Other ATB

BROAD SPECTRUM ATB

  • Macrolides, lincosamides, aminoglycosides, tetracyclines

Macrolides

  • Active Agents:

    • 15-member lactone ring (azalides): Azithromycin

    • 16-member lactone ring: Spiramycin

    • 14-member lactone rings: Erythromycin, Roxithromycin, Clarithromycin

    • Ketolide: Telithromycin

  • Produced by various Streptomyces strains

  • Mechanism of Action:

    • Reversible binding to the 50S subunit

    • Inhibition of peptidyl transferase and protein chain elongation

    • Bacteriostatic effect

Macrolides Antimicrobial Spectrum

  • General:

    • Gram-positive bacteria:

      • Similar to penicillins (e.g., Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes)

    • Gram-negative bacteria:

      • Corynebacterium diphtheriae, Bordetella pertussis, Campylobacter jejuni, Helicobacter pylori, Haemophilus influenzae, Neisseria catarrhalis

    • Anaerobic pathogens (except Bacteroides fragilis)

    • Intracellular Pathogens:

      • Mycoplasma, Legionella pneumophila, Chlamydia pneumoniae, Chlamydia trachomatis, Toxoplasma gondii

    • Spirochetes:

      • Borrelia burgdorferi, Leptospira, Treponema pallidum

    • Mycobacteria:

      • Mycobacterium avium complex (MAC)

      • Enterobacteriaceae, Pseudomonas - many isolates of methicillin-resistant staphylococci

  • MLSB Resistance:

    • Macrolide-lincosamide-streptogramin B resistance via rRNA methylation/mutation leading to decreased affinity for the 50S subunit

    • Mechanisms: efflux, enzymatic inactivation

Macrolides PK, SE, Interactions

  • Acid Stability:

    • Erythromycin < Azithromycin < Clarithromycin

  • Absorption: Varies based on formulation, number of doses, and gastrointestinal filling

  • Tissue Penetration: Excellent except for CNS; concentrated in phagocytes

  • Excretion: Primarily in bile and stool; no dosing modifications required for kidney disease

  • Interactions:

    • Irreversible CYP450 inhibition leading to increased plasma levels of drugs metabolized by this pathway.

    • Common side effects (SE): Nausea, diarrhea, abdominal pain; ototoxicity with erythromycin and high-doses clarithromycin; rare skin allergic reactions.

    • Liver concentration increases leading to risk for QT interval prolongation events like "torsades de pointes".

Macrolides Therapeutic Use

  • General Use: Not indicated for life-threatening infections due to slow onset

  • Specific Uses:

    • Atypical pneumonia (Mycoplasma, Legionella)

    • Streptococci and sensitive staphylococci infections

    • Dental infections (Spiramycin enters saliva)

    • Chlamydia trachomatis and rickettsia infections

    • Treatment of toxoplasmosis in immunocompromised and pregnant women (Spiramycin)

    • Helicobacter pylori eradication in combination with amoxicillin and PPI

    • Mycobacterium avium infections, typically a three-drug regimen

    • Previous usage in colorectal surgery prophylaxis combined with neomycin.

Clarithromycin PK and Spectrum

  • Characteristics:

    • Semisynthetic macrolide, lipophilic, tissue concentrations 10x greater than serum

    • Oral bioavailability 55%; plasma half-life 3x longer than erythromycin

    • Inhibits CYP3A, can increase plasma levels of concurrently applied drugs.

  • Spectrum of Activity:

    • Effective against a range of G+ and G- bacteria, including atypical mycobacteria and Mycoplasma, Chlamydia.

Clarithromycin Principal Indications

  • Treats:

    • Respiratory tract infections, HP infections, skin and soft tissue infections

    • Second-line agent for Lyme disease, Toxoplasmosis, MAC infections

    • Bacterial endocarditis prophylaxis in penicillin allergy cases.

Azithromycin Spectrum and PK

  • Characteristics:

    • Azalide related to erythromycin, slightly less potent against G+ but superior against G- bacilli.

    • Absorption ~37%; affected by food intake

    • Extensive tissue distribution and intracellular accumulation; hepatic metabolism predominates.

  • Indications:

    • Effective for acute exacerbations of COPD, community-acquired pneumonia, and other infections.

Spiramycin Spectrum and PK

  • Antimicrobial Spectrum:

    • Broad spectrum against G+ and G- bacteria, not effective against E. coli

    • Excellent tissue and saliva diffusion, with significant levels in infected tissues.

  • Pharmacokinetics:

    • Rapid but incomplete absorption, 30-39% bioavailability; plasma half-life about 8 hours.

Telithromycin MOA and Indications

  • Mechanism of Action:

    • First ketolide, dual binding to bacterial ribosomal RNA enhances efficacy against resistant strains.

