44 Chloramphenicol Tetracyclines Macrolides Clindamycin

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


Anita Q. Sangalang, MD, FPOGSFACULTY OF PHARMACY

UNIVERSITY OF SANTO TOMAS



Selectively inhibit bacterial protein synthesis Protein synthesis in microorganisms is not

identical to mammalian cells 70S ribosomes in bacteria 80S ribosomes in mammalians



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



BACTERIAL PROTEIN SYNTHESIS INHIBITORS

BROAD SPECTRUM MODERATE SPECTRUM NARROW SPECTRUM

CHLORAMPHENICOL MACROLIDES KETOLIDES LINCOSAMIDES

TETRACYCLINES STREPTOGRAMINS

LINEZOLID



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

Except of tetracycline



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



MECHANISM OF ACTION Macrolides, telithromycin, and clindamycin

Bind at 50S-block translocation of peptidyl-

tRNA from the acceptor site to the donor site tRNA cannot access the occupied receptor site,

it is not added to the peptide chain



MECHANISM OF ACTION Tetracyclines

Bind to 30S Blocks the binding of amino-acid-charged

tRNA to the acceptor site



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



MECHANISM OF ACTION Linezolid

Bacteriostatic Binds to a unique site at 50S Blocks formation of tRNA-ribosome-

mRNA complex



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

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



CHLORAMPHENICOL

B. ANTIMICROBIAL ACTIVITY Bacteriostatic Bactericidal for some strains

H. influenzae N. meningitidis Bacteroides



CHLORAMPHENICOL

B. ANTIMICROBIAL ACTIVITY Not effective for chlamydia Resistance

Plasmid mediated-formation of acetyl- transferases that inactivate the drug



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

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



CHLORAMPHENICOL

D. TOXICITY

1. GI disturbances Direct irritation and superinfection

Candidiasis



CHLORAMPHENICOL

D. TOXICITY

2. Bone marrow Inhibition of red cell maturation decrease

in circulating RBC Reversible



CHLORAMPHENICOL

D. TOXICITY

3. Aplastic anemia Rare idiosyncratic reaction Irreversible and maybe fatal



CHLORAMPHENICOLD. TOXICITY4. Gray baby syndrome Premature infants Deficiency of hepatic glucoronyltransferase Tolerated in older infants Decreased RBC, cyanosis and cardiovascular

collapse



TETRACYCLINES

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



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



TETRACYCLINES

B. PHARMACOKINETICS Enterohepatic cycling All drugs eliminated in the urine

Doxycycline Excreted in the feces

Together with minocycline have longer half-lives



TETRACYCLINES

C. ANTIBACTERIAL ACTIVITY Gram (+) and gram (-) bacteria

Rickettsia Chlamydia Mycoplasma Some protozoa

Organisms accumulate the drug intracellularly

via energy-dependent transport systems



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



TETRACYCLINES

D. CLINICAL USES

1. Primary uses Tetracyclines

M. pneumoniae (in adults) Chlamydia Rickettsia Vibrio cholera

Drug of choice


CHLORAMPHENICOL, TETRACYCLINES, MACROLIDES, CLINDAMYCIN, STREPTOGRAMINS, & LINEZOLIDTETRACYCLINESD. CLINICAL USES2. Secondary uses Tetracyclines

Alternative drug for syphilis Respiratory infections caused by susceptible

organisms Prophylaxis against chronic bronchitis Leptospirosis Treatment of acne



TETRACYCLINESD. CLINICAL USES3. Selective uses Tetracycline

Gastrointestinal ulcers caused by H. pylori Doxycycline

Lyme disease



TETRACYCLINES

D. CLINICAL USES

3. Selective uses Minocycline

Meningococcal carrier state Doxycycline

Prevention of malaria Treatment of amoebiasis



TETRACYCLINES

D. CLINICAL USES

3. Selective uses Demeclocycline

ADH-secreting tumors Inhibits renal actions of ADH



TETRACYCLINESE. TOXICITY1. 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



TETRACYCLINES

E. TOXICITY

2. Bony structures and teeth Fetal exposure

Tooth enamel dysplasia Irregularities in bone growth

Contraindicated in pregnancy



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)



