Can trimethoprim and Keflex (Cephalexin) be taken at the same time?

Can Trimethoprim and Keflex (Cephalexin) Be Taken Together?

Yes, trimethoprim and cephalexin can be safely taken together—there are no contraindicated drug-drug interactions between these two antibiotics, and they have been studied in combination for treating skin and soft tissue infections. 1

Evidence Supporting Concurrent Use

Clinical Trial Data

• A large multicenter randomized controlled trial directly evaluated the combination of cephalexin (500 mg four times daily) plus trimethoprim-sulfamethoxazole (320 mg/1600 mg twice daily) for 7 days in 496 patients with uncomplicated cellulitis 1
• The combination was well-tolerated with no significant increase in adverse events compared to cephalexin alone 1
• Both treatment arms showed clinical cure rates exceeding 75% in the modified intention-to-treat analysis 1

Historical Use in Urinary Tract Infections

• Multiple double-blind trials from the 1970s-1980s compared trimethoprim, cephalexin, and their use in various combinations for urinary tract infections, demonstrating safety when used concurrently 2
• Trimethoprim 200 mg daily has been shown comparable in efficacy to cephalexin 2g daily for acute urinary tract infections, with both agents demonstrating good tolerability profiles 3

Important Monitoring Considerations

When Using These Antibiotics Together

Hematologic Monitoring:

• Monitor complete blood counts, particularly in elderly patients or those with renal impairment, as trimethoprim can cause folate deficiency and bone marrow suppression 4
• This risk is increased in elderly patients who are more susceptible to adverse effects from trimethoprim 5

Renal Function Assessment:

• Both drugs are primarily renally eliminated, making dose adjustments necessary in patients with reduced renal function 4
• The American Geriatrics Society specifically identifies trimethoprim-sulfamethoxazole as requiring caution in older adults with reduced kidney function due to hyperkalemia risk 6

Electrolyte Monitoring:

• Check serum potassium levels, especially in patients taking ACE inhibitors, ARBs, or other medications affecting potassium homeostasis 5
• Trimethoprim can cause hyperkalemia through its potassium-sparing diuretic effect 7

Special Populations Requiring Extra Caution

Elderly Patients:

• Require more frequent monitoring when taking both medications due to increased susceptibility to adverse effects 4
• Higher risk for electrolyte disturbances and bone marrow suppression 5

Patients with Renal Impairment:

• Dose adjustments may be needed based on creatinine clearance 4
• More significant drug interactions and accumulation risk in reduced renal function 4

Clinical Approach When Prescribing Both Agents

1. Baseline Assessment: Obtain complete blood count, renal function (creatinine/eGFR), and electrolytes (particularly potassium) before initiating therapy 4

2. Drug Interaction Review: Evaluate for concurrent medications that may interact with trimethoprim, including methotrexate (avoid combination due to bone marrow suppression), warfarin (requires INR monitoring), and digoxin (levels may increase) 5

3. Standard Dosing: Use typical doses unless renal impairment necessitates adjustment 4

4. Patient Education: Instruct patients to report rash (risk of Stevens-Johnson syndrome), unusual bleeding/bruising, or yellowing of skin/eyes 4

5. Follow-up Monitoring: Reassess blood counts and renal function if treatment extends beyond 7-10 days or in high-risk patients 4

Common Pitfalls to Avoid

• Do not combine trimethoprim with methotrexate due to additive antifolate effects and severe bone marrow suppression risk 5
• Avoid using "low-salt" potassium substitutes while on trimethoprim, as this increases hyperkalemia risk 7
• Do not ignore skin rashes—immediate discontinuation is warranted given the risk of serious cutaneous reactions like Stevens-Johnson syndrome 5
• Remember that NSAIDs can interact with trimethoprim, potentially affecting renal function and increasing adverse effect risk 7