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