TETRACYCLINES

E. TOXICITY

3. Hepatic toxicity High doses in pregnant women and

those with preexisting renal disease may

impair liver function Hepatic necrosis



TETRACYCLINES

E. TOXICITY

4. Renal toxicity Fanconi’s syndrome

Renal tubular acidosis Intake of outdated tetracycline



TETRACYCLINESE. TOXICITY3. Photosensitivity Demeclocycline

Enhanced skin sensitivity to ultraviolet light4. Vestibular toxicity Doxycycline and minocycline

Dose-dependent reversible dizziness and vertigo



MACROLIDESA. CLASSIFICATION AND PHARMACOKINETICS Erythromycin , azithromycin, and clarithromycin

Large cyclic lactone ring structure with attached sugars

Good oral bioavailability Distribute to most body tissues



MACROLIDESA. 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



MACROLIDESA. 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



MACROLIDES

B. ANTIBACTERIAL ACTIVITY Erythromycin

Campylobacter Chlamydia Mycoplasma Legionella Gram (+) cocci, and some gram (-) organisms



MACROLIDES

B. ANTIBACTERIAL ACTIVITY Erythromycin

Erythromycin stearate Erythromycin lactobionate Erythromycin estolate

Best absorbed oral preparation



MACROLIDES

B. ANTIBACTERIAL ACTIVITY Azithromycin and clarithromycin

Same spectra of activity but include greater activity

Chlamydia M. avium complex (MAV) Toxoplasma



MACROLIDESB. 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



MACROLIDESB. 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



MACROLIDESC. CLINICAL USES Erythromycin

M. pneumonia Corynebacterium C. jejuni C. trachomatis L. pneumophilia U. urealyticum B. pertussis



MACROLIDESC. CLINICAL USES Erythromycin

Gram (+) cocci like pneumococci (not penicillin-resistant S. pneumoniae

[PRSP]) Beta-lactamase-producing staphylococci

(not methicillin –resistant S. aureus [MRSA] strains)



MACROLIDESC. CLINICAL USES Azithromycin Similar spectrum of activity but more active

H. influenzae M. catarrhalis Neisseria



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)



MACROLIDESC. CLINICAL USES Clarithromycin

Prophylaxis against and treatment of M. avium complex

Component for drug regimens for ulcers caused by H. pylori



MACROLIDESD. TOXICITY GI irritation is common

Stimulation of motolin receptors Skin rashes Eosinophilia



MACROLIDESD. TOXICITY Erythromycin estolate

Hypersensitivity-based acute cholestatic hepatitis

Rare in children Increased risk in pregnant patients



MACROLIDESD. TOXICITY Erythromycin

Inhibits several forms of cytochrome P450 Increases the plasma levels

Anticoagulants Carbamazepine Cisapride Digoxin Theophylline



MACROLIDESD. 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



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



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



CLINDAMYCINA. CLASSIFICATION AND PHARMACOKINETICS Lincosamides Lincomycin and clindamycin

Inhibit bacterial protein synthesis Mechanism similar to macrolides but are not

chemically related



CLINDAMYCINA. CLASSIFICATION AND PHARMACOKINETICS Resistance

Methylation of the binding site on 50S Enzymatic inactivation

Cross-resistance with macrolides is common



CLINDAMYCIN

A. CLASSIFICATION AND PHARMACOKINETICS Orally absorbed Good tissue penetration Eliminated partly by metabolism and partly by

biliary and renal excretion



CLINDAMYCINB. 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



CLINDAMYCINB. 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



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



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



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

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44 Chloramphenicol Tetracyclines Macrolides Clindamycin

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