Risk factors for treatment failure in women with uncomplicated lower urinary tract infection.

Given rising antibiotic resistance and increasing use of delayed prescription for uncomplicated lower urinary tract infections (UTI), patients at risk for treatment failure should be identified early. We assessed risk factors for clinical and microbiological failure in women with lower UTI. This case-control study nested within a randomized clinical trial included all women in the per-protocol population (PPP), those in the PPP with microbiologically confirmed UTI, and those in the PPP with UTI due to Escherichia coli. Cases were women who experienced clinical and/or microbiologic failure; controls were those who did not. Risk factors for failure were assessed using multivariate logistic regression. In the PPP, there were 152 clinical cases for 307 controls. Among 340 women with microbiologically confirmed UTI, 126 and 102 cases with clinical and microbiological failure were considered with, respectively, 214 and 220 controls. Age ≥52 years was independently associated with clinical (adjusted OR 3.01; 95%CI 1.84-4.98) and microbiologic failure (aOR 2.55; 95%CI 1.54-4.25); treatment with fosfomycin was associated with clinical failure (aOR 2.35; 95%CI 1.47-3.80). The association with age persisted among all women, and women with E. coli-related UTI. Diabetes was not an independent risk factor, nor were other comorbidities. Postmenopausal age emerged as an independent risk factor for both clinical and microbiological treatment failure in women with lower UTI and should be considered to define women at-risk for non-spontaneous remission, and thus for delayed antibiotic therapy; diabetes mellitus was not associated with failure.

Introduction

Acute, uncomplicated lower urinary-tract infection (UTI) is one of the most frequent indications for antibiotic prescription among healthy women [1]. With their widespread use, there is increasing resistance to fosfomycin and nitrofurantoin [2], the two antibiotics currently recommended as first-line therapy [1]. At the same time, delayed antibiotic treatment strategies [3] are being increasingly used for this mucosal infection given its sizeable rate of spontaneous remission [4, 5], the low risk of progression to pyelonephritis [1], and clear evidence that frequent antimicrobial therapy increases the risk of acquiring multi-resistant organisms [6, 7]. As resistance to first-line agents increases and delayed-therapy approaches become more popular, there is a growing need to identify appropriate candidates by identifying risk factors for clinical failure or non-recovery. Fortunately, pyelonephritis remains a rare complication among healthy women [8, 9]. Age has been associated with treatment failure in multiple observational studies, sometimes yielding conflicting results [4, 10, 11]. Other baseline factors have been identified inconsistently, including diabetes, chronic kidney disease, previous hospitalization, history of recurrent cystitis, and increased comorbidity [11-15], as have particular symptoms, such as frequency and urgency [16]. Treatment failure, however, was defined heterogeneously, and follow-up bacteriologic data were rarely available [15].

From 2013 to 2017, we conducted the multicentre randomized clinical trial (RCT) “AIDA”, which showed clinical and microbiologic superiority of nitrofurantoin over single-dose fosfomycin in non-pregnant women with acute, uncomplicated lower UTI [17]. Here we report the results of a nested case-control study assessing the influence of age and other potential risk factors for clinical and microbiologic failure in the AIDA trial [18].

Methods

The AIDA study was an open-label/analyst-blinded, multicentre RCT conducted from 2013 to 2017 in Geneva (GE), Switzerland; Lodz (LO), Poland; and Petah-Tiqva (TA), Israel. It included 513 hospitalized and ambulatory adult non-pregnant women with lower UTI symptoms and a positive urine dipstick test. Those with suspected upper UTI, recent or ongoing antibiotic use, immunosuppression, severe renal insufficiency, indwelling urinary catheter or otherwise complicated UTI were excluded. Participants were randomly assigned to macrocrystalline nitrofurantoin 100 mg 3 times a day for 5 days or a single 3-g dose of oral fosfomycin and followed clinically and microbiologically at 14 (±2) and 28 (±7) days after completion of antibiotic therapy. The per-protocol population (PPP) consisted of women with at least 80% medication adherence, no major protocol deviations, and available primary-outcome data (474/513, 92.4%). This study was performed in accordance with the STROBE statement for case-control studies (S1 Appendix).

