Microbiological Characteristics of Unresolved Acute Uncomplicated Cystitis

Abstract

This study sought to compare the antimicrobial susceptibility rates between acute uncomplicated cystitis patients with failed initial antimicrobial treatment, who were considered unresolved cases, and newly presenting acute uncomplicated cystitis patients without recent antimicrobial use within 3 months and to determine whether different treatment strategies should be applied according to recent antimicrobial exposure (RAE). Female acute uncomplicated cystitis patients with Escherichia coli growth, who visited our hospital's urology department from 2010 to 2014, were divided according to RAE. The antimicrobial susceptibility of E. coli was compared between the group with RAE and the group with no antimicrobial exposure (NAE) within 3 months. The total number of acute uncomplicated cystitis patients with E. coli growth was 259: 40 patients comprised the RAE group and 219 patients formed the NAE group. The mean age was significantly older and previous recurrent cystitis history was higher in the RAE group (p < 0.05). Furthermore, the antimicrobial susceptibility of E. coli to amoxicillin–clavulanic acid, cefotaxime, cefoxitin, ciprofloxacin, and trimethoprim–sulfamethoxazole was significantly lower in the RAE group, with susceptibility results of 64.7%/88.0% (RAE/NAE), 77.5%/89.0%, 79.4%/95.3%, 31.3%/64.2%, and 42.5%/70.6%, respectively. RAE was an independent factor for antimicrobial resistance. This study showed that antimicrobial susceptibilities were significantly lower in acute uncomplicated cystitis patients with failed initial antimicrobial treatment, who are defined as unresolved cases. Our results suggest that first-line antimicrobials might show poor efficacy in cases of unresolved, acute uncomplicated cystitis and alternative or secondary antimicrobials should be considered in these cases.

Introduction

Urinary tract infections (UTI) are among the most common causes of infectious disease, with an estimated 150 million UTI occurring annually on a global basis, which results in more than 6 billion dollars in direct healthcare expenditures.⁸ UTI affect women more frequently; nearly 30% of women will have had a symptomatic UTI requiring antimicrobial therapy by the age of 24, and almost half of all women will experience an episode of UTI during their lifetimes.⁵ Acute uncomplicated episodes comprise most of the incidences of UTI, and these UTI are usually treated on an outpatient basis with antimicrobial agents. In the United States, ∼15% of all community-prescribed antibiotics are dispensed for UTI.¹⁵ With the extensive exposure to antimicrobial agents of a relatively healthy population, the judicious use of antimicrobials is crucial because their use can have direct effects on the antimicrobial susceptibility rates.^9,19 Continued surveillance studies for antimicrobial susceptibility patterns are needed to help guide the choice of empiric antimicrobial agents. However, surveillance studies of acute uncomplicated cystitis might be inaccurate for several reasons, mainly because successfully treated patients without urine cultures are not included in these studies. Unresolved UTI might constitute another reason.

Unresolved UTI occur when initial antimicrobial therapy for UTI has been inadequate in eliminating symptoms and/or bacterial growth in the urinary tract.¹⁸ The most common cause of unresolved UTI is presumed to be bacterial; unless the initial antimicrobial drug is known, fluoroquinolones are usually recommended for empirical therapy before the culture and susceptibility results are known.²¹ As a secondary referral hospital, a large proportion of our patients with acute uncomplicated cystitis are referred from primary clinics after failed initial antimicrobial treatment. The aim of this study was to compare the antimicrobial susceptibility rates between patients with recent antimicrobial exposure (RAE) who were considered to have cases of unresolved UTI and patients without RAE, and to determine whether different treatment strategies should be applied based on RAE.

