NFILD and non-antibiotic options for recurrent UTI

Joan is 73 and comes to see you with a worsening dry cough over the past few months, and she is now feeling a bit more puffed out than usual, which is affecting her daily dog walk. Her examination is unremarkable apart from some fine creps in both bases. Is this heart failure? She’s an ex-smoker so could it be COPD or lung cancer? Or could it be the nitrofurantoin she has been on for the last 2 years for recurrent UTIs? A few months later the respiratory team confirm that Joan has NFILD.

What on earth is NFILD? No, I’ve not made a typo nor is it a New Zealand style alternative pronunciation of NAFLD (non alcoholic fatty liver disease). If you’re a bit perplexed and haven’t the foggiest what I’m talking about, you will not be alone - a quick Mr Google search of NFILD assumed I had made a typo and directed me to NFL American Football references! No, NFILD stands for NitroFurantoin induced Interstitial Lung Disease, a condition that goes in the ‘rare but serious’ bag, and one I suspect many of us are not very aware of. So what is NFILD and what do we need to do as GPs to look out for this condition? And given long term nitrofurantoin is generally prescribed for recurrent UTI, what about non-antibiotic options for recurrent UTI? Well, a recent DTB article has highlighted the issues of long term nitrofurantoin (Drug and Therapeutics Bulletin 2022;60:59) and recent research helps inform the debate/options for alternative, non-antibiotic options for recurrent UTI (BMJ 2022;376:e068229). 

The DTB article reviews some recent UK data confirming that awareness of the adverse effects of long term nitrofurantoin is poor both in primary and secondary care. I suspect one of the reasons for this is that we all consider nitrofurantoin to be a relatively ‘safe’ drug - apart from having to avoid use with eGFR <45 it is well tolerated, is narrow spectrum and has a low risk of resistance. It is easy to miss the line in the BNF under monitoring requirements for long term use….’On long-term therapy, monitor liver function and monitor for pulmonary symptoms, especially in the elderly’. Data published in the BJGP Open last year (BJGPO.2021.0083) from UK primary and secondary care showed that many prescribers were unaware of potential hepatotoxicity (42%) and pulmonary toxicity (28%). About 50% of prescribers reported that they did not measure baseline LFTs or pulmonary function, and of those patients on nitrofurantoin >6 months almost half (45%) had no monitoring beyond 6 months, with only 21% having both LFT and lung monitoring. 

The major barrier to monitoring of long term nitrofurantoin (apart from awareness) is a lack of any concrete guidance. The BNF comment is wooly and unhelpful for day to day practice. Uncertainty as to who is responsible for baseline and ongoing monitoring is another sticking point flagged in this study….However the authors of the BJGP article offer some practical suggestions (whilst acknowledging yet more burdens on overstretched General Practice…):

• Consent patients and make them aware of the long term effects of nitrofurantoin and to stop immediately if they develop new respiratory symptoms.
• Baseline LFT and respiratory assessment (respiratory symptoms and exam, MRC dyspnoea score, oxygen sats and CXR).
• Monitoring (ideally every 3 months) - LFTs, respiratory symptoms and exam, MRC dyspnoea score, oxygen sats.

It’s also worth noting that the MPS has dealt with a number of cases of inadequate monitoring of long term nitrofurantoin and they recommend as a minimum 6 monthly reviews of LFTs and respiratory symptoms. 

But could we have saved all this hassle, and a serious complication for Joan, in the first place? The search for non-antibiotic options for recurrent UTI is ongoing but original UK based trial data, recently published in the BMJ (BMJ 2022;376:e068229) gives further support for one such option. Methenamine hippurate is hydrolysed to formaldehyde in the distal renal tubules which acts as a bacteriocidal compound by denaturing bacterial proteins and nucleic acids. This study recruited 240 women, average age 50, with recurrent UTIs (median 6 self reported UTIs in the preceding 12 months and 2-3 +ve cultures) who were randomly assigned to methenamine hippurate or prophylactic antibiotics based on MSU sensitivities and drug allergies etc (interestingly over half (55%) were put on nitrofurantoin). It was powered to assess non-inferiority. Over the 12 month follow-up period non-inferiority of methenamine hippurate vs antibiotic prophylaxis was demonstrated;  although there was a trend to fewer UTIs in the antibiotic group the absolute difference was <0.5 UTI episodes, which was not thought to be clinically significant. Of note, 43% of women in the methenamine hippurate group remained UTI free over the 12 months and higher resistance rates were demonstrated in the antibiotic group. Only 2 serious adverse events thought due to the drugs occurred (abdo pain requiring admission and a serious LFT derangement) - both in the antibiotic group.

So, all in all this seems like a good option for women with recurrent UTIs to be offered. It is possible methenamine hippurate may not be quite as effective as antibiotic prophylaxis, but it seems much safer, with fewer monitoring requirements. Right, who’s off to audit their long term nitrofurantoin patients….