Pediatric Hematology Oncology Journal 5 (2020) 65e68

Contents lists available at ScienceDirect

Pediatric Hematology Oncology Journal

journal homepage: https://www.elsevier.com/journals/pediatric-
hematology-oncology-journal/

Clinical profile and outcome of carbapenem-resistant gram negative

bacteremia in children with cancer in pediatric intensive care unit of a
resource-limited country
Uzair Ali Memon a, Abdul Rahim Ahmed b, *, Muhammad Khalid a, Karima Qadir c,
Naeem Jabbar d, Samina Junejo e, Anwar ul Haque b
a
Department of Pediatrics, The Indus Hospital, Plot C-76, Sector 31/5, Opposite، Crossing، Darussalam Society Sector 39 Korangi, Karachi, Pakistan
b
Pediatric Intensive Care Unit, The Indus Hospital, Plot C-76, Sector 31/5, Opposite، Crossing، Darussalam Society Sector 39 Korangi, Karachi, Pakistan
c
Department of Infection Control and Prevention, The Indus Hospital, Plot C-76, Sector 31/5, Opposite، Crossing، Darussalam Society Sector 39 Korangi,
Karachi, Pakistan
d
Department of Pediatric Oncology, The Indus Hospital, Plot C-76, Sector 31/5, Opposite، Crossing، Darussalam Society Sector 39 Korangi, Karachi, Pakistan
e
Department of Pediatrics, Nishtar University Hospital, Nishtar Rd, Justice Hamid Colony, Multan, Pakistan

a r t i c l e i n f o a b s t r a c t

Article history: Objective: The prevalence of Carbapenem-Resistant Gram Negative Blood Stream Infection (CRGN-BSI) is
Received 14 April 2020 increasing worldwide. However, there is a paucity of data in a vulnerable population “Children with
Received in revised form cancer”. The objective of this study is to describe the clinical profile and outcome of children with cancer
9 July 2020
admitted in PICU with CRGN-BSI.
Accepted 17 July 2020
Available online 20 July 2020
Methods: We retrospectively reviewed medical record of all children with cancer admitted in PICU who
had CRGN-BSI from September 2017 to August 2019. Isolates with meropenem MIC
19 mg/dl were
considered as Carbapenem Resistant. Responder was defined as negative blood culture in 5 days. Clinical
Keywords:
Carbapenem resistance”
profile and outcomes were obtained. Descriptive statistics were applied.
“Gram-negative bacteria” Results: Out of 1234 PICU admissions, 54 children with cancer developed CRGN-BSI (0.3%). The mean age
“Critically ill-children with cancer” of CRGN-BSI was 6.97 ± 4 years. 67% (n ¼ 36) of these were male and 54% (n ¼ 29) were malnourished.
Colistin The primary diagnosis was hematological malignancy in 80% (n ¼ 43) and 76% of the children used ICU
therapies (mechanical ventilation [n ¼ 14, 26%] and vasoactive inotropic support [n ¼ 27, 50%]). All of
them were neutropenic on admission and 98% patients received blood products. Pending blood culture
results, 50% (n ¼ 27) of the patients were started on meropenem. E-coli (n ¼ 30, 56%) and Kelbseilla
species (n ¼ 14, 26%) were the most common isolates in our cohort and 46% (n ¼ 25) of the patients were
the responders. 18% (n ¼ 10) were community acquired infection and 82% (n ¼ 44) were health-care
associated infections. The case-fatality rate was 35% (n ¼ 19). Age, gender, nutritional status and
empirical meropenem were not associated with mortality.
Conclusion: CRGN-BSI in children with underlying malignancy is a serious illness with high mortality. No
single factor could determine the mortality in our study. We suggest study with larger sample size, early
blood culture testing and rational use of Carbapenem.
© 2020 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Publishing Services by
Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

