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The Answer for Inhaled Antibiotics in Pneumonia Is Still Blowing in the Wind
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Editorial
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The Answer for Inhaled Antibiotics in Pneumonia Is Still Blowing in the Wind Andrew F. Shorr, MD, MPH, FCCP Washington, DC Marya D. Zilberberg, MD, MPH, FCCP Goshen, MA
Infection remains a daily challenge in the care of critically ill patients. Point prevalence studies suggest that nearly 50% of patients in ICUs globally suffer from acute infection.1,2 Pneumonia accounts for more than half of these infections and therefore serves as the major reason for antibiotic use.1 Concurrently, antibiotic therapy for pneumonia represents a key driver of antimicrobial resistance. Every day the vicious cycle ensues wherein we use broad-spectrum agents to avoid providing inadequate antimicrobial therapy but risk creating further resistance. Although the need for initially appropriate antibiotic therapy is clearly recognized as the main determinant of outcome in severe infection, clinicians struggle to find ways to balance the need to get it right the first time against the cost of promoting further resistance.3,4 In essence, the dilemma places the needs of the patient requiring immediate care against the needs of potential future patients. FOR RELATED ARTICLE SEE PAGE 1239
AFFILIATIONS: From the Section of Pulmonary and Critical Care Medicine (Dr Shorr), Medstar Washington Hospital Center; and EviMed Research (Dr Zilberberg). FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: A. F. S. has served as a speaker for, consultant to, or received research support from Achaogen, Actavis, Astellas, Astra Zeneca, Bayer, BMS, Cardeas, Cempra, Medicines Company, Melinta, Merck, Paratek, Pfizer, Roche, Shionogi, Spero, Tetraphase, and Theravance. M. D. Z. has received consulting fees and/ or research funding from Achaogen, Astellas, The Medicines Company, Melinta, Merck, Pfizer, Shionogi, Tetraphase, and Theravance. CORRESPONDENCE TO: Andrew F. Shorr, MD, MPH, FCCP, Medstar Washington Hospital Center, 110 Irving St, NW, Washington, DC 20010; e-mail: [email protected] Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2016.11.034
journal.publications.chestnet.org
Some have suggested that simply using shorter durations of antibiotic therapy will reduce this pressure.5 Unfortunately, this recommendation ignores data indicating that for select highly resistant pathogens (eg, Pseudomonas aeruginosa), longer treatment courses are likely warranted.6 Others have advocated for optimizing antibiotic dosing with the current armamentarium to improve outcomes. Certainly studies indicate that applying principles of pharmacokinetics and pharmacodynamics to patients in the ICU can enhance results.7,8 However, the overall value and impact of this stratagem has yet to be clearly defined. Finally, various antibiotic drug developers propose building new tools for treating infection.9 Unfortunately, many of the agents in the antibiotic drug development pipeline represent moderate enhancements and incremental changes. Moreover, these newer agents are mainly designed to address specific pathogens (eg, carbapenemase-producing Enterobacteriaceae). In this issue of CHEST, Kollef et al10 report the finding of a unique paradigm for addressing the huge unmet need we face in antibiotic choices for pneumonia. These investigators performed a rigorous phase 2 study of inhaled amikacin and fosfomycin (AFIS) for the treatment of ventilator-associated pneumonia (VAP). Theoretically, an inhaled route allows for the delivery of high concentrations of antibiotics directly to the target tissue. This could lead to faster pathogen eradication and potentially spare the patient potential side effects associated with systemic administration. Additionally, for organisms where no alternatives exist, an inhalation approach might provide a way to overcome in vitro resistance. Unfortunately, the data surrounding inhaled anti-infectives for pneumonia are mixed. Many earlier trials have been of poor quality.5 In fact, the most recent guidelines for hospital-acquired pneumonia and VAP note that prior studies of inhaled antibiotics for pneumonia provide little detail on the actual method of drug delivery and suffer from a number of other methodologic flaws.5 Nonetheless, the guidelines weakly recommend use of adjunctive inhaled agents based on a limited meta-analysis of nine trials and a belief that the likely harms of inhaled therapies are low.5 The findings from Kollef et al10 now place this conclusion into question and certainly shift the burden
1201
