Dec 17, 2015

C A
R

GI SE
No Effect on H. Influenza
Bad Compliance

Cephalosporin

Erythromycin

Bridges the gap between

H. Influenza Resistance
S. Pneumonia resistance
No Coverage on A typical Infections

Mechanism of Antimicrobial Activity

Mechanism of Action
Inhibits protein synthesis by reversibly binding to the 50S
ribosomal subunit
Suppression of RNA-dependent protein synthesis
Macrolides typically display bacteriostatic activity, but
may be bactericidal when present at high concentrations
against very susceptible organisms
Time-dependent activity

Dec 17, 2015

Spectrum of Antibacterial Activity

Macrolides are effective against most of the G(+) bacteria, cocci
or bacillus, they have antibiotic activity against G(-) cocci
,especially Neisseria Spp too.
Macrolide antibiotics are effective against Mycoplasma,
Clamidia, Campylobacter and Legionella in contrast to
penicillins.
They are less effective against G(-) bacteria, though some strains
of H. influenza and Brucella are sensitive to the antibacterial
activity of this class of antibiotics.

Dec 17, 2015

Macrolides
Pharmacology
Distribution
Extensive tissue and cellular distribution clarithromycin
and azithromycin with extensive penetration
Minimal CSF penetration
Elimination
Clarithromycin is the only macrolide partially eliminated
by the kidney (18% of parent and all metabolites); requires
dose adjustment when CrCl < 30 ml/min
Hepatically eliminated: ALL
NONE of the macrolides are removed during hemodialysis!
Variable elimination half-lives (1.4 hours for erythro; 3 to 7
hours for clarithro; 68 hours for azithro)
Dec 17, 2015

Indication & Usage

Indication

Causative Pathogen

Class

Pharyngitis/Tonsillitis

Streptococcus pyogenes

G+

Acute maxillary sinusitis

H. influenzae,
G Moraxella catarrhalis
G Streptococcus pneumoniae G +

Acute bacterial exacerbation of

chronic bronchitis

H. Influenzae
H. parainfluenzae
Moraxella catarrhalis
Streptococcus pneumoniae

Acute Otitis Media

Haemophilus influenzae
G Moraxella catarrhalis
G Streptococcus pneumoniae G+

Dec 17, 2015

GG GG+

Indication

Causative Pathogen

Class

Community-Acquired Pneumonia

H. Influenzae,
Mycoplasma pneumoniae,
Streptococcus pneumoniae
Chlamydia pneumoniae (TWAR)

G
Others
G+
Others

Uncomplicated skin and skin

structure infections

Staphylococcus aureus
Streptococcus pyogenes

G+
G+

Disseminated mycobacterial
infections

Mycobacterium avium,
Mycobacterium intracellulare

Others
Others

Active duodenal ulcer

(Peptipac)

Associated with H. pylori

Others

Dec 17, 2015

Klaricare: approved FDA recommended doses / indication

Indication

Morning

Evening

Duration of
treatment/day

Acute bronchitis

250 mg

250 mg

AECB / COPD

500mg

500mg

7-14

CAP

250-500mg

250-500mg

7-14

Acute maxillary
sinusitis

500mg

500mg

14

Tonsillitis /
pharingitis

250mg

250mg

10

Dec 17, 2015

AECB: Acute Exacerbation of Chr. Dis.

COPD: Chronic Obstetr. Polm. Dis.
CAP: Community Acquired Pneumonia

ADULT DOSAGE GUIDELINES for

KLARICARE XL

Infection

KLARICARE XL Tabs
Dosage (q24h)

Duration (Days)

H.influenzae

2 x 500mg

14

M.catarrhalis

2 x 500mg

14

S.pneumoniae

2 x 500mg

14

Acute maxillary sinusitis

due to :

24/1/2012

ADULT DOSAGE GUIDLINES

Infection

KLARICARE XL Tabs
Dosage (q24h)

Duration (Days)

H.influenzae

2 x 500 mg

H.parainfluenzae

2 x 500 mg

M.catarrhalis

2 x 500 mg

S.pneumoniae

2 x 500 mg

Acute exacerbation of
chronic bronchitis due to:

24/1/2012

10

Clarithromycin ER tablets
Trade name : KlaricareXL500 .

