Abstract
Children who undergo clean intermittent catheterization (CIC) are at increased risk of infection with antimicrobial-resistant bacteria. Here, we show increasing rates of resistance to third-generation cephalosporins by Enterobacteriaceae cultured from urine from children who were undergoing CIC.
Background
Children undergoing CIC frequently have positive urine culture results and receive many antimicrobial agents. Subsequently, this population is at high risk for infections caused by antimicrobial-resistant bacteria. Resistant pathogens, such as vancomycin-resistant Enterococcus (VRE), carbapenem-resistant Enterobacteriaceae (CRE), and organisms that produce extended-spectrum β-lactamases (ESBLs), which are third-generation cephalosporin resistant (3GCR), are of particular concern.
Methods
In this retrospective study, all urine culture results and antimicrobial-susceptibility testing results were obtained between January 2008 and December 2014 from the electronic health record of children ≤18 years of age who were undergoing CIC (n = 14 832). Isolates were identified as VRE, CRE, or 3GCR. Organisms of the same type that were obtained in the same year and with identical antibiotic susceptibilities from the same patient were excluded. Simple linear regression was used to determine the association between year and rates of resistance.
Results
A total of 3997 positive culture results were included in this analysis. Of all Enterococcus isolates for which susceptibility results were available, 4.6% were VRE, 11.1% of all isolates that belonged to the Enterobacteriaceae family were 3GCR, and 0.4% of eligible isolates were CRE. There were significantly higher rates of resistance to third-generation cephalosporins and CRE in 2014 than in 2008 (P < .01). Simple linear regression revealed a significant association between year and rate for resistance to third-generation cephalosporins but not for CRE or VRE. The rate of increase in resistance to third-generation cephalosporins in patients who required CIC was higher than that in patients who did not need CIC.
Conclusions
The rate of resistance to third-generation cephalosporins has increased significantly in the past 7 years in children undergoing CIC, which indicates that careful monitoring is warranted for continued increases in antimicrobial-resistant organisms in this unique patient population.
Keywords: antimicrobial resistance, clean intermittent catheterization, urinary tract infection
INTRODUCTION
The emergence of antimicrobial-resistant organisms is becoming a concerning public health problem. The Centers for Disease Control and Prevention (CDC) has estimated that more than 2 million people per year develop infection with resistant organisms, 23 000 of whom die as a direct result of these infections [1]. In addition, the rates of antimicrobial-resistant organisms have been increasing. In 2014, the World Health Organization reported very high rates of resistance in all of their regions; for example, all regions reported that more than 50% of all Klebsiella isolates were resistant to third-generation cephalosporins, and one-third of their regions reported more than 50% resistance to carbapenems [2]. The CDC considers carbapenem-resistant Enterobacteriaceae (CRE) to be an urgent threat and extended-spectrum β-lactamases (ESBLs) that produce Gram-negative bacilli and vancomycin-resistant Enterococcus (VRE) serious threats [1]. Given that infections with antimicrobial-resistant organisms are associated with longer hospital lengths of stay [3], an increased number of deaths [4], and high healthcare costs [5], attention must be placed on tracking trends in antimicrobial resistance.
Urinary tract infection (UTI) is common in children and occurs in approximately 3% of all children annually [6]. Children who require clean intermittent catheterization (CIC) are at high risk for UTI because of their underlying neurogenic bladder and need for repeated catheterization [7]. Symptomatic UTI is treated aggressively in this population to prevent development and/or progression of chronic kidney disease and to prevent systemic spread of the infection (eg, urosepsis). Asymptomatic colonization can be treated, because identifying symptomatic infections is sometimes difficult. Increased exposure to antimicrobials is a known factor in the development of infections caused by antimicrobial-resistant bacteria [1]. In addition, the use of urethral catheterization is also a known risk factor for bacteriuria and recurrent UTI [8]. Therefore, children undergoing CIC have high rates of antimicrobial resistance among the pathogens grown in urine culture [9]. Recent data showed that ESBLs and Enterobacteriaceae resistant to third-generation cephalosporins have become increasingly prevalent within the pediatric population [3, 10] and that urinary tract anomalies and prophylactic antimicrobial use are risk factors for UTI with antimicrobial-resistant organisms [11]. However, there are limited data on recent trends in antimicrobial-resistance patterns in children undergoing CIC. Here, we describe trends of antimicrobial-resistant organisms seen in urine cultures from children who underwent CIC at Cincinnati Children's Hospital Medical Center between 2008 and 2014.
