Inhaled Antibiotics: Do as We Say Not as We Study*

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Inhaled antibiotics in the setting of pneumonia are often a therapy of interest as clinicians must balance the adequate treatment of multidrug resistant (MDR) pathogens with antibiotic-related adverse drug reactions. Compared with IV antibiotics, inhaled antibiotics offer an attractive option in pneumonia treatment with the potential to reach very high pulmonary concentrations (1, 2). Serum aminoglycoside concentrations below trough values associated with IV therapy have been documented, easing concerns of nephrotoxicity with the inhaled route (1, 3). Aminoglycosides and colistin have been the primary targets of investigation since MDR Gram-negative pathogens often necessitate treatment beyond conventional therapy, and the suboptimal lung penetration of these agents has resulted in questionable efficacy of IV treatment. With increasing and improved research in this topic area (4), the question of the optimal role of inhaled antibiotics for pneumonia remains. Current 2016 clinical practice guidelines for pneumonia treatment set forth by the Infectious Diseases Society of America and the American Thoracic Society (IDSA/ATS) have opened the door for increased use of inhaled therapies (5). The panel’s recommendations may seem straightforward; however, recent prospective trials have studied use of this therapy in a different clinical context.
The study by Hassan et al (6) in this issue of Critical Care Medicine aimed to help provide higher quality evidence for use of aminoglycoside inhaled therapies. In this prospective, randomized, nonblinded study, 133 postcardiac surgery patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) caused by MDR Gram-negative bacilli were randomized to receive combination therapy with piperacillin/tazobactam and either inhaled or IV amikacin. After adjusting for relevant clinical factors including antimicrobial susceptibilities, Hassan et al (6) found that nebulized amikacin was associated with a better chance of clinical cure. However, no difference in mortality was found.
Several recent investigations have found microbiologic treatment success in Gram-negative pneumonia with inhaled antibiotics (7–9), whereas others have shown no benefit (10). This study by Hassan et al (6) contributes to the increasing number of prospective randomized trials investigating inhaled antibiotic effectiveness when given with conventional antibiotic treatment. The improvement in clinical cure is in congruence with a trend in the literature, whereas the reduction in ICU length of stay and earlier complete recovery are important additions to the literature (6).
Like several other recent prospective randomized trials investigating the use of inhaled antibiotics, the intervention in the study by Hassan et al (6) focuses on the addition of inhaled antibiotics to traditional IV therapy for Gram-negative pneumonia (2, 6, 8, 9). The optimal patient population for inhaled antibiotic therapy is unknown. IDSA/ATS guidelines recommend use in a narrow population considered most likely to benefit. Specifically, inhaled antibiotics are recommended as part of definitive treatment in patients with VAP (not HAP) caused by a MDR bacteria that is “only” susceptible to aminoglycosides or polymyxins (5). The present study, on the other hand, used inhaled amikacin as adjunctive therapy in patients with VAP or HAP for treatment of pathogens with broader susceptibility patterns. This application of inhaled aminoglycosides suggests the possibility for an expanded place in therapy. Other recent studies have also investigated use of inhaled antibiotics in an expanded role, enrolling patients with Gram-negative VAP (unconfirmed MDR) and risk factors for drug resistance (2, 8, 9). Although the guidelines and most clinicians continue to consider known resistance with very limited treatment options as the indication, increasing literature describes adjunctive use in cases at risk of treatment failure in which other treatment options are available.
Although this expanded place in therapy may appear attractive, one must consider the potential to increase resistance in an already high-risk situation.
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