What is the appropriate follow-up antibiotic for acute cystitis with positive nitrites but a negative urine culture after treatment failure with Macrobid (Nitrofurantoin)?

From the Guidelines

For acute cystitis with positive nitrites but negative urine culture after Macrobid (nitrofurantoin) failure, I recommend switching to trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg (one double-strength tablet) twice daily for 3 days, or fosfomycin 3 grams as a single-dose sachet mixed in water, as these options have been shown to be effective in treating acute cystitis, with minimal resistance and propensity for collateral damage 1. The presence of nitrites suggests bacterial infection despite the negative culture, which could be due to prior antibiotic use, inadequate sample collection, or fastidious organisms.

When switching antibiotics after treatment failure, it's essential to choose a medication with a different mechanism of action. TMP-SMX works by inhibiting bacterial folate synthesis, while fosfomycin disrupts cell wall formation—both mechanisms differ from nitrofurantoin's action. Alternative options, such as ciprofloxacin 250 mg twice daily for 3 days or cephalexin 500 mg four times daily for 5 days, may be considered, but fluoroquinolones, including ciprofloxacin, should be reserved for important uses other than acute cystitis due to their propensity for collateral damage and the promotion of fluoroquinolone resistance 1.

Key considerations when selecting an antibiotic include:

• Efficacy in treating acute cystitis
• Resistance rates of uropathogens
• Propensity for collateral damage
• Mechanism of action, to ensure a different mechanism than the initial antibiotic used
• Potential for promoting antibiotic resistance

If symptoms persist after the second antibiotic course, further evaluation with repeat cultures, imaging, or urological consultation may be necessary to rule out complications or anatomical abnormalities. It is crucial to prioritize the patient's morbidity, mortality, and quality of life when making treatment decisions, and to choose the most effective and safest antibiotic option available 1.

From the FDA Drug Label

To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim tablets and other antibacterial drugs, sulfamethoxazole and trimethoprim tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris

The patient has acute cystitis with +nitrites but negative urine culture after failure with Macrobid. Given the negative urine culture, it is unclear what organism is causing the infection, and therefore, it is unclear if trimethoprim-sulfamethoxazole or ciprofloxacin would be effective.

• Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to Escherichia coli.
• However, the negative urine culture does not provide information on the susceptibility of the organism to ciprofloxacin. Considering the lack of information on the causative organism and its susceptibility, the best course of action would be to consult with an infectious disease specialist or order further testing to determine the best antibiotic choice 2, 3, 3.

From the Research

Follow-up Antibiotic for Acute Cystitis

• The patient has acute cystitis with +nitrites but a negative urine culture after failure with Macrobid (nitrofurantoin) 4, 5, 6.
• Second-line options for acute uncomplicated cystitis include oral cephalosporins such as cephalexin or cefixime, fluoroquinolones, and β-lactams, such as amoxicillin-clavulanate 4.
• Other treatment options for UTIs due to ESBLs-E coli include nitrofurantoin, fosfomycin, pivmecillinam, amoxicillin-clavulanate, finafloxacin, and sitafloxacin 4.
• A 5-day course of nitrofurantoin is equivalent clinically and microbiologically to a 3-day course of trimethoprim-sulfamethoxazole and should be considered an effective fluoroquinolone-sparing alternative for the treatment of acute cystitis in women 7.
• However, the patient has already failed Macrobid (nitrofurantoin), so alternative antibiotics such as fosfomycin, pivmecillinam, or amoxicillin-clavulanate may be considered 4, 6.

Considerations for Antibiotic Choice

• The choice of antibiotic should be based on local susceptibility patterns and the patient's individual risk factors for resistance 4, 6.
• Fluoroquinolones should be reserved for more invasive infections due to concerns about resistance 6.
• β-Lactam agents (amoxicillin-clavulanate and cefpodoxime-proxetil) are not as effective as empirical first-line therapies for acute uncomplicated cystitis 6.

Treatment Duration

• The duration of treatment for acute uncomplicated cystitis is typically 5-7 days 5, 6.
• However, treatment duration may vary depending on the patient's individual circumstances and the antibiotic chosen 8.