CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID

Anita Q. Sangalang, MD, FPOGS

FACULTY OF PHARMACY UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID

Selectively inhibit bacterial protein synthesis Protein synthesis in microorganisms is not identical to mammalian cells  70S ribosomes in bacteria  80S ribosomes in mammalians

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Basis for selective toxicity against microorganisms without causing major effects on mammalian cells  Differences Ribosomal subunits Chemical composition Functional specificities of component nucleic acids and proteins

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID

BACTERIAL PROTEIN SYNTHESIS INHIBITORS

BROAD SPECTRUM

MODERATE SPECTRUM

NARROW SPECTRUM

CHLORAMPHENICOL

MACROLIDES

KETOLIDES

LINCOSAMIDES STREPTOGRAMINS LINEZOLID

TETRACYCLINES

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MECHANISM OF ACTION Bacteriostatic inhibitors of protein synthesis 50S ribosome unit  Except of tetracycline

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MECHANISM OF ACTION Chloramphenicol  Inhibits transpeptidation (catalyzed by peptidyl transferase)  Blocks the binding of aminoacyl moiety of tRNA to mRNA complex peptide at the donor site cannot be transferred to the amino acid acceptor

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID

MECHANISM OF ACTION Macrolides, telithromycin, and clindamycin  Bind at 50S-block translocation of peptidyltRNA from the acceptor site to the donor site  tRNA cannot access the occupied receptor site, it is not added to the peptide chain

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MECHANISM OF ACTION Tetracyclines  Bind to 30S  Blocks the binding of amino-acid-charged tRNA to the acceptor site

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MECHANISM OF ACTION Streptogramins  Bactericidal  Bind to 50S  Constrict the exit channel on the ribosome through which polypeptides are extruded tRNA synthase activity is inhibited

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MECHANISM OF ACTION Linezolid  Bacteriostatic  Binds to a unique site at 50S  Blocks formation of tRNA-ribosomemRNA complex

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID CHLORAMPHENICOL A. CLASSIFICATION Simple and distinctive structure No other antimicrobials in this class Oral as well as parenteral Distributed throughout all tissues Crosses placental and blood-brain barriers

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID

CHLORAMPHENICOL A. CLASSIFICATION Enterohepatic cycling Fraction excreted in urine unchanged Inactivated by hepatic glucoronosyltransferase

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CHLORAMPHENICOL B. ANTIMICROBIAL ACTIVITY Bacteriostatic Bactericidal for some strains  H. influenzae  N. meningitidis  Bacteroides

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CHLORAMPHENICOL B. ANTIMICROBIAL ACTIVITY Not effective for chlamydia Resistance  Plasmid mediated-formation of acetyltransferases that inactivate the drug

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CHLORAMPHENICOL CLINICAL USES C. Few uses as systemic drug because of toxicity Backup drug for severe infections caused by salmonella Treatment of pneumococcal and meningococcal meningitis in beta-lactam-sensitive persons

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CHLORAMPHENICOL CLINICAL USES C. Sometimes used for ricketssial infections Infections caused by anaerobes like B. fragilis Commonly used as topical agent

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CHLORAMPHENICOL D. TOXICITY 1. GI disturbances Direct irritation and superinfection  Candidiasis

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CHLORAMPHENICOL D. TOXICITY 2. Bone marrow Inhibition of red cell maturation in circulating RBC Reversible

decrease

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CHLORAMPHENICOL D. TOXICITY 3. Aplastic anemia Rare idiosyncratic reaction Irreversible and maybe fatal

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID CHLORAMPHENICOL D. TOXICITY 4. Gray baby syndrome Premature infants Deficiency of hepatic glucoronyltransferase Tolerated in older infants Decreased RBC, cyanosis and cardiovascular collapse

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID

TETRACYCLINES A. CLASSIFICATION Structural congeners Broad range of antimicrobial activity Minor differences in activity against organisms

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES B. PHARMACOKINETICS Oral absorption is variable especially for older drugs Impaired by food and multivalent cations  Calcium, iron and aluminum Wide tissue distribution Cross the placental barrier

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES PHARMACOKINETICS B. Enterohepatic cycling All drugs eliminated in the urine  Doxycycline Excreted in the feces Together with minocycline have longer half-lives

