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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 43-48

Blood stream infections in hematopoietic stem cell transplant patients: A 2-year study from India


1 Department of Clinical Microbiology, BLK Super Speciality Hospital, New Delhi, India
2 Department of Bone Marrow Transplant, BLK Super Speciality Hospital, New Delhi, India

Date of Submission10-Feb-2020
Date of Decision28-May-2020
Date of Acceptance29-Jun-2020
Date of Web Publication17-Aug-2020

Correspondence Address:
Purabi Barman
Department of Clinical Microbiology, BLK Super Speciality Hospital, Pusa Road, New Delhi - 110 005
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_7_20

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  Abstract 


Background: Hematopoietic stem cell transplant (HSCT) recipients are particularly prone to bloodstream infections (BSIs). This has been attributed to neutropenia and immune-suppression. Regardless of the improvements made in the management perspective, infection still plays a major role in morbidity and mortality in these patients. It has been related to the rise of multidrug-resistant organisms. Aim: The aim of this study was to determine the pattern of BSIs and the burden of antibiotic resistance in HSCT patients. Materials and Methods: We conducted this retrospective study for 2 years in 438 transplant events among 429 HSCT recipients who developed febrile neutropenia. Paired blood culture samples were collected on the onset of fever. Carbapenem-resistant Enterobacteriaceae (CRE) carriage rate was also determined in 127 patients. Results: BSIs were detected in 131 transplant events, which were classified as mucosal barrier injury laboratory-confirmed BSIs in 61, central line-associated, and other primary BSIs among 35 each. A diverse variety of 145 isolated organisms included Gram-negative and Gram-positive bacteria with 4 Candida species. All the Gram-negative isolates were susceptible to colistin, while 68.83% of CRE was detected. CRE carriage rate was observed in 37.80% of 127 individuals. Vancomycin resistance was noticed in 40% Enterococcus species. The overall mortality rate was 20.05%. Conclusions: Screening for CRE carriage in these patients could help in timely initiation of empirical colistin therapy. However, local epidemiology plays an important role in deciding the empirical antibiotic therapy.

Keywords: Blood stream infections, carbapenem resistant Enterobacteriaceae, hematopoietic stem cell transplant


How to cite this article:
Barman P, Choudhary D, Chopra S, Thukral T. Blood stream infections in hematopoietic stem cell transplant patients: A 2-year study from India. Oncol J India 2020;4:43-8

How to cite this URL:
Barman P, Choudhary D, Chopra S, Thukral T. Blood stream infections in hematopoietic stem cell transplant patients: A 2-year study from India. Oncol J India [serial online] 2020 [cited 2020 Oct 31];4:43-8. Available from: https://www.ojionline.org/text.asp?2020/4/2/43/291905




  Introduction Top


Hematopoietic stem cell transplant (HSCT) is considered as a life-saving modality for patients with hematological malignancies. These patients are subjected to conditioning regimens to overcome graft versus host disease (GVHD), which leads to neutropenia, mucositis, and immune suppression; increasing the risk of infections including bloodstream infections (BSIs).[1] Iatrogenic skin disruption by central venous catheters is another contributing factor to BSIs.[2] The incidence of bacteremia as reported in HSCT patients in various studies, varies from 5% to 64.95%.[1],[3],[4],[5] Despite the development and advances in various successful conditioning and prophylactic strategies, infection plays a major role in morbidity and mortality in these patients. This further contributes to the upsurge of multidrug-resistant organisms (MDRO), which puts up challenges in the treatment of these patients. Although HSCT has a major burden of MDRO and other infections, not much data are available from India, barring a few studies.

The purpose of this study was to evaluate the epidemiology of bacteremia in HSCT patients, antimicrobial profile of the isolates emphasizing on antimicrobial stewardship to combat the burden of MDRO.


  Materials and Methods Top


We conducted a retrospective study on HSCT patients in our hospital from December 2014 to January 2017. The study included 429 consecutive patients of all age groups who underwent HSCT and had at least one episode of BSI. Pediatric patients (<18 years) constituted for 112 (26.11%) of the total study population. Male: female ratio was found to be 1.8:1.

