Macrolides

Macrolides

1-Erythromycin

2-Clarithromycin

3-Azithromycin

4-Telithromycin

5-Roxithromycin

Macrolides related drugs

Licosamides:

Clindamycin

Macrolides: Group of Antibiotics

Erythromycin and related compounds

Erythromycin has been used since 1952.

1-Erythromycin       1952

Erythromycin is a natural compound

T ½ = 2- 4 hours

Binds to bacterial ribosome and interferes with protein synthesis.

(Bacteriostatic)

“Time Dependent” Bacteriostatic effect

Acts on: Gram Positive > Gram negative

Antibacterial effect similar to penicillin

Erythromycin Estolate

Erythromycin Sccinate

Erythromycin Stearate

Absorption is best with Estolate even with the presence of food.

Why it is combined with Estolate or Sccinate?

1- To Enhance Absorption.

2- To prevent Degradation of the drug in stomach.

Ø Can we use erythromycin base as a drug? Without combination?

Ø Yes! “Enteric Coated Tablet”

Used in Patients Allergic to Penicillin to treat:

Staphylococcus aureus

Streptococcus pyogens

Streptococcus pneumoniae

Streptococcus viridans

Treponemapallidum

Bacillus anthracis

Atypical Microorganisms:

Mycoplasma pneumoniae

Legionella Spp

Diphtheria including carriers.

Pertusssis

Chlamydial Infection

Campylobacter jejuni (GIT infection)

Dose is 250 mg – 500 mg 6 hourly

Stearate and Ethylsuccinate produce lower concentration.

Second choice treatment in patient allergic to penicillin

1^st choice treatment in:

 1-Diphtheria.

2-Pertusssis.

3-Atypical Pneumonia. Mycoplasma Chlamydia Legionella.

Adverse effects:

1-Non toxic

2-Estolate is associated with cholestatic hepatitis probably as a result of allergy.

Patient with liver disease should not be prescribed the Estolate form.

3-GIT disturbance in 28% of patients.

GIT Stimulation

Diarrhea

Inhibition of P450 3A.

-Warfarin.

-Carbamazepine.

-Ergot.

-Theophylline.

More serious side-effects:

 Include Arrhythmia with prolonged Q-T intervals including Torsades-de-Pointes.

Twisting of points

2-Clarithromycin

Similar spectrum of antibiotic activity 1991

             G +ve>     G –ve

Heamaphilusinfluenzae

Atypical pneumonia

Mycobacterium in AIDS

GIT Adverse Effect

T ½ = 3 hours

Dose is 500 mg twice daily

3-Roxithromycin

Was developed in1987

Same indications of erythromycin

Dose is 150 mg twice daily.

4-Azithromycin - 1988

          G –ve& G +ve Bacteria 

HeamaphilusInfluenzae

Neisseria gonorrhea

Less effective on g +ve than Erythromycin.

Higher concentration in tissue than in plasma.

Bile and stool excretion.

T ½ = 50 hours (in Respiratory and soft tissue).

GIT Adverse effects = 9 %

Adverse effects:

Diarrhea Nausea vomiting, avoid in patient with liver disease.

Supplied in box of 6 capsules

Dosage is either:

3 days treatment 500 mg / day

5 days treatment 500 mg in first dayThen 250 mg daily for 4 days

5-Telithromycin -2004

half-life = 10 hours

Ketolides:

-Semi-synthetic.

-Related to Macrolides.

-Binds to 50s ribosomal subunit. More ribosomal binding

Streptococcus pneumonia which could be resistant to erythromycin are sensitive.

Not staph!

Once daily therapy 400mg

No need to adjust dose in hepatic disease.

Half dose in renal impairment

More diarrhea than Macrolides

Blurred vision transient

Rare but severe side effects reported in January 2006 involve damage to the liver:

Three different incidents have been reported:

One ending in Death, One in a liver transplant and one case of drug-induced hepatitis.

 FDA's Office of Epidemiology and Surveillance identified 12 cases of acute liver failure, resulting in four deaths, and an additional 23 cases of acute, serious liver injury in patients taking Telithromycin up to April 2006.

By April 2008, independent analysis using FDA data has linked Ketek (Telithromycin) to18 deathsAnd at least 134 cases of liver damage!

 The doctor who treated most patients in Phase 3 clinical study:

Maria "Anne" Kirkman Campbell, is currently serving a 5 years sentence In Prison after pleading guilty to defrauding (Falsifying ) the results of the clinical trial!

February 12, 2007, the Food and Drug Administration announced a revision to the labeling of Telithromycin to improve patient safety:

 The changes included the removal of two of the three previously approved indications:

 Acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis.

Telithromycin will remain on the market for the treatment of:

 Community acquired pneumonia of mild to moderate severity (acquired outside of hospitals or long-term care facilities).

 In addition, the FDA worked with the manufacturer to update the product labeling with a:

 "Black box warning" the strongest form of warning. Telithromycin warning states that it should not be used in patients with myasthenia gravis.

Lincosamides

Clindamycin:

Lincosamide rather than a Macrolides

Protein synthesis inhibition.

-Similar bacterial effect of erythromycin on usual micro organisms. BUT NOT ON Atypical micro organisms.

-Penicillin resistant staph.

-Anaerobic bacteria Bacteriodesfragilis

Staph bone and joint infection

Dental infection

Liver metabolism entero-hepatic circulation.

Increased concentration in bile

T ½= 3 hours.

Adverse Effects:

Severe intra abdominal infection.

Pseudo membranous colitis (Clostridium difficile)

Spiramycin

-Is a macrolide antibiotic.

-It was discovered in 1952.

-The antibacterial action involves inhibition of protein synthesis.

-Its action is mainly Bacteriostatic, but on highly sensitive strains it exerts a bactericidal action.

It is used to treat toxoplasmosis during pregnancy.

Usual dosage is 500mg three times daily.

         500 mg = 1,5,00000 IU

1 mg = 3000 IU

Mcqs:

1-Which one of the following Macrolides has the longest duration of action?

A-Erythromycin

B-Clarithromycin

C-Azithromycin

D-Roxithromycin

2-Cholestatic hepatitis is an adverse effect of:

A-Erythromycin Sccinate.

B-Erythromycin Stearate.

C-Erythromycin Estolate.

D- Clarithromycin.

3-Which one of the following statements concerning macrolides is incorrect:

A-They are used to treat Mycoplasma.

B-Used as alternative to penicillin in penicillin allergic patients.

C-Used to treat Legionella pneumonia.

D-Are Contra Indicated in pediatric age group.

E-Used to treat diphtheria carriers.

4-The most commonly encountered adverse effect of erythromycin Estolate is:

A-Cholestatic hepatitis.

B-Allergic reactions.

C-Alteration of liver enzymes.

D-Gasro-intestinal stimulation and upset.

E-None of the above.

5-All of the following Macrolides are licensed in treatment of upper respiratory tract infection except:

A- Erythromycin

B- Telithromycin

C- Azithromycin

D- Clarithromycin

E- Roxithromycin

6-You were asked to treat a patient with pharyngitis using a drug which is absolutely 100% safe and effective, your answer will be:

A-It’s easy, I will prescribe Azithromycin.

B-I will prescribe Azithromycin but you have to commit to the exact dose and instructions.

C-I will prescribe Clindamycin.

D-I will use a local treatment.

E-I am sorry, please seek another opinion.