This nested case-control study assessed three populations: (1) all women randomized in the AIDA study and adhering to the study protocol (PPP) [17], (2) all women in the PPP with microbiologically confirmed (“culture-positive”) UTI, and (3) all women in the PPP with UTI due to Escherichia coli. Only women adhering to the RCT’s protocol were included to avoid the problems of missing data/outcomes and non-adherence. Assuming that E. coli are almost never contaminants in acute cystitis, this third cohort represents the best “confirmation” of a true UTI, excluding all results of lower quality with mixed flora and potential contaminants [19]. Patients with indeterminate clinical outcomes were excluded from all populations, and patients with negative or missing cultures at baseline were excluded from the second and third populations.

In the present report, the first population (PPP) was assessed to evaluate risk factors for clinical failure. The second and third populations were assessed to evaluate risk factors for both microbiologic and clinical failure. Case patients in the nested study were subclassified into “clinical” and “microbiologic”, defined respectively as those who experienced clinical and/or microbiologic failure (as defined previously) [17] in the 28 days following therapy completion; all available controls were included, defined according to case definitions as women either with clinical or microbiologic success. Women with missing bacteriological outcomes were excluded.

We assessed the impact on failure of demographic, clinical, and microbiologic characteristics defined previously (Appendix I). The association between the infecting pathogen and clinical and microbiological failure was explored in sensitivity analyses, adjusting for both presence of E. coli at baseline and resistance to the study drug received. The relationship between persistent, asymptomatic bacteriuria and subsequent clinical failure was also assessed in exploratory analyses.

Statistical analysis

Continuous variables are reported as the mean (±SD) or median (IQR) according to their distribution. Baseline characteristics were compared using X2, t-test or Wilcoxon test. LOESS smoothing function, a locally weighted non-parametric scatterplot technique, was used to explore variation in clinical failure by age and treatment and to categorize continuous variables, as described elsewhere [20]. We defined an age cut-off of 52 years, as the average age of menopause is considered physiologically to be between 50 and 52 years [21]. The effects of this cut-off can be observed graphically in the (S1 Fig in S1 Appendix).

Two multivariate logistic regression models assessed associations between demographic and clinical characteristics and clinical and microbiological failure through day 28 in those with culture-positive UTI. In exploratory analyses, similar models including the same variables assessed clinical failure in the PPP population, and clinical and microbiological failure in the E. coli subgroup, through day 28. Candidate variables for the multivariate models were chosen according to the “best model” following Bayesian Model Averaging (BMA) methods [22, 23]. Potential confounders were tested stepwise in the multivariate models, and retained if the change they induced on the beta coefficient was >20%, as defined previously [24]. Variables were examined for collinearity using a collinearity matrix. Analyses were performed using R.3.6, and RStudio Team (2015), the package “BMA” for Bayesian Model Averaging [25], and “MASS” for the creation of generalized linear models [26]. The AIDA study was approved by the Geneva Cantonal Ethics Commission (13–014) and Swissmedic (2013DR4095). Using only anonymized information, this nested study did not require further ethical approval.

Results

Among the 513 women randomized, 459 remained in the PPP and had a determinate outcome, 340 (66%) had culture-positive UTI, and 204 of these (60%) had E. coli infections (Fig 1). In the PPP, there were 152 clinical cases for 307 controls. Among the 152 cases, five had pyelonephritis. Among those with culture-positive UTI, there were 126 and 102 clinical and microbiologic case patients for 214 and 220 controls, respectively. In the E. coli subgroup, there were 70 and 71 clinical and microbiologic case patients for 134 and 128 controls. Treatment received was balanced among cases and controls (Table 1).

Fig 1

Study flowchart.

* Negative or missing cultures at baseline were excluded.

Table 1

Population characteristics.

