Bacteremia is associated with significant morbidity and mortality in immunocompromised patients. Enterococci cause a median of 5% (0%–38%) bacteremia episodes in adults and 3% (0%–9%) in children with malignancies and following hematopoietic stem cell transplantation (HSCT),1 with the incidence in some centers even higher.2,3 A significant proportion of enterococci in immunocompromised patients is resistant to ampicillin, leading to increased use of vancomycin. Some studies report increased vancomycin resistance in enterococci and increased mortality in infections caused by resistant bacteria, compared with those which are susceptible.4,5 Data on enterococcal bacteremia (EB) in children with hemato-oncologic disease or following HSCT are based only on small studies, most published more than a decade ago, some of them mixed with adult data.5,6 The current study describes EB in children with malignancies and following allogeneic HSCT and compares episodes caused by enterococci that are resistant and susceptible to ampicillin and vancomycin.
MATERIALS AND METHODS
In this retrospective study, we analyzed episodes of EB that occurred during 2001–2015 in children (0–18 years of age) with malignancies and/or following HSCT in the hemato-oncology department of the Hadassah University Hospital in Jerusalem. This department is a tertiary referral pediatric center, which provides medical care for children in the Jerusalem area and West Bank, with patients also referred from other parts of Israel and from outside the country. For calculation of EB rate, we used as a denominator the total number of patients and as a numerator the number of EB that developed during treatment course. Patients with malignancies, who developed bacteremia during HSCT, were considered part of the HSCT group in our analysis. For each episode, we collected data on Enterococcus susceptibility patterns, as well as on demography, clinical presentation, laboratory findings, treatment and outcome. We then compared these parameters in episodes caused by ampicillin-resistant versus ampicillin-susceptible bacteria and in vancomycin-resistant enterococci (VRE) versus vancomycin-susceptible enterococci (VSE).
All children in the study routinely received antibacterial prophylaxis with trimethoprim-sulfamethoxazole (5 mg/kg/dose, based on trimethoprim twice daily, twice weekly). In case of abnormal temperature or other indicators of infection (deterioration of clinical condition, signs or symptoms of focal infection),7 2 sets of blood samples were drawn via an existing indwelling catheter and processed in the hospital’s microbiology laboratories. Throughout the study period, first-line antibiotic protocol for febrile neutropenic children admitted from home was piperacillin and gentamicin. For patients at risk for renal function impairment and those who developed signs of breakthrough infection while on antibiotic treatment, piperacillin-tazobactam was prescribed. Third-line protocol was meropenem, prescribed in patients who were severely ill, or who developed indications of infection during second-line protocol treatment. In the former, it was usually combined with an aminoglycoside and colistin or quinolone, based on the susceptibility pattern of previously isolated bacteria. Vancomycin was added to empirical treatment according to accepted guidelines.7 Routine screening for colonization with vancomycin-resistant enterococci was not performed in our center during the study period. Local institutional review board committee approved the study design.
On clinical suspicion, drawn blood samples were immediately injected into culture bottles and taken to the hospital’s microbiology laboratory. Bacterial identification was performed using standard biochemical and/or enzymatic assays (until 2012) and matrix-assisted laser desorption ionization time-of-flight since 2012 (Vitek MS; BioMérieux, Marcy-l'Etoile, France). Antimicrobial susceptibility testing was performed using the Kirby-Bauer disk-diffusion method, according to the relevant Clinical and Laboratory Standard Institute guidelines, for the following data analysis. Strains with intermediate susceptibility were defined as resistant.
