Antibiotic Inhalers Galore (Part 1):  More Combinations and Permutations than a Rubik’s Cube

There is much interest in inhaled antibiotics these days.  Prima facie, the logic for this approach is compelling: Getting the antibiotic (and a lot of it) directly to the site of infection, while avoiding systemic toxicity, sounds like optimized efficacy plus optimized safety combined.  However, some high-profile failures were published recently and should give pause for reflection.[1]

Before analyzing these specific antibiotic trials and their results, let’s start with an overview of the field. 

Systemic antibiotics must overcome diffusion barriers and penetrate the lung parenchyma to get to the infection site, while nebulized antibiotics are right at the air/tissue interface where bacteria gain entry to the lung

With so many antibiotics in development for pulmonary delivery, it is hard to keep things organized mentally. Dry vs wet inhalers, aqueous vs liposomal delivery systems, different indications and more advanced inhaler technologies are all vying for attention. Indeed, it is hard to see differentiation in this melee even for experts.

For starters, here are the indications – some old, some new – pursued by antibiotic aerosol developers:

  • As adjuvant therapy in CF patients
  • As prophylaxis for exacerbations of CF
  • As adjuvant therapy in VAP
  • As prophylaxis for nosocomial pneumonia in ventilated patients
  • As treatment of NCFB
  • As adjuvant therapy in NTM

Traditionally, we had CF patients in mind when talking about pulmonary delivery of antibiotics. With Pseudomonas and other difficult-to-treat Gram-negatives becoming established in the lungs of CF patients, efforts to reduce the bacterial burden and possibly reduce the need for systemic antibiotics made good sense. Both Tobi (tobramycin) and Cayston (aztreonam) have potent anti-pseudomonal activity and were approved based on improvement in clinical (FEV1) and microbiologic (CFU) parameters.

Since the days of Tobi and Cayston this field has become a lot more complex. The following antibiotics are studied or used as inhaled agents (and there may be more):

While these antibiotics are of proven efficacy; they are also generics and cheap. But this is an inhaler, not an antibiotic business: Pennies will go into the antibiotic and pounds into the inhaler technology. And big bucks will be charged for the product that makes it to the market.

This is an attractive business model: With drug safety and microbial efficacy already established, it is now a matter of finding respiratory conditions in which symptoms respond to a reduction in bacterial load. While CF was the poster boy for this concept, companies are really interested in the much larger VAP and bronchiectasis markets.

A reliable inhaler technology is sine-qua non, of course. Developing an inhaler is tricky business, just ask Bayer about its foray into the field. Their Bayhaler was a beautiful device in its simplicity but unfortunately, it did not work.

Maybe it is surprising that a few antibiotic classes are still missing from the list. Let’s see:

  • Systemically administered sulfonamides and oxazolidinones have good lung penetration and are safe drugs; hence there is no great need for inhaled delivery to avoid systemic toxicity
  • Noone would consider daptomycin a good choice for aerosol delivery but other similar glycol(lipo)peptides do not get inactivated by surfactant and could be explored.
  • Doxycycline can be formulated for pulmonary delivery but tetracyclines are pulmonary irritants and doxycycline is cytotoxic for bronchial epithelial cells.
  • TB drugs could be considered for pulmonary delivery as adjuvant therapy but data are sparse and no drugs are currently being tested for inhalational use.

While the rationale for antibiotic delivery via the pulmonary route is solid, supporting evidence-based data are sparse or non-existent. Nonetheless, intensivists often use antibiotic aerosols already as empirical adjunctive therapy in ventilated ICU patients; experts have spoken out in favor [6] and against the practice [7].

Areas of atelectasis and segments with pneumonic consolidation are cut off from ventilation and cannot be reached by nebulized medicines

With this as a primer, we can discuss recent trial results from Aradigm – Bayer – Cardeas – Insmed in an upcoming blog. Be forewarned: it’s a scary world out there!

Abbreviations
CF          cystic fibrosis
CFU       colony-forming units
DPI        dry powder inhaler
FEV1     forced expiratory volume (first second)
NTM       non-tuberculous mycobacteria
NCFB     non-CF-bronchiectasis

Publications:
[1] Kollef M.  A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of Gram-negative ventilator-associated pneumonia:- IASIS Trial, CHEST (2016), doi: 10.1016/j.chest.2016.11.026
[2] http://www.icid.salisbury.nhs.uk/ClinicalManagement/Respiratory/Pages/NebulisedAntibioticDrug-Gentamicin.aspx
[3] Antoniu S: Inhaled gentamicin in non-cystic fibrosis bronchiectasis: effects of long-term therapy. Expert Opin Pharmacother. 2011;12:1191
[4] Approved in the EU
[5] Zhang Y High azithromycin loading powders for inhalation and their in vivo evaluation in rats. Int J Pharm. 2010 Aug 16;395:205
[6] Wunderink RG, Point: Should inhaled antibiotic therapy be routinely used for the treatment of bacterial lower respiratory tract infections in the ICU setting? Yes, CHEST (2016), doi: 10.1016/j.chest.2016.11.006.
[7]  Kollef MH, Counterpoint: Should inhaled antibiotic therapy be routinely used
for the treatment of bacterial lower respiratory tract infections in the ICU setting? No, CHEST (2016), doi: 10.1016/j.chest.2016.11.007

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