  • Indications: Effective for community-acquired respiratory infections.

Macrolides Summary

  • Uses: Effective for otitis media, upper/lower respiratory tract infections, pneumonia, Mycobacterium avium complex, and STDs.

  • Pharmacokinetics: 3-day half-life for Azithromycin, 500 mg dosage regimen for H. pylori treatment often includes Clarithromycin.

  • Mechanism: Binds to 50S, blocking translocation in protein synthesis.

  • Adverse Effects: Nausea, vomiting, diarrhea, liver toxicity, P450 interactions, and QT prolongation risks.

Lincosamides: Clindamycin

  • Bacteriostatic Action: More effective than lincomycin, inhibits 50S ribosomal subunit.

  • Spectrum: Effective against anaerobic G– bacteria (excluding Bacteroides fragilis) and resistant G+ strains.

  • Resistance: Mainly via target site modification.

Clindamycin PK and Therapeutic Use

  • Pharmacokinetics: Good absorption and tissue penetration, metabolized in liver, excreted in bile.

  • Indications: Useful for anaerobic infections, G+ infections post-surgery, dentistry, and gynecological infections.

Resistance and Side Effects

  • Resistance: Significant presence of MLSB and other resistance mechanisms.

  • Side Effects: Potential for CDI, nausea, hypersensitivity, transient blood count changes.

Aminoglycosides

  • Mechanism: Irreversible binding to the 30S subunit, bactericidal effect, sensitive to aerobic bacteria, including G− and select G+ infections.

  • Active Agents: Streptomycin, Gentamicin, Amikacin, Tobramycin, Neomycin.

Aminoglycosides Therapeutic Use and SE

  • Indications: Used for severe infections involving aerobic G- bacteria; often combined with other antibiotics for efficacy.

  • Side Effects: Include nephrotoxicity, ototoxicity, and potential neuromuscular issues.

Tetracyclines and Their Spectrum

  • Active Agents: Doxycycline, Tigecycline, among others.

  • Mechanism: Reversible binding to the 30S subunit, inhibiting protein synthesis.

  • Spectrum: Broad activity against G+/G− bacteria, effective for intracellular pathogens.

Doxycycline PK and Indications

  • Pharmacokinetics: High absorption, good tissue penetration, long half-life, renal/biliary excretion.

  • Indications: Used for respiratory infections, genital infections, GIT infections, and skin infections.

Chloramphenicol Review

  • Mechanism: Binds to the 50S subunit, bacteriostatic effect but with serious toxicity.

  • Uses: Very limited use due to adverse effects like aplastic anemia and gastrointestinal issues.

Rifaximin Action and Applications

  • MOA: Inhibition of bacterial RNA synthesis.

  • Indications: Treatment of hepatic encephalopathy, IBS, and traveler's diarrhea.

Resistance to Antibiotics

  • Key Resistance Issues: Resistance in pneumococci, Staphylococcus aureus (MRSA), and several other pathogens.

  • ESKAPE Pathogens: Notable multidrug-resistant organisms.

Staphylococcal Infections Overview

  • Common Pathogen: Staphylococcus aureus.

  • Effects: Causes various pyogenic infections, foodborne illness, and toxic syndromes.

MRSA Concerns and Management

  • Origins: Resistance attributed to antibiotic use in health settings.

  • Management: Increasing awareness of historical origins and resistance mechanisms involving the mecA gene.

Antistaphylococcal Antibiotics

  • Active Agents: Include multiple penicillins, cephalosporins, and unique agents for MRSA treatment.

Glycopeptide Antibiotics Action

  • Mechanism: Inhibition of cell wall synthesis, effective against G+ organisms.

  • Key Agents: Vancomycin, Teicoplanin, Dalbavancin.

Vancomycin Details

  • MOA: Peptidoglycan synthase inhibitor; key for life-threatening infections.

  • Spectrum and Applications: Critical for MRSA, enterococcal infections, demonstrated synergy with aminoglycosides.

Side Effects of Vancomycin

  • Common Reactions: Nephrotoxicity, ototoxicity, and local irritation. Monitoring important due to narrow therapeutic window.

Linezolid MOA and Applications

  • Mechanism: Binds to the 50S ribosomal subunit, effective against a variety of G+ pathogens including MRSA.

  • Side Effects: Notable hematologic effects, potential interactions with MAO inhibitors.

Fusidic Acid Overview

  • Mechanism: Bacteriostatic action against G+ microorganisms, commonly used locally for infections.

Daptomycin Overview

  • Mechanism: Binds to bacterial membranes; utilizes rapid depolarization; effective against MRSA and resistant enterococci.

Quinupristin/Dalfopristin Summary

  • Mechanism: Streptogramin class, effective for complex resistant infections, administered via IV infusion.