EB was defined as isolation of enterococci species in at least 1 blood culture bottle.5,8–12 Primary EB was defined as the patient’s first episode of the infection. Recurrent bacteremia was analyzed as a separate episode and defined as a positive culture of the Enterococcus species, collected at least 30 days after the previous positive culture, with at least 1 negative blood culture documented between them.13 Prolonged bacteremia was defined when the time that elapsed between the first and last positive enterococcal cultures was 2 days or more. Definition of prior antibiotic exposure was any antibiotic treatment lasting for ≥48 hours during the month before bacteremia, but not at the time of bacteremia. Breakthrough bacteremia was defined as collection of the first positive enterococcal culture after the patient had received antibiotic treatment for at least 48 hours. Previous bacteremia was defined as any bacteremia episode within the 3 months preceding the first positive enterococcal culture. Severe and profound neutropenia were defined as absolute neutrophil count <500 and <100 cells/mm3, respectively. Thrombocytopenia was defined as a platelet count of ≤50,000/mL. Nosocomial EB was defined when infection occurred more than 48 hours after hospital admission.
Intensity of immune-suppressive treatment was classified according to the revised Intensity of Treatment Rating Scale 2.0, a treatment intensity rating system that was developed and validated aiming to classify pediatric oncologic diseases and treatments into 4 groups, from minimally intensive to most intensive.14
Descriptive statistics are given as means and SDs (M ± SD) [medians and interquartile range (first quartile–third quartile)] or as frequency (n) with percentage ((%, regarding to the scale of the variable or to the shape of the distribution. Differences between groups in continuous variables were analyzed using t tests or the nonparametric Mann-Whitney U test when the data did not follow the normal distribution.
First, univariate analysis was performed, in which we used logistic regression models and χ2 tests/Fisher exact tests to determine predictors of ampicillin/vancomycin resistance. Risk factors that approached significance (P < 0.05) in the univariate analysis were entered into a multivariable analysis. Fairth bias-reduced logistic regression model15 utilized to handle the problem of “separation” in logistic regression (for the second category of intensity of treatment, there were no cases of ampicillin/vancomycin resistance, so the odds ratio cannot be computed as the denominator is zero) in which maximum likelihood estimates tend to infinity.16 Statistical analysis was performed using SPSS statistical package (version 23.0 for Windows), Rstudio software version 3.4.3 and WinPEPI software version 11.63. All statistical tests used were 2 sided. P value of <0.05 was considered significant.
Study Population and Burden of Bacteremia
Fifty-six children developed 74 episodes of EB. Its rate of occurrence was significantly higher in patients with hematologic malignancies (HM; 22/429, 5.1%) compared with those with solid tumors (ST; 12/694; 1.7%) [relative risk (RR) = 3.0, 95% confidence interval (CI): 1.5–6.0, P = 0.001] and in patients after allo-HSCT (24/199; 12.1%) compared with those with malignancies (34/1123; 3.0%) (RR = 3.98, 95% CI: 2.4–6.6, P < 0.001). Within the group of children with ST, a significantly higher EB rate was observed in patients with neuroblastoma when compared with other ST (RR = 6.2; 95% CI: 2.1–18.9, P = 0.002) (Table 1).
Blood cultures yielded Enterococcus faecium in 46 of 74 (62.1%) episodes, E. faecalis in 27 of 74 (36.5%), and E. gallinarum in 1 (1.4%) episode. Dividing the study period into three 5-year subperiods, we observed an increase in the proportion of E. faecium compared with E. faecalis bacteremia (Fig. 1), but this difference was not statistically significant. Among 74 episodes, 43 (58.1%) were monobacterial (only Enterococcus species were cultured from blood). Another 31 (41.9%) were polymicrobial, in which enterococci were cocultured with other pathogens—enterobacteriaceae in 23 (31.1%), nonfermentative Gram-negative rods in 5 (6.8%), other Gram-negative bacteria in 6 (8.1%); Gram-positive cocci in 6 (8.1%); and Candida spp. in 5 (6.8%). Prolonged bacteremia occurred in 27 (36.5%) episodes.
