Davis-Lopez, Heather

English

LynchburgCollege: Digital Showcase

INTRODUCTIONA middle-aged female arrives at a busy urgent care complaining of dysuria, increased urinary frequency, and urinary urgency for the last two days. Since approximately two-fifths of women develop a urinary tract infection (UTI) in their lifetime,1 an uncomplicated urinary tract infection (UTI) is likely at the top of the differential diagnosis based on this patient’s presentation. Uncomplicated urinary tract infections (UTIs) are common diagnoses throughout medical specialties, including emergency medicine, family medicine, and urgent care. Uncomplicated UTIs are identified as they occur in patients without comorbidities and structural abnormalities.1 For example, Escherichia coli (E. coli) is one of the most common organisms that can cause uncomplicated UTIs in women. While medical guidelines suggest treating most uncomplicated UTIs with empiric antibiotics, common bacteria have become resistant to these antibiotics and therefore become fruitless in battling this infection. Though treating UTIs is based on limited testing in the clinic, such as a dipstick urinalysis, it is important that further testing is performed to determine which bacteria is causing the infection and determine if antibiotic resistance is present. A study by Trautner and Associates found that 20% of patients who received empiric antibiotics had to receive a secondary antibiotic within 28 days due to the bacteria being resistant to the initial treatment.2 It is imperative that the infection be eradicated to prevent further infection, such as renal impairment.3  Given these concerning findings, this review article aims to assess antibiotic resistance associated with uncomplicated UTIs and determine if the current guidelines for empiric antibiotic treatment need to be updated to combat this infection successfully. BACKGROUNDDiagnosis and Differentiation Urinary tract infections (UTIs) can be differentiated into two different categories- uncomplicated and complicated. Uncomplicated UTIs, commonly referred to as cystitis, typically occur in patients who do not have anatomical abnormalities or comorbidities, including diabetes, pregnancy, and other immunocompromised states.1 For example, symptomatology commonly associated with uncomplicated UTIs, includes dysuria, increased urinary frequency, urinary urgency, and suprapubic tenderness.1 On the other hand, complicated UTIs occur in those who are male, immunocompromised, and possess comorbidities.4 Complicated UTIs are also associated with fever, nephrolithiasis, sepsis, urinary obstruction, pyelonephritis, and UTIs associated with catheters.4 Box 1 highlights the differences between uncomplicated and complicated UTIs.  	In order to diagnose a UTI, a good urine sample is needed from the patient to run a dipstick urinalysis (UA). This is best obtained by collecting a sample of a clean catch of midstream urine.1,4 Typically with uncomplicated UTIs, leukocyte esterase, nitrites, and blood are typical positive findings on the dipstick UA.1 While dipstick UAs are helpful with the initial diagnosis of a UTI, performing a urine culture is what helps to determine whether the causative organism is resistant to the antibiotics prescribed. TreatmentFourth-fifths of uncomplicated UTIs are caused by E. coli.5 Recommendations currently suggest treating uncomplicated UTIs empirically with antibiotics such as nitrofurantoin, fosfomycin, trimethoprim/sulfamethoxazole, cephalosporins, and fluoroquinolones.1,5,6 While E. coli is a common agent with UTIs, over the years there has been an increase in antibiotic resistance associated with some of these first-line medications. METHODSPubMed was the primary database used to gather resources. To further narrow the search for relevant articles, medical subject headings (MeSH) were used. Summary of SearchThe search was conducted on PubMed with MeSH terms of “urinary tract infection” and “antibiotic resistance.” Secondary searches using filters for “Therapy” were also conducted. In total, 610 publications resulted that had been published between 2018 and 2023. The search was then narrowed to include publications containing meta-analysis, randomized controlled trials (RCT), and systematic reviews. This narrowed the search to 39 publications. Five of the articles were reviewed further and analyzed for the purpose of this study. DISCUSSIONCurrent recommendations encourage the use of empiric treatment for uncomplicated UTIs by prescribing medications to help combat such as nitrofurantoin, trimethoprim/sulfamethoxazole, cephalexin, and fluoroquinolones, which are discussed in Box 2.1,2,5,6 While these medications have been long-standing recommendations for the treatment of uncomplicated UTIs, from 2003 - 2012, E. coli had an increase in resistance to both nitrofurantoin and trimethoprim/sulfamethoxazole.7 Furthermore, with the current new age of antibiotic resistance, a study by Traunter et al.,2 showed that approximately one-fifth of patients who were prescribed one of the above medications needed a newly prescribed medication within 28 days of their visit, and 20% of uncomplicated UTIs are caused by infectious organisms that are not susceptible to initial empiric antibiotics that are prescribed.2 Moreover, patients whose urine culture grew a