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Correlation between multidrug-resistant bacteria colonization and bloodstream infections in children with hematolymphoid malignancies in a tertiary cancer center in India
Nihad Salifu1, Gaurav Narula2, Maya Prasad2, Sanjay Biswas3, Rohini Kelkar3, Shripad Banavali2
1 Department of Child Health, Korle Bu Teaching Hospital, Accra, Ghana
2 Department of Pediatric Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India
3 Department of Microbiology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Submission||06-Sep-2019|
|Date of Decision||09-Oct-2019|
|Date of Acceptance||02-Feb-2020|
|Date of Web Publication||18-Nov-2020|
Department of Pediatric Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Bloodstream infections with drug-resistant bacteria are associated with a higher morbidity and mortality. Based on previous studies in our institution demonstrating a rising incidence of multi-drug resistant organism (MDR) bacteria in bloodstream infections and high prevalence of enteric colonization with MDR, the “de-escalation” strategy for empirical antibiotics was adopted in the management of febrile neutropenia in children with hematolymphoid malignancies with MDR colonization. An audit to determine whether surveillance rectal swabs correlated with blood cultures in febrile neutropenia. Methods: Patient data from January 2015 to July 2016 were examined. Rectal swabs of children with hematolymphoid malignancies were obtained at presentation. Blood cultures were taken during febrile neutropenia. Data were analyzed using SPSS version 24.0®. The significance level was set at P < 0.05. Results: Most patients (62.1%) with confirmed bloodstream infection (BSI) were colonized with either extended-spectrum beta-lactamase producing organisms (ESBLO) (31.9%) or MDR (30.2%). Majority 116 (62.7%) developed BSI caused by either MDR or ESBLO. In contrast, only 12 (10.6%) patients colonized by sensitive bacteria, developed BSI caused by either MDR or ESBLO. These differences were statistically significant (P < 0.001). Thus, the baseline rectal swab had a sensitivity and a specificity of 90.6% and 59.4%, respectively, in predicting BSI with either MDR or ESBLO. Conclusions: We conclude that high prevalence of MDR colonization at presentation significantly results in MDR BSI, which further results in a significant increase in intensive care unit admissions and mortality. This would justify the use of a “de-escalation” antibiotic policy. Whether such a strategy has been successful or not in impacting outcomes, would need further study.
Keywords: Bloodstream, colonization, enteric, infections
|How to cite this URL:|
Salifu N, Narula G, Prasad M, Biswas S, Kelkar R, Banavali S. Correlation between multidrug-resistant bacteria colonization and bloodstream infections in children with hematolymphoid malignancies in a tertiary cancer center in India. Indian J Med Paediatr Oncol [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.ijmpo.org/preprintarticle.asp?id=300668
| Introduction|| |
Bloodstream infections with drug-resistant bacteria are associated with a higher morbidity and mortality. Our institution has previously reported a rising incidence in bloodstream infections caused by MDR, a high prevalence of rectal colonization by MDR and extended-spectrum beta-lactamase-producing organisms (ESBLO) and a high conversion rate from sensitive bacteria to resistant strains over time in pediatric patients with cancer. This informed the decision by the pediatric hematolymphoid disease management group to adopt the “de-escalation” strategy of the Expert Group of the 4th European Conference of Infections in Leukemia (ECIL-4) guidelines for empirical antibiotics in the management of patients with febrile neutropenia.
The objectives of this audit were to determine the correlation between enteric colonization with drug-resistant bacteria and bloodstream infections and to evaluate the association between colonization with drug-resistant bacteria and intensive care unit (ICU) admission and mortality from infections.
The audit was approved by the Institutional Ethics Committee of the Tata Memorial Hospital with approval number P. No 3325/2019.
| Design/methods|| |
This audit was conducted in the pediatric oncology unit of a large tertiary cancer care center in Western India delivering services to patients from all over India and other countries in Asia and Africa.
The unit utilized the de-escalation policy of the ECIL-4 guidelines and prospectively applied it to patients with hematolymphoid malignancies who developed febrile neutropenia. The policy is to start with a combination of Colistin and Carbapenem on the first sign of fever in neutropenic patients who were known to be colonized with MDR. The higher end of the Colistin maximum dose recommended for children was used at 150,000 IU/kg, divided 6 hourly, modified when indicated by creatinine clearance. If the patients subsequently improved, and blood culture did not grow any organism or showed an organism with a different sensitivity, the antibiotics would be rapidly “de-escalated” to a more standard first-line combination in use in the unit.
Other measures to reduce colonization
Other strategies employed by our unit to limit colonization included segregation and cohorting of MDR colonized patients during admissions, use of best infection control policies, including handwash, gowning, and masks when dealing with these patients.
