Escalation and De-Escalation Strategy for Initiating Antibiotics in Patients with Pediatric Cancer: A Prospective Observational Study

Keywords

child - neoplasms - sepsis

Introduction

Febrile neutropenia is a common oncological emergency seen in children with cancer.[1] It is a significant cause of morbidity and mortality in children undergoing chemotherapy.[2] Mortality rates can be as high as 10% in hematolymphoid malignancies and 5% in patients with solid tumors.[3] In cases where bacteremia is confirmed, mortality rates are higher, that is, 18% in patients with Gram-negative bacteremia compared with 5% in those with Gram-positive bacteremia.[4]

The etiology of febrile neutropenia is varied. In India, Gram-negative bacteria are the most common organisms isolated in febrile neutropenia.[5] [6] [7] [8] In a study from our center, 61% (50/82) of culture-positive cases were due to Gram-negative organisms. The most common Gram-negative organisms were Klebsiella, Pseudomonas, Acinetobacter, and Escherichia coli.[6] Rates of multidrug-resistant (MDR) bacteria are rising, with our center also previously reporting high rates of resistance to first-line antibiotics.[6] Other factors that may affect mortality in febrile neutropenia in low- and middle-income countries (LMICs) include: malnutrition, lower education, lower socioeconomic strata, previous occurrence of febrile neutropenia, prolonged presence of low total counts, and the presence of a focus of infection.[5] [7] [8]

Local epidemiology and patient history of antimicrobial resistance should guide empiric antibacterial therapy choice. As per guidelines and general practice, an “escalation policy or strategy” for antibiotic usage is practiced.[9] Patients with high-risk febrile neutropenia are initially started on an antibiotic with antipseudomonal β-lactam with or without an aminoglycoside. Based on clinical status, antibiotics are then escalated to second- and third-line antibiotics. For clinically unstable patients or centers with high rates of resistance, second- or third-line drugs like colistin and tigecycline may be used upfront.[9] However, in these patients, if the culture is sterile and if patients are stable, antibiotics may be “de-escalated” ensuring good antibiotic stewardship. However, there is always a risk of increased and often indiscriminate use of colistin and tigecycline, the last line of defense against sepsis.

The gut microbiota is a common source of infection in children with cancer.[10] In India, children undergoing chemotherapy have rates of gut colonization with bacteria ranging between 17 to 68%, with rates of MDR bacteria in surveillance stool culture being around 17 to 50%.[11] [12] The link between stool colonization and adverse events/outcomes has been studied and the results are varied. A previous study from our center reported increased mortality in patients with stool MDR colonization and a good correlation with blood culture.[13] Hence, we include previous stool MDR colonization in the criteria to start patients with the de-escalation strategy of antibiotics.

At our center, during episodes of febrile neutropenia, we practice an escalation strategy for antibiotics if the child is stable. However, a standard de-escalation strategy for using antibiotics is followed in case of clinical instability, organ dysfunction, or positive baseline stool MDR colonization ([Fig. 1]).[13] Hence, with this study we aimed to study the compliance and impact of our institute's antibiotic policy.

Fig. 1 Escalation and de-escalation policy practiced at our institute.

Materials and Methods

Study Design and Setting

A prospective cohort study set in the Division of Pediatric Oncology, Department of Medical Oncology, Cancer Institute, Adyar in Chennai, Tamil Nadu, India.

Participants and Eligibility Criteria

Participants were enrolled between October 1, 2021 and September 30, 2022. The study included all children (aged 0–18 years) diagnosed with cancer and developing fever while on cancer chemotherapy and then subsequently going on to receive colistin and tigecycline. Those with proven fungal infection and those who did not consent were excluded from the study.

Sample Size Calculation

Convenient sampling was used for sequential enrolment over the course of 1 year to enroll at least 100 episodes of fever in children with cancer receiving colistin and tigecycline. A total of 74 patients were enrolled with 101 fever episodes requiring colistin and tigecycline (third-line antibiotics).

