Pneumonia remains a leading cause of morbidity and mortality. Evolving patterns of antimicrobial resistance have complicated efforts to improve outcomes, especially in severe pneumonia necessitating mechanical ventilation. Whether requiring mechanical ventilation for community-acquired pneumonia (CAP) or a new pneumonia in a previously ventilated patient (VAP), patients suffering for respiratory failure and pneumonia face crude mortality rates approaching 30–40% [1,2]. Such severe infections also remain associated with significant morbidity and cost [1,2].
One key determinant of outcomes in these syndromes is the appropriateness of initial antibiotic therapy. Multiple analyses document that failure to administer, in a timely manner, an antibiotic with in vitro activity against the culprit pathogen independently increases a patient's risk of death two-fold to five-fold [3,4]. The delivery of appropriate antibiotic therapy in an era of increasing antimicrobial resistance has become more complicated in that physicians can no longer insure that commonly utilized antibiotics will actually treat multidrug-resistant pathogens. Of particular concern are organisms such as Pseudomonas aeruginiosa and Acinetobacter bumanni.
At the same time, accumulating evidence indicates that the prescription of appropriate antibiotic therapy to critically ill patients is complicated by a number of other factors. Specifically, the use of mechanical ventilation changes a patient's volume of distribution that, in turn, has implications for antibiotic dosing . Concurrent use of inotropes and vasopressors also impacts antibiotic drug clearance and underscores that some individuals receiving traditional doses of renally cleared antibiotics may, actually, be receiving inadequate doses of antimicrobials. This concept of ‘augmented renal clearance’ (ARC) has been shown, in several analyses, to have important implications [6,7]. When patients with severe infection and ARC receive standard antibiotic regimens they face lower cure rates. To address this challenge one can employ higher doses than usually given. This paradigm, though, may expose the patient to multiple toxicities. Additionally, the challenge posed by ARC when coupled with the increasing prevalence of resistant organism has led to use of select, older antiinfective agents, such as colistin and polymixins. These agents carry substantial risks. All of these factors taken together have fostered a search for novel means to address the predicament clinicians now face in treating pneumonia in ventilated patients. One avenue has, necessarily, focused on the development and testing of novel new agents whereas other approaches have emphasized the optimization of pharmacodynamics and pharmacokinetics at the bedside .
An alternative paradigm, though, has stressed innovative means for antibiotic delivery. Specifically, interest has emerged in inhaled antibiotics. Potential advantages of inhaled administration include the delivery of high doses of drug directly to the target tissue. Theoretically, one optimizes efficacy by guaranteeing that drug levels at the site of infection are many fold higher than the minimum inhibitory concentration (MIC) of the responsible pathogen. Beyond eradicating the pathogen, such high drug levels in the lung might also help to mitigate the emergence of drug resistance. Inhaled administration would also possibly allow the clinician to avoid select systemic toxicities of some specific antimicrobials. For example, inhaled administration of aminoglycosides would overcome not only the fact that these drugs have poor lung penetration when given intravenously but would also potentially protect the patient from concerns about nephrotoxicity. Inhaled use of antibiotics might also help to prevent Clostridium difficile diarrhea because only the lungs, and not the gastrointestinal tract, would see drug deposition.
The success of inhaled antibiotics in cystic fibrosis has further helped to increase interest in this approach for treating ventilated patients with severe pneumonia. One key lesson learned in the development of inhaled therapies for cystic fibrosis has been the importance of particle size. Particles of the wrong size will never successfully reach the lower airways and will likely only deposit in the medium and larger airways – and thus will not effectively treat pneumonia. This is a particular concern in ventilated patients because inhaled antibiotic administration essentially requires reliance on nebulization. Traditional nebulization, though, does not insure that one achieves the correct particle size. Standard nebulizers additionally are not necessarily designed so as to make certain that the drug is administered during the proper part of the respiratory cycle. Failure to properly time drug delivery with breath administration could obviate any potential benefit associated with inhaled drug dispensation .
Reflecting the possibilities associated with inhaled antibiotics for treating pneumonia in ventilated patients, a recent survey of over 400 ICUs revealed that many have already adopted aerosolized antibiotics. In this international investigation, more than 25% of responding units reported regular use of the inhaled approach [10▪]. Inhaled therapies were used predominantly for pneumonias because of multidrug-resistant organisms and as an adjunct to standard intravenous therapies. In other words, aerosolized antibiotics were given only as an adjunct when a pathogen was identified rather than as part of an empiric therapy regimen. Emphasizing the burden of resistant organisms, colistin and aminoglycosides were the most commonly prescribed inhaled agents [10▪]. Notably, the use of inhaled agents for treating pneumonia had increased when compared to a prior survey 3 years earlier [10▪]. It is also important to note that another contemporary survey of practices surrounding the use of nebulized antibiotics reported that only 28% of ICUs relied upon optimal technique when administering inhaled antibiotic therapy .