	Clinical Failure			Microbiological Failure
	Cases (n = 126)	Controls (n = 214)	p-value	Cases (n = 102)	Controls (n = 220)	p-value
Age >52 years (%)	75 (59.5)	74 (34.6)	<0.001	64 (62.7)	82 (37.3)	<0.001
Dysuria (%)	94 (74.6)	174 (81.3)	0.19	74 (72.5)	181 (82.3)	0.06
Frequency (%)	116 (92.1)	185 (86.4)	0.16	95 (93.1)	192 (87.3)	0.17
Urgency (%)	106 (84.1)	158 (73.8)	0.04	85 (83.3)	167 (75.9)	0.17
Supra-pubic discomfort (%)	60 (47.6)	102 (47.7)	1	43 (42.2)	104 (47.3)	0.46
Gross hematuria (%)	23 (18.3)	32 (15.0)	0.52	11 (10.8)	38 (17.3)	0.18
Flank pain (%)	16 (12.7)	17 (7.9)	0.21	12 (11.8)	18 (8.2)	0.41
Chills (%)	21 (16.7)	19 (8.9)	0.05	12 (11.8)	22 (10.0)	0.78
Recurrent UTI * (%)	24 (19.0)	27 (12.6)	0.15	17 (16.7)	32 (14.5)	0.74
Diabetes mellitus (%)	18 (14.3)	16 (7.5)	0.07	18 (17.6)	16 (7.3)	0.01
Fosfomycin (%)	78 (61.9)	87 (40.7)	<0.001	58 (56.9)	99 (45.0)	0.06
Inclusion in Geneva (%)	43 (34.1)	104 (48.6)	<0.01	38 (37.3)	108 (49.1)	0.01
Inclusion in Lodz (%)	49 (38.9)	83 (38.8)		55 (53.9)	77 (35.0)
Inclusion in Tel-Aviv (%)	34 (27.0)	27 (12.6)		9 (8.8)	35 (15.9)
Risk score for Resistance = 0 (%) **	15 (11.9)	36 (16.8)	0.05	14 (13.7)	36 (16.4)	0.79
Risk score for resistance = 1 (%) **	94 (74.6)	132 (61.7)		69 (67.6)	141 (64.1)
Risk score for resistance = 2 (%) **	17 (13.5)	46 (21.5)		19 (18.6)	43 (19.5)
Nitrites on dipsticks (%)	3 (2.4)	8 (3.7)	0.51	4 (3.9)	7 (3.2)	0.03
Leukocytes on dipsticks (%)	64 (50.8)	97 (45.3)		35 (34.3)	111 (50.5)
Both on dipsticks (%)	59 (46.8)	107 (50.0)		63 (61.8)	100 (45.5)

*UTI, urinary tract infection.

**Risk factors for resistance was originally measured in the clinical trial and included: systemic antibiotic exposure (at least 1 dose) or hospitalization in an acute or long term care center in the previous 12 months, UTI fulfilling criteria for healthcare-associated infection, carriage of resistant organisms in the prior 12 months, stay of at least 1 month in a high-risk country (any country in the Mediterranean basin excluding France; South or Southeast Asia; the Middle East; Africa; and Central or South America).

Women who experienced clinical or microbiologic failure by day 28 were on average 10 years older (mean age 56.8 ±22.5 and 58.0 ±20.8 versus 45.8 ±19.6 and 47.2 ±20.7 years, respectively, [p<0.001]); the same pattern was seen in the E. coli subgroup (Fig 2, S1 Fig in S1 Appendix). In crude comparisons, women with clinical failure were significantly more likely to present with urgency and chills, to have an increased risk for carriage of multidrug-resistant bacteria, to be treated with fosfomycin, and to be recruited at the Tel Aviv site (Table 1, S1-S5 Tables in S1 Appendix). We had no missing data. The 54 participants excluded from this analysis almost shared the same characteristics (S6 Table in S1 Appendix). In the per-protocol and E. coli populations, associations between clinical failure, age and fosfomycin persisted (S2-S5 Figs in S1 Appendix). Women with microbiologic failure were more likely to have diabetes mellitus and a strongly positive baseline dipstick result (with both nitrites and leucocyte esterase detected), and to be recruited in TA (Table 1).

Fig 2

Variation of clinical and microbiological failure across different age groups and treatment groups.

