macrolide antibiotics
TRANSCRIPT
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MACROLIDES
G Vijay Narasimha KumarAsst. Professor,
Dept. of. PharmacologySri Padmavathi School of
Pharmacy
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INTRODUCTION
The Macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxysugars are attached.
The prototype drug Erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring.
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It was obtained in 1952 from Streptomyces
erythreus. Clarithromycin and Azithromycin are semisynthetic derivatives of Erythromycin.
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CLASSIFICATIONMACROLIDESi. ERYTHROMYCINii. CLARITHROMYCINiii. AZITHROMYCINiv. ROXITHROMYCINv. SPIRAMYCIN
KETOLIDESvi. TELITHROMYCIN
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MECHANISM OF ACTION
Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit Suppression of RNA-dependent protein synthesis by inhibition of translocation of mRNA.
Typically bacteriostatic activity Bactericidal at high concentrations against
very susceptible organisms
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SPECTRUM OF ANTIBACTERIAL ACTIVITY
Macrolides are similar to Penicillins regarding their spectrum of activity.
They are effective against Penicillin-resistant strains.
GRAM +VE COCCI
GRAM +VE BACILLI
Streptococcus pneumoniae,
Bacilus anthracis,
Strepto. pyogens Listeria monocytogenes
Staphylococci ( most or penicillin resistant species and these are now macrolide resistant also)
Clostridium tetani
GRAM –VE COCCI
GRAM -VE BACILLI
Nesseria gonorrhoeae
Legionella pneumophila
Moraxella catarrhalis
Bordetella pertussis
Bartonella henselae
Haemophilus influenzae, h. ducreyi.Campylobacter jejuniHelicobacter pylori
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ACID FAST BACILLI
SPIROCHETES MISCELLANEOUS
Mycobacterium kanasii
Treponema pallidum
Mycoplasma pneumoniae
Mycobacterium avium intracellulare
Ureaplasma urealyticum
Mycobacterium avium complex
Chlamydia trachomatis
Mycobacterium leprae
Chlamydia pneumoniae
Chlamydia psittaci
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BACTERIAL RESISTANCE
Methylation of a guanine residue on ribosomal RNA leads to lower affinity toward Macrolides
An active efflux systemPresence of a plasmid-associated
Erythromycin esterase.
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Clarithromycin and Azithromycin show cross-resistance with Erythromycin, but Telithromycin can be effective.
Against Macrolide-resistant organisms.Lack of cell wall permeability to Macrolides is
the reason why G(-) bacteria are resistant to antibacterial effects of these agents.
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PHARMACOKINETICS ABSORPTIONERYTHROMYCIN – variable absorption, food may
decrease the absorption. Base: destroyed by gastric acid;
Enteric coated Esters and ester salts: more acid stableCLARITHROMYCIN – acid stable and well-absorbed
regardless of presence of food.AZITHROMYCIN –acid stable, food decreases absorption
of capsules.
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DISTRIBUTION:Extensive tissue and cellular distributionClarithromycin and Azithromycin with extensive penetration .No BBB and CSF penetration
Erythromycin accumulates in the prostatic fluid and also in macrophages.
Azithromycin accumulates in Neutrophils, Macrophages, Fibroblasts. Has Large volume of distribution and longest half life (greater than 40 hrs)
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ELIMINATION:Clarithromycin is the only Macrolide partially
eliminated by the
Kidney(18% of parent and all
metabolites).
Hepatically eliminated: ALL.
NONE of the macrolides are removed during
hemodialysis
Erythromycin and Azithromycin are primarily
concentrated and excreted through bile as active drugs.
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Administration and fate of the Macrolide antibiotics.
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ADVERSE EFFECTS GASTROINTESTINAL EFFECTS: Anorexia, nausea, vomiting, and diarrhoea
occasionally accompany oral administration. Gastrointestinal intolerance, which is due to a direct
stimulation of gut motility, is the most common reason for discontinuing Erythromycin and substituting another antibiotic.
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LIVER TOXICITY: Erythromycins, particularly the estolate, can produce acute
cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction.
