Download Inhaled antibiotics: strengths and fears

Inhaled antibiotics: strengths and fears
Dr. Lucy B. Palmer
Pulmonary Critical Care Division
School of Medicine
Stony Brook University
Stony Brook
11794-8172 New York
UNITED STATES OF AMERICA
[email protected]
AIMS
To review the current clinical data available about efficacy of this mode of delivery and the potential
benefits
•
•
•
•
Why may inhaled antibiotic therapy be an important mode of treating ventilator-associated
infections?
Are there Improved outcomes in treatment of respiratory infections with inhaled therapy?
Is there an effect on bacterial resistance?
Can systemic antibiotic use be reduced?
SUMMARY
Ventilator-associated pneumonia (VAP) remains the leading cause of death related to infection in
critically ill patients and more than 50% of the antibiotic use in the intensive care unit is administered
for this infection. The morbidity and mortality related to respiratory infections remain significant
despite reports of a zero incidence of VAP in some publications.
Increasing microbial resistance of Gram-negative pathogens in the ICU is a major challenge for
critical care physicians because it is driven primarily by systemic antibiotics used to treat infections in
these critically ill patients.. Rates of resistance correlate directly with amounts of antibiotic used. The
increasing difficulty of treatment of multidrug-resistant organisms (MDROs) is occurring at a time
when there is a dearth of new systemic antibiotics available. In the past 40 years, there have been only
2 new available classes of antibiotics introduced, oxazolidinones (linezolid) and the cyclic
lipopeptides (daptomycin). Both these antibiotics are used for the treatment of gram-positive
organisms, leaving options for resistant gram-negative organisms even more limited. This shrinking
armamentarium of systemic antibiotics in a sea of rising minimum inhibitory concentrations (MICs)
compels us to examine the current data on the efficacy of inhaled antibiotics.
History of inhaled antibiotics
The earliest studies of topical antibiotic therapy were driven by the same clinical problem that plagues
us more than 40 years later. Resistant Gram-negative organisms, in particular Pseudomonas species,
were causing respiratory infections in intubated patients and patients with tracheostomy, and clinical
response to intravenous (IV) therapy was poor. At that time, aminoglycosides given intravenously
were the primary treatment. These antibiotics have poor lung penetration and treatment failure
occurred in up to 60% of patients. This led to the use of targeted therapy to the lung which could
provide increased concentrations. These early trials were promising. Early investigations used
endotracheal instillation of the antibiotic. The concentrations of the aminoglycoside in the bronchial
secretions were shown to be 1000-fold higher than the serum concentrations of patients receiving IV
therapy, and bactericidal activity was more than 30-fold greater than that in serum. These
investigators had also demonstrated the clinical benefit from the instillation of aminoglycosides for
the treatment of bronchial infections in intubated patients, which is now called ventilator-associated
tracheobronchitis (VAT), as well as in bronchopneumonia.
Gamechanger
But a large prophylactic trial of atomized polymyxin in the 1970’s raised concerns that inhaled
therapy would lead to highly resistant organisms causing life threatening pneumonia. Little attention
was paid to further exploring the use of this mode of delivery for almost 40 years. Now that the
treatment of MDRO has become increasingly problematic, targeted therapy to the lung is being
revisited.
Rationale for using inhaled antibiotics
The theoretical reasons for using targeted antimicrobial therapy in mechanically ventilated patients
are compelling. With proper delivery, the drug is delivered directly to the site of infection,
concentrations in the lung are high, and systemic toxicity is minimized. Furthermore, the microflora
of the gut is unlikely to be altered, thus reducing the emergence of MDRO and infection with
Clostridium difficile. The high antibiotic concentrations achieved with targeted therapy far exceed the
MIC and result in a large ratio of maximum concentration to MIC, an index shown to be important for
eradication of these organisms in the milieu of thick purulent secretions, biofilm, and diminished
mucociliary clearance. Conversely, if only IV therapy is used and concentrations are not bactericidal,
biofilm formation may be induced, making the infections even harder to eradicate. There is some
early evidence that the use of these aerosolized agents with systemic antibiotics may reduce the need
for additional systemic antibiotic added for poor response to initial treatment.
Devices
Devices used for aerosolized delivery have never been held to the same rigorous FDA regulations to
which medications are subject. Medications given intravenously with appropriate attention to dosing
are not subject to large variability of concentrations in the blood stream. Unlike IV therapy, whereby
dose is primarily related to concentration in the blood and the blood flow within the infected organ,
inhaled delivery is affected by particle size, humidity, flow rates and multiple other factors.
Furthermore delivery devices and mechanical ventilators are designed with increasingly complex
interactive technology that may alter drug deposition. Devices have evolved from a simple syringe or
atomizer to jet and ultrasonic nebulizers, vibrating mesh technology, and, in animal studies, magnetic
field–guided aerosols with superparamagnetic iron oxide nanoparticles in the solutions to be
aerosolized.
Device/drug combination
Despite all these variables that may influence lung dose and site of deposition, there are no specific
standards for aerosolized drug delivery in intubated patients. Because of the complexity of all these
variables, currently available proprietary drugs are sold as a combination drug and device product to
optimize the delivery of the antimicrobial.
In this session we will go over the currently available clinical data and emphasize both the merits of
this mode of delivery as well as the specific areas where more research is needed.
REFERENCES
Systematic reviews and meta-analyses
1. The use of inhaled antibiotic therapy in the treatment of ventilator-associated pneumonia and
tracheobronchitis: a systematic review. Pulmonary Medicine (2016) 16:40
2. Zampierei et. Al. Nebulized antibiotics for ventilator-associated pneumonia: a systematic review
and meta-analysis Critical Care 2015 19:150
3. Valachi et.al.The Role of Aerosolized Colistin in the Treatment of Ventilator-Associated
Pneumonia: A Systematic Review and Meta-analysis. Crit CareMed 2015; 43:527–533)
4. Florescu, et al. What Is the Efficacy and Safety of Colistin for the Treatment of VentilatorAssociated Pneumonia?A Systematic Review and Meta-Regression. Clin Infect Dis. [2012] 54
[5]: 670-6
Reviews on the use of inhaled antibiotics in ventilator patients
5. Wenzler et.al. Inhaled Antibiotics for Gram-Negative Respiratory Infections Inhaled antibiotics
for Gram-negative respiratory infections. Clin Microbiol Rev 201629:581– 632. Extensive
review of the science behind the use of inhaled antibiotics as well as the clinical data available.
6. Palmer LB, Ventiltor-associated infection: the role for inhaled antibiotcs Curr Opin Pulm Med
2015, 21:239–249 Curr Opin Pulm Med 2015, 21:239–249. Clinical review
7. Bradley S. et.al. Inhaled Antibiotics for Lower Airway Infections Ann Am Thorac Soc Vol 11,
No 3, pp 425–434, Mar 2014 Clinical review
8. Luyt, c. et.al. Aerosolized antibiotics to treat ventilator-associated pneumonia. Current Opinion
in Infectious Diseases 2009, 22:154–158. Clinical review
9. Abu-saleh T and Dhand,R..
Inhaled Antibiotic Therapy for Ventilator-Associated
Tracheobronchitis and Ventilator-Associated Pneumonia: an Update Adv Ther (2011) 28(9):728747. Clinical review
10. Dudley, M. et.al Aerosol antibiotics: considerations in pharmacological and clinical evaluation
.Current Opinion in Biotechnology 2008, 19:637–643. Review with a pharmacological
perspective