Summary
This observational cohort study reveals that nitrofurantoin, the first-choice treatment for uncomplicated UTI in males in the Netherlands, failed in 25% of episodes, which was higher than the failure percentages of ciprofloxacin, amoxicillin/clavulanic acid, and trimethoprim/sulfamethoxazole (10%, 20%, and 14%, respectively). The failure percentage of trimethoprim, the second-choice treatment, was also 25%, but the number of trimethoprim prescriptions was small. Nitrofurantoin failure significantly increased with age, ranging from 13% in those aged 18–39 years to 29% in those aged >80 years. GPs were shown to deviate from the Dutch UTI guideline in 38% of uncomplicated UTI episodes, mostly prescribing ciprofloxacin instead of nitrofurantoin or the infrequently prescribed second-choice trimethoprim.
Strengths and limitations
Major strengths of the current study are the large sample size allowing robust age-specific subgroup analyses and the use of well-documented primary care electronic routine care data for 7 consecutive years. Using the medical text from UTI consultations it was possible to discern uncomplicated from complicated UTI episodes and to not only take antibiotic switches but also treatment failures leading to an acute hospital referral into account.
Some limitations deserve further discussion. First, as this was a medical record study, it was not possible to ascertain whether tissue invasion was definitely absent. Tissue involvement might have gone undetected by the GP. This is, however, no different than in actual routine care. Besides, not only ICPC codes for cystitis, but also for prostatitis and pyelonephritis were included to obtain consultation data for all types of UTIs. As free medical text entered by the GP is more reliable than ICPC coding, all signs and symptoms of tissue invasion were scored manually to distinguish uncomplicated from complicated UTIs. Episodes with ICPC codes for prostatitis and pyelonephritis accounted for 4% of all uncomplicated UTI episodes. Even if the inclusion of such episodes would have introduced some misclassification, it was anticipated this would be of minor influence on the findings.
Second, data from out-of-hours services, such as prescriptions and referrals, and deaths were not available, which might have led to an underestimation of the observed treatment-failure fractions. It is, however, unlikely that a potential bias would differ for the various UTI-related antibiotic prescriptions. Also, no data were available on intolerances, allergies, or interactions with other medications, which might justify some non-adherent prescriptions. Besides, GPs might have other good reasons to deviate from guideline recommendations, for example, initiating a more aggressive treatment in vulnerable patients with clinically uncomplicated UTIs.
Third, by classifying all re-prescriptions with a different antibiotic and all acute referrals to urology or internal medicine as a treatment failure, some overestimation of treatment failure might have occurred. Some re-prescriptions might have been issued for other reasons than treatment failure, such as adverse effects. Also, patients might have been referred to urology or internal medicine for another reason but, as the time window for referrals was short and the number of referrals low, the authors believe that the potential impact of such misclassification will be minor.
Fourth, this study is observational (that is, non-randomised) and confounding by indication may therefore be present: the groups of males treated with nitrofurantoin versus another antibiotic might not be comparable regarding disease severity and other factors contributing to treatment failure. This may, for example, explain why hospital referrals were less common in males treated with nitrofurantoin compared with males treated with ciprofloxacin. It seems likely that patients with more severe symptoms are prescribed ciprofloxacin more often than patients with milder complaints.
Fifth, in line with clinical practice, it was not know whether patients used their antibiotics as prescribed. Sixth, there is ongoing debate whether the effectiveness of nitrofurantoin is reduced in patients with a low estimated glomerular filtration rate (eGFR).10,11 According to the Dutch primary care UTI guideline, nitrofurantoin is contraindicated in patients with an eGFR <30 mL/min/1.73 m2.2 Unfortunately, information about patient’s actual eGFR was not available in the current study. As GPs as well as pharmacies receive an alert if nitrofurantoin is prescribed to a patient with an eGFR <30 mL/min/1.73 m2, the authors consider it unlikely that many patients would have had a eGRF <30 mL/min/1.73 m2. However, it cannot be excluded that nitrofurantoin failure was more likely in males with eGFR between 30 and 90 mL/min/1.73 m2. Further research into this potential association is warranted.
Comparison with existing literature
The Netherlands is one of few countries worldwide recommending nitrofurantoin as a first-choice treatment for uncomplicated UTIs in males. Most available studies are therefore of Dutch origin. A previous smaller study from the same author group showed a similar nitrofurantoin failure percentage (27%) as this study.5 However, the current study adds valuable information. First, in the previous study, data on signs and symptoms were not available, making a distinction between complicated and uncomplicated UTIs impossible. Second, only nitrofurantoin prescription data from older males were available as opposed to all antibiotic types in all age groups in the current study, making comparisons between antibiotic regimens possible. Additionally, the Dutch primary care UTI guideline cites an unpublished study by the Netherlands Institute for Health Services estimating the nitrofurantoin failure percentage to be 27% in males of all ages.2 However, their treatment failure definition also included antibiotics that were likely not prescribed for UTIs, and the failure period was defined as 60 days. A third Dutch outpatient study showed that 5.4% of male patients treated with nitrofurantoin were prescribed a different antibiotic within 3 days across all ages.12 This much lower treatment failure risk may likely be explained by the 3-day treatment failure period as opposed to the 30-day period in the current study.
To the authors’ knowledge, only two studies on nitrofurantoin efficacy in males from outside the Netherlands have been published. A retrospective study in 485 American male veteran patients with lower UTIs showed a clinical cure fraction of 77%.13 However, 32% of the males had a catheter inserted at the time nitrofurantoin was prescribed, making it difficult to generalise the results to males with uncomplicated UTIs. Another retrospective study from Sweden in 69 males with a lower UTI showed nitrofurantoin failure in only one patient, but the sample size was very small.14
The 62% guideline adherence observed in the current study was comparable with the 50% adherence in the only other study, to the authors’ knowledge, that has been published about adherence to the guidelines for males.15 That study included 169 Dutch males with an uncomplicated UTI. Also comparable is the very low prescription fraction of 3% in the current study and 4.4% in Ganzeboom et al 15 for the second-choice trimethoprim. This might be related to the failure fraction of 25%, which is comparable with nitrofurantoin.
Implications for research and practice
The current study shows higher rates of nitrofurantoin failure compared with ciprofloxacin, amoxicillin/clavulanic acid, and trimethoprim/sulfamethoxazole in males with uncomplicated UTI, especially in those of older age. As this is based on observational data causal inferences cannot be drawn and the implications for what the consequences are for clinical practice remains to be elucidated.
Based on the current findings, a randomised controlled trial comparing various antibiotic regimens is warranted to robustly determine the optimal treatment strategy for males with an uncomplicated UTI.
In conclusion, nitrofurantoin failure was common in males with an uncomplicated UTI and this increased with age. GPs deviated from the Dutch UTI guideline in 38% of the uncomplicated UTI episodes, mostly prescribing ciprofloxacin instead of nitrofurantoin.
