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Systematic Review

Adherence to recent antibiotic guidelines for acute uncomplicated cystitis

Amayun, Ira RN, BSN, MPH (FNP-DNP Student)1

Author Information
Journal of the American Association of Nurse Practitioners: November 2021 - Volume 33 - Issue 11 - p 879-885
doi: 10.1097/JXX.0000000000000526



Urinary tract infections (UTIs) are the most common outpatient infections seen in primary health care, with an overall annual cost of $1.6 billion in the United States (Medina & Castillo-Pino, 2019). However, the unnecessary use of antibiotics accounts for the increasing national and global prevalence of antibiotic resistance. Therefore, practice guidelines and research have aimed to reduce antibiotic use while effectively treating infections, such as UTIs.

In 2017, the Centers for Disease Control and Prevention (CDC) reviewed and published guidelines for prescribing antibiotics. These guidelines emphasized treating acute uncomplicated cystitis (AUC) with nitrofurantoin (NTF), sulfamethoxazole-trimethoprim (SMX-TMP; for which local resistance is <20%), or fosfomycin (FM) as appropriate first-line agents. Acute uncomplicated cystitis, or acute uncomplicated UTI (uUTI), is usually caused by Escherichia coli. Symptoms include dysuria, frequent voiding of small volumes, and urinary urgency, whereas nitrites and leukocyte esterase in urinalysis are the most accurate indicators of AUC (CDC, 2017). This study aimed to evaluate whether provider adherence to prescribing NTF, SMX-TMP, or FM has improved since the 2017 CDC guidelines were released and to evaluate patient outcomes relative to prescription adherence in the treatment of AUC.


Search strategy

A literature review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, and a systematic search for articles was conducted in the PubMed and Cochrane search engines using Boolean operators (AND, OR). The inclusion criteria included articles that were published between 2017 and 2020, had text in English, and were peer-reviewed. The search terms “first-line antibiotics AND acute uncomplicated cystitis OR uncomplicated urinary tract infection” and “prescription adherence AND first-line antibiotics AND acute uncomplicated cystitis OR uncomplicated urinary tract infection” were initially used. The search terms were then modified to “outcomes AND first-line antibiotics AND acute uncomplicated cystitis OR uncomplicated urinary tract infection.” The search terms resulted in 15 publications from 2017 to 2020 from both the PubMed and the Cochrane databases. Additional search terms were “nitrofurantoin AND cystitis,” “fosfomycin AND cystitis,” and “sulfamethoxazole-trimethoprim AND cystitis.”

Data items

Prescriber adherence was measured based on the practitioners' decision to treat AUC with the first-line antibiotics FM, SMX-TMP, or NTF in accordance with the Infectious Disease Society of America (IDSA) 2011 guidelines that were reviewed and publicized by the CDC in 2017. Acute uncomplicated cystitis patient outcomes were measured with improved or complete resolution of symptoms and/or microbiological response 28 days posttreatment at the most. As mentioned above, classic symptoms of AUC include dysuria, frequent voiding of small volumes, and urinary urgency, whereas nitrites and leukocyte esterase are the most accurate indicators in urinalysis. Microbiological response is defined as reduced bacterial pathogens in a quantitative urine culture at the test-of-cure visit posttreatment.

Risk of bias

The Cochrane Risk of Bias Tool (2020) was used to assess publication bias (Table 1, Supplemental Digital Content, Of the 11 publications, 9 had a low risk of bias, 3 of which had some concerns with randomization. One publication had some concerning risk for bias due to lack of identification and measurement of comparable antibiotics. The quasi-experimental study had some concerning risk for bias because of possible overlapping interventions.

Summary measurements

The primary outcome measurement was adherence to appropriate prescription of first-line antibiotics for the treatment of AUC, as opposed to prescription of fluoroquinolones (FQ) and β-lactams. Clinicians did not meet adherence if a first-line antibiotic was not prescribed in the absence of contraindication that the patient did not meet the criteria for first-line antibiotic treatment. The secondary outcome measurement was the patients' outcome as a result of prescribing first-line antibiotics, whether improvement or complete resolution of symptoms and bacterial eradication in urinalysis. Cost-effectiveness was also an outcome measurement that included monetary factors and/or quality-adjusted life-months (QALMs).

