MACROLIDES, CLINDAMYCIN &
CHLORAMPHENICOLCHLORAMPHENICOLDr. Deepak K. Gupta
Introduction
• Closely related compounds characterized by a macrocyclic lactone ring - deoxy sugars are attached to it
• Prototype drug – erythromycin derived from • Prototype drug – erythromycin derived from Streptomyces erythreus
• Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin
ERYTHROMYCIN
• Poorly soluble in water
• Dispensed as various esters and salts
• Bactericidal, particularly • Bactericidal, particularly at higher concentrations
• enhanced at alkaline pH
Mechanism of Action
• Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA
• Binding site near the peptidyltransferasecentercenter
• Transpeptidation: Peptide chain elongation is prevented
• Also inhibits the formation of the 50S ribosomal subunit
Antimicrobial Activity• Active against susceptible strains of gram-positive
organisms and Gram-negative organisms such as Neisseria sp.
• Resistance : Three mechanisms have been identified– reduced permeability of the cell membrane or active – reduced permeability of the cell membrane or active
efflux; – production (by Enterobacteriaceae) of esterases that
hydrolyze macrolides;– modification of the ribosomal binding site (so-called
ribosomal protection)
• Cross-resistance is complete between erythromycin and the other macrolides
Pharmacokinetics
• Destroyed by stomach acid - enteric coating
• Food interferes with absorption
• Serum half-life is approximately 1.5 hours normallynormally
• Excreted in the bile and lost in feces, and only 5% is excreted in the urine
• Distributed widely except to the brain and cerebrospinal fluid
• Traverses the placenta and reaches the fetus.
Clinical Uses
• Drug of choice in corynebacterial infections -diphtheria, corynebacterial sepsis, erythrasma
• In respiratory, neonatal, ocular, or genital chlamydial infections
• Treatment of community-acquired pneumonia• Treatment of community-acquired pneumonia• Penicillin substitute in penicillin allergic
individuals• prophylaxis against endocarditis during dental
procedures in individuals with valvular heart disease
Clinical Uses
• 0.25–0.5 g every 6 hours
• Oral erythromycin base (1 g) is sometimes combined with oral neomycin or kanamycinfor preoperative preparation of the colonfor preoperative preparation of the colon
• Intravenous dosage of erythromycin gluceptate or lactobionate is 0.5–1.0 g every 6 hours for adults
Adverse Reactions
• Anorexia, nausea, vomiting, and diarrhea are common
• Gastrointestinal intolerance – direct stimulation of gut motilitystimulation of gut motility
• May produce acute cholestatic hepatitis
• Fever, eosinophilia, and rashes
CLARITHROMYCIN
• Derived from erythromycin by addition of amethyl group
• improved acid stability and oral absorptioncomparablycomparably
• Similar antibacterial action and mechanism of actions but its more active against Mycobacterium avium complex, Mycobacterium leprae ,Toxoplasma gondii, and H influenzae
CLARITHROMYCIN
• Recommended dosage is 250–500 mg twice daily or 1000 mg of the extended-release formulation once daily
• Half-life : 6 hours• Half-life : 6 hours
• Penetrates most tissues well
• Metabolized in the liver
• Lower incidence of gastrointestinal intolerance and less frequent dosing
AZITHROMYCIN
• derived from erythromycin by addition of a methylated nitrogen into the lactone ring – 15 C lactone ring
• Antibacterial spectrum similar to those of clarithromycinclarithromycin
• slightly less active than erythromycin and clarithromycin - staphylococci and streptococci
• Slightly more active against H influenzae
• highly active against Chlamydia sp
AZITHROMYCIN• Differs - mainly in pharmacokinetic properties• Penetrates into most tissues (except CSF) and phagocytic
cells extremely well• Half-life approaching 3 days - once-daily dosing• 1-g dose of azithromycin is as effective as a 7-day course
of doxycyclineof doxycycline• Community-acquired pneumonia - 500-mg loading dose,
followed by a 250-mg single daily dose for the next 4 days• Not given - 1 hour before or 2 hours after meals• Free of the drug interactions that occur with
erythromycin and clarithromycin– 15-member lactone ring – does not inactivate cytochrome
P450 enzymes
CLINDAMYCIN
• Chlorine-substituted derivative of lincomycin
• Elaborated by Streptomyces lincolnensis
Mechanism of Action
• Inhibits protein synthesis– interfering with the formation of initiation
complexes and with aminoacyl translocation reactions
• Binding site on the 50S subunit of the bacterial • Binding site on the 50S subunit of the bacterial ribosome is identical with that for erythromycin
• Resistance• Mutation of ribosomal receptor site
• Modification of the receptor by a constitutively expressed methylase
• Enzymatic inactivation of clindamycin
Antibacterial Spectrum
• Streptococci, staphylococci, and pneumococci
• Both gram-positive and gram-negative anaerobes - susceptible
• Enterococci and gram negative aerobic • Enterococci and gram negative aerobic organisms (poor permeability) are resistant
• Cross resistance to macrolides
Pharmacokinetics
• Penetrates well into most tissues, with brainand cerebrospinal fluid as well as abscesses
• Metabolized by the liver
• Excreted in bile and urine• Excreted in bile and urine
• Half-life - 2.5 hours
• Oral dosages: 0.15–0.3 g every 8 hours, Intravenously: 600 mg every 8 hours
Clinical Uses
• Treatment of skin and soft-tissue infections caused by streptococci and staphylococci
• Community-acquired strains of methicillin-resistant S aureus (MRSA) - common cause of resistant S aureus (MRSA) - common cause of skin and soft tissue infections
• Anaerobic infections caused by Bacteroides sp
• Combination with an aminoglycoside or cephalosporin – treat penetrating wounds of the abdomen and the gut
Clinical Uses
• Infections originating in the female genital tract -septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung abscesses
• Alternative to Penicillin allergy – prophylaxis of • Alternative to Penicillin allergy – prophylaxis of endocarditis in patients with valvular heart disease undergoing certain dental procedures
• Clindamycin plus primaquine – effective alternative to trimethoprim-sulfamethoxazole
Adverse Effects
• Diarrhea, nausea, and skin rashes.