In 28 (37.8%) episodes, 2 or more cultures were positive for Enterococci spp. We compared episodes with a single (46, 62.2%) and multiple positive cultures. There were no differences between the 2 groups in the proportion of patients with hematologic malignancies versus ST, following HSCT, receiving steroids; the presence of fever, shock, chills or local infection, neutropenia or thrombocytopenia; and breakthrough bacteremia, hospitalization in pediatric intensive care unit and mortality. There was a higher proportion of more intensive protocols in patients with multiple when compared with single positive culture: intensity level 2: 0 versus 8/45 (17.8%); level 3: 8/28 (28.6%) versus 11/45 (24.4%); and level 4: 20 (71.4%) versus 26/45 (57.8%), P = 0.02. There were trends to higher proportion of polymicrobial bacteremia (16; 57.1% versus 15; 32.6%, P = 0.05) and E. faecium (21; 75% versus 25; 54.3%, P = 0.05) in patients with multiple positive cultures. In 9 (19.5%) of 46 episodes with a single positive culture, only 1 culture set was obtained at the episode onset.
Clinical and Laboratory Characteristics of Episodes
Of the 74 EB episodes, 56 (75.6%) presented with abnormal temperature; 6 (8.1%) with chills; and 1 (1.3%) with septic shock. Other complaints included diarrhea (21 cases; 28.4%); vomiting (12;16.2%); and bloody stools (3; 4.1%). The stool of 5 of the children with diarrhea was positive for Clostridioides difficile toxin. EB was nosocomial in 63 (85.1%) episodes, occurring a median 1 month after admission; 53 (71.6%) episodes developed on antibiotic therapy; and in 35 patients (47.3%), bacteremia developed during the course of severe neutropenia (Table 2).
Central line was in place in 71 (96%) of all episodes; it was Broviac/Hickman in 61 (85.9%) children and implantable Port-a-cath (used starting from 2006) in 10 (14.1%).
The rate of ampicillin and vancomycin resistance (total and separately, for E. faecalis and E. faecium) is presented in Figure 2. A total of 42 of 73 (57.6%) isolates were resistant to ampicillin and 16 of 74 (21.6%) to vancomycin, with resistance significantly more common among E. faecium isolates. There was no statistically significant increase in the proportion of enterococci that were resistant to ampicillin or vancomycin during the study period (Fig. 3). Susceptibility to linezolid was tested in 16 VRE isolates, with all but one (15/16) proving susceptible. In 1 episode, 2 strains of VRE were isolated on linezolid treatment, 3 weeks apart, with the same susceptibility profile for all antibiotics other than linezolid. The minimum inhibitory concentration was 1 mg/L in the first isolate and 8 mg/L in the second. The patient recovered following treatment with daptomycin, based on susceptibility. Daptomycin susceptibility was tested in 10 of 16 VRE isolates, two of which (20%) were found resistant (both of them, E. faecium).
Treatment and Outcome
Five Enterococcus bacteremia episodes developed while patients were on antibiotic therapy to which the bacteria were susceptible in vitro. In the remaining episodes, appropriate therapy was initiated within 24–48 hours of infection onset in 44; in 15 episodes, it was delayed for 3–8 days; and in 3, no specific treatment for enterococci was started, and repeated bacterial cultures were negative. In 7 of 74 episodes, treatment data are absent.
In 2 EB episodes (2.7%), the patients died within 7 days. Both were receiving palliative treatment for uncontrolled malignant disease and had developed vancomycin-susceptible E. faecium bacteremia. Both were treated with vancomycin 24 hours following the first positive culture. One of them, a child with relapsed acute lymphoblastic leukemia following HSCT, had polymicrobial bacteremia together with Stenotrophomonas maltophilia. The second, with pancreatoblastoma, had monomicrobial bacteremia. An additional 2 patients, both with severe combined immune deficiency following HSCT, died within 30 days of the first positive bacteremia culture, bringing the 30-day mortality rate to 4 of 74 (5.4%). Neither of these 2, however, was bacteremic at the time of death, and their deaths were not attributed EB. In all 4 episodes that ended with mortality within 30 days, previous EB was recorded: in 2, it was caused by Enterococcus with the same susceptibility pattern as the earlier infection; in the other 2, the susceptibility pattern differed. The 30-day mortality was thus 4 of 22 (18.2%) in recurrent EB episodes and 0 of 52 (0%) in primary bacteremia episodes (P = 0.006).