Objectives

The primary objective was to study the usage of third-line antibiotics in children with cancer. Second, we wanted to evaluate the adherence to our institute's antibiotic policy, differences in escalation and de-escalation strategy of antibiotics, blood and MDR stool culture positivity, clinical stability (ventilator and inotrope use), mortality, and factors assessing mortality.

Sample Collection

Blood samples were obtained before the first dose of antibiotics as per our institute's policy. This included a complete hemogram, biochemistry, and a blood culture. Computed tomography (CT) scan was done in selected patients only.

Data Acquisition

Demographic and treatment details were retrieved from medical records and included: age at enrolment, gender, diagnosis, and phase of chemotherapy. From the medical records, we noted the type of antibiotic policy used (escalation or de-escalation), antibiotics used, blood culture, and nadir total counts, absolute neutrophil counts (ANCs), and results of CT scan if obtained. Baseline stool culture reports were collected to see if the stool was colonized by MDR bacteria or not. MDR was defined as per standard international guidelines (one or more of these have to apply): (1) Methicillin-resistant Staphylococcus aureus is always considered MDR and (2) nonsusceptible to ≥ 1 agent in > 3 antimicrobial categories.[14] We also captured data regarding whether the child went on the ventilator and whether inotropes were used or not. The name of antibiotics, duration of antibiotics, and outcome were also noted.

Outcomes

The primary outcome of this study was the rate of third-line antibiotic use among children with cancer presenting with febrile episodes. This outcome was intended to reflect the burden of use of third-line antibiotics, serving as a key measure to evaluate current antibiotic usage practices. The secondary outcomes included adherence to the institutional antibiotic policy, duration of antibiotic therapy, rate of use of inotropes and ventilator (implying clinical stability), microbiological findings such as blood and stool MDR culture positivity, and mortality. These outcomes were expected to vary depending on whether an escalation or de-escalation antibiotic strategy was employed. These findings were expected to offer novel insights into the impact of antibiotic stewardship strategies in pediatric oncology, with the potential to inform future clinical practice and policy.

Institute Escalation and De-Escalation Policy for Children with Cancer at Our Institute

Our institute has followed an escalation and de-escalation policy with antibiotics tailored to the culture sensitivity pattern of the annual antibiogram audit. In general, it is as depicted in [Fig. 1]. For the year the study was conducted, first-line antibiotics were cefoperazone-sulbactam and amikacin, second-line was meropenem with the addition of teicoplanin (for Gram-positive cover), and third-line was the use of colistin and tigecycline.

Statistical Analysis

The data was analyzed using Stata statistical software, version 14.0 (StataCorp LLC, Texas, United States). All qualitative variables were expressed as frequency in numbers and percentages (N, %). Normality was assessed using the Kolmogorov–Smirnov test. All quantitative variables were expressed as mean ± standard deviation for normally distributed data and median with range for nonnormally distributed data. On exploratory analysis, a comparison between escalation and de-escalation policy was made between continuous variables using the Student's t-test/analysis of variance test if data was normally distributed, or the Wilcoxon rank-sum (Mann–Whitney U), if the data was skewed. For categorical data, the chi-square test or Fischer's exact test was used. Significant variables were considered if the p was ≤ 0.05. Mortality risk factors were assessed first using univariable logistic regression, followed by multivariable logistic regression. Regression analysis was reported as an odds ratio (OR) with 95% confidence interval (CI) (OR with 95% CI, p-value).

Ethical Approval

The study was approved by the Cancer Institute (WIA), institutional ethics committee (No. ECR/235/Inst/TN/2013/RR-19), Ethics number: IEC/2021/Nov 04. The participants gave their fully informed consent before participating in the study. The study was conducted in accordance with the principles outlined in the Helsinki Declaration.

Results

Baseline and Demographic Characteristics

The study enrolled 74 patients with a median age of 11.5 years (range: 1–19); the majority were boys (44/74, 60%). Among the patients enrolled, 71% (53/74) of the patients had a diagnosis of leukemia, including acute lymphoblastic leukemia (ALL), relapsed ALL, acute myeloid leukemia (AML), relapsed AML, and chronic myeloid leukemia in blast crisis. Lymphoma was the diagnosis in 10% (7/74) of patients, while the remaining 19% (14/70) had a diagnosis of a solid tumor.

