title: 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: Sulfamethoxazole-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.
  
  
  
  Adult 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.
  
  
  
  Of 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.
  
  
  
  Although 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.
  
  
  
  The University Hospital Medical Information Network Clinical Trials Registry number is UMIN000007727 , registered 10 April 2012.
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Musashino Red Cross Hospital, 1-26-1 Kyonancho, Musashino, Tokyo, 180-0023, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Utsunomiya
authors.affiliation: Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kida-gun, Kagawa, 761-0793, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Dobashi
authors.affiliation: Third Department of Internal Medicine, Obihiro-Kosei General Hospital, West-6, South-8, Obihiro, Hokkaido, 080-0016, Japan.|Department of Internal Medicine, Hokusei Hospital, 5-1-1 Seiryu, Chitose, Hokkaido, 066-0081, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Odani
authors.affiliation: First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo, 183-8524, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yokogawa
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Ome Municipal General Hospital, 4-16-5 Higashi-Ome, Ome, Tokyo, 198-0042, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagasaka
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Ome Municipal General Hospital, 4-16-5 Higashi-Ome, Ome, Tokyo, 198-0042, Japan.
authors.forename: Kenchi
authors.initials: K
authors.lastname: Takenaka
authors.affiliation: Department of Rheumatology, Ome Municipal General Hospital, 4-16-5 Higashi-Ome, Ome, Tokyo, 198-0042, Japan.|Department of Rheumatology, Soka Municipal Hospital, 2-21-1 Soka, Soka, Saitama, 340-8560, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Soejima
authors.affiliation: Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaecho, Itabashi-ku, Tokyo, 173-0015, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sugihara
authors.affiliation: Department of Rheumatology, Yokohama City Minato Red Cross Hospital, 3-12-1, Shinyamashita, Naka-ku, Yokohama, Kanagawa, 231-8682, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hagiyama
authors.affiliation: Department of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Kumamoto, Kumamoto, 860-8556, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Department of Rheumatology, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Chiba, 296-8602, Japan.|Department of Internal Medicine, Takikawa Municipal Hospital, 2-2-34 Oh-machi, Takikawa, Hokkaido, 073-0022, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsui
authors.affiliation: Department of Rheumatology, Tokyo Kyosai Hospital, 2-3-8 Nakameguro, Meguro-ku, Tokyo, 153-8934, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nonomura
authors.affiliation: Department of Rheumatology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Department of Rheumatology, Soka Municipal Hospital, 2-21-1 Soka, Soka, Saitama, 340-0043, Japan.|Department of Rheumatology, JA Toride Medical Center, 2-1-1 Hongo, Toride, Ibaraki, 302-0022, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Suzuki
authors.affiliation: Clinical Research Center, Medical Hospital of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8549, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tomita
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Kihara
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Waka
authors.initials: W
authors.lastname: Yokoyama
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Hirano
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Sakai
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Koike
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kohsaka
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. harigai.masayoshi@twmu.ac.jp.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. harigai.masayoshi@twmu.ac.jp.|Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan. harigai.masayoshi@twmu.ac.jp.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Harigai
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000517:prevention & control*; D012216:Rheumatic Diseases / Q000276:immunology*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination
keywords: Drug discontinuation rate; Efficacy; Pneumocystis pneumonia; Prophylaxis; Randomized controlled trial; Rheumatic disease; Safety; Sulfamethoxazole-trimethoprim