The need for new Macrolides

Inclusion of H. influenzae Expand spectrum of susceptible organisms Overcome bacterial resistance Improve intracellular penetration Enhance synergy with host immune system Improve chemical and metabolic stability Improved serum and tissue concentrations

Twice / once daily oral dosaging

Reduce side effects.
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Spectrum of activity (1)

Gram Positive microorganisms:
Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes

Gram Negative microorganisms:

Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis Neisseria gonorrhea
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Spectrum of activity (2)

Atypical microorganisms:
Mycoplasma pneumoniae Chlamydia pneumoniae Chlamydia trachomatis Legionella pneumiphila

Mycobacterium:
Mycobacterium avium Mycobacterium intracellulare

Helicobacter pylori Sales Training

Mechanism of action
Clarithromycin interferes

50S
Binds

Nascent polypeptide chain

tRNA Acceptor site Donor Site

X

Translocation Reaction mRNA 30S

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Mechanism of Action
Inhibit protein synthesis Binds to 50 S ribosomal subunit
30S
Clarithromycin binds to 50S subunit of ribosome and inhibit protein synthesis

50S

RIBOSOME

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Synergy
Clarithromycin and its 14-hydroxy
metabolite showed syngergistic activity,

against Moraxella catarrhalis,

Staphylococcus aureus, coagulase negative Staphylococci and S.pyogenes, Legionella species and Haemophillus influenzae.
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Staphylococcus spp.
Pyogenic diseases in man prosthesis, catheters, implants (Staph. epidermis) and urinary tract infections Pyogenic Infections such as Boils, Carbuncles, Wound Infection, Abscesses, Impetigo, Mastitis, Septicemia, Osteomyelitis.
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Streptococcus spp.
Streptococcus pyogenes : tonsillitis, erysipelas, impetigo, scarlet fever and septicemia. Beta-hemolytic streptococci : acute bronchitis, peritonsillar abscess, sinusitis, otitis media, mastoiditis. Secondary Bronchopneumonia Streptococci agalactiae : neonatal infection. Streptococcus pneumoniae / diplococcus / Pneumococcus

Oropharyngeal flora middle ear, paranasal sinuses, lung parenchyma, but it may also spread to joints, Sales Training peritoneum, endocardium, biliary tract, and meninges.

Haemophilus influenzae
Encapsulated type-b meningitis, pneumonia, epiglotitis, cellulitis, arthritis
Non-encapsulated otitis media, sinusitis, & conjunctivitis & infect patients with chronic bronchitis.

Pneumonia, septicemia, common with immunocompromised Patients

Multiresistant strains of H.influenzae are reported worldwide.
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Bacteriological eradication Rate for Key Pathogens

H.influenzae Clarithromycin 97 Strep. Pn 99 Staph. ar 100

Roxithromycin
Cefaclor Amoxicillin Ciprofloxacin

29
67 92 100
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90
54 23 91

98
100 100 81

Anaerobic Bacteria
Propionibacterium acne : skin and GI tract
Organism Mean MIC90 Value (mg/L)

Propionibacterium

Clarithr 14-OH Erythr AzithroClinda Roxithr Clarithr 0.03 0.06 0.03 0.03 0.06
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Mycoplasma pnemoniae
MIC 90 range of < 0.0031 to 0.5 mg/L

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Legionella genus
L. pneumophila intracellular pathogen inhabiting the lungs, liver, spleen and leucocytes. Organism Mean MIC Value (mg/L)
90

Clarith- 14-OH Erythr- Azithro- Clinda Roxithrromycin Clarithr omycin mycin omycin Legionella spp. 0.12 0.5 0.49 2 16 0.31 Clamydia Pneumoniae 0.007 0.06 0.5 0.25

Mycoplasma

<0.125

<0.1
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0.5

<0.15

<0.02

Mycobacterium spp.
Mycobacterium Avium Complex (Mycobacterium avium and Mycobacterium intracelularae). Invades and multiplies within macrophages and leucocytes. Opportunistic infections, Acquired Immune Deficiency Syndrome.
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Mycobacterium spp.
Azithromycin was not recommended it had

given rise to the emergence of resistant strains

due to sub-MIC serum levels. Whereas

Clarithromycin as a monotherapy have been

shown to be effective as a prophylaxis against

disseminated MAC in patients with AIDS.

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Mycobacterium chelonae and Mycobacterium chelonae abscessus

Skin and soft tissue infections, pulmonary diseases, systemic diseases and surgical wounds in

Immunocompromised patients longterm corticosteriods. MIC90 values 0.25 and 0.5 mg/L.
Clarithromycin is 10 to 50 fold more active than Training azithromycin and Sales roxithromyicn.

Post-antibiotic Effect
Persistent suppression of bacterial regrowth after short exposure to the drug Clarithromycin exhibits PAE of 3.5 to 3.8 hours. PAE against S. pyogenes were 6.25 and 3.5 hours 3-fold greater than those of erythromycin.
In presence of 14-OH metabolite PAE is Sales Training

Clarithromycin and the immune system

Immuno-enhancer Potentiation of neutrophil migration and bactericidal action. Anti-inflammatory
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Enhancement of T-Cell Activity

T-cell is lymphocyte produced in bone marrow and members of immune system. Destroys or neutralises foreign substances, bacteria.
Clarithromycin - potentiates the activity of T-cells.
Clarithromycin - excellent penetration into the polymorphonuclear leukocytes, macrophages, and lymphocytes.
Sales Training Clarithromycin - increases phagocytosis.

