Optimal regimens of sulfamethoxazole-trimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with systemic rheumatic diseases: results from a non-blinded, randomized controlled trial

Abstract

BackgroundSulfamethoxazole-trimethoprim (SMX/TMP) is a standard drug for the prophylaxis of Pneumocystis pneumonia (PJP) in immunosuppressed patients with systemic rheumatic diseases, but is sometimes discontinued due to adverse events (AEs). The objective of this non-blinded, randomized, 52-week non-inferiority trial was to quest an effective chemoprophylaxis regimen for PJP with a low drug discontinuation rate. Results at week 24 were reported.MethodsAdult patients with systemic rheumatic diseases who started prednisolone ≥0.6 mg/kg/day were randomized into three dosage groups: a single-strength group (SS, SMX/TMP of 400/80 mg daily), half-strength group (HS, 200/40 mg daily), and escalation group (ES, started with 40/8 mg daily, increasing incrementally to 200/40 mg daily). The primary endpoint was non-incidence rates (non-IR) of PJP at week 24.ResultsOf 183 patients randomly allocated at a 1:1:1 ratio into the three groups, 58 patients in SS, 59 in HS, and 55 in ES started SMX/TMP. A total of 172 patients were included in the analysis. No cases of PJP were reported up to week 24. Estimated non-IR of PJP in patients who received daily SMX/TMP of 200/40 mg, either starting at this dose or increasing incrementally, was 96.8–100% using the exact confidence interval as a post-hoc analysis. The overall discontinuation rate was significantly lower with HS compared to SS (p = 0.007). The discontinuation rates due to AEs were significantly lower with HS (p = 0.006) and ES (p = 0.004) compared to SS. The IR of AEs requiring reduction in the dose of SMX/TMP (p = 0.009) and AEs of special interest (p = 0.003) were different among the three groups with significantly higher IR in SS compared to HS and ES.ConclusionsAlthough there were no PJP cases, the combined group of HS and ES had an excellent estimated non-IR of PJP and both were superior in safety to SS. From the perspective of feasibility and drug discontinuation rates, the daily half-strength regimen was suggested to be optimal for prophylaxis of PJP in patients with systemic rheumatic diseases.Trial registrationThe University Hospital Medical Information Network Clinical Trials Registry number is UMIN000007727, registered 10 April 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1206-8) contains supplementary material, which is available to authorized users.

An open-label, randomized controlled trial of sulfamethoxazole–trimethoprim for Pneumocystis prophylaxis: results of 52-week follow-up

“…PCP non-IRs at week 24 between SS and ES (the primary endpoint of this study) and the other comparisons between groups at week 24 have been reported previously [ 17 ]. The PCP non-IRs, treatment discontinuation rates and AEs at 52 weeks are reported here.…”

“…The inclusion and exclusion criteria of the present study were described previously [ 17 ]. In brief, the inclusion criteria were follows: age ≥20 years; admission to one of the participating institutions for treatment of new-onset or relapsed systemic rheumatic disease in the study period; written informed consent; an oral prednisolone starting dosage at ≥0.6 mg/kg/day or an equivalent dosage of CS regardless of concomitant immunosuppressive drugs; no previous use of SMX/TMP, pentamidine isethionate or dapsone; and serum creatinine values within the upper limit of the normal range according to the institutional standard.…”

“…This study was an open-label, multicentre, randomized controlled trial, and the study design was described previously [ 17 ]. In brief, the patients were randomized into one of three arms at a 1:1:1 ratio by using computer-based, central, dynamic allocation with block randomization.…”

“…[ 16 ] retrospectively compared SMX/TMP 400 mg/80 mg daily with 400 mg/80 mg in a dose escalation regimen in 59 patients with SLE and found that the latter was safer. In our previous report, using an open-label, randomized controlled trial, we compared the efficacy, drug retention and safety of three regimens (SMX/TMP 400 mg/80 mg daily, 200 mg/40 mg daily or 200 mg/40 mg with dose escalation) in 183 patients with systemic rheumatic diseases who started at a dosage of 0.6 mg/kg/day or more of prednisolone or an equivalent dosage of CS [ 17 ]. At week 24, the 200 mg/40 mg daily regimen was superior in efficacy, drug retention and safety.…”

Guidelines of the Brazilian Society of Rheumatology for the treatment of systemic autoimmune myopathies

“…The implementation of a physical exercise program (resistance or aerobic physical training or the combination of these two) seems to be safe and beneficial in adult patients with SAM and should be used as a complement to pharmacological treatments in all stages of the disease to maximize muscle performance and aerobic capacity, as well as minimize the risk of side effects caused by GC treatment, for example. Individuals with active disease indication of physical exercises should preferably be instituted as early as possible and be supervised by a physiotherapist in close collaboration with an attending physician to strengthen the muscle groups involved with passive and active exercises (degree of recommendation B) for pneumocystosis should be considered, particularly in the presence of risk factors (e.g., interstitial lung diseases -ILD, other immunosuppressive drugs, patients with anti-MDA-5), for patients who use ≥20 mg/day of prednisone or its equivalent for a period of more than four weeks (B) [19,20] (D) [21] (C) [22][23][24].…”