of proof in the debate about the role for inhaled treatments for pneumonia. In the randomized trial, patients received adjunctive AFIS along with conventional therapy. It appeared that the drug did actually reach the target tissues as demonstrated by the high tracheal concentrations. Nonetheless, AFIS failed to alter the primary end point and in no way affected cure rates or mortality. These results are of course disappointing, but do provide some insight for future clinical trials in pneumonia. The drug was well tolerated generally, and readers should appreciate that the safety and tolerability seen with AFIS does not necessarily transfer to other agents given via inhalation. Specifically, inhaled colistin can potentially cause significant bronchospasm. What can we learn from this trial? Interestingly, the investigators noted trends suggesting more ventilatorfree days and higher clinical cure rates among patients infected with pan-resistant Acinetobacter who were treated with AFIS.10 This observation, coupled with evidence of drug delivery to the airway, indicates the ability of inhaled treatments to eradicate organisms and to affect, potentially, clinical end points. If inhaled antibiotics had no value, one should not have observed any effect among those with Acinetobacter VAP. In essence, this silver lining highlights that, when faced with no other systemic antibiotic options, inhaled antibiotics may yet prove effective. The new guideline recommendation to consider the use of inhaled antibiotics when no other option exists now has stronger, new data to support it.5 Moreover, the possible impact of AFIS in Acinetobacter underscores that the issue with the current trial may have more to do with study design than with the efficacy of inhaled antibiotics. The authors comment on this, but the point requires emphasis. As investigators, drug developers, and regulatory authorities (eg, Food and Drug Administration) argue over the appropriate design and end points for pneumonia clinical trials, one fact becomes clear: if patients are allowed to receive several days of antibiotic therapy prior to enrollment in a trial of a novel adjunctive therapy, it becomes very challenging to detect a difference. The patients who received initially appropriate antibiotic treatment are likely already on the road to recovery by the time they are entered into the clinical trial. Conversely, enrolling subjects within a short time window (eg, 1 day) after pneumonia onset is nearly operationally impossible. Hence, we need to come to some agreement about an entirely new model for
1202 Editorial
clinical drug discovery and development in pneumonia. The classic noninferiority study design essentially tells clinicians nothing about how and when to use a new agent. Likewise, superiority trials focused only on changes in surrogate measures, such as the clinical pulmonary infection score, are not likely to provide useful information. Rather, we must urgently consider several options. First, reliance on adaptive trial designs where the study is modified as it progresses so as to maintain flexibility without compromising validity presents a novel approach to the current dilemma. Second, utilization of hierarchical end points where multiple end points are tested in a prioritized fashion as advocated for by some within the Antimicrobial Resistance Leadership Working Group can also help to facilitate clinical trials in pneumonia.11 In short, Kollef et al10 have conducted an important study. Despite the discouraging results, the findings indicate that there may be a potential role for inhaled antibiotics in severe pneumonia. Fortunately, other trials are underway to assess this hypothesis. However, will these newer studies fail to detect important differences simply because they are hindered by issues with trial design and executability? One certainly hopes not, but we fear this may be the case unless regulatory agencies begin to better appreciate how acute the dilemma is when it comes to our limited current armamentarium for resistant pathogens in pneumonia.
References 1. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323-2329. 2. Hanberger H, Antonelli M, Holmbom M, et al. Infections, antibiotic treatment and mortality in patients admitted to ICUs in countries considered to have high levels of antibiotic resistance compared to those with low levels. BMC Infect Dis. 2014;14:513. 3. Zilberberg MD, Shorr AF, Micek ST, et al. Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gramnegative severe sepsis and septic shock: a retrospective cohort study. Crit Care. 2014;18(6):596. 4. Vazquez-Guillamet C, Scolari M, Zilberberg MD, et al. Using the number needed to treat to assess appropriate antimicrobial therapy as a determinant of outcome in severe sepsis and septic shock. Crit Care Med. 2014;42(11):2342-2349. 5. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111. 6. Kollef MH, Chastre J, Clavel M, et al. A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilatorassociated pneumonia. Crit Care. 2012;16(6):R218. 7. Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus intermittent b-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194(6):681-691.
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8. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, openlabelled randomized controlled trial of continuous versus intermittent beta lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016;42(10):1535-1545. 9. Spellberg B, Bartlett J, Wunderink R, et al. Novel approaches are needed to develop tomorrow’s antibacterial therapies. Am J Respir Crit Care Med. 2015;191(2):135-140.
journal.publications.chestnet.org
10. Kollef MH, Ricard J-D, Roux D, et al. A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of Gram-negative ventilator-associated pneumonia: IASIS trial. Chest. 2017;151(6):1239-1246. 11. Evans SR, Rubin D, Follmann D, et al. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis. 2015;61(5):800-806.