Materials and Methods

Study population and design

The Institutional Review Board of St. Vincent's Hospital, the Catholic University of Korea, approved the study protocol (VC15RISI0155). An electronic search was performed for female patients under the disease code for “acute cystitis” who visited our hospital's urology department from January 2010 to December 2014. Patients with the following criteria were included in the study: (1) growth of Escherichia coli of ≥10³ CFU/ml in urine culture; (2) one or more symptoms of acute cystitis, such as dysuria, urgency, frequency, and suprapubic pain; and (3) pyuria of ≥5 white blood cells/high-power field in a urine sediment exam. Cultures from same patients were excluded, except if the later cultures were performed after a successful treatment of previous episodes. A retrospective chart review of all patients with growth of E. coli in urine culture was performed. Patients with E. coli growth were divided into two groups according to recent antimicrobial use. The first group consisted of those who were recently treated with an antimicrobial at a primary clinic and failed to resolve. This group was called the RAE group and represented patients with unresolved acute cystitis. The second group consisted of patients with newly presenting symptoms of acute cystitis, who did not receive any antimicrobial treatment within 3 months before coming to our hospital. This group was called the no antimicrobial exposure (NAE) group. Previous recurrent cystitis history was checked as well as the following risk factors for complicated UTI: diabetes mellitus, chronic kidney disease, voiding dysfunction, urinary catheterization, urinary stones, and vesicoureteral reflux. Then, patients with at least one of the risk factors were excluded from further analysis. Finally, the antimicrobial susceptibility of E. coli was compared between the RAE and NAE groups.

Antimicrobial susceptibility testing

All strains were identified using a MicroScan identification system (Baxter Diagnostics, Inc., West Sacramento, CA). The minimal inhibitory concentrations (MIC) of antimicrobials were measured using the broth microdilution method, following the protocol of the Clinical and Laboratory Standards Institute (CLSI).³ Based on the MIC values, susceptibility to a specific antimicrobial was described as sensitive/resistant/intermediate. The antimicrobials that were examined were amikacin, amoxicillin–clavulanic acid, ampicillin, aztreonam, cefazolin, cefepime, cefotaxime, cefoxitin, ceftazidime, ciprofloxacin, cephalothin, ertapenem, gentamicin, imipenem, levofloxacin, piperacillin, piperacillin/tazobactam, tigecycline, tobramycin, and trimethoprim–sulfamethoxazole (TMP-SMX). Urinary pathogens were also tested for the presence of extended-spectrum beta-lactamase (ESBL).

Data analysis

All data were analyzed using PASW (Predictive Analytics Software) Statistics for Macintosh, version 18.0 (SPSS, Inc., Chicago, IL). A comparison of risk factors and antimicrobial susceptibilities was performed between the RAE and NAE groups: comparisons of continuous variable were performed using the Mann–Whitney test, and comparisons of categorical variable were performed using the Chi-square test and Fisher's exact test. p-Values <0.05 were considered significant. Multivariable logistic regression analysis was performed to evaluate the effects of RAE, age, and recurrence on antimicrobial resistance in acute uncomplicated cystitis patients with E. coli growth.

Results

The clinical characteristics of cases with E. coli growth are described in Table 1. The total number of patients with E. coli growth was 314. There were no significant differences in risk factors between the RAE and NAE groups. After excluding patients with one or more risk factors for complicated UTI, a final comparison of antimicrobial susceptibility between the groups was done and is described in Table 2. The number of acute uncomplicated cystitis patients with E. coli growth was 259. There were 40 patients in the RAE group, which comprised 15.4% of the acute uncomplicated cystitis patients with E. coli growth, and there were 219 patients in the NAE group. The mean age of the RAE group (60.0 ± 13.0) was significantly older compared with the NAE group (53.7 ± 15.1), with p < 0.05.

Table 1.

Clinical Characteristics of Patients with Escherichia coli Growth

Characteristics	Total, n (%)	RAE, n (%)	NAE, n (%)	p-Value
Number of patients	314 (100)	52 (16.6)	262 (83.4)
Age, mean ± SD	56.7 ± 15.1	62.7 ± 13.7	55.5 ± 15.1	0.003^a
Recurrence	164 (52.2)	39 (75.0)	125 (47.7)	0.000^b
DM	33 (10.5)	8 (15.4)	25 (9.5)	0.210^b
CKD	2 (0.6)	1 (1.9)	1 (0.4)	0.304^c
Catheterization	2 (0.6)	0 (0.0)	2 (0.8)	1.000^c
Dysfunctional voiding	27 (8.6)	4 (7.7)	23 (8.8)	1.000^c
Stone	1 (0.3)	0 (0.0)	1 (0.4)	1.000^c
Reflux	3 (1.0)	1 (1.9)	2 (0.8)	0.420^c

Mann–Whitney test.

Chi-square test.

Fisher's exact test.

CKD, chronic kidney disease; DM, diabetes mellitus; NAE, no antimicrobial exposure; RAE, recent antimicrobial exposure; SD, standard deviation.

