{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:19:39Z","timestamp":1787649579257,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372189"],"award-info":[{"award-number":["82372189"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471783"],"award-info":[{"award-number":["82471783"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82372189"],"award-info":[{"award-number":["82372189"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82471783"],"award-info":[{"award-number":["82471783"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"the Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project","award":["2025ZD01905200"],"award-info":[{"award-number":["2025ZD01905200"]}]},{"name":"Beijing High-Level Public Health Technical Talent Training Program","award":["Discipline Backbone Talent 02-32"],"award-info":[{"award-number":["Discipline Backbone Talent 02-32"]}]},{"name":"Beijing High-Level Innovation and Entrepreneurship Talent Support Program","award":["Young Top Talent Projects G202522157"],"award-info":[{"award-number":["Young Top Talent Projects G202522157"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Fungi","JoF"],"abstract":"<jats:p>Pneumocystis jirovecii pneumonia (PCP) prophylaxis is established in people with human immunodeficiency virus (HIV), but guidance for non-HIV, non-malignant immunocompromised adults remains fragmented. We searched eight databases and registries through 18 May 2026 (PROSPERO CRD420261396046). Because the evidence did not support a clinically exchangeable network, we evaluated four linked routes: comparative effectiveness, active-regimen safety, trimethoprim-sulfamethoxazole (TMP-SMX) discontinuation burden, and descriptive second-line evidence. Fifty-four full-length peer-reviewed reports were included. The primary effectiveness synthesis comprised 27 studies, 34,473 participants, and 243 PCP events. Compared with no prophylaxis, standard-dose TMP-SMX (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.18\u20130.48; low certainty) and low-dose TMP-SMX (OR 0.08, 95% CI 0.03\u20130.18; low certainty) were associated with lower PCP incidence. Lower-intensity TMP-SMX strategies were associated with fewer treatment-limiting discontinuations than standard\/conventional-dose TMP-SMX (OR 0.234, 95% CI 0.145\u20130.377). Across 33 TMP-SMX studies\/cohorts, the pooled discontinuation proportion was 12.3% (95% CI 9.4\u201315.9%). Breakthrough PCP occurred in 0.5% of 1056 second-line recipients. TMP-SMX had the clearest protective association; however, low-dose evidence did not establish superiority or non-inferiority, and second-line data did not permit comparative estimates or regimen ranking.<\/jats:p>","DOI":"10.3390\/jof12080627","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T10:55:18Z","timestamp":1787223318000},"page":"627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prophylaxis Regimens for Pneumocystis jirovecii Pneumonia in Non-HIV, Non-Malignant Immunocompromised Adults: A Systematic Review and Network Meta-Analysis"],"prefix":"10.3390","volume":"12","author":[{"given":"Xiaojing","family":"Wu","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Viral Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5826-5621","authenticated-orcid":false,"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Viral Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keming","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Viral Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuluan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Viral Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"ofaf390","DOI":"10.1093\/ofid\/ofaf390","article-title":"An Observational Analysis of a Large Cohort of Pneumocystis jirovecii Pneumonia","volume":"12","author":"Pulsipher","year":"2025","journal-title":"Open Forum Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.pulmoe.2019.04.003","article-title":"Pneumocystosis pneumonia: A comparison study between HIV and non-HIV immunocompromised patients","volume":"25","author":"Torres","year":"2019","journal-title":"Pulmonology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.cmi.2023.04.015","article-title":"How to diagnose and treat a patient without human immunodeficiency virus infection having Pneumocystis jirovecii pneumonia?","volume":"29","author":"Schumacher","year":"2023","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"myae038","DOI":"10.1093\/mmy\/myae038","article-title":"Features and global impact of invasive fungal infections caused by Pneumocystis jirovecii: A systematic review to inform the World Health Organization fungal priority pathogens list","volume":"62","author":"McMullan","year":"2024","journal-title":"Med. Mycol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100400","DOI":"10.1016\/j.lanepe.2022.100400","article-title":"Evolving epidemiology of pneumocystis pneumonia: Findings from a longitudinal population-based study and a retrospective multi-center study in Germany","volume":"18","author":"Kolbrink","year":"2022","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Xue, T., Kong, X., and Ma, L. (2023). Trends in the Epidemiology of Pneumocystis Pneumonia in Immunocompromised Patients without HIV Infection. J. Fungi, 9.","DOI":"10.3390\/jof9080812"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1136\/ard-2022-223335","article-title":"2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases","volume":"82","author":"Fragoulis","year":"2022","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101763","DOI":"10.1016\/j.bpg.2021.101763","article-title":"New agents for immunosuppression","volume":"54\u201355","author":"Jefremow","year":"2021","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1080\/08923973.2021.1966033","article-title":"Transplantation