1. Introduction

There is a very high rate of use of antimicrobials in Pediatric

* Corresponding author.
E-mail addresses: [email protected] (U.A. Memon), rahim.ahmed1983@gmail. Intensive Care Units (PICU), reported >90% in few studies [1,2]. The
com (A.R. Ahmed), [email protected] (M. Khalid), karima.qadir@tih. Carbapenem is indicated only for treatment of serious infections.
org.pk (K. Qadir), [email protected] (N. Jabbar), [email protected] The safety profile of this class of drug has contributed to increased
(S. Junejo), [email protected] (A. Haque).
consumption in intensive care settings and its reported usage is
Peer review under responsibility of Pediatric Hematology Oncology Chapter of
Indian Academy of Pediatrics.
>50% of all antibiotics in PICUs. Their irrational use leads to

https://doi.org/10.1016/j.phoj.2020.07.003
2468-1245/© 2020 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Publishing Services by Elsevier B.V. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
66 U.A. Memon et al. / Pediatric Hematology Oncology Journal 5 (2020) 65e68

development of resistance [3]. Carbapenem-Resistant Gram Nega- Table 1

tive Bacteria (CRGNB) infections rate is increasing worldwide [4]. It Clinical and demographic characteristics of children with Carbapenem-
Resistant Gram-Negative Bacteremia in Pediatric Intensive Care Unit
becomes more problematic when there are limited infection pre- (N ¼ 54).
vention measures as well as lack of antibiotics stewardship [5].
Such infections are associated with high health-care cost and Age (in years) mean ± SD 6.97 ± 4

