Low-dose trimethoprim-sulfamethoxazole for the treatment ofPneumocystis jiroveciipneumonia (LOW-TMP): protocol for a phase III randomised, placebo-controlled, dose-comparison trial

Abstract

IntroductionPneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15–20 mg/kg/day, is associated with serious adverse drug events (ADE) in 20%–60% of patients. ADEs include hypersensitivity reactions, drug-induced liver injury, cytopenias and renal failure, all of which can be treatment limiting. In a recent meta-analysis of observational studies, reduced dose TMP-SMX for the treatment of PJP was associated with fewer ADEs, without increased mortality.Methods and analysisA phase III randomised, placebo-controlled, trial to directly compare the efficacy and safety of low-dose TMP-SMX (10 mg/kg/day of TMP) with the standard of care (15 mg/kg/day of TMP) among patients with PJP, for a composite primary outcome of change of treatment, new mechanical ventilation, or death. The trial will be undertaken at 16 Canadian hospitals. Data will be analysed as intention to treat. Primary and secondary outcomes will be compared using logistic regression adjusting for stratification and presented with 95% CI.Ethics and disseminationThis study has been conditionally approved by the McGill University Health Centre; Ethics approval will be obtained from all participating centres. Results will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT04851015.

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“…Despite new diagnostic tools developed in last years, treatment of PCP has remained without changes and high dose of trimethoprim-sulfamethoxazole (15 mg/kg/d iv) continues being treatment of choice for most patients [119]. However, this high dose is often associated with negative adverse events which can be treatment limiting, so a clinical trial is nowadays active to compare standard dose with low dose (10 mg/kg/d) [250]. In patients not infected with HIV, the use of corticosteroids in moderate-severe pneumonia with hypoxemia remains controversial.…”

Can the Future of ID Escape the Inertial Dogma of Its Past? The Exemplars of Shorter Is Better and Oral Is the New IV

“…Thus, we cannot and do not presume to know the optimal duration of therapy for all infections, neither based on the historical past, nor from transposition of modern trials to other diseases. For unstudied infectious diseases, trials are still needed to delineate the optimal duration of therapy [ 19 , 100 ].…”

“…Some have already been successfully debunked based on reproducible, high-quality studies, such as the fallacy of static versus cidal antibiotics [ 139 ], combination therapy or double coverage in the treatment of Pseudomonas and/or sepsis [ 140–144 ], the recommendation for continuation of antibiotics for neutropenic fever until the resolution of neutropenia [ 82 , 145 ], the use of aminoglycoside or rifampin for synergistic treatment in staphylococcal endocarditis or sepsis [ 142 , 146–148 ], the inability to shorten antimicrobial therapy in patients with immune dysfunction [ 11 ], and the need for routine antibiotic therapy for uncomplicated diverticulitis [ 149 ]. Other long-standing dogmas are now being rightfully questioned, with studies poised to commence that may well overturn them, such as high-dose trimethoprim-sulfamethoxazole for pneumocystis pneumonia [ 100 ], the preference of pyrimethamine-containing regimens over trimethoprim-sulfamethoxazole for the treatment of toxoplasma encephalitis [ 150 ], the advantage of antistaphylococcal penicillin over cefazolin for the treatment of S aureus bacteremia [ 151 ], the routine fundoscopic examination in candidemia [ 152 ], and additional anaerobic coverage for aspiration pneumonia [ 153 ].…”

Clinical characteristics and risk factors for late‐onset pneumocystis jirovecii pneumonia in kidney transplantation recipients

“…3,4 It initially attracted attention among human immunodeficiency virus (HIV) patients, 5 then in solid organ transplantation recipients, haematopoietic stem cell transplantation patients, and those who received corticosteroids and chemotherapy drugs. 6 PJP often occurs in patients after solid organ transplantation such as kidney transplantation. 7,8 Trimethoprim-sulfamethoxazole (TMP-SMX) is the common choice of drug for PJP initial prophylaxis and has been proven effective by reducing PJP incidence from 0.6%-14% 9 to 0.4%-2.2%.…”

“…Severe cases can develop respiratory failure and even die 3,4 . It initially attracted attention among human immunodeficiency virus (HIV) patients, 5 then in solid organ transplantation recipients, haematopoietic stem cell transplantation patients, and those who received corticosteroids and chemotherapy drugs 6 …”