resistant organism to the initial empiric antibiotic were 60% more likely to need a new antibiotic within 28 days of their initial visit.2  However, almost three-fourths of patients whose urine cultures grew isolates that were resistant to the initial antibiotic did not require a new medication.2 This is likely to be believed due to the uncomplicated UTI being self-limited or perhaps there being an elevated concentration of medication within the urine may be adequate to overcome the bacterial resistance.2 Although a current population is solely affected by an uncomplicated UTI, providers must still be vigilant in knowing that antibiotic resistance is on the rise. As stated previously, one-fifth of patients will need a new antibiotic to treat their infection within 28 days of their initial visit.2 One of the goals of treating uncomplicated UTIs empirically is to prevent further progression of infection, providers should strive to select a medication that will minimize the use of broad-spectrum antibiotics and avoid future increasing rates of resistance.6 While uncomplicated UTIs are not severe initially, they can rapidly progress toward more severe disease. Due to this, initial treatment for uncomplicated UTIs is frequently experimental and the choice of empiric therapy depends on presenting factors like severity of presenting symptoms, drug toxicity/side effects, and the effectiveness of the medication.3 This section will take a deeper dive into a few of the recommended antibiotics, and discuss the level of resistance of E. coli to the medications. NitrofurantoinNitrofurantoin is an antibiotic specifically utilized to treat UTIs. This medication has been used as a first-line treatment for uncomplicated UTIs for an extended period of time. As previously stated, E. coli resistance rates with nitrofurantoin had increased from 2003 - 2012.7 Yet, this medication continues to have a low resistance worldwide at approximately 18%,3,5 and appears to have a high sensitivity rate, greater than 80%, when used for treatment against E. coli.3 It is important to note that nitrofurantoin has poor tissue concentration and therefore primarily works in the lower urinary tract, which is perfect for uncomplicated UTIs.1 Therefore, the medication should not be used if there is suspected pyelonephritis.1 Due to nitrofurantoin's low resistance rates and high sensitivity, this medication should still be recommended as a first-line medication for the treatment of uncomplicated UTIs. Cephalosporins First, second, and third generations of cephalosporins can be used in the empiric treatment of an uncomplicated UTI. However, when cephalexin, a first-generation cephalosporin is used, a study by Mortazavi et al., determined that E. coli had a resistance rate of 61%.3 Third-generation cephalosporins typically have a low resistance to organisms that cause UTI, and in Romania have a susceptibility greater than 80%.5 However, it is important to note that third-generation cephalosporins are one of the most common medications used to treat a variety of infections, and therefore, resistance to this medication has been increasing.3 Based on this, first-generation cephalosporins should be avoided in empiric treatment of uncomplicated UTIs, and the use of third-generation cephalosporins should be used with caution. Trimethoprim/SulfamethoxazoleE. coli has been associated with a high level of resistance to Trimethoprim/sulfamethoxazole. It is estimated that E. coli has a resistance of approximately 20 - 64% when treating uncomplicated UTIs empirically with trimethoprim/sulfamethoxazole.3,5 Patients whose urine cultures showed resistance to this medication after being on treatment empirically are more likely to have significant bacteriuria approximately 1 month after receiving the medication initially.2 Due to E. coli’s high level of resistance to trimethoprim/sulfamethoxazole, it is not recommended to use this medication as a first-line treatment in uncomplicated UTIs. However, if E. coli resistance rates are below 20% for the region, trimethoprim/sulfamethoxazole may be used as an alternative medication, but not as a first-line.1 FluoroquinolonesFluoroquinolones are used to treat many illnesses, including uncomplicated UTIs. However, it is important to note these medications have a resistance rate of 20 - 28% when combating uncomplicated UTIs caused by E. coli.3,5 While resistance is increasing worldwide, ciprofloxacin specifically has been associated with multidrug resistance.5 With telemedicine being an up-and-coming way to help treat patients for a variety of illnesses, it is likely that this multidrug resistance will continue to increase, especially as there is no ability to perform a urine culture via telemedicine unless a patient provides a urine sample within the clinic.6 The current European and United States guidelines suggest that fluoroquinolones be reserved for treating UTIs when there are no alternative options, yet, this medication is prescribed to approximately two-fifths of women who present to the emergency department with an uncomplicated UTI.6 Coincidently, in 2016 and 2018, a black box warning was issued to not use this family of medications when treating a UTI,6 yet providers continue to do so. It is clear, based on the information listed above, that fluoroquinolones should be avoided as a first-line medication in the empiric treatment of an uncomplicated UTI.  