Chloramphenicol, Tetracyclines, Macrolides, Clindamycin

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
Protein Synthesis: Role of Ribosomes

Ribosomes read the
sequence of messenger
RNAs and assemble
proteins out of amino
acids bound to transfer
RNAs.
Discovery of the ribosomes:
Albert Claude and Christian de
Duve, George Emil Palade The
(Nobel Prize in 1974)
Detailed structure and mechanism of the ribosome: Venkatraman Ramakrishnan,
Thomas A. Steitz and Ada E. Yonath (The Nobel Prize in Chemistry 2009 )
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
CHLORAMPHENICOL
MODERATE SPECTRUM
MACROLIDES
TETRACYCLINES
KETOLIDES
NARROW SPECTRUM
LINCOSAMIDES
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 peptidyltRNA 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-ribosomemRNA 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 acetyltransferases 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

in circulating RBC
Reversible
decrease
CHLORAMPHENICOL
D. 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
This condition is due to a lack of glucoronidation reactions occurring in the baby,
thus leading to an accumulation of toxic chloramphenicol metabolites.
The UDP-glucuronyl transferase enzyme system of infants, especially premature infants,

is immature and incapable of metabolizing the excessive drug load.
Insufficient renal excretion of the unconjugated drug.
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.
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
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
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 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
Fanconis syndrome
Renal tubular acidosis
Intake of outdated tetracycline
TETRACYCLINES
E.
TOXICITY
3.
Photosensitivity
Demeclocycline
Enhanced skin sensitivity to ultraviolet light
4.
Vestibular toxicity
Doxycycline and minocycline

Dose-dependent reversible 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
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
MACROLIDES
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.
Erythromycin
Campylobacter
Chlamydia
Mycoplasma
Legionella
Gram (+) cocci, and some gram (-) organisms
MACROLIDES
B.
Erythromycin
Erythromycin stearate
Erythromycin lactobionate
Erythromycin estolate
Best absorbed oral preparation
MACROLIDES
B.
Azithromycin and clarithromycin

Same spectra of activity but include greater
activity
Chlamydia
M. avium complex (MAV)
Toxoplasma
MACROLIDES
B.
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
MACROLIDES
B.
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
(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 and treatment of M. avium
complex
Component for drug regimens for ulcers caused
by H. pylori
MACROLIDES
D. TOXICITY
GI irritation is common
Stimulation of motolin receptors
Skin rashes
Eosinophilia
MACROLIDES
D. TOXICITY
Erythromycin estolate
Hypersensitivity-based acute cholestatic
hepatitis
Rare in children
Increased risk in pregnant patients
MACROLIDES
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 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
CLINDAMYCIN
Lincosamides
Lincomycin and clindamycin

Inhibit bacterial protein synthesis
Mechanism similar to macrolides but are not
chemically related
CLINDAMYCIN
Resistance
Methylation of the binding site on 50S
Enzymatic inactivation
Cross-resistance with macrolides is common
CLINDAMYCIN
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 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 penicillinase-resistant penicillin (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
Clarithromycin
PO: Biaxin 250-500 mg q 12 hours; Biaxin XL 1000 mg qday

Spectrum of Activity: Gram (+) and Gram (-)
Indications: otitis media, CAP, pharyngitis/tonsillitis, sinusitis, uncomplicated
skin infections, prevention of MAC, duodenal ulcer disease
S. aures, S. pyogenes, S. pneumoniae, Mycobacterium avium complex
C. pneumoniae, C. trachomatis, L. pneumoniae
H. influenzae, H.pylori
Drug Interactions: Substrate of CYP 3A4 and Inhibits CPY 3A4(major)

CYP 1A2 (weak)
Renal Adjustments:
CrCl < 30 ml/min: the normal dose or double the dosing interval
ADR:
Theophylline, statins, digoxin, warfarin, cyclosporine
Prolongs the QT interval use with caution in CAD