and immunosuppression: A review of novel transplant-related immunosuppressant drugs","volume":"43","author":"Parlakpinar","year":"2021","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_10","first-page":"208","article-title":"Immunosuppressive drugs and associated complications in abdominal organ transplantation","volume":"28","author":"Olson","year":"2022","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41581-023-00720-1","article-title":"Pathogenesis of autoimmune disease","volume":"19","author":"Pisetsky","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1016\/S1473-3099(23)00692-8","article-title":"Global incidence and mortality of severe fungal disease","volume":"24","author":"Denning","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_13","first-page":"866","article-title":"Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: A systematic review and network meta-analysis of randomized controlled trials","volume":"30","author":"Prosty","year":"2024","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1097\/RHU.0000000000002279","article-title":"Pneumocystis jirovecii Pneumonia in Patients Without HIV, Transplant, or Cancer: Missed Opportunities for Prevention","volume":"31","author":"Challener","year":"2025","journal-title":"J. Clin. Rheumatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1186\/s13054-023-04608-1","article-title":"Pneumocystis jirovecii pneumonia in intensive care units: A multicenter study by ESGCIP and EFISG","volume":"27","author":"Giacobbe","year":"2023","journal-title":"Crit. Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"ofad639","DOI":"10.1093\/ofid\/ofad639","article-title":"Epidemiology, Risk Factors, and Prophylaxis Use for Pneumocystis jirovecii Pneumonia in the Non-HIV Population: A Retrospective Study in Qu\u00e9bec, Canada","volume":"11","author":"Quigley","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.idc.2023.03.005","article-title":"Current Concepts in the Diagnosis and Management of Pneumocystis Pneumonia in Solid Organ Transplantation","volume":"37","author":"Trubin","year":"2023","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1016\/j.chest.2020.05.558","article-title":"Risk Factors and Prevention of Pneumocystis jirovecii Pneumonia in Patients With Autoimmune and Inflammatory Diseases","volume":"158","author":"Ghembaza","year":"2020","journal-title":"Chest"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s12281-024-00482-8","article-title":"Pneumocystis jirovecii Pneumonia in HIV-Negative, Non-transplant Patients: Epidemiology, Clinical Manifestations, Diagnosis, Treatment, and Prevention","volume":"18","author":"Rhoads","year":"2024","journal-title":"Curr. Fungal Infect. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Huang, H.-B., Shi, J.-H., Hu, Y.-G., Zhu, Y.-B., and Yu, D.-X. (2025). Low-dose trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis jirovecii pneumonia in HIV-uninfected patients: A systematic review and meta-analysis. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1545436"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1590\/s1678-9946202466018","article-title":"Myelotoxicity and kidney dysfunction related to the use of trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia: A case report of severe adverse events with a common drug","volume":"66","author":"Mendes","year":"2024","journal-title":"Rev. Inst. Med. Trop. Sao Paulo"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chiu, C.-Y., and Ching, P.R. (2023). Incidence of Pneumocystis Pneumonia in Immunocompromised Patients without Human Immunodeficiency Virus on Intravenous Pentamidine Prophylaxis: A Systematic Review and Meta-Analysis. J. Fungi, 9.","DOI":"10.3390\/jof9040406"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s40780-025-00516-4","article-title":"Clinical outcomes after switching from sulfamethoxazole-trimethoprim to atovaquone due to intolerance in patients with non-HIV Pneumocystis pneumonia: A single-center retrospective study","volume":"12","author":"Shirakawa","year":"2026","journal-title":"J. Pharm. Health Care Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"ofae499","DOI":"10.1093\/ofid\/ofae499","article-title":"Intermittent Versus Daily Trimethoprim\/Sulfamethoxazole Regimens for Pneumocystis Pneumonia Prophylaxis: A Systematic Review and Meta-analysis","volume":"11","author":"Masaki","year":"2024","journal-title":"Open Forum Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e068943","DOI":"10.1136\/bmjopen-2022-068943","article-title":"Prophylaxis for Pneumocystis carinii pneumonia in non-Hodgkin\u2019s lymphoma undergoing R-CHOP21 in China: A meta-analysis and cost-effectiveness analysis","volume":"13","author":"Huang","year":"2023","journal-title":"BMJ Open"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.jclinepi.2021.02.012","article-title":"A proposed framework to guide evidence synthesis practice for meta-analysis with zero-events studies","volume":"135","author":"Xu","year":"2021","journal-title":"J. Clin. Epidemiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.resinv.2024.10.007","article-title":"Effectiveness and safety of lower dose sulfamethoxazole\/trimethoprim for Pneumocystis jirovecii pneumonia prophylaxis in patients with systemic rheumatic diseases receiving moderate-to high-dose glucocorticoids","volume":"62","author":"Ohmura","year":"2024","journal-title":"Respir. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1093\/jac\/dkaf087","article-title":"Prophylaxis against Pneumocystis jirovecii pneumonia and toxoplasmosis with low-dose trimethoprim-sulfamethoxazole (cotrimoxazole 20\/100 mg) in heart transplant patients: The PAPTO-LOCO observational comparative study","volume":"80","author":"Aggoun","year":"2025","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"752","DOI":"10.3109\/s10165-012-0730-x","article-title":"A dose-escalation regimen of trimethoprim-sulfamethoxazole is tolerable for prophylaxis against Pneumocystis jiroveci pneumonia in rheumatic diseases","volume":"23","author":"Takenaka","year":"2013","journal-title":"Mod. Rheumatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.11150\/kansenshogakuzasshi1970.73.1123","article-title":"Efficacy of sulfamethoxazole-trimethoprim administration in the prevention of Pneumocystis carinii pneumonia in patients with connective tissue disease","volume":"73","author":"Okada","year":"1999","journal-title":"Kansenshogaku Zasshi"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13075-016-1206-8","article-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","volume":"19","author":"Utsunomiya","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3999\/jscpt.45.89","article-title":"A feasibility study assessing tolerability of daily versus twice weekly trimethoprim-sulfamethoxazole regimen for prophylaxis against Pneumocystis pneumonia in patients with systemic autoimmune diseases on glucocorticoid therapy","volume":"45","author":"Yamamoto","year":"2014","journal-title":"Jpn. J. Clin. Pharmacol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sagawa, T., Ishida, T., Jobu, K., Morisawa, S., Akagaki, K., Kato, T., Maruyama, T., Yagi, Y., Kihara, T., and Suzuki, S. (2025). Evaluation of Adverse Events Associated with the Sulfamethoxazole\/Trimethoprim Combination Drug. J. Clin. Med., 14.","DOI":"10.3390\/jcm14144819"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101190","DOI":"10.1016\/j.mam.2023.101190","article-title":"Antifungal prophylaxis and pre-emptive therapy: When and how?","volume":"92","author":"Sprute","year":"2023","journal-title":"Mol. Asp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2511043","DOI":"10.1080\/07853890.2025.2511043","article-title":"Mortality of Pneumocystis jirovecii pneumonia in intensive care units: A post-hoc analysis of an international multicenter study by ESGCIP and EFISG","volume":"57","author":"Giacobbe","year":"2025","journal-title":"Ann. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wolfe, R.M., and Winthrop, K.L. (2026). Pneumocystis prophylaxis in rheumatic disease. Best Pract. Res. Clin. Rheumatol., 102164.","DOI":"10.1016\/j.berh.2026.102164"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ijid.2022.10.004","article-title":"Prophylactic effect of low-dose trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia in adult recipients of kidney transplantation: A real-world data study","volume":"125","author":"Chen","year":"2022","journal-title":"Int. J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.2147\/IDR.S549404","article-title":"Efficacy and Safety of Low-Dose Trimethoprim-Sulfamethoxazole (TMP-SMZ) for the Prevention of Pneumocystis jirovecii pneumonia (PJP) in Non-HIV, Non-Transplant Immunosuppressed Patients: A Real-World Cohort Study","volume":"18","author":"Cao","year":"2025","journal-title":"Infect. Drug Resist."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Nikolakopoulou, A., Higgins, J.P.T., Papakonstantinou, T., Chaimani, A., Del Giovane, C., Egger, M., and Salanti, G. (2020). CINeMA: An approach for assessing confidence in the results of a network meta-analysis. PLoS Med., 17.","DOI":"10.1371\/journal.pmed.1003082"},{"key":"ref_40","first-page":"CD005590","article-title":"Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients","volume":"2014","author":"Stern","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e13587","DOI":"10.1111\/ctr.13587","article-title":"Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice","volume":"33","author":"Fishman","year":"2019","journal-title":"Clin. Transplant."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e14410","DOI":"10.1111\/tid.14410","article-title":"Alternative Pneumocystis Pneumonia Prophylaxis in Solid Organ Transplants","volume":"27","author":"He","year":"2024","journal-title":"Transpl. Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100856","DOI":"10.1016\/j.waojou.2023.100856","article-title":"Antibiotic prophylaxis in immunosuppressed patients\u2014Missed opportunities from trimethoprim-sulfamethoxazole allergy label","volume":"17","author":"Lee","year":"2024","journal-title":"World Allergy Organ. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/pds.5547","article-title":"Core concepts in pharmacoepidemiology: Key biases arising in pharmacoepidemiologic studies","volume":"32","author":"Acton","year":"2022","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/pds.5407","article-title":"Core concepts in pharmacoepidemiology: Confounding by indication and the role of active comparators","volume":"31","author":"Sendor","year":"2022","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1002\/jrsm.1748","article-title":"A re-analysis of about 60,000 sparse data meta-analyses suggests that using an adequate method for pooling matters","volume":"15","author":"Schulz","year":"2024","journal-title":"Res. Synth. Methods"}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/12\/8\/627\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T08:29:28Z","timestamp":1787646568000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/12\/8\/627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":46,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["jof12080627"],"URL":"https:\/\/doi.org\/10.3390\/jof12080627","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]}}}