MACROLIDES Macrolide antibiotics contain a many membered lactone ring to which are attached one or more deoxy sugars. Erythromycin is the most well known member. Newer members include clarithromycin, and azithromycin.

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). Azithromycin and clarithromycin have enhanced activity vs 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. Azithromycin doesn’t

Antifungals,verapamil, diltiazem Erythromycin CytP3A4 Demethylase

DRUG-DRUG INTERACTIONS Drugs that prolong QT interval.

COMPARISON OF MACROLIDES Erythromycin Clarithromycin Azithromycin Effect of food on absorption Yes No G.I. intolerance Prolonged tissue levels T ½ (h) 2 3-5 10->40 Drug-drug Interactions

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 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 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 SSRI toxicity 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

DRUG-DRUG INTERACTIONS Drugs that inhibit CYP3A4 isozymes may increase plasma erythromycin concentrations and increase the risk of ventricular arrhythmias and sudden death (antifungals, verapamil, diltiazem).

Serum Concentration After Oral Administration 1.5 Estolate 1.0 Serum Levels mcg/ml 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-D-alanine terminus of cell wall precursor units, at the crucial site of attachment and thereby inhibits vital peptidoglycan polymerase and transpeptidation reactions.

X Vancomycin Glycopeptide Polymrer Glycopeptide Mur NAc Polymer D-Alanine 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.

PHARMACOKINETICS Poorly absorbed after oral administration. Given I.V. Mainly excreted by the kidney (80-90%).

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.

60S 40S Eucaryotic Ribosome 80S--M.W. 4,200,000 Procaryotic Ribosome 50S 30S 70S--M.W.2,500,000

P A aa 50S 30S mRNA template Transferase site Nascent polypeptide chain MACROLIDE

RESISTANCE Results from multiple mechanisms. Cross resistance among all the macrolides.

ADVERSE REACTIONS GI upset (nausea, diarrhea, and abdominal pain) is common. Frequency is less with the newer macrolides

CHOLESTATIC HEPATITIS It is caused primarily by the estolate. It is probably a hypersensitivity reaction (to estolate ester).

QT PROLONGATION AND VENTRICULAR ARRHTHYMIAS Macrolides prolong cardiac repolarization and are associated with torsades de pointes.

His/Purk. Ventricle R T P Prolong QT Interval Macrolides S Q

Torsade de pointes - Polymorphic Ventricular Tachycardia Prolonged QT

MECHANISM OF ACTION Bacteriostatic. It binds exclusively to the 50S ribosomal subunit and inhibits protein synthesis. Some cross-resistance with erythromycin

Clindamycin,erythromycinand chloramphenicol 50S A Clindamycin,erythromycinand chloramphenicol 30S

ADVERSE REACTIONS Diarrhea and skin rashes are common. Antibiotic associated pseudomembranous colitis (AAPC).

Clindamycin

AAPC Characterized by watery diarrhea, abdominal pain, fever, blood and mucus in stools. It can be fatal. Results from a toxin secreted by clindamycin resistant strains of Clostridium difficile. Potentially caused by several antibiotics.

AAPC Results from a toxin secreted by clindamycin resistant strains of Clostridium difficile. Potentially caused by several antibiotics.

Vancomycin and metronidazole

AAPC Vancomycin and metronidazole are effective in treating it.

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. Myelosuppression when used for an extended period of time.

Streptogramins

P A DALFOPRISTIN aa 50S 30S mRNA template Transferase site Nascent polypeptide chain QUINUPRISTIN MACROLIDE

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).