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Editorial
]
The Answer for Inhaled Antibiotics in Pneumonia Is Still Blowing in the Wind Andrew F. Shorr, MD, MPH, FCCP Washington, DC Marya D. Zilberberg, MD, MPH, FCCP Goshen, MA
Infection remains a daily challenge in the care of critically ill patients. Point prevalence studies suggest that nearly 50% of patients in ICUs globally suffer from acute infection.1,2 Pneumonia accounts for more than half of these infections and therefore serves as the major reason for antibiotic use.1 Concurrently, antibiotic therapy for pneumonia represents a key driver of antimicrobial resistance. Every day the vicious cycle ensues wherein we use broad-spectrum agents to avoid providing inadequate antimicrobial therapy but risk creating further resistance. Although the need for initially appropriate antibiotic therapy is clearly recognized as the main determinant of outcome in severe infection, clinicians struggle to find ways to balance the need to get it right the first time against the cost of promoting further resistance.3,4 In essence, the dilemma places the needs of the patient requiring immediate care against the needs of potential future patients. FOR RELATED ARTICLE SEE PAGE 1239
AFFILIATIONS: From the Section of Pulmonary and Critical Care Medicine (Dr Shorr), Medstar Washington Hospital Center; and EviMed Research (Dr Zilberberg). FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: A. F. S. has served as a speaker for, consultant to, or received research support from Achaogen, Actavis, Astellas, Astra Zeneca, Bayer, BMS, Cardeas, Cempra, Medicines Company, Melinta, Merck, Paratek, Pfizer, Roche, Shionogi, Spero, Tetraphase, and Theravance. M. D. Z. has received consulting fees and/ or research funding from Achaogen, Astellas, The Medicines Company, Melinta, Merck, Pfizer, Shionogi, Tetraphase, and Theravance. CORRESPONDENCE TO: Andrew F. Shorr, MD, MPH, FCCP, Medstar Washington Hospital Center, 110 Irving St, NW, Washington, DC 20010; e-mail: [email protected] Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2016.11.034
journal.publications.chestnet.org
Some have suggested that simply using shorter durations of antibiotic therapy will reduce this pressure.5 Unfortunately, this recommendation ignores data indicating that for select highly resistant pathogens (eg, Pseudomonas aeruginosa), longer treatment courses are likely warranted.6 Others have advocated for optimizing antibiotic dosing with the current armamentarium to improve outcomes. Certainly studies indicate that applying principles of pharmacokinetics and pharmacodynamics to patients in the ICU can enhance results.7,8 However, the overall value and impact of this stratagem has yet to be clearly defined. Finally, various antibiotic drug developers propose building new tools for treating infection.9 Unfortunately, many of the agents in the antibiotic drug development pipeline represent moderate enhancements and incremental changes. Moreover, these newer agents are mainly designed to address specific pathogens (eg, carbapenemase-producing Enterobacteriaceae). In this issue of CHEST, Kollef et al10 report the finding of a unique paradigm for addressing the huge unmet need we face in antibiotic choices for pneumonia. These investigators performed a rigorous phase 2 study of inhaled amikacin and fosfomycin (AFIS) for the treatment of ventilator-associated pneumonia (VAP). Theoretically, an inhaled route allows for the delivery of high concentrations of antibiotics directly to the target tissue. This could lead to faster pathogen eradication and potentially spare the patient potential side effects associated with systemic administration. Additionally, for organisms where no alternatives exist, an inhalation approach might provide a way to overcome in vitro resistance. Unfortunately, the data surrounding inhaled anti-infectives for pneumonia are mixed. Many earlier trials have been of poor quality.5 In fact, the most recent guidelines for hospital-acquired pneumonia and VAP note that prior studies of inhaled antibiotics for pneumonia provide little detail on the actual method of drug delivery and suffer from a number of other methodologic flaws.5 Nonetheless, the guidelines weakly recommend use of adjunctive inhaled agents based on a limited meta-analysis of nine trials and a belief that the likely harms of inhaled therapies are low.5 The findings from Kollef et al10 now place this conclusion into question and certainly shift the burden
1201