Blood culture specimens were obtained on clinical suspicion of BSI. Paired blood cultures were usually drawn from each patient within the first day of the febrile episode and were inoculated in BD Bactec Plus aerobic culture bottles and then incubated in the BACTEC™ 9120 (Becton Dickinson, Sparks, Maryland, USA), an automated continuous monitoring blood culture system. The source of infection was described based on the Centers for Disease Control and Prevention (CDC) guidelines. In case two different organisms were isolated within 14 days, it was considered a single event of BSI as per CDC criteria.[6] The positive samples were then analyzed on the Vitek® 2 Compact (BioMérieux, Marcy l'Etoile, France).

Patients were also routinely assessed for the development of mucositis during the course of treatment using predefined criteria.[7] Stool samples of the patients were concurrently screened for carbapenem-resistant Enterobacteriaceae (CRE) using chromagar (CHROMagar and Rambach, Paris-France); however, data could be retrieved only for 127 such patients. Patients were followed till the time of their discharge and/or death.

Data analysis was performed using MEDCALC easy-to-use statistical software (Version 18) MedCalc Software Ltd., Ostend, Belgium.[8]


  Results Top


During the study period, 438 hCT were performed among 429 patients. Nine patients had HSCT twice of which 07 were due to rejection and 02 due to relapse. Patients with >1 hCT procedure were considered as different transplant episodes and hence different patients. Allogeneic matched-related donor transplants were done in 238 (54.34%), allogeneic matched unrelated donor transplants in 11 (02.51%), haploidentical in 76 (17.35%), and autologous in 113 (25.80%) patients. The predominant underlying hematological disorders were thalassemia major in 99 (23.08%) followed by multiple myeloma in 80 (18.65%), acute myelogenous leukemia in 61 (14.22%), and bone marrow failure in 59 (13.75%) cases. Multiple myeloma (79, 69.91%) was the most common underlying pathology among autologous HSCT patients while thalassemia major (99, 30.46%) being the most prevailing one among all allogeneic HSCT patients. Antimicrobial prophylaxis with acyclovir and fluconazole was given to all the patients. The empirical antibiotic regimen with piperacillin-tazobactam and amikacin was initiated with the onset of the first febrile episode.

BSIs were noticed in 131 (29.91%) of 438 transplant events in the immediate posttransplant period. Out of these 131 patients, 25 (19.08%) were recipients of autologous transplants and 106 (80.92%) of allogeneic transplants. The empirical antibiotic regimen was escalated to carbapenems on the persistence of fever for 48 h. The appropriateness of this regimen was then compared to the antimicrobial susceptibility pattern, as obtained in Vitek® 2 Compact. The therapy was considered appropriate if the etiological agent was found susceptible to the antibiotics used.

As per CDC criteria, all the cases were proven to have primary BSIs. Thirty-five (26.72%) of these were categorized as central line-associated BSIs (CLABSIs) and 61 (46.56%) as mucosal barrier injury laboratory-confirmed BSIs (MBI-LCBIs).[6] Gut translocation proved a considerable source of MBI-LCBIs in these patients. Mucositis was noted in 228 (52.05%) of the total transplant events of which 61 (26.75%) progressed to BSIs (Risk ratio 0.8026; P = 0.134). A total of 145 organisms were identified in 131 individuals, of which 02 patients had mixed BSIs, whereas 12 presented with two episodes of bacteremia. Various bacterial and fungal etiological agents of BSIs in our patients are enlisted in [Table 1]. Among 145 total organisms isolated, 109 (75.17%) Gram-negative bacilli, 32 (22.07%) Gram-positive cocci, and 04 (02.76%) Candida spp. were reported. Klebsiella pneumoniae (48, 33.10%) was found to be the most common cause of all BSIs, followed by Escherichia coli (20.00%) and Pseudomonas aeruginosa (11.73%). The antimicrobial susceptibility testing (AST) patterns of the distinct organisms are shown in [Table 2], [Table 3], [Table 4]. Maximum susceptibility in Gram-negative isolates was noticed toward colistin, being 100% susceptible. The Gram-negative isolates were variably sensitive to carbapenems; CRE was detected among 68.83% of Enterobacteriaceae, which accounted for 22.02% of the total Gram-negative isolates. Screening of stool samples for CRE carriage was evaluated only in 127 patients. CRE carriage was observed among 48 (37.80%) of these individuals. MBI-LCBI was reported in 30 of the 48 carriers. The blood isolates also matched phenotypically to that of the stool isolates in 23 (76.67%) carriers. We did not come across any colistin resistance in our study.
Table 1: List of isolates recovered from blood stream infections

