Given the breadth of knowledge and clinical experience required to answer this question in full (and given that it is not typically something I deal with in my specialty), I will rely heavily on this UpToDate article. To summarize:
- Research involving non-HIV immunosuppressed patients mostly involve patients with cancer (especially receiving hematopoietic stem cell transplants [HCT] ) and solid organ transplant recipients.
- There are no published guidelines for PCP prophylaxis among patients with rheumatologic diseases receiving immunosuppressive drugs.
- A meta-analysis performed in 2014 including 13 trials and involving 1,412 patients suggests that PCP prophylaxis using trimethoprim-sulfamethoxazole (TMP/SMX), commonly referred to as Bactrim, is recommended in non-HIV immunosuppressed patients when the risk of PCP exceeds approximately 6%. The number-needed-to-treat (NNT) to prevent PCP was reported as 19 patients (95% CI 17 to 42).
- Patient populations considered at great enough risk to necessitate PCP prophylaxis include patients:
- receiving a glucocorticoid dose equivalent greater than or equal to 20mg daily for one month or longer with another concomitant cause of immunocompromise;
- receiving temozolomide and radiotherapy, until recovery of lymphopenia;
- with acute lymphoblastic leukemia (ALL);
- receiving allogeneic HCT for as long as immunosuppressive therapy is given;
- certain autologous HCT recipients;
- solid organ transplant recipients, usually for 6-12 months following transplantation;
- with certain primary immunodeficiencies (severe combined immunodeficiency [SCID], CD4 T-lymphocytopenia, hyper-IgM syndrome, etc.)
- those receiving a purine analog in combination with cyclophosphamide.
The above bullet points are sourced from multiple studies; I have obviously not taken the time to perform a full literature review and suggest you dig further into those resources if you need more information.
In regards to the safety of using methotrexate with cotrimoxazole; this appears to be a very real but rare risk. I am not aware of any studies that bear out the extent of this risk or the incidence of co-toxicity, but the authors of the UpToDate article do suggest that low prophylactic doses of TMP-SMX should be safe in patients receiving MTX. Some published authors would disagree. I have personally discussed this risk with a rheumatologist in my hospital who agrees with the above statement. Obviously, this is only one doctor's experience and opinion.
If a patient can not take TMP-SMX or you would prefer to use a different agent due to the risk of myelosuppression, alternatives include dapsone or atovaquone
The typical PCP prophylactic dose is usually 1 Bactrim double-strength tablet daily or three times per week.