Most patients recover from this, but hepatitis reoccurs if the drug is
Re administered. Macrolides get deposited in perilymph and causes ototoxicity. Other allergic reactions include fever, eosinophilia, and rashes. Prolong QT WAVE
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DRUG INTERACTIONS• Erythromycin metabolites can inhibit
cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs including,
• Theophylline, • Oral anticoagulants, • Cyclosporine, and • Methylprednisolone,• Erythromycin increases serum concentrations
of oral Digoxin by increasing its bioavailability.
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THERAPEUTIC USES OF ERYTHROMYCINIt is used to treat a. The upper part of the respiratory tract infections, b. Soft tissue G(+) infections, c. Urethritis caused by (MRSA, Ureaplasma
Urealyticum)
d. Mycoplasma pneumonia caused pneumonia, Campylobacter jejuni -- Enteritis,
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e. Chlamydia infections Majorly C. Trachomatis - (may result in Urethritis, epididymitis, cervicitis, pelvic inflammatory disease (PID) and other conditions. )
C. Pneumonia – causes respiratory illness (prolonged cough, bronchitis, and pneumonia as well as a sore throat, laryngitis, ear infections, and sinusitis)
f. Gonorrhoea caused by Nesseria gonorrhoea
g. Treatment and prophylaxis of ophthalmic infections and also neonatal conjuctivitis
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h. To treat acnei. Pelvic inflammatory disease due to
susceptible organisms (e.g., Streptococcus
Pneumoniae, Streptococcus pyogenes,
Haemophilus influenzae, Chlamydia,
Legionella, Mycoplasma, Nesseria
gonorrhoeae, Treponema)
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ADVERSE DRUG REACTIONS: Ventricular arrhythmias, QT interval
prolongation, Pseudomembranous colitis, Nausea/Vomiting, abdominal pain, cramping,
diarrhea, hepatitis, rash, pruritis, phlebitis at IV site, allergic reactions.
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THERAPEUTIC USES OF ROXITHROMYCIN
Roxithromycin has same spectrum as of Erythromycin butit is more potent against moraxella catarrhalis andlegionella and less potent against bordetella pertusis
THERAPEUTIC USES OF SPIRAMYCIN It also resembles Erythromycin in its spectrum, though ithas weaker activity. However, it is highly efficacious againsttoxaplasma gondii and cryptosporidium causesWaterydiarrhoea with abdominalcramps.
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CLINICAL APPLICATIONS OF CLARITHROMYCIN
It is used to treat Respiratory tract infections
(pharyngitis/tonsillitis ).
skin/skin structure infections due to susceptible
organisms (e.g., S. pneumo, S. pyogenes, S. aureus, M.
catarrhalis, Hemophilus influenza, Chlamydia
pneumoniae, Mycoplasma).
To prevent or treatment of disseminated MAC infection.
(Anemia is common in patients with disseminated MAC
disease)
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d. To Eradicate of H. pylori associated with peptic ulcer disease.
ADVERSE DRUG REACTIONS :Hepatic failure, Pseudomembranous colitis,Stevens-Johnson syndrome, Toxic epidermal necrolysis, Drug rash (with eosinophilia)
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THERAPEUTIC USES OF AZITHROMYCIN
It has an extended spectrum compared to Erythromycin. It has a higher activity against Chlamydia trachomatis,
Mycoplasma pneumoniae, Nesseria gonorrhoeae, toxoplasma gondii.
Campylobacter jejuni (It is among the most common bacterial infections of humans, often a foodborne illness.)
H. Influenza (Bacteremia , Meningitis,Epiglotittis, Cellulitis, Infectious arthritis).
Moraxella catarrhalis (can cause infection of the respiratory system, middle ear, eye, central nervous system).
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It is used to acute bacterial infection Single dose treatment mild to moderate sinusitis Chancroid ( STD; Caused by haemophilus ducreyi) To treat non gonococcal infections (urethritis, cervicitis) Prevention or treatment of MAC infection in patients
with advanced HIV.
ADVERSE REACTIONS: Pseudomembranous colitis, Abdominal pain, Nausea /Vomiting, Rash
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