Download MACROLIDES Macrolide antibiotics contain a many membered

NEWER MACROLIDES
• Improved acid stability, tissue
penetration.
• Broader spectrum of activity.
ANTIMICROBIAL
ACTIVITY
• Most active against gram-positive cocci
and bacilli.
• Mycoplasma, Legionella and Chlamydia.
ANTIMICROBIAL
ACTIVITY
• Mycobacterium avium intracellulare
(MAC).
ABSORPTION
• Macrolides are incompletely but adequately
absorbed from the GI tract.
• Erythromycin base is inactivated by stomach
acid.
• Made in various acid resistant forms.
• Food interferes with absorption.
ABSORPTION
• Erythromycin estolate is absorbed best.
• Usually no one preparation offers a
significant therapeutic advantage.
• The newer macrolides are absorbed more
rapidly than erythromycin.
DISTRIBUTION
• Well distributed except into the CNS.
• In meningitis enough gets into the CNS to
be therapeutically effective.
METABOLISM AND
EXCRETION
• Most of the erythromycin is metabolized.
• Erythromycin is concentrated in the liver
and excreted in active form in the bile.
THERAPEUTIC USES
• A useful alternative to the penicillins.
– Infections caused by pneumococci and group
A streptococci with penicillin allergy.
– Minor infections caused by penicillin
resistant or sensitive Staph. Aureus.
– Prophylaxis of rheumatic fever and subacute
bacterial endocarditis.
MYCOPLASMA PNEUMONIA
MYCOPLASMA PNEUMONIA
• A macrolide or tetracycline is the drug of
choice for Mycoplasma infections.
• Reduces the duration of fever and
accelerates the clearing of the chest
radiographs.
CONTRAINDICATIONS
• Pregnancy (the estolate)-because of the
possibility of hepatotoxicity.
• Hepatic dysfunction.
DRUG-DRUG
INTERACTIONS
• Erythromycin (and clarithromycin)
inhibit Cytochrome P-450 enzymes.
Antifungals,verapamil,
diltiazem
Erythromycin
Demethylase
CytP3A4
DRUG-DRUG INTERACTIONS
• Drugs that prolong QT interval.
COMPARISON OF MACROLIDES
Erythromycin Clarithromycin Azithromycin
Effect of food
on
absorption
Yes
No
No
G.I.
intolerance
Yes
No
No
Prolonged
tissue levels
No
Yes
Yes
T ½ (h)
2
3-5
10->40
Drug-drug
Interactions
Yes
Yes
No
KETOLIDES (Telithromycin)
Unique structure compared to
macrolides, allowing it to be used in
resistant respiratory infections.
Differs from erythromycin by
substitution of a 3-keto group for the
neutral sugar L-cladinose.
ANTIBACTERIAL SPECTRUM
• Similar antibacterial spectrum to
erythromycin but many macrolideresistant strains are susceptible to
ketolides.
THERAPEUTIC USES
• Respiratory tract infections, including
community acquired bacterial
pneumonia, acute exacerbations of
chronic bronchitis, sinusitis and
streptococcal-pharyngitis.
CLINDAMYCIN
• A lincosamide closely related to
lincomycin.
ANTIBACTERIAL
ACTIVITY
• Similar to erythromycin.
• Anaerobic bacteria, especially
Bacteroides.
PHARMACOKINETICS
• Absorbed rapidly and nearly completely
following oral administration.
• Widely distributed throughout the body
except for the CNS.
Clindamycin
Enterohepatic circulation
THERAPEUTIC USES
Bacteroides fragilis
OXAZOLIDINONES
• New class of synthetic antibacterial
agents.
• Inhibit protein synthesis by a unique
mechanism.
LINEZOLID (Zyvox)
• The first and one of 2 oxazolidinones
presently available.
ANTIBACTERIAL
ACTIVITY
• Wide spectrum of activity vs. gram
positive organisms including methicillinresistant staphylococci, penicillin
resistant pneumococci and vancomycin
resistant Enterococcus faecalis and
E.faecium.
• Several anaerobic organisms.
PHARMACOKINETICS
• Good oral bioavailability (also given IV).
• Metabolized.
• No dosage adjustment necessary with impaired
renal or hepatic function.
THERAPEUTIC USES
• MRSA.
• Vancomycin resistant E.faecium.
Vancomycin resistant enterococcal
infections (VRE)
• Disproportionately affects patients in the
ICU, immunosuppressed hosts,
particularly liver and other solid organ
recipients and patients with post
chemotherapy neutropenia, and patients
with intravascular and bladder catheter
devices.
VRE
• Emerged during 1990’s
• Enterococci already possess intrinsic and
acquired resistance to most other
antimicrobials (β-lactams, aminoglys,
lincosamides and cotrimoxazole).
TREATMENT OF VRE
• Approved-linezolid and
quinopristin/dalfopristin
• Available agents which don’t have a
specific VRE approval (chloramphenicol,
doxycycline, high-dose
amoxicillin/sulbactam)
PRECAUTIONS
Linezolid
Tyramine
MAO
SSRI
toxicity
Serotonin
Linezolid
STREPTOGRAMINS
Quinupristin/Dalfopristin
(Synercid)
• First streptogramin to be approved in the
U.S.
