Subject: Pharmacology Topic: Macrolides, Ketolides, Chloramphenicol, Clindamycin, Streptogamins and Oxazolidinones Lecturer: Dr.

Deo Panganiban Date of Lecture: I forgot Transcriptionist: olegior Editor: Pages: 6 MACROLIDES Group of three drugs 1. Erythromycin 2. Azithromycin 3. Clarithromycin

Macrocyclic lactone ring (14-16 atoms) to which deoxy sugars are attached Desosamine Clanidose

Peptidyl tRNA at DONOR SITE donates the growing peptide chain to the aminoacyl tRNA at the ACCEPTOR SITE in a reaction catalyzed by peptidyl transferase. The tRNA, discharged of its peptide, is released from the donor site to make way for translocation of the newly-formed peptidyl tRNA. Acceptor site is then free to be occupied by the next charged aminoacyl tRNA CHEMISTRY of MACROLIDES ERYTHROMYCIN 2 sugar moieties attached to a 14-atom lactone ring CLARITHROMYCIN Methyl group added to the hydroxyl group at the C6 position AZITHROMYCIN Methyl substituted nitrogen atom added to the lactone ring Significance of modifications: Improved acid stability & tissue penetration Broader spectrum of activity

MECHANISM OF ACTION Inhibition of RNA-dependent protein synthesis (50S Subunit) Prevents translocation of peptidyl tRNA from the acceptor site to the donor site SITE OF ACTION 70s ribosomal mRNA complex

1. ERYTHROMYCIN (has oral and parenteral forms) ORAL 1. E. Base 2. E. Stearate 3. E. Estolate 4. E. Ethylsuccinate PARENTERAL 1. E. Ethylsuccinate 2. E. Lactobionate 3. E. Gluceptate

STEPS IN BACTERIAL PROTEIN SYNTHESIS

SY 2011-2012

Pharmacokinetics Absorption : o o o Active form BASE Rapid inactivation by ACID Administered w/ Enteric coating Salts & Esters-better absorbed

Distribution : o Except CNS & Brain

Metabolism : o Demethylation - Liver

More potent against Erythromycin sensitive strains of Streptococcus & Staphylococcus Modest activity against H. influenzae & N. gonorrheae More active against Mycobacterium avium complex AZITHROMYCIN Less active than Erythromycin against G (+) organisms More active than Erythromycin & Clarithromycin against H. influenzae & Campylobacter Highly active against Chlamydia DISTRIBUTION ERYTHROMYCIN Concentration in middle ear exudate reaches only 50% of serum concentration CLARITHROMYCIN Concentration in the middle ear is higher Undergoes rapid first-pass metabolism to an active metabolite, 14-hydroxyclarithromycin AZITHROMYCIN Extensive tissue distribution High drug concentrations within cells exceeding serum concentrations ELIMINATION HALF-LIFE: 1. ERYTHROMYCIN 1.6 hrs. 2. CLARITHROMYCIN 3 7 hrs. (Renal & non-renal) 5 9 hrs. (For hydroxyclarithromycin) 3. AZITHROMYCIN 68 hrs biliary excretion is major route of elimination (almost three days!)

Excretion : o o Largely in feces Urine: 2.5 % (Oral) 12 15 % (IV)

Spectrum of Activity Sensitive against: G ( - ) except o Mycoplasma P., Actinomyces, Treponema P., Legionella P., Rickettsia, Chlamydia

o o o Resistant against: G ( - ) bacilli Staph. aureus

Resistance 3 Mechanisms: 1. Reduced permeability of cell membrane or active efflux 2. Production of esterases that hydrolyze Macrolides (Entrobacteriaceae) 3. Modification of ribosomal binding site (ribosomal protection) : chromosomal mutation or constitutive methylase Clinical Uses ERYTHROMYCIN IS D.O.C. for: 1. Legionnaires Disease 2. Diphtheria 3. Pertusis 4. Mycoplasma & Chlamydial Pneumonia in children 5. Campylobacter Enteritis 6. Chlamydial pelvic infections during pregnancy ANTIBACTERIAL ACTIVITY CLARITHROMYCIN