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Table 2: Antimicrobial susceptibility pattern of major Gram negative isolates

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Table 3: Antimicrobial susceptibility pattern of major Gram positive isolates

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Table 4: Antifungal susceptibility pattern of candida species

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Among Gram-positive isolates, coagulase-negative Staphylococci (CoNS), dominated the list with 13 (40.63%) followed by Staphylococcus aureus and Streptococcus spp.(06, 20.00% each). Out of 13 isolates of CoNS and 6 isolates of S. aureus, 11 (84.62%) and 2 (33.33%) were resistant to methicillin, respectively. All the Gram-positive isolates were seen to be sensitive to linezolid. Although resistance to glycopeptides was noticed in 40.00% of Enterococcus spp., other Gram-positive isolates were 100% susceptible. The Streptococcal isolates were susceptible to all the antibiotics. All the Candida spp. were found to be susceptible to commonly used anti-fungal agents except for fluconazole to which 100% resistance was observed. GVHD was observed in 81 (18.49%) of 438 transplant procedures while only 27 (33.33%) of these individuals developed BSI. No significant correlation could be elicited between GVHD and the development of bacteremia. Overall mortality was noticed in 86 (20.05%) patients, while in cases of bacteremia, it was 43.51%. Bacteremia proved to be an independent risk factor for mortality (P < 0.0001). The highest death rates (22, 25.58%) were observed among patients with AML. Allogeneic transplants (40, 46.51%) topped the list in terms of mortality. Eleven (44.00%) of the relapsed cases died, contributing to 12.79% of the total mortality. Sixty-six patients needed intensive care and were shifted to the intensive care unit (ICU) for further management. Of these 66 patients, 54 (81.82%) expired. Hence, admission to ICU has also crucially increased the risk of mortality (P = 0.05). Concomitant GVHD was documented in 22 (25.58%) patients who died. Acquisition of CRE versus carbapenem sensitive Enterobacteriaceae (CSE) in bloodstream was not remarkably related to the mortality (P = 0.1020). Perhaps, this could be related to colistin susceptibility of all of our CRE isolates and timely escalation to colistin therapy.


  Discussion Top


HSCT is used in the management of multiple irremediable hitherto hemato-oncology illnesses. However, patients undergoing HSCT are unusually vulnerable to BSIs. It is invariably associated with prolonged and profound neutropenia, GVHD, and severe conditioning-related toxicity.[9] Bacteremia is the source of fever in 5%–64.95% of all neutropenic patients during the early posttransplant period.[1],[3],[4],[5] We have reported bacteremia in 29.91% cases with the highest rates in haploidentical cases (47.37%), followed by 28.15% in allogeneic transplants. Balletto et al. and Fre're et al. observed in their respective studies that bacteremia was more frequent in allogeneic as compared to autologous transplants. Balletto et al. recorded BSIs in 5%–10% of autologous and 20%–30% of allogeneic HSCT patients.[1],[4]

On categorizing the source of BSI, MBI-LCBIs topped the list with 46.56%, followed by CLABSIs and primary BSIs (26.72% each). Dandoy et al. also had similar reviews with higher MBI-LCBIs (47%).[10]