increased morbidity and mortality. Reported mortality rate is over Gender n, %

50% in several studies [6,7]. Such infections are common in highly Male 36 (66.7)
Malnourished n, %
vulnerable groups like children with cancer especially during
Yes 29 (53.7)
neutropenic phase and is the leading cause of death in pediatric Primary disease n, %
oncology of low-middle income countries (LMICs) like Pakistan. AML 19 (35.2)
The published data from LMICs is scarce [8e10]. The objective of B-ALL 19 (35.2)
B-NHL 05 (9.3)
this study is to assess the frequency of Carbapenem-Resistant
Othersa 11 (20.4)
Gram-Negative Bacteremia in children with cancer admitted in Clinical presentation n, %
PICU of LMIC. (see Table 3) Febrile neutropenia 54 (100)
Gastroenteritis 02 (3.70)
2. Methods Methotrexate toxicity 02 (3.70)
Others c 07 (12.96)
Interventionb n, %
We conducted a retrospective cross-sectional study in PICU of Mechanical ventilation (Yes) 14 (25.9)
The Indus Hospital (TIH), Karachi from September 2017 to August Inotropic support (Yes) 27 (50.0)
2019. TIH is a tertiary-care, Non-Governmental Organization (NGO) Systemic steroids (Yes) 47 (87.0)
hospital and is a largest pediatric oncology center of the country Packed cell transfusion (Yes) 53 (98.1)
Outcome n, %
which provides comprehensive care to whole spectrum of pediatric Survived 35, (64.8)
oncology. Patients were identified from the records of microbiology a
Two cases each of Burkitt Lymphoma, Infantile leukemia, T-ALL, T-
laboratory. All episodes of infection were defined as the isolation of
NHL, Wilm’s tumor and 1 case of GCT-mixed type.
CRGNB in blood in critically ill children with cancer with presence b
One patient required dialysis and 3 central lines.
of clinical signs and symptoms of sepsis from 3 days prior to PICU c
One case each of Esophagitis, epidural hematoma, measles, sepsis,
admission or during PICU stay. Neutropenia is defined absolute fungal pneumonia, obstructive jaundice and Wilm’s tumor relapse.
neutrophil count <500/mm3. Septic shock is defined according to
International Pediatric Sepsis Consensus [11]. Health-care Associ-
Table 2
ated Infections (HAIs), including Central Line Associated Blood Microbiological characteristics of children with Carbapenem-Resistant Gram-
Stream Infection (CLABSI) were defined according to Center for Negative Bacteremia in Pediatric Intensive Care Unit (N ¼ 54).
Disease Control (CDC) for Prevention and National Health Safety
Isolated CRE pathogens n, %
Network (NHSN) surveillance definition [12]. We used institutional E-coli 30 (55.6)
“Don’t Resuscitate Order (DNR)” policy for patients with very low- Klebsiella species 14 (25.9)
risk of survival based on recommendation of two physicians, Enterobacter 04 (7.4)
including primary oncologist after discussing with family and Multiple pathogens 06 (11.1)
Timing of positive blood culture, n, %
signed consent. Blood culture was performed using BacT/ALERT™
Before PICU admission 10 (18.5)
culture system; species identification was carried out with VITEK- After PICU admission 44 (81.5)
GNI (BioMerieux™). Antibiotic susceptibility was performed us- Antibiotics before culture report n, %
ing disc diffusion (inhibition zone in mm) according to Clinical and Piperacillin-Tazobactam 25 (46.3)
Laboratory Standards Institute (CLSI). Isolates with lower inhibition Meropenem & Colistin 16 (29.6)
Meropenem 11 (20.4)
zone to carbapenems (meropenem, imipenem and ertapenem); as Piperacillin-Tazobactam & Amikacin 02 (3.7)
well as to 3rd generation Cephalosporin (ceftriaxone, cefotaxime) a
Antibiotics after culture report n, %
were considered carbapenem resistant. The resistance breakpoints Meropenem & Colistin 49 (90.7)
used for detecting carbapenem resistance among Enterobacteri- Meropenem 02 (3.7)
Colistin 02 (3.7)
aceae was
19 for imipenem and meropenem, and
18 for erta-
a
penem. The resistance breakpoints used for ceftriaxone and One patient expired before the final blood culture report was available.
cefotaxime were
19 and
22 respectively. All resistance break-
points were according to CLSI guidelines 2019 [13]. Data including
demographic variables (age and gender), clinical variables (diag- of malignancy in our cohort was acute leukemia (70%), solid tumor
nosis, cancer, presence of device, medications, blood transfusion) (20%) and lymphoma (10%). Most common reason for admitting
and outcome variables (discharge status and length of stay) were diagnosis in all febrile neutropenic was severe sepsis (>95%). The C-
collected on structured data sheet. All data entered into SPSS v.21 reactive protein was done in 33 patients and the median was
for descriptive statistical analysis. This study was approved by 233 mg/l (range: 5.3e453)[normal <0.5 mg/l]. Vasoactive-inotropic
institutional ethical review committee (IRD_IRB_2019_09_014, drugs for cardiovascular support were instituted in 50% (n ¼ 27)
October 1, 2019). and 26% (n ¼ 14) required mechanical ventilation for respiratory
support. The most common CRGNB isolates were E. coli (56%) and
3. Results Kelbseilla species (26%). Of all the CRG-BSI, 18% (n ¼ 10) were
community acquired and 82% (n ¼ 44) were health-care associated
During two-year study period, 1234 patients were admitted in infections. The Meropenem was used in 50% before culture results.
PICU. Fifty-four patients (0.3%) were identified as positive blood Combination therapy (Meropenem and Colistin) were used in 96%
culture for CR-GNB in critically ill children with cancer. Table 1 cases and Colistin alone was used in only 4%. The case-fatality rate
describes demographic and clinical characteristics of cases. The was 35% (19/54) in our cohort. Almost 80% (16/19) had “DNR” order
mean age was 6.97 ± 4 years. Sixty-seven percent (n ¼ 36) were because of poor-prognostications and low-risk of survival (see
male. Fifty-four percent (n ¼ 29) were malnourished. The spectrum Table 2).
 U.A. Memon et al. / Pediatric Hematology Oncology Journal 5 (2020) 65e68 67

