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

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

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

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

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

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 http://pharmacologycorner.com/protein-synthesisinhibitors-macrolides-mechanism-of-actionanimation-classification-of-agents/

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MECHANISM OF ACTION Tetracyclines Bind to 30S Blocks the binding of amino-acid-charged tRNA to the acceptor site http://pharmacologycorner.com/protein-synthesisinhibitors-tetracyclines-mechanism-of-actionanimation-classification-of-agents/

Tetracyclines and Chloramphenicol

Tetracyclines
Antimicrobia activity broad spectrum antibiotics: effective against a large no of organisms:

Atypical organisms (like Chlamydia spp, Legionella spp, Rickettsiae, Mycoplasma pneumoniae) Some atypical mycobacteria Camplylobacter jejuni Helicobacter pylori. A variety of gram-positive, gram-negative organisms: vibrio cholerae, plague, tularemia, brucellosis. For protozoal infection- E. Histolytica, P.falciparum. Effective against many anaerobes (doxycycline)

Classification Older tetracyclines: 1. Short acting (half life 6 hours)-Tetracycline, chlortetracycline, oxytetracycline 2. Intermediate acting- half life 16 hoursdemeclocycline Newer ones : 3. Long acting half life-18-24 hours- doxycycline and minocycline are more lipophilic and most active. 4. Longest acting: Tigecycline- newest half life-36 hours

Tetracyclines
Mechanism of action Bacteriostatic agents. Inhibit protein synthesis via reversible binding to 30 s ribosome, block the binding of aminoacyl tRNA to the acceptor site on mRNA. This prevents addition of aminoacid to growing polypeptide. Resistance : Dec. accumulation due to dec. influx, or inc. efflux. Dec. access to ribosome due to presence of ribosome protection proteins Enzymatic inactivation of tetracycline

ADME of tetracyclines
Absorption: Doxycycline & minocycline- 100%. Food does not interfere with their abs. Abs. of others is dec. by concurrent adm. of dairy products alum, Ca++, Mg, Bi & iron salts- due to chelation of divalent or trivalent cations. Distribution Protein binding 40-80% Conc. in liver, exc. in int. via bile-EHC. Widely distributed in tissues except CSF- On I.V: appear in spinal fluid. Tetracyclines cross placenta High conc. found in breast milk.

Metabolism

Minocycline, doxycycline and tigecycline metabolized in liver. Doxycycline is exc. in feces- preferred to treat extra renal infection in patients with renal failure. Enzyme inducers dec. their half lives.

Excretion
All tetracyclines are exc. in urine and feces (bile).

Precautions

Pregnancy, lactation and in children 8 years. In patients with renal or hepatic disease Dont use expired preparations.

Adverse effects of tetracylines

I Gastrointestinal. (Dose dependent GI irritation) II Photosensitivity: sunburn, onycholysis & pigmentation of nails III. Hepatic toxicity: with Large oral or IV doses esp. in pregnant women hepatic necrosis. IV.Effect on bones and teeth: Brown discoloration of the teeth (milk (from mid pregnancy to 6 months postnatally & permanent- aged- 2 M- 5 years). 40% dec. in bone growthV Superinfection

Uses
DOC for infections produced by : chlamydiae; rickettsia; mycoplasma, legionella infections. Vibrio cholera. In combination with aminoglycosides: plague, brucellosis, tularemia. Other uses: Exacerbation of chronic bronchitis CAP Treatment of acne & skin infections. Tetracycline for eradication of H.pylori Doxycycline: lyme disease (1st choice); and prophylaxis of chloroquine resistant P. falciparum malaria

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

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

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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

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TETRACYCLINES B. PHARMACOKINETICS 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 C. ANTIBACTERIAL ACTIVITY Gram (+) and gram (-) bacteria Rickettsia Chlamydia Mycoplasma Some protozoa Organisms accumulate the drug intracellularly via energy-dependent transport systems

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TETRACYCLINES C. ANTIBACTERIAL ACTIVITY 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 E. TOXICITY 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 E. TOXICITY 3. Hepatic toxicity High doses in pregnant women and those with preexisting renal disease may impair liver function Hepatic necrosis

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

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

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

TETRACYCLINES E. TOXICITY 3. Photosensitivity Demeclocycline Enhanced skin sensitivity to ultraviolet light 4. Vestibular toxicity Doxycycline and minocycline Dose-dependent reversible dizziness and vertigo

Tigecycline

Effective against: Certain tetracycline resistant strains of organisms; MRSA; vancomycin resistant staph; VREnterococci, Strep (penicillin susceptible & resistant); G+ve rods; enterobacteriaceae; multidrug resistant acinetobacter spp; anaerobes (G+ve, G-ve); atypical agents: rickettisiae, chlamydia, legionella, rapidly growing mycobacteria. Proteus and pseudomonas are intrinsically resistant.