Table 2.

Comparison of Antimicrobial Susceptibility of E. coli from Acute Uncomplicated Cystitis Patients Without Risk Factors for Complicated Urinary Tract Infections Between the Recent Antimicrobial Exposure and No Antimicrobial Exposure Groups

Number of patients	Total, n (%) 259 (100)	RAE, n (%) 40 (15.4)	NAE, n (%) 219 (84.6)	p
Age, mean ± SD	54.7 ± 15.0	60.0 ± 13.0	53.7 ± 15.1	0.025^a
Recurrence	128 (49.4)	29 (72.5)	99 (45.2)	0.001^b
Antimicrobials
Amikacin	259/259 (100.0)	40/40 (100.0)	219/219 (100.0)
Amoxicillin–clavulanic acid	191/226 (84.5)	22/34 (64.7)	169/192 (88.0)	0.001^b
Ampicillin	91/258 (35.3)	4/39 (10.3)	87/219 (39.7)	0.000^b
Aztreonam	235/259 (90.7)	33/40 (82.5)	202/219 (92.2)	0.070^c
Cefazolin	150/179 (83.8)	22/31 (71.0)	128/148 (86.5)	0.033^b
Cefepime	239/259 (92.3)	34/40 (85.0)	205/219 (93.6)	0.098^c
Cefotaxime	226/259 (87.3)	31/40 (77.5)	195/219 (89.0)	0.044^b
Cefoxitin	210/226 (92.9)	27/34 (79.4)	183/192 (95.3)	0.004^c
Ceftazidime	241/259 (93.1)	35/40 (87.5)	206/219 (94.1)	0.168^c
Ciprofloxacin	105/180 (58.3)	10/32 (31.3)	95/148 (64.2)	0.001^b
Cephalothin	43/79 (54.4)	2/8 (25.0)	41/71 (57.7)	0.132^c
Ertapenem	147/147 (100)	26/26 (100.0)	121/121 (100.0)
Gentamicin	179/259 (69.1)	19/40 (47.5)	160/219 (73.1)	0.001^b
Imipenem	259/259 (100.0)	40/40 (100.0)	219/219 (100.0)
Levofloxacin	68/111 (61.3)	7/13 (53.8)	61/98 (62.2)	0.559^b
Piperacillin	33/76 (43.4)	2/9 (22.2)	31/67 (46.3)	0.284^c
Piperacillin/tazobactam	252/259 (96.0)	38/40 (90.0)	214/219 (97.7)	0.295^c
Tigecycline	148/148 (100.0)	27/27 (100.0)	121/121 (100.0)
Tobramycin	83/111 (74.8)	9/13 (69.2)	74/98 (75.5)	0.735^c
TMP-SMX	171/259 (66.0)	17/40 (42.5)	154/219 (70.6)	0.001^b

Mann–Whitney test.

Chi-square test.

Fisher's exact test.

TMP-SMX, trimethoprim–sulfamethoxazole.

When the RAE and NAE groups were compared, several antimicrobials showed significant differences in susceptibility: the susceptibility to amoxicillin–clavulanic acid was 64.7% in the RAE group versus 88.0% in the NAE group (p = 0.001); the susceptibility to cefotaxime was 77.5% in the RAE group versus 89.0% in the NAE group (p = 0.044); the susceptibility to cefoxitin was 79.4% in the RAE group versus 95.3% in the NAE group (p = 0.004); the susceptibility to ciprofloxacin was 31.3% in the RAE group versus 64.2% in the NAE group (p = 0.001); and the susceptibility to TMP-SMX was 42.5% in the RAE group versus 70.6% in the NAE group (p = 0.001). The total proportion of E. coli with positive ESBL was 14.7%, and the rate of positive ESBL was 23.1% in the RAE group versus 11.1% in the NAE group.

