Nitrofurantoin – An Old Drug Resurrected Needs Prospective Scrutiny

UTI - sliderWhen older drugs get reintroduced into clinical practice because pathogens have developed resistance to newer agents, it comes at the price of uncertainty.

Often, older drugs were approved based on rather limited data, often considered incomplete by today’s standards.  Take colistin as an example: approved in the early 60ies, we still don’t know how to dose the drug properly for efficacy and safety.

fimbriated EC
Piliated E. coli with MS fimbriae

Older drugs also often carry the mantle of safety because studies were never performed that would have shown issues.  Take erythromycin as an example: touted as one of the safest antibiotics, it is now known to have enormous potential for QT prolongation.  Especially the IV form – fortunately rarely used – has been associated with QTc prolongation of >40 msec.  There is plenty of documentation showing that Torsade de Pointes (TdP) ventricular arrhythmia is not uncommon.

Older drugs don’t have a sponsor interested in investing in new studies.  Hence, when we resort to a colistin, fosfomycin, or nitrofurantoin after a long hiatus of infrequent use, we get confronted with adverse events long forgotten, labeling restrictions without clear scientific basis and the need for updated sensitivity data and new breakpoint assessments.

All these issues are now encountered with nitrofurantoin, a drug with a long history of use for uncomplicated UTI but sidelined by amoxicillin, then TMP/SMX, and later by the quinolone family of drugs.  Since E. coli have become resistant to all 3 antibiotic classes in recent years, the latest guidelines encourage us to use of nitrofurantoin as a first line agent for this indication.

The efficacy of nitrofurantoin against uropathogenic E. coli is considered en par with TMP/SMX or cephalosporins according to a recent Cochrane analysis[1].  While this is good news, it is also old news as most of these comparative trials were done in the 90ies.  Fortunately, most uropathogens are susceptible:  In a large US outpatient study, urinary E.coli were mostly susceptible to nitrofurantoin except for a subset of highly MDR isolates.[2]   Likewise, the efficacy of nitrofurantoin in ESBL E. coli was unreliable, with resistance in 29% of isolates[3].  In UK isolates of CRE, nitrofurantoin MICs were high and most isolates tested resistant.[4]  As would be expected, such resistance is by no means universal and evenly distributed.

Regarding safety, nitrofurantoin is not a placebo. Case reports of idiosyncratic reactions, both hepatic and pulmonary, have been published by us [5] and other authors but are fortunately rare.  The disease is often characterized as a hypersensitivity pneumonitis or hepatitis, not always reversible and sometimes chronic. The main concern is that it may not be recognized as a drug reaction and the connection to nitrofurantoin may not be made in time.

Then there are GI side effects which we often consider as tolerability, not as safety issues.  Nonetheless, nausea and vomiting are frequent (30%) and may lead to premature discontinuation.  Interestingly, this is a direct drug effect on the emetic brain stem center.[6]

When data is missing, or incomplete, when dossiers are old and partially irrelevant, no wonder that it becomes difficult to reconstruct even some pieces that made it into the Package Label.  Oplinger was unable to find substantiation for the cut-off and contraindication for patients with Clcr < 50 ml/min. Concerns about systemic accumulation of the drug or its nitro metabolites may have led to this restriction.[7]

In this day and age when MDR pathogens are even found in an outpatient setting, we are going back to colistin, nitrofurantoin, fosfomycin – drugs for which we have much fewer scientific data than anything approved in the last 25 years.

Welcome to our Brave New World.  Admittedly, the old drugs worked well against the old bugs, but now we have to see how good they are for our present assortment of bugs and super-bugs.

It would be nice to have some new antibiotics to get us Back to the Future.

[1] Zalmanovici Trestioreanu A.  Antimicrobial agents for treating uncomplicated urinary tract infection in women (Review). The Cochrane Library 2010, Issue 10, 2010
[2] G Sanchez.  J Antimicrob Chemother. 2014;69: 3259
[3] Puerto A. Diagn Microbiol Infect Dis 2006; 54: 135
[4] D Livermore.  Internat J Antimicrob Agents 37; 2011: 415
[5] H Reinhart.  Gastroenterology. 1992;102 (4 Pt 1):1396
[6] D Greenwood.  In Finch: Antibiotic and Chemotherapy, Chapter 31, 356
[7] M Oplinger.  Ann Pharmacother. 2013;47:106

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