Nitrofurans

Nitrofurans are synthetic nitro-substituted five-membered ring compounds with broad bactericidal and antiprotozoal activity. Nitrofurantoin is the only member in routine antibacterial use, confined to the urinary tract because it reaches no useful concentration in blood or tissue. Nifurtimox, a nitrofuran, is used against trypanosomes (Chagas disease and, in combination with eflornithine, late-stage Gambian human African trypanosomiasis). Nitrofurazone (topical) and furazolidone are largely obsolete.

Mechanism. Bacterial nitroreductases reduce the nitro group to reactive intermediates that damage ribosomal proteins, DNA and metabolic enzymes. The multiple targets explain the very low rate of acquired resistance.

Pharmacokinetics. Nitrofurantoin is rapidly absorbed, with absorption increased by food, and has a plasma half-life of only 20 minutes. About 30 to 40 percent is excreted unchanged in urine, giving urinary concentrations far over the MIC, but this falls steeply as renal function declines, so efficacy is lost when eGFR is low while toxicity from accumulation rises.

Spectrum. Escherichia coli (resistance under 5 percent in most settings), Enterococcus faecalis and faecium (including some VRE), Staphylococcus saprophyticus, Citrobacter koseri. Unreliable or inactive against Klebsiella, Enterobacter, Serratia, Proteus, Morganella, Providencia and Pseudomonas.

• Nitrofurantoin macrocrystals and modified-release formulations: the modified-release form allows twice-daily dosing and causes less nausea.
• Nifurtimox: antiprotozoal use only, with separate dosing and toxicity.
• Nitrofurazone and furazolidone: historical topical and antidiarrhoeal uses, withdrawn in many countries because of carcinogenicity concerns.

Adult regimens (normal renal function).

• Uncomplicated cystitis: nitrofurantoin modified-release 100 mg orally every 12 hours with food for 3 to 5 days (50 mg of the immediate-release form every 6 hours for 3 to 5 days in some regimens).
• Recurrent cystitis prophylaxis: 50 to 100 mg at night, for the shortest period possible and with review at 6 months.
• Children over 3 months: 3 mg/kg daily in four divided doses of the immediate-release form (for prophylaxis, 1 mg/kg once at night).
• Nifurtimox (specialist use): 15 mg/kg daily in three doses for 10 days, with eflornithine for late-stage Gambian trypanosomiasis.

Selection. First-line choice for uncomplicated lower urinary infection in non-pregnant women where local E. coli resistance is acceptable, including ESBL-producing E. coli that remain susceptible. Not suitable for pyelonephritis, prostatitis, male urinary infection of uncertain source, urosepsis, or catheter-associated infection with Proteus or Pseudomonas. Not for asymptomatic bacteriuria.

Contraindications. eGFR under 30 mL/min; between 30 and 44 mL/min only for a short course when no alternative exists and with specialist advice; infants under 3 months; late pregnancy (36 weeks to delivery) and labour; G6PD deficiency; previous pulmonary, hepatic or neuropathic reaction to nitrofurantoin; porphyria.

Serious effects.

• Acute pulmonary reaction (fever, dyspnoea, eosinophilia, infiltrates within days) and chronic interstitial pulmonary fibrosis after months of use, which may be irreversible.
• Hepatotoxicity including autoimmune-type chronic active hepatitis.
• Peripheral neuropathy, especially in renal impairment, diabetes and older adults.
• Haemolytic anaemia in G6PD deficiency; nausea and vomiting; urine turns dark yellow or brown.

Interactions. Magnesium trisilicate-containing antacids reduce absorption; probenecid raises plasma levels and lowers urinary levels; quinolones are antagonistic in vitro; hepatotoxic drugs add risk.

Monitoring. For any course over 6 months: lung and liver symptoms review, liver tests and chest radiograph if cough or dyspnoea; check eGFR before each prescription.

Special groups. Pregnancy: acceptable in the first and second trimesters when other options are limited; avoided at term. Breastfeeding: avoided in infants under 1 month or G6PD-deficient infants. Older adults: neuropathy and pulmonary toxicity are commoner; avoid long-term prophylaxis where possible. Region: it is an important oral option for ESBL-producing E. coli cystitis in East Africa where available.