Active ingredient :Clarithromycin 500mg/tab.

Dosage form : 7 Extended Release Tablets.
Price : 40 NIS .
24/1/2012

11

Drug Interaction
Drug

Interaction

Theophylline

Increases of serum theophylline concentrations

Verapamil

Hypotension, bradyarrhythmias, and lactic acidosis

Carbamazepine

Increased plasma concentrations of carbamazepine.

Terfenadine

Terfenadine were threefold higher

Dec 17, 2015

12

M, Gotfried, TA, Busman, S, Norris, & GF, Notario, (2007), Role

for 5-day, once-daily extended-release clarithromycin in acute
bacterial exacerbation of chronic bronchitis. Curr Med Res
Opin. 2007 Feb;23(2):459-66
clarithromycin
ER
The clinical cure rate

clarithromycin IR

90%

90%

Bacteriological cure rate 92%

93%

Abdominal pain

1.7%

0.2%

A once daily, 5-day clarithromycin ER regimen appears to be a suitable choice

for treating patients with ABECB.

Effects of macrolides for the treatment of

chronic airway diseases
Antibacterial

Respiratory infection

Nonantibacterial

Anti-inflammatory

Chemotaxis
Cytokine production
ROS production
Adhesion molecule expression

Antisecretory

Mucus secretion
Chronic airway inflammation
Chronic airway hypersecretion
Disease-modifying benefits

Summary of effects of macrolides relevant

to respiratory tract inflammation
Inhibit synthesis and/or secretion of proinflammatory
cytokines
Effects on neutrophils
Decrease neutrophil oxidative burst
Inhibit neutrophil migration (chemotaxis) to inflammatory sites
Increase apoptosis of neutrophils
Neutrophil degranulation
Inhibit neutrophil adhesion
Inhibit phagocytosis
Decrease eosinophilic inflammation
Increase mucociliary transport
Reduce goblet cell secretion
Decrease bronchoconstriction (decrease endothelin-1
release, inhibit cholinergic responses of airway smooth
muscle)

RSV Facts
Most common cause of
bronchiolitis & pneumonia in
children under 1
25-40% of children develop
bronchiolitis or pneumonia
during first RSV infection
31/1,000 under 1 yr. are
hospitalized with RSV
2% will die

Dec 17, 2015

16

Pathogenesis
Bronchiolitis
Virus induced necrosis of bronchioloar epithelium
Hypersecretion of mucous
Round cell infiltration and edema of the surrounding
submucosa

Dec 17, 2015

17

Clarithromycin in the treatment of RSV Bronchiolitis: a double

blind ,randomised placebo controlled trial
Eur Respir J 2007; 29: 9197

STUDY OBJECTIVES:
to investigate the efficacy of clarithromycin in
the treatment of RSV bronchiolitis.
- 3weeks treatment

RESULTS
Primary end points

Dec 17, 2015

19

RESULTS
Primary end points

Dec 17, 2015

20

RESULTS
Primary end points

Dec 17, 2015

21

RESULTS
Primary end points

Dec 17, 2015

22

RESULTS

Dec 17, 2015

23

Clarithromycin in the treatment of RSV Bronchiolitis: a double blind

,randomised placebo controlled trial

CONCLUSION:
In RSV bronchiolitis, treatment with clarithromycin had a
statistically significant effect on LOS, use of 2-agonist
treatment and plasma IL-4, IL-8 and eotaxin levels.

Dec 17, 2015

24

Chronic inflammatory diseases of the

airways affected by macrolides:

Bronchiolitis
COPD
Asthma
Chronic Rhinosinusitis

Chronic Rhinosinusitis
Chronic rhinosinusitis is a common disorder of chronic
inflammation of the upper respiratory tract.
It is associated with significant symptoms and impairment
of the quality of life of sufferers.
Chronic inflammation of the mucosa of the nasal cavity
and paranasal sinusitis is one of the hallmarks of chronic
rhinosinusitis.
The inflammation is demonstrated by an increased
number of chronic inflammatory cells, elevated levels of
pro-inflammatory cytokines, increased expression of
adhesion molecules and metaplastic changes in the
epithelium.
12/17/15

The current medical treatments for chronic

sinusitis aim to:
Reduce the inflammation and consequently
improve symptoms.

