Failure Rate of Oral Nitrofurantoin in Treating UTIs caused by ESBL-Producing Escherichia coli and Klebsiella pneumoniae : A Retrospective Cohort Study

Introduction

Urinary tract infections (UTIs) have a very high prevalence, being the second-most common infec- tious disease and affecting more than 150 million people worldwide annually [1]. UTIs continue to place a significant burden on the healthcare system in the Kingdom of Saudi Arabia (KSA), accounting for approximately 10% of all infections and repre- senting the second-most common reason for emer- gency department visits [2]. An issue of growing concern is the rising prevalence of UTIs caused by extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) and Klebsiella pneu- moniae (ESBL-KP) [3].

Extended-spectrum beta-lactamases (ESBLs) are enzymes that confer resistance to most beta-lactam antibiotics, including penicillins, cephalosporins, and the monobactam aztreonam [4]. A seven year surveillance in China found that 27% of Klebsiella urinary isolates were ESBL ‐ positive and showed high multidrug resistance [5]. Globally, ESBL-pro- ducing Enterobacteriaceae are responsible for nearly 40% of community-acquired UTIs in some regions, representing a major challenge to oral ther- apy selection [6]. Risk factors for infections caused by ESBL-pro- ducing uropathogens include recurrent UTIs, vesicoureteral reflux, prior antibiotic exposure, younger age, and infection with Klebsiella species [7]. While there are many available options for treating UTIs, including both intravenous and oral agents, limited options exist for those caused by ESBL-producing organisms, due to their high re- sistance. In a Saudi cohort (n=137 UTIs), resistance

to nitrofurantoin and fosfomycin was approxi- mately 20% and 23%, respectively; both drugs out- performing TMP–SMX (resistance ~43%) [8]. In a 2018 Indian study of 464 ESBL-UTIs-positive urine samples, fosfomycin appeared to be a prom- ising oral treatment option, showing 93% and 57% sensitivity against ESBL-EC and ESBL-KP, re- spectively [9,10]. Moreover, fosfomycin main- tained ≥94 susceptibility in a study conducted in Pakistan [11]. Nitrofurantoin may also serve as an alternative for treating uncomplicated UTIs caused by ESBL-EC [9]. Globally, meta-analyses have re- ported clinical cure rates between 79–92% for ni- trofurantoin in uncomplicated lower UTIs [12]. Another study reported clinical cure rates of 69% in patients with ESBL-EC cystitis [13]. Further evidence, from a study in Taiwan evaluat- ing the susceptibility of seven antimicrobial agents, found that nitrofurantoin had a susceptibility rate of approximately 80% against ESBL-EC isolates, but only 13.6% against ESBL-KP isolates [14]. In a re- cent Korean study analysing 117 ESBL-positive urine isolates, nitrofurantoin susceptibility was high in E. coli (96.3%) but low in K. pneumoniae (33%) [15]. Despite extensive research, a history of ESBL in- fection remains one of the strongest predictors for hospitalization, regardless of the patient's clinical status. This is primarily due to the high resistance of these organisms and the potential for cata- strophic complications if not treated properly. UTIs comprise approximately 10% of all emer- gency department visits in Saudi Arabia, presenting a significant regional burden [2]. The lack of re- gional studies on ESBL-UTIs leaves room for fur- ther research. Additionally, there are currently no national guidelines for the oral treatment of ESBL infections. In this study, we focus on the oral agent nitrofu- rantoin, which is commonly used in the treatment of UTIs caused by ESBL. Nitrofurantoin is a cost- effective and widely available option. Leading IDSA and ESCMID guidelines recommend nitro- furantoin as a first-line therapy for uncomplicated cystitis in women [16], and recent reviews support its use in uncomplicated ESBL-UTIs in both sexes [9]. We hypothesize that it would be associated with a low to moderate failure rate and could serve as effective oral therapy for a substantial proportion of ESBL-UTIs, potentially reducing the need for hospitalization and intravenous antibiotics.