Details of Episodes of Third-Line Antibiotic Use

During the 1-year study period, there were 797 episodes of antibiotic use, among which 101 (12.6%) episodes involved the use of colistin or tigecycline ([Table 1]). In 20/74 (27%) patients, there were more than one episode of fever necessitating third-line antibiotics. Patients with hematolymphoid malignancies had the highest frequency of third-line antibiotic use. Specifically, patients with ALL, including both new and relapsed cases, comprised 45.6% (46/101) of episodes, while patients with AML, both new and relapsed, comprised 25% (25/101) of episodes. Third-line antibiotic use in patients with solid tumors was observed in 19% of episodes (19/101). The majority of patients were managed in the intensive care unit (ICU), accounting for 86 out of 101 episodes (85%). Inotropes were used in close to 50% of episodes, with 9% needing ventilatory support. Antifungals were used in 65 episodes with prophylactic antifungals used in 50/65 (77%) and therapeutic antifungals used in 13/65 (23%) of episodes.

Table 1 Details of episodes of third-line antibiotic usage

Variables	Results (N = 101)
Diagnosis in episodes Hematolymphoid malignancy [N, (%)]
ALL  AML  Relapsed ALL  Relapsed AML  CML blast crisis  Hodgkin's lymphoma  Non-Hodgkin's lymphoma  Kikuchi disease	37 (36.6) 21 (20.8) 9 (8.9) 4 (3.9) 4 (3.9) 4 (3.9) 2 (1.9) 1 (0.9)
Solid tumor [N, (%)]
Ewing's  Germ cell tumor  Rhabdomyosarcoma  Osteosarcoma  Neuroblastoma	6 (5.9) 5 (4.9) 4 (3.9) 3 (3.9) 1 (0.9)
Inotrope use [N, (%)]	50 (49.5)
Ventilator use [N, (%)]	9 (8.9)
Blood culture positivity [N, (%)]	10 (9.9)
Organisms cultured from blood
MDR Klebsiella pneumoniae  MDR Acinetobacter baumannii  Non-MDR Pseudomonas aeruginosa  Non-MDR Escherichia coli  Methicillin-sensitive Staphylococcus aureus	4 1 3 1 1
Baseline stool MDR culture positivity [N, (%)]	46 (45)
MDR organisms cultured from stool
Escherichia coli  Enterococcus faecium  Klebsiella pneumoniae  Pseudomonas aeruginosa	17 17 10 2
Antifungal use [N, (%)]	65 (64.4)
Indication for antifungal use [N, (%)]
Prophylactic  Therapeutic	52/65 (80) 13/65 (20)
Abnormal CT chest finding [N, (%)]	19/36 (52.8)

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia, CT, computed tomography; MDR, multidrug-resistant.

Culture Positivity

Positive blood culture was noted in 10 episodes ([Table 1]). Gram-negative organisms were commonly seen (9/10), with the most common organisms isolated in blood being Klebsiella pneumoniae. There were 5 MDR cases and 4 non-MDR Gram-negative bacterial isolates. Positive baseline surveillance stool cultures were associated with 46 episodes. The most frequent isolates were Escherichia coli and Enterococcus faecium (37% each). Baseline positive colonization with MDR bacteria in stools was not associated with blood culture positivity (p = 0.766) or mortality (p = 0.202).