Following BMA, the most parsimonious model retained age, fosfomycin treatment, and recruitment site (TA) as independent predictors for clinical failure, and age for microbiologic failure (S2-S4 Figs in S1 Appendix). Those aged >52 years had an increased risk for clinical and microbiologic failure with adjusted odds ratios (aOR) of 3.01 (95%CI 1.84–4.98) and 2.55 (95%CI 1.54–4.25), respectively (Table 2). The risk was even higher in the E. coli subgroup (aOR 4.03 [95%CI 2.05–8.18] and 3.08 [95%CI 1.64–5.87] for clinical and microbiologic failure respectively, S7 and S8 Tables in S1 Appendix). When applying the same model to the overall PPP population, the effect of age > 52 years on risk of clinical failure persisted (aOR 3.07 [95%CI 2.01–4.75], S9 Table in S1 Appendix). In patients >52 years old, nitrofurantoin remained superior to fosfomycin in terms of clinical, but not microbiologic, success (Table 2, S1 Fig in S1 Appendix). In Bayesian model averaging, diabetes mellitus did not emerge as a risk factor for clinical or microbiological failure. These observations remained when adjusting for the presence of E. coli and resistance to the study drug (S10 and S11 Tables in S1 Appendix).

Table 2

Results of multivariate risk factor models in women in the per-protocol population with microbiologically confirmed UTI.

	Clinical failure			Microbiological failure
Terms	Odds Ratio	95% CI	p-value	Odds Ratio	97.5% CI	p-value
Age [18;52.5]	Reference
Age [52.5;105]	3.01	1.84–4.98	<0.001	2.55	1.54–4.25	<0.001
Nitrofurantoin	Reference
Fosfomycin	2.35	1.47–3.8	<0.001	1.58	0.97–2.60	0.07
Centre (GE)	Reference
Centre (LO)	1.02	0.59–1.76	0.94	1.58	0.93–2.7	0.09
Centre (TA)	3.09	1.61–5.98	<0.001	0.61	0.25–1.38	0.25

In all women with positive baseline cultures (n = 352), the predominant isolates were E. coli (n = 204), mixed flora (n = 47), Klebsiella pneumoniae (n = 23), Proteus spp. (n = 13), and Gram-positive flora (n = 17). No significant variation was observed for these pathogens across different age categories (Fig 3). Co-pathogens were not considered in this analysis (n = 51). Seventeen (9%) women treated with nitrofurantoin and four (2%) treated with fosfomycin had resistant uropathogens; seven (41%) and four (50%) of these had clinical failure and six (35%) and one (25%) microbiologic failure. Among the 438 women with available outcomes data (85%) and a positive or negative baseline culture, age>52 years and treatment with fosfomycin remained significantly associated with clinical failure, while a negative baseline culture was protective (OR 0.23 [95%CI 0.11–0.44], S12 Table in S1 Appendix).

Fig 3

Bacterial population isolated from urinary culture among different age groups.

Among the 328 women with available day-14 and day-28 microbiologic and clinical outcomes data, 23 had clinical success but persistent or recurrent bacteriuria by day 14. Among these, only 4 (17%) would go on to experience clinical failure by day 28 (p = .26).

Discussion

Age > 52 years was a significant risk factor for clinical and microbiological failure in the overall cohort and in the subgroup of women with E. coli UTI. Although it remains significant, nitrofurantoin’s clinical superiority over fosfomycin through day 28 becomes less pronounced with patients’ increasing age. Other factors affecting clinical outcomes were treatment and recruitment site, the former confirming RCT findings and the latter reflecting variation among centres. Interestingly, diabetes was strongly associated with microbiological failure in univariate analysis, but not with clinical failure. Yet in adjusted analyses, the association with microbiologic failure was not retained. Among the 23 women with resolution of symptoms but persistent or recurrent bacteriuria on day 14, only 4 (17%) would proceed to clinical failure by day 28.

These findings are in line with those of Jorgensen et al., who found that age >65 years predicted a return visit to the emergency department in the 30 days following treatment for uncomplicated UTI [27], although this retrospective study relied upon coding for UTI diagnosis and included men and women. In a RCT comparing diclofenac to norfloxacin in 256 women with uncomplicated lower UTI, Kronenberg et al. [9] observed increased symptom resolution by day 3 and reduced need for later antibiotic therapy in women under 45 years, but differences were not statistically significant in this relatively small population.