Critical appraisal tool

The John Hopkins Research Evidence Appraisal Tool (John Hopkins Nursing, 2017) was used to grade the articles (Table 2, Supplemental Digital Content, High-quality, good-quality, and low-quality ratings were used. Studies with consistent results, a sufficient sample size, a definitive conclusion, and consistent recommendations with thorough references to scientific evidence were graded as having high quality. Studies with reasonably consistent results, a sufficient sample size, an acceptably definitive conclusion, and reasonably consistent recommendations with some references to scientific proof were graded as having good quality. Studies with limited evidence, inconsistent results, a small sample size, and a vague conclusion were graded as having low quality. Table 3 (Supplemental Digital Content, provides a synthesis of each publication. The design, study sample, and major findings of each article were identified for their utility in the review of evidence.


The literature searches in the PubMed and Cochrane databases resulted in 56 published studies (Figure 1). After the initial review, 19 duplicates were excluded. Additionally, 18 other publications were excluded, most of which included information on complicated UTI and pregnant women. Subsequent reviews further excluded 8 publications that were ineligible to meet the objectives. After exclusions, 11 peer-reviewed articles were included in the review: 10 quantitative studies and 1 qualitative study. Of these, one trial (Huttner et al., 2018), two systematic reviews and meta-analyses (Cai et al., 2020; Mitrani-Gold et al., 2020), and one retrospective study (Pedela et al., 2017) assessed bacterial eradication and treatment of clinical symptoms with NTF, FM, SMX-TMP, FQ, and β-lactams. Two meta-analyses (Perrault et al., 2017; Sadler et al., 2017) and one prospective study (Sanyal et al., 2019) assessed the cost-effectiveness of treating AUC with SMX-TMP, NTF, FM, and pivmecillinam. Finally, one trial (Robinson et al., 2020), two retrospective studies (Pedela et al., 2017; Yu et al., 2020), one quasi-experimental study (Giancola et al., 2020), and one semi-structured interview (Grigoryan et al., 2019) assessed clinicians' adherence to prescribing first-line antibiotics (NTF, FM, and SMX-TMP) to treat AUC.

Figure 1.
Figure 1.:
Reviews based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis diagram. MDR = multidrug resistant.

Study demographics

All individuals and cases included in the 11 studies in this review met the criteria for AUC. Not all studies included were limited to females, but majority of their populations were female. For example, the study populations included in 8 of the 11 studies (Cai et al., 2020; Giancola et al., 2020; Huttner et al., 2018; Mitrani-Gold et al., 2020; Perrault et al., 2017; Robinson et al., 2020; Sadler et al., 2017; Sanyal et al., 2019) were nonpregnant women 18 years and older. The Medicare Part B enrollees included in the retrospective cohort study performed by Yu et al. (2020) were stratified by gender, and the majority (81.2%) were female. The retrospective preintervention/postintervention study done by Pedela et al. (2017) predominantly included women 18–89 years old. A case of a 44-year-old woman with AUC was the sample scenario used in the semi-structured interview conducted in the qualitative study by Grigoryan et al. (2019).

Prescriber adherence

Robinson et al. (2020) evaluated the appropriateness of empiric FQ use compared with NTF use for treating AUC and determined trends and predictors for the use of FQ. Women aged 19–64 years who were given NTF, ciprofloxacin, or levofloxacin for AUC at 5 family medicine clinics were included in the study. Data concerning symptoms, comorbidities, allergies, creatinine clearance, recent antibiotic use, and urine cultures were used to determine whether empiric antibiotic treatment was appropriate based on national guidelines and local susceptibility data. Of the 567 women included in the study, 395 were given NTF and 172 were given FQ. Of these, 343 (86.8%) and 18 (10.5%) were appropriately prescribed NTF and FQ, respectively. For women inappropriately prescribed FQ, 15 (87.8%) lacked contraindication to NTF. Therefore, the study suggested the need for additional intervention and education to improve and decrease the use of FQ.

Yu et al. (2020) aimed to track and report outpatient antibiotic prescriptions in Medicare Part B older adult enrollees diagnosed with cystitis in an outpatient setting between 2016 and 2017 in New York State (NYS). The inclusion criteria included an oral antibiotic prescription less than 3 days after diagnosis of cystitis in Part D claims. According to the retrospective cohort study, 50,658 prescriptions were written on discharge diagnosis of cystitis in NYS from 2016 to 2017. First-line antibiotic prescriptions of NTF, SMX-TMP, and FM increased, along with β-lactamase prescriptions, and FQ use decreased in both older female and male adults. The study suggested that the widespread prevalence of FQ and β-lactamase prescriptions requires outpatient antimicrobial stewardship.