Preserving effective oral agents such as nitrofu- rantoin is critical to reduce reliance on car- bapenems and slow antimicrobial resistance, espe- cially in community-onset UTIs [17]. This study aims to help guide appropriate antibiotic use and reduce the risk of recurrence and complications commonly associated with ESBL-producing or- ganisms.

Methods

Study Design and Setting: We conducted a single-arm retrospective cohort study at a tertiary hospital in Riyadh, Saudi Arabia. The study period was from February 1, 2021 to June 1, 2024, corresponding to the time-frame for which electronic medical records were available prior to the review start date. All data were obtained from the hospital’s electronic health record system. The study was reviewed and approved by the Insti- tutional Review Board (IRB No. 24-576). A single-arm retrospective cohort design was se- lected on the basis of the study’s primary goal—to evaluate the failure rate of oral nitrofurantoin in treating ESBL-UTIs. This approach was necessi- tated by the limited number of eligible monother- apy patients, which precluded a meaningful com- parative analysis. Moreover, the objective outcome (90-day recurrence) and retrospective nature sup- ported the choice of a single-arm approach. Participants: We included adults aged 18 years or older who pre- sented to a tertiary hospital ED and were diagnosed with a UTI caused by an ESBL-producing organ- ism, confirmed by urine culture, and who were dis- charged on oral nitrofurantoin therapy. ESBL-pro- ducing bacteria were identified based on the pa- tients’ microbiology report. Patients were excluded if they were younger than 18 years, were confirmed to be pregnant, or were admitted outside the speci- fied study period. We also excluded those with in- complete or missing data, those with incomplete clinical outcomes data, and those with more than three non-consecutive episodes of ESBL-positive urine cultures, in order to avoid cases of chronic colonization or relapsing UTIs beyond the scope of a single treatment course. Patients with a docu- mented allergy or clinical contraindication to any of the selected medications were also excluded, as were those who received multiple antibiotics on discharge (e.g., nitrofurantoin alongside a full course of another antibiotic).

Data Collection: We developed a data extraction sheet for the pur- pose of data collection. From the hospital’s elec- tronic records, we collected: patient demographics (age, sex, comorbidities), details of the index UTI episode (date of visit, laboratory results), urine cul- ture and sensitivity results (organism identified, ESBL confirmation, antibiotic susceptibilities), de- tails of antimicrobial treatment (confirmation that nitrofurantoin was prescribed, dose and duration, and whether it was dispensed, as well as any other antimicrobials), and outcome data. Outcome data included any return visits to the ED or hospital ad- missions within 90 days of the index encounter, re- peat urine culture results within 90 days (to identify recurrent infections), and any documented treat- ment failures or changes. Hospital admission rec- ords were reviewed for those who required inpa- tient care after initial discharge, including length of stay and whether ICU care was needed, to assess the severity of the infection. All data were handled in a confidential manner and stored in a password- protected electronic database accessible only to the research team. Definitions: The primary outcome was treatment failure, de- fined as a repeat positive culture with the same or- ganism as the index infection within 90 days. This corresponded to a “recurrent ESBL-UTI” within 3 months, which could represent either relapse or re- infection with an ESBL strain. We considered this a clinically relevant failure threshold, consistent with previous studies. Patients without a repeat cul- ture or symptoms within 90 days were assumed to have successful outcomes. A secondary outcome was recurrence within 180 days (6 months), used to assess later relapses. We also examined hospitali- zation rates, with hospitalization defined as any in- patient admission related to the UTI within 90 days of the ED discharge, as well as length of stay. Statistical Analysis: Data analysis was primarily descriptive. Continu- ous variables (e.g., patient age) were reported as mean and standard deviation, as appropriate to the distribution. Categorical variables (e.g., failure rate, admission rate) were summarized as frequen- cies and percentages. Given the small sample size, no complex inferential statistics were performed; however, basic comparisons were noted.