METHODS
Data Collection for Patients Undergoing CIC
All urine culture results, antimicrobial-susceptibility data, and demographic information were pulled from electronic health records at Cincinnati Children's Hospital and Medical Center between January 2008 and December 2014 from patients aged ≤18 years with an International Classification of Diseases, Ninth Revision, code for neurogenic bladder (596.54), spina bifida (741), paraplegia (344.1), or quadriplegia (344). The patient records were then reviewed manually to ensure that the patients were on a CIC regimen; patients on transient CIC were removed from the study. During the manual data review, the reasons for CIC were extracted from the electronic health record. The data were cleaned manually, and duplicate entries were removed. To ensure accuracy, 10% of the urine cultures were chosen randomly, and urine-culture sensitivity was confirmed by reviewing the electronic health record. Urine cultures performed within 7 days of a previous urine culture that had the same results (ie, same pathogen or no growth) were excluded from analysis. Positive urine cultures from the same patient within a single calendar year that grew the same pathogen with the same susceptibilities were excluded (Figure 1). Urine cultures from outside institutions were also excluded from the analysis. Culture results were included in the analysis if they had at least 10 000 colony-forming units (CFU)/mL of a single pathogen in a specimen obtained by catheter. Cultures with more than 1 identified pathogen were included, whereas cultures with unidentified mixed organisms were excluded from analysis. Cultures that grew a nonbacterial pathogen (eg, yeast) were excluded from analysis. This study was approved by the Cincinnati Children's Hospital Medical Center Institutional Review Board.
Figure 1.
Consolidated Standards of Reporting Trials-type diagram clarifying derivation of the number of analyzed cultures (n = 3828) from the initial number of cultures obtained from the electronic medical records (n = 14 832). Abbreviations: CFU, colony-forming unit; CIC, clean intermittent catheterization.
All Urine Cultures
To determine the effect of the change in the Clinical Laboratory Standards Institute (CLSI) breakpoints that occurred in 2010, the sensitivity of each urine culture from a patient between 2008 and 2014 who was not undergoing CIC that grew a pathogen that was a member of the Enterobacteriaceae family was obtained from a database maintained by the Antimicrobial Stewardship Committee at Cincinnati Children's Hospital Medical Center. This database lists antimicrobial susceptibilities according to category, such as third-generation cephalosporins, but does not list susceptibilities to each antibiotic tested within that category.
Definitions
Any Escherichia coli, Enterobacter species, Klebsiella pneumoniae, or Klebsiella oxytoca isolate that was carbapenem nonsusceptible and resistant to a third-generation cephalosporin (ceftriaxone, ceftazidime, or cefotaxime) was defined as CRE [12]. Any Enterococcus species not susceptible to vancomycin was defined as VRE. We classified members of Enterobacteriaceae as being third-generation cephalosporin resistant (3GCR) if the isolates were nonsusceptible to cefotaxime, ceftazidime, or ceftriaxone. This classification is a more comparable measure of phenotypic resistance than those used for CRE and VRE. However, the use of this definition does not allow for differentiation between various mechanisms of resistance, including ESBL and AmpC-mediated resistance.
Laboratory Methods
Antimicrobial-susceptibility testing of bacterial isolates was performed using the Vitek 2 and Etest systems (BioMérieux, Marcy-l’Étoile, France) as part of routine clinical care. Breakpoint interpretations were made following the appropriate CLSI guidelines [13, 14]. Confirmation of vancomycin resistance in Enterococcus spp. and the expression of an ESBL in Gram-negative bacilli were performed using the Etest system. Detection of carbapenem resistance was determined using the Etest system for minimum inhibitory concentrations (MICs) and the modified Hodge test [14].