This change in behavior was likely in part motivated by the increasing prevalence of resistant pathogens encountered in severe pneumonia. Additionally, guidelines from several professional societies suggested that there might be a potential role for aerosolized antibiotics when treating VAP [12,13]. More importantly, though, was the publication of a meta-analysis by Zampieri et al. that suggested that adjunctive inhaled antimicrobials increased rates of clinical cure significantly. Readers should note, however, that a subsequent meta-analysis focusing only on randomized studies (as opposed to including observational analyses) and which included six studies of varying quality concluded that there was insufficient evidence to recommend the utilization of aerosolized antibiotics as either primary or adjuvant therapy in severe pneumonia [15▪].
Because these earlier meta-analyses, three clinical trials employing inhaled antibiotics as adjunctive therapy in pneumonia have either been published or have reported preliminary findings. Although conflicting in their general conclusions, these studies indicate that there is little evidence to recommend the broad application of this approach.
The first trial compared not adjunctive inhaled antibiotics but rather inhaled versus intravenous formulations of the same aminoglycoside. In a study of 133 postcardiac surgery patients, Hassan et al.[16▪▪] concluded that inhaled amikacin (as compared to intravenous amikacin) results in higher cure rates when used along with empiric piperacillin-tazobactam. The authors also state that inhaled amikacin results in less nephrotoxicity and faster liberation from the ventilator. There was no difference in mortality between the two cohorts. The study enrolled both patients with hospital-acquired pneumonia and VAP and relied on a randomized design. Importantly, the investigators utilized the inhaled approach early, as soon as an organism was identified, but still reserved aerosolization for drug resistant organisms. Despite these strengths the trial was not blinded and comes from only a single center [16▪▪]. Moreover, they employed a simple pneumatic nebulizer for ventilated patients, and more patients in the intravenous treatment arm received initially inappropriate therapy (but this difference represented a trend rather than a statistical difference). Not surprisingly, given the sample size, there was no difference in mortality. These factors taken together limit the generalizability of the trial findings, especially since several of their endpoints are prone to ascertainment bias and therefore may be affected by the lack of blinding. More importantly, although the authors claim that inhaled amikacin results in fewer days of mechanical ventilation, there was no actual difference in ventilator-free days in the cohort [16▪▪]. This dichotomy suggests there was some imbalance in post-ICU mortality.
Conversely, in a more rigorously designed, multicenter trial, Kollef et al.[17▪▪] assessed the effectiveness and safety of inhaled amikacin combined with fosfomycin. More specifically, Kollef et al. studied a dose 300 mg amikacin/120 mg fosfomycin twice daily for 10 days. Unlike Hassan et al.[16▪▪,17▪▪] this trial utilized a specially designed formulation of amikacin and fosfomycin in order to insure proper particle size for lung tissue deposition. They also employed a placebo to facilitate comparisons, and the trial was one of the few in this area that relied upon double blinding. Unlike earlier reports, including that by Hassan et al., they used a high-efficiency vibrating mesh nebulizer that also was devised to help insure target tissue drug delivery. As noted earlier, utilization of simple jet nebulizers often fails to guarantee that sufficient doses of antibiotic reach areas of infection in the lung. The trial cohort included 142 patients with VAP (as opposed to including HAP) who were severely ill with many in concurrent shock. Despite multiple efforts to optimize the engineering and drug delivery, the investigators found that the inhaled therapy had no effect on the primary endpoint – a change in the clinical pulmonary infection score from baseline [17▪▪]. Furthermore, in contrast to Hassan et al., there were no differences in any secondary endpoints such as earlier liberation from the ventilator or ICU length of stay. Finally, there was no difference in either mortality or clinical cure at Day 14 [17▪▪]. Despite the overall general lack of efficacy or impact on any meaningful clinical measure, the investigators did observe that among 13 patients with pan-drug-resistant Acinetobacter greater microbiological eradication compared to placebo [17▪▪]. This last finding implies that when the patient fails to receive initially appropriate therapy because no such alternatives exist, there may be a role for inhaled antibiotics as a rescue option.
