oral nitrofurantoin, 100 mg 3 times a day for 5 days
a single 3-g dose of oral fosfomycin
The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI).
To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis.
DESIGN, SETTING, AND PARTICIPANTS:
Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel.
Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection.
MAIN OUTCOMES AND MEASURES:
The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events.
Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively).
CONCLUSIONS AND RELEVANCE:
Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion.
ClinicalTrials.gov Identifier: NCT01966653.
Urinary tract infections (UTIs) are common and contribute a significant burden to population health. In the United States, UTIs account for approximately 10 million ambulatory visits
70% (n = 171/244) of patients receiving nitrofurantoin achieved clinical cure in contrast to 58% (n = 139/241) of patients receiv- ing fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). These findings were affirmed during an earlier observation point 14 days after completion of therapy. The effect of nitrofuran- toin was even more pronounced in subgroup analysis of pa- tients with Escherichia coli infection, in which 78% (n = 80/ 103) vs 50% (n = 55/111) of patients in the nitrofurantoin vs fosfomycin groups, respectively, experienced clinical cure (difference, 28% [95% CI, 15%-40%]; P < .001). Despite the clinical efficacy of nitrofurantoin, there was no significant difference in the duration of symptoms (4 days vs 3 days) or development of pyelonephritis (0.4% vs 2%) between pa- tients receiving nitrofurantoin or fosfomycin, respectively.
Importantly, microbiologic responses were not inte- grated into the primary outcome and were evaluated as sec- ondary outcomes. Huttner and colleagues12 posit that a purely clinical outcome is most meaningful for patients, and that a composite clinical and microbiologic outcome would ex- clude patients without baseline positive urine cultures, which notably represented 27% of randomized patients in their study. Nevertheless, microbiologic responses included cure, de- fined as eradication of the infection strain without recur- rence of bacteriuria (<103 colony-forming units/mL), and emer- gence of antimicrobial resistance at 28 days after completion of therapy. Similar to clinical response, patients receiving nitrofurantoin (129/175 [74%]) compared with fosfomycin (103/163 [63%]) had more frequent microbiologic cure at 28 days when evaluating those with positive baseline cultures (difference, 11% [95% CI, 1%-20%]; P = .04). This finding was also true at 14 days. Although the microbiologic response was not as robust as the clinical response, clinical response in acute uncomplicated cystitis is most important in clinical practice, and microbiologic test of cure is not standard of care. With re- spect to antimicrobial resistance, 2 patients receiving nitro- furantoin developed resistant strains during treatment whereas emergence of fosfomycin resistance was not observed.
Overall, Huttner and colleagues12 provide a rigorous affirmation of the effect of nitrofurantoin vs fosfomycin. These findings differ from prior randomized clinical trials com- paring the 2 drugs. In 1999, Stein13 published the results of a double-blind, placebo-controlled trial comparing a single 3-g dose of fosfomycin vs 7 days of nitrofurantoin, 100 mg twice daily. In contrast to the study by Huttner and colleagues,12patients were required to have microbiologic confirmation of UTI on enrollment, and follow-up occurred from 5 to 42 days. In per-protocol analyses, the only difference was early and an estimated $2 billion in total costs each year.1,2 Com- pared with men, women in-
cur a greater burden of disease, with more than half of women experiencing at least 1 UTI during their lifetime.3 Among women aged 18 to 70 years, acute uncomplicated UTI results in nearly 4 days of genitourinary symptoms and 3 days of re- stricted activity per episode.4
Acute uncomplicated UTI or cystitis refers to sympto- matic bladder infection in women without structural abnor- malities, urinary instrumentation, or systemic diseases such as immunodeficiency.5 Worldwide, acute uncomplicated cystitis is one of the most common indications for antimicrobial pre- scriptions. In the past decade, more antibiotic prescriptions with varying lengths of treatment for cystitis6,7 have contrib- uted to the emergence of multidrug-resistant uropathogens (eg, vancomycin-resistant Enterococci, extended-spectrum beta- lactamase–producing Enterobacteriaceae, and carbapenem- resistant Enterobacteriaceae).
Accordingly, clinical practice guidelines for acute uncom- plicated cystitis were updated by the Infectious Diseases So- ciety of America and European Society for Microbiology and Infectious Diseases in 2010.8 Nitrofurantoin monohydrate/ macrocrystals, 100 mg twice daily for 5 days, and fosfomycin tremetamol, 3 g in a single dose, were both recommended regi- mens for acute uncomplicated cystitis; however, fosfomycin was recognized to have inferior efficacy compared with other recommended regimens.8 Additionally, data supporting fos- fomycin for treatment of multidrug-resistant uropathogens are limited and lack generalizability.9,10 In the United States, the Food and Drug Administration has not approved fosfomycin for the treatment of Klebsiella infections, and the interpreta- tion of fosfomycin susceptibility varies worldwide, with dif- ferent sensitivity thresholds proposed by laboratory regula- tory bodies.11
In this issue of JAMA, Huttner and colleagues12 report the results of a multinational, open-label, randomized clinical trial involving 513 nonpregnant women with acute uncomplicated cystitis from Switzerland, Poland, and Israel to compare the clinical efficacy of nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), vs a single 3-g dose of oral fosfomycin (n = 258). The primary outcome was clinical cure 28 days after comple- tion of therapy, defined as complete resolution of signs or symp- toms of infection. In the intention-to-treat analysis at 28 days,
microbiologic response, in which nitrofurantoin demon- strated higher bacteriologic cure rates than fosfomycin (86% vs 78%). Clinical response remained high for both drugs across all time points. Another double-blind, placebo-controlled trial com- paring a single 3-g dose of fosfomycin vs 7 days of nitrofuran- toin, 50 mg 4 times daily, in women with clinically confirmed cystitis also found no difference in clinical response at any time point 4 to 42 days after starting treatment in per-protocol analyses.14 In contrast to the study by Huttner and colleagues,12both trials defined clinical response as cure or improvement, and time points earlier than 14 days were evaluated.
