Aerosolized Antibiotic Therapy: A Forward Aerial Assault or Forced Contingency for Ventilator-Associated Pneumonia?

The increasing prevalence and complexity of multiple-drug-resistant (MDR) organisms in nosocomial infections have fueled interest in novel therapeutic approaches. Adjunctive aerosolized antibiotic (AAA) therapy for pneumonia has gained popularity, supported by apparent advantages of higher pulmonary antibiotic concentrations and lower systemic exposure. Balanced by a paucity of high-level evidence, consensus statements recommend AAA therapy be considered in patients with MDR pathogens not responding to intravenous therapy.^1,2

The most commonly reported aerosolized agents, aminoglycosides and colistin, have narrow therapeutic indexes and poor pulmonary penetration^3,4 associated with systemic administration. However, these agents often have higher bactericidal potencies and retained in vitro susceptibility against many MDR pathogens (eg, Pseudomonas aeruginosa and Acinetobacter species).⁵ These qualities, in combination with their concentration-dependent pharmacodynamic properties (ie, the higher the antibiotic concentration to bacterial minimum inhibitory concentration, the greater bacterial killing), make intermittent aerosolization of these agents attractive.

Although there has been some progress in formal aerosolized antibiotic drug development intended for the treatment of pneumonia in critically ill patients,⁶ prospective studies evaluating the effects on patient outcome have been limited by underpowered design, lack of control group, heterogeneous definitions for pneumonia, variable treatment regimens, poorly described aerosolization methods, and concomitant antibiotic therapy.² Published meta-analyses nicely frame many of these limitations.^7,8 Consequently, most recent reports and series have described the use of aerosolized aminoglycosides or colistin as adjunctive or salvage therapy in patients with pneumonia recurrence or pneumonia caused by MDR pathogens.^9–13

In this issue of Respiratory Care, Arnold and colleagues report their AAA experience at a large, urban, academic medical center for the treatment of P. aeruginosa and Acinetobacter ventilator-associated pneumonia (VAP).¹⁴ The investigators performed a retrospective cohort study of 93 critically ill medical and surgical patients with clinically defined, microbiologically confirmed VAP who received AAA (n = 19) with colistin 150 mg twice daily (n = 9), or tobramycin 300 mg twice daily (n = 10), or no AAA (n = 74); all patients received intravenous antibiotic therapy. Although these dosages have been used for aerosolization, there are limited data describing the pulmonary pharmacokinetics, including lobular distribution and clearance, in critically ill, mechanically ventilated patients.^2,15 Patients receiving AAA therapy had higher Acute Physiology and Chronic Health Evaluation II scores, were more likely to have MDR pathogens, had longer delays in appropriate antimicrobial therapy, and were more likely to receive intravenous aminoglycoside or colistin. Durations of definitive intravenous antibiotic therapy were not statistically different (AAA 17.8 ± 13.3 d vs no AAA 12.8 ± 8.5 d, P = .16), but may have reflected treatment bias toward higher severity of illness and MDR pathogens in AAA patients. Patients receiving AAA had longer durations of mechanical ventilation and associated ICU and hospital stay. Clinical and microbiologic resolution of pneumonia was not evaluated. Despite the apparent differences in severity of illness and appropriate antibiotic therapy, crude 30-day mortality post-VAP diagnosis was lower in the AAA patients (0.0% vs 17.6%, P = .063, P = .03 long-rank test per survival analysis). However, when patients requiring palliative care were included in both groups, there was no difference in crude mortality (32.1% vs 33.3, P = .91).

This study represents the complexity of the limited evidence base supporting aerosolized antibiotic therapy for pneumonia and real-world challenges when using narrow therapeutic index antibiotics in critically ill patients with VAP, in particular, episodes caused by MDR pathogens. The strengths of the study include consistent dosing and administration of AAA, bacteriologically confirmed VAP, and objective patient outcome end points. Limitations include observational, retrospective design; small sample size; inability to assess individual effects of colistin and tobramycin; lack of formal matched control group; and limited information for clinical or microbiologic resolution of pneumonia. The findings related to mortality are not definitive, given the limitations in study design. However, they are compelling, because the clinical scenario of VAP caused by MDR pathogens is increasingly common, and AAA therapy appeared to safely mitigate a higher baseline risk. Interestingly, the addition of palliative care to the mortality assessment brings to light the importance of this disposition in ICU-related outcomes studies, pending standardization and differentiation between palliative and hospice care. Perhaps the most relevant application of this study is the shared experience of a provocative therapeutic strategy in complex critically ill patients with tenuous and potentially perilous infectious circumstances.

With the increasing prevalence of MDR pathogens and dearth of new antibiotics in development, prospective comparative effectiveness studies are needed to establish the utility of alternative administration methods of available agents (eg, prolonged infusion of β-lactams) that optimize antibiotic pharmacodynamic properties while limiting adverse effects. Aerosolization of colistin and aminoglycosides for pneumonia is a relevant pursuit, as limitations in the current evidence base strongly support the need for multicenter randomized controlled prospective trials. Particular focus should include standardization of effective delivery techniques, pharmacokinetic assessment, and the use of AAA as adequate empiric antimicrobial therapy, or even monotherapy, to validate the presumed pharmacokinetic-pharmacodynamic benefits, compared to intravenous administration. In the meantime, it appears that AAA therapy with colistin and aminoglycosides for the treatment of VAP are reasonable options in complex critically ill patients with difficult to treat pathogens and conditions limiting the utility and safety of systemic administration. Amid the ongoing struggle against MDR pathogens in VAP, AAA therapy may be a viable contingency when the improbability for success with conventional antibiotic therapy approaches or exceeds the breaking point.

• Copyright © 2012 by Daedalus Enterprises Inc.