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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 420-424
 

Epidemiology of bacterial isolates among pediatric cancer patients from a tertiary care oncology center in North India


1 Department of Pediatric Hematology and Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
2 Department of Microbiology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India

Date of Web Publication1-Feb-2016

Correspondence Address:
G Kapoor
Department of Pediatric Hematology and Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175364

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 » Abstract 

Background: Infections are a major cause of morbidity and mortality in pediatric oncology. Resistance pattern of bacterial isolates determine empiric antibiotic therapy and influence outcome. AIMS: This study was planned to determine profile of bacterial isolates and their antibiotic resistance pattern among pediatric cancer patients. DESIGN: It was a retrospective, single institutional study. Materials and Methods: The study was carried out in the department of pediatric hematology-oncology of a tertiary care cancer centre in north India over a period of 24 months (2012-2014). Microbiological data pertaining to pediatric cancer patients, less than 18yrs of age was analysed. Results: Hence, 238 bacterial isolates were cultured from among 1757 blood, urine and other specimens. Gram negative bacteria were the most common (74%) pathogens identified and E. coli and Klebsiella comprised 80% of them. A high incidence of extended spectrum beta lactamase producing organisms (84%), beta-lactam beta-lactamase inhibitor (78%) and carbapenem resistance was observed (29%). Blood stream infection with multi-drug resistant Klebsiella was associated with high mortality. The gram positive bacteria isolated were predominantly staphylococcus aureus and were antibiotic sensitive. Reduction in the number of culture positive isolates in the second year of our study was probably due to rigorous implementation of infection control measures. Conclusion: These results on microbiologic profile and antibiotic sensitivity pattern of the isolates will be extremely helpful in revision of antibiotic guidelines for our patients and in developing strategies for coping with high prevalence of multi-drug resistance. Antibiotic stewardship and strict implementation of infection control practices will be important components of this effort.


Keywords: Antibiotic resistance, extended spectrum beta lactamase, infections, pediatric hematology oncology


How to cite this article:
Kapoor G, Sachdeva N, Jain S. Epidemiology of bacterial isolates among pediatric cancer patients from a tertiary care oncology center in North India. Indian J Cancer 2014;51:420-4

How to cite this URL:
Kapoor G, Sachdeva N, Jain S. Epidemiology of bacterial isolates among pediatric cancer patients from a tertiary care oncology center in North India. Indian J Cancer [serial online] 2014 [cited 2019 Dec 12];51:420-4. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/420/175364



 » Introduction Top


Infections remain a major cause of morbidity and mortality in pediatric oncology. They cause treatment delays, longer hospitalizations, and suboptimal delivery of chemotherapy all of which add to cost and contribute to reduced survival. In recent years, clinicians also encounter infections due to multi-resistant bugs in oncology practice. Appropriate empiric antibiotic therapy is therefore critical to successful outcome. Hence, the current study was planned with the objective of studying the epidemiology of bacterial isolates and the resistance pattern, among children <18 years of age undergoing oncology treatment at our institute.


 » Materials and Methods Top


This is a single institutional study carried out in the departments of pediatric hematology-oncology and microbiology of a tertiary care cancer center in North India. Study population included children with various malignancies undergoing treatment in our hospital, who were <18 years of age, and who had bacterial cultures sent for various reasons, over a period of 24 months (October 2012 to September 2014). All the bacterial culture reports during the study period were retrieved from the database of the department of microbiology. The number of patients registered in the department, in the 1st and 2nd year of the study, was 304 and 306, respectively.

