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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.
ErythromycinCytP3A4
Demethylase
Antifungals,verapamil,
diltiazem
DRUG-DRUG INTERACTIONS
• Drugs that prolong QT interval.
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
COMPARISON OF MACROLIDES
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 macrolide-resistant 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.
Enterohepatic circulation
Clindamycin
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 methicillin-resistant 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
Tyramine
Serotonin
MAO
Linezolid
Linezolid
SSRI toxicity
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
Erythromycin Base
Stearate
Estolate
Hours
Ser
um L
evel
s m
cg/m
l
0.5 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
0.5
1.0
1.5
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-D-alanine terminus of cell wall precursor units, at the crucial site of attachment and thereby inhibits vital peptidoglycan polymerase and transpeptidation reactions.
Mur NAc
X
Glycopeptide Polymer
D-Alanine
Mur NAc
X
Glycopeptide Polymrer
Transpeptidase
X Vancomycin
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 infections-used 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.
aa
A50S
30S
mRNA
template
Transferase site
P
Nascent polypeptide chain
MACROLIDE
ADVERSE REACTIONS
• GI upset (nausea, diarrhea, and abdominal pain) is common.
His/Purk.
Ventricle
P
R
QS
T
Prolong QT Interval
Macrolides
Torsade de pointes -Polymorphic Ventricular
Tachycardia
Prolonged QT
AP 50S
30S
Clindamycin,erythromycinand chloramphenicol
ADVERSE REACTIONS
• Diarrhea and skin rashes are common.
• Antibiotic associated pseudomembranous colitis (AAPC).
Clindamycin
Vancomycin and metronidazole
Linezolid
MECHANISM OF ACTION
• Bacteriostatic and bactericidal.
AP 50S
30S
Linezolid
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
aa
A50S
30S
mRNA
template
Transferase site
P
Nascent polypeptide chain
QUINUPRISTINMACROLIDE
DALFOPRISTIN
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).