Results

Baseline Patient Characteristics: Over the study period, a total of 13,421 patients were diagnosed with a UTI in the ED under inves- tigation. Among these, 347 cases (2.59%) were confirmed to be caused by ESBL-producing organ- isms (either E. coli or K. pneumoniae ). Of the ESBL-UTI cases, 41 patients (11.8%) received oral nitrofurantoin as part of their treatment regimen; these 41 patients form the initial cohort for analy- sis. The majority of this cohort were female (ap- proximately 61% female vs 39% male) and adults of varied ages (range 30–92 years; mean age 66). Comorbid conditions were common, including di- abetes mellitus (DM) (68%), hypertension (70%), and a history of prior UTIs. In terms of organism distribution, 30 patients (73.2%) had ESBL-pro- ducing E.coli infections and 11 patients (26.8%) had ESBL-producing K. pneumoniae infections. Before assessing outcomes, we applied the exclu- sion criteria to isolate those patients who received nitrofurantoin monotherapy. Twenty-four of the 41 patients were excluded from the primary efficacy analysis due to one or more exclusion factors: 14 patients had received a full course of IV mero- penem in addition to nitrofurantoin (combination therapy); 2 patients were prescribed nitrofurantoin only as prophylaxis (not for active infection); 1 pa- tient was found to be pregnant; 2 had incorrect or incomplete data entries; 3 patients never actually took the nitrofurantoin (medication not dispensed); and 2 patients had three non-consecutive ESBL- positive cultures (indicating a complex recurrent pattern beyond our study scope). Exclusions are shown in Figure 1. After these exclusions, 18 patients remained in the final study group who were treated for an ESBL- UTI with nitrofurantoin alone. This final analytical sample of 18 patients represents 43.9% of the orig- inal 41. Their baseline characteristics were similar to the pre-exclusion cohort: 72% were female; the mean age was approximately 64 years (SD ±18); and the infection organism was ESBL-EC in 14 cases (78%) and ESBL-KP in 4 cases (22%). The distribution of organisms in the final cohort is shown in Figure 2, with ESBL-EC comprising the majority. Comorbid conditions were similar, with hypertension (73%) and DM (68%) predominating. No patients in the final cohort were immunocom- promised or had indwelling catheters at discharge, aside from one patient with a neurogenic bladder managed with clean intermittent catheterization.

sion criteria and final cohort included in the nitro-

furantoin monotherapy analysis

Primary Outcome – Nitrofurantoin Failure Rate: Of the 18 patients treated with nitrofurantoin mon- otherapy, 4 experienced treatment failure by the 90-day follow-up, yielding a failure rate of 22.2%. These 4 patients had a repeat positive urine culture of the same ESBL-producing organism within 90 days of the index UTI, along with recurrent UTI symptoms requiring additional intervention. Con- versely, 14 patients (77.8%) had no evidence of re- currence within 90 days, meeting our criteria for clinical success. Notably, of the 4 failures, 3 were originally ESBL- EC infections and 1 was ESBL-KP. The difference in failure rates between E. coli (21% failure) and K. Pneumoniae (25% failure) infections was not sub- stantial in this small sample. Of note, 3 of the 4 treatment failures occurred in patients with diabe- tes.

Beyond 90 days, we observed additional recur- rences in a small number of cases. By 180 days af- ter the initial treatment, 3 patients (16.7%) who had not failed within the first 90 days had developed another ESBL-UTI (i.e., between 3 and 6 months post-treatment). These were considered late recur- rences rather than primary failures. All three late recurrences were E. coli infections in female pa- tients. If we extend the definition of “failure” to in- clude recurrences up to 180 days, the overall failure rate would be 38.9% (7 of 18 patients). However, for the primary endpoint of 90-day outcomes, those late cases are counted as initial successes. Detailed outcomes including both early and late failures are illustrated in Figure 3. Secondary Outcomes – Hospital Admission and Clinical Course: Our secondary outcomes examined the broader co- hort of patients who received nitrofurantoin (in- cluding those later excluded due to combination therapy). The goal was to assess hospital admission rates and severity of illness. Of a total of 32 patients with active ESBL-, 16 (50%) ultimately required hospital admission re- lated to the UTI or its complications. Hospital ad- mission rates are stratified by treatment group in Figure 4. Notably, in the monotherapy group of 18, 4 patients (the same 22% who failed) required hospitaliza- tion. In the combination-therapy subgroup (those who had initially received IV antibiotics such as meropenem), a number of patients had already