All patients registered in the department for treatment, had blood culture specimens sent for neutropenic or non-neutropenic febrile episodes (>100.5F) and the samples were drawn from the central line, or peripheral vein. In neutropenic patients with persistent fever blood cultures were repeated after 1–2 days and as determined by the clinical status of the patient and physician advice. Urine, stool, pus, and other samples were usually sent for symptomatic patients. All specimens were cultured on different media using standard bacteriological procedures. Blood cultures were routinely collected in aerobic and fungal media and incubated using the BacT/ALERT 3D system (Biomeriux U.S.A). The bacterial isolates were identified manually and by automated system (Mini API).In vitro sensitivity patterns were studied by Kirby bauer disc diffusion method and by using Mini API according to Clinical Laboratory Standard Institute guidelines. Gram-negative organisms isolated from any sample were subjected to an automated system for sensitivity and identification as required. All isolates from blood were Gram stained to separate the Gram-positive/negative organisms. The Gram-negative bacteria (GNB) were then processed by automated identification and sensitivity method, while the Gram-positive bacterial (GNB) isolates were subjected to manual method for identification and sensitivity. Extended spectrum beta lactamase producing (ESBL) isolates were identified by the system itself whereas methicillin resistant Staphylococcus aureus (MRSA) identification was done using – Hi chrome MeReSA agar.

Extended spectrum beta lactamase was interpreted as present whenever the inhibition zone around the disk containing clavulanate was at least 5 mm larger than that of the disk containing the same cephalosporin but without clavulanate. Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 strains were used as controls. An analysis of microbiological spectrum and the antibiotic sensitivity pattern of the bacterial isolates were performed. Clinical outcome of resistant isolates was analyzed. Standard definitions were used for the terms ESBL, beta-lactam beta-lactamase inhibitor (BLBLI), and carbapenem resistance.

Infection control practices have been rigorously implemented in the past 2 years since our Institution has been accredited by the national accreditation board for hospitals and health care (NABH, 2012). It has also led to stricter surveillance and data monitoring for hand hygiene, blood stream infections, urinary tract infections, ventilator associated pneumonias, and strengthening of training program for infection control team members, hospital staff as well as patients and attendants.

The first line empiric antibiotic for febrile neutropenia, in our institution, during the study period, was monotherapy with cefoperazone-sulbactam. Escalation approach was followed and carbapenems were reserved as second line agents; vancomycin or teicoplanin was added in patients with line related infections, cellulitis, severe mucositis or as determined by culture reports. As a policy prophylactic antibiotics and antifungals were not used.

Categorical variables were described as frequency and percentage. For continuous variables, mean values were compared using two-sample t-test for independent samples. Differences in proportions were compared using a Chi-square test or Fisher's exact test, as appropriate. A P < 0.05 was considered statistically significant. The analyses were performed using SPSS software for Windows, version 16.0 (IBM Armonk, NY, USA).

The study was carried out according to the institutional guidelines and was approved by the local Institutional Review Board/Ethics Committee.


 » Results Top


This is a retrospective observational study of the epidemiology of microbiological isolates in children with various malignancies over a period of 2 years, October 2012 to September 2014. The site from which the specimen or sample was obtained varied and depended on the clinical symptoms of the patient [Table 1]. During the study period, a total of 1747 culture samples were sent of which 1240 (71%), 271 (15.5%) and 236 (13.5%) were from blood, urine and other sites, respectively. Of these, 238/1747 (13.6%) isolates grew bacteria and the year-wise distribution is shown in [Table 1]. The absolute number of culture samples as well as the positive isolate rate were statistically lower in the latter year (P = 0.008). This is despite the fact that there was no difference in quantum of susceptible population as new patients registered during each of the 12-month periods was almost the same (304 and 306). Probability of detection of a bacterial culture positive isolate was dependent on whether the specimen was from blood (9.4%), urine (18.4%) or other site (31.4%) and this difference was statistically significant (P < 0.001). These isolates belonged to 138 patients, with various hematolymphoid disorders (92) and solid tumors (46).
Table 1: Distribution of bacterial isolates by site of specimen and time period (238 positive bacterial isolates out of 1747 samples)