Comparison of Episodes Caused by Enterococci Susceptible or Resistant to Ampicillin and Vancomycin
Table 2 compares demographic, background, clinical, laboratory and outcome characteristics in episodes caused by ampicillin-susceptible and ampicillin-resistant enterococci and in episodes caused by VSE and VRE.
Univariate analysis showed the following parameters to be significantly more frequent in episodes caused by ampicillin-resistant enterococci versus those which are ampicillin susceptible: age above 5 years at time of bacteremia, higher treatment intensity, breakthrough on meropenem, previous antibiotic therapy and, specifically, prior aminoglycoside exposure. In the multivariate analysis, higher treatment intensity was significantly associated with ampicillin-resistant enterococci bacteremia (Table 3). In both the univariate and multivariate analyses, prior penicillin exposure and breakthrough on vancomycin treatment were significantly more frequent in episodes caused by VRE versus VSE. No differences were found in duration of bacteremia, rate of recurrence, pediatric intensive care hospitalization and mortality in episodes caused by enterococci that are either susceptible or resistant to ampicillin and to vancomycin.
Current knowledge of the epidemiology, microbiology and outcome of EB in immunocompromised patients is largely based on studies in HSCT adults. Only a minority of these studies focuses on the pediatric HSCT population, with the data pertaining to children with malignancies more limited still.1,2,5,6,8,17 In this study, presenting 15 years of our experience with EB in children with malignant disease and following HSCT, we demonstrate that, in this patient population, EB usually occurs late in hospitalization (median 1 month after admission) as a breakthrough event on antibiotic therapy and preceded by bacteremia by other pathogens. It chiefly affects severely immunosuppressed children receiving high-intensity treatments for malignancy or following allo-HSCT.
In two-thirds of the episodes in our study, a single positive enterococcal culture was detected. Some of our findings, such as normal body temperature at bacteremia onset in some episodes, a high proportion of polymicrobial bacteremia and good outcome, could raise the question regarding the clinical significance of EB in the presence of single positive culture. We, however, obtained blood cultures only in the presence of clinical signs and symptoms compatible with bacterial infection with or without fever, such as deterioration in patient condition, chills, hypotension and local infection, as recommended by the Infectious Diseases Society of America guidelines7; and no differences in their frequencies were observed in patients with one when compared with multiple positive cultures. A high rate of polymicrobial infection in our study (41.9%) was consistent with other studies (13%–57%) and may be explained by multiple intestinal species translocation in patients with mucosal barrier injury.8,11,18 Interestingly, the proportion of polymicrobial episodes was higher in patients with multiple positive enterococcal cultures, which may be explained by several intestinal species translocation in patients with mucosal barrier injury. The proportion of more intensive protocols was higher in patients with multiple positive enterococcal cultures, which also can be related to more severe mucosal barrier injury predisposing to bacterial translocation. Finally, there was no difference between episodes with single or multiple positive cultures in the proportion of those needing pediatric intensive care unit hospitalization or ending with mortality. These data support the assertion that single culture positive for Enterococci can be addressed as a true bacteremia.
Data on enterococci resistance rates and risk factors are scarce in immunocompromised children. In our study, ampicillin resistance rates were in the high range (57.6%) of those reported in adults following HSCT, 8%–48%.17 High-intensity treatment protocols tended to predispose to ampicillin resistance, prompting glycopeptide use. In contrast to immunocompromised adults, vancomycin resistance among enterococci was once rare in children; in the review of studies published until 2011,1 its reported rate was zero, compared with a median 23% (range: 0%–50%) in adults with HM and HSCT. Later studies, however, demonstrate higher vancomycin resistance rates among enterococci causing bacteremia in children with lymphoma (8/18, 44.4%)19 and following HSCT (31%–38%).5,20 Our study demonstrates a high vancomycin resistance rate (21.6%). Similar to other studies, it was higher among E. faecium infection than E. faecalis.6,21 This finding, together with evidence of the increasing proportion of E. faecium among all enterococci,3,22 underlines the importance of monitoring of local epidemiology and resistance trends.
Rectal surveillance for VRE detection was not performed during the study period, but initiated recently.