Giancola et al. (2020) conducted a quasi-experimental study that included women aged 18–64 years who were prescribed NTF, SMX-TMP, or ciprofloxacin within 7 days of encounter at 5 family medicine clinics. Adherence to duration of treatment (DOT) based on IDSA (2011) guidelines was evaluated. Stewardship intervention included revising/adding default prescription instructions to targeted antimicrobials in an electronic health record (EHR) and a one-day in-service at two (intervention group) of the five clinics. A total of 787 preintervention patients were compared with 862 postintervention patients. After intervention, the adherence rate to the recommended DOT increased from 31% to 89% for NTF and from 22% to 60% for SMX-TMP. Additionally, adherence to recommended DOT increased in clinics that received education (33.7% vs. 90.2%; p < .01); these clinics increased adherence from 22.1% to 58.8% (p < .01). Revising or adding default prescription instructions and their DOT to targeted antimicrobials in an EHR and providing clinician in-service also increased adherence to first-line antibiotic DOT guidelines.

Pedela et al. (2017) evaluated changes in outpatient FQ and NFT use and resistance among E. coli isolates after a change in institutional guidance that stipulated using NFT over FQ for AUC. The study compared the period from January 2003 to June 2007, when FQ were recommended as a first-line therapy for acute uUTIs, with the period from July 2007 to December 2012, when NTF was recommended as the first-line therapy. The retrospective time series study included 5,714 adults treated for AUC and 11,367 outpatient E. coli isolates. After the change in institutional guidelines, FQ use showed an immediate 26% reduction, and FQ-resistant E. coli were stabilized. The use of NTF increased without changing NTF resistance.

Grigoryan et al. (2019) sought to understand why primary care providers (PCPs) choose certain antibiotics or durations of treatment and to identify the sources of information guiding antibiotic prescription decisions. The study conducted a semi-structured interview with 18 PCPs in 2 family medicine clinics in Texas. Most PCPs reported that they prescribed SMX-TMP or NTF, but sometimes for a longer duration than recommended by the IDSA (2011). The PCPs also described multiple considerations when prescribing antibiotics, including allergies, sex, pregnancy, older age, past antibiotic experience and susceptibilities, familiarity with the antibiotic, shorter treatment duration and better compliance, UTI frequency, diabetes, and cost. Many PCPs mentioned that NTF was not as “strong” or as “quick” as SMX-TMP, and most were unfamiliar with FM. Few PCPs relied directly on guidelines to treat uUTIs; only two recalled and mentioned the IDSA (2011) guidelines. Additionally, the PCPs had widely differing opinions on the extent to which antibiotic resistance was a problem in their practice.

Bacterial eradication and symptoms resolution

A retrospective preintervention/postintervention study by Pedela et al. (2017) concluded that, with the immediate 26% reduction in FQ use from July 2007 to December 2012, FQ-resistant E. coli stabilized. Additionally, the nonsignificant increase in NTF use did not change the pattern of NTF-resistant E. coli. The use of oral cephalosporin, which is not a first-line antibiotic for AUC, also increased during the postintervention period.

Huttner et al. (2018) compared the clinical and microbiological efficacy of NTF and FM for treating AUC in women. Their multinational, open-label, analyst-blinded, randomized clinical trial examined 513 women aged 18 years and older with symptoms of AUC. The participants were recruited at hospital and outpatient units in Geneva, Switzerland, from October 2013 to April 2017. Of the participants, 255 were randomized to take oral NTF in doses of 100 mg 3 times daily for 5 days, whereas 258 were randomized to take FM in a single 3-g dose. Of these participants, 475 (93%) completed the trial and returned 14 and 28 days after therapy. At 28 days, 171 of 244 (70%) of the NTF group and 139 of 241 (58%) of the FM group achieved clinical resolution. Microbiologic resolution occurred in 129 of 175 (74%) and 103 of 163 (63%) in the NTF and FM groups, respectively. The study concluded that the 5-day NTF treatment had significantly higher clinical and microbiological resolution than single-dose FM treatment, with a few adverse gastrointestinal events of nausea and vomiting for both groups. The study did not refer to local antibiotic resistance data and did not include information on treatment with SMX-TMP.

