Nitrofurantoin first for lower urinary tract infections

Urinary tract infections (UTIs) are common and occur when bacteria infect any part of the urinary tract. UTIs are described as being “uncomplicated” or “complicated” depending on various factors, including the location of the infection in the urinary tract (see Panel 1).

Angie, a 48-year-old female, presents with symptoms of dysuria, urinary frequency and suprapubic tenderness, that started yesterday. She was well enough to attend work earlier in the day and has no fever, flank pain, costovertebral angle tenderness, nausea or vomiting. She had sexual intercourse with her long-term partner a week ago, and last had a UTI a couple of years ago. Angie does not have any long-term medical conditions, her heart rate and blood pressure are within normal range, as was her renal function when checked last year. You consider Angie to have an uncomplicated UTI.

We know that in women aged 15 to 55, Escherichia coli causes most UTIs (about 82 per cent), with Staphylococcus saprophyticus the next most common causal pathogen (about 11 per cent).⁴ This allows us to treat Angie’s symptomatic UTI empirically, without the need for a urine culture.¹

Until recently, trimethoprim would have been the empirical antibiotic treatment for uncomplicated UTI. However, 2018 national data show that only around 73 per cent of about 88,000 urinary isolates of E. coli in New Zealand were susceptible to trimethoprim.⁵ Community laboratories from various regions within New Zealand (excluding Auckland) reported similar findings for 2022 data (77–83 per cent susceptibility – in about 27,000 isolates).⁶ Further, Auckland City Hospital laboratory susceptibility results from 2022 showed that only 68 per cent of 3757 E. coli isolates were susceptible to trimethoprim.⁷

By extrapolation, treatment of UTI with trimethoprim would therefore have approximately a one-in-four failure rate. It is not ideal for patient outcomes, or for healthcare providers’ workloads, if the patient has to return for further treatment. For socioeconomically disadvantaged people or those from rural areas, a repeat visit may be prohibitive.

In comparison with trimethoprim, sensitivity analyses have demonstrated that 99–100 per cent of E. coli and S. saprophyticus isolates in the community are sensitive to nitrofurantoin,^5,6 and this antibiotic is presently recommended as first-line empirical treatment for uncomplicated UTI.¹ Therefore, you recommend Angie takes nitrofurantoin.

The modified release nitrofurantoin 100mg formulation (Macrobid), funded since 2020, allows for more convenient twice-daily dosing compared with the four-times-daily dosing required with the older, immediate-release nitrofurantoin 50mg formulation (Nifuran). The advised duration of treatment with both preparations in Angie’s case is for five days only.^8,9 A seven-day course is indicated in all men.^1,8,9

Check the New Zealand Formulary⁸ or the Medsafe data sheet¹⁰ for contraindications and cautions to using nitrofurantoin, some of which are mentioned later, and for possible interactions with other medicines. Also discuss with Angie the behavioural approaches she can implement to try and avoid any further UTIs (see Panel 2).

Second-line therapy

If Angie is unable to use nitrofurantoin, alternative options are cefalexin 500mg twice a day for five days, or trimethoprim 300mg once a day for three days. Follow the HealthPathways guidance (healthpathwayscommunity.org) based on likely microbial susceptibility patterns in your region.

Cefalexin, a first-generation cephalosporin, is not suitable as a first-line treatment for Angie because it has a broader spectrum of antibacterial activity than needed for treating a simple UTI.^8,11 Furthermore, cefalexin may not be quite as effective as nitrofurantoin for treating UTIs. About 94–98 per cent of E. coli isolates in the community are sensitive to cefalexin (versus 99–100 per cent sensitivity to nitrofurantoin).^5,6 Additionally:

• E. coli can produce extended-spectrum beta-lactamases (ESBLs), which render some common antibiotics, including cephalosporins, ineffective for treating infections caused by these bacteria. Of note, nitrofurantoin has activity against ESBL-producing E. coli, whereas cefalexin does not.⁵
• Nearly all antibiotics can increase susceptibility to colonisation and overgrowth of Clostridioides difficile (previously called Clostridium difficile); however, cephalosporins along with amoxicillin + clavulanic acid, fluoroquinolones and clindamycin increase risk to the greatest extent.¹²
• When considering antibiotics for second-line therapy, select treatment according to susceptibility results, or local antimicrobial susceptibility patterns, of the identified organism. Due to increasing antimicrobial resistance, quinolones (eg, norfloxacin) should be reserved for more serious infections.¹³

Trimethoprim 300mg once daily for three days has been an alternative option to first-line nitrofurantoin, should nitrofurantoin be unsuitable;¹ although, in practice, this is not favoured due to the high resistance rates seen with trimethoprim.