Antibiotic Use Policy/Strategy

The escalation strategy for antibiotics was used in 93/101 (92.1%) episodes and the de-escalation strategy in 8/101 (7.9%) episodes ([Table 2]). Of the patients whose antibiotics were escalated, 49 out of 93 (53%) were in accordance with the hospital policy, while in 47% of patients in whom antibiotics were escalated, the hospital policy would have mandated starting on a third-line antibiotic. However, all patients whose antibiotics were de-escalated were in compliance with the institute's antibiotic policy. Among the total patient cohort, the antibiotic adherence rate was 57%. The most common indication for starting colistin or tigecycline in both policies was hypotension (42 episodes, 41.5%). The most common indication for using the de-escalation strategy for antibiotics was also hypotension at presentation (8/8 episodes). The median duration of antibiotic use in all episodes was 10 days (range: 1–26 days). The median duration of antibiotic use was less in patients where the de-escalation policy was started upfront (5.5 vs. 10 days, p = 0.001). However, there was no difference in third-line antibiotic use duration, blood culture positivity, inotrope use, or ventilator requirement.

Table 2 Details of antibiotic ise policy

	Escalation policy	De-escalation policy	p-Value
Number of episodes	93 (92.1%)	8 (7.9%)
Adherence to institute policy	53%	100%
Male gender (%)	60%	50%	0.68
Median (range) age of patients	11.5 (1–19)y	12 (6–17)y	0.83
Median (range) duration of antibiotic	10 (1.5–26) d	5.5 (1–10) d	0.001
Median (range) duration of third-line antibiotic use	6 (1–20) d	5.5 (1–10) d	0.46
Median (range) ANC (/mm3)	300 (6–26000)	1550 (240–24650)	0.02
Blood culture positivity (%)	10.8%	0	1.00
Baseline stool MDR colonizer (%)	47.3%	25%	0.29
Inotrope use (%)	47.3%	75%	0.16
Ventilator use (%)	8.6%	12.5%	0.54
Abnormal CT chest finding (%)	56.3%	25%	0.33
Anti-fungal use (%)	65.6%	50%	0.45

Abbreviations: ANC, absolute neutrophil count; CT, computed tomography; MDR, multidrug-resistant.

Note: Bold values are significant.

Outcomes

During the study period, 10 children died ([Table 3]). This represents 1.3% of the total episodes of fever and 10% of the total episodes where third-line antibiotics were used. Of the 10 children who died, 5 passed away in the hospital and 5 died at home (they were pre-terminal and requested for discharge) ([Table 3]). Sepsis was the cause of death for 6 children, while 4 children died from progressive disease and had concomitant sepsis. All deaths occurred in patients for whom the escalation policy was implemented. Among the 6 patients who died from sepsis alone, 4 did not adhere to the antibiotic policy of the institute. Eight children had MDR in their stool at baseline, with two having a positive blood culture with a drug-resistant organism ([Table 3]).

Table 3 Mortality details

S. No	Diagnosis	Reason for starting antibiotic	Antibiotic policy	Antibiotic adherence	Reason for escalation	Stool culture	Blood culture	Cause of death
Died in-hospital
1	Kikuchi syndrome	Febrile neutropenia	Escalation	Yes	Hypotension	No growth	Sterile	Septic shock
2	AML	Febrile neutropenia	Escalation	No	Respiratory distress	MDR Escherichia coli	Sterile	Ventilator acquired pneumonia
3	ALL	Febrile neutropenia	Escalation	No	Hypotension	MDR Escherichia coli	Sterile	Dengue Shock Syndrome and CMV
4	ALL	Perianal abscess	Escalation	No	Hypotension	MDR Klebsiella pneumoniae	Sterile	Septic shock
5	CML posttransplant	Febrile neutropenia	Escalation	No	Hypotension	MDR Enterococcus faecium	Sterile	Posttransplant complication: Lung GVHD and sepsis
Sent home pre-terminally
6	RMS	Febrile Neutropenia	Escalation	No	Respiratory distress	MDR Enterococcus faecium	Sterile	Progressive disease and sepsis
7	Relapsed ALL	Febrile Neutropenia	Escalation	No	Persistent Fever	MDR Enterococcus faecium	Sterile	Progressive disease and sepsis
8	CML post-transplant	Febrile Neutropenia	Escalation	No	Hypotension	MDR Klebsiella pneumoniae	MDR Klebsiella pneumoniae	Septic shock
9	Relapsed ALL	Febrile Neutropenia and Fungal sinusitis	Escalation	Yes	Persistent fever	No growth	Sterile	Septic shock and progressive disease
10	ALL	Urinary tract infection	Escalation	No	Persistent fever	MDR Acinetobacter	MDR Acinetobacter baumannii and Candida auris	Septic shock and progressive disease

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; CMV, cytomegalovirus; GVHD, graft versus host disease; MDR, multidrug resistant; RMS, rhabdomyosarcoma.

