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  Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 438-441
 

Epidemiology of blood stream infections in pediatric patients at a Tertiary Care Cancer Centre


1 Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Microbiology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Feb-2016

Correspondence Address:
B Arora
Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175311

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 » Abstract 

Background: Blood stream infections (BSI) are among the most common causes of preventable deaths in children with cancer in a developing country. Knowledge of its etiology as well as antibiotic sensitivity is essential not only for planning antimicrobial policy, but also the larger infection prevention and control measures. Aims: To describe the etiology and sensitivity of BSI in the pediatric oncology unit at a tertiary cancer center. Materials and Methods: All the samples representative of BSI sent from pediatric oncology unit during the period of January to December, 2013 were included in the study, and analyzed for microbiological spectrum with their antibiotic sensitivity. Results: A total of 4198 samples were representative of BSI. The overall cultures positivity rate was 6.97% with higher positivity rate (10.28%) from central lines. Of the positive cultures, 208 (70.9%) were Gram-negative bacilli (GNB), 71 (24.2%) were Gram-positive organisms, and 14 (4.7%) were Candida species. Lactose fermenting Enterobacteriaceae i.e., Escherichia coli (28.4%), Klebsiella pneumoniae (22.1%), and Enterobacter (4.8%) accounted for 55.3% of all GNB. Pseudomonas accounted for 53 (25.5%) and Acinetobacter 19 (9.1%) of GNB. Among Gram-positive isolates, staphylococci were the most frequent (47.8%), followed by Streptococcus pneumoniae 17 (23.9%), beta-hemolytic streptococci 11 (15.5%), and enterococci 9 (12.68%). Of GNB, 45.7% were pan-sensitive, 24% extended spectrum beta–lactamase (ESBL) producers, 27% were resistant to carbapenems, and 3.4% resistant to colistin. Pseudomonas was most sensitive, and Klebsiella was least sensitive of GNB. Of the staphylococcal isolates, 41.67% were methicillin-resistant Staphylococcus aureus (MRSA) and 10% of Coagulase Negative Stapylococci (CONS) were methicillin. Conclusion: A high degree of ESBL producers and carbapenem-resistant Enterobacteriaceae is concerning; with emerging resistance to colistin, raising the fear of a return to the preantibiotic era. An urgent intervention including creating awareness and establishment of robust infection control and antibiotic stewardship program is the most important need of the hour.


Keywords: Blood stream infections, hematolymphoid, malignancy, oncology, pediatric


How to cite this article:
Thacker N, Pereira N, Banavali S, Narula G, Vora T, Chinnaswamy G, Prasad M, Kelkar R, Biswas S, Arora B. Epidemiology of blood stream infections in pediatric patients at a Tertiary Care Cancer Centre. Indian J Cancer 2014;51:438-41

How to cite this URL:
Thacker N, Pereira N, Banavali S, Narula G, Vora T, Chinnaswamy G, Prasad M, Kelkar R, Biswas S, Arora B. Epidemiology of blood stream infections in pediatric patients at a Tertiary Care Cancer Centre. Indian J Cancer [serial online] 2014 [cited 2018 May 28];51:438-41. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/438/175311



 » Introduction Top


The improvement in long-term survival of patients with neoplastic diseases has been partly attributable to advances in the delivery of intensive chemotherapy as well as in supportive care with prophylactic and empirical antimicrobial usage. However, this has produced a population of immunocompromised patients, who are more susceptible to infections. Blood stream infections (BSIs), consequent to immunosuppressive therapy have become a major cause of morbidity and mortality in this population; not only increasing the duration of hospital stay, but also significantly increasing the cost of treatment.[1] Children with cancer account for up to 18% of severe sepsis in children,[2] with Intensive Care Unit mortality rates as high as 64% in high-risk children.[3] High cure rates achieved in most childhood cancers are significantly offset by toxic deaths, attributable mainly to bacterial infections, which are the most common cause of preventable deaths in a developing country.

The choice of empirical antimicrobial requires the knowledge of the epidemiology of common pathogens in the given setting, which constantly changes, necessitating periodic review. Furthermore, knowledge of contemporary epidemiological and sensitivity profile of bacterial pathogens would not only help us formulate an antibiotic policy, but also plan the larger infection prevention and control measures.

