EDITORIALS Practice Guidelines, Clinical Trials, and Unexpected Results in Cystic Fibrosis Susanna A. McColley Clinical and Translational Research Program, and Division of Pulmonary Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; and Northwestern University Feinberg School of Medicine, Chicago, Illinois
People with cystic fibrosis (CF) are living longer: in 2012, median life expectancy was 41 years (1). New therapies and broad distribution of clinical practice guidelines, like the recently updated guideline on pulmonary maintenance therapies (2), have been important tools in achieving greater quality and length of life in CF. Current guidelines recommend azithromycin for patients with CF aged 6 and older who have chronic infection with Pseudomonas aeruginosa, and also recommend chronic suppressive therapy with inhaled tobramycin or aztreonam lysine in these patients in accordance with specific clinical findings. The uptake of azithromycin therapy is high, reaching 71% of eligible patients in 2012 (1). This is not surprising; azithromycin is inexpensive, well tolerated, and widely available. Furthermore, practice guidelines are well disseminated within the CF community through its Care Center Network (3), in which care centers receive feedback on guideline adherence on an annual basis. Chronic airway infection is a hallmark of CF lung disease. Because infection with P. aeruginosa is associated with increased morbidity and mortality, prevention and treatment of infection with this organism is an important strategy and a target for development of new therapies. The design of clinical trials for CF lung disease is similar to that for other complex, chronic diseases. With some exceptions, trial subjects remain on their personal “usual care” regimen when randomized to drug or placebo, or to different drugs being compared. This design has both pragmatic and ethical underpinnings, but may cause difficulty in interpretation of trial results,
and could substantially affect trial results if there is either inhibition or synergy—in either an antimicrobial or broader clinical sense—when a new therapy and a “usual” one are combined. In this issue of AnnalsATS (pp. 342–350), Nick and colleagues (4) describe a post hoc analysis of data compiled for a comparative trial of two inhaled antibiotics designed to suppress P. aeruginosa (5), which showed reduced efficacy of tobramycin solution for inhalation (TIS) compared with aztreonam lysine for inhalation (AZLI). The TIS effect was significantly less than that seen in the pivotal clinical trials of TIS in CF (6). Hypothesizing that this finding may be due to azithromycin antagonism of inhaled tobramycin antimicrobial effect on P. aeruginosa in CF airways (7–9), the authors used data and microbiologic specimens from the trial, which randomized 268 subjects with CF to three 28-day courses of one of these antibiotics, to evaluate the effect of concomitant therapy with azithromycin on treatment response to TIS and AZLI. While treatment response was variable between the three cycles of both antibiotics in individual subjects, 55% of subjects taking both azithromycin and TIS showed decline below baseline FEV1 after the first or third course of inhaled antibiotics, compared with 26 to 34% of subjects who took TIS without azithromycin, or AZLI with or without azithromycin. Subjects who took both TIS and azithromycin had less improvement in a disease-specific quality of life measure compared with the other three groups, and more intravenous or inhaled antibiotics, a proxy for pulmonary exacerbation. Finally, after crossover from TIS to AZLI,
subjects taking azithromycin showed improvement in FEV1. Antibiotic activity was then studied using biofilm cultures of P. aeruginosa isolates from subjects. Biomass volume, measured after incubation with tobramycin or aztreonam lysine, alone or in combination with azithromycin, was reduced more with tobramycin alone than with tobramycin and azithromycin; nearly half of isolates incubated with both showed antibiotic antagonism. However, some isolates showed an additive effect, and others had no effect, with this combination. There was no antagonism of antimicrobial effect with the combination of aztreonam lysine and azithromycin. These findings suggest biological plausibility of the apparent in vivo antagonism. How should a clinician apply these findings? Caution is advised. It is unreasonable to abandon the use of azithromycin for patients with CF. In the study by Saiman and coworkers (10), the largest study of azithromycin in patients with CF chronically infected with P. aeruginosa, about 60% of all subjects in both the treatment and placebo arms took TIS. The treatment effect of azithromycin was statistically significant in a subject population that was well balanced with respect to concomitant TIS therapy. The reduction of pulmonary exacerbation frequency in the azithromycin group was not predicted by FEV1 response (11). This suggests that, on a population basis, adding azithromycin therapy to TIS for chronic P. aeruginosa infection is beneficial. Furthermore, Binder and colleagues (12) recently reported that chronic use of azithromycin is protective against nontuberculous mycobacterial infections in CF.