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Epidemiology of bacterial isolates is detailed in [Table 2]. Gram-positive isolates accounted for 26.4% of all positive cultures and S. aureus was the most common amongst these (77%). Gram-positive organisms were most frequently isolated from blood stream and other sites and only occasionally from urine (P < 0.001). Gram-negative infections accounted for 74% of all positive isolates, with E. coli (71/176) and Klebsiella (70/176) being the most frequently identified organisms followed by Pseudomonas (29/176), Acinetobacter (4), Enterobacter (1), and Proteus (1). Among Gram-negative isolates, E. coli was most commonly isolated from urinary specimens (61%), while Klebsiella accounted for most (50%) of the blood stream organisms. Probability of isolating a Gram-negative organism from blood, urine, and other sites constituted 6.5%, 16.6%, and 21.6%, respectively (P < 0.001).
Table 2: Epidemiology of culture positive isolates by year

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On analysis of resistance pattern, Gram-positive isolates were predominantly antibiotic sensitive [Table 3]. Of all 49 staphylococcus isolates, we observed two MRSA infections, both in children with acute myeloid leukemia in remission. One was from blood stream and the patient recovered, while the other who succumbed had the organism isolated in the broncho-alveolar lavage secretion. Enterococcus though an uncommon isolate, was vancomycin-resistant enterococci (VRE) in 2/13 samples, both were from the blood stream of a child with osteosarcoma who recovered from the infection on removal of the line.
Table 3: Resistance pattern of Gram--positive isolates from blood and other sites

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Analysis of resistance of Gram-negative organisms revealed 148/176 (84%) isolates were ESBL, 138/176 (78%) were BLBLI, and carbapenem resistant 52/176 (29%) [Table 4]. Carbapenem resistance was observed to be more common with Klebsiella (34/70, 49%), than E. coli (8/71, 11%) or Pseudomonas (9/29, 31%), respectively (P < 0.001). The prevalence of resistance among strains of E. coli and Klebsiella in regard to ESBL and BLBLI was quite similar. Fluoroquinolone and aminoglycoside resistance in Gram-negative isolates was observed to be about 70% (123/176) and 64.7% (114/176), respectively. Fortunately, none of the carbapenemase producing organisms were resistant to colistin.
Table 4: Resistance pattern of Gram--negative isolates from blood and all other sites

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Blood stream isolates: Among the 71 isolates of E. coli, 31 were from the blood. The resistance pattern revealed presence of ESBL in 28/31 (90%), BLBLI in 27/31 (87%), and carbapenem resistance in 3/31 (9%) isolates from the blood. In our clinical practice, we do not use ticarcillin-clavulanic acid; hence, if we exclude resistance to it, then 18/31 (58%) isolates were resistant to piperacillin-tazobactam and cefoperazone-sulbactam. However, this pattern was not obvious with Klebsiella or Pseudomonas.

Among the 70 isolates of Klebsiella species, 40 were from the blood. The resistance pattern revealed presence of ESBL in 34/40 (85%), BLBLI in 32/40 (80%), and carbapenem resistance in 21/40 (52%) isolates from the blood. These accounted for six infection-related deaths, five of whom had a primary diagnosis of acute leukemia. All (6/6) of these isolates were ESBL, BLBLI, and carbapenem-resistant.

Among the 29 isolates of Pseudomonas, 7 were from the blood. The resistance pattern revealed presence of ESBL in 6/7 (85.7%) and BLBLI in 4/7 (57%) while carbapenem resistance was not observed in isolates from the blood.


 » Discussion Top


Children with cancer represent a population that is uniquely vulnerable to infection because of alterations in host defense mechanisms. This may be related to the underlying illness, to intensive treatment with immunosuppressive/myelosuppressive drugs (neutropenia, lymphopenia, mucositis) and frequent presence of the central line. In this setting, infection is an important complication which may be life-threatening unless dealt with, timely and appropriately. Appropriate empiric treatment requires updated status of local flora and its susceptibility, as failure to cover resistant pathogens may have consequences that are detrimental to the patient outcome.

The main objective of this study was to report on the pattern of bacterial isolates and antibiotic resistance pattern in pediatric oncology, rather than on episodes of infection. During the 2-year study period, 238 positive isolates were identified constituting 13.6% of the 1757 blood, urine, and other specimens that were sent for bacterial culture. The blood culture positivity rate appears to be lower (9.4%) than that reported by others (22–39%).[1],[2],[3] However, as we have not correlated it with episodes of clinical infection, a direct comparison may not be appropriate. A higher yield from urine (18.4%) and other sites (31.4%) is explainable as these cultures were ordered for site specific symptoms.