12/17/15

Rhinosinusitis Definition
American Academy of
Otolaryngology (AAO) definitionan inflammation of the nose and sinuses

Rhinosinusitis
Include nasal airway
inflammation (Rhinitis)

12/17/15

Clarithromycin and Prednisolone inhibit

cytokine production in chronic rhinosinusitis
Laryngoscope 112:Oct 2002 1827-1830

12/17/15

Introduction
Administration of macrolide is effective in treatment of
chronic rhinosinusitis
Corticosteroids are present the drug of choice in the treatment
of chronic airway inflammation
Study Purpose: To investigate the ability of Clarithromycin in
reducing cytokine production by chronic rhinosinusitis
mucosa.

12/17/15

Results
The concentration dependent reduction in IL-5 , IL-8 and GMCSF production by specimens cultured in the presence of
clarithromycin was significant.
Prednisolone also showed significant concentration effect on
reduction of IL-5, IL-8 and GM-CSF

GM- CSF : Granulocyte macrophage- Colony Stimulating factors

12/17/15

Clarithromycin and Prednisolone inhibit cytokine production

in chronic rhinosinusitis
Wilcoxon signed rank test :

No significant differences were noted between the two

treatment groups for any of the cytokines produced.

12/17/15

12/17/15

12/17/15

Discussion
Clarithromycin has previously been shown to inhibit cytokine
production in various cell types.
IL-5 and GM-CSF was shown to be significantly reduced in
nasal polyp tissue after treatment with corticosteroids

12/17/15

Conclusion
The present study has provided further evidence that
Clarithromycin is capable of inhibiting cytokine
production.
Efficacy comparable to the well known established antiinflammatory agent prednisolone.

12/17/15

The Anti-inflammatory effect of Macrolide

Antibiotics in Chronic Rhinosinusitis
Ben Wallwork
December 2005

12/17/15

MH, Gotfried, (2004), Macrolides for the treatment of

chronic sinusitis, asthma, and COPD. Chest. 2004 Feb;125(2
Suppl):52S-60S
In addition to their well-known antimicrobial activity, macrolides
possess immunomodulatory properties that may confer beneficial
effects to patients with respiratory diseases associated with
chronic inflammation.
1. attenuation of inflammatory responses in the lung.
2. mucoregulatory properties, and effects on bronchial
responsiveness.
3. Macrolides increase mucociliary clearance, improve sinusitis
symptoms, and decrease nasal secretions and polyp size in patients
with sinusitis.
4. modify the inflammatory response associated with chronic
sinusitis.
Dec 17, 2015

38

 In patients with asthma, macrolides have been reported to

reduce airway hyperresponsiveness and improve pulmonary
function, and have historically been selected for their "steroidsparing" effect.
Preliminary data from studies of patients with COPD have
shown improvements in symptom scores and FEV(1) after
macrolide treatment.
As biological response modifiers, macrolides have the
potential to improve the outcomes of patients with
inflammatory airway diseases..

Dec 17, 2015

39

ER clarithromycin has obvious advantages over

IR products when they prescribed for the same
indications.
I.

Higher antimicrobial activity in that clarithromycin is a

time-dependent antibiotic.

II. Better tolerability ,fewer gastrointestinal adverse reactions

and reports of abnormal taste (1*,2*) .
Gotfried M, Notario G, Spiller J, Palmer R, Busman T.Curr Med Res Opin 2005;21:245-254
PubMed.
(2*)
Guay DR, Gustavson LE, Devcich KJ, Zhang J,Cao G, Olson CA.Clin Ther2001;23:566-577
PubMed .
(1*)

24/1/2012

40

ER clarithromycin has obvious advantages over IR

products when they prescribed for the same
indications.
III. Bioequivalence between the ER (1000 mg od) and IR
(500mg bid) (1*).
IV. Enhanced medication compliance due to its convenience.

(1*)

Guay DR, Gustavson LE, Devcich KJ, Zhang J,Cao G, Olson CA.Clin
Ther2001;23:566-577 PubMed .

24/1/2012

41

Dec 17, 2015

42

Thank you