• Present in a ratio of 30:70.
ANTIBACTERIAL
ACTIVITY
• Bactericidal vs. susceptible strains of
staphylococci and streptococci.
• Bacteriostatic vs. Enterococci faecium.
ANTIBACTERIAL
ACTIVITY
• Active vs. a wide range of gram positive
bacteria including staphylococci
resistant to methicillin, quinolones and
vancomycin; pneumococci resistant to
penicillin and E.faecium strains resistant
to vancomycin.
PHARMACOKINETICS
• Administered IV (over 1 hr).
THERAPEUTIC USES
• Vancomycin strains of E.faecium and
complicated skin infections caused by
Staph.
• Serious infections caused by multiple
drug-resistant gram-positive organisms.
DRUG INTERACTIONS
• Inhibits cytochrome CYP3A4.
Review-Drugs vs. Gram+
Organisms
•
•
•
•
•
•
Penicillins (G,V and antiStaph)
1st. Generation Cephs.
Macrolides
Vancomycin
Linezolid
Streptogramins
Serum Levels mcg/ml
1.5
Estolate
1.0
Stearate
0.5
Erythromycin Base
0.5 1.0 2.0
3.0
4.0
5.0
6.0 7.0
8.0
Hours
Serum Concentration After Oral Administration
of Different Erythromycin Preparations
VANCOMYCIN
• Tricyclic glycopeptide antibiotic.
• Antibacterial activity-primarily active
against gram positive bacteria.
MECHANISM OF ACTION
• Bactericidal.
• Inhibits cell wall synthesis (2nd stage of cell
wall synthesis).
• Binds with high affinity to the D-alanyl-Dalanine terminus of cell wall precursor units,
at the crucial site of attachment and thereby
inhibits vital peptidoglycan polymerase and
transpeptidation reactions.
Glycopeptide Polymrer
Glycopeptide
Polymer
Mur NAc
Mur NAc
X
D-Alanine
Vancomycin
Transpeptidase
RESISTANCE
• Increased incidence in recent years.
• Due to expression of a unique enzyme
that modifies the cell wall precursor so
that it no longer binds vancomycin.
THERAPEUTIC USES
• Serious staphylococcal infections such as
methicillin resistant staph infections and
in penicillin allergy or if the penicillins or
cephalosporins can’t be used for other
reasons.
• Streptococcal endocarditis infectionsused with an aminoglycoside .
• AAPC.
VANCOMYCIN-TOXICITY
TOXICITY
• Chills, rash and fever. Phlebitis at the
site of injection.
• Ototoxicity-auditory impairment.
• Nephrotoxicity.
Erythromycin
(Ilosone) can
cause
cholestatic
hepatitis
TOXICITY
• Red man or red neck syndrome during
rapid I.V. infusion
DRUG INTERACTIONS
• Inhibits cytochrome P450-3A4.
MECHANISM OF ACTION
• Usually bacteriostatic.
• Inhibit protein synthesis by binding
reversibly to the 50S ribosomal subunit.
• Probably inhibits translocation step.
Nascent polypeptide
chain
A
50S
MACROLIDE
Transferase
site
aa
mRNA
template
P
30S
ADVERSE REACTIONS
• GI upset (nausea, diarrhea, and
abdominal pain) is common.
His/Purk.
Ventricle
R
Macrolides
Prolong
QT Interval
T
P
Q
S
Torsade de pointes Polymorphic Ventricular
Tachycardia
Prolonged QT
P
50S
A
Clindamycin,erythromycin
and chloramphenicol
30S
ADVERSE REACTIONS
• Diarrhea and skin rashes are common.
• Antibiotic associated pseudomembranous
colitis (AAPC).
Clindamycin
Vancomycin and
metronidazole
Linezolid
MECHANISM OF ACTION
• Bacteriostatic and bactericidal.
P
50S
A
Linezolid
30S
MECHANISM OF ACTION
• Distorts the tRNA fmet binding site which
overlaps both ribosomal subunits,
preventing initiation complex formation .
• Binding site is unique so cross-resistance
doesn’t occur.
ADVERSE EFFECTS
• GI Disturbances and headache are
common.
• Myelosuppression.
Streptogramins
Nascent polypeptide
chain
50S
DALFOPRISTIN
A
QUINUPRISTIN
MACROLIDE
Transferase
site
aa
mRNA
template
P
30S
MECHANISM OF ACTION
• Act synergistically to inhibit bacterial
protein synthesis.
• They bind to separate sites on the 50 S
ribosomal subunit and form a ternary
complex with the ribosome.
MECHANISM OF ACTION
• Quinupristin binds at the same site as the
macrolides and has a similar effect.
• Dalfopristin directly blocks peptide bond
formation by inhibiting peptidyl transferase.
• Dalfopristin results in a conformational change
in the 50S ribosome subunit.
Pain, Inflammation
ADVERSE EFFECTS
• GI disturbances (diarrhea and nausea).
• Elevated liver enzymes.
THERAPEUTIC USES
• Disseminated MAC infection in patients
with AIDS (azithromycin and
clarithromycin).