Fosfomycin Fosfomycin is also considered an “older” drug when it comes to the treatment of uncomplicated UTIs. E. coli typically has a low resistance rate with fosfomycin, and most strains of the bacteria have been shown to be susceptible to the medication.5 Fosfomycin has been approved as a one-time dose by the FDA and is effective when other medications are associated with significant resistance.1 With this, a benefit of the one-time dose has not only improved adherence rates but also the medication has high urinary concentrations for 2 to 4 days.1 While resistance with E. coli against fosfomycin remains low, it has been noted that this medication is considered weaker than other first-line medications and should therefore be avoided if the provider suspects early or potential pyelonephritis.5 AminoglycosidesSimilar to Fosfomycin, Aminoglycosides are also considered “older” medications and have been used in the past to treat uncomplicated UTIs. Common medications from this drug family for the treatment of UTIs include gentamicin and amikacin. Amikacin has been shown to have a resistance rate of approximately 20% with E. coli, yet a study conducted in Europe and North America showed a sensitivity rate of 97 - 98%.3 On the other hand, the same study concluded that Gentamicin was shown to high a higher resistance rate of greater than 30%.3 Typically with the treatment of uncomplicated UTIs, the adherence rate of taking medications as prescribed is approximately 60%.7 Herein lies a benefit of taking aminoglycosides, as a one-time dose can be effective in the treatment of an uncomplicated UTI, therefore decreasing poor adherence rates. At that, greater than 80% of patients who are treated with aminoglycosides have no recurrent infection within 30 days.7 These medications have good penetration into the bacterial cell wall,3 yet have been associated with serious adverse effects such as nephrotoxicity, hearing loss, and vestibular toxicity.7 Therefore, it is suggested that these medications be used with caution, and perhaps waiting to use them until urine culture has resulted.3CONCLUSIONCurrent guidelines recommend treating uncomplicated UTIs with empiric antibiotics. The antibiotics frequently recommended for empiric treatment of uncomplicated UTIs caused by E. coli include nitrofurantoin, fosfomycin, trimethoprim/sulfamethoxazole, and fluoroquinolones.1,5,6 A review of the literature has shown that there has been an increase in antibiotic resistance especially in association with fluoroquinolones and trimethoprim/sulfamethoxazole.5,6 Nitrofurantoin has continued to have low resistance rates worldwide,5 and should still be considered as first-line therapy in the empiric treatment of uncomplicated UTIs. Yet there may be other options, newer research has concluded that both fosfomycin and aminoglycosides may be alternative options for empirically treating this disease. In order to determine if the uropathogen is resistant to the empiric antibiotic, a urine culture must be obtained to determine the susceptibility, which will result in properly treating uncomplicated UTIs. Ultimately, healthcare providers need to be up to date with the current guidelines regarding the treatment of uncomplicated UTIs and should be aware of the growing antibiotic resistance associated with these empiric antibiotics. There is still a great deal of research to be completed in assessing if there are new alternatives to first-line antibiotic therapies, as well as if there are new technologies in determining uropathogenic resistance.ReferencesBono MJ, Leslie SW, Reygaert WC. Urinary Tract Infection. StatPearls.2023. Accessed October 8, 2023. http://www.ncbi.nlm.nih.gov/books/NBK470195/ Trautner BW, Kaye KS, Gupta V, et al. Risk Factors Associated With Antimicrobial Resistance and Adverse Short-Term Health Outcomes Among Adult and Adolescent Female Outpatients With Uncomplicated Urinary Tract Infection. Open Forum Infect Dis. 2022;9(12):ofac623. doi:10.1093/ofid/ofac623 Mortazavi-Tabatabaei SAR, Ghaderkhani J, Nazari A, Sayehmiri K, Sayehmiri F, Pakzad I. Pattern of Antibacterial Resistance in Urinary Tract Infections: A Systematic Review and Meta-analysis. Int J Prev Med. 2019;10:169. doi:10.4103/ijpvm.IJPVM_419_17 Sabih A, Leslie SW. Complicated Urinary Tract Infections. StatPearls. 2023. Accessed November 3, 2023. http://www.ncbi.nlm.nih.gov/books/NBK436013/ Kot B. Antibiotic Resistance Among Uropathogenic. Polish Journal of Microbiology. 2019;68(4):403-415. doi:10.33073/pjm-2019-048 Stapleton AE, Wagenlehner FME, Mulgirigama A, Twynholm M. Escherichia coli Resistance to Fluoroquinolones in Community-Acquired Uncomplicated Urinary Tract Infection in Women: a Systematic Review. Antimicrob Agents Chemother. 2020;64(10):e00862-20. doi:10.1128/AAC.00862-20 Goodlet KJ, Benhalima FZ, Nailor MD. A Systematic Review of Single-Dose Aminoglycoside Therapy for Urinary Tract Infection: Is It Time To Resurrect an Old Strategy? Antimicrob Agents Chemother. 2019;63(1):e02165-18. doi:10.1128/AAC.02165-18

Urinary Tract Infections and Antibiotic Resistance

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Urinary Tract Infections and Antibiotic Resistance

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