We further examined the risk factors for mortality ([Table 4]). We included all deaths in the analysis because all of these cases required the use of third-line antibiotics, and the cause of death could not be determined as either sepsis or progressive disease. The independent variables were the antibiotic strategy, baseline stool MDR colonization, blood culture positivity, inotrope use, and ventilator use. Among these variables, ventilator use was the only variable associated significantly with mortality in the univariable and multivariable regression analyses (OR 13.2 with 95% CI: 2.6–66.2, p = 0.002).

Table 4 Predictors for mortality

Variable	Univariable analysis for risk of mortality		Multivariable analysis for risk of mortality
	OR (95% CI)	p-Value	OR (95% CI)	p-Value
Escalation policy of antibiotic use	1
Ventilator use	11.5 (2.4–54.2)	0.002	13.2 (2.6–66.2)	0.002
Inotrope use	2.6 (0.6–10.7)	0.18
Baseline stool MDR colonizer	3.1 (0.8–12.8)	0.12
Blood culture positivity	2.6 (0.5–14.4)	0.34

Abbreviations: 95% CI, 95% confidence interval; MDR, multidrug-resistant bacteria; OR, odds ratio.

Note: Bold values are significant.

Discussion

Febrile neutropenia is a major cause of treatment-related mortality in pediatric hematological malignancies and solid tumors,[15] especially in LMICs like India. It is common in patients undergoing intensive chemotherapy, such as AML and ALL.[16] [17] [18] In this study, most cases needing third-line antibiotics had hematolymphoid malignancies, with ALL and AML being the most common diagnoses.

Antibiotic policies vary between countries, regions, and hospitals. Hospitals often determine antibiotic usage through antimicrobial audits. Antibiotic de-escalation aims to start with broad coverage and then switch to a narrower spectrum or combination therapy.[19] This practice is common in hospitals with high rates of MDR bacteria and limited resources.[20] In our study, antibiotics were de-escalated for eight patients based on our policy. Among the patients in whom antibiotics were escalated, 47% actually met the criteria for de-escalation due to the presence of baseline MDR bacteria as a stool colonizer. De-escalation was prompted by hypotension in all patients where it was implemented upfront.

Most of the data on antimicrobial de-escalation comes from ICUs where it forms a core component of antimicrobial stewardship. Mortality rates are lower in most studies, with varying results on length of hospital stay and severity score. There is no reported increased risk of antimicrobial resistance.[21] However, most studies have focused on nonneutropenic patients. Studies on adult cancer patients in ICUs have shown a shorter hospital stay but no decrease in mortality.[22] In our study, patients who followed the de-escalation policy had fewer days on antibiotics, with no difference in blood culture positivity rate, inotrope or ventilator use, or mortality. However, the median ANC at presentation in patients who received the de-escalation therapy (those who presented with hemodynamic instability) was 1550/mm³ in contrast to the median ANC of 300/mm³ in patients who received the escalation protocol (p = 0.02). This observation is not unexpected, as our hospital has a practice of admitting children with low blood cell counts preemptively to prevent severe illness. Moreover, the ANC documented in this study was the median ANC at presentation, and it was anticipated that the ANC would decrease in the following days as the episode progressed.