rantoin therapy

been admitted or had prolonged initial stays; among those, 3 patients experienced treatment fail- ure, developing a recurrent infection despite the ag- gressive initial treatment. Overall, of the 16 admit- ted patients in the entire nitrofurantoin-treated co- hort, 8 (50%) had prolonged hospital stays beyond 7 days or needed ICU-level care due to severe UTI manifestations (e.g., urosepsis). The proportion of admitted patients requiring prolonged or ICU-level care is summarized in Figure 5. Severe cases were more frequently observed in pa- tients with ESBL-KP: 3 out of 7 patients (42%) with active ESBL-KP infection required a compli- cated stay, defined as ICU-level care or hospitali- zation exceeding 7 days. In comparison, 5 out of 25 patients (20%) with ESBL-EC infection required a complicated stay. Despite the small sample size, ESBL-KP were more frequently observed to result in a complicated clinical course. The distribution of severe outcomes by organism is depicted in Figure 6.

Disease severity among hospitalized patients

tients

None of the patients who remained infection-free on nitrofurantoin required any subsequent admis- sion for ESBL-UTIs. The difference in admission rate, between those with treatment failure and those with successful treatment, was obvious, underlin- ing the clinical significance of treatment failure.

Microbiological Findings: In the four cases of treatment failure, repeat cul- tures showed that the organism remained the same ESBL producer. Furthermore, there was no evi- dence of developing nitrofurantoin resistance; the follow-up cultures of all four patients tested nitro- furantoin susceptible, suggesting that the failures were not due to acquired resistance but perhaps due to inadequate source control or suboptimal medica- tion effect. Likewise, in the patients with late recur- rences, all cultures tested positive for the initial causative organism (suggesting relapse).

These results indicate that while oral nitrofurantoin monotherapy can successfully treat a majority of ESBL-UTIs, there remains a noteworthy failure rate of 1 in 5 patients who will experience failure within the first 90 days, and 2 in 5 within 180 days. Clinical vigilance is essential, therefore, to identify early signs of recurrence. Patients who fail nitrofu- rantoin often require further intervention, whereas those who respond can avoid hospitalization.

Discussion

This was a retrospective study of ESBL-producing UTI cases at a large tertiary hospital in Riyadh, which found that oral nitrofurantoin monotherapy had a clinical failure rate of approximately 22% within 90 days, with late recurrences adding a fur- ther 16% failure within a 180-day period. Con- versely, about 78% of patients achieved successful treatment at 3 months, and 62% at 6 months, sug- gesting that nitrofurantoin can be an effective oral treatment option in a substantial proportion of cases. Nonetheless, 1 in 5 failures within 90 days is still a marked number. These findings provide val- uable evidence from Saudi Arabia, where data on oral treatment outcomes for ESBL-UTIs have been insufficient, with no such previous studies con- ducted in the region. The observed failure rate aligns with some prior international studies: for ex- ample, Tasbakan et al. [13] reported a 31% failure rate for nitrofurantoin in ESBL E. coli UTIs, simi- lar to our result of 22% by 90 days and 38% by 180 days. It is encouraging that over 75% of our pa- tients did not experience early recurrence; this sug- gests that nitrofurantoin remains a useful oral agent against ESBL-producers in the context of uncom- plicated lower UTIs, and particularly for E. coli , which comprised the majority of our cases. In line with these results, a multicenter ESBL- Enterobac- terales UTI cohort reported a 77.3% clinical cure rate with nitrofurantoin—nearly identical to our rate of 78% [18]. Our findings showed no major difference in failure rate between ESBL-KP and ESBL-EC cases, (25% and 21%, respectively). On the other hand, 42% of patients with ESBL-KP had a complicated hospital course (defined as an admission exceeding 7 days or ICU-level care), as opposed to only 20% of those with ESBL-EC. This is in line with the findings of a multicenter surveillance, which confirmed >90% susceptibility to nitrofurantoin in ESBL E. coli ver- sus <57% in ESBL Klebsiella pneumoniae [12].