In this study, Gram-negative bacteria accounted for the maximum (75.17%) episodes of bacteremia followed by Gram-positive BSIs (22.07%) and a low incidence of candidemia (2.76%). Most Western studies reported Gram-positive BSIs to be more prevalent, accounting for 47%–64% of the total cases of bacteremia.[1],[3],[4],[5],[9] However, few studies had reported a rising trend in the incidence of Gram-negative bacteremia.[5] In addition, some authors documented the predominance of Gram-negative organisms constituting 53.4%–88.4% of the total BSIs.[11],[12],[13] Though there is a paucity of data from the developing world, the inclusion of glycopeptides in the empiric regimen is a common practice, mostly influenced by western guidelines. Our data with respect to the appealing and interesting difference in the bacterial spectrum has a significant clinical implication. Hence, local epidemiology plays a pivotal role in designing and selecting an empirical antibiotic regimen for these patients.[13]

Mucositis is a ubiquitous problem related to high dose chemotherapy. The chemotherapeutic regimens ablate bone marrow and also injure the mucosal barrier. This, in turn, manifests as mucositis of the oral cavity and gastrointestinal tract (GIT) and with concomitant neutropenia, offers a ready portal for entry of local flora.[14] Gut microflora can also translocate and are associated with bacteremia and sepsis.[7],[14] Mucositis was encountered in 52.05% of total transplant episodes, 26.75% of whom developed bacteremia. We could not establish a significant association of mucositis with the occurrence of bacteremia. Sonis S reported mucositis in around 40% of patients on chemotherapeutic therapy.[15] In another study conducted among high-risk individuals by McGuire et al., mucositis was seen in 60% of patients.[16] The status of MDRO carriage in these patients also becomes important to be known. CRE are the most contemporary and rapidly spreading menace. The problem was highlighted by Collin et al. in their study on BSI in HSCT patients documenting 25% rise in imipenem resistance.[5] India is reeling under the burden of antibiotic resistance, especially CRE. With a reported rate of 57% carbapenem resistance in K. pneumoniae from India, the frontline use of colistin, the most effective armamentarium against CRE, needs a thorough consideration.[17] The decision to start colistin in most cases is based on microbiological reports, which may delay the appropriate treatment and may result in an increase in mortality due to sepsis. We documented 37.80% CRE carrier rate in stool and also found a 76.67% correlation with the isolates from the bloodstream in our patients. A correlation of 60.87% was established between blood and stool isolates in our previous study, with 54.09% of the CRE carriage rate.[18] Starting colistin empirically in view of high CRE burden might have a boomerang effect on antimicrobial resistance (AMR) further. This makes it evident that screening of gut flora for CRE, preferably using molecular methods, can be a potential future model for tailoring antibiotic therapy. This could also help to evaluate the correlation between gut flora and its implication in bacteremia. Translocation of vancomycin-resistant Enterococcus spp. (VRE) from gut resulting in BSI was noted in as high as 82% HSCT patients in a study by Kamboj et al.[19] We agree with many other authors who have documented that these bacteria certainly originate from the GIT, as was evident clinically and by molecular analysis.[20] Hence, the gut is largely responsible for the emergence of MDROs either through the ingestion of these pathogens or due to the transformation of gut micro flora as induced by antibiotics.[21] In our study, however, Enterococcus spp. was not a major pathogen.

All Gram-negative isolates in our study were susceptible to colistin, but resistance to carbapenems was quite prevalent, with 22.02% of CRE among total Gram-negative isolates. This has now begun to be a rapidly spreading threat. Oliveira et al. and Mahallawy et al., respectively, reported 37% and 69% MDRO in the bloodstream of HSCT patients.[3],[11] The evolution of AMR is an alarming concern in all hospitalized patients, especially among neutropenic patients with hematological malignancies. This may be attributed to prior exposure to antibiotics or transfer from other hospitals. Most of our Gram-negative, as well as Gram-positive isolates, were resistant to quinolones demonstrating 3.80% susceptibility in E. coli to 33.3% in S. aureus except 81.20% susceptible P. aeruginosa isolates. Other authors have reported a wide range of quinolones resistance from 13%-46% to 90%, as a repercussion of extensive use of quinolones as prophylaxis in neutropenic patients.[22],[23] Furthermore, the dread of carbapenem-resistant organisms is intensified, especially in HSCT patients.[24] With the rising prevalence of resistant organisms, the availability of effective treatment options has become limited.

