Blood stream infections during induction chemotherapy in children

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Blood stream infections during induction chemotherapy in children with acute myeloid leukemia –changing spectrum

Blood stream infections during induction chemotherapy in children with acute myeloid leukemia –changing spectrum in developing countries Divya S Fellow in Pediatric Hematology and Oncology Ramya U Fellow in Pediatric Hematology and Oncology Revathi Raj Consultant in Pediatric Hematology-Oncology Apollo Speciality Hospital Chennai, India

Financial disclosures Dr Divya S has no financial relationships with commercial entities to disclose

Financial disclosures Dr Divya S has no financial relationships with commercial entities to disclose

Principles of Acute myeloid leukemia management Acute myeloid leukemia needs : high dose chemotherapy

Principles of Acute myeloid leukemia management Acute myeloid leukemia needs : high dose chemotherapy at shorter intervals

What makes AML induction challenging? Adequate and timely supportive care is crucial Higher Treatment

What makes AML induction challenging? Adequate and timely supportive care is crucial Higher Treatment cost Lower remission rates Higher mortality rates

Introduction Infections are the main cause of mortality during induction chemotherapy in Acute Myeloid

Introduction Infections are the main cause of mortality during induction chemotherapy in Acute Myeloid Leukemia Major improvement in overall survival rates in children with AML worldwide has been due to optimal supportive care

What is outcome of children undergoing AML induction chemotherapy? UK AML MRC 10 and

What is outcome of children undergoing AML induction chemotherapy? UK AML MRC 10 and 12 trial data Remission rate at end of induction EFS Sepsis related mortality 92% (90%) 63% 5% (11%) Data on AML induction in pediatrics from India is scant Gibson B, Webb DKH, Howman A J, Graaf S, Harrison C J , Wheatley K(2011). Results of a randomised trial in children with acute myeloid leukemia : Medical research council AML 12 trial: British journal of hematology, 155, 366 -76

Aims and objectives To determine the survival outcome in children with AML at the

Aims and objectives To determine the survival outcome in children with AML at the end of induction To analyse the blood stream infection pattern during induction Analyse the burden of supportive care

Patients and methods Retrospective observational analysis of children aged between 1 -18 years with

Patients and methods Retrospective observational analysis of children aged between 1 -18 years with a diagnosis of AML Treatment provided at our centre from August 2002 to August 2015 Children with AML M 3 were excluded from the study

Data collected Patient demographics Disease characteristics Febrile neutropenia and Septic events Supportive care-antibiotic usage,

Data collected Patient demographics Disease characteristics Febrile neutropenia and Septic events Supportive care-antibiotic usage, blood product usage and PICU care(ionotropic/ventilatory) Remission status and outcome at end of induction

Analysis Chi square test Log rank test

Analysis Chi square test Log rank test

Treatment UK AML MRC regimen 12/15/17 - 3 drug Induction Daunorubicin Cytarabine 100 mg/m

Treatment UK AML MRC regimen 12/15/17 - 3 drug Induction Daunorubicin Cytarabine 100 mg/m 2 IV twice a day D 1 -D 10 Etoposide 100 mgm 2 - IV D 1 -D 5 50 mg/m 2 - IV D 1, 3, 5

Prophylaxis Fungal prophylaxis- Fluconazole till 2011 then Micafungin Anti-viral prophylaxis-Acyclovir PCP prophylaxis-Trimethoprin+sulfamethoxazole No prophylactic

Prophylaxis Fungal prophylaxis- Fluconazole till 2011 then Micafungin Anti-viral prophylaxis-Acyclovir PCP prophylaxis-Trimethoprin+sulfamethoxazole No prophylactic antibiotics

Central Lines All children have a central line(triple lumen subclavian) placed during induction chemotherapy

Central Lines All children have a central line(triple lumen subclavian) placed during induction chemotherapy Lines removed – multi drug resistant gram negative bacteria on blood culture Lines changed-worsening septic event needing increasing ionotrope/respiratory support

