Previous studies in the literature have described risk-factors for ESBL acquisition in children and adults. Although ESBL-producing bacterial infections tend to affect adults 65 years and older at a higher rate, children are believed to be an important reservoir [1, 2]. Strategies for treatment in children using non-carbapenems are important for antimicrobial stewardship and decreasing the risk of future morbidity and mortality related to antibiotic resistance.

We noticed growing numbers of pediatric patients with positive cultures for ESBL-producing bacteria at our hospital over several years (Fig. 1). Extended-spectrum Beta-Lactamase (ESBL) producing bacteria have been increasing for the past two decades and emerging as a world health concern, given their resistance to available antimicrobials for treatment [1-3]. Infections involving ESBL-producing bacteria are of great concern because of their increasing antibiotic resistance and relatively higher mortality rate compared with non-ESBL-producing bacterial infections [2, 4]. ESBL-producing bacteria create plasmid-mediated enzymes (β-lactamases) that cleave the β-lactam ring making them resistant to β-lactam antibiotics such as penicillins and cephalosporins [1, 2, 5]. Furthermore, these bacteria have a genetic capacity to acquire resistance to other antibiotic classes [2]. For some cases of infection involving ESBLs, extensive co-resistance leaves carbapenems as the only choice for treatment. Carbapenems are considered the treatment of choice for these organisms overall, though many ESBLs also show susceptibility to other antibiotic options and non-carbapenem antibiotics are appropriate for some infections [2].

Fig. (1). Cases of ESBL-producing cultures over study time period.

ESBL producing bacteria pose a challenge for the treating clinician in making choices for empiric antimicrobial coverage before culture susceptibility results are available because resistance patterns to non-carbapenems are somewhat unpredictable. Prompt appropriate antimicrobial treatment for ESBL infections is essential for successful outcomes, therefore, clinicians must use informed judgments regarding initiating carbapenems.

Infections secondary to ESBL-producing bacteria are most common in those with chronic conditions who are also at risk for multiple or prolonged hospitalizations [3, 4, 6]. We sought to find if any stable or modifiable risk factor for ESBL acquisition was associated with increased resistance to non-carbapenem antibiotics in children. Many studies have contributed to our knowledge of risk factors associated with ESBL acquisition, but few describe risk for ESBL antibiotic co-resistance in children associated with risk factors [1-7].

We sought to find alternatives to carbapenem use and hypothesized that a child’s personal history of chronic disease would be a useful factor to predict antibiotic resistance. Antibiotics assessed for susceptibility included ciprofloxacin, trimethoprim/ sulfamethoxazole (TMP-SMX), amoxicillin-clavulanate, gentamicin, amikacin, tobramycin, nitrofurantoin, and piperacillin-tazobactam (PTZ). Risk factors were included based on ESBL acquisition and are described in detail below.

Knowing risk factors that place children at risk of ESBL infection with highly resistant bacteria is important for judging initial treatment. Likewise, rates of antibiotic susceptibility among ESBL isolates are useful information in deciding the initial choice of empiric treatment. This information aims to guide initial treatment with non-carbapenem antimicrobials, particularly for children who are clinically stable.

This is an institutional review board approved single-center observational analytic study performed using retrospective chart review in a 248-bed freestanding pediatric hospital in Central Texas, serving the 46 surrounding counties.

Inclusion criteria consisted of all pediatric patients ages 0-18 years with a laboratory-confirmed ESBL-positive bacteria cultured from any body site between January 1, 2009, and July 1, 2016. Cases were identified by the hospital infection preventionist and included cases encountered in the emergency department, hospital-based specialty clinic, and inpatient setting. Cases of ESBL-positive isolates were included rather than individual patients to gather data specifically on risk factors and the patterns of antibiotic susceptibility among ESBL-producing bacteria.