National ESR resistance data from 2018 show just over a quarter (27.2 per cent) of E. coli urinary isolates – those that don’t produce ESBL – are resistant to trimethoprim versus nearly three-quarters (71.5 per cent) of those that do produce ESBL.⁵

These findings are supported by 2022 susceptibility data from Bay of Plenty, Waikato and Lakes region community laboratories. They report that 23 per cent of all 11,387 E. coli isolates (including those that do and do not produce ESBL) in patients with uncomplicated UTIs are resistant to trimethoprim, versus 62 per cent of 97 E. coli isolates that do produce ESBL.⁶ Only 5 per cent of these ESBL-producing isolates are resistant to nitrofurantoin.

Notably, S. saprophyticus isolates have minimal resistance to trimethoprim (7 per cent) and nitrofurantoin (1 per cent).⁶

Reserve trimethoprim for patients who have a urine culture confirming sensitivity to this agent.

Avoid urinary alkalisers – the antibacterial activity of both nitrofurantoin and its metabolites is enhanced under acidic conditions,¹⁴ so advise patients against using urinary alkalisers for symptom control (eg, Ural sachets, and other citrate and bicarbonate salt preparations). Additional fluid intake may be helpful for reducing burning sensation when urinating. Also, counsel patients not to use antacid preparations containing magnesium trisilicate (eg, Quick-Eze) when taking nitrofurantoin because of the possibility of impaired absorption.¹⁰

Exclude pyelonephritis – nitrofurantoin is not used to treat patients with acute pyelonephritis as tissue distribution is poor and therapeutic concentrations in the upper urinary tract are not achieved.¹⁵ With the change of nitrofurantoin to first-line lower UTI treatment, it’s important to exclude any symptoms suggestive of pyelonephritis. An upper UTI, pyelonephritis involves the kidneys and can cause sepsis and permanent renal injury. Symptoms include loin pain or tenderness, fever, rigors and sometimes nausea/vomiting.² Nitrofurantoin should only be used for the treatment of a lower UTI. The drug concentrates in the lower urinary tract and does not significantly affect the gut microbiome.¹⁵

Avoid nitrofurantoin in significant renal impairment – do not use nitrofurantoin in patients with significant renal impairment (creatine clearance <60ml/min) due to increased risk of toxicity and decreased efficacy. Nitrofurantoin is substantially excreted by the kidney; thus, the risk of toxicity may be increased in patients with impaired renal function. Consider checking renal function if nitrofurantoin is used in the elderly as renal function may be impaired in this patient group.¹⁰

Watch for lung and liver dysfunction, and neuropathy – pulmonary adverse reactions have been seen in patients treated with nitrofurantoin over both short and long-term treatment periods. Other adverse reactions include peripheral neuropathy, which is mainly associated with prolonged use in patients with renal impairment, and, rarely, hepatic adverse reactions.^10,14 Monitor lung and liver function in patients taking long-term or prophylactic nitrofurantoin. Also check for signs of peripheral neuropathy regularly and stop treatment at any signs of pulmonary, hepatic or neurological damage. ^10,14

Be mindful of haemolysis with G6PD deficiency – there is a risk of nitrofurantoin inducing haemolytic anaemia in people with glucose 6-phosphate dehydrogenase deficiency.¹⁴ More common in men than women, G6PD deficiency can be prevalent in people originating from many parts of Africa and South-East Asia, and southern Europe; it is rare in other people. Newborns with G6PD deficiency are also at risk of haemolytic anaemia if they have been exposed to nitrofurantoin in the period close to delivery or through breast milk. Because of this, avoid nitrofurantoin use in women in late pregnancy and in breastfeeding women for the first month after giving birth.¹⁴

Check-up!

Are you prescribing for the appropriate length of time? Have you stopped prescribing trimethoprim first line?

Hypothetically, if this was Angie’s third UTI in eight months and she hadn’t been on prophylaxis, would the treatment be different?

This would classify Angie as experiencing recurrent UTI, which is defined as having three or more UTIs within a year, or two or more over a six-month period.¹

Revisit your discussion of self-care strategies and triggers with Angie. Include in your conversation the potential for aggravating factors such as perimenopausal changes that may result in atrophic vaginitis. Topical (vaginal) oestrogen can reduce the incidence of recurrent UTI in women with atrophic vaginitis due to oestrogen deficiency – see your local HealthPathways and the NZ Formulary for more information.

