What medications should be held in a patient with sepsis due to gram-negative bacilli in the blood, who is currently taking leflunomide, methotrexate (MTX) weekly, and hydroxychloroquine, and has been started on meropenem?

Management of Immunosuppressive Therapy in Sepsis with Gram-Negative Bacteremia

You should immediately hold methotrexate and leflunomide in this patient with gram-negative sepsis, while continuing hydroxychloroquine and meropenem. 1

Rationale for Holding Methotrexate and Leflunomide

Critical Safety Concerns

• Methotrexate significantly impairs immune response during active infection and should be withheld during serious bacterial infections, particularly in patients with sepsis where intact immune function is essential for survival 2

• Leflunomide combined with methotrexate carries substantial risk of life-threatening pancytopenia, especially during acute illness with sepsis, with documented fatal cases occurring when patients develop concurrent acute conditions 1

• The combination of leflunomide plus methotrexate increases infection-related mortality risk through additive immunosuppression and bone marrow suppression, with median time to severe hematologic complications ranging from 11 days to 4 years 1

• Acute renal dysfunction and sepsis can trigger sudden-onset pancytopenia in patients on this combination therapy, even in those previously stable for years 1

Evidence Supporting Continuation vs. Discontinuation

• ACR guidelines recommend continuing DMARDs only in stable, non-infected patients undergoing elective surgery, not in active sepsis 2

• COVID-19 rheumatology guidance supports holding immunosuppressants during active infection, though it permits continuation in stable disease without infection 2

• The perioperative literature showing safety of continued DMARDs applies to elective surgery in stable patients, not to life-threatening gram-negative sepsis where mortality is the primary concern 2

Hydroxychloroquine Management

Continue hydroxychloroquine during sepsis treatment as it does not significantly impair antibody responses or increase infection risk compared to methotrexate and leflunomide 2

• Hydroxychloroquine has minimal immunosuppressive effects and does not lower immune responses below the threshold of seroprotection 2

• ACR guidelines support continuation of hydroxychloroquine even during perioperative periods when other DMARDs are held 2

Antibiotic Management

Continue meropenem as appropriate empiric therapy for gram-negative bacteremia in this septic patient 2, 3

• Meropenem provides broad-spectrum coverage against gram-negative bacilli including Pseudomonas and ESBL-producing organisms 3

• The Surviving Sepsis Campaign strongly recommends empiric broad-spectrum therapy within one hour of septic shock recognition 2, 4

• Standard dosing is 1000 mg every 8 hours, though critically ill septic patients may require higher doses or extended infusions to achieve optimal pharmacokinetic targets 5

Monitoring During DMARD Hold

• Obtain daily complete blood counts to monitor for pancytopenia recovery and assess infection response 1

• Monitor renal function closely as both sepsis and meropenem can affect kidney function, and renal impairment increases risk of DMARD toxicity 1

• Reassess antibiotic regimen daily for potential de-escalation based on culture results and clinical improvement 2, 4

• Plan for 7-10 days of antibiotic therapy for gram-negative bacteremia in the absence of source control issues 2

When to Resume DMARDs

• Restart methotrexate and leflunomide only after complete resolution of sepsis, normalization of white blood cell count, and clearance of bacteremia with negative repeat blood cultures 1

• Consider restarting hydroxychloroquine first if there are concerns about disease flare, as it carries the lowest infection risk 2

• Avoid restarting the combination immediately; consider sequential reintroduction with close monitoring for hematologic toxicity 1

Common Pitfalls to Avoid

• Do not continue methotrexate based on perioperative guidelines that apply only to stable patients undergoing elective procedures, not active sepsis 2

• Do not underestimate the risk of leflunomide-methotrexate combination during acute illness, as fatal pancytopenia can occur even in previously stable patients 1

• Do not delay holding immunosuppressants while waiting for culture results, as early appropriate management reduces mortality 2, 4

• Do not restart DMARDs prematurely before complete infection resolution, as this increases risk of recurrent sepsis and hematologic complications 1