of proof in the debate about the role for inhaled treatments for pneumonia. In the randomized trial, patients received adjunctive AFIS along with conventional therapy. It appeared that the drug did actually reach the target tissues as demonstrated by the high tracheal concentrations. Nonetheless, AFIS failed to alter the primary end point and in no way affected cure rates or mortality. These results are of course disappointing, but do provide some insight for future clinical trials in pneumonia. The drug was well tolerated generally, and readers should appreciate that the safety and tolerability seen with AFIS does not necessarily transfer to other agents given via inhalation. Specifically, inhaled colistin can potentially cause significant bronchospasm. What can we learn from this trial? Interestingly, the investigators noted trends suggesting more ventilatorfree days and higher clinical cure rates among patients infected with pan-resistant Acinetobacter who were treated with AFIS.10 This observation, coupled with evidence of drug delivery to the airway, indicates the ability of inhaled treatments to eradicate organisms and to affect, potentially, clinical end points. If inhaled antibiotics had no value, one should not have observed any effect among those with Acinetobacter VAP. In essence, this silver lining highlights that, when faced with no other systemic antibiotic options, inhaled antibiotics may yet prove effective. The new guideline recommendation to consider the use of inhaled antibiotics when no other option exists now has stronger, new data to support it.5 Moreover, the possible impact of AFIS in Acinetobacter underscores that the issue with the current trial may have more to do with study design than with the efficacy of inhaled antibiotics. The authors comment on this, but the point requires emphasis. As investigators, drug developers, and regulatory authorities (eg, Food and Drug Administration) argue over the appropriate design and end points for pneumonia clinical trials, one fact becomes clear: if patients are allowed to receive several days of antibiotic therapy prior to enrollment in a trial of a novel adjunctive therapy, it becomes very challenging to detect a difference. The patients who received initially appropriate antibiotic treatment are likely already on the road to recovery by the time they are entered into the clinical trial. Conversely, enrolling subjects within a short time window (eg, 1 day) after pneumonia onset is nearly operationally impossible. Hence, we need to come to some agreement about an entirely new model for
1202 Editorial
clinical drug discovery and development in pneumonia. The classic noninferiority study design essentially tells clinicians nothing about how and when to use a new agent. Likewise, superiority trials focused only on changes in surrogate measures, such as the clinical pulmonary infection score, are not likely to provide useful information. Rather, we must urgently consider several options. First, reliance on adaptive trial designs where the study is modified as it progresses so as to maintain flexibility without compromising validity presents a novel approach to the current dilemma. Second, utilization of hierarchical end points where multiple end points are tested in a prioritized fashion as advocated for by some within the Antimicrobial Resistance Leadership Working Group can also help to facilitate clinical trials in pneumonia.11 In short, Kollef et al10 have conducted an important study. Despite the discouraging results, the findings indicate that there may be a potential role for inhaled antibiotics in severe pneumonia. Fortunately, other trials are underway to assess this hypothesis. However, will these newer studies fail to detect important differences simply because they are hindered by issues with trial design and executability? One certainly hopes not, but we fear this may be the case unless regulatory agencies begin to better appreciate how acute the dilemma is when it comes to our limited current armamentarium for resistant pathogens in pneumonia.
References 1. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323-2329. 2. Hanberger H, Antonelli M, Holmbom M, et al. Infections, antibiotic treatment and mortality in patients admitted to ICUs in countries considered to have high levels of antibiotic resistance compared to those with low levels. BMC Infect Dis. 2014;14:513. 3. Zilberberg MD, Shorr AF, Micek ST, et al. Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gramnegative severe sepsis and septic shock: a retrospective cohort study. Crit Care. 2014;18(6):596. 4. Vazquez-Guillamet C, Scolari M, Zilberberg MD, et al. Using the number needed to treat to assess appropriate antimicrobial therapy as a determinant of outcome in severe sepsis and septic shock. Crit Care Med. 2014;42(11):2342-2349. 5. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111. 6. Kollef MH, Chastre J, Clavel M, et al. A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilatorassociated pneumonia. Crit Care. 2012;16(6):R218. 7. Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus intermittent b-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194(6):681-691.
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151#6 CHEST JUNE 2017
]
8. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, openlabelled randomized controlled trial of continuous versus intermittent beta lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016;42(10):1535-1545. 9. Spellberg B, Bartlett J, Wunderink R, et al. Novel approaches are needed to develop tomorrow’s antibacterial therapies. Am J Respir Crit Care Med. 2015;191(2):135-140.
journal.publications.chestnet.org
10. Kollef MH, Ricard J-D, Roux D, et al. A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of Gram-negative ventilator-associated pneumonia: IASIS trial. Chest. 2017;151(6):1239-1246. 11. Evans SR, Rubin D, Follmann D, et al. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis. 2015;61(5):800-806.
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