Treatment related complications Mucositis-monitored daily and graded on WHO scale Grade 1 -erythema Grade-2

Treatment related complications Mucositis-monitored daily and graded on WHO scale Grade 1 -erythema Grade-2 -ulcers, solid diet Grade -3 -ulcers, only liquid diet Grade-4 -not able to take any diet orally Supported with : IV Fluids Analgesics

Supportive care Febrile neutropenia - fever(oral temp>38. 3 with ANC<500) First line antibiotics- Pipericillin

Supportive care Febrile neutropenia - fever(oral temp>38. 3 with ANC<500) First line antibiotics- Pipericillin +tazobactum Cefoperazone +sulbactam (2012 -2015) Second line-Carbapenams (2002 -2012)

Hospital infection control team and ID specialist input in all children High end antibiotics.

Hospital infection control team and ID specialist input in all children High end antibiotics. Colistin/aminoglycosides/Tigecycline/Daptomycin Blood cultures drawn prior to upgrading the antibiotics

Septic event Febrile neutropenic child with disproportionate tachycardia Child needing fluid boluses- low pulse

Septic event Febrile neutropenic child with disproportionate tachycardia Child needing fluid boluses- low pulse volume metabolic acidosis on blood gas analysis

PICU care Use of Ionotropes (dopamine/Noradrenaline/adrenaline) Respiratory support-Non-invasive ventilation(High –flow nasal oxygen /NIV- face

PICU care Use of Ionotropes (dopamine/Noradrenaline/adrenaline) Respiratory support-Non-invasive ventilation(High –flow nasal oxygen /NIV- face mask) Invasive ventilation

End of induction assessment Morphological remission(<5%) in a normocellular marrow Minimal residual disease(MRD) by

End of induction assessment Morphological remission(<5%) in a normocellular marrow Minimal residual disease(MRD) by 8 parameter flow cytometry using patient specific immunophenotype from 2008 MRD<0. 05% - in remission Refractory-No morphological remission/MRD>0. 05% at end of induction

Results Total -54 children treated for AML Median age -8. 7 years (range- 1

Results Total -54 children treated for AML Median age -8. 7 years (range- 1 to 15) Male predominance-60%

Denovo/secondary AML 15 secondary 85 Denova

Denovo/secondary AML 15 secondary 85 Denova

FAB Subtype classification Column 1 10 M 1 20 M 4 5 5 55

FAB Subtype classification Column 1 10 M 1 20 M 4 5 5 55 M 2 M 4 M 1 M 7 M 0 M 6

Mucositis-94%-TRM 10 G-4 24 G-2 grade-3 66 G-3 grade-4

Mucositis-94%-TRM 10 G-4 24 G-2 grade-3 66 G-3 grade-4

Febrile Neutropenia-88% Total of 96 episodes documented during induction Mean duration of neutropenia-19. 7

Febrile Neutropenia-88% Total of 96 episodes documented during induction Mean duration of neutropenia-19. 7 days

Source of sepsis Column 1 10 15 chest 10 65 Gut gut CLABSI chest

Source of sepsis Column 1 10 15 chest 10 65 Gut gut CLABSI chest sinus

Intensified supportive care Septic event-50 recorded 46. 3% of the children had a septic

Intensified supportive care Septic event-50 recorded 46. 3% of the children had a septic event PICU care-was warranted in 27 such episodes 25% of them received PICU care

Intensified supportive care High end antibiotics used in 40 episode of febrile neutropenia 38%

Intensified supportive care High end antibiotics used in 40 episode of febrile neutropenia 38% children needed colistin/tigecycline/aminoglyosides 24% needed ventilatory support 10% needed invasive ventilation Granulocytes used in 11 children-10%

Organisms isolated Culture proven sepsis-35% of febrile neutropenic children 87%-gram negative organism-klebsiella(40%), E. coli(22%)

Organisms isolated Culture proven sepsis-35% of febrile neutropenic children 87%-gram negative organism-klebsiella(40%), E. coli(22%) 13% had gram positive cocci

