycin
12
X
X
X
• MAC infections (in combination)
Macrolides
Chlamydia trachomitis (single-dose SR azithro 1g)
Clinical use - azithromycin
• RTIs (Strep. pneumonia, atypical, Legionella)
• Chlamydial infections (respiratory, ocular, genital)
• alternative in penicillin allergy
13
Tetracyclines
• tetracycline (1st generation, short-acting)
• doxycycline (2nd generation, long-acting)
• minocycline (2nd generation, long-acting)
14
2nd vs. 1st generation
Antimicrobial spectrum
PK
ADEs
Tetracyclines
Trans-membranal penetration
Blockade of aminoacyl-transfer RNA binding
Binding to 30S ribosomal subunit
Bacteriostatic effect
Chain elongation inhibition
Mode of action
15
mino doxy tetra
95% 93% 75% absorption
76% 93% 60% protein binding
to inactive 50% (liver) poor (liver) metabolism
16hr 18hr 8hr T1/2
6% 40% 60% renal excretion
19% fecal 30% fecal 40% fecal other excretion
PK
Tetracyclines
16
hypersensitivity
pigmentation (prolonged use)
photosensitivity
Tetracyclines
• Dermatologic:
ADEs
tetracycline-related
onycholysis 17
irreversible
primary teeth
Tetracyclines
• Teeth discoloration
low probability in single, short-term course
less frequent with doxy
contraindicated in pregnancy and <8yr (12)
ADEs
18
Tetracyclines
irritation (PO)
• GI
ADEs
nausea, vomiting
tetra>doxy, mino
19
stagger
Ca/Fe/Mg/Al-containing foods and drugs
Tetracyclines
• divalent cations - complexation
DDIs
20
resistance
• original broad-spectrum presently limited by
intolerance
Tetracyclines
• generally similar within group
Antimicrobial spectrum
21
Atypical Aerobic Gram-negative Aerobic Gram-positive
- Chlamydia spp.
- Mycoplasma spp.
- Rickettsia spp.
- Campylobacter spp.
- Helicobacter pylori
- Moraxella catarrhalis
- Propionobacterium spp.
- Legionella pneumophila
- Strep. pneumonia
• limited anaerobic activity
Tetracyclines
• doxy:
Antimicrobial spectrum
22
• RTIs (Strep. pneumonia, atypical, Legionella)
• Various Chlamydial infections
• Acne (moderate to severe)
• Malaria prophylaxis
Tetracyclines
Clinical use
• Uncomplicated UTIs (E.coli, susceptibility, allergy)
23
Rickettsial diseases (Q-fever, Rickettsial pox,
Rocky-Mountain Spotted Fever)
Lyme disease (Borrelia burgdorferi)
• Various uncommon infections:
Tetracyclines
Clinical use
24
25
L-threo-alpha-D-galacto-
octopyranoside, methyl 7-chloro-
6,7,8-tricleoxy-6-[[(1-methyl-4-propyl-
2-pyrroliclinyl)carbonyl]amino]-thio-,2-
dihydrogen phosphate,(2S-trans)
Group: Lincosamides
• Dosage forms:
capsules (HCl)
injection (phosphate)
topical/vaginal
Clindamycin
26
[Chain elongation inhibition in protein synthesis]
Clindamycin
• Similar to macrolides
Mode of action
• Usually bacteriostatic
27
• Distribution: wide (not to CSF), 90% bound
• Metabolism: hepatic (active metabolites)
• Excretion: combined urinary/biliary
• t1/2~2.5hr
Clindamycin
• Absorption: 90%
PK
28
diarrhea (20% after PO)
CDI
Clindamycin
• GI
ADEs
• neutropenia, thrombocytopenia
• hypersensitivity
• LFT (mild)
- none significant (QT elongation?) DDIs
29
many Gram-positive
X inactive vs. Gram-negative
(inactive vs. MRSA, Enterococci)
most anaerobes
Clindamycin
• some protozoa (Toxoplasma, P. falciparum)
Antimicrobial spectrum
30
• Gram-positive and/or anaerobic pathogens
• alternative for β-lactam hypersensitivity
• bacterial vaginosis, acne (topical)
Clindamycin
Clinical use
31
Group: Nitroimidazoles
• Dosage forms:
tabs, susp.
injection
topical/vaginal
Metronidazole
32
Nitro group reduction
Cytotoxic effects of reduced product and/or free radicals:
DNA structure interruption, protein synthesis inhibition
Cellular death
(bactericidal
Cell penetration
Metronidazole
Mode of action
33
• Absorption >90%
• Metabolism: hepatic, >5 metabolites (30-60%)
• Excretion: unchanged, urinary : 20-40%,
biliary: 6-15%
• T1/2~8hr
• Distribution: wide to tissues and cells, CSF
Metronidazole
PK
34
• CNS
gynecomastia
• other:
Metronidazole
ADEs
• GI (12%)
urine discoloration
rash
35
protozoa - T. vaginalis, Giardia lambia
anaerobic - Bacteroides spp. and other
Metronidazole
• Gram-negative - H. pylori only
X Gram-positive - none
Antimicrobial spectrum
1959
36
• empiric anaerobic coverage (in combination)
• Tx of protozoal and anaerobic infections
• H. pylori eradication (protocol)
Metronidazole
• Clostridium difficile infection (1st/2nd line?)
Enterocolitis
Clinical use
37
DRUGS FOR EXAM
• azithromycin
• doxycycline
• clindamycin
• metronidazole