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Monday, August 11, 2025

Inhaled anti-infectives


1. Introduction

  • Inhaled anti-infectives are antimicrobial agents (antibiotics, antifungals, antivirals) formulated for direct delivery into the respiratory tract.

  • Designed to achieve high local drug concentrations at the site of infection (airways and lungs) while minimizing systemic exposure and toxicity.

  • Primarily used in chronic or recurrent respiratory infections, especially in patients with underlying structural lung diseases such as cystic fibrosis (CF), non-CF bronchiectasis, and lung transplant recipients.

2. Rationale for Inhalation Route

  • High local concentration surpassing minimum inhibitory concentration (MIC) for target pathogens.

  • Reduced systemic side effects compared to intravenous therapy.

  • Bypasses poor penetration of systemic drugs into infected mucus layers.

  • Allows chronic suppressive therapy without continuous IV access.

3. Mechanism of Action

  • Dependent on agent class:

    • Antibiotics: inhibit bacterial cell wall synthesis, protein synthesis, or DNA replication.

    • Antifungals: disrupt fungal cell membrane integrity or interfere with ergosterol synthesis.

    • Antivirals: inhibit viral replication or block fusion/entry into host cells.

  • Nebulization delivers active drug particles to airways where they act directly on pathogens.

4. Commonly Used Inhaled Anti-infective Agents

A. Inhaled Antibiotics

  • Tobramycin – aminoglycoside; active against Pseudomonas aeruginosa; used in CF and bronchiectasis.

  • Colistimethate sodium (colistin) – polymyxin antibiotic for multidrug-resistant Gram-negative bacteria (Pseudomonas, Acinetobacter).

  • Aztreonam lysine – monobactam antibiotic; highly active against Pseudomonas aeruginosa in CF patients.

  • Gentamicin – aminoglycoside; less common for inhalation; used in selected resistant infections.

  • Amikacin liposome inhalation suspension – for refractory Mycobacterium avium complex (MAC) lung disease.

B. Inhaled Antifungals

  • Amphotericin B deoxycholate/lipid formulations – prophylaxis and treatment of invasive pulmonary aspergillosis in immunocompromised patients.

  • Voriconazole (investigational inhaled formulations) – potential targeted use in invasive aspergillosis.

C. Inhaled Antivirals

  • Ribavirin – used (rarely) for severe respiratory syncytial virus (RSV) infections in high-risk patients.

5. Indications

A. Cystic Fibrosis

  • Chronic suppression of Pseudomonas aeruginosa colonization.

  • Eradication therapy after first isolation of Pseudomonas.

B. Non-CF Bronchiectasis

  • Long-term suppression in recurrent Gram-negative bacterial infections.

C. Multidrug-Resistant Lung Infections

  • Inhaled colistin or aminoglycosides as part of combination therapy.

D. Mycobacterial Lung Disease

  • Liposomal amikacin for refractory MAC lung disease.

E. Fungal Prophylaxis/Treatment

  • Inhaled amphotericin B for immunocompromised patients (lung transplant, neutropenia).

F. Viral Infections

  • Ribavirin aerosol for severe RSV in high-risk populations (e.g., immunocompromised).

6. Formulations and Delivery Systems

  • Nebulized solutions – jet or ultrasonic nebulizers.

  • Dry powder inhalers (DPI) – e.g., tobramycin DPI.

  • Pressurized metered-dose inhalers (less common) – certain investigational products.

  • Liposomal formulations – enhance lung retention and reduce dosing frequency.

7. Pharmacokinetics (General)

  • Absorption: primarily local in the lungs; systemic absorption variable depending on drug and formulation.

  • Distribution: high concentration in airway secretions and epithelial lining fluid.

  • Metabolism: minimal for some agents (e.g., aminoglycosides excreted unchanged); others undergo hepatic metabolism if absorbed systemically.

  • Elimination: renal excretion for aminoglycosides; biliary/renal for others.

8. Adverse Effects

Local

  • Bronchospasm (prevented/reduced by pre-treatment with bronchodilator).

  • Cough, throat irritation.

  • Altered taste.

  • Voice changes (dysphonia).

Systemic

  • Ototoxicity and nephrotoxicity with aminoglycosides (rare at inhaled doses but risk increases with concurrent systemic therapy).

  • Systemic toxicity if drug absorbed in high amounts, especially in renal impairment.

9. Contraindications

  • Known hypersensitivity to the active drug or excipients.

  • Caution in patients with reactive airway disease without bronchodilator pretreatment.

  • Severe renal impairment when systemic absorption risk is high.

10. Drug Interactions

  • Aminoglycosides: additive ototoxicity/nephrotoxicity with other ototoxic or nephrotoxic agents (e.g., loop diuretics, amphotericin B IV).

  • Aztreonam lysine: avoid mixing with other inhaled drugs in the same nebulizer to prevent chemical incompatibility.

  • Amphotericin B: may have additive toxicity with other nephrotoxic drugs.

11. Monitoring

  • Sputum cultures to assess bacterial load and resistance patterns.

  • Renal function in prolonged aminoglycoside inhalation.

  • Audiometry if risk of ototoxicity.

  • Pulmonary function testing to monitor bronchospasm risk.

12. Advantages

  • Delivers high local concentration to site of infection.

  • Reduces systemic exposure and associated toxicity.

  • Useful in multidrug-resistant infections where systemic therapy is limited.

  • Allows chronic suppressive therapy without IV access.

13. Limitations

  • Requires specialized nebulization equipment and adherence to time-consuming inhalation regimens.

  • Not effective for systemic infections outside the lung.

  • Resistance can still develop, especially with long-term use.

  • Some drugs are costly and require hospital or pharmacy compounding.




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