Correspondence and requests for reprints should be addressed to Susanna A. McColley, M.D., Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago Avenue, #43, Chicago, IL 60611. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 3, pp 402–403, Mar 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201401-023ED Internet address: www.atsjournals.org
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EDITORIALS Abandoning the use of TIS for AZLI or other antibiotics is also irrational. TIS has become a mainstay of chronic suppressive therapy since the pivotal trial was published (6), has good efficacy in eradicating new P. aeruginosa infection in children (13), and reduces mortality in patients with CF with chronic infection (14). As the authors note, the subjects in the study by Assael and coworkers (5) may not be representative of the entire CF population for whom TIS therapy might be considered. Can we predict the risk of antagonism between azithromycin and tobramycin in individual patients? The biofilm culture strategy used in this study is not available in clinical microbiology laboratories, nor was
it specifically correlated with treatment response. Until we learn more about the risk of antagonism, we are left with the “N of 1” study design for individual patients. This is, of course, difficult in a progressive disease in which there is individual variability in both FEV1 and pulmonary exacerbation frequency. Nevertheless, in patients who are not having the expected response to clinical interventions and who are taking both azithromycin and TIS, withdrawal of azithromycin or administration of an alternate antipseudomonal agent, with close attention to a predefined clinical response, may be justified. As with all clinical practice, evaluating patient
References 1 Cystic Fibrosis Foundation Patient Registry. 2012 annual data report; Bethesda, MD. 2013 [accessed 20 Jan 2014]. Available from: http:// www.cff.org/UploadedFiles/research/ClinicalResearch/2012Patient-Registry.pdf 2 Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B; Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013;187:680–689. 3 Cystic Fibrosis Foundation. Care Center Network [accessed 20 Jan 2014]. Available from: http://www.cff.org/LivingWithCF/ CareCenterNetwork/ 4 Nick JA, Moskowitz SM, Chmiel JF, Forssen ´ AV, Kim SH, Saavedra MT, Saiman L, Taylor-Cousar JL, Nichols DP. Azithromycin may antagonize inhaled tobramycin when targeting Pseudomonas aeruginosa in cystic fibrosis. Ann Am Thorac Soc 2014;11:342–350. 5 Assael BM, Pressler T, Bilton D, Fayon M, Fischer R, Chiron R, Larosa M, Knoop C, McElvaney N, Lewis SA, Bresnik M, Montgomery AB, Oermann CM. Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial. J Cyst Fibros 2013;12: 130–140. 6 Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, WilliamsWarren J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, et al.; Cystic Fibrosis Inhaled Tobramycin Study Group. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999;340:23–30. 7 Nichols DP, Caceres S, Caverly L, Fratelli C, Kim SH, Malcolm K, Poch KR, Saavedra M, Solomon G, Taylor-Cousar J, et al. Effects of azithromycin in Pseudomonas aeruginosa burn wound infection. J Surg Res 2013;183:767–776.
Editorials
adherence and response to therapies that should benefit their underlying disease is essential when recommending or changing a therapeutic regimen. Above all, clinicians must be aware that our knowledge of combination therapies is limited, and ongoing research is needed to better define how therapies may interact with each other in positive or negative ways. The upcoming trial described by Nick and coworkers will help to interpret whether and how we should change practice based on these unexpected results (4). n Author disclosures are available with the text of this article at www.atsjournals.org.
8 Tre-Hardy ´ M, Nagant C, El Manssouri N, Vanderbist F, Traore H, Vaneechoutte M, Dehaye JP. Efficacy of the combination of tobramycin and a macrolide in an in vitro Pseudomonas aeruginosa mature biofilm model. Antimicrob Agents Chemother 2010;54: 4409–4415. 9 Dales L, Ferris W, Vandemheen K, Aaron SD. Combination antibiotic susceptibility of biofilm-grown Burkholderia cepacia and Pseudomonas aeruginosa isolated from patients with pulmonary exacerbations of cystic fibrosis. Eur J Clin Microbiol Infect Dis 2009; 28:1275–1279. 10 Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003;290:1749–1756. 11 Saiman L, Mayer-Hamblett N, Campbell P, Marshall BC; Macrolide Study Group. Heterogeneity of treatment response to azithromycin in patients with cystic fibrosis. Am J Respir Crit Care Med 2005;172: 1008–1012. 12 Binder AM, Adjemian J, Olivier KN, Prevots DR. Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons with cystic fibrosis. Am J Respir Crit Care Med 2013;188:807–812. 13 Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, Williams J, Hiatt P, Gibson RL, Spencer T, et al.; Early Pseudomonas Infection Control (EPIC) Investigators. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med 2011;165:847–856. 14 Sawicki GS, Signorovitch JE, Zhang J, Latremouille-Viau D, von Wartburg M, Wu EQ, Shi L. Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. Pediatric Pulmonology 2013;.47:44–52.