THERAPEUTIC USE ERYTHROMYCIN - every 6 hours CLARITHROMYCIN - 2X a day AZITHROMYCIN - once a day ALTERNATIVE TREATMENT 1. Penicillin allergy

2. Non-Gonococcal Urethritis and Chlamydial Pelvic Infections ADVERSE REACTIONS 1. Cholestatic Hepatitis - Estolate (Fever, jaundice, impaired liver function) 2. GIT Nausea, Vomiting, Diarrhea 3. Allergic Reactions 4. Superinfections : Pseudomembranous Colitis DRUG INTERACTIONS 1. Decrease theophylline clearance 2. Inhibits hepatic metabolism of Carbamazepine, Methylprednisolone, Digoxin, Warfarin = serum levels 3. Competitive antagonism with Lincosamides and Chloramphenicol 4. Parenteral dosage form physically & chemically incompatible with solutions containing Vit. B complex, Ascorbic acid, Cephalosporins, Tetracycline, Chloramphenicol KETOLIDES SEMI-SYNTHETIC MACROLIDES 14-membered ring Substitution of a 3-keto group for Lcladinose Effective against macrolide-resistant strains: 1. Structural modifications of these compound makes them poor substrates for effluxpump mediated resistance 2. Higher affinity/binding to ribosomes of some bacteria Telithromycin ( type of a Ketolide) Bioavailability (oral) 57% Good intracellular penetration Hepatic metabolism * Reversible inhibitor of CYP3A4 enzymes Elimination : Biliary & Urinary Dose: Once a day (800 mg) Peak serum conc. = 2 ug/ml ACTIVE IN-VITRO: S. pyogenes S. pneumoniae S. aureus H. influenzae Moraxella catarrhalis Mycoplasmas Legionella spp. Helicobacter pylori N. gonorrhoeae Bacteroided fragilis

T. gondii Non-tuberculous mycobacteria INDICATIONS: Respiratory tract infections: Community-acquired pneumonia Chronic bronchitis Sinusitis Streptococcal pharyngitis

CHLORAMPHENICOL Mechanism of Action: Inhibition of peptide bond formation at the 50 S subunit Blocks binding of the aminoacyl moiety of the charged tRNA molecule to the acceptor site of Ribosomal mRNA complex PHARMACOKINETICS ABSORPTION: 75 90% from the GIT Oral preparation PALMITATE form of drug Parenteral preparation SUCCINATE form of drug Serum Level : IV = ORAL DISTRIBUTION: 45% protein bound Brain and CSF 65% Aqueous & vitreous humour Synovial, pleural, ascitic fluid Placenta, breast milk METABOLISM: 90% Glucoronide Conjugation 2% Deacetylation - reduce dosage in hepatic failure ELIMINATION: 90% Excretion in urine (small amount) Bile or feces SPECTRUM OF ACTIVITY BACTERICIDAL for: Haemophilus influenzae Neisseria meningitides Bacteroides fragilis BACTERIOSTATIC for: Treponema diphteriae Rickettsia Pneumococci Chlamydia Streptococci E. coli epidermidis

C.

S.

Shigella Salmonella RESISTANT : P. Aeruginosa Acitenobacter P. Rettgeri Providencia S. Marcesens

S. aureus

B. Aplastic Anemia Pancytopenia Non-dose related Irreversible -> fatal MOA: Idiosyncratic reaction 2. GRAY SYNDROME in INFANTS: Inadequate Glucuronyl transferase > 50 mg/kg/day = accumulate Flaccidity, vomiting, hypothermia, gray color, shock, collapse 3. NEUROLOGIC Optic neuritis, peripheral neuritis, headache, opthalmoplegia, confusion 4. OTHERS: RARE GIT, Allergic reactions, Superinfections CLINICAL USES (CHLORAMPHENICOL is D.O.C.) 1. Typhoid Fever 2. CNS infections: Meningitis Brain Abscess 3. Anaerobic infections 4. Deep ocular infections ALTERNATIVE Tx to chloramphenicol ( substitute to chloram) 1. Pneumococcal/Meningococca Meningitis Benzyl Penicillin 2. Rickettsial Infections-Tetracycline