The influence of age on persistence or relapse might be explained by several factors, including immunosenescence, with its gradual T-cell dysregulation and general deterioration of mucosal immunity [28], and probably by other pathways such as increased urinary stasis and post-menopausal change in the vaginal flora [29]. Considering both the risk of failure and the high incidence of symptomatic infections among elderly (12.8/100 patient years between 86–90 years) [30], this population should be considered carefully before delayed antibiotic therapy. The decline in nitrofurantoin’s clinical superiority over fosfomycin with increased age requires confirmation in future trials; it is likely multifactorial and may be due to reduced renal function and other pharmacokinetic factors in the elderly, such as reduced absorption [31].

Diabetes is generally associated with more frequent UTI, primarily through immunological impairment, neurogenic bladder, and increased bladder glucose concentration [32], but in our population it was not associated with a return of symptoms, perhaps reflecting compromised local sensorimotor pathways. The association between diabetes and microbiological failure was thus expected, with association between glycemic control and asymptomatic bacteriuria already observed elsewhere [33, 34].

An increased proportion of clinical (but not bacteriologic) failure was observed among Tel Aviv participants. This centre effect could be explained by the inclusion of women with more severe illness or by cultural differences in the self-reporting of symptoms, possibly generating a reporting bias, as observed elsewhere [35].

This study has limitations, chief among them its retrospective nature: data were limited to those collected in the RCT, with no information available on concurrent renal function, additional symptomatology, sexual activity and other behavioural practices, and duration of symptoms before inclusion. Its strengths are its international and relatively large population with a sizeable event rate, improving generalization of findings to other settings, as well as its regular microbiologic follow-up data even among asymptomatic participants.

Conclusions

Given rising antibiotic resistance and increasing use of delayed antibiotic prescription, the ability to identify early on patients at risk for failure is becoming ever more important. While they require confirmation in prospective studies, these results suggest that post-menopausal women with acute cystitis are at increased risk for treatment failure, though diabetic women are not. The low proportion of clinical failure among women with asymptomatic persistent or recurrent bacteriuria supports current recommendations to avoid treatment of asymptomatic bacteriuria (and thus surveillance cultures in general), even in those with recent symptomatic infection.

(DOCX)

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9 Jun 2021

PONE-D-21-14320

Risk factors for treatment failure in women with uncomplicated lower urinary tract infection

PLOS ONE

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Reviewer #1: The article has been well written and provides evidence for risk factors for clinical and microbiological failure of treatment in a relatively large population of women with lower UTI. However, you conclude that based on the result that postmenopausal age is a risk factor for treatment failure, this risk factor should be considered when considering delayed antibiotic therapy. I do not understand how you came to this part of the conclusion. In delayed antibiotic therapy you do not treat and you rely on spontaneous recovery within a week. In my opinion the risk in delayed therapy is that spontaneous recovery does not happen or that an upper UTI infection develops. Can you elaborate on your conclusion concerning delayed therapy?

Your study included hospitalized and ambulatory adult women with lower UTI symptoms. I expect delayed therapy to be applied only to ambulatory adult women. Do you know whether your conclusions also apply to ambulatory women only?

An ethical statement is missing.

It took me a lot of time to understand figure 1, comparing it with the numbers you mention in the Abstract and in Methods. I think it would help if you put all the main groups in the left column and the groups with clinical and microbiological failure on the right, together with the numbers of controls. In Figure 1 it seems like the 340 women with microbiologically confirmed UTI is divided into a group with clinical failure (126 and 214 controls?), a group with micromiological failure (102 with 220 controls) and women with E-coli related UTI (70 with 134 controls?) and 136 women with non-E.coli related UTI.

For the women with E.coli related UTI you only show the women with clinical failure (70 and 134 controls?) but you do not show the women with microbiological failure (71 and 128 controls?).

In the Abstract,section Methods you mention that controls were those who did not expoerience clin of microbiol failure. In lines 105 and 106 you mention that only women adhering to the RCT's protocol were included. I noticed that cases plus controls not always add up to the total number of women in a main group. In the Result section, I would expect a mention of how many cases or controls were missing because of this.

Line 195: 4 should be in line with the other numbers below 10.

Reviewer #2: This study assessed risk factors for clinical and microbiological failure in women with lower UTI via a case-control study nested within a randomized clinical trial. Postmenopausal age was an independent risk factor for clinical and microbiological treatment failure in women with lower UTI; diabetes was not associated with failure. The authors’ assessment of microbiological failure provides an understudied insight that would be of interest to a general urology and primary care audience.

