American Journal of Respiratory and Critical Care Medicine

Kudos to Aaron and colleagues for tackling pulmonary exacerbations (1), one of the core clinical problems in cystic fibrosis (CF) for which there is a paucity of data on some fundamental issues confronting clinicians. They demonstrate that exacerbations in adults chronically infected with Pseudomonas aeruginosa are not associated with a new infecting organism. This finding has implications beyond the logistics of collecting sputum cultures, but first a brief review of the context.

Pulmonary exacerbations are critically important in CF and they are very common; 48 percent of the patients in the study of Aaron and colleagues experienced an exacerbation that was treated with intravenous antibiotics over the 26-month prospective trial (1). These more severe exacerbations are almost certainly just the tip of the iceberg (2). Sophisticated statistical models demonstrate that exacerbations are associated with mortality (3). Indeed, exacerbations stand out as one of several key parameters that clinicians can impact with preventive and therapeutic strategies. Exacerbations also impact quality of life, a meaningful endpoint for a lifelong chronic disease, and the effects linger well beyond the actual hospitalization for treatment (4). A major proportion of health care expenditures for CF, particularly for adults with moderate to severe pulmonary disease, are directly attributable to the treatment of pulmonary exacerbations (5). From the perspective of clinicians, patients, and health care administrators, Aaron and colleagues have clearly chosen a worthy topic.

Their findings are consistent with the compelling body of evidence demonstrating the biofilm nature of chronic pseudomonal infections in CF (reviewed in reference 6). Using pulsed-field gel electrophoresis, they show that P. aeruginosa recovered during a time of clinical stability and during an exacerbation were of the same genotype in 34 of 36 adult patients at 8 Canadian CF centers (1). The investigators appropriately caution readers not to extrapolate these results to children recently infected with P. aeruginosa. The sputum microbiology in this situation is much less stable (7). For adults chronically infected with P. aeruginosa, however, Aaron and coworkers validate the approach of experienced clinicians who typically initiate antibiotic therapy for an exacerbation based on the most recent culture results. Assuming that recent culture results are available, it also calls into question the need for an additional sputum culture at the time of an exacerbation, a recommendation (8) that has been widely adopted at many CF care centers.

More importantly, the work of Aaron and coworkers (1) provides a foundation for defining the role of in vitro antibiotic susceptibility testing in the selection of a treatment regimen for an exacerbation. One of the limitations of antibiotic susceptibility testing in the clinical arena is the relatively slow turnaround time for results. The data from Aaron and coworkers (1) suggest that in many cases such testing could be done on bacteria derived from a sputum culture collected during clinical stability in anticipation of an exacerbation.

A number of important questions surround the issue of antibiotic susceptibility testing in CF. Does standard antibiotic susceptibility testing predict clinical response to treatment? The ticarcillin and tobramycin regimen employed by Regelmann and coworkers (9) achieved drug levels well above the mean inhibitory concentration of the predominant strain of P. aeruginosa and resulted in marked improvement in pulmonary function and reduction in sputum bacterial density. In contrast, a recent retrospective analysis of the placebo group in the multicenter Phase III inhaled tobramycin trial showed no correlation between the mean inhibitory concentration of the predominant pseudomonal strain and clinical response to antibiotics for the treatment of an exacerbation (10). The lack of standardization in the treatment regimen, however, makes it difficult to know whether the clinical response to the susceptibility data was appropriate. Of note, the treatment-related improvement in pulmonary function in this study was approximately half that reported by Regelmann and coworkers (9). Does antibiotic synergy testing predict clinical response to treatment of resistant organisms? A CF Foundation–sponsored referral lab for synergy testing of resistant organisms has been in existence for over 10 years at Columbia University. Synergy testing has been performed on thousands of bacterial strains, but correlation of the in vitro results with clinical outcomes is lacking (11). Do alternative synergy testing strategies predict clinical response to treatment? A Canadian clinical trial led by Aaron and colleagues is currently underway to assess the utility of the multiple combination bactericidal testing assay (12) in guiding therapy for exacerbations in patients infected with multi-resistant P. aeruginosa or Burkholderia cepacia complex. Do strategies that test antibiotic susceptibility of organisms growing in biofilms (13) predict clinical response to treatment? Burns and colleagues (personal communication) are preparing to launch a trial comparing clinical outcomes from treatment regimens selected on the basis of standard versus biofilm susceptibility testing.

