This study was conducted retrospectively using medical records in a university-affiliated hospital. We gathered the data of all APN patients admitted to St. Vincent’s Hospital from January 2001 to December 2010 and analyzed the clinical characteristics of APN patients treated with intravenous cefuroxime. The Institutional Review Board (IRB) of St. Vincent’s Hospital, Suwon, South Korea examined and approved the clinical research protocol of this retrospective study (approval number VC13RISI0210). The IRB granted a waiver of informed consent in this retrospective chart review study.

We defined “APN” as the presence of fever (≥ 38.0°C), pyuria, and bacteriuria. Pyuria was defined as more than 5 to 10 leukocytes per high-power field upon microscopic examination of urine. Bacteriuria was defined as the presence of 10⁵ or more of pathogenic bacteria per mL for clean voided urine or 104 or more pathogenic bacteria per mL for catheterized urine [6-10]. We also analyzed the presence of comorbid conditions (cerebrovascular disorder, chronic liver disease, chronic lung disease, chronic kidney disease, heart failure, autoimmune disorder, diabetes mellitus, malignancy, and menopause) and/or urinary tract abnormalities (renal calculi, vesicoureteral reflux, neurogenic bladder). We excluded the patients who had catheter-associated UTIs or who had an obstructive nephropathy demanding percutaneous nephrostomy, catheterization or surgery. We also excluded patients diagnosed with APN more than 48 hours after being admitted to the hospital.

We gathered and analyzed the following information for all eligible patients by chart review: age, past medical records, comorbidities, UTI symptoms, physical signs of UTIs, clinical laboratory tests, duration of antimicrobial treatment, time to defervescence, length of hospitalization, and mortality.

We evaluated and determined the effectiveness of cefuroxime with respect to the following conditions: early clinical success, overall clinical outcome (clinical cure or failure), length of hospitalization, and time taken for defervescence of fever after starting antimicrobial therapy. Early clinical success was defined as the defervescence of fever with the improvement of UTI symptoms or signs within 72 hours after the initiation of intravenous cefuroxime therapy. The cases that did not fulfill the aforementioned criteria of early clinical success were considered to be early clinical failures. A clinical cure was defined by the absence of clinical signs or symptoms suggesting UTI during a 4 to 14 days follow-up period after antimicrobial treatment [11]. A clinical failure was defined as the reappearance of UTI symptoms and/or signs within the 4 to 14 days follow-up period after completion of antimicrobial treatment or death. Defervescence of fever was defined as the afebrile state in which the body temperature remained at 37.0°C or below for more than 24 hours [7]. The time to defervescence was defined as the time from the beginning of intravenous cefuroxime therapy to an afebrile state. The patient’s body temperatures were measured every 6 hours during the hospital admission using a tympanic thermometer.

Quantitative urine cultures were performed to identify the causative agents of UTI. Blood cultures were performed prior to the start of antimicrobial therapy. The etiological pathogens were confirmed by the presence of ≥ 10⁴ colony forming unit/mL organisms isolated in urine cultures or by the identification of uropathogens from blood cultures [12,13]. The species identification and antibacterial susceptibility of the uropathogens were confirmed by either a semiautomated system (Microscan, DADE Behring, West Sacramento, CA, USA) or disk diffusion susceptibility tests. This approach is consistent with the criteria provided by the Clinical and Laboratory Standard Institute [14]. The minimum inhibitory concentration cutoff value for cefuroxime resistance was ≥ 16 mg/L.

The categorical variables are expressed as numbers (percentage), and were compared using Fisher exact test or the Pearson chi-square test. The results of continuous variables are presented as the median (interquartile range [IQR]) and were analyzed by the Mann-Whitney test. A logistic regression analysis was conducted to estimate the effects of independent variables on clinical outcomes. A multivariate analysis was performed using logistic regression to determine the influences of independent variables on early clinical failure in the APN patients who were initially treated with intravenous cefuroxime. All p values were two-tailed and tests with a probability of less than 0.05 were considered as representing statistical significance. The data were analyzed using the SPSS version 21.0 (IBM Co., Armonk, NY, USA).