Data were prospectively collected from January 2015 to July 2016 were examined. Rectal swabs were obtained by introducing a sterile swab stick into the rectum of patients registered with hematolymphoid malignancies [profile in [Table 1] on day of presentation, or within 7 days if missed on day-1. Repeat rectal swabs within 15 days were taken to track in cases of “no isolate” on the initial swab. This occurred sometimes as patients had received antibiotics before referral to our center. Others were repeated during febrile neutropenia episodes during admission to evaluate change in flora in previously non-MDR colonized patients who did not show improvement on empirical antibiotics or to evaluate the persistence of MDR strains (this was done only for MDR positive patients).
|Table 1: Profile of patients, baseline rectal swabs, and blood stream infections (1094 patients)|
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Blood cultures were taken during febrile episodes from peripheral veins and central lines when present. Records of all cultures were examined. Sensitivity patterns were studied using the Kirby–Bauer's disc diffusion method. Clinical and Laboratory Standards Institute (CLSI) guidelines were used to select the antibiotic disc. A limited panel was used to determine ESBLO, carbapenem-resistant enterobacteriaceae (CRE), and vancomycin-resistant enterococci (VRE).
ESBL production was confirmed by CLSI recommendations using cephalosporin–clavulanate combination disks. A difference of ≥5 mm between zone diameter of either of the cephalosporin disks and their respective cephalosporin–clavulanate disk was taken to be phenotypic confirmation of ESBL production. We used cefotaxime (30 μg), ceftazidime (30 μg), and ceftazidime/clavulanic acid (30 μg/10 μg) disks for ESBL determination. Carbapenem resistance was reported as per the CLSI guidelines. Vancomycin resistance was confirmed by minimal inhibitory concentrations with the “E” test. In an event when more than one organism with differing sensitivity profile was isolated from the culture, the worse sensitivity pattern was taken into account for analysis.
Definition of resistance
Multi-drug resistant organism (MDR) was defined as nonsusceptibility to at least a carbapenem, polymyxin (colistin), and an antipseudomonal cephalosporin (ceftazidime). Nonsusceptibility to a third-generation cephalosporin or in combination with a clavulanate but not any of the agents mentioned to define MDR defined ESBLO. ESBLO intermediate strains were considered to be resistant.
Statistical methods used
We analyzed the data of children with hematolymphoid malignancies who developed BSI from January 2015 to July 2016. We correlated their blood culture results during the episodes of febrile neutropenia with their baseline rectal colonization before starting therapy. Finally, we determined the outcome of the febrile neutropenia episodes in terms of ICU transfer and death. Simple descriptive statistics was used to present the demographic, clinical characteristics, the details of baseline rectal colonization and BSIs of the patients. Paired data were analyzed to test strength of the association of MDR colonization with MDR BSI and outcome parameters such as ICU admissions and mortality using a two-sided Pearson Chi-square. Statistical analysis was conducted using SPSS version 24.0® and significance level was set at P < 0.05 with a confidence interval of 95%.
| Results|| |
In the 18-month study, 1094 patients with hematolymphoid malignancies were registered for treatment and had baseline rectal swab taken. The profile of bacterial isolates from rectal swab cultures is represented in [Table 1]. The incidence of rectal swab colonization at baseline was 67.3% from 1094 patients. Escherichia coli was isolated in 680 patients, 19.7% of patients at baseline were colonized with MDR E. coli and 30% were ESBLO. Klebsiella pneumoniae was isolated from 285 patients, 8.7% of patients were colonized with MDR K. pneumonia while 11.8% were ESBLO. VRE was isolated in 32 patients. The profile of these patients is summarized in [Table 1].
During the study, 298 patients had positive blood cultures, of these, 253 had rectal colonization at baseline. These are summarized in [Table 2].
The majority (57%) of organisms causing BSI in our cohort were sensitive bacteria whiles 43% were either MDR or ESBLO.
Further analysis of the 253 patients with rectal colonization who developed BSIs and their outcome is illustrated in a Sankey diagram [Figure 1].
|Figure 1: Illustration of baseline rectal colonization and the development of blood stream infection and outcome of infection. ESBLOL: Extended spectrum beta-lactamase producing organisms, MDR: multi-drug resistant organisms|
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At baseline, most of the patients (62.1%) with confirmed BSI were colonized with either ESBLO (31.9%) or MDR (30.2%). Forty-five patients (15.1%) were not colonized at baseline. We assessed the relationship between rectal colonization at baseline with confirmed bloodstream infection. For patients colonized with either MDR or ESBLO, the majority 116 (62.7%) developed BSI caused by either MDR or ESBLO, while the remaining 37.3% of them developed BSI caused by sensitive bacteria. In contrast, among patients without baseline colonization or Colonized by sensitive bacteria, only 12 (10.6%) of them developed BSI caused by either MDR or ESBLO while most (89.4%) developed BSI caused by sensitive organisms. These differences were statistically significant (P< 0.001). In other words, the baseline rectal swab had a sensitivity and a specificity of 90.6% and 59.4%, respectively, in predicting BSI with either MDR or ESBLO [Table 3].
|Table 3: Correlation of rectal colonization at baseline by multi-drug resistant organisms and extended spectrum betalactamase producing organisms with blood stream infection caused by multi-drug resistant organisms and extended spectrum beta-lactamase producing organisms|
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Comparing MDR to ESBLO rectal colonization, the likelihood of patients colonized with ESBLO to develop sepsis due to ESBLO was 25.3%, while that of those colonized with MDR to develop MDR sepsis was 51.1% (P = 0.049) [Table 3].