These findings have significant clinical implica- tions with regard to patient selection for outpatient management versus inpatient therapy, as well as highlighting the need for close follow-up and mon- itoring. A failure rate of 22% at 90 days and 38% at 180 days represents a significant number of patients re- quiring an escalation of care. Our sample size is too small for definitive risk factor analysis; however, some observations can be made. All four early fail- ures in our study had significant comorbidities, par- ticularly DM and HTN—both of which conditions are known to predispose to complicated UTIs and treatment failure—as well as advanced age, with a mean age of 65.5 years. The severity of illness among admitted patients is also important to note, with half requiring a prolonged stay and/or ICU care. Notably, every patient who failed initial out- patient management eventually required admis- sion. These finding highlights that when oral ther- apy fails, infections can progress significantly in severity. Preventive strategies may be necessary for long- term management, especially in those with relaps- ing infections. Our findings emphasize the need for ongoing follow-up in ESBL-UTI patients treated with oral agents, as late recurrences may indicate unresolved infection or reinfection requiring ad- justed management. Repeat urine culture and sus- ceptibility testing helps guide the management of these patients. Moreover, a urology referral may be required to optimize management and address risk factors. Treatment options include different oral agents, longer treatment durations, and escalation to intravenous therapy [4]. Despite our small sample size, we demonstrated some evidence that treating selected ESBL-UTI pa- tients with oral nitrofurantoin and close follow-up can avert the need for hospitalization in many cases. Avoiding unnecessary admission reduces re- source consumption, hospital-acquired infections, and invasive interventions, as well as preserving the efficacy of IV antibiotic options. With a grow- ing prevalence of ESBL-UTIs, an outpatient oral treatment pathway could be invaluable. Cost-effec- tiveness models indicate that nitrofurantoin reduces hospitalization rates while preserving broader- spectrum agents [19]. While we did not directly study fosfomycin, references indicate that it main- tains good activity against both ESBL-EC and ESBL-KP [9,13]. Thus, further studies are needed

regarding the efficacy of both nitrofurantoin and fosfomycin. This study has several limitations that must be acknowledged. First, the sample size is small, with only 18 patients in the final analysis. This limits our data analysis to a purely descriptive one, as well as limiting our ability to assess demographics and dif- ferences between organisms. We also relied on documentation from a single center, meaning that if a patient experienced a recurrence but presented to a different hospital, that outcome would have been missed (potentially underestimating failures); however, documentation was reviewed for evi- dence of visits to other hospitals, including alterna- tive medication regimens or repeat cultures. Addi- tionally, adherence to nitrofurantoin was not di- rectly observed; three patients who did not collect their medication were excluded, but drug compli- ance was assumed in those who were included. Nonetheless, it is possible that some failures were partly due to non-adherence. Finally, since this was a single-center study in a tertiary hospital ED, the patient population and resistance patterns may dif- fer from those in other settings. The potential for confounding variables must also be noted: We did not account for all variables that could have influenced treatment outcomes. Patient- specific factors may include adherence, severity of infection, and prior antibiotic exposure. While we applied exclusion criteria to isolate monotherapy cases and reviewed for documented complications, we could not fully account for underlying differ- ences between patients who succeeded versus those who failed therapy. In addition, treatment selection bias might exist, with providers potentially select- ing patients deemed lower risk for nitrofurantoin therapy. These unmeasured or uncontrolled varia- bles may confound the observed associations be- tween nitrofurantoin use and clinical outcomes. Clinical significance: Oral nitrofurantoin monotherapy can successfully treat a majority of UTIs caused by ESBL-produc- ing E. coli and K. pneumoniae in the outpatient set- ting, with a 22% failure rate observed in our study. This suggests that, in carefully selected patients (those with uncomplicated lower UTIs, susceptible isolates, and no contraindications), nitrofurantoin is a valid choice that can avert the use of car- bapenems and potentially prevent hospitalization. However, a considerable minority of patients will fail this therapy, highlighting the need for close fol- low-up. Multisite data confirm that nitrofurantoin