Uses

Multidrug resistant nosocomial pathogens (MRSA, extended spectrum beta lactamase producing G ve organisms & acinetobacter spp. Treatment of skin & skin structure infections & intraabdominal infections. Not for UTI (not effective conc in urine).

Chloramphenicol
Mechanism of action Inhibits protein synthesis, binds reversibly to 50 S ribosomal subunit, prevents binding of aminoacyl tRNA to 50 S ribosomes, inhibits peptidyl transferase step in protein synthesis. Also inhibits mitochondrial protein synthesis by acting on 70 S ribosomemammalian erythropoietic cells are particularly sensitive to the drug. Bacteriostatic, bactericidial for H.influanzae, N.meningitidis & S.pneumoniae

Antimicrobial spectrum: broad spectrum (G + ve & ve orga. aerobes and most anaerobes) Effective against H. influenzae, N. meningitidis, Salmonella typhi, Brucella species, Bordetella pertussis & anaerobes- highly susceptible. Effective against Rickettsiae, Mycoplasma & Chlamydia. Resistance to chloramphenicol: Acetylation of chloramphenicol due to plasmid encoded acetyl transferase. Acetylated drug fails to bind to bacterial ribosomes. Dec. permeability of the microorganisms (E. Coli).

Chloramphenicol ADME
Well absorbed orally. Distributed in body fluids- CSF conc. 60%, crosses placental barrier & aqueous humor. Metabolized in the liver by glucuronidation by glucuronyl transferase. Drug interactions Irreversible inhibition of CYP P450 leads to inc. half-life of warfarin, phenytoin, tolbutamide, etc. Enzyme inducers (rifampin, phenobarbitone) shorten the T of chloramphenicol.

Adverse effects
1. Hematological toxicity: i Idiosyncratic reaction (dose independent)- aplastic anemia: leukopenia, thrombocytopenia & aplasia of marrow. May be fatal or may lead to acute myeloblastic leukemia later on. ii A 2nd dose related hematological effect: reversible suppression of bone marrow with conc. > 25 g/ml. iii. Hemolytic anemia in G6PD deficiency 2. Toxic and irritable effects Fatal chloramphenicol toxicity (conc >100 g/ml) - in neonate esp. in premature - called "gray baby syndrome" -due to failure of glucuronidation (lack of glucuronyl transferase in first 3-4 weeks of life, & dec. renal function) Optic neuritis, peripheral neuritis. 3. Hypersensitivity reactions. 4. GI disturbances: N,V, D. 5. Superinfection: oral or vaginal candidiasis due to alteration of normal flora.

Therapeutic uses
Because of potential toxicity, bacterial resistance & availability of effective alternative drugs, it is rarely used. Should never be used for minor infections, or infections which could be treated by other drugs.
Second choice drug in 1 Typhoid fever: 2. Bacterial meningitis. 3. rickettsial infection and 4. Anaerobic infection- Brain abscess. 5. Intraocular infection 6. Topical use: conjunctivitis and external ear infections.

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

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

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

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

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

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CHLORAMPHENICOL C. CLINICAL USES 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

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

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

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

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

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

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

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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

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

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MACROLIDES C. CLINICAL USES Erythromycin M. pneumonia Corynebacterium C. jejuni C. trachomatis L. pneumophilia U. urealyticum B. pertussis

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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)

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MACROLIDES C. CLINICAL USES Azithromycin Similar spectrum of activity but more active H. influenzae M. catarrhalis Neisseria

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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)

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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

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MACROLIDES D. TOXICITY Erythromycin estolate Hypersensitivity-based acute cholestatic hepatitis Rare in children Increased risk in pregnant patients

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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

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

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

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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

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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

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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

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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

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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