In a typical adult with uncomplicated cystitis and a creatinine clearance greater than 30 mL/min, does nitrofurantoin provide good gram‑negative coverage?

Nitrofurantoin Provides Excellent Gram-Negative Coverage for Uncomplicated Cystitis

Nitrofurantoin delivers outstanding activity against Escherichia coli—the causative pathogen in 75–95% of uncomplicated cystitis cases—with worldwide resistance rates below 1%, making it the preferred first-line agent for gram-negative coverage in this setting. 1

Spectrum of Gram-Negative Activity

• Nitrofurantoin retains excellent activity against E. coli despite more than 60 years of clinical use, a unique achievement among urinary antibiotics. 1, 2

• The drug maintains 95–98% susceptibility rates against E. coli globally, far superior to trimethoprim-sulfamethoxazole (which now exceeds 20% resistance in many communities) and fluoroquinolones (approaching 24% resistance in some regions). 1

• Nitrofurantoin also covers Staphylococcus saprophyticus and Enterococcus species, both common uropathogens in uncomplicated cystitis. 2

Critical Coverage Gaps

• Nitrofurantoin does NOT cover Proteus species, Pseudomonas aeruginosa, Serratia, or Klebsiella species reliably—these organisms are intrinsically resistant or demonstrate poor susceptibility. 3

• The drug should never be used for suspected pyelonephritis or upper-tract infections because it does not achieve adequate renal tissue concentrations, even though the causative organism may be E. coli. 1

• Treatment failures with nitrofurantoin in one study were primarily due to intrinsically resistant uropathogens (5 of 8 failures were Proteus species), not true resistance among susceptible gram-negatives. 3

Clinical Efficacy Against Gram-Negatives

• A 5-day course of nitrofurantoin 100 mg twice daily achieves approximately 93% clinical cure and 88% microbiological eradication in women with uncomplicated cystitis caused by susceptible gram-negative organisms. 1

• In a head-to-head trial, nitrofurantoin (5 days) was clinically and microbiologically equivalent to trimethoprim-sulfamethoxazole (3 days), with 84% vs 79% clinical cure rates respectively. 4

• Even in patients with creatinine clearance 30–60 mL/min, nitrofurantoin eradicated gram-negative uropathogens in 69% of cases, with most failures attributable to intrinsically resistant organisms rather than reduced drug efficacy. 3

Stewardship Advantages

• Nitrofurantoin causes minimal disruption to intestinal flora compared with fluoroquinolones and broad-spectrum cephalosporins, reducing the risk of Clostridioides difficile infection and preserving the microbiome. 1

• The drug is classified by the WHO as an "Access" antibiotic, reflecting its favorable resistance profile and suitability for first-line empiric therapy. 1

• Nitrofurantoin does not select for extended-spectrum β-lactamase (ESBL)-producing organisms, making it an ideal choice when ESBL-E. coli is suspected or confirmed. 5

Key Contraindications That Limit Use

• Nitrofurantoin is contraindicated when creatinine clearance is <30 mL/min because urinary drug concentrations become insufficient for bacterial eradication; use with caution (and verify susceptibility) when CrCl is 30–60 mL/min. 6, 3

• The drug must be avoided in the last trimester of pregnancy and in patients with G6PD deficiency. 2

• Do not use nitrofurantoin if there is any suspicion of upper-tract involvement (fever >38°C, flank pain, costovertebral angle tenderness), as tissue penetration is inadequate. 1

Practical Algorithm for Gram-Negative Coverage

1. Confirm uncomplicated lower UTI (dysuria, frequency, urgency without fever or flank pain) in a patient with CrCl ≥30 mL/min. 1

2. Prescribe nitrofurantoin 100 mg twice daily for 5 days as first-line therapy for empiric gram-negative coverage, assuming E. coli is the likely pathogen. 1

3. Obtain urine culture only if symptoms persist after therapy, recur within 2 weeks, or if the patient has atypical features suggesting a resistant or intrinsically non-susceptible organism. 1

4. Switch to an alternative agent (fluoroquinolone or trimethoprim-sulfamethoxazole based on susceptibility) if culture reveals Proteus, Pseudomonas, or another intrinsically resistant gram-negative organism. 3, 5

Common Pitfalls

• Clinicians sometimes avoid nitrofurantoin in patients with CrCl 30–60 mL/min based on outdated package-insert warnings; current evidence supports its use in this range when the pathogen is susceptible. 3

• Prescribing nitrofurantoin for "borderline" upper-tract symptoms (mild flank discomfort, low-grade fever) leads to treatment failure because the drug does not reach therapeutic concentrations in renal parenchyma. 1

• Assuming nitrofurantoin covers all gram-negatives is a critical error—it does NOT cover Proteus, Pseudomonas, or Serratia, and empiric use in complicated UTIs or healthcare-associated infections is inappropriate. 3, 5