It was encouraging to observe a reduction in the number of culture positive isolates in the 2nd year of our study, as we believe it was due to the rigorous implementation of infection control measures. It will be interesting to see if this trend holds out in the coming years.

Gram-negative bacteria were the most common (74%) pathogens identified from blood, urine or any other site. This is similar to published literature from the developing world.[4],[5],[6],[7] Relatively low prevalence of Gram-positive isolates may be attributed to our policy of not using prophylactic antibiotics, better prevention of Gram-positive infection owing to bundle approach and vigilance and monitoring of line handling. Analysis of the antibiograms of Gram-positive organisms revealed relatively sensitive S. aureus strains to be the most frequent. Four isolates (4/63, 6%), two each of MRSA (2/49,4%) and VRE (2/13, 15%) were identified among three patients and significantly there was one infection related mortality. Although the prevalence of resistance is lower than that reported by other published reports from developed and developing nations, the consequences make every isolate a threat.[4],[8],[9],[10] Moreover, an increasing trend in resistance is being reported globally, and although second line agents like linezolid are available for GPB, the physicians must use these drugs judiciously.

The two most commonly isolated GNB were E. coli and Klebsiella followed by Pseudomonas. Similar observations have been made in other studies as well.[11],[12],[13] The blood stream samples most frequently grew Klebsiella while urinary samples were usually positive for E. coli. A review of etiological factors, from 33 oncology centers, clinics, and hospitals in North America reports a similar spectrum of GNB.[14] These findings indicate that the pattern of isolates in immunocompromised patients are more or less similar in different parts of the world.

Of major concern was the observation that there was a very high prevalence of ESBL and BLBLI isolates among the GNB. This resistance was uniform irrespective of the source of specimen, causative organism or time period. Other published reports confirm this trend.[15],[16],[17] Concomitant resistance to fluoroquinolones and aminoglycosides in ESBL and BLBLI isolates leaves no choice but to use carbapenems as first line agent in sick patients. Furthermore, our data indicate that carbapenem resistance is on the rise. As mentioned above, Klebsiella constituted half of the blood stream infections in our study and carbpenem resistance was observed in 49% of isolates and an extremely high mortality associated with it. This is really worrisome in light of the availability of fewer options left with the physicians.

The limitations of our study were its retrospective design, single institutional nature, and inclusion of samples of both neutropenic and nonneutropenic patients. As it was designed only to look at the resistance pattern of isolates, correlation with clinical factors was not available. However, it has brought to attention certain clinically relevant facts. First, that GNB are still the most common isolates in pediatric cancer patients in our Institution. Second, there is a very high prevalence of ESBL, BLBLI, and carbapenem resistance among the GNB and an alarming mortality risk associated when these are isolated from the blood stream. Frequency of MRSA and VRE though low are likely challenges for the future. Our current use of cefoperazone-sulbactam as first line antibiotic and strategy of escalating empiric antibiotic therapy for non-responding neutropenic patients needs urgent revision. There is a dire need to conduct prospective studies to correlate clinical and microbiological data to help formulate local guidelines and therapeutic strategies for coping with changes in resistance pattern. Reduction in infection rate with strict implementation of infection control practices was reassuring and this along with antibiotic stewardship will be important in controlling spread of multi-drug resistance.

 
 » References Top

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Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Eighteenth Informational Supplement. M100-S18. Wayne, PA: CLSI; 2008.  Back to cited text no. 1
    
2.
Madani TA. Clinical infections and bloodstream isolates associated with fever in patients undergoing chemotherapy for acute myeloid leukemia. Infection 2000;28:367-73.  Back to cited text no. 2
    
3.
Gaytán-Martínez J, Mateos-García E, Sánchez-Cortés E, González-Llaven J, Casanova-Cardiel LJ, Fuentes-Allen JL. Microbiological findings in febrile neutropenia. Arch Med Res 2000;31:388-92.  Back to cited text no. 3
    