Abstract and Introduction:

-Given that the authors are from Switzerland, it would be useful for them to identify (either in the abstract of Introduction) whether their cohort – and thus their recommendations – should apply to only a Switzerland demographic, or whether their research could extend outside (or not).

-Similarly, there is some evidence to suggest that women’s menopausal status may also impact of doctor’s choice of therapy and effects of that therapy. The authors do comment on this (and include age as a variable in their analyses), but a more thorough description of this would be useful in describing the demographic, as well as treatment failure (particularly as it relates to age).

Methods:

-The authors state that “only women adhering to the RCT’s protocol were included to avoid the problems of missing data/outcomes and non-adherence” – how many patients were excluded due to this? And was missing data quantified in any way? That is, did most of these patients with missing data have 1-2 missing data points vs. most of their data points missing? And did the demographics of excluded patients differ from those who were included?

-It’s unclear based on the author’s current description why a cutoff of 52 years was chosen and this could use further explanation, particularly given that it is critical to the main results and interpretation.

-What statistical analysis software was used?

Results:

-Although age was entered based on the 52.5 cutoff, it might be worth classifying women as pre-menopausal or post-menopausal and including that as a variable in the models, if that data was collected by the authors.

-Table 2 is quite helpful, but it would be useful to see the full models (all variables entered).

Discussion:

-The authors note that recruitment site (and variation among centres) impact clinical outcomes. Why was this the case? Additional explanation is needed for results to be interpretable.

-Given that the finding that diabetes was strongly associated with microbiological failure, more discussion should be included. Was this predicted/hypothesized? If yes, why or why not?

-When discussing limitations, the authors note that strength of their study was that it was multi-centre; however, these centres clearly varied (given recruitment site impacted outcomes). Why might that be more of a limitation? – the authors might want to discuss this a bit more.

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Reviewer #1: No

Reviewer #2: No

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29 Jun 2021

On behalf of the authors, we would like to thank the reviewers for their careful reading and valuable, in-depth comments. We provide point-by-point responses to specific reviewers and editor in the document attached and labelled "Response to Reviewers".

Furthermore, we have ensured that our manuscript meets PLOS ONE’s style requirements, and have made the minimal anonymized data set available to the best of our ability on Zenodo (https://zenodo.org/, DOI: 10.5281/zenodo.5024262). We used data collected from Geneva (Switzerland), Lodz (Poland), and Tel Aviv (Israel). By Swiss and Polish laws, there is no restriction to share anonymized information. However, the situation is more complicated for Israeli data. Additional approvals from both the Ethics Committee and the Data Privacy Committee would be required, and in the experience of our co-investigator, Prof. Leonard Leibovici, are unlikely to be granted, as his organization does not typically allow ‘placing its patients’ data into public view’, even when anonymized. We will thus be able to provide only the Swiss and Polish dataset; we hope that you will deem this sufficient. If individual researchers want to recycle the complete dataset, we will offer them to contact us any time to find an appropriate solution.

After inclusion of multiple details in the revised manuscript as requested by the reviewers, the MS length has increased to 2’172 words (text only), despite all attempts to shorten the main text.

Kind regards,

Romain Martischang

Submitted filename: Response to Reviewers.docx

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9 Aug 2021

Risk factors for treatment failure in women with uncomplicated lower urinary tract infection

PONE-D-21-14320R1

Dear Dr. Martischang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Justyna Gołębiewska

Academic Editor

PLOS ONE

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: (No Response)

Reviewer #2: Yes

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Reviewer #1: (No Response)

Reviewer #2: Yes

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Reviewer #1: (No Response)

Reviewer #2: Yes

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Reviewer #1: (No Response)

Reviewer #2: Yes

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Reviewer #1: (No Response)

Reviewer #2: The authors did a great job address reviewer comments and feedback. With these revisions, I recommend the manuscript be accepted for publication.

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Reviewer #1: No

Reviewer #2: No

13 Aug 2021

PONE-D-21-14320R1

Risk factors for treatment failure in women with uncomplicated lower urinary tract infection

Dear Dr. Martischang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Justyna Gołębiewska

Academic Editor

PLOS ONE