Rigorous data with an explicit definition of a pulmonary exacerbation and standardized treatment regimens are needed to resolve these questions. Why do we need an explicit definition of a pulmonary exacerbation? There is marked variability among physicians in their approach to diagnosis and management of an exacerbation (14). Thus, it is safe to assume that not all clinically significant pulmonary exacerbations are treated with antibiotics and not all decisions to treat with antibiotics are founded on firm clinical evidence of a pulmonary exacerbation. Aaron and coworkers (1) analyzed only exacerbations that were treated with intravenous antibiotics, a potential weakness in the study. We cannot judge the investigators too harshly on this point, however, because this approach has been widely used in the CF community. Nonetheless, it is time that we hold ourselves to a higher standard. Pulmonary exacerbations are an important endpoint in many CF clinical trials and an explicit definition of an exacerbation should be incorporated into study designs and statistical analysis plans. This will strengthen the individual trials and permit more straightforward comparisons between trials. An explicit definition of an exacerbation will also facilitate quality improvement activities aimed at this important aspect of CF care. It's time to be explicit!

1. Aaron SD, Ramotar K, Ferris W, Vandemheen K, Saginur R, Tullis E, Haase D, Kottachchi D, St. Denis M, Chan F. Adult cystic fibrosis exacerbations and new strains of Pseudomonas aeruginosa. Am J Respir Crit Care Med 2004;169:811–815.
2. Rosenfeld M, Emerson J, Williams-Warren J, Pepe M, Smith A, Montgomery AB, Ramsey B. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr 2001;139:359–365.
3. Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001;153:345–352.
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5. Lieu TA, Ray GT, Farmer G, Shay GF. The cost of medical care for patients with cystic fibrosis in a health maintenance organization. Pediatrics 1999;103:e72.
6. Parsek MR, Singh PK. Bacterial biofilms: an emerging link to disease pathogenesis. Annu Rev Microbiol 2003;57:677–701.
7. Burns JL, Gibson RL, McNamara S, Yim D, Emerson J, Rosenfeld M, Hiatt P, McCoy K, Castile R, Smith AL, et al. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis 2001;183:444–452.
8. Cystic Fibrosis Foundation. Clinical practice guidelines for cystic fibrosis.. Bethesda, MD: Cystic Fibrosis Foundation; 1997.
9. Regelmann WE, Elliott GR, Warwick WJ, Clawson CC. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone. Am Rev Respir Dis 1990;141:914–921.
10. Smith AL, Fiel SB, Mayer-Hamblett N, Ramsey B, Burns JL. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest 2003;123:1495–1502.
11. Saiman L, Mehar F, Niu WW, Neu HC, Shaw KJ, Miller G, Prince A. Antibiotic susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. Clin Infect Dis 1996;23:532–537.
12. Lang BJ, Aaron SD, Ferris W, Hebert PC, MacDonald NE. Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with multiresistant strains of Pseudomonas aeruginosa. Am J Respir Crit Care Med 2000;162:2241–2245.
13. Aaron SD, Ferris W, Ramotar K, Vandemheen K, Chan F, Saginur R. Single and combination antibiotic susceptibilities of planktonic, adherent, and biofilm-grown Pseudomonas aeruginosa isolates cultured from sputa of adults with cystic fibrosis. J Clin Microbiol 2002;40:4172–4179.
14. Dakin C, Henry RL, Field P, Morton J. Defining an exacerbation of pulmonary disease in cystic fibrosis. Pediatr Pulmonol 2001;31:436–442.

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