Changes to the CLSI guidelines and breakpoints altered how results on isolates that were suspected to express ESBLs or carbapenemase were reported during the time course of this study [15]. These changes were clinically implemented at our center in September 2011. Before 2010, Enterobacteriaceae isolates with MICs of ≤8 µg/ml for cefazolin, cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone were considered susceptible. Additional confirmatory testing for the detection of ESBLs or carbapenemases was indicated for isolates with an elevated cephalosporin or carbapenem MIC. If an ESBL was identified, susceptibility results for all cephalosporins and penicillins were changed to resistant. If a carbapenemase was identified, susceptibilities for all β-lactam antibiotics were changed to resistant. After the changes in the recommendations, isolates with cefotaxime, ceftizoxime, and ceftriaxone MICs of <1 µg/mL were considered susceptible to the corresponding drug, whereas isolates with a ceftazidime MIC of <4 µg/mL were considered ceftazidime susceptible. In addition, the breakpoints for carbapenems were lowered to enable identification of potential ESBL, AmpC, or carbapenemase producers without requiring additional testing. Testing with the Etest system was continued after the changes in the recommendations for isolates with an elevated MIC for one of the third-generation cephalosporins tested. If an ESBL was identified, the susceptibility results for all first-, second-, and third-generation cephalosporins were changed to resistant.
Analysis
Data analysis was performed using SPSS 22.0 (SPSS, Inc., Chicago, Illinois). Because patient age was not normally distributed, we used the Mann–Whitney U test to compare median ages of the children who were and those who were not undergoing CIC. Categorical variables were compared using the ϰ2 test. Simple linear regression was used to determine the association between year and rates of resistance.
RESULTS
Patient characteristics are listed in Table 1. Overall, 44.6% of all urine cultures grew >10 000 CFU/mL of 1 or more identifiable uropathogens, whereas 4.0% of all cultures had mixed growth without an identifiable pathogen. Of the 3828 positive culture results from 832 patients that were included in this analysis, E coli was the most common pathogen (34.5%), followed by Enterococcus spp. (14.3%), K pneumoniae (10.0%), Pseudomonas aeruginosa (6.2%), Staphylococcus spp. (5.4%), Enterobacter spp. (4.8%), Proteus spp. (4.2%) Citrobacter spp. (3.9%), Streptococcus spp. (3.0%), and K oxytoca (1.8%). The remaining bacterial species (which belonged to the genera Achromobacter, Acinetobacter, Aerococcus, Corynebacterium, Delftia, Elizabethkingia, Flavobacterium, Gardnerella, Gemella, Globicatella, Haemophilus, Leuconostoc, Morganella, Myroides, Neisseria mucosa, Ochrobactrum, Pantoea, Providencia, Raoultella, Rothia, Serratia, Sphingomonas, or Stenotrophomonas) each accounted for <2% of the total positive cultures.
Table 1:
Patient Characteristics
| CIC Patients (n = 862) | Non-CIC Patients (n = 4218) | P-value | |
|---|---|---|---|
| Male (%) | 46.4 | 8.0 | <.01 |
| White (%) | 76.3 | 80.3 | .14 |
| Black (%) | 8.8 | 11.8 | .02 |
| Asian (%) | 5.2 | 1.6 | <.01 |
| Hispanic (%) | 4.0 | 1.9 | <.01 |
| Age (years) | 9.8 [6.6-14.27] | 15.6 [9.3-22.8] | <.01 |
| Reason for CIC (%) | |||
| Myelomeningocele | 32.9 | – | – |
| Anorectal Malformation | 26.7 | – | – |
| Encephalopathy | 6.5 | – | – |
| Tethered Cord | 5.5 | – | – |
| PUV | 4.6 | – | – |
| GU anatomic anomaly | 3.9 | – | – |
| NOS | 3.5 | – | – |
| Spinal Cord Injury | 3.0 | – | – |
| Oncologic | 2.8 | – | – |
| Eagle Barrett Syndrome | 1.8 | – | – |
| Caudal Regression Syndrome | 1.5 | – | – |
| Other | 7.3 | – | – |
Age presented as: median [Interquartile range].
Abbreviations: CIC, clean intermittent catheterization; GU, genitourinary anomalies; NOS, not otherwise specified; PUV, posterior urethral valves.
The presence of phenotypic resistance to carbapenems was seen in 0.4% of all eligible Enterobacteriaceae isolates. Of these isolates, 70% were identified as K pneumoniae, 20% as E coli, and 10% as Enterobacter cloacae. Resistance to third-generation cephalosporins was seen in 11.1% of all eligible isolates. Of all Enterococcus isolates in the cohort of patients who required CIC, 4.5% were resistant to vancomycin. The frequency of CRE increased over our study period, from 0% in 2008 to 1.8% in 2014 (P < .01), as did the rate of resistance to third-generation cephalosporins, from 9.7% in 2008 to 12.0% in 2014 (P < .01) (Figure 2). There was significant variability in the rates of VRE between 2008 (5.0%) and 2014 (4.9%), although no increasing trend was noted. Simple linear regression revealed a significant association between year and rate of isolates that were 3GCR but not of CRE or VRE isolates (Table 2).
