NIHR Signal Prescribing anti-inflammatories for urine infection reduces antibiotic use but increases complication risk

Published on 5 June 2018

Urinary tract infection symptoms resolved by three days for 80% of women given antibiotics compared with 54% given anti-inflammatories. Anti-inflammatories reduced antibiotic use, but 5% of women developed more severe infection of the kidneys.

Urinary infections are the second most common reason for prescribing antibiotics in general practice, after respiratory infection. As such, this use may be contributing to increasing antibiotic resistance.

This Swiss trial provided an important head-to-head comparison of antibiotic treatment with the anti-inflammatory diclofenac in 253 women.

The findings don’t indicate that a switch to prescribing anti-inflammatories for women with clear symptoms of urinary infection would be a suitable move to tackle antibiotic resistance.

Symptoms are prolonged to about four days compared with two with antibiotics. This comes at the cost of increased risk of potentially serious complications.

Delayed antibiotic prescribing could be used alongside a non-steroidal anti-inflammatory drug (NSAID) first strategy.

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Why was this study needed?

Urinary infections are very common in women, affecting at least one in five in their lifetime.

It’s estimated over 90% of otherwise healthy women presenting to their GP with symptoms of painful and frequent urination will have bacteria in their urine. Therefore it’s standard practice to prescribe a short, three-day course of antibiotics on the basis of symptoms alone. Urine dipstick is sometimes helpful if a woman has only mild or a single symptom, in which case the presence of white blood cells or nitrite indicates a high likelihood of infection.

Around 10-20% of all antibiotic prescriptions in general practice are for urinary infections. Reducing antibiotic prescription for uncomplicated infections in women might help reduce growing antibiotic resistance.

As urinary symptoms may be caused by inflammation, NSAIDs might be a way to reduce antibiotic use.

What did this study do?

This randomised controlled trial was conducted in 17 general practices in Switzerland. It included 253 adult women (aged 18 to 70 years) with symptoms and urine dipstick positive for white blood cells and/or nitrites. Pregnant women and those with possible kidney infection were excluded, as were women with various other medical conditions.

Women were given the antibiotic norfloxacin (400mg daily) or the NSAID diclofenac (75mg daily) for three days. Both drugs had the same appearance and dosing frequency, so neither women nor doctors knew which treatment was given. A “rescue” antibiotic (fosfomycin) was available to all women if symptoms persisted after three days.

The initial plan was to recruit 400 women, but recruitment was slow and terminated early. However, the researchers calculated they had sufficient women to reliably detect a difference in outcomes.

What did it find?

  • Antibiotics were better than NSAIDs for resolving symptoms by three days. Symptoms resolved for 80% of women in the norfloxacin group (96/120) compared with 54% in the diclofenac group (72/133).
  • The time to symptom resolution was doubled when NSAIDs were used: average (median) four days compared with two days for antibiotics.
  • Unsurprisingly prescribing NSAIDs reduced antibiotic use. Ninety-eight per cent of women in the norfloxacin group had taken antibiotics by 30 days compared with 62% of the diclofenac group. Forty-one per cent of the diclofenac group felt the need to take the rescue antibiotic fosfomycin by day three compared with 8% of the norfloxacin group.
  • NSAIDs increased the risk of complications related to infection. There were six cases of kidney infection (pyelonephritis) in the diclofenac group (5%) compared with none in the norfloxacin group.

What does current guidance say on this issue?

The NICE quality standard on urinary tract infections in adults, states that urine culture is required for those who don’t respond to initial antibiotics.

NICE recommendations are drawn from the 2012 SIGN guideline. SIGN advises prescribing antibiotics (trimethoprim or nitrofurantoin for three days) to healthy women aged <65 who have three or more symptoms. They advise using a urine dipstick to diagnose infection in women with mild symptoms.

What are the implications?

There is need to reduce antibiotic use to tackle growing antibiotic resistance. But this study doesn't indicate that prescribing anti-inflammatories for urinary tract infection is the answer.

Women who have several symptoms are almost certain to have a bacterial infection. Giving anti-inflammatories may reduce antibiotic use, but symptom resolution is less likely, and there is a higher risk that infection will ascend to the kidneys.

As the authors note, they chose an antibiotic with known effectiveness in their region. In countries and settings with higher levels of antibiotic resistance, the difference between antibiotics and NSAIDs may be less marked.

Citation and Funding

Kronenberg A, Butikofer L, Odutayo A, et al. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. BMJ. 2017;359:j4784.

This study was funded by the by the Swiss National Foundation, Swiss Academy of Medical Sciences, SwissLife foundation, and Else Kroener-Fresenius foundation.

Bibliography

Gágyor I, Bleidorn J, Kochen MM, et al. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ. 2015;351:h6544.

NICE. Urinary tract infections in adults. QS90. London: National Institute for Health and Care Excellence; 2015.

SIGN. Management of suspected urinary tract infections in adults. SIGN 88. Edinburgh: Scottish Intercollegiate Guidelines Network; 2012.

Why was this study needed?

Urinary infections are very common in women, affecting at least one in five in their lifetime.