We screened a total of 1,014 hospitalized women diagnosed with community-onset APN. There were 413 cases treated with cefuroxime as the initial antimicrobial agent. The remaining 601 cases received other antibiotics. Of the 413 patients treated with cefuroxime, 85 were excluded because they had a non-E. coli uropathogen, renal abscess, or other obstructive lesions requiring urological intervention. Thus, the study assessed a total of 328 cefuroxime-administered patients with community-onset APN due to E. coli.

Of the 328 patients, 22 had cefuroxime-resistant E. coli APN, and 306 had cefuroxime-susceptible E. coli APN. Table 1 shows a comparative demographic and clinical data of the cefuroxime-resistant and cefuroxime-susceptible groups. The median ages of the cefuroxime-resistant and cefuroxime-susceptible groups were 66 years (IQR, 61 to 71) and 64 years (IQR, 50 to 73), respectively (p = 0.534). The two groups showed no statistically significant differences in the following characteristics: initial body temperature, costovertebral angle tenderness, lower UTI symptoms, white blood cell counts, C-reactive protein (CRP) level, azotemia, hematuria, bacteremia, or age. The frequencies of comorbid conditions were not significantly different between the cefuroxime-resistant and -susceptible groups (Table 1).

In this study, the cefuroxime susceptibility rate for the 328 E. coli isolates was 93.3%. This rate was not significantly different from 561 E. coli samples isolated from women who received other antibiotics (93.3% vs. 95.9%, p = 0.087). The antimicrobial resistance profiles of the 22 cefuroxime-resistant and 306 cefuroxime-susceptible E. coli isolates are displayed in Table 2. Cefuroxime-resistant E. coli were susceptible to less than 80.0% of various antibiotics with the exceptions of amikacin (95.5%), piperacillin/tazobactam (95.5%), and imipenem (100%). In the cefuroxime-resistant group, the E. coli susceptibilities to cefotaxime, ceftriaxone, ceftazidime, and cefepime were 27.3%, 29.4%, 63.6%, and 29.4%, respectively. Conversely, the susceptibilities of E. coli to cefotaxime, ceftriaxone, ceftazidime, and cefepime in the cefuroxime-susceptible group were 99.7%, 100%, 99.7%, and 100%, respectively. These values were all significantly higher than in the cefuroxime-resistant group.

There was no significant changes in the susceptibility rates of E. coli to cefuroxime observed between the 2001 to 2005 and 2006 to 2010 periods (92.9% in 2001 to 2005 vs. 93.5% in 2006 to 2010, p = 0.820). Additionally, there was also no significant change in the cefuroxime susceptibility rates of E. coli when the initial 2-year period was compared to the last 2-year period of this study (93.0% in 2001 to 2002 vs. 93.3% in 2009 to 2010, p = 0.946).

The clinical outcomes were analyzed and compared between the cefuroxime-resistant and -susceptible groups (Table 3). The median duration of cefuroxime therapy was 7 days (IQR, 5 to 7) in the cefuroxime-resistant group and 7 days (IQR, 6 to 7) in the cefuroxime-susceptible group (p = 0.461). The total antimicrobial therapy was 14 days (IQR, 14 to 15) in the cefuroxime-resistant group and 14 days (IQR, 14 to 14) in the cefuroxime-susceptible group (p = 0.125). Finally, 245 of the 328 patients (74.7%) had follow-up at 4 to 14 days and 143 patients (43.6%) had follow-up at 28 to 42 days after the end of antibiotic treatment.