remains highly effective against ESBL-producing uropathogens and is a sound oral option [20].

Conclusion

In this single-center retrospective study, oral nitro- furantoin demonstrated a failure rate of 22% in treating ESBL-producing E. coli and K. pneu- moniae UTIs. Approximately 1 in 5 patients expe- rienced a recurrent infection within 90 days, while a further 16% saw recurrence within 180 days. The majority (78%) had no early recurrence, suggesting that nitrofurantoin can be an effective oral treat- ment option for many ESBL-UTIs, especially those caused by E.coli . Nonetheless, clinical vigilance is warranted, as a subset required hospitalization and some experienced late recurrences. These findings support the use of nitrofurantoin as a cost-effective, accessible oral therapy in select ESBL-UTIs, while highlighting the need for close follow-up and anti- biotic stewardship to ensure timely escalation of care if treatment fails. Larger studies are needed to confirm these outcomes and to guide the develop- ment of local guidelines regarding oral therapy for ESBL-UTIs.

VI. REFERENCES 1. Mlugu EM, Mohamedi JA, Sangeda RZ, Mwambete KD. Prevalence of urinary tract infection and antimicrobial resistance pat- terns of uropathogens with biofilm forming capacity among outpatients in Morogoro, Tanzania: a cross-sectional study. BMC In- fect Dis . 2023;23(1):660. doi:10.1186/s12879-023-08641-x 2. Sula I, Alreshidi MA, Alnasr N, Hassaneen AM, Saquib N. Urinary tract infections in the Kingdom of Saudi Arabia, a review. Mi- croorganisms. 2023;11(4):952. doi:10.3390/microorganisms11040952 3. Vachvanichsanong P, McNeil EB, Dis- saneewate P. Extended-spectrum beta-lac- tamase Escherichia coli and Klebsiella pneumoniae urinary tract infections. Epi- demiol Infect. 2020;148:e320. doi:10.1017/S0950268820003273 4. Hooper DC. Extended-spectrum beta-lac- tamases [Internet]. UpToDate; 2024 [cited 2025 Jul 9]. Available from: https://www.uptodate.com/contents/ex- tended-spectrum-beta-lactamases