Figure 2.
The number of isolates over the study period that were third-generation cephalosporin resistant (3GCR) (P < .01) and were carbapenem-resistant Enterobacteriaceae (CRE) was increased (P < .01); no significant increase in the number of vancomycin-resistant Enterococcus (VRE) isolates was seen (R2 = 0.717 [3GCR], 0.005 [VRE], and 0.329 [CRE]).
Table 2.
Simple Linear Regression Using Increase in Year Between 2008 and 2014 as Predictor
| Outcome | Odds Ratio | 95% Confidence Interval |
|---|---|---|
| 3GCR | 0.85 | .19 to 1.17 |
| CRE | 1.56 | −1.21 to 4.96 |
| VRE | 0.09 | −.76 to .089 |
Abbreviations: 3GCR, third-generation cephalosporin resistant; CRE, carbapenem-resistant Enterobacteriaceae; VRE, vancomycin-resistant Enterococcus.
In a comparison between patients who were and those who were not undergoing CIC, 4680 cultures from 4218 patients who did not undergo CIC were included in the analysis. The rates of 3GCR and CRE isolates in all non-CIC urine cultures were 4.4% and 0.1%, respectively. These rates are significantly lower than those in the children who were undergoing CIC (P < .001 for both 3GCR and CRE isolates). When comparing the rates of resistance between the children who were and those who were not undergoing CIC before and after the implementation of the 2010 CLSI guidelines, the rate of increase in both 3GCR and CRE isolates from children who were undergoing CIC was greater than that for those who were not. The rates of change for the children undergoing CIC before and after the guidelines were 0.46 and 0.49 increase in frequency per year for 3GCR isolates (Figure 3) and 0.5 and 0.49 increase in frequency per year for CRE isolates. The preguideline and postguideline rates of change for isolates that were 3GCR were 0.8 and −0.3 and for CRE isolates were 0.1 and 0 for the children not undergoing CIC.
Figure 3.
(A) Comparison of rates of third-generation cephalosporin resistant (3GCR) isolates in urine cultures from children who were and those who were not undergoing clean intermittent catheterization (CIC). Shown also are comparisons of trends in resistance to third-generation cephalosporins between the children who underwent CIC and those who did not before (B) and after (C) the change in CLSI guidelines (instituted in September 2011). Data in B and C for 2011 represent all cultures before or after September.
DISCUSSION
We describe here trends in antimicrobial resistance of bacteria grown in urine cultures from children who were undergoing CIC and show a significant increase over 6 years in the rate of both CRE and 3GCR isolates. There are limited data on trends in antimicrobial resistance of uropathogens in children undergoing CIC. One series reported similar trends of increasing antimicrobial resistance in this population but in a smaller cohort and over a shorter period of time [16]. Several cross-sectional studies examined resistance rates in children who were undergoing CIC; 8.7% of all isolates were ESBL-producing organisms, and 16% to 33.3% of all E coli strains produced ESBL [3, 17]. In our series, we found a lower rate of resistance in E coli than previously reported, because 9.0% of all E coli strains were 3GCR. Similar work was done to examine resistance patterns in all children who presented with UTI, although those results are not directly comparable to ours because the study was not limited to children undergoing CIC. Studies that examined rates of ESBLs in urine cultures in a general population of children found rates of ESBLs that ranged from 7.8% to 10.4% [18, 19]. In our series, we found that 11.3% of all isolates that were members of Enterobacteriaceae were 3GCR.
The use of resistance to third-generation cephalosporins in our series did not allow for discrimination between various mechanisms of resistance and resulted in overestimates of the rate of ESBLs, because AmpC can also confer resistance to third-generation cephalosporins [20]. However, both the CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) do not recommend ESBL screening [21, 22]. The CLSI contends that the use of adjusted MICs is sufficient for patient management and that more specific ESBL screening, although useful for infection-control and epidemiologic studies, would not improve clinical care [23]. Indeed, a retrospective analysis of patients with bacteremia from K pneumoniae or E coli with reduced susceptibility to third-generation cephalosporins found that there was no difference in prognosis between ESBL, AmpC, and bacteria with both ESBL and AmpC [24]. Therefore, tracking and understanding trends in resistance to third-generation cephalosporins is sufficient for a clinician to appropriately manage UTI in such patients.