Cai et al. (2020) performed a systematic review and meta-analysis to compare the effectiveness and safety profile, or adverse effects, of FM to those of SMX-TMP, NTF, FQ, and β-lactams in women with AUC. The study included 15 random controlled trials (RCTs) and 2,295 adults. Of the studies, 14 that examined a total of 2,052 patients found no difference for microbial eradication (odds ratio [OR] 1.03, 95% confidence interval [CI] 0.83–1.30, p = .09). No difference for safety outcomes was found in 11 RCTs with a total of 1,816 patients (OR 1.17, 95% CI 0.86–1.58, p = .33). FM was associated with high patient compliance and was as effective and safe as SMX-TMP, NTF, FQ, and β-lactams in the treatment of AUC. The study did not mention local antibiotic resistance.

Mitrani-Gold et al. (2020) conducted a systemic literature review and meta-analysis to estimate the treatment effect of NTF. Their analysis included 12 studies, including 11 trials. The study estimated the microbiological response rate for NTF and placebo treatments through cross-trial comparison and interstudy. Heterogeneity was assessed using Cochran's chi-square test. Microbiological response was defined as the reduction of bacterial pathogens to 103 colony-forming unit/ml (or no growth) in the microbial intent-to-treat population on a quantitative urine culture at the test-of-cure visit, 5–9 days posttreatment. The overall microbiological response, with a 95% CI, was 0.766 (0.665–0.867) for NTF and 0.342 (0.288–0.397) for the placebo. Therefore, NTF was effective in the treatment of uUTIs with a conservative noninferiority margin of 12.5%, which was consistent with the April 2018 FDA guidance that showed a noninferiority margin of 10% (U.S. Food and Drug Administration, 2019). The study did not assess SMX-TMP and FM for their microbiological response rate.


Perrault et al. (2017) performed cost-minimization analysis using a decision tree model to compare the cost of treatment per patient in Ontario, Canada. As an option for first-line empirical treatment of uUTIs, the cost of FM was compared with the current cost of treatment with sulfonamides, FQ, and NTF. All four antibiotics were found to be equally cost-effective.

Sadler et al. (2017) assessed the relative cost-effectiveness of SMX-TMP, FM, NTF, and pivmecillinam, which are currently recommended in England for treatment of uUTIs in adult women. Cost-effectiveness was assessed as cost per resolved UTI. The study aimed to guide clinicians in their empirical prescribing choice based on cost-effectiveness and local resistance levels. Actual prescribing practices varied between local areas. Nitrofurantoin was prescribed more than 2.3 million times in 2015. Additionally, prescribing SMX-TMP was still common despite evidence of high local resistance. The following treatments were the most effective for resolution (approx. 850 cases resolved per 1,000) and had the lowest total cost: trimethoprim given in a 200-mg dose twice daily for 7 days, FM given in a single 3-g dose, and NTF given in a 100-mg dose twice daily for 7 days. Trimethoprim was estimated to be the most cost-effective treatment when resistance was <30%. If resistance to trimethoprim was >30%, then FM and NTF were the most cost-effective. These three antibiotics had the lowest total cost.

Sanyal et al. (2019) calculated the costs of antibiotic treatment and health services based on cost data from Canada. A probabilistic analysis was used to evaluate the impact of treatment strategies on costs and QALMs. Management of uUTIs by community pharmacists in Canada resulted in high cure rates and a high degree of patient satisfaction. Using prescribing guidelines, community pharmacists in New Brunswick, Canada, prescribed NTF, SMX-TMP, and FM in 88%, 8%, and 2% of cases, respectively, whereas physicians prescribed NTF, SMX-TMP, and FM in 55%, 26%, and 2% of cases, respectively. All patients were assumed to achieve resolution of symptoms in 1 month, including those who received a second round of treatment. The mean costs of community pharmacist, family physician, and emergency physician–initiated management were $72.47, $141.53, and $368.16, respectively. The mean QALMs of pharmacist, family physician, and emergency physician–initiated management were 0.75137, 0.75142, and 0.75146, respectively. Therefore, the community pharmacist–initiated and -guided management was less costly and provided comparable QALMs compared with that initiated by family and emergency physicians when prescribing NTF, SMX-TMP, or FM to treat uUTIs.