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People with cystic fibrosis (CF) are living longer: in 2012, median life expectancy was 41 years (1). New therapies and broad distribution of clinical practice guidelines, like the recently updated guideline on pulmonary maintenance therapies (2), have been important tools in achieving greater quality and length of life in CF. Current guidelines recommend azithromycin for patients with CF aged 6 and older who have chronic infection with Pseudomonas aeruginosa, and also recommend chronic suppressive therapy with inhaled tobramycin or aztreonam lysine in these patients in accordance with specific clinical findings. The uptake of azithromycin therapy is high, reaching 71% of eligible patients in 2012 (1). This is not surprising; azithromycin is inexpensive, well tolerated, and widely available. Furthermore, practice guidelines are well disseminated within the CF community through its Care Center Network (3), in which care centers receive feedback on guideline adherence on an annual basis. Chronic airway infection is a hallmark of CF lung disease. Because infection with P. aeruginosa is associated with increased morbidity and mortality, prevention and treatment of infection with this organism is an important strategy and a target for development of new therapies. The design of clinical trials for CF lung disease is similar to that for other complex, chronic diseases. With some exceptions, trial subjects remain on their personal “usual care” regimen when randomized to drug or placebo, or to different drugs being compared. This design has both pragmatic and ethical underpinnings, but may cause difficulty in interpretation of trial results,
and could substantially affect trial results if there is either inhibition or synergy—in either an antimicrobial or broader clinical sense—when a new therapy and a “usual” one are combined. In this issue of AnnalsATS (pp. 342–350), Nick and colleagues (4) describe a post hoc analysis of data compiled for a comparative trial of two inhaled antibiotics designed to suppress P. aeruginosa (5), which showed reduced efficacy of tobramycin solution for inhalation (TIS) compared with aztreonam lysine for inhalation (AZLI). The TIS effect was significantly less than that seen in the pivotal clinical trials of TIS in CF (6). Hypothesizing that this finding may be due to azithromycin antagonism of inhaled tobramycin antimicrobial effect on P. aeruginosa in CF airways (7–9), the authors used data and microbiologic specimens from the trial, which randomized 268 subjects with CF to three 28-day courses of one of these antibiotics, to evaluate the effect of concomitant therapy with azithromycin on treatment response to TIS and AZLI. While treatment response was variable between the three cycles of both antibiotics in individual subjects, 55% of subjects taking both azithromycin and TIS showed decline below baseline FEV1 after the first or third course of inhaled antibiotics, compared with 26 to 34% of subjects who took TIS without azithromycin, or AZLI with or without azithromycin. Subjects who took both TIS and azithromycin had less improvement in a disease-specific quality of life measure compared with the other three groups, and more intravenous or inhaled antibiotics, a proxy for pulmonary exacerbation. Finally, after crossover from TIS to AZLI,
subjects taking azithromycin showed improvement in FEV1. Antibiotic activity was then studied using biofilm cultures of P. aeruginosa isolates from subjects. Biomass volume, measured after incubation with tobramycin or aztreonam lysine, alone or in combination with azithromycin, was reduced more with tobramycin alone than with tobramycin and azithromycin; nearly half of isolates incubated with both showed antibiotic antagonism. However, some isolates showed an additive effect, and others had no effect, with this combination. There was no antagonism of antimicrobial effect with the combination of aztreonam lysine and azithromycin. These findings suggest biological plausibility of the apparent in vivo antagonism. How should a clinician apply these findings? Caution is advised. It is unreasonable to abandon the use of azithromycin for patients with CF. In the study by Saiman and coworkers (10), the largest study of azithromycin in patients with CF chronically infected with P. aeruginosa, about 60% of all subjects in both the treatment and placebo arms took TIS. The treatment effect of azithromycin was statistically significant in a subject population that was well balanced with respect to concomitant TIS therapy. The reduction of pulmonary exacerbation frequency in the azithromycin group was not predicted by FEV1 response (11). This suggests that, on a population basis, adding azithromycin therapy to TIS for chronic P. aeruginosa infection is beneficial. Furthermore, Binder and colleagues (12) recently reported that chronic use of azithromycin is protective against nontuberculous mycobacterial infections in CF.
