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Bactrim/Septra for Idiopathic Pulmonary Fibrosis?
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that lacks proven, effective treatments. Many novel medications have been trialed and painfully failed. So I commend Ludmila Shulgina and colleagues for trying an old medication, trimethoprim-sulfamethoxazole (TMP-SMX), with some preliminary evidence for potential benefit.
What They Did
This was a multicenter randomized controlled trial in the UK comparing 12 months of double-strength TMP-SMX (960mg) twice daily to placebo in 181 patients with fibrotic idiopathic interstitial pneumonia (by clinical diagnosis, 94% had IPF/UIP and 6% had fibrotic NSIP). The primary outcome was change in forced vital capacity. Secondary outcomes included other physiologic and quality-of-life measures, and mortality was a tertiary outcome. Results were analyzed as intention-to-treat (all randomized subjects according to treatment assignment regardless of drop-out, n=181) and per-protocol (restricted to subjects demonstrating at least 80% adherence to the study medication who did not drop out of the study prior to death, n=118). Sixty-percent of patients were on prednisolone (most < 20 mg daily), and nearly one-third were on a steroid-sparing immunosuppressant (azathioprine or mycofenolate mofetil) at randomization.
What They Found
In the intention-to-treat analysis, there were no differences in pulmonary function or mortality. Patients in the TMP-SMX group did have improved symptom scores and fewer required increases in oxygen therapy.
In the per-protocol analysis, they similarly found an improvement in symptom scores and decreased need for more oxygen. Additionally, on this analysis they found a nearly 80% reduction in mortality compared to placebo. This effect did not seem to be isolated to those on immunosuppressive medications, and results were similar when confined to the subgroup with definite/probable IPF. Most deaths were due to worsening IPF or pneumonia.
Adverse events were common in the TMP-SMX group with nearly one-third withdrawing. Three patients on TMP-SMX and azathioprine had severe neutropenia. There were also more gastrointestinal side effects and rash in the TMP-SMX group. There were significantly fewer infections, including pneumonia, in the TMP-SMX group.
What It Means
I really, really wanted this to be a positive study. Unfortunately it’s not. There was no difference in the primary end-point on either analysis, and the more conservative intention-to-treat analysis showed no benefit of TMP-SMX on overall survival. We can only speculate whether or not the per-protocol analysis was biased by differential withdrawal and compliance in treatment groups. Even the authors state that they cannot recommend TMP-SMX for patients with IPF based on this study.
I do agree, however, that there is enough signal and rational here to look at this again in patients meeting current criteria for IPF, off of immunosuppressive medications, and perhaps at a lower dose of TMP-SMX, such as once daily or three times weekly, to minimize side effects. Chronic antimicrobial treatment could be beneficial in preventing severe infections, especially pneumonia, in these patients with extremely poor pulmonary reserve where a respiratory hospitalization often equals death. Any interest IPFnet?
Ludmila Shulgina et al. Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomized controlled trial. Thorax 2013;68:155-162.