Summary of evidence

All 11 studies, which included trials, systemic reviews and meta-analyses, retrospective studies, a quasi-experimental study, and a semi-structured interview study, were high quality and presented strong evidence of their findings. The 10 quantitative studies used robust statistical analysis to measure outcomes. Sadler et al. (2017) and Perrault et al. (2017) assessed cost-effectiveness with reference to local antibiotic resistance levels. Robinson et al. (2020),Giancola et al. (2020), and Pedela et al. (2017) assessed prescription adherence with reference to local antibiotic resistance. Giancola et al. (2020) assessed prescriber adherence with reference to IDSA (2011) guidelines for DOT and local antibiotic resistance. No bias secondary to funding was found.

The 2 systematic reviews and meta-analyses, 1 trial, and 1 retrospective study (Cai et al., 2020; Huttner et al., 2018; Mitrani-Gold et al., 2020; Pedela et al., 2017) concluded that FM, SMX-TMP, and NTF were equally effective for microbiological and symptom resolution of AUC 9–28 days after treatment. Fosfomycin trometamol was associated with high patient compliance. Trimethoprim, FM, and NTF had the lowest total cost. Sulfamethoxazole-trimethoprim was estimated to be the most cost-effective treatment when local resistance was <30%. If resistance to SMX-TMP was >30%, a single 3-g dose of FM or a twice-daily, 100-mg dose of NTF for 7 days was the most cost-effective treatment. The uUTI management guided by community pharmacists in Canada yielded high cure rates, lower costs, and comparable QALMs compared with management guided by family and emergency physicians when prescribing NTF, SMX-TMP, or FM (Sanyal et al., 2019).

Of the 11 publications, 5 showed that lack of institutional guidelines yielded poor adherence in prescribing first-line antibiotics to treat AUC. The qualitative study suggested that few providers rely on the IDSA (2011) guidelines to treat uUTIs, and most providers described multiple factors in their decision-making when prescribing antibiotics, such as age, past antibiotic experience, shorter treatment, and familiarity with antibiotics. The FQ study by Robinson et al. (2020) stated that the percentage of women (87.8%) who were inappropriately prescribed FQ had a lack of contraindication to NTF. According to Giancola et al. (2020), revising or adding EHR default prescription instructions and their DOT increased adherence to first-line antibiotic prescriptions, along with clinician in-service. The study by Yu et al. (2020) tracked NYS adherence to CDC guidelines concerning the use of first-line antibiotics. Although the study reported increased prescriptions of first-line antibiotics and β-lactams and decreased use of FQ, the study did not mention whether prescribers used institutional guidelines to determine their choice of antibiotics.


This article included peer-reviewed studies from 2017 to February 2020, but there have been limited publications since the CDC released its review of the IDSA (2011) AUC treatment guidelines. Additionally, although published in or after 2017, 4 of the studies included in this article were retrospective, measuring data from before 2017. Finally, the studies reviewed in this article assessed bacterial and symptom resolutions at 9–28 days posttreatment at the most.


Since the 2017 CDC AUC treatment guidelines were released, not enough studies have been performed to assess increased prescriber adherence to using first-line antibiotics in the treatment of AUC. Additionally, the searched studies predominantly included women. Of the 11 studies included in this article, 10 showed the prescribers' increasing awareness of and efforts to adhere to antibiotic prescription guidelines, such as the 2011 IDSA guidelines that were reviewed and published by the CDC in 2017. In addition to the increasing pattern of adherence, the trials, systematic reviews, and meta-analyses in this study presented strong evidence that first-line antibiotics FM, NTF, and SMX-TMP are equally cost-effective and efficacious in the treatment of AUC without concern for antibiotic resistance. Studies that referenced prescription guidelines in the use of first-line antibiotics and local antibiotic resistance yielded desired patient outcomes in bacterial and symptom resolution and cost-effectiveness.

Implications for practice

This article provides evidence and a platform for nurse practitioners to initiate a collaborative effort toward structured AUC treatment guidelines in primary health care. To increase prescription adherence, EHRs could be designed that would prompt prescribers to use regularly updated local antibiotic resistance information and to prescribe NTF, SMX-TMP, and FM as first-line agents. This article suggests further studies to evaluate treatment outcomes using first-line agents NTF, SMX-TMP, and FM for AUC in males and AUC in the presence of comorbidities, such as older age and diabetes.


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Acute uncomplicated cystitis; first-line agents; prescriber adherence; treatment guidelines

Supplemental Digital Content

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