It’s estimated over 90% of otherwise healthy women presenting to their GP with symptoms of painful and frequent urination will have bacteria in their urine. Therefore it’s standard practice to prescribe a short, three-day course of antibiotics on the basis of symptoms alone. Urine dipstick is sometimes helpful if a woman has only mild or a single symptom, in which case the presence of white blood cells or nitrite indicates a high likelihood of infection.

Around 10-20% of all antibiotic prescriptions in general practice are for urinary infections. Reducing antibiotic prescription for uncomplicated infections in women might help reduce growing antibiotic resistance.

As urinary symptoms may be caused by inflammation, NSAIDs might be a way to reduce antibiotic use.

What did this study do?

This randomised controlled trial was conducted in 17 general practices in Switzerland. It included 253 adult women (aged 18 to 70 years) with symptoms and urine dipstick positive for white blood cells and/or nitrites. Pregnant women and those with possible kidney infection were excluded, as were women with various other medical conditions.

Women were given the antibiotic norfloxacin (400mg daily) or the NSAID diclofenac (75mg daily) for three days. Both drugs had the same appearance and dosing frequency, so neither women nor doctors knew which treatment was given. A “rescue” antibiotic (fosfomycin) was available to all women if symptoms persisted after three days.

The initial plan was to recruit 400 women, but recruitment was slow and terminated early. However, the researchers calculated they had sufficient women to reliably detect a difference in outcomes.

What did it find?

  • Antibiotics were better than NSAIDs for resolving symptoms by three days. Symptoms resolved for 80% of women in the norfloxacin group (96/120) compared with 54% in the diclofenac group (72/133).
  • The time to symptom resolution was doubled when NSAIDs were used: average (median) four days compared with two days for antibiotics.
  • Unsurprisingly prescribing NSAIDs reduced antibiotic use. Ninety-eight per cent of women in the norfloxacin group had taken antibiotics by 30 days compared with 62% of the diclofenac group. Forty-one per cent of the diclofenac group felt the need to take the rescue antibiotic fosfomycin by day three compared with 8% of the norfloxacin group.
  • NSAIDs increased the risk of complications related to infection. There were six cases of kidney infection (pyelonephritis) in the diclofenac group (5%) compared with none in the norfloxacin group.

What does current guidance say on this issue?

The NICE quality standard on urinary tract infections in adults, states that urine culture is required for those who don’t respond to initial antibiotics.

NICE recommendations are drawn from the 2012 SIGN guideline. SIGN advises prescribing antibiotics (trimethoprim or nitrofurantoin for three days) to healthy women aged <65 who have three or more symptoms. They advise using a urine dipstick to diagnose infection in women with mild symptoms.

What are the implications?

There is need to reduce antibiotic use to tackle growing antibiotic resistance. But this study doesn't indicate that prescribing anti-inflammatories for urinary tract infection is the answer.

Women who have several symptoms are almost certain to have a bacterial infection. Giving anti-inflammatories may reduce antibiotic use, but symptom resolution is less likely, and there is a higher risk that infection will ascend to the kidneys.

As the authors note, they chose an antibiotic with known effectiveness in their region. In countries and settings with higher levels of antibiotic resistance, the difference between antibiotics and NSAIDs may be less marked.

Citation and Funding

Kronenberg A, Butikofer L, Odutayo A, et al. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. BMJ. 2017;359:j4784.

This study was funded by the by the Swiss National Foundation, Swiss Academy of Medical Sciences, SwissLife foundation, and Else Kroener-Fresenius foundation.

Bibliography

Gágyor I, Bleidorn J, Kochen MM, et al. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ. 2015;351:h6544.

NICE. Urinary tract infections in adults. QS90. London: National Institute for Health and Care Excellence; 2015.

SIGN. Management of suspected urinary tract infections in adults. SIGN 88. Edinburgh: Scottish Intercollegiate Guidelines Network; 2012.

Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial

Published on 9 November 2017

Kronenberg, A.,Butikofer, L.,Odutayo, A.,Muhlemann, K.,da Costa, B. R.,Battaglia, M.,Meli, D. N.,Frey, P.,Limacher, A.,Reichenbach, S.,Juni, P.

Bmj Volume 359 , 2017

Objective To investigate whether symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care.Design Randomised, double blind, non-inferiority trial.Setting 17 general practices in Switzerland.Participants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers.Main outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat.Results 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03).Conclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI.Trial registration ClinicalTrials.gov NCT01039545.

Expert commentary

Urinary infections are a major reason for antibiotic use. This study confirmed earlier findings that a nonsteroidal anti-inflammatory drug [NSAID] (ibuprofen in that trial, diclofenac in the current trial) gave reasonable symptom control, but poorer control than with initial antibiotics. Unfortunately, prolonged illness was more common with the NSAID treatment, as was pyelonephritis (5%) - higher than the prior ibuprofen trial (2%) and higher than in placebo groups of previous trials (0.6%) - presumably by interfering with host defences.

Clinicians should probably not prescribe a course of diclofenac for these infections. If recommending an NSAID, they could suggest using ibuprofen backed up with a delayed antibiotic prescription.

Paul Little, Professor of Primary Care Research, University of Southampton