The importance of a baseline stool MDR colonization to guide antibiotic policy as done in this study is debatable. The correlation between stool culture and blood culture has been hypothesized to happen because of the translocation of resistant strain to the blood from the compromised gut mucosa due to mucositis.[23] In a previous study conducted on children diagnosed with acute leukemia at our institute, the baseline stool MDR positivity rate was similar (50%) to the current study. Patients with stool MDR colonization had double the risk of mortality compared with noncarriers and a good correlation with blood culture positivity.[13] Similarly, a study conducted on 618 children with cancer from another hospital in India showed that before treatment, patients had a baseline stool MDR rate of 56%; ICU admission and mortality were higher in patients colonized by these MDR organisms.[24] However, in contrast to the above evidence, there have been two studies reported from India, which have shown that bacterial gut colonization failed to predict MDR sepsis, bloodstream infection, or mortality.[11] [12] In the current study as well, we found that 45% of patients who received third-line antibiotics had upfront MDR bacteria in their stool. Only 10 children had a positive blood culture. Among these 10 cases, 9 were due to Gram-negative bacteria, the most common being MDR Klebsiella pneumoniae (seen in 50% of cases). Stool colonization with MDR bacteria at diagnosis did not correlate with blood culture positivity or with increased mortality. However, among the patients who died, 80% had stool MDR culture positivity, with 2 patients having a positive blood culture. Therefore, it is challenging to determine if baseline MDR stool colonization affects survival. Future prospective studies are necessary to evaluate the need for treating children with third-line antibiotics if their stool culture is positive.

In this study, there were a total of 797 episodes of fever requiring antibiotics, in 1 year. Among these episodes, 12.6% (101 episodes) required third-line antibiotics (colistin and tigecycline). However, overall mortality remained low at 1.3%. Mortality rates due to febrile neutropenia in India have varied from 5 to 10.3%.[8] [25] [26] The reasons for low mortality at our center are probably due to the increased availability of beds, early admission for febrile neutropenia, administration of antibiotics within 1 hour of fever by admission to the hospital, early admission to ICU, early removal of central lines, early identification of sick children and prompt intervention, and our institute's antibiotic policy as described. Though our multivariable regression analysis revealed that only ventilator use was significantly associated with mortality, all deaths happened in patients in whom the escalation policy was used. In the majority of these episodes (8/10) children did not adhere to institute guidelines and did not receive third-line antibiotics when it was indicated (as per our policy). It is, however, uncertain if adherence to the institute policy would have impacted their survival.

Implementing a de-escalation antibiotic policy can lead to multidrug resistance, but adherence to guidelines is crucial. In our study, antibiotic guidelines were adhered to only in 57% of episodes. In all instances of nonadherence, patients exhibited MDR colonization in their stool, however, antibiotics were escalated at the treating physician's discretion, potentially because of the child's clinically stable condition. So, whether or not this contributed to mortality is debatable. The overuse of antibiotics is associated with an increased risk of antimicrobial resistance, longer hospital stays, increased risk of complications, and higher health care costs.[27] In our study, patients on the de-escalation strategy of antibiotic use had significantly fewer days on antibiotics, resulting in shorter hospital stays suggesting that implementing the de-escalation strategy for antibiotic use may help save costs in health care by reducing antibiotic overuse and improving patient outcomes.

Our study has a few limitations and gray areas for future research. The number of events (deaths) was low, and a larger sample size would have allowed us to better understand the true benefit of our antibiotic policy. This study is only hypothesis-generating, particularly in countries like India, where improving survival rates is linked to reducing treatment related mortality (TRM), it may be worthwhile to explore policies such as antibiotic de-escalation in larger randomized studies. Furthermore, our study did not include a cost-effective analysis and doing so in future studies may help us understand the benefits of this policy balanced by the risks of increased antimicrobial resistance.

Despite these limitations, our study strengths are that it highlights various antibiotic use strategies, including de-escalation practices, in children with cancer. The study's generalizability is strengthened by its LMIC setting, where febrile neutropenia is common. This study is among the first to examine the usage and outcomes of de-escalating antibiotic strategies in children with cancer in India.

Conclusion

A de-escalation antimicrobial policy can be implemented in children with cancer who present with febrile neutropenia with specific indications. Further prospective, randomized studies are necessary to evaluate the true impact of de-escalating antimicrobial policies. This study can serve as a foundation for future research in this area.

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