Table 3 monotherapy is as efficacious as combination therapy [31]. The

Bivariate logistic regression analysis for the determinants of mortality in children pediatric infectious disease consultation in serious infections due to
with CRGN-BSI in Pediatric Intensive Care Unit (N ¼ 54).
CRGNB may be helpful in the use of antimicrobial agents regarding
Factors Odds ratio 95% Confidence Interval p-value choice, dose, duration and monitoring of therapy [32].
Age 0.99 0.86e1.14 0.86 We found that most of CRGNB bacteremia is hospital-acquired
Gender, (Male) 1.27 0.39e4.12 0.69 infection in our cohort like other pediatric published reports.
Malnourished (Yes) 0.55 0.17e1.73 0.31 There is an urgent need of implementation of infection prevention
Pre-culture antibiotics
and control like practices like strict hand washing, minimal inter-
Tazobactam-piperacillin (Ref) 1
Meropenem 1.12 0.24e5.36 0.89 ruption of CVC and CLABSI bundles. There is also need of strong
Meropenem þ Colistin 0.42 0.12e1.52 0.19 antibiotic stewardship program with early initiation of appropriate
Mechanical ventilation antibiotics in our hospital setting [33].
Yes (Ref) 1
We acknowledged the several limitations of our study. The
No 8.61 2.17e34.11 0.002
Inotropes use
single center, small sample size and retrospective nature were the
Yes 1 major limitations. We were unable to report infection according to
No 7.19 1.95e26.11 0.003 NHSN surveillance reporting system. Nevertheless, the strength of
Steroids this report is that it may contribute into epidemiological database
Yes 1
of this scarce, life-threatening problem from LMICs.
No 3.72 0.41e33.52 0.24

