Can Macrobid (nitrofurantoin) and Bactrim (trimethoprim/sulfamethoxazole) be used together in a patient with a urinary tract infection?

Can Macrobid and Bactrim Be Used Together?

No, Macrobid (nitrofurantoin) and Bactrim (trimethoprim-sulfamethoxazole) should not be used together for urinary tract infections, as there is no clinical benefit to combination therapy and it unnecessarily increases the risk of adverse effects without improving outcomes. 1

Rationale Against Combination Therapy

Both agents are effective as monotherapy for uncomplicated lower UTIs, and guidelines consistently recommend single-agent treatment rather than combination approaches. 1, 2

• For uncomplicated cystitis in women, first-line options include nitrofurantoin 100 mg twice daily for 5 days OR trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days—used individually, not together 1, 2
• The WHO Essential Medicines recommendations list both as separate treatment options for lower UTIs, with amoxicillin-clavulanate as first choice and nitrofurantoin as second choice 1
• Multiple high-quality guidelines from IDSA/ESCMID, AUA/CUA/SUFU, and American College of Physicians recommend these agents as alternatives to each other, not as combination therapy 1

Evidence Supporting Monotherapy

Systematic reviews demonstrate equivalence between these agents when used individually, with no data supporting combination use: 1

• Nitrofurantoin versus trimethoprim-sulfamethoxazole showed no difference in short-term (RR 0.99,95% CI 0.95-1.04) or long-term (RR 1.01,95% CI 0.94-1.09) symptomatic cure rates 1
• Both agents achieve high urinary concentrations and are active against common uropathogens (except Pseudomonas and Serratia) 3

Risks of Unnecessary Combination

Using both agents simultaneously exposes patients to additive adverse effects without therapeutic benefit: 1

• Nitrofurantoin carries risks of pulmonary toxicity (0.001%) and hepatic toxicity (0.0003%), plus common GI disturbances and rash 1
• Trimethoprim-sulfamethoxazole causes skin eruptions in up to 12% of patients (often appearing on day 7 or later), plus GI symptoms 4
• Combining agents doubles the risk profile without improving cure rates above 90% achieved with monotherapy 4

When Each Agent Should Be Used Alone

Choose ONE agent based on local resistance patterns, patient factors, and infection type: 1, 2

Nitrofurantoin (5 days):

• Preferred when local TMP-SMX resistance exceeds 20% 1, 2
• Contraindicated in pyelonephritis (inadequate tissue concentrations) and G6PD deficiency 5
• Should not be used in patients with CrCl <30 mL/min 5

Trimethoprim-Sulfamethoxazole (3 days):

• Appropriate when local resistance is <20% 1, 2
• Must be discontinued immediately if Aerococcus urinae is identified, as this organism has intrinsic sulfonamide resistance 6
• More cost-effective than nitrofurantoin but higher resistance rates in many regions 3

Critical Exception: Aerococcus Urinae

If culture results reveal Aerococcus urinae, Bactrim must be stopped immediately due to inherent resistance, and the patient should be switched to amoxicillin or nitrofurantoin based on susceptibilities 6

• IDSA guidelines mandate discontinuing TMP-SMX for Aerococcus infections due to treatment failure risk 6
• Switch to amoxicillin 500 mg three times daily for 5-7 days or nitrofurantoin 100 mg twice daily for 5 days 6

Antibiotic Stewardship Considerations

Using a single appropriate agent aligns with antimicrobial stewardship principles: 1

• Shorter courses with single agents reduce adverse events and antimicrobial resistance 1
• Treatment duration should be the minimum effective: 3 days for TMP-SMX, 5 days for nitrofurantoin 1, 2
• Reserve fluoroquinolones for resistant organisms or treatment failures, not empiric combination therapy 1