There were 8 of 22 patients (36.4%) in the cefuroxime-resistant group that changed to alternative intravenous therapy. There were three patients (13.6%), two (9.1%), two (9.1%), and one (4.5%) who switched to piperacillin/tazobactam, imipenem, gentamicin, and amikacin after 3 to 7 days of cefuroxime monotherapy. Among the eight patients, four had defervescence before transitioning into the alternative antibiotics, and four had defervescence after receiving alternative intravenous antibiotics. Fourteen of 22 patients (63.6%) in the cefuroxime-resistant group received continuing cefuroxime therapy. There were 12 patients (54.5%) and two (9.1%) with defervescence within 72 and 96 hours of cefuroxime therapy, respectively. Seven patients (2.3%) in the cefuroxime-susceptible group were switched to alternative intravenous therapy. There were four, two, and one cases in the cefuroxime-susceptible group switched to gentamicin, amikacin, and ceftriaxone after 3 to 6 days of cefuroxime therapy. After the intravenous antimicrobial therapy there were 18 patients (81.8%) in the cefuroxime-resistant group and 304 patients (99.3%) in the cefuroxime-susceptible group who changed to oral therapy. The early clinical response rates were 68.2% (15/22) and 90.8% (278/306) at 72 hours in the cefuroxime-resistant and -susceptible groups, respectively. These results indicate the clinical response rate was significantly higher in the cefuroxime-susceptible group (p = 0.001) (Table 3). The rates of defervescence were significantly higher in the cefuroxime-susceptible group than in the cefuroxime-resistant group at both 96 hours and 120 hours (96.4% vs. 81.8% at 96 hours, and 98.0% vs. 81.8% at 120 hours; p = 0.013 and p = 0.002, respectively). However, the rates of defervescence at 24 and 48 hours were not significantly different between the cefuroxime-resistant and -susceptible groups, though higher rates of defervescence were noted in the latter (Table 3). The median time to defervescence was 51.5 hours (IQR, 39 to 70) and 46 (IQR, 38 to 68) in the cefuroxime-resistant and cefuroxime-susceptible groups, respectively. In the cefuroxime-susceptible group, the median time to defervescence in bacteremic and non-bacteremic APN patients was 55 hours (IQR, 43 to 70) and 45 (IQR, 36 to 65), respectively. The median length of hospital stay in the cefuroxime-resistant and cefuroxime-susceptible groups was 10 days (IQR, 8 to 13) and 10 (IQR, 8 to 14), respectively. The median hospital stay was not significantly different between the groups. There were no deaths or other complications in either the cefuroxime-resistant or -susceptible groups (Table 3). The clinical cure rates at the follow-up visit during the 4 to 14 days period following the end of antimicrobial therapy were not significantly different in the cefuroxime-resistant or -susceptible groups, 88.2% versus 97.8% (15/17 vs. 223/228, p = 0.078), and microbiological cure rates were also not significantly different in the two groups, 90.9% versus 93.4% (10/11 vs. 128/137, p = 0.550) (Table 3).

The clinical outcomes were also compared between the early clinical success and the early clinical failure groups (Table 4) after the completion of antimicrobial therapy, which included initial cefuroxime treatment, alternative intravenous and oral antibiotics that were tailored according to the susceptibility results of E. coli isolated from each patient. Among 328 women with APN, 293 cases were assigned to the early clinical success group and only 35 to the early clinical failure group. The clinical cure rates were 97.2% (208/214) and 96.8% (30/31) at the follow-up visit 4 to 14 days following the end of therapy in the respective groups (p > 0.999), and microbiological cure rates were 93.7% (119/127) and 90.5% (19/21) in the two groups, respectively (p = 0.635). Furthermore, the clinical cure rates were 89.3% (108/121) and 95.5% (21/22) at the follow-up visit 28 to 42 days after completion of antibacterial therapy in the early clinical success and early clinical failure groups, respectively (p = 0.696) (Table 4).

There were no significant differences in median age, proportion of elderly women, frequency of a prior history of hospitalization, previous history of UTI, or antibiotic usage before the hospital visit between the early clinical success and early clinical failure groups. The proportions of patients with a CRP level above 20 mg/dL in the blood and patients with bacteremia were significantly higher in the early clinical failure group (p < 0.001 and p < 0.001). Moreover, in vitro resistance of E. coli to cefuroxime was significantly higher in the early clinical failure group (20.0% vs. 5.1%, respectively; p = 0.001) (Table 4).

A multivariate analysis was conducted to determine the influences of independent variables on early clinical failure in APN patients initially treated with intravenous cefuroxime (Table 5).

The variables analyzed included bacteremia, CRP level, chronic liver disease, and uropathogen resistant to cefuroxime. Bacteremia, CRP level ≥ 20 mg/dL, presence of chronic liver disease, and uropathogen resistant to cefuroxime differed significantly between groups with p < 0.001, p < 0.001, p < 0.006, and p < 0.001, respectively (Table 5).