Outcome at the end of induction Remission was achieved in 80% at the end

Outcome at the end of induction Remission was achieved in 80% at the end of the 1 st ADE cycle 85% at end of 2 nd ADE cycle Mortality was 10% at end of induction

N=54 Remissio n after 1 st ADE=43 45 achieved remission at end of induction

N=54 Remissio n after 1 st ADE=43 45 achieved remission at end of induction Refractory in 4 Sepsis death-3 Mortality-5 All sepsis related death

Outcome at end of induction Sepsis related- 10% Refractory disease-5% Event free survival at

Outcome at end of induction Sepsis related- 10% Refractory disease-5% Event free survival at end of induction-84%

The year 2012 saw a surge in hospital acquired infectionsgram negative, multidrug resistant (carbapenam

The year 2012 saw a surge in hospital acquired infectionsgram negative, multidrug resistant (carbapenam resistant) bacteria We have therefore analysed our data on blood stream infections before and after 2012

Blood Stream Infections Before 20122015 P value Febrile Neutropenia 56 87% 40 90% 0.

Blood Stream Infections Before 20122015 P value Febrile Neutropenia 56 87% 40 90% 0. 92 Septic event 28 43. 75% 22 50% 0. 84 Culture +ve sepsis 11 34% 9 40% 0. 66 Gram –ve sepsis 10 90% 8 89% 0. 71 Gram +ve sepsis 1 10% 1 11% 0. 74 MDR 2 20% 7 87. 5% 0. 01

Infections-Before & After 2012 Septic rates have been constant Culture positive sepsis-is around 33%

Infections-Before & After 2012 Septic rates have been constant Culture positive sepsis-is around 33% Gram negative organisms predominate

90 80 70 60 50 40 30 20 10 0 Before 2012 -2015 septic

90 80 70 60 50 40 30 20 10 0 Before 2012 -2015 septic event culture +ve gram -ve MDR

The rise of MDR bacteria 100 90 80 70 60 50 40 30 20

The rise of MDR bacteria 100 90 80 70 60 50 40 30 20 10 0 PS MDR 2002 -2012 -2015

Supportive care Before 2012 -2015 P value PICU care 10 17% 17 39% 0.

Supportive care Before 2012 -2015 P value PICU care 10 17% 17 39% 0. 01 High end antibiotic 10 23% 30 72% <0. 01 Granulocyte infusion 2 9. 3% 9 40% <0. 01

Supportive care-Before & after 2012 Need for PICU care (Ionotrope usage, Respiratory support rates

Supportive care-Before & after 2012 Need for PICU care (Ionotrope usage, Respiratory support rates have increased significantly after 2012 Use of high end antibiotics –(colistin/tigecycline) has also increased Blood product support(Granulocyte infusions) has also increased

Supportive care 35 30 25 20 2002 -2012 15 2012 -2015 10 5 0

Supportive care 35 30 25 20 2002 -2012 15 2012 -2015 10 5 0 PICU care high end antibiotics Granulocyte

Cost analysis 120 100 80 cost 60 remission EFS 40 2002 -2006 -2009 -2012

Cost analysis 120 100 80 cost 60 remission EFS 40 2002 -2006 -2009 -2012 -2015

Conclusion-1. Remission rate at our centre is 86% at end of 2 cycles of

Conclusion-1. Remission rate at our centre is 86% at end of 2 cycles of induction which is comparable Study Induction remission % UK AML MRC 10 trial 83% UK AML MRC 12 trial 92% Venkat raman et al 88% Sharavat et al 81%

Conclusion-2. Sepsis-mortality Blood stream related Infections and septic shock is the major cause of

Conclusion-2. Sepsis-mortality Blood stream related Infections and septic shock is the major cause of mortality -11% Study Sepsis related mortality % UK AML MRC 10 trial 11% UK AML MRC 12 trial 5% Venkat raman et al 11% Kavcic et al 3% Chan et al 16%