The primary objective of this study was to describe the etiology and sensitivity of BSI in pediatric patients at a cancer referral center.


 » Materials and Methods Top


In this retrospective observational study, all the samples sent for culture from pediatric oncology services of Tata Memorial Hospital, Mumbai, from January 1, 2013 to December 31, 2013 were evaluated. All the samples that represented BSI were included for analysis. These samples included peripheral blood, blood drawn through catheters/ports, and catheter tip cultures. The antibiotic sensitivity testing of these samples was done by Kirby–Bauer's disc diffusion method and antibiotics discs for in vitro testing were determined by Clinical and Laboratory Standards Institute (CLSI) guidelines. Extended spectrum beta–lactamase (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), cefoperazone (30 μg), and ceftazidime/sulbactum (30 μg/10 μg) disks for ESBL determination. Carbapenem-resistance was reported as per the CLSI guidelines. Methicillin-resistant Staphylococcus aureus (MRSA) were detected with cefoxitin (30 μg) discs. Vancomycin resistance was confirmed by minimal inhibitory concentrations with the 'E' test. An analysis of the microbiological spectrum and the antibiotic sensitivity pattern of the bacterial isolates was performed.

Coagulase negative stapylococci (CONS) was considered a pathogen only if it was isolated in two successive cultures.[4] An isolate was defined as multidrug-resistant if it was nonsusceptible to at least one agent in >3 therapeutically-relevant antimicrobial category.[5]

The data were analyzed with IBM SPSS statistics version 18.0. The variables were analyzed using descriptive statistics for frequency of various isolates.


 » Results Top


A total of 6709 culture samples were sent in the year 2013, of which 4198 samples were representative of BSI. The culture positivity rate was 6.97%. The culture positivity rate was higher at 10.28% from samples obtained from central lines (catheter/port) as compared to peripheral lines (6.47%) [Figure 1].
Figure 1: Site-wise culture positivity rates

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Of the positive cultures, 208 (70.9%) were Gram-negative bacilli (GNB), 71 (24.2%) were Gram-positive organisms, and 14 (4.7%) were Candida species. The positivity rate of individual microbes is given in [Figure 2], with most prevalent being Escherichia coli (20.13%), followed by Pseudomonas (18.08%), Klebsiella pneumoniae (15.70%), and Acinetobacter (6.5%).
Figure 2: Prevalence of organisms in blood stream infection

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Among Gram-positive isolates, staphylococci were the most frequent (47.8%), followed by S. pneumoniae 17 (23.9%), beta-hemolytic streptococci 11 (15.5%), and enterococci 9 (12.68%).

Lactose fermenting Enterobacteriaceae i.e., E. coli (28.4%), K. pneumoniae (22.1%), and Enterobacter (4.8%) accounted for 55.3% of all Gram-negative bacteria. Pseudomonas accounted for 53 (25.5%), and Acinetobacter 19 (9.1%) of Gram-negative bacteria. Sensitivity pattern of GNB is illustrated in [Figure 3].
Figure 3: Sensitivity patterns of Gram-negative bacilli

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95 (45.7%) of GNB isolates were pan-sensitive. 44 (83%) of Pseudomonas isolates were sensitive making it the most sensitive organism. However, only 8 (17.4%) of Klebsiella were pan-sensitive making it the least sensitive group.

The overall rate of ESBL producing organisms was 24.0%, with maximum incidence among E. coli (47.8%), followed by Acinetobacter (42.1%) and Klebsiella (34.8%). These isolates on testing with a combination of beta-lactam/beta-lactamase inhibitor revealed 44.1% of E. coli, 46.7% of Klebsiella, 52.6% of Acinetobacter, and 89.8% of Pseudomonas to be sensitive to the combination.

Carbapenem-resistance was seen in 56 (26.9%) of Gram-negatives, with Klebsiella 22 (47.8%) having the most and Pseudomonas 9 (17%) having the least resistance. 7 (3.4%) of all GNB (3 - E. coli and 4 - Acinetobacter) were resistant to all antibiotics tested (including colistin and polymyxin B), except tigecycline.

The overall activity of ciprofloxacin among Gram-negative isolates tested was 56.3%. However, the activity of ciprofloxacin against ESBL and carbapenem-resistant Enterobacteriaceae (CRE) was poor (36% and 9%, respectively). The susceptibility of the Gram-negative isolates tested for amikacin was high at 76.6%. Amikacin also fared better against ESBL and carbapenem-resistant bugs with 84% and 35.7% isolates showing sensitivity, respectively.