Specific bacterial strains of high concern, including VRE and CRE, were present in our population, although at very low rates. The lack of a significant increase in the rate of VRE is likely a result of a combination of factors. Although hospital-level infection-control policies and judicious use of broad-spectrum antimicrobials have likely contributed to controlling the spread of VRE in this patient population, the underlying molecular epidemiology of infections with VRE might also play a role. However, the emergence of CRE in urine cultures during this time period is concerning, although not unexpected. The distribution of CRE isolates is similar to that in previous reports, and K pneumoniae is the most common type of CRE isolate, followed by E coli and Enterobacter cloacae isolates [12]. A recent multisite study found that CRE isolates were found most commonly in urine of patients with lower UTI and that a significant proportion of the study population (91%) with CRE-positive culture results had underlying comorbidity and previous healthcare exposure. In addition, 20.5% of the population had urinary tract dysfunction or anatomic abnormalities [12]. Given that CRE seems to be more common in patients with UTI and previous healthcare exposure, children undergoing CIC are a population at high risk for CRE infection. Indeed, the authors of a recent case series of CRE in a pediatric population reported that 30% of their patients with CRE had neurogenic bladder (1 with neurogenic bladder, 1 with spina bifida, and 1 with lipomeningocele) [25]. However, given the overall low rate of CRE isolated in our cohort, it is possible that the appearance of CRE in 2014 in our cohort was a sporadic occurrence rather than the start of a steady increase. Additional monitoring for CRE in this population is warranted.
As noted already, the CLSI guidelines changed during the time period included in this study. Because the newer guidelines lowered the MICs for cefotaxime, ceftriaxone, ceftizoxime, and carbapenems, there was potential for this change in breakpoints to affect our reported trends. Indeed, various studies on the effect of the change in CLSI reporting on reported resistance trends have not found an increase after implementation of the new guidelines [26, 27]. However, we found that, after controlling for the CLSI guideline change in 2010, the increase seen in the children who were undergoing CIC was greater than that in those who were not undergoing CIC. Although the change in the guidelines might have had a small effect, it does not fully account for our reported trends.
We based our microbiologic threshold for significant bacterial growth on changes in reporting bacterial growth in urine cultures during the years included in this study. In our data, 36% of cultures with any identifiable bacterial growth (ie, cultures not reported as “mixed growth”) were reported as 10 000 to 100 000 CFU/mL. Therefore, to avoid excluding a significant proportion of our data, we chose to include all cultures with a bacterial burden greater than 10 000 CFU/mL. In addition, the Infectious Diseases Society of America stated that a colony count greater than 10 000 CFU/mL in in the presence of symptoms in a patient undergoing CIC is indicative of UTI [28]. Although bacterial growth of 10 000 CFU/mL can be considered clinically insignificant growth in the absence of symptoms, it does represent the presence of that bacterial strain and thus can be used to track resistance patterns.
There are some limitations in this study. We could not distinguish ESBL from AmpC and therefore relied on resistance to third-generation cephalosporins as a phenotype to trend. Given this limitation, we were unable to detect the specific genes responsible for resistance and are unable to determine if the increase in the rate of 3GCR isolates was a result of the development of new resistant strains of bacteria or if the increase represented progressive development of resistance within the same bacterial strain. We also were limited by the retrospective nature of this study and the inherent limitations in that study design. In addition, the distinctive regional variations of CRE epidemiology limits the generalizability of results regarding CRE to other centers. Finally, we relied on billing codes to identify patients with neurogenic bladder who required CIC. Although we manually confirmed the patients who were identified, it is possible that we missed a portion of patients who were undergoing CIC.
CONCLUSIONS
Here we describe 7 years of urine culture results in patients who were undergoing CIC. CRE, VRE, and 3GCR isolates were present in a small number of these cultures, although trends in resistance to third-generation cephalosporins and CRE increased significantly over the study period. Additional monitoring of resistant organisms and accurate distinction between UTI and asymptomatic colonization are necessary in this unique patient population.
Acknowledgments
Financial support. Dr Forster received research training support from the National Institutes of Health through National Research Service Award Institutional Training Grant T32 HRSA 09-046 CFDA 93.186.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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