Patients with either MDR or ESBLO colonization were more likely to be transferred to the ICU (49.7%) as compared to those without baseline colonization or colonized by sensitive bacteria (1.8%), as shown in [Table 4].
|Table 4: Rectal colonization with multidrug resistant and extended spectrum beta-lactamase producing organism and likelihood of intensive care unit admission|
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Patients colonized with MDR or ESBLO had an equal chance of ICU transfer [Table 4], but mortality was higher in the MDR group as compared to the ESBLO group [Table 5].
|Table 5: Rectal colonization with multidrug resistant and extended spectrum beta-lactamase producing organism and likelihood of mortality|
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Death was also more likely in those colonized with MDR or ESBLO at baseline compared to those who were not [Table 5].
| Discussion|| |
Recent reports from our institution, showed the high incidence of both MDR and ESBLO in bloodstream infections compared to what is being reported in Western literature. Another study from our institute also reported an alarming incidence of drug-resistant bacteria in rectal surveillance cultures of pediatric patients, 58.4% and 20.2% for ESBL and CRE, respectively, thus further strengthening the call for institutions to review antibiotic usage policy.
Antibiotic stewardship, institutional antibiotic usage, and infection prevention and control have gained prominence in recent times as the world is faced with an increasing spate of drug-resistant organisms without any appreciable increase in the development of new antimicrobials to combat this pandemic. The focus has now shifted to the judicious use of antimicrobials with emphasis on early commencement of appropriate empirical antimicrobials while awaiting culture reports in immunosuppressed patients. It has been demonstrated in reports,,, that organisms invading the bloodstream following commencement of cancer treatment with its attendant effect on breaching the integrity of the gastrointestinal mucosal barrier has led to translocation of pathogens colonizing the gut into the bloodstream consequently leading to sepsis. Enteric colonization by drug-resistant pathogens has therefore been named in ECIL-4 guidelines as the most important risk factor for infection by drug-resistant bacteria with special emphasis on ESBLO, CRE, resistant nonfermenters, MRSA with mic ≥2 mg/L and VRE.
Several other reports,,, and guidelines such as the Indian Council of Medical Research have informed the need to have surveillance cultures to guide the choice of empirical antibiotics for the management of patients with febrile neutropenia. However, some do not recommend this strategy owing to contradictory or inconclusive evidence to support enteric colonization as a source of clinical infections in the immunocompromised host. In this context, a retrospective review of 794 allogeneic hematopoietic transplant patients had found only 12 patients developing MDR Pseudomonas infections, out of which only about half had prior colonization indicating that there was another source for the infection. Fluoroquinolone prophylaxis was however administered to 83% of this cohort, which may have influenced the outcome. Although a few studies are inconclusive on the utility of surveillance cultures, these have major limitations such as inadequate sample size and prior utilization of antimicrobial prophylaxis. There is however a consistent pattern of increased morbidity, higher overall mortality and increased cost of care in patients who develop infections caused by drug-resistant pathogens without timely choice of appropriate empirical antimicrobials.,,
The correlation between gut colonization of resistant pathogens and their subsequent implication in bloodstream infections in a pediatric hematolymphoid cohort is being reported in a low-middle income country with a high prevalence of drug-resistant pathogens [Table 2], [Table 3] and [Figure 1] that has utilized the ECIL-4 guidelines.
In an observational prospective cohort of 126 adult patients with hematolymphoid malignancies in Mexico, it was found that colonization with ESBL -E. coli increased the risk of BSI by the same strain, had a shorter time to death, longer hospital stay, and higher infection-related costs. This was corroborated in our study as patients with either MDR or ESBLO colonization were more likely to be transferred to the ICU (49.7%) compared to those without baseline colonization or colonized by sensitive bacteria (1.8%), and this was associated with a higher mortality especially in the patient with MDR colonization [Figure 1] and [Table 4] and [Table 5]. This was found in an earlier study among pediatric patients in our institution and strengthened the call for early suspicion of sepsis and appropriate upfront use of high-grade antibiotics in this group of immunosuppressed patients with MDR colonization to curtail these adverse outcomes.
VRE colonization did not lead to an increased incidence of bloodstream infection by the same suggesting that our center can continue to withhold initial coverage for VRE in those colonized with this pathogen as the literature is still inconclusive with regard to initial coverage for VRE due to its low pathogenicity.,
| Conclusions|| |
We conclude that a high prevalence of MDR colonization at presentation significantly results in MDR BSI, which further results in a significant increase in ICU admissions and mortality. This would justify the use of a “de-escalation” antibiotic policy as defined by ECIL4 recommendations. Whether such a strategy has been successful or not in impacting outcomes, would need further study.
We gratefully acknowledge the contributions of former Group Member, Dr. Brijesh Arora for the groundwork and vision for many of the supportive care policies analyzed directly or indirectly in this study.
We are grateful to Dr. Kokou Amegan-Aho and Mr. Emmanuel Asimadi for their respective roles in proofreading the revised manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]