The antibiotic sensitivity patterns of the Gram-positive organisms revealed that linezolid was the most active agent with no resistance seen. The activity of ciprofloxacin and clindamycin against the Gram-positive isolates tested was 72.5% and 67.2%, respectively.

Of the staphylococcal isolates, 10 (41.67%) were MRSA with none of the isolates being Vancomycin resitant staphylococcus aureus (VRSA) or Vancomycin intermediate stapylococcus aureus (VISA) and 10% of CONS were methicillin-resistant-coagulase-negative staphylococci (MR-CNS). Overall, 3.8% of total BSI was caused byMRSA/MR-CNS organisms. Vancomycin-resistant enterococci (VRE) accounted for 2 (22.2%) of all the enterococcal isolates. Both the VRE isolates were also resistant to teicoplanin but were sensitive to linezolid.


 » Discussion Top


BSIs are a major cause of morbidity and mortality in children with malignancies. Children with cancer are at higher risk of BSI due to neutropenia and immunosuppression secondary to the disease as well as chemotherapy. Crude mortality rate due to BSI in neutropenic patients could be as high as 36%.[6] The epidemiology of organisms causing BSI has come a complete circle, with a shift from Gram-negative organisms in the 1970s to Gram-positive organisms in the last decade and re-emergence of Gram-negative organisms in the current era.[7],[8],[9]

Culture positivity rate in our study was 6.97%, which is low when compared to 11–38% in the west.[10],[11],[12] It can be attributed to the fact that most of our patients do not have a central line, unlike west where patients usually have a central line, and drawing adequate volumes of blood for cultures as per IDSA 2013 guidelines is a challenge in children.[11] This is also confirmed by the almost 2 times positivity rate from cultures obtained from central lines compared to peripheral cultures. Another potential factor contributing to low culture positivity rate may be the collection of only single culture at our institute in patients (since most are without central lines) against the recommendation of two cultures. This emphasizes the need to collect adequate volume paired or double cultures to improve culture positivity rates which is extremely important for appropriate and timely antibiotic therapy for these sick children.

Gram-negative organisms were 3 times more frequent (71%) than Gram-positive isolates (24%) in our study. This is much higher than 45% rate for GNB in a recently published multicentric European study,[8] which, though, showed a trend of increasing Gram-negative infections. Potential reasons for this difference could be the lower use of central catheters and ports in our institute as well as no quinolone prophylaxis compared to the west. Our rates were, however, comparable to similar studies from India in both oncological [13],[14],[15] and nononcological settings.[16],[17] Further, among the Gram-positive isolates, frequency of CONS was markedly lower compared to Europe (3.4% vs. 23%). Apart from lower central line use, our requirement of two consecutive positive blood cultures for defining significant CONS bacteremia may have led to this difference.[8] Among S. aureus isolates, rate of MRSA was high at 41.6% and 10% for MR-CNS. This emphasizes the need for early MRSA coverage in children with suspected Gram-positive infections, but there is no need for empirical early coverage as the overall incidence of these infections is very low at 3.8% of all BSIs at our center.

Enterobacteriaceae accounted for more than half of the total Gram-negative BSI. As in the European study, frequency of Enterobacteriaceae isolates was twice as that of Pseudomonas. In comparison to the pediatric data from a European study, the rate of ESBL producers and CRE is markedly higher in our study, which is a cause for concern [Table 1]. As compared to similar study in adults from our institute in 2010 [Table 1], the rate of ESBL Enterobacteriaceae has increased 3-fold and CRE by nearly 15-fold. One of the reasons for this could be selection pressure due to increased use of carbapenems. Interestingly, the Pseudomonas (87%) isolates were highly sensitive, with only 17% being carbapenem-resistant. Amikacin had good activity in the majority of Gram-negative isolates and fair activity in CRE isolates, making it good drug for combination antibiotic therapy. Among Enterobacteriaceae, Klebsiella was most problematic with nearly half of the isolates showing resistance to carbapenems. A similar trend in Klebsiella has been reported from other studies from Delhi,[18],[19] which is explained by the high prevalence of carbapenemases, which are NDM-1 and easily transmissible.
Table 1: Comparison of resistance patterns with other studies

