Antimicrobial therapy fails to improve hospitalization, death in adults with IPF

The addition of co-trimoxazole or doxycycline to usual care did not significantly improve time to respiratory hospitalization or death in adults with idiopathic pulmonary fibrosis, according to results of the CleanUP-IPF trial.

“Although initial randomized trial data suggested improved outcomes with co-trimoxazole (trimethoprim-sulfamethoxazole) therapy in patients with fibrosing interstitial lung diseases, a large placebo-controlled trial failed to document an improvement in clinical outcomes with this agent. Preliminary data suggested that doxycycline can improve outcomes and inhibit metalloproteinases in patients with IPF,” Fernando J. Martinez, MD, MS, chief of the pulmonary and critical care medicine division at NewYork-Presbyterian Hospital/Weill Cornell Medicine, and colleagues wrote in JAMA. “Because antimicrobial therapy has been suggested to favorably alter the lung microbial community in other chronic disorders, this study was designed to address the hypothesis that an antimicrobial therapeutic strategy, with either co-trimoxazole or doxycycline, reduces the risk of nonelective respiratory hospitalization or death among patients with IPF.”

The pragmatic, randomized, unblinded CleanUP-IPF trial included 513 patients (mean age, 71 years; 23.6% women) with IPF. Patients were randomly assigned from August 2017 to June 2019 to receive usual care plus antimicrobial therapy (n = 254) or usual care alone (n = 259). The antimicrobials used in this study were co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg) twice daily plus folic acid 5 mg daily (n = 128) or doxycycline 100 mg once daily for those weighing less than 50 kg or 100 mg twice daily for those weighing at least 50 kg (n = 126).

The primary endpoint of the CleanUP-IPF trial was time to first nonelective respiratory-related hospitalization or all-cause mortality.

The trial was terminated in December 2019 due to futility.

During a mean follow-up of 13.1 months, 108 primary endpoint events occurred; of those, 52 events (20.4 events per 100 patient-years) occurred in the usual care plus antimicrobial therapy group vs. 56 events (18.4 events per 100 patient-years) in the usual care group, with no significant differences between the groups (adjusted HR = 1.04; 95% CI, 0.71-1.53; P = .83).

The researchers reported no significant interaction between the effect of the prespecified antimicrobial agent on time to first nonelective respiratory-related hospitalization or all-cause mortality in the co-trimoxazole group (aHR = 1.15; 95% CI, 0.68-1.95) vs. the doxycycline group (aHR = 0.82; 95% CI, 0.46-1.47; P = .66).

The most common serious adverse events in patients assigned usual care plus antimicrobials vs. usual care included respiratory events (16.5% vs. 10%) and infections (2.8% vs. 6.6%). Researchers observed higher rates of diarrhea (10.2% vs. 3.1%) and rash (6.7% vs. 0%) among those assigned usual care plus antimicrobial therapy compared with those assigned usual care alone.

According to the researchers, these findings extend upon results from the EME-TIPAC study, which suggested that a broad antimicrobial therapy strategy was not effective for improving clinical outcomes.

“These findings do not support treatment with these antibiotics for the underlying disease,” the researchers wrote.