Correspondence and requests for reprints should be addressed to Susanna A. McColley, M.D., Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago Avenue, #43, Chicago, IL 60611. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 3, pp 402–403, Mar 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201401-023ED Internet address: www.atsjournals.org
402
AnnalsATS Volume 11 Number 3 | March 2014
EDITORIALS Abandoning the use of TIS for AZLI or other antibiotics is also irrational. TIS has become a mainstay of chronic suppressive therapy since the pivotal trial was published (6), has good efficacy in eradicating new P. aeruginosa infection in children (13), and reduces mortality in patients with CF with chronic infection (14). As the authors note, the subjects in the study by Assael and coworkers (5) may not be representative of the entire CF population for whom TIS therapy might be considered. Can we predict the risk of antagonism between azithromycin and tobramycin in individual patients? The biofilm culture strategy used in this study is not available in clinical microbiology laboratories, nor was
it specifically correlated with treatment response. Until we learn more about the risk of antagonism, we are left with the “N of 1” study design for individual patients. This is, of course, difficult in a progressive disease in which there is individual variability in both FEV1 and pulmonary exacerbation frequency. Nevertheless, in patients who are not having the expected response to clinical interventions and who are taking both azithromycin and TIS, withdrawal of azithromycin or administration of an alternate antipseudomonal agent, with close attention to a predefined clinical response, may be justified. As with all clinical practice, evaluating patient
References 1 Cystic Fibrosis Foundation Patient Registry. 2012 annual data report; Bethesda, MD. 2013 [accessed 20 Jan 2014]. Available from: http:// www.cff.org/UploadedFiles/research/ClinicalResearch/2012Patient-Registry.pdf 2 Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B; Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013;187:680–689. 3 Cystic Fibrosis Foundation. Care Center Network [accessed 20 Jan 2014]. Available from: http://www.cff.org/LivingWithCF/ CareCenterNetwork/ 4 Nick JA, Moskowitz SM, Chmiel JF, Forssen ´ AV, Kim SH, Saavedra MT, Saiman L, Taylor-Cousar JL, Nichols DP. Azithromycin may antagonize inhaled tobramycin when targeting Pseudomonas aeruginosa in cystic fibrosis. Ann Am Thorac Soc 2014;11:342–350. 5 Assael BM, Pressler T, Bilton D, Fayon M, Fischer R, Chiron R, Larosa M, Knoop C, McElvaney N, Lewis SA, Bresnik M, Montgomery AB, Oermann CM. Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial. J Cyst Fibros 2013;12: 130–140. 6 Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, WilliamsWarren J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, et al.; Cystic Fibrosis Inhaled Tobramycin Study Group. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999;340:23–30. 7 Nichols DP, Caceres S, Caverly L, Fratelli C, Kim SH, Malcolm K, Poch KR, Saavedra M, Solomon G, Taylor-Cousar J, et al. Effects of azithromycin in Pseudomonas aeruginosa burn wound infection. J Surg Res 2013;183:767–776.
Editorials
adherence and response to therapies that should benefit their underlying disease is essential when recommending or changing a therapeutic regimen. Above all, clinicians must be aware that our knowledge of combination therapies is limited, and ongoing research is needed to better define how therapies may interact with each other in positive or negative ways. The upcoming trial described by Nick and coworkers will help to interpret whether and how we should change practice based on these unexpected results (4). n Author disclosures are available with the text of this article at www.atsjournals.org.
8 Tre-Hardy ´ M, Nagant C, El Manssouri N, Vanderbist F, Traore H, Vaneechoutte M, Dehaye JP. Efficacy of the combination of tobramycin and a macrolide in an in vitro Pseudomonas aeruginosa mature biofilm model. Antimicrob Agents Chemother 2010;54: 4409–4415. 9 Dales L, Ferris W, Vandemheen K, Aaron SD. Combination antibiotic susceptibility of biofilm-grown Burkholderia cepacia and Pseudomonas aeruginosa isolated from patients with pulmonary exacerbations of cystic fibrosis. Eur J Clin Microbiol Infect Dis 2009; 28:1275–1279. 10 Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003;290:1749–1756. 11 Saiman L, Mayer-Hamblett N, Campbell P, Marshall BC; Macrolide Study Group. Heterogeneity of treatment response to azithromycin in patients with cystic fibrosis. Am J Respir Crit Care Med 2005;172: 1008–1012. 12 Binder AM, Adjemian J, Olivier KN, Prevots DR. Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons with cystic fibrosis. Am J Respir Crit Care Med 2013;188:807–812. 13 Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, Williams J, Hiatt P, Gibson RL, Spencer T, et al.; Early Pseudomonas Infection Control (EPIC) Investigators. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med 2011;165:847–856. 14 Sawicki GS, Signorovitch JE, Zhang J, Latremouille-Viau D, von Wartburg M, Wu EQ, Shi L. Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. Pediatric Pulmonology 2013;.47:44–52.
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