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A high degree of ESBL (24.0%) producers and CRE (26.9%) in our study is concerning. CRE rates are even higher than ESBL producers, which has a potential to increase the morbidity and mortality, calling for an urgent review of institutional antibiotic usage, antibiotic stewardship, as well as infection control policy. Seven isolates demonstrated resistance to colistin and polymyxin B but were sensitive to tigecycline. This is of grave concern and highlights the possibility of rising colistin resistance in near future, which would put these children at a much higher risk of death as there are hardly any good antibiotic options for colistin-resistant BSIs as tigecycline is considered poor effective in this scenario. The rising rate of ESBL and CRE organisms is a trend evident in the country as highlighted in the National Febrile Neutropenia Group meeting held along with Indian Cooperative Oncology Group meeting at Bhopal in September, 2014. The picture of resistance among the Gram-positive isolates is not as grim with most of the isolates being susceptible to commonly used antibiotics and low rate of VRE isolates.

Overall, Gram-negative isolates in our study show fair sensitivity to beta-lactam with beta-lactamase inhibitor combinations and aminoglycosides. This supports the use of empirical combination therapy with these two drugs as first-line therapy. However, in light of increased isolates of CRE (>20%), it would be prudent to follow a de-escalation antibiotic approach especially in at-risk children as detailed in European Conference on Infections in Leukemia guidelines.[20]

A high prevalence of resistant organisms also emphasizes the need of active surveillance cultures, for early planning of infection control measures and guiding the use of empirical antibiotics. These surveillance cultures would help contain the spread of these lethal organisms as well as minimize the morbidity and mortality due to late initiation of appropriate antibiotics in these immunocompromised children where blood culture positivity is low, and delay in instituting appropriate antibiotics can be fatal.[20],[21] Our study is limited by two factors; one some of the samples may be from the same patient collected during the same episode at different times or during different episodes, thus overestimating the prevalence of resistant organisms and second, the information on infection-related mortality is unavailable.

Overall, the rapidly increasing resistance in Gram-negative isolates combined with an exhausting pipeline of active antibiotics highlights a very grim picture for the future. It raises fear of a return to the preantibiotic era with large scale deaths from bacterial infections and inability to deliver intensive chemotherapy for cancers. An urgent intervention including creating awareness and establishment of robust infection control and antibiotic stewardship program at local, national, and global level is the most important need of the hour to contain this potentially catastrophic epidemic.

 
 » References Top

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Fiser RT, West NK, Bush AJ, Sillos EM, Schmidt JE, Tamburro RF. Outcome of severe sepsis in pediatric oncology patients. Pediatr Crit Care Med 2005;6:531-6.  Back to cited text no. 3
    
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Nateghian A, Robinson JL, Arjmandi K, Vosough P, Karimi A, Behzad A, et al. Epidemiology of vancomycin-resistant enterococci in children with acute lymphoblastic leukemia at two referral centers in Tehran, Iran: A descriptive study. Int J Infect Dis 2011;15:e332-5.  Back to cited text no. 4
    
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Averbuch D, Cordonnier C, Livermore DM, Mikulska M, Orasch C, Viscoli C, et al. Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: Guidelines of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011). Haematologica 2013;98:1836-47.  Back to cited text no. 5
    
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Bakhshi S, Padmanjali KS, Arya LS. Infections in childhood acute lymphoblastic leukemia: An analysis of 222 febrile neutropenic episodes. Pediatr Hematol Oncol 2008;25:385-92.  Back to cited text no. 15
    
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Tiwari DK, Golia S, Sangeetha KT, Vasudha CL. A study on the bacteriological profile and antibiogram of bacteremia in children below 10 years in a tertiary care hospital in bangalore, India. J Clin Diagn Res 2013;7:2732-5.  Back to cited text no. 16
    
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20.
Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: Summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica 2013;98:1826-35.  Back to cited text no. 20
    
21.
Siegel JD, Rhinehart E, Jackson M, Chiarello L; Healthcare Infection Control Practices Advisory Committee. Management of multidrug-resistant organisms in health care settings, 2006. Am J Infect Control 2007;35 10 Suppl 2:S165-93.  Back to cited text no. 21
    


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