4.
Prabhash K, Medhekar A, Ghadyalpatil N, Noronha V, Biswas S, Kurkure P, et al. Blood stream infections in cancer patients: A single center experience of isolates and sensitivity pattern. Indian J Cancer 2010;47:184-8.  Back to cited text no. 4
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Butt T, Afzal RK, Ahmad RN, Salman M, Mahmood A, Anwar M. Bloodstream infections in febrile neutropenic patients: Bacterial spectrum and antimicrobial susceptibility pattern. J Ayub Med Coll Abbottabad 2004;16:18-22.  Back to cited text no. 5
    
6.
Chen CY, Tang JL, Hsueh PR, Yao M, Huang SY, Chen YC, et al. Trends and antimicrobial resistance of pathogens causing bloodstream infections among febrile neutropenic adults with hematological malignancy. J Formos Med Assoc 2004;103:526-32.  Back to cited text no. 6
    
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Velasco E, Byington R, Martins CS, Schirmer M, Dias LC, Gonçalves VM. Bloodstream infection surveillance in a cancer centre: A prospective look at clinical microbiology aspects. Clin Microbiol Infect 2004;10:542-9.  Back to cited text no. 7
    
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Gopalakrishnan R, Sureshkumar D. Changing trends in antimicrobial susceptibility and hospital acquired infections over an 8 year period in a tertiary care hospital in relation to introduction of an infection control programme. J Assoc Physicians India 2010;58 Suppl: 25-31.  Back to cited text no. 8
    
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Patel AK, Patel KK, Patel KR, Shah S, Dileep P. Time trends in the epidemiology of microbial infections at a tertiary care center in west India over last 5 years. J Assoc Physicians India 2010;58 Suppl: 37-40.  Back to cited text no. 9
    
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Joshi S, Ray P, Manchanda V, Bajaj J, Chitnis DS, Gautam V, et al. Methicillin-resistant Staphylococcus aureus (MRSA) in India: Prevalence and susceptibility pattern. Indian J Med Res 2013;137:363-9.  Back to cited text no. 10
    
11.
Al-Hasan MN, Huskins WC, Lahr BD, Eckel-Passow JE, Baddour LM. Epidemiology and outcome of Gram-negative bloodstream infection in children: A population-based study. Epidemiol Infect 2011;139:791-6.  Back to cited text no. 11
    
12.
Levy I, Leibovici L, Drucker M, Samra Z, Konisberger H, Ashkenazi S. A prospective study of Gram-negative bacteremia in children. Pediatr Infect Dis J 1996;15:117-22.  Back to cited text no. 12
    
13.
Laupland KB, Gregson DB, Vanderkooi OG, Ross T, Kellner JD. The changing burden of pediatric bloodstream infections in Calgary, Canada, 2000-2006. Pediatr Infect Dis J 2009;28:114-7.  Back to cited text no. 13
    
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Mutnick AH, Rhomberg PR, Sader HS, Jones RN. Antimicrobial usage and resistance trend relationships from the MYSTIC Programme in North America (1999-2001). J Antimicrob Chemother 2004;53:290-6.  Back to cited text no. 14
    
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Gudiol C, Tubau F, Calatayud L, Garcia-Vidal C, Cisnal M, Sánchez-Ortega I, et al. Bacteraemia due to multidrug-resistant Gram-negative bacilli in cancer patients: Risk factors, antibiotic therapy and outcomes. J Antimicrob Chemother 2011;66:657-63.  Back to cited text no. 15
    
16.
Spanik S, Krupova I, Trupl J, Kunová A, Novotny J, Mateicka F, et al. Bacteremia due to multiresistant gram-negative bacilli in neutropenic cancer patients: A case-controlled study. J Infect Chemother 1999;5:180-84.  Back to cited text no. 16
    
17.
Rodríguez-Baño J, Picón E, Gijón P, Hernández JR, Ruíz M, Peña C, et al. Community-onset bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: Risk factors and prognosis. Clin Infect Dis 2010;50:40-8.  Back to cited text no. 17
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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