Conclusion-3. gram negative sepsis Gram negative sepsis are more common than gram positive during

Conclusion-3. gram negative sepsis Gram negative sepsis are more common than gram positive during AML induction Study Gram negative sepsis Hamalainen et al 40% Maranda et al 17%(30%) Madani et al 30%(70%) Biswal et al 27%(30%)

Conclusion-3. gram negative sepsis Gram negative bacteria translocating from the intestines are the main

Conclusion-3. gram negative sepsis Gram negative bacteria translocating from the intestines are the main source of infection during AML induction Gut mucositis is a vital contributing factor for septic event (p<0. 05)

Conclusion -4. MDR bugs/super smart bugs Study MDR sepsis Gedik et al 21% Olson

Conclusion -4. MDR bugs/super smart bugs Study MDR sepsis Gedik et al 21% Olson et al 90% to fluoroquinolones/piperacillin Rampant abuse of antibiotics in the community has lead to an increase in drug resistant bacteria

Conclusion-5. Cost of care There has been an increase in resource utilisation to provide

Conclusion-5. Cost of care There has been an increase in resource utilisation to provide the supportive care to combat these multi drug resistant organisms leading to rising costs of care Cost of care for AML induction has risen for 5000 USD to 15000 USD ( 3 fold rise) in the last decade

Bugs are smart-we need to be smarter Together we can Infectious specialist Pediatric oncology

Bugs are smart-we need to be smarter Together we can Infectious specialist Pediatric oncology Nursing team PICU Dept Microbiology

Novel measures –prevention is better than cure Xpert Carba-R testing Neutropenic Diet Aggressive surface

Novel measures –prevention is better than cure Xpert Carba-R testing Neutropenic Diet Aggressive surface cleaning and strict hand hygeine policies Use of Biopatches - reduce central line entry site infections

Xpert Carba – R testing Qualitative in vitro diagnostic to detect colonisation of organism

Xpert Carba – R testing Qualitative in vitro diagnostic to detect colonisation of organism harbouring carbapenamese gene Conducted on stool sample or per rectal swab KPC NDM VIM IMP-1 OXA-48

Xpert Carba-R Local infection control protocols Risk stratification of children and use of antibiotics

Xpert Carba-R Local infection control protocols Risk stratification of children and use of antibiotics based on their Carba-R status early use of colistin in carba-R positive children

Neutropenic diet Lactose free Hypo allergen diet Semi-elemental diet in very sick kids Simple

Neutropenic diet Lactose free Hypo allergen diet Semi-elemental diet in very sick kids Simple easily digestable diet reduces translocation of gut bacteria in severe mucositis setting Tramsen L, Manrique ES, Bochennek K, Klingebiel T, Reinhardt D, Creutzig U et al (2016) . Lack of effectiveness of neutropenic diet and social restrictions as anti-infective measures in children with acute myeloid leukemia: An analysis of the AML-BFM 2004 trial. American society of clinical oncology.

Bio-patch Biopatch placed over the central line entry site to prevent Central line associated

Bio-patch Biopatch placed over the central line entry site to prevent Central line associated blood stream infections (CLABSI) Chlorhexidine gel pad over the central line entry site to prevent infection

Thinking cap Studies by Burnett et al have shown that 2 drug(DA) induction chemotherapy

Thinking cap Studies by Burnett et al have shown that 2 drug(DA) induction chemotherapy is equally effective as 3 drug(ADE) chemotherapy Will Omission of etoposide, drug associated with greater percentage of mucositis , reduce the blood stream infection rates? Burnett AK, Russell NH, Hunter AE, Kieldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. (2013)Optimisation of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML 15 trial. J Clin Oncol; 31(27): 3360 -8

Acknowledgement HOPE TEAM Dr. Abdul Ghafur, Consultant, Dept of Infectious diseases Department of clinical

Acknowledgement HOPE TEAM Dr. Abdul Ghafur, Consultant, Dept of Infectious diseases Department of clinical Microbiology Nursing staff Children & their families