General Dermatology

Safety of Trimethoprim-Sulfamethoxazole for Pneumocystis jirovecii Pneumonia Prophylaxis in Patients Taking Methotrexate

It is standard medical practice for immunosuppressed patients to receive prophylaxis against Pneumocystis jirovecii pneumonia (PCP), for which trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line treatment.¹ Although TMP-SMX is relatively contraindicated in patients taking methotrexate (MTX) due to synergistic toxicities, little is known about the safety of TMP-SMX dosing for PCP prophylaxis in combination with MTX.²

Cleveland Clinic clinicians identified 100 consecutive patients prescribed TMP-SMX for PCP prophylaxis concurrently with MTX for ++>++1 month in 2017 for chronic inflammatory/autoimmune diseases. All patients took one double-strength 800 mg/160 mg tablet of TMP-SMX, 3 times weekly for PCP prophylaxis.

Six of the 100 patients experienced adverse events triggering discontinuation of combination therapy. Discontinuation reasons included transaminitis (N = 4) and/or leukopenia (N = 2). One patient discontinued due to cognitive deficits, fatigue, and headaches. Four patients who discontinued combination therapy had underlying hepatic abnormalities. Two of the 6 patients with significant adverse events discontinued both MTX and TMP-SMX, 3 stopped MTX but continued TMP-SMX, and 1 patient stopped TMP-SMX but continued MTX. In all patients, liver function tests were normal at combination therapy initiation and normalized following discontinuation.

Both patients who developed leukopenia had normal baseline white blood cell counts (WBC). One patient developed leukopenia (WBC = 1.74 k/uL) with absolute lymphopenia (0.37 k/uL) and neutropenia (1.24 k/uL), all of which resolved following combination therapy discontinuation. The second patient had leukopenia (WBC = 2.94 k/uL) and absolute lymphopenia (0.61 k/uL), both of which resolved after discontinuation.

MTX dose, treatment duration, and folic acid/leucovorin dose were not significantly different in patients with or without adverse events leading to combination therapy discontinuation. No patient contracted PCP or had an adverse event leading to end-organ damage.

This study represents one of the largest to document combination MTX and PCP prophylaxis-dosed TMP-SMX therapy appears both successful and well-tolerated in patients with chronic inflammatory/autoimmune diseases.³ The findings suggest baseline CBCs and CMPs may be useful in identifying at-risk patients for adverse effects if placed on MTX and TMP-SMX combination therapy. In patients with underlying liver abnormalities and/or CBC abnormalities, alternative PCP prophylaxis strategies should be considered.

Patient Demographics and Characteristics


Adverse Event Yes (N = 6)Adverse Event No (N = 94)
Age, years (IQR)ᵃ;
Range [31-78 years]
48.0 (42.3-54.3)56.5 (49.8-67.0)
Mean 57.0+/-10.9 years(Range: 31-55)(Range: 35-78)
Female gender (%)2 (33.3)57 (60.6)
Underlying Liver Disease4 (67%)12 (13%)
Therapeutic Regimen
MTX duration, median months (IQR)9.0 (6.0-34.0)24.0 (8.0-67.8)
MTX max dose, mean mg/week (SD)14.6 (7.1)17.9 (4.4)
MTX min dose, mean mg/week (SD)12.1 (2.7)14.5 (4.6)
Folic acid, yes (%)6 (85.7)85 (91.4)
Leucovorin, yes (%)1 (14.3)18 (19.4)
Additional Immunosuppressive Medications
Systemic glucocorticoids684
Underlying Chronic Inflammatory/ Autoimmune Disease
Cutaneous vasculitis01
Systemic vasculitisᵇ134
Rheumatoid arthritis03
Systemic lupus erythematosus01
Polymyositis and dermatomyositis02

IQR = interquartile range;
MTX = methotrexate

P <.05 between cases that did and did not have an adverse event
ᵇSystemic vasculidities: Granulomatosis with Polyangiitis (N = 25), Eosinophilia with Granulomatosis and Polyangiitis (N = 5), Takayasu’s arteritis (N = 1), Polyarteritis nodosa (N = 1), Microscopic polyangiitis (N = 1 ), giant cell arteritis (N = 1), cutaneous vasculitis + vasculitic neuropathy (N = 1).

This table is published with permission by the J Am Acad Dermatol

Characteristics of Patients with Adverse Events Triggering Discontinuation of Combination MTX and TMP-SMX Therapy


Case #Reason for Stopping TherapyDiagnosisAdditional ImmunosuppressionPast Medical HistoryTime to adverse event (months)
1Transaminitis (AST 86, ALT 64)SarcoidosisPrednisone, Infliximab, AzathioprineHypertension, non-alcoholic steatohepatitis, hypertriglyceridemia60
2Transaminitis (AST 43, ALT 81)SarcoidosisPrednisoneSleep apnea, hypertension, diabetes, hyperlipidemia, hepatic sarcoidosis5
3LeukopeniaSarcoidosisPrednisone, InfliximabIV drug abuse, Hepatitis C34
4Memory loss, cognitive deficits, fatigue, headacheSarcoidosisPrednisoneIrritable bowel syndrome3
5Transaminitis (AST 60, ALT 288), skin rash, ulcers, photosensitivitySarcoidosisPrednisoneCardiac sarcoidosis 9
6Transaminitis (AST 74, ALT 107), leukopeniaaCutaneous vasculitis and vasculitic neuropathyPrednisone, CyclophosphamidebNon-alcoholic steatohepatitis, hypertension, diabetes, hypothyroidism5

AST = Aspartate Aminotransferase (normal value 14-40 U/L);
ALT= Alanine Aminotransferase (normal value 1054 U/L);
MTX = methotrexate;
TMP-SMX = trimethoprim-sulfamethoxazole

ᵃAdverse Event = clinical or laboratory abnormality attributed by the treating physician to MTX toxicity and prompting discontinuation of the patient’s combination MTX and TMP-SMX therapy.
ᵇCyclophosphamide was discontinued 1 week prior to initiation of combination therapy.

This Table is published with permission by the J Am Acad Dermato.l3

  1. Kimura M, Tanaka S, Ishikawa A, Endo H, Hirohata S, Kondo H. Comparison of trimethoprim–sulfamethoxazole and aerosolized pentamidine for primary prophylaxis of Pneumocystis jiroveci pneumonia in immunocompromised patients with connective tissue disease. Rheumatol Int. 2008;28(7):673-676. doi:10.1007/s00296-007-0505-4.

  2. Watts CS, Sciasci JN, Pauley JL, et al. Prophylactic Trimethoprim-Sulfamethoxazole Does Not Affect Pharmacokinetics or Pharmacodynamics of Methotrexate. J Pediatr Hematol Oncol. 2016;38(6):449-452. doi:10.1097/MPH.0000000000000606.

  3. Havele SA, Ellis A, Chaitoff A, et al. Safety of Trimethoprim-Sulfamethoxazole for Pneumocystis Jirovecii Pneumonia Prophylaxis in Patients Taking Methotrexate [published online ahead of print, 2020 Apr 19]. J Am Acad Dermatol. 2020;S0190-9622(20)30621-6.