Effect Pulmonary congestion

Improves the visco-elastic properties of mucus and sputum, relieving pulmonary

congestion.

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Pharmacokinetic Properties
Absorption, Distribution, Metabolism.

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Absorption
Absorption Clarithromycin Erythromycin. 52-55%, 30-35%

Erythromycin is acid labile but Clarithromycin is stable in acidic environment.

Clarithromycin at an alkaline PH in intestine is non-ionized, can penetrate intestinal cell walls.

In presence of food, erythromycin bioavailability reduces by 20% azithromycin bioavailability reduces by 43% Roxithromycin has to be administered 15 minutes prior to food.
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Plasma Concentration
Mean area under the plasma concentration curve (AUC) clarithromycin 3.82 to 4.7 mg/L. h 14-OH Clarithromycin 11.06 to 11.66 mg/L. h
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C max
500 mg. twice daily for upto 3.5 days
mean Cmax

Clarithromycin 2.4 to 3.5 mg/L

14-OH Clarithromycin 0.7 to 0.8 mg/L

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Distribution (Intracellular Reach)

LRT
Study participants Tissue : Plasma Dosage (mg) ratio

Epithelial lining fluid Bronchoscopy patients 500 bid x 7 doses 5.17 Alveolar macrophages Bronchoscopy patients 500 bid x 7 doses 94.1 Bronchial secretions AECB patients

2.79

56.8

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250 bid x 3 days

3.1

2.5

Distribution (Intracellular Reach)

LRT
Study participants Tissue : Plasma Dosage (mg) ratio

CLR 140H
2.79 56.8 2.5

Epithelial lining fluid Bronchoscopy patients 500 bid x 7 doses 5.17 Alveolar macrophages Bronchoscopy patients 500 bid x 7 doses 94.1

Bronchial secretions AECB patients

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250 bid x 3 days

3.1

Distribution (Intracellular Reach)

URT
Study participants Tissue : Plasma Dosage (mg) ratio

CLR 331

140H 375

Tonsils Tonsillar resection patients 250 bid x 3 days

Nasal mucosa Rhinoplasty patients

250 bid x 3 days

27.5

16

Middle ear fluid Children with otitis media 7.5 mg/kg bid x 7 days 8.82
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3.78

 A Laboratory study compared the intracellular

reach between clarithromycin, amoxicillin and

azithromycin against S. aureus and L.

pneumophila. Clarithromycin intra- and

extracellularly, proportion to its concentrations (0.34 to 1.33 mg/L vs 0.15 to 0.66 and mg/L, respectively) Amoxicillin was found only extracellularly and Azithromycin primarily within cells.
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Metabolism and Elimination

Only one of the, 14-OH metabolite, is biologically active. Mean elimination half-life Clarithromycin 2.6 to 2.8 hours. 14-OH Clarithromycin 3.5 to 4.9 hours. The t erythromycin (1.3-3.4h)
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 32% of the dose recovered in urine was parent plus metabolite.

In elderly, dosage adjustment not necessary unless impaired renal function.

Dosage adjustment in hepatic disease not required.
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Adverse Effects
Nausea (3%), diarrhoea (3%)

dyspepsia (2%), abdominal pain (2%)

and headache (2%).

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Drug Interactions
Theophylline, cyclosporine, tacrolimus and carbamazepine. Plasma concentrations of these increased
Rifabutin and rifampicin induce metabolism of clarithromycin. Inhibits metabolism of omeprazole. Digoxin toxicity
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Dosage and Administration

Pharyngitis or tonsillitis : 250 mg every 12 hours for 10 days. Acute exacerbation of chronic bronchitis (AECB). Clarithromycin 250 mg every 12 hours for 7 to 14 days. A higher dosage (500 mg every 12 hours for 7 to 14 days) should be used for AECB caused by H. influenzae. Children 7.5 mg/kg every 12 hours for 10 days.
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CLINICAL TRIALS

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Lower Respiratory tract infections

Cumulated rates of eradication of common respiratory tract pathogens

Organism
Streptococcus pyogenes

Percentage
95

Heamophilus influenzae
Moraxella catarrhalis

85
99

Streptococcus pneumoniae
Staphylococcus aureus Sales Training 100)

99
96(83-

Clinical Sucess Rate

Acute bronchitis 97% - 99%

Acute exacerbation of chronic bronchitis (AECB) 94%-96% Unspecified lower respiratory tract infections Community Acquired Pneumonia (CAP) Chronic Obstructive Pulmonary Disorders 94-97% 99% 93%-98%

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Efficacy of oral clarithromycin

Study No. Dosage (mg) Clinical success rate (%)

Pn:85.7 Clarithromycin 250 or 500 bid B/ COPD:94.5 AB : 96.6 Pn:93.7 Cefaclor 250 or 500 tid COPD:90.9 B/ AB : 87.1
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Clarithromycin 500 bid