N/V, diarrhea, headache
Counseling Points:
Take XL formulation with food; do not chew or crush
Vancomycin
Class: Glycopeptide
antibiotic
MOA: Inhibition of
bacterial cell wall synthesis
by binding D-ala-D-ala
Goodman & Gilmans The Pharmacological Basis of Therapeutics 11th Ed. (2006)
Peptidoglycan Synthesis
Penicillin binding
protein
Vancomycin
IV, PO
Spectrum: Gram (+)
Drug of Choice
Indications
IV: Serious methicillin-resistant Staphylococcal infections: pneumonia,

endocarditis, osteomyelitis, SSSI
PO: pseudomembranous colitis (metronidazole preferred)
Staphylococcal infections in Penicillin allergic patients
NOTE: Do not use in non-Penicillin allergic patients. Vancomycin does not kill
as rapidly as antistaphylococcal -lactams, and may negatively impact clinical
outcome
Unique Qualities
MRSA
Monitor trough serum concentrations

Poor oral absorption
Adjust dose for renal impairment
ADRs
Red Man Syndrome

Ototoxicity
Nephrotoxicity w/ other nephrotoxic agents
Vancomycin
Mechanism of action: Inhibits bacterial cell wall synthesis

Spectrum of action: Gram positive organisms
Including: Listeria, Rhodococcus, Peptostreptococcus

Bacteriostatic against enterococcus
Mechanism of resistance:
Enterococcus: Van A E
Peptidoglycan precursor has decreased affinity for vancomycin

D-ala-D-ala replaced by D-ala-D-lac
Staphylococcus aureus:
VISA isolates:
Increased amount of precursor with decreased affinity
Thicker cell wall

hVISA: heterogenous bacterial population
Vancomycin
Dose:
Based on total body weight and renal function

15 20 mg/kg
Normal renal function: q 12 dosing
Goal trough concentrations:
10 15 mcg/mL: bacteremia, skin and soft tissue

infections
15 20 mcg/mL: osteomyelitis, meningitis,
pneumonia

Chloramphenicol, Tetracyclines, Macrolides, Clindamycin

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Chloramphenicol, Tetracyclines, Macrolides, Clindamycin

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CHLORAMPHENICOL,

Selectively inhibit bacterial protein synthesis

Protein Synthesis: Role of Ribosomes

Basis for selective toxicity against microorganisms

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

Fraction excreted in urine unchanged

Inactivated by hepatic glucoronosyltransferase

Bactericidal for some strains

Not effective for chlamydia

Few uses as systemic drug because of toxicity

Backup drug for severe infections caused by

Treatment of pneumococcal and meningococcal

Sometimes used for ricketssial infections

Infections caused by anaerobes like B. fragilis

Commonly used as topical agent

Direct irritation and superinfection

Inhibition of red cell maturation

Rare idiosyncratic reaction

Irreversible and maybe fatal

Deficiency of hepatic glucoronyltransferase

Tolerated in older infants

Decreased RBC, cyanosis and cardiovascular

The UDP-glucuronyl transferase enzyme system of infants, especially premature infants,

Broad range of antimicrobial activity

Minor differences in activity against organisms

Oral absorption is variable especially for older

Impaired by food and multivalent cations

Wide tissue distribution

Cross the placental barrier

All drugs eliminated in the urine

Together with minocycline have longer half-lives

Gram (+) and gram (-) bacteria

Organisms accumulate the drug intracellularly

Plasmid-mediated resistance is widespread

Mild nausea and diarrhea to severe, possibly

Disturbances in the normal flora

Younger children (under age 8)

High doses in pregnant women and

Doxycycline and minocycline

Erythromycin , azithromycin, and clarithromycin

Erythromycin and clarithromycin

Azithromycin and clarithromycin

Resistance in gram (+) organisms

Cross-resistance between individual macrolides

Partial cross-resistance with other drugs that bind

Similar spectrum of activity but more active

Urogential infections caused by C. trachomatis

Structurally related to macrolides

Same MOA as erythromycin

Similar spectrum of antimicrobial activity

Some macrolide-resistant strains are susceptible

Poor substrate for bacterial efflux pump that mediate

CAP and other upper respiratory tract infections

Given orally once daily

Eliminated in the bile and urine

Inhibitor of cytochrome CYP3A4 isozyme

Lincomycin and clindamycin

Cross-resistance with macrolides is common

Good tissue penetration