5. Li G, Zhao S, Wang S, Sun Y, Zhou Y, Pan X. A 7-year surveillance of the drug re- sistance in Klebsiella pneumoniae from a primary health care center. Ann Clin Micro- biol Antimicrob. 2019;18(1):34. doi:10.1186/s12941-019-0334-y 6. Pitout JD, Laupland KB. Extended-spec- trum β-lactamase-producing enterobacteri- aceae: an emerging public-health concern. Lancet Infect Dis . 2008;8(3):159–166. doi:10.1016/S1473-3099(08)70041-0 7. Bitsori M, Galanakis E. Treatment of uri- nary tract infections caused by ESBL-pro- ducing Escherichia coli or Klebsiella pneu- moniae. Pediatr Infect Dis J. 2019;38(12):e332–e335. doi:10.1097/INF.0000000000002437 8. Sy K, Fawzi K, Khan N, Kulsum SN, Faraz A. Sensitivity profile of fosfomycin, nitro- furantoin, and co-trimoxazole against uro- pathogens isolated from UTI cases in a sec- ondary care center, KSA. Cureus. 2024;16(2):e53999. doi:10.7759/cu- reus.53999 9. Tulara NK. Nitrofurantoin and fosfomycin for extended-spectrum beta-lactamase pro- ducing Escherichia coli and Klebsiella pneumoniae. J Glob Infect Dis. 2018;10(1):19–21. doi:10.4103/jgid.jgid_127_17 10. Falagas ME, Vouloumanou EK, Togias AG, Karadima M, Kapaskelis AM, Ra- failidis PI, et al. Fosfomycin versus other antibiotics for the treatment of cystitis: a meta-analysis of randomized controlled tri- als. J Antimicrob Chemother. 2010;65(9):1862–1877. doi:10.1093/jac/dkq237 11. Gohar H, Afridi FI, Fatima M, Fatima A, Afzal N, Fasih F. Effectiveness of fosfomy- cin against extended-spectrum beta-lac- tamase producing Escherichia coli in uri- nary cultures. Pak J Med Dent. 2021;14(2):44–50. 12. Huttner A, Verhaegh EM, Harbarth S, Mül- ler AE, Theuretzbacher U, Mouton JW. Ni- trofurantoin revisited: a systematic review

and meta-analysis of controlled trials. J An- timicrob Chemother . 2015;70(9):2456– 2464. doi:10.1093/jac/dkv147 13. Tasbakan MI, Pullukcu H, Sipahi OR, Yamazhan T, Ulusoy S. Nitrofurantoin in the treatment of extended-spectrum β-lac- tamase-producing Escherichia coli -related lower urinary tract infection. Int J Antimi- crob Agents . 2012;40(6):554–556. doi:10.1016/j.ijantimicag.2012.08.003 14. Liu HY, Lin HC, Lin YC, Yu SH, Wu WH, Lee YJ. Antimicrobial susceptibilities of urinary extended-spectrum beta-lactamase- producing Escherichia coli and Klebsiella pneumoniae to fosfomycin and nitrofu- rantoin in a teaching hospital in Taiwan. J Microbiol Immunol Infect. 2011;44(5):364–368. doi:10.1016/j.jmii.2011.01.029 15. Park KS, Kim DR, Baek JY, Shin A, Kim KR, Park H, et al. Susceptibility to fosfomycin and nitrofurantoin of ESBL- positive Escherichia coli and Klebsiella pneumoniae isolated from urine of pediatric patients. J Korean Med Sci . 2023;38(48):e361. doi:10.3346/jkms.2023.38.e361 16. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelo- nephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis . 2011;52(5):e103–e120. doi:10.1093/cid/ciq257 17. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ, et al. Infectious Diseases Society of America guidance on the treatment of AmpC β-lac- tamase-producing Enterobacterales, car- bapenem-resistant Acinetobacter bau- mannii, and Stenotrophomonas maltophilia infections. Clin Infect Dis. 2022;74(12):2089–2114. doi:10.1093/cid/ciab1013

18. Thabit AK, Al Sulaiman K, Alfaraj L, Rad- wan SA, Almadfaa LO, Mokhtar RH, et al. Nitrofurantoin versus comparators in the treatment of cystitis due to extended-spec- trum β-lactamase-producing Enterobacter- ales: A multicenter cohort study. Ann Phar- macother . 2025 Feb 21. doi:10.1177/10600280241232196 [Epub ahead of print] 19. AlAnazi M. Clinical efficacy and cost anal- ysis of antibiotics for treatment of uncom- plicated urinary tract infections in the emer- gency department of a tertiary hospital in Saudi Arabia. Ther Clin Risk Manag . 2021;17:1209–1217. doi:10.2147/TCRM.S331435 20. Aththanayaka AMWGKP, Weerasinghe GGYH, Weerakkody NS, Samarasinghe SHGG, Priyadharshana U. Effectiveness of selective antibiotics use in ESBL-related UTIs. BMC Microbiol . 2024;24(1):360. doi:10.1186/s12866-024-03373-5