Especially worrying is the development of linezolid and daptomycin resistance, including 1 case with possible development of resistance on linezolid treatment. Resistance to these agents is fortunately very rare in children,23–25 and their use should be limited to situations where there is no other choice. Unfortunately, the isolates were unavailable; thus, it was impossible to determine the mechanism of resistance.
In adults with leukemia or following HSCT, several risk factors predispose to VRE bacteremia. Among them are intestinal VRE colonization, gastrointestinal disturbance, comorbidities, exposure to aminoglycosides, antianaerobe antibiotics, β-lactams and vancomycin, prolonged hospitalization, underlying diagnosis of acute myeloid leukemia, allo-HSCT, engraftment delay and more.2,5,9,12,26–28 In children following HSCT, neutrophil engraftment within 1 month was protective, and previous bacteremia predisposed to VRE bacteremia.20 Similar to adult datum, previous penicillin exposure (the main empirical treatment administered in our center) correlated with VRE bacteremia in our study. Alteration of intestinal flora following exposure to antimicrobials probably facilitates VRE expansion in the gastrointestinal tract, regardless of previous exposure to vancomycin. Limitation of broad-spectrum antibiotic therapy duration and early discontinuation when possible29 are thus important in preventing resistant bacterial infections. As most therapeutic protocols for immunocompromised patients are empiric, each hospital must develop local guidelines for appropriate agent addition following notification of Gram-positive cocci in chain-growth in blood cultures, pending susceptibility analysis, especially in patients at risk for resistant enterococcal infections. Strict infection control measures should be implemented to prevent the spread of resistant bacteria.
Data on EB rates in children with ST are scarce. In the handful of pediatric studies performed, only 2 of 185 (1.1%) children with HM and ST and 1 of 80 (1.3%) with neuroblastoma developed EB.30,31 In our study, we found high EB rates in children with neuroblastoma, similar to those in HM and HSCT patients, and higher than in children with other ST. We have previously demonstrated a higher rate of nonfermentative Gram-negative rods bacteremia in children with neuroblastoma compared with some other ST.32 This may be because children with neuroblastoma, especially young infants or those with metastatic disease, receive high-intensity myelo-suppressive chemotherapy, similar to that given for HM. This underscores the importance of enterococci as a possible cause of bacteremia in children with neuroblastoma, particularly in centers where empirical therapy is based on cephalosporins, which lack antienterococcal activity.
Some studies, mainly those involving adults following HSCT, report high rates of mortality (18%–53%), severe sepsis (36%) and septic shock (12%) in adults following HSCT with EB.2,5,8,10,18,21,33 Some, including those performed in children, as well as meta-analysis, demonstrate increased mortality in VRE compared with VSE infections.4,5,18,21 VRE infection, mainly affecting severely ill patients, may be a marker for the critical condition of high-risk patients, although its direct contribution to the deterioration of the patient’s condition cannot be excluded. In contrast, mortality rates in our study were low and unrelated to vancomycin resistance. Only 2 patients with uncontrolled underlying disease died within 7 days of contracting EB. Not previously reported as a negative prognostic marker, we found recurrent EB to be associated with high mortality rates—possibly representing severe patient condition predisposing to repeated enterococci bloodstream translocation.
Our study has several limitations. It is a retrospective, single-center study. We could not assess association between VRE colonization and bacteremia, as rectal surveillance was not performed routinely in our center during the study period. Only a minority of VRE strains was tested for linezolid and daptomycin susceptibility.
Considering the scarcity of recent data on EB in immunocompromised children, however, especially in those with malignancies, we believe that our relatively large series adds important information of general relevance. We have demonstrated that EB occurs mainly as a nosocomial infection in children receiving high-intensity chemotherapy, especially in those with neuroblastoma, HM and following HSCT. Antibiotic resistance is common, with vancomycin resistance occurring regardless of previous vancomycin use. Prognosis in immunocompromised children with EB is better than that reported in previous studies— most of which were performed in adults. Recurrent EB is associated with increased mortality.
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