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES ANTIBACTERIAL ACTIVITY C. Gram (+) and gram (-) bacteria  Rickettsia Chlamydia  Mycoplasma Some protozoa Organisms accumulate the drug intracellularly via energy-dependent transport systems

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID

TETRACYCLINES ANTIBACTERIAL ACTIVITY C. Plasmid-mediated resistance is widespread  Decrease activity of the uptake systems  Development of efflux pumps for active extrusion of the drug

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES D. CLINICAL USES 1. Primary uses Tetracyclines  M. pneumoniae (in adults)  Chlamydia  Rickettsia  Vibrio cholera Drug of choice

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES D. CLINICAL USES 2. Secondary uses Tetracyclines  Alternative drug for syphilis  Respiratory infections caused by susceptible organisms  Prophylaxis against chronic bronchitis  Leptospirosis  Treatment of acne

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES D. CLINICAL USES 3. Selective uses Tetracycline  Gastrointestinal ulcers caused by H. pylori Doxycycline  Lyme disease

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES D. CLINICAL USES 3. Selective uses Minocycline  Meningococcal carrier state Doxycycline  Prevention of malaria  Treatment of amoebiasis

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES D. CLINICAL USES 3. Selective uses Demeclocycline  ADH-secreting tumors Inhibits renal actions of ADH

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES E. TOXICITY 1. GI disturbances Mild nausea and diarrhea to severe, possibly life-threatening colitis Disturbances in the normal flora  Candidiasis (oral and vaginal) Bacterial superinfection  S. aureus or C. difficile  Rare

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES TOXICITY E. 2. Bony structures and teeth Fetal exposure  Tooth enamel dysplasia  Irregularities in bone growth Contraindicated in pregnancy

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES E. TOXICITY 2. Bony structures and teeth Younger children (under age 8)  Enamel dysplasia and crown deformation when permanent teeth appears  Bind with calcium and deposit in newly formed bones (impaired long bone formation ) and teeth (discolouration of teeth)

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES TOXICITY E. 3. Hepatic toxicity High doses in pregnant women and those with preexisting renal disease may impair liver function  Hepatic necrosis

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TETRACYCLINES TOXICITY E. 4. Renal toxicity Fanconis syndrome  Renal tubular acidosis  Intake of outdated tetracycline

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID TETRACYCLINES TOXICITY E. 3. Photosensitivity Demeclocycline  Enhanced skin sensitivity to ultraviolet light 4. Vestibular toxicity Doxycycline and minocycline  Dose-dependent reversible dizziness and vertigo

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES A. CLASSIFICATION AND PHARMACOKINETICS Erythromycin , azithromycin, and clarithromycin  Large cyclic lactone ring structure with attached sugars  Good oral bioavailability  Distribute to most body tissues

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES A. CLASSIFICATION AND PHARMACOKINETICS Azithromycin  Absorption is impeded by food  Levels in tissues and phagocytes are higher than in plasma  Eliminated slowly in the urine mainly as unchanged drug  Half-life is 2-4 days

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES A. CLASSIFICATION AND PHARMACOKINETICS Erythromycin and clarithromycin  Elimination of intact drug is rapid  Biliary excretion Erythromycin  Hepatic metabolism and urinary excretion Clarithromycin  Half-life is 2-5 hours

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES B. ANTIBACTERIAL ACTIVITY Erythromycin  Campylobacter  Chlamydia  Mycoplasma  Legionella  Gram (+) cocci, and some gram (-) organisms

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES B. ANTIBACTERIAL ACTIVITY Erythromycin  Erythromycin stearate  Erythromycin lactobionate  Erythromycin estolate Best absorbed oral preparation

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES B. ANTIBACTERIAL ACTIVITY Azithromycin and clarithromycin  Same spectra of activity but include greater activity Chlamydia M. avium complex (MAV) Toxoplasma

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES B. ANTIBACTERIAL ACTIVITY Resistance in gram (+) organisms  Efflux pump mechanisms  Production of methylase that adds methyl group to the ribosomal binding site Resistance to enterobacteriaceae  Formation of drug-metabolizing esterases