All isolates were reviewed for susceptibility to the following antibiotics which represent treatment options: TMP-SMX, ciprofloxacin, amoxicillin-clavulanate, gentamicin, tobramycin, amikacin, nitrofurantoin, PTZ, cefepime, and meropenem. This study relied on susceptibility testing done as standard of care, including Vitek 2 automated identification and antibiotic susceptibility tests. All isolates were tested for TMP-SMX, ciprofloxacin, gentamicin, tobramycin, amikacin, cefepime, and meropenem; nitrofurantoin was tested on urine specimens. Data for PTZ and amoxicillin-clavulanate were available in 78% and 63% of cases, respectively. Isolates were considered to have resistance if the report was intermediate or resistant.

A review of the literature was performed to identify established ESBL-related risk-factors. Each case was manually reviewed for the documented presence of nine ESBL-related risk-factors documented in the electronic hospital chart: Genitourinary (GU) abnormalities, antibiotic use in the previous three months (specifically beta-lactams, TMP-SMX, or quinolones), history of international travel or residence within the previous year, surgery within the previous year, recent or ongoing use of indwelling devices prior to current hospitalization, lifetime neonatal Intensive Care Unit (ICU) and ICU admission, history of recurrent Urinary Tract Infection (UTI), history of previous ESBL-producing bacteria, or non-GU comorbidities. ESBL risk factors were chosen based on their effect on ESBL acquisition in the literature and general availability in the pediatric chart. Other variables collected included age, sex, race/ethnicity, hospital length of stay, site of culture, treatment received for ESBL-producing bacteria, the presence of infectious diseases consult, discharge diagnosis, and ESBL-producing bacteria susceptibility profile. Due to the retrospective nature of this descriptive study, there were some data gaps in the variables assessed. The decision was made to report documented risk-factors in the chart. Cases for which a risk-factor was not addressed or not documented were coded as not having that risk-factor. Cases were manually reviewed by two study team members and a portion of that review was audited by the first reviewer.

The primary outcome measured in the study was resistance to non-carbapenem antibiotics. This outcome was chosen because resistance to non-carbapenem antibiotics would identify groups of children more likely to need meropenem for treatment from those who could be treated empirically with a non-carbapenem. Likewise, it would show which non-carbapenems may be most appropriate for empiric treatment. Secondly, we sought to find a relationship between ESBL-associated risk factors and resistance to non-carbapenem antibiotic options.

Data were input into a Redcap database and analyzed using logistic regression to determine associations between ESBL-producing bacteria cultures resistant to non-carbapenems and the presence of ESBL-related risk-factors as well as differences between groups classified as children with chronic comorbidities versus children without chronic medical conditions [8]. Rstudio software was utilized for statistical testing [9].

ESBL-producing bacteria were present in 223 cases. One case was excluded from analysis for antibiotic resistance because susceptibilities were not performed. Among the 222 cases studied, 14 isolates were repeated, individual children. The majority of the patients were female (69%) with the most common site of culture being the urinary tract (77%), followed by respiratory cultures. Table 1 shows demographics and ESBL-related risk-factors among the cases studied. Escherichia coli was the most common bacteria isolated (83%), followed by Klebsiella pneumoniae (11%). At least one known ESBL related risk-factor investigated was present in 71% of all cases. Nearly half (48%) of the patients were identified as having a history of chronic comorbidities. Half of the total cases resulted in hospital admission. Bloodstream infection was seen in 4% (9) of cases.

All isolates were resistant to cefepime; All isolates were susceptible to meropenem. Susceptibility to PTZ was 85.9% (177 tested). Amikacin showed susceptibility in 95.5% of cases.

Among oral therapeutic options, amoxicillin-clavulanate showed the highest susceptibility at 43.2% (testing done in 63% of cases). Among the samples tested for all 3 oral options (SMX-TMP, ciprofloxacin and amoxicillin-clavulanate), 23% of cases were resistant to all. Rates of susceptibility to each antibiotic are represented in Table 2.

We did not find any single risk factor or history of chronic comorbidities in patients’ history to be significantly associated with resistance to Amikacin, PTZ, or all three oral options combined. There were no isolates with resistance to all non-carbapenems and therefore, a risk factor associated with the need to meropenem treatment could not be assessed.