Revived old antibiotics: Nitrofurantoin

Bacterial resistance increases and old antibiotics are being revived to expand therapy options or ease the selection pressure for commonly used drugs. Nitrofurantoin was commercialized in an era predating requirements for robust methodology in drug development. Despite the drug’s resurgence and widespread consumption, uncertainties persist regarding PK/PD relationships, dosing, efficacy and toxicity. The re-developing process of a revived antibiotic in an academic setting starts with a systematic review to identify knowledge gaps and select the most important non-clinical and clinical studies.

The EU-funded AIDA project (FP7 HEALTH.2011.2.3.1-1—Preserving Old Antibiotics for the Future) is systematically “re-developing” some old antibiotics and includes vital PK, PD studies and PK/PD analysis as well as 3 randomized controlled clinical trials.

One of the studied drugs in nitrofurantoin for uncomplicated lower urinary tract infections caused by multi-drug resistant bacteria. The current body of clinical knowledge is unclear. For this reason we performed a structured, systematic review and meta-analysis of controlled clinical trials to evaluate nitrofurantoin’s efficacy and toxicity when given short term (≤14 days) for the treatment of UTI.

This study has just been published in the Journal of Antimicrobial Chemotherapy.

Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW: Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015 Jun 11.

OBJECTIVES: Nitrofurantoin’s use has increased exponentially since recent guidelines repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review and meta-analysis to assess nitrofurantoin’s efficacy and toxicity in the treatment of lower UTI.
METHODS: We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials.
RESULTS: Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89-0.97). If given for only 3 days, nitrofurantoin’s clinical efficacy was diminished (61%-70%). Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare.
CONCLUSIONS: When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.

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