44 Chloramphenicol, Tetracyclines, Macrolides, Clindamycin,

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


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

http://pharmacologycorner.com/protein-synthesis-inhibitors-macrolides-mechanism-of-action-animation-classification-of-agents/


MECHANISM OF ACTION Tetracyclines

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

tRNA to the acceptor site http://pharmacologycorner.com/protein-synthesis-

inhibitors-tetracyclines-mechanism-of-action-animation-classification-of-agents/

Tetracyclines and

Chloramphenicol

Tetracyclines

Antimicrobia activitybroad 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)

ClassificationOlder tetracyclines: 1. Short acting (half life 6 hours)-Tetracycline,

chlortetracycline, oxytetracycline2. Intermediate acting- half life 16 hours-

demeclocyclineNewer 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 tetracyclinesAbsorption: 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.

ExcretionAll tetracyclines are exc. in urine and feces (bile).

Precautions Pregnancy, lactation and in children 8 years. In patients with renal or hepatic disease Don’t use expired preparations.

Adverse effects of tetracylines

I Gastrointestinal. (Dose dependent GI irritation)II Photosensitivity: sunburn, onycholysis & pigmentation of

nailsIII. 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 growth-

V 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


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


TETRACYCLINESB. 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


TETRACYCLINESB. PHARMACOKINETICS Enterohepatic cycling All drugs eliminated in the urine

Doxycycline Excreted in the feces

Together with minocycline have longer half-lives


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

Rickettsia Chlamydia Mycoplasma Some protozoa

Organisms accumulate the drug intracellularly via energy-dependent transport systems


TETRACYCLINESC. ANTIBACTERIAL ACTIVITY Plasmid-mediated resistance is widespread

Decrease activity of the uptake systems Development of efflux pumps for active

extrusion of the drug


TETRACYCLINESD. CLINICAL USES1. 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


TETRACYCLINESD. CLINICAL USES3. Selective uses Minocycline

Meningococcal carrier state Doxycycline

Prevention of malaria Treatment of amoebiasis


TETRACYCLINESD. CLINICAL USES3. 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


TETRACYCLINESE. TOXICITY2. Bony structures and teeth Fetal exposure

Tooth enamel dysplasia Irregularities in bone growth

Contraindicated in pregnancy


TETRACYCLINESE. TOXICITY2. 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 formedbones (impaired long bone formation ) and teeth(discolouration of teeth)


TETRACYCLINESE. TOXICITY3. Hepatic toxicity High doses in pregnant women and

those with preexisting renal disease may impair liver function

Hepatic necrosis


TETRACYCLINESE. TOXICITY4. 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

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).

ChloramphenicolMechanism 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 ribosome- mammalian 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).

ChloramphenicolADME 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 ½ of chloramphenicol.

Adverse effects1. 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 deficiency2. 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 and4. Anaerobic infection- Brain abscess. 5. Intraocular infection6. Topical use: conjunctivitis and external ear infections.


CHLORAMPHENICOLA. 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


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


CHLORAMPHENICOLB. ANTIMICROBIAL ACTIVITY Bacteriostatic Bactericidal for some strains

H. influenzae N. meningitidis Bacteroides


CHLORAMPHENICOLB. ANTIMICROBIAL ACTIVITY Not effective for chlamydia Resistance

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


CHLORAMPHENICOLC. 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


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


CHLORAMPHENICOLD. TOXICITY1. GI disturbances Direct irritation and superinfection

Candidiasis


CHLORAMPHENICOLD. TOXICITY2. Bone marrow Inhibition of red cell maturation decrease

in circulating RBC Reversible


CHLORAMPHENICOLD. TOXICITY3. 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


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


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


MACROLIDESB. ANTIBACTERIAL ACTIVITY Erythromycin

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


MACROLIDESB. ANTIBACTERIAL ACTIVITY Erythromycin

Erythromycin stearate Erythromycin lactobionate Erythromycin estolate

Best absorbed oral preparation


MACROLIDESB. 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


MACROLIDESC. CLINICAL USES Azithromycin

Long half-life, single dose is effective Urogential infections caused by C. trachomatis

4-day course is effective for community-acquiredpneumonia (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


CLINDAMYCINA. 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

44 Chloramphenicol, Tetracyclines, Macrolides, Clindamycin,

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Transcript of 44 Chloramphenicol, Tetracyclines, Macrolides, Clindamycin,