chapter 44 chloramphenicol

8/3/2019 Chapter 44 Chloramphenicol

1/8

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 majoreffects on mammalian cells

Differences

Ribosomal

subunits

Chemical

composition

Functional

specificities of

component

nucleic acids andproteins

MECHANISM OF ACTION

Bacteriostatic inhibitors ofprotein 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 complexpeptide 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 donorsite

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-chargedtRNA to the

acceptor site

MECHANISM OF ACTION

Streptogramins

Bactericidal

Bind to 50S

Constrict the exit channel

on the ribosome through

which polypeptides are

extrudedtRNA synthase

activity is inhibited

MECHANISM OF ACTION

Linezolid

Bacteriostatic


2/8

Binds to a unique site at

50S

Blocks formation of tRNA-

ribosome-

mRNA complex

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

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

CHLORAMPHENICOLC. 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 andsuperinfection

Candidiasis

CHLORAMPHENICOL

D. TOXICITY

2. Bone marrow

Inhibition of red cell maturation

decrease

in circulating RBC

Reversible

CHLORAMPHENICOLD. TOXICITY

3. Aplastic anemia

Rare idiosyncratic reaction

Irreversible and maybe fatal

CHLORAMPHENICOL

D. TOXICITY

4. Gray baby syndrome

Premature infants

Deficiency of hepatic

glucoronyltransferase Tolerated in older infants

Decreased RBC, cyanosis and

cardiovascular

collapse

TETRACYCLINES

A. CLASSIFICATION

Structural congeners


3/8

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

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

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


4/8

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

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 deformationwhen 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 womenand

those with preexisting renal

disease may

impair liver function

Hepatic necrosis

TETRACYCLINES

E. TOXICITY

4. Renal toxicity

Fanconis syndrome

Renal tubular acidosis

Intake of outdatedtetracycline

TETRACYCLINES

E. TOXICITY

3. Photosensitivity

Demeclocycline

Enhanced skin sensitivity

to ultraviolet light

4. Vestibular toxicity

Doxycycline and minocycline

Dose-dependentreversible dizziness and

vertigo

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

MACROLIDES


PHARMACOKINETICS

Azithromycin

Absorption is impeded by

food

Levels in tissues andphagocytes are higher

than in plasma

Eliminated slowly in the

urine mainly as

unchanged drug

Half-life is 2-4 days


5/8

MACROLIDES


PHARMACOKINETICS

Erythromycin and

clarithromycin

Elimination of intact drugis 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


Erythromycin

Erythromycin stearate

Erythromycin

lactobionate

Erythromycin estolate

Best absorbed oral

preparation

MACROLIDES


Azithromycin and clarithromycin

Same spectra of activity

but include greater

activity

Chlamydia

M. avium complex

(MAV)

Toxoplasma

MACROLIDES


Resistance in gram (+)

organisms

Efflux pump mechanisms

Production of methylase

that adds methyl groupto the ribosomal binding site

Resistance to

enterobacteriaceae

Formation of drug-metabolizing

esterases

MACROLIDES


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

MACROLIDES

C. CLINICAL USES

Erythromycin M. pneumonia

Corynebacterium

C. jejuni C.

trachomatis

L. pneumophilia U.

urealyticum

B. pertussis

MACROLIDES

C. CLINICAL USES

Erythromycin Gram (+) cocci like

pneumococci

(not penicillin-resistant S.

pneumoniae [PRSP])

Beta-lactamase-

producing staphylococci


6/8

(not methicillin resistant

S. aureus [MRSA]

strains)

MACROLIDES

C. 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)

MACROLIDES

C. CLINICAL USES

Clarithromycin

Prophylaxis against andtreatment ofM. avium

complex

Component for drug

regimens for ulcers

caused

by H. pylori

MACROLIDES

D. TOXICITY

GI irritation is common

Stimulation of motolinreceptors

Skin rashes

Eosinophilia

MACROLIDES

D. TOXICITY

Erythromycin estolate

Hypersensitivity-based

acute cholestatic

hepatitis

Rare in children

Increased risk in

pregnant patientsMACROLIDES

D. TOXICITY

Erythromycin

Inhibits several forms of

cytochrome P450

Increases the plasma

levels

Anticoagulants

Carbamazepine

Cisapride

Digoxin

Theophylline

MACROLIDES

D. TOXICITY

Clarithromycin

Similar drug interactions

of erythromycincan 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


7/8

Some macrolide-resistant

strains are susceptible because

it binds more tightly to

ribosomes

TELITHROMYCIN

Poor substrate for bacterialefflux 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

CLINDAMYCIN

A. CLASSIFICATION ANDPHARMACOKINETICS

Lincosamides

Lincomycin and clindamycin

Inhibit bacterial protein

synthesis

Mechanism similar to

macrolides but are not

chemically related

CLINDAMYCIN

A. CLASSIFICATION ANDPHARMACOKINETICS

Resistance

Methylation of the

binding site on 50S

Enzymatic inactivation

Cross-resistance with

macrolides is common

CLINDAMYCIN


PHARMACOKINETICS Orally absorbed

Good tissue penetration

Eliminated partly by metabolism

and partly by biliary and renal

excretion

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

CLINDAMYCIN

B. CLINICAL USE AND TOXICITY Clindamycin

Toxicity

GI irritation

Skin rashes

Neutropenia

Hepatic

dysfunction

Superinfection

such as C. difficile

andpseudomembranou

s 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


8/8

Used for PRP, MRSA and

vancomycin-resistant

staphylococci (VRSA) and

resistant E. faecium

LINEZOLID

First of a new class ofantibiotics

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 inhibitorsLINEZOLID

Resistance

Rare

Decreased affinity of the

drug for its binding site

Available in oral and parenteral

form

Thrombocytopenia and

neutropenia occur in

immunocompromised patients

chapter 44 chloramphenicol

Documents