If Angie has recurrent UTIs, initiate empiric treatment and collect an MSU sample with culture on each occasion to help guide treatment. This will also verify that the symptoms Angie is experiencing are actually caused by a UTI. It is essential to exclude other causes for her symptoms such as sexually transmitted infections, gynaecological, urological and neurological conditions. A positive MSU should not blind a healthcare provider to other diagnoses.

Indications for further investigation

Signs and symptoms that require early referral for further investigation of recurrent UTIs include:¹⁶

• persistent haematuria despite adequate control of infections
• persistent sterile pyuria
• ongoing pain
• persistent bacteriuria despite appropriate antibiotic therapy
• air or faeces in the urine.

What can be done over the longer term to prevent recurrence, assuming Angie has implemented all suggested self-care strategies?

As a last resort, consider prophylactic treatment for UTI. Nitrofurantoin can be used, but as noted, it is not without risk. The recommended nitrofurantoin treatment duration for long-term prophylaxis is up to six months, with continuation only when the expected benefits clearly outweigh the risks. Ensure monitoring to detect signs of nitrofurantoin toxicity.^14,17

Consider treating Angie with methenamine hippurate over nitrofurantoin, as the ALTAR trial showed this agent has non-inferiority to nitrofurantoin for preventing recurrent UTIs in women.¹⁸ Methenamine hippurate is a urinary antiseptic so there is no risk of resistance developing. To be active, it requires urine to be acidic, so advise Angie not to use urinary alkalisers, and supplement with ascorbic acid if necessary.¹⁹ Methenamine hippurate can cause a burning sensation due to bladder irritation¹⁸ – if this occurs, evaluate whether it is a side effect or another UTI.

If UTIs are recurrent despite prophylactic treatment, or if UTIs recur following a three-month course of prophylactic treatment, consider referral for non-acute urology assessment to exclude structural problems, interstitial cystitis and other causes.^1,20

Check-up!

Are you prescribing methenamine for UTI prophylaxis more often than nitrofurantoin?

Are you requesting an MSU for each event in patients with recurrent UTI?

Are you sending non-acute urology referrals when appropriate?

How would you manage Angie if she was already on nitrofurantoin prophylaxis for UTI?

If you suspect a breakthrough infection, take an MSU for microscopy and culture, and stop prophylactic antibiotic use.²⁰ Treat Angie with an antibiotic that is not nitrofurantoin (eg, cefalexin). If an infection has developed while she has been on prophylaxis, it’s not appropriate to treat the infection with the same antibiotic.

Follow up on the culture and treat Angie with the narrowest spectrum, most appropriate antibiotic. After this treatment, restart prophylaxis.²⁰

Check-up!

Are you stopping antibiotic prophylaxis in patients with breakthrough UTI and treating with a different, appropriate agent?

National dispensing data suggest some patients stay on nitrofurantoin for extended periods, even though the recommended maximum duration is up to six months for long-term use.^14,21 Long-term antibiotic use is usually associated with acquired resistance.

Despite several decades of widespread use, acquired resistance to nitrofurantoin is somewhat rare.¹⁵ This is likely due to nitrofurantoin’s unusual, multimodal mechanism of antimicrobial action. Cross-resistance with sulphonamides and with other antibiotics has not been seen, and transferable resistance is extremely rare.¹⁰

However, long-term use of nitrofurantoin increases risks of peripheral neuropathy and pulmonary and hepatic toxicity, which require patients to be monitored. Closely monitor lung function in your long-term patients and advise them to report new or worsening symptoms of cough or shortness of breath. Also, periodically monitor patients for changes in renal and hepatic function. Educate patients about symptoms of peripheral neuropathy and investigate periodically for signs of nerve damage.^10,14

Women with an uncomplicated UTI presenting to an accredited community pharmacist for treatment should receive nitrofurantoin as their first option.

However, nitrofurantoin can only be supplied by pharmacists once they have completed the new Urinary Tract Infections Management Accreditation training.²² A pharmacist’s existing accreditation to supply trimethoprim does not allow them to supply nitrofurantoin.

Pharmacists accredited to provide treatment for uncomplicated UTI have an ethical requirement to complete the new training as soon as reasonably possible to ensure optimal UTI management is provided and antimicrobial stewardship strategies are followed. Continuing to supply trimethoprim is discouraged; this agent is reserved for situations in which nitrofurantoin is not appropriate.²³