These earlier trials suggest that the open-label design used by Huttner and colleagues12 may have influenced patient re- porting of genitourinary symptoms. In particular, patients ran- domly assigned to the nitrofurantoin group may have re- ported greater clinical improvement by virtue of taking a medication 3 times daily for 5 days. This perception of greater treatment intensity may have differentially reduced the fre- quency of clinical failure in the nitrofurantoin vs fosfomycin group, which was defined, in part, as the need for additional treatment for UTI. In contrast, patients who were still symp- tomatic after single-dose fosfomycin may have sought addi- tional treatment sooner, thereby declaring earlier clinical fail- ure. Nevertheless, these concerns appear to be mitigated by the consistency of effects when confining the analysis to mi- crobiologic response and similar time to early clinical failure between groups (6.3 days vs 6.5 days).
Another limitation is the dosing regimen. Although cur- rent guidelines recommend nitrofurantoin, 100 mg twice daily, for uncomplicated cystitis, nitrofurantoin, 100 mg 3 times daily,
was selected because it was the regimen most frequently ap- proved in Europe. It is unclear whether reported results are dose dependent. In addition, only 76% (n = 194/255) and 71% (n = 183/258) of patients in the nitrofurantoin and fosfomy- cin groups, respectively, had positive baseline urine cultures. This suggests many patients may have had noninfectious ure- thral symptoms on enrollment.
Despite these limitations, this study differs from prior trials because the authors used intention-to-treat analyses, evaluated missing data through multiple imputation and sen- sitivity analyses, and included microbiologic outcomes. Thus, the preponderance of evidence described by Huttner and colleagues12 suggests that nitrofurantoin may have better clini- cal effectiveness than fosfomycin for the treatment of acute un- complicated cystitis among middle-aged women. In regions of the world where nitrofurantoin susceptibility is preserved, par- ticularly for E coli, nitrofurantoin can be the agent of choice.
Outstanding issues remain the optimal nitrofurantoin dosing regimen and whether current recommendations of 100 mg twice daily are equally effective as 100 mg 3 times daily. The role of fosfomycin also requires examination. Clini- cal and microbiologic responses with alternative fosfomycin prescribing practices, such as fosfomycin 3 g followed by 3 g every 3 days for a total of 3 days, 6 days, or 9 days, for multi- drug-resistant uropathogens should be tested.15 Neverthe- less, despite the open-label design, which may have intro- duced bias, in this trial of acute uncomplicated cystitis with drug-susceptible uropathogens, the jury has deliberated. The verdict is in. Future trials for treatment of multidrug- resistant uropathogens are needed.
To the Editor
In a randomized clinical trial, 5 days of nitrofu- rantoin resulted in higher rates of clinical resolution of un- complicated lower urinary tract infection (UTI) in women com- pared with a single dose of fosfomycin.1
One of the key premises of the study, the difference in rates of clinical cure, was overestimated. Not only did the clinical cure rate for fosfomycin differ significantly from the rates in reviews,2,3 which ranged from 77.8% to 94.7%, but it appears to have been derived from unpublished data. Differences in clinical cure rates would affect the sample size calculation and render the study underpowered.
Another internal validity issue is the population selected. Al- though the study theoretically assessed uncomplicated UTIs, the patient population had a risk of more than 86% for resistant bacteria and included women with symptoms of complicated UTI (fever, lumbar and flank pain, and nausea). Approximately 10% of the study population was hospitalized, which also sug- gests this group did not have uncomplicated UTIs.
The primary end point, clinical response in the 28 days af- ter completion of therapy, may not reflect the clinical reality of recurrences and reinfections; 28 days might include cases of both recurrences and reinfections. The secondary outcome of reso- lution at 14 days might be a better marker for treatment success.
The idea that fosfomycin resistance is overestimated in prac- tice has not been confirmed in reviews that look at resistance, especially in European countries where it is frequently used.3,4
Although this trial sheds light on what might be the best option in the treatment of uncomplicated UTI, it does not make a strong case against fosfomycin, which remains a useful treatment for uncomplicated UTI, more so in the set- ting of quinolone resistance, which is occurring worldwide.4Because it is a single-dose antimicrobial, adherence is less of an issue than with other options.