LRTI 97

Pertussis
Bordetella pertussis High Cure Rate of 95-98%
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Efficacy of clarithromycin in acute bronchitis

Study Study DesignDosage (mg) Clinical success rate (%) Acute bronchitis
1. 98 99 2. 96 Clarithromycin 250 bid Sales Training 5 days Clarithromycin 250 bid Clarithromycin 250 bid 5 days 10 days

Efficacy of clarithromycin in acute bronchitis

Study Study DesignDosage (mg) Clinical success rate (%)
Comparisons with cephalosporins

1. 99.5

Clarithromycin 250 bid

Cefaclor 500 tid < 7 days

< 7 days
97.9

2. 95

Clarithromycin 500 bid

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< 14 days

Efficacy of clarithromycin in acute bronchitis

Study Study Design Dosage (mg) Clinical success rate (%)

Acute exacerbations of chronic bronchitis

Comparisons with -lactam agents 1. Clarithromycin 250q12h < 10 days 97 Amoxicillin 250 q6h < 10 days 91 2. Clarithromycin 500 bid 14 days 100 Amoxicillin 500 qid 14 days 98 Sales Training

Upper Respiratory Tract Infections

Clinical success rate of Clarithromycin,
Acute pharyngitis 85%-95%, Acute tonsilitis 90-97% Acute sinusitis 87-96% Laryngotracheitis 96% Acute maxillary sinusitis 84% (S.aureus,& S.aureus combined with S.Pneumoniae)
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Study DesignDosage (mg)

Clinical success rate (%)

Acute maxillary sinusitis

Comparisons with -lactam agents 1. Clarithromycin 500 bid < 14 days Amoxicillin 500 tid < 14 days 97 93 8 days

2. Clarithromycin 500 q12h Sales Training 85.8

Study Design

Dosage (mg)

Clinical success rate (%)

Upper respiratory tract - general

Comparisons with macrolides 1. Clarithromycin 250 bid OM:91.4

10 days
S:94.4 Ph/T:97.3 OM : 97

2.

Sales Training Azithromycin 500 od 3 days

Lower Respiratory tract infections

Cumulated rates of eradication of common respiratory tract pathogens

Organism
Streptococcus pyogenes

Percentage
95

Heamophilus influenzae
Moraxella catarrhalis

85
99

Streptococcus pneumoniae
Staphylococcus aureus Sales Training 100)

99
96(83-

Efficacy of oral clarithromycin in LRTI

Study No. (%)
Pn:100

Dosage (mg)

Clinical success rate

Clarithromycin 250 bid AB:97 AECB:97

Pn:75

Azithromycin 500 od

AB:96

AECB:95
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Efficacy of oral clarithromycin

Study No. Dosage (mg) Clinical success rate (%)

Pn:85.7 Clarithromycin 250 or 500 bid B/ COPD:94.5 AB : 96.6 Pn:93.7 Cefaclor 250 or 500 tid COPD:90.9 B/ AB : 87.1
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Clarithromycin 500 bid

LRTI 97

Pertussis
Bordetella pertussis High Cure Rate of 95-98%
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Efficacy of clarithromycin in acute bronchitis

Study Study DesignDosage (mg) Clinical success rate (%) Acute bronchitis
1. 98 99 2. 96 Clarithromycin 250 bid Sales Training 5 days Clarithromycin 250 bid Clarithromycin 250 bid 5 days 10 days

Efficacy of clarithromycin in acute bronchitis

Study Study DesignDosage (mg) Clinical success rate (%)
Comparisons with cephalosporins

1. 99.5

Clarithromycin 250 bid

Cefaclor 500 tid < 7 days

< 7 days
97.9

2. 95

Clarithromycin 500 bid

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< 14 days

Efficacy of clarithromycin in acute bronchitis

Study Study Design Dosage (mg) Clinical success rate (%)

Acute exacerbations of chronic bronchitis

Comparisons with -lactam agents 1. Clarithromycin 250q12h < 10 days 97 Amoxicillin 250 q6h < 10 days 91 2. Clarithromycin 500 bid 14 days 100 Amoxicillin 500 qid 14 days 98 Sales Training

Upper Respiratory Tract Infections

Clinical success rate of Clarithromycin,
Acute pharyngitis 85%-95%, Acute tonsilitis 90-97% Acute sinusitis 87-96% Laryngotracheitis 96% Acute maxillary sinusitis 84% (S.aureus,& S.aureus combined with S.Pneumoniae)
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Study DesignDosage (mg)

Clinical success rate (%)

Acute maxillary sinusitis

Comparisons with -lactam agents 1. Clarithromycin 500 bid < 14 days Amoxicillin 500 tid < 14 days 97 93 8 days

2. Clarithromycin 500 q12h Sales Training 85.8

Study Design

Dosage (mg)

Clinical success rate (%)

Upper respiratory tract - general

Comparisons with macrolides 1. Clarithromycin 250 bid OM:91.4

10 days
S:94.4 Ph/T:97.3 OM : 97

2.

Sales Training Azithromycin 500 od 3 days