• Impaired liver function
• Neutropenia
• Risk factor for diarrhea and colitis due to C • Risk factor for diarrhea and colitis due to C difficile
Chlramphenicol
• Crystalline chloramphenicol is a neutral, stable compound
• Soluble in alcohol but poorly soluble in water
• Chloramphenicol succinate - parenteral• Chloramphenicol succinate - parenteraladministration (highly water-soluble)
Mechanism of Action
• potent inhibitor of microbial protein synthesis
• binds reversibly to the 50S subunit of the bacterial ribosome
• inhibits peptide bond formation • inhibits peptide bond formation
• bacteriostatic broad-spectrum
• Resistance due to– less permeable to the drug
– Chloramphenicol acetyltransferase - inactivatesthe drug
Antimicrobial Activity
• Active against both aerobic and anaerobic gram-positive and gram-negative organisms
• Active also against Rickettsiae but notChlamydiaeChlamydiae
• Bactericidal - H influenzae, Neisseriameningitidis , and some strains of bacteroides
Pharmacokinetics• Rapidly and completely absorbed• Widely distributed to virtually all tissues and body fluids,
including the central nervous system• Prodrug
– Oral route : Chloramphenicol palmitate is hydrolyzed in the intestine to yield free chloramphenicol
– Parentral : Chloramphenicol succinate, which hydrolyzes to yield – Parentral : Chloramphenicol succinate, which hydrolyzes to yield free chloramphenicol
• Inactivated either by– conjugation with glucuronic acid– by reduction to inactive aryl amines
• Active chloramphenicol (10%) and its inactive degradation products (90%) are eliminated in the urine
• A small amount of active drug is excreted into bile and feces.• Usual dosage : 50–100 mg/kg/d
Clinical Uses
• Potential toxicity, bacterial resistance, and the availability of many other effective alternatives - rarely used
• Serious rickettsial infections such as typhus and Rocky Mountain spotted feverMountain spotted fever
• Alternative to a β-lactam antibiotic for treatment of bacterial meningitis - hypersensitivity reactions to penicillin : 50–100 mg/kg/d in four divided doses.
• Topically in the treatment of eye infections– broad spectrum
– penetration of ocular tissues and the aqueous humor
Adverse Reactions• Gastrointestinal disturbances - nausea, vomiting, and
diarrhea• Oral or vaginal candidiasis• Dose-related reversible suppression of red cell production -
exceeding 50 mg/kg/d after 1–2 weeks.• Aplastic anemia - idiosyncratic reaction unrelated to dose• Gray baby syndrome• Gray baby syndrome
– Newborn infants lack an effective glucuronic acid conjugation mechanism
– dosages above 50 mg/kg/d, the drug may accumulate– vomiting, flaccidity, hypothermia, gray color, shock, and vascular
collapse
• To prevent this dose should be carefully decided in infants and kept below 50 mg/kg/d
Adverse Reactions
• Inhibits hepatic microsomal enzymes -metabolize several drugs
• Half-lives of these drugs are prolonged
– Phenytoin– Phenytoin
– Tolbutamide
– Chlorpropamide
– Warfarin
Summary
References
• Basic & Clinical Pharmacology Bertram G. Katzung Twelfth Edition
• Essential of medical pharmacology - K.D. Tripathi6th edition
Lippincott - Modern Pharmacology With Clinical • Lippincott - Modern Pharmacology With Clinical Applications 6E
• Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann, Thieme 2000)
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