The largest study exploring inhaled antibiotics for severe pneumonia finished in mid-2017. The INHALE study compared aerosolized amikacin to placebo in severe Gram-negative pneumonia . This phase III trial was designed based on earlier results from a smaller phase II study. In the phase II, placebo controlled trial by Niederman et al., researchers utilized a proprietary formulation of amikacin (400 mg daily or 400 mg twice daily) along with a novel delivery system optimized for the creation of appropriately sized particles. The unique delivery device was synchronized with the respiratory cycle to assure the proper timing for lung delivery during appropriate phases of the breath delivery. This preliminary study enrolled 69 patients and confirmed that the innovative drug-delivery combination system resulted in high levels of amikacin in tracheal aspirates . Intriguingly, although there was no difference in cure rates, individuals receiving amikacin required fewer intravenous antibiotics .
Unfortunately, though, the larger INHALE trial failed to demonstrate any value to aerosolized amikacin in severe pneumonia in mechanical ventilation patients . This analysis represents the largest trial on the question of inhaled therapy and enrolled over 700 patients from across the globe . As with the Kollef et al. report, this study was both double blinded and placebo controlled. Both trials also only included mechanical ventilation patients. In contrast to the report by Hassan et al., INHALE explored the role for nebulized amikacin as part of an essentially empiric therapy regimen. INHALE was intended to demonstrate superiority in survival rates with adjunctive aerosolized treatment. This may have represented a very high bar for documenting the benefit of any innovative intervention in disease states such as VAP. VAP, for example, is associated with high baseline mortality rates and many persons die ‘with VAP’ rather than ‘of VAP’. Thus, altering mortality may be nearly impossible to show without an exceedingly large sample size. However, amikacin also failed to show any benefit in multiple secondary endpoints to include: pneumonia-related mortality, early clinical cure rates, days on mechanical ventilation, and days in the ICU . Subgroup analyses, furthermore, did not identify any relevant population that benefited from nebulized amikacin. Readers should note that the results of INHALE are currently only available as a press release and formal results have not been presented in a peer reviewed venue (as of yet).
One finding consistent across all three trials was the general tolerability of inhaled antibiotics. This agent seemed associated with minimal toxicity. The most commonly reported adverse events were cough and bronchospasm [16▪▪,17▪▪,18,19]. In instances where it was measured, serum drug levels of the agents delivered via nebulization were de minims.
The most recent guidelines for nosocomial pneumonia from the American Thoracic Society and the Infectious Disease Society of America suggest ‘for patients with VAP due to gram-negative bacilli that are susceptible only to aminoglycosides or polymyxins, we suggest both inhaled and systemic antibiotics, rather than systemic antibiotics alone.’ . This represents a weak recommendation . The most recent clinical trials on this question indicate the appropriateness of this recommendation. Broad, early use of inhaled amikacin when a gram-negative pathogen is suspected seems inappropriate based on the findings of Kollef et al.[17▪▪,19] and the INHALE trial. These two reports also underscore that many of the potential benefits of targeted pulmonary antibiotic administration are ephemeral at best. Even with modern nebulizers and devices created to optimize drug delivery and timing of drug release during the respiratory cycle, no investigators have shown a benefit when the patient is already receiving initially appropriate systemic therapy. Rather, as the findings of Hassan et al. suggest, particularly when coupled with the results of the subgroup of patients given inappropriate therapy in the Kollef et al.[17▪▪] analysis, antibiotic nebulization represents one option for rescue therapy.
Why have inhaled antibiotics employed early not proven beneficial? It seems that the issue is not related to achieving adequate drug delivery to the lower airways and to the alveoli. On one hand, it may be that inhaled drug is incapable of penetrating the mucus associated with pneumonia. On the other hand, one can speculate that the MICs measured in a test tube may not actually represent the MIC encountered in the pulmonary milieu when the alveoli are filled with secretions. Put another way, there may be important interactions between respiratory secretions and bacteria that alter the target pathogens MIC in vivo. Further work is clearly required to better understand why the inhaled approach has failed to prove effective in broader populations given the theoretical appeal of this paradigm. Additionally, for clinicians wishing to rely upon aerosolized rescue therapy, they must recognize that effective nebulized antibiotic therapy is actually a complex process that requires attention to detail and a focus on multiple complex steps including nebulizer selection, dose selection, and adjustments to ventilator settings. Pending other large trials, it seems prudent to continue to look to inhaled antibiotics for use in select cases where other options are very limited.
Financial support and sponsorship
Conflicts of interest
M.P.S. has no competing interests. A.F.S. has served a consultant to, speaker for, or received research support from: Achaogen, Astellas, Alios, Aridis, Bayer, Cidara, Entasys, Melinta, Merck, Nabriva, Paratek, Pfizer, Spero, and Tetraphase
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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A large international survey describing current practices regarding the use of nebulized antibiotics for pneumonia in the ICU.
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