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).