Multivariable logistic regression analysis was performed to evaluate the effects of RAE, age, and recurrence on antimicrobial resistance (Table 3). Amoxicillin–clavulanic acid, cefotaxime, cefoxitin, ciprofloxacin, and TMP-SMX were chosen for analysis because these antimicrobials showed significant difference in susceptibility (p < 0.05) between the RAE and NAE group (Table 2); ampicillin, cefazolin, and gentamicin also showed significant difference in susceptibility, but because they are not routinely used as first-line therapy for acute uncomplicated cystitis, they were excluded from analysis. As a result, RAE was found to be an independent factor for resistance rate of amoxicillin–clavulanic acid (p = 0.001, odds ratio [OR]: 4.0; 95% confidence interval [CI], 1.8–9.2), cefotaxime (p = 0.049; OR: 2.4; 95% CI, 1.0–5.5), cefoxitin (p = 0.007; OR: 4.5; 95% CI, 1.5–13.3), ciprofloxacin (p = 0.003; OR: 3.6; 95% CI, 1.6–8.2), and TMP-SMX(p = 0.001; OR: 3.2; 95% CI, 1.6–6.4). Age however, was not found to be a factor for antimicrobial resistance, except for ciprofloxacin, in which the p-value, OR, and 95% CI was 0.014, 1.028, 1.006–1.051, respectively. Recurrence history was not found to be a factor for antimicrobial resistance for all antimicrobials.

Table 3.

Multivariable Logistic Regression Analysis to Evaluate the Effects of Recent Antimicrobial Exposure, Age, and Recurrence on Antimicrobial Resistance in Acute Uncomplicated Cystitis Patients with E. coli Growth

	RAE		Age		Recurrence
	OR (95% CI)	p-Value	OR (95% CI)	p-Value	OR (95% CI)	p-Value
Amoxicillin–Clavulanic acid	4.008 (1.752–9.167)	0.000	1.000 (0.975–1.027)	0.974	1.620 (0.753–3.484)	0.217
Cefotaxime	2.359 (1.003–5.545)	0.049	1.011 (0.985–1.037)	0.422	0.817 (0.382–1.747)	0.602
Cefoxitin	4.474 (1.508–13.273)	0.007	1.007 (0.970–1.046)	0.714	2.703 (0.822–8.890)	0.102
Ciprofloxacin	3.566 (1.551–8.201)	0.003	1.028 (1.006–1.051)	0.014	1.629 (0.851–3.118)	0.140
TMP-SMX	3.205 (1.607–6.395)	0.001	1.005 (0.987–1.023)	0.581	1.247 (0.729–2.133)	0.420

CI, confidence interval; OR, odds ratio.

Discussion

Surveillance studies of the antimicrobial susceptibility of uropathogens are an integral part of establishing the guidelines for acute uncomplicated cystitis. These guidelines aid practitioners in determining the appropriate empiric antimicrobial agents for the treatment of acute uncomplicated cystitis. However, surveillance studies of acute uncomplicated cystitis might be inaccurate for several reasons. First, routine urine culture is not recommended in acute uncomplicated cystitis without complicating factors.^1,14 Therefore, data from surveillance studies might inadvertently include proportions of population with a higher propensity for antimicrobial resistance, which would result in the misrepresentation of the true antimicrobial susceptibility in acute uncomplicated cystitis. Second, acute uncomplicated cystitis is a community-acquired infection, whereas surveillance studies are usually hospital based, which suggest that samples from inpatients or those with complicated infections might be included.^16,19 Again, this inclusion might lead to an incorrect and frequent overestimation of antimicrobial resistance rates. Unresolved UTI might be another reason for inaccurate surveillance studies.

Approximately, 15% of our patients with E. coli growth were referred from primary clinics after failed initial antimicrobial treatment. The antimicrobial susceptibility of these patients was expected to be lower compared with those with newly presenting acute cystitis, who are not exposed to antimicrobial treatment. We postulated that this proportion of unresolved acute cystitis was significant and could influence the total antimicrobial susceptibility rate in surveillance studies. Therefore, we aimed to determine whether there is an actual difference in antimicrobial susceptibility rates according to recent antimicrobial use and whether the difference is sufficiently significant to stratify treatment. To our knowledge, none of the previous surveillance studies have compared antimicrobial susceptibility with regard to recent antimicrobial exposal.