5. Conclusion

4. Discussions CRGN-BSI in children with underlying malignancy is a serious

illness with high mortality. No single factor could determine the
We found 54 cases of CRGNB in critically ill children with cancer mortality in our study. We suggest study with larger sample size,
during two years period in our PICU. Several published data early blood culture testing and rational use of Carbapenem.
revealed that infections due to GNB in pediatric intensive care units
are increasing from different parts of world [14,15]. Similarly there Declaration of competing interest
was changing paradigm from gram positive infections to gram
negative infections in neutropenic children with cancer can be None.
replaced by the last two decades [16,17]. There is a significant rise in
incidence of antibiotic resistant bacteria especially gram negative
References
organism in critically ill patients as well as immunocompromised
patients like cancer [14,18e20]. CRGNB was described in 1994 and [1] Abbas Q, Ul Haq A, Kumar R, Ali SA, Hussain K, Shakoor S. Evaluation of
the principle mechanism is production of carbapenemase by antibiotic use in pediatric intensive care unit of a developing country. Indian J
certain gram-negative bacteria. Surveillance Network database of Crit Care Med 2016;20:291e4.
[2] Koopmans LR, Finlayson H, Whitelaw A, Decloedt EH, Dramowski A. Paediatric
USA showed that there was a rapid increase in the rate of infections antimicrobial use at a South African hospital. Int J Infect Dis 2018;74:16e23.
due to CRGNB in PICU since 2010 [21]. [3] Zhang D, Cui K, Lu W, Bai H, Zhai Y, Hu S, et al. Evaluation of carbapenem use
There is a wide variation in rate of CRGNB infection in critically in a tertiary hospital: antimicrobial stewardship urgently needed. Antimicrob
Resist Infect Contr 2019;8:5.
ill children with malignancy from different parts of world. Few [4] Livorsi DJ, Chorazy ML, Schweizer ML, Balkenende EC, Blevins AE, Nair R, et al.
clinical reports described the low rate of CRGNB infections in the A systematic review of the epidemiology of carbapenem-resistant Entero-
febrile neutropenic cohort from India and Mexico [22,23]. Averbuch bacteriaceae in the United States. Antimicrob Resist Infect Contr 2018;7:55.
[5] Alp E, Cookson B, Erdem H, Rello J, Survey Group. Infection control bundles in
et al. reported 22% of CRGNB in critically ill children with malig-
intensive care: an international cross-sectional survey in low- and middle-
nancy with low mortality rate (3%) [24]. The rates of CRGNB in such income countries. J Hosp Infect 2019;101:248e56.
vulnerable cases were 50% and 66% in Italy and Egypt respectively [6] Nabarro LEB, Shankar C, Pragasam AK, Mathew G, Jeyaseelan V,
Veeraraghavan B, et al. Clinical and bacterial risk factors for mortality in
[25]. Our results are in accordance with studies of pediatric cohort
children with carbapenem-resistant Enterobacteriaceae bloodstream in-
in Turkey, Greece and Spain [9,15,20,26]. Similarly, in a systematic fections in India. Pediatr Infect Dis J 2017;36:e161e6.
review of adult neutropenic patients, CRGNB bacteremia was [7] Logan LK, Weinstein RA. The epidemiology of carbapenem-resistant Entero-
associated with a high mortality rate [4]. We have a very important bacteriaceae: the impact and evolution of a global menace. J Infect Dis
2017;215:S28e36.
observation in our clinical report that the clinical risk factors like [8] Sekar R, Mythreyee M, Srivani S, Sivakumaran D, Lallitha S, Saranya S. Car-
malnutrition, age, intensive care therapies like mechanical venti- bapenem-resistant Enterobacteriaceae in pediatric bloodstream infections in
lation and vasoactive drugs were not risk factors for mortality un- rural southern India. Indian Pediatr 2017;54:1021e4.
[9] Montagnani C, Prato M, Scolfaro C, Colombo S, Esposito S, Tagliabue C, et al.
like other studies [27,28]. It may be due to the small sample size and Carbapenem-resistant Enterobacteriaceae infections in children: an Italian
the fact that most of the deaths were reported in children had retrospective multicenter study. Pediatr Infect Dis J 2016;35:862e8.
“don’t-resuscitate orders” because of poor prognostic signs and [10] Maltezou HC, Kontopidou F, Katerelos P, Daikos G, Roilides E, Theodoridou M.
Infections caused by carbapenem-resistant Gram-negative pathogens in
low-risk of survival. hospitalized children. Pediatr Infect Dis J 2013;32:e151e4.
The spectrum of strain of CRGNB in blood is varied in different [11] Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus
reports. Enterobacteriaceae (primarily E. coli and K. pneumoniae) conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr
Crit Care Med 2005;6:2e8.
was common (82%) in our reports like Nabarro et al. [6]. However, [12] Centers for Disease Control and Prevention CDC. National and state
other epidemiological reports showed predominance of the non- healthcare-associated infections progress report. CDC website. 2016. http://
fermenters P. aeruginosa and A. baumannii [24]. www.cdc.gov/hai/progress-report/index.html. Accessed June 1, 2017.
[13] Weinstein MP, Clinical and Laboratory Standards Institute. Performance
The treatment of CRGNB in children is extrapolated from adult.
standards for antimicrobial susceptibility testing. 2019.
The combination therapy vs. monotherapy is equivocal. The ma- [14] El-Nawawy A, Ashraf GA, Antonios MAM, Meheissen MA, El-Alfy MMR. Incidence
jority of our patients received the combination therapy (Colistin of multidrug-resistant organism among children admitted to pediatric intensive
and meropenem) vs. monotherapy (Colistin) [29]. Several adult and care unit in a developing country. Microb Drug Resist 2018;24:1198e206.
[15] Costa P de O, Atta EH, Silva ARA da. Infection with multidrug-resistant gram-
few pediatric reports favor the use of combination therapy in the negative bacteria in a pediatric oncology intensive care unit: risk factors and
lieu of severity of infection [29,30]. Recently, a RCT showed that the outcomes. J Pediatr 2015;91:435e41.
68 U.A. Memon et al. / Pediatric Hematology Oncology Journal 5 (2020) 65e68