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES B. ANTIBACTERIAL ACTIVITY Cross-resistance between individual macrolides is complete Partial cross-resistance with other drugs that bind to the same site occur in methylase-producing strains  Clindamycin and streptogramins

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES C. CLINICAL USES Erythromycin  M. pneumonia Corynebacterium  C. jejuni C. trachomatis  L. pneumophilia U. urealyticum  B. pertussis

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES C. CLINICAL USES Erythromycin  Gram (+) cocci like pneumococci (not penicillin-resistant S. pneumoniae [PRSP])  Beta-lactamase-producing staphylococci (not methicillin resistant S. aureus [MRSA] strains)

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES C. CLINICAL USES Azithromycin Similar spectrum of activity but more active  H. influenzae  M. catarrhalis  Neisseria

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES C. CLINICAL USES Azithromycin  Long half-life, single dose is effective Urogential infections caused by C. trachomatis  4-day course is effective for community-acquired pneumonia (CAP)

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES C. CLINICAL USES Clarithromycin  Prophylaxis against and treatment of M. avium complex  Component for drug regimens for ulcers caused by H. pylori

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MACROLIDES D. TOXICITY GI irritation is common  Stimulation of motolin receptors  Skin rashes  Eosinophilia

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES D. TOXICITY Erythromycin estolate  Hypersensitivity-based acute cholestatic hepatitis  Rare in children  Increased risk in pregnant patients

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES D. TOXICITY Erythromycin  Inhibits several forms of cytochrome P450  Increases the plasma levels Anticoagulants Carbamazepine Cisapride Digoxin Theophylline

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID MACROLIDES D. TOXICITY Clarithromycin  Similar drug interactions of erythromycin can occur Azithromycin  Structure of lactone ring is slightly different  Drug interactions are uncommon  Does not inhibit hepatic cytochrome P450

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TELITHROMYCIN Ketolide Structurally related to macrolides Same MOA as erythromycin Similar spectrum of antimicrobial activity Some macrolide-resistant strains are susceptible because it binds more tightly to ribosomes

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TELITHROMYCIN Poor substrate for bacterial efflux pump that mediate resistance CAP and other upper respiratory tract infections Given orally once daily Eliminated in the bile and urine Inhibitor of cytochrome CYP3A4 isozyme

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID CLINDAMYCIN A. CLASSIFICATION AND PHARMACOKINETICS Lincosamides Lincomycin and clindamycin  Inhibit bacterial protein synthesis  Mechanism similar to macrolides but are not chemically related

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CLINDAMYCIN A. CLASSIFICATION AND PHARMACOKINETICS Resistance  Methylation of the binding site on 50S  Enzymatic inactivation Cross-resistance with macrolides is common

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CLINDAMYCIN A. CLASSIFICATION AND PHARMACOKINETICS Orally absorbed Good tissue penetration Eliminated partly by metabolism and partly by biliary and renal excretion

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID CLINDAMYCIN B. CLINICAL USE AND TOXICITY Clindamycin  Severe infections Anaerobes like bacteroides  Backup drug against gram (+) cocci  Prophylaxis for endocarditis in valvular heart disease who are allergic to penicillin  Active against P. carinii and T. gondii

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID CLINDAMYCIN B. CLINICAL USE AND TOXICITY Clindamycin  Toxicity GI irritation Skin rashes Neutropenia Hepatic dysfunction Superinfection such as C. difficile and pseudomembranous colitis  Treated by oral vancomycin

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS Quinupristin-dalfopristin  Combination of 2 streptogramins  Bactericidal  Postantibiotic effect Duration of bacterial activity is longer than the half-lives of the 2 compounds  Used for PRP, MRSA and vancomycin-resistant staphylococci (VRSA) and resistant E. faecium

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID LINEZOLID First of a new class of antibiotics Oxazolidinones Gram (+) cocci, including strains resistant to beta-lactams and vancomycin Binds to a unique site on the 23S ribosomal RNA of 50S No cross-resistance with other protein synthesis inhibitors

CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLID LINEZOLID Resistance  Rare  Decreased affinity of the drug for its binding site Available in oral and parenteral form Thrombocytopenia and neutropenia occur in immunocompromised patients