We divided all the patients with E. coli growth into groups based on recent antimicrobial use, and we compared the antimicrobial susceptibility rates between those with recent antimicrobial exposure and those without within 3 months. As a result, susceptibility rates of the RAE group to some antimicrobials were significantly lower than those of the NAE group. The susceptibility to ciprofloxacin was 64.2% in the RAE group, but this number was decreased by half in the NAE group, with a susceptibility rate of only 31.3%. This large discrepancy in antimicrobial susceptibility to ciprofloxacin might have occurred, in part, because fluoroquinolones are the most frequently prescribed antimicrobial agents in real practice in South Korea.¹¹; this country's treatment guideline that recommends fluoroquinolones for the first-line treatment of acute uncomplicated cystitis might have prompted this prescription rate. This result suggests that fluoroquinolones might be inadequate for empiric therapy in unresolved acute uncomplicated cystitis patients in South Korea and if the initial antimicrobial agent used is not known, antimicrobial agents other than fluoroquinolones should be used.

The antimicrobial susceptibility to amoxicillin–clavulanic acid, cefotaxime, cefoxitin, and TMP-SMX was also significantly lower in the RAE group. These results suggest that antimicrobial susceptibility to drugs that are frequently used might be significantly lower in patients with unresolved, acute uncomplicated cystitis and such susceptibility might be masked by the total susceptibility rates. Selecting drugs for empiric treatment based on only the total antimicrobial susceptibility could result in treatment failure. If a hospital's proportion of patients with unresolved acute uncomplicated cystitis is significantly high, knowledge of antimicrobial susceptibility patterns in these patients might aid in selecting the appropriate empiric antimicrobial agents. The level at which the proportion of patients with unresolved acute uncomplicated cystitis is deemed significantly high is yet to be determined.

The overuse of broad-spectrum antimicrobials, including fluoroquinolones and cephalosporins, has led not only to increased resistance to these drugs but also to the parallel development of coresistance to other classes of antimicrobials.² This phenomenon is called collateral damage, and it describes the adverse ecological effects of antimicrobial therapy, such as the selection of drug-resistant organisms and colonization or infection with multidrug-resistant organisms.¹⁷ Thus, fluoroquinolones and cephalosporins are no longer recommended as the first-line treatment for acute uncomplicated cystitis in the EAU and IDSA guidelines. Instead, drugs that cause minimal resistance and propensity for collateral damage are recommended as the first-line treatment, such as nitrofurantoin, fosfomycin, and pivmecillinam.^6,7 Unfortunately, these drugs are either unavailable or underused in South Korea, and despite the increasing antimicrobial resistance, fluoroquinolones are still recommended as the first-line treatment for acute uncomplicated cystitis.²⁰ In a study from 2003, the antimicrobial susceptibility of E. coli to ciprofloxacin was reported to be 84.8%.¹³ This figure has decreased progressively with continued overuse of fluoroquinolones; the rate of susceptibility was 76.6% in a study from 2008,¹⁰ 74.6% in a study from 2011,¹² and 69.8% in a study from 2013.¹¹ In the current study, the antimicrobial susceptibility of E. coli to ciprofloxacin and levofloxacin was 58.3% and 61.3%, respectively.

There were several limitations in the current study. First, its retrospective nature rendered this study prone to selection bias. Because blood laboratory exams are not routinely performed in acute uncomplicated cystitis patients, we had to rely on a chart review to select patients with complicating factors and thus exclude them from analysis. In addition, the initial antimicrobial agent used in patients with unresolved acute cystitis was unknown, which could have been valuable information for analysis and treatment. Second, the mean age of the patients in the RAE group was older than in previous surveillance studies, and there was a significant difference in the mean age between the RAE and NAE groups (p < 0.05). The reason for this finding is not clear, but we suspect that it might have been due to selection bias. Despite this difference, multivariable logistic regression analysis revealed that age was not a significant factor for resistance to most antimicrobials, on contrary to another study that found that old age could be a risk factor for antimicrobial resistance.⁴ Third, this study was a single center study, so it would be rash to comment on a general trend in antimicrobial susceptibility rates in South Korea using only our results. However, our results still represent valuable local antimicrobial susceptibility patterns, and we believe that, based on our results, differentiating unresolved UTI in future surveillance studies would be helpful in selecting the appropriate empiric drugs.

In summary, our study showed that antimicrobial susceptibilities were significantly low in acute uncomplicated cystitis patients with failed initial antimicrobial treatment, who are defined as unresolved cases. RAE was an independent factor for antimicrobial resistance. Our results suggest that first-line antimicrobials might have poor efficacy in cases of unresolved, acute uncomplicated cystitis and alternative or secondary antimicrobials should be considered in these cases.

Footnotes

Disclosure Statement

No competing financial interests exist.

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