[16] Anirban M, Amit S. Changing Microbiological Pattern of Pediatric Febrile Dis Lond Engl 2016;48:152e5.
Neutropenia. J Antimicrob Agents. 2016;2(126):1212e2472. [26] Aguilera-Alonso D, Escosa-García L, Saavedra-Lozano J, Cercenado E, Baquero-
[17] Babu KG, Lokanatha D, Lakshmaiah KC, Suresh Babu MC, Jacob LA, Bhat GR, Artigao F. Carbapenem-resistant gram-negative bacterial infections in chil-
et al. Bloodstream infections in febrile neutropenic patients at a tertiary dren. Antimicrob Agents Chemother 2020;3. 64ee02183-19.
cancer institute in South India: a timeline of clinical and microbial trends [27] Punpanich W, Nithitamsakun N, Treeratweeraphong V, Suntarattiwong P. Risk
through the years. Indian J Med Paediatr Oncol 2016;37:174e82. factors for carbapenem non-susceptibility and mortality in Acinetobacter
[18] Levene I, Castagnola E, Haeusler G. Antibiotic resistant gram-negative blood baumannii bacteremia in children. Int J Infect Dis 2012;16:e811e5.
Stream infections in children with cancer: a review of epidemiology, risk [28] Zhang Y, Guo L-Y, Song W-Q, Wang Y, Dong F, Liu G. Risk factors for
factors and outcome. Pediatr Infect Dis J 2018;37:1. carbapenem-resistant K. pneumoniae bloodstream infection and predictors of
[19] Lee JH, Kim SK, Kim SK, Han SB, Lee JW, Lee DG, et al. Increase in antibiotic- mortality in Chinese paediatric patients. BMC Infect Dis 2018;18:248.
resistant gram-negative bacterial infections in febrile neutropenic children. [29] Doi Y. Treatment options for carbapenem-resistant gram-negative bacterial
Infect Chemother 2016;48:181e9. infections. Clin Infect Dis Off Publ Infect Dis Soc Am 2019;69(Suppl 7):
[20] Vinker-Shuster M, Stepensky P, Temper V, Shayovitz V, Masarwa R, S565e75.
Averbuch D. Gram-negative bacteremia in children with hematologic malig- [30] Ripa M, Rodríguez-Nún ~ ez O, Cardozo C, Naharro-Abell an A, Almela M,
nancies and following hematopoietic stem cell transplantation: epidemiology, Marco F, et al. Influence of empirical double-active combination antimicrobial
resistance, and outcome. J Pediatr Hematol Oncol 2019;41:e493e8. therapy compared with active monotherapy on mortality in patients with
[21] Logan LK, Renschler JP, Gandra S, Weinstein RA, Laxminarayan R, Centers for septic shock: a propensity score-adjusted and matched analysis. J Antimicrob
Disease Control, et al. Carbapenem-resistant Enterobacteriaceae in children, Chemother 2017;72:3443e52.
United States, 1999-2012. Emerg Infect Dis 2015;21:2014e21. [31] Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, et al.
[22] Rose W, Veeraraghavan B, George B. Bloodstream infections in children with Colistin alone versus colistin plus meropenem for treatment of severe in-
febrile neutropenia: isolates and their antimicrobial susceptibility profile. fections caused by carbapenem-resistant Gram-negative bacteria: an open-
Indian J Canc 2015;52:495. label, randomised controlled trial. Lancet Infect Dis 2018;18:391e400.
[23] Islas-Mun~ oz B, Volkow-Ferna ndez P, Ibanes-Gutie rrez C, Villamar-Ramírez A, [32] Horikoshi Y, Suwa J, Higuchi H, Kaneko T, Furuichi M, Aizawa Y, et al. Sus-
Vilar-Compte D, Cornejo-Jua rez P. Bloodstream infections in cancer patients. tained pediatric antimicrobial stewardship program with consultation to in-
Risk factors associated with mortality. Int J Infect Dis 2018;71:59e64. fectious diseases reduced carbapenem resistance and infection-related
[24] Averbuch D, Avaky C, Harit M, Stepensky P, Fried I, Ben-Ami T, et al. Non- mortality. Int J Infect Dis 2017;64:69e73.
fermentative Gram-negative rods bacteremia in children with cancer: a 14- [33] Li M, Wang X, Wang J, Tan R, Sun J, Li L, et al. Infection-prevention and control
year single-center experience. Infection 2017;45:327e34. interventions to reduce colonisation and infection of intensive care unit-
[25] Caselli D, Cesaro S, Fagioli F, Carraro F, Ziino O, Zanazzo G, et al. Incidence of acquired carbapenem-resistant Klebsiella pneumoniae: a 4-year quasi-
colonization and bloodstream infection with carbapenem-resistant Entero- experimental before-and-after study. Antimicrob Resist Infect Contr 2019;8:8.
bacteriaceae in children receiving antineoplastic chemotherapy in Italy. Infect