MECHANISM OF BACTERIAL RESISTANCE Low-level Resistance: Mutants less permeable to the drug Chloramphenicol acetyltransferase: plasmid-encoded enzyme = inactivates the drug ADVERSE REACTIONS 1. HEMATOLOGIC Bone Marrow & Red cell production suppression A. Anemia, serum iron, cellular marrow Dose related > 25mcg/mL Reversible Prolonged treatment (1 2 weeks) MOA: Extension of pharmacologic effect

CLINDAMYCIN Chlorine-substituted derivative of Lincomycin (from Streptomyces lincolnensis) Antibacterial Activity SUSCEPTIBLE: Streptococci Staphylococci Pneumococci Bacteroides/other anaerobes RESISTANT: Enterococci G(-) aerobic pathogens Clostridium difficile Mechanism of action Interferes with formation of initiation complexes & aminoacyl translocation reaction = inhibition of protein synthesis Identical binding site with erythromycin on the 50s bacterial ribosome subunit Mechanism of Resistance Mutation of ribosomal receptor site Modification of receptor by methylases Enzymatic inactivation G(-) aerobes poor permeability of outer membrane

Pharmacokinetics Oral : serum conc.= 2-3 ug/ml IV: 5-15 ug/ml (600 mg q 8 hrs.) 90% protein-bound Elimination: Liver, bile, urine Good penetration into most tissues except brain & CSF Clinical Uses: Severe Anaerobic infections: Bacteroides With Aminoglycoside/Cephalosporin: for penetrating wounds of the abdomen & the gut Septic abortion Pelvic abscesses Aspiration pneumonia Prophylactic: for endocarditis in pxs w/ valvular heart disease undergoing dental procedure

With Primaquine = for Pneumocystis carinii pneumonia (AIDS) With Pyrimethamine = for Toxoplasmosis of the brain (AIDS)

Adverse Effects: Diarrhea, nausea Skin rashes Impaired liver function Neutropenia Antibiotic-related colitis (caused by colonization of C. difficile)

STREPTOGAMINS Adverse effects: Infusion-related events: pain at injection site phlebitis arthralgia-myalgia syndrome OXAZOLIDINONES LINEZOLID MOA: Prevents formation of ribosome complex that initiates protein synthesis : Binds to 23S ribosomal RNA of the 50S subunit Resistance : mutation of linezolid binding site on 23S ribosomal RNA Antibacterial activity BACTERIOSTATIC: G (+) pathogens : Staphyloccoci, anaerobic cocci G (+) rods: Corynebacteria, Listeria monocytogenes BACTERICIDAL: Streptococci Pharmacokinetics Oral = 100% bioavailability Metabolism: Oxidation = 2 inactive metabolites Does not induce/inhibit CYP450 enzymes Dose: 600 mg 2x/day

QUINOPRISTIN-DALFOPRISTIN Dalfopristin streptogramin A Quinupristin streptogramin B Quinopristin-Dalfopristin = 30:70 ratio (ex. 30mg quinoprsitin to 70mg Dalfopristin) Bactericidal (most organisms, except Enterococcus faecium) Antibacterial activity G (+) cocci (inc. resistant strains of Streptococci) Staphyloccoci (Methicillin-resistant & suscebtible strains) PCN-resistant strains of S. pneumoniae E. faecium (not E. faecalis) Pharmacokinetics Administered IV Rapid metabolism: Quinopristin (0.85 hrs) Dalfopristin (0.7 hrs) Not metabolized by CYP450 enzymes BUT significantly inhibits CYP3A4(metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, cyclosporine, nonnucleoside reverse transcriptase inhibitors) Elimination: Fecal route : 75 % Urine : < 20 % Dose adjustments NOT necessary in: Renal failure, peritoneal- or hemodialysis Dose adjusted in Hepatic insufficiency

 Pear serum conc. = 18 ug/ml Indications Nosocomial pneumonias Community-acquired pneumonia Vancomycin-resistant E. faecium infxns. Skin infections Multiple drug-resistant G(+) bacteria Toxicity Thrombocytopenia - > 2 weeks admn. Neutropenia (in predisposed pxs. or pxs with bone marrow suppression)