Among the Gram-positive isolates, CoNS dominated the list being the most frequently isolated (40.63%) and demonstrated a high methicillin resistance (84.62%). There is a lower rate of methicillin-resistant S. aureus (33.33%) in our patients, which is consistent with other studies. Mikulska et al. also noticed a lower incidence of methicillin resistance in their S. aureus (56%) isolates in comparison to CoNS (80%).[25] In a multicenter study conducted by Weisser et al., the overall incidence of methicillin-resistant S. aureus (MRSA) and VRE was low, ranging from 0% to 0.4% in case of MRSA and 0%–1.5% in VRE.[26] Although CoNS is more frequently associated than MRSA, the strains are relatively less virulent and rarely associated with fatal infections even in immuno-compromised individuals.[27] On the contrary, MRSA is associated with decreased susceptibility to vancomycin and higher mortality in neutropenic patients.[28]

Overall, mortality was documented in 86 (20.05%) of our patients; 54 of these expired patients were shifted to ICU. Bacteremia and ICU admission were noted to be important risk factors for mortality. Death rate (46.51%) in our allogeneic transplant recipients almost correlates to the 40% mortality in allogeneic as well as autologous transplant patients in a study conducted by Chirag et al. Predominant risk factors of mortality in their study were bleeding, infections, and acute GVHD.[29] No significant difference of mortality rate was observed between CRE versus CSE bacteremic cases. This could be due to the colistin susceptibility of all of our CRE cases and timely escalation.

The burden of CRE in HSCT patients is considerable in our set up, which could be used to tailor the empiric antibiotic therapy. Moreover, the presence of CRE as a carrier in these patients may pose a considerable risk of developing bacteremia in these patients due to gut translocation. Screening of CRE in this group of patients might help in deciding empirical therapy in sepsis till final AST reports are available. Routine surveillance cultures play a significant role in determining the bacterial flora of transplant patients and henceforth, deciding the appropriate prophylactic and empirical antibiotic therapy to prevent the emergence of MDRO.[30] Limitation of our study was that CRE surveillance could not be carried out in all patients and was not done by genotypic methods. During the study period, Vitek® 2 Compact was an acceptable mode for colistin susceptibility testing. Hence, the preferred method of micro broth dilution was not used. Since all our CRE cases clinically responded to colistin, we presume these were true colistin sensitive strains. With the recent emergence of colistin resistance and the availability of a few alternative agents, empiric treatment of CRE cases is baffling.


  Conclusions Top


Our study is probably the first study from India with such considerable size. It can be concluded that Gram-negative pathogens were the predominant causative organisms of bacteraemia at our setup. The local epidemiology and associated risk factors are important for devising preventive strategies. Endogenous gut microbial flora constituted the major source of these infections in our HSCT patients. In the light of the emergence of MDROs with limited treatment options, the role of surveillance cultures for guiding empiric therapy cannot be refuted. Hence, a fine balance in choosing antibiotics is needed depending on the clinical presentation and local epidemiology in treating this group of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Balletto E, Mikulska M. Bacterial infections in hematopoietic stem cell transplant recipients. Mediterr J Hematol Infect Dis 2015;7:e2015045.  Back to cited text no. 1
    
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Oliveira AL, de Souza M, Carvalho-Dias VM, Ruiz MA, Silla L, Tanaka PY, et al. Epidemiology of bacteremia and factors associated with multi-drug-resistant gram-negative bacteremia in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2007;39:775-81.  Back to cited text no. 3
    
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Dandoy CE, Haslam D, Lane A, Jodele S, Demmel K, El-Bietar J, et al. Healthcare Burden, Risk Factors, and Outcomes of Mucosal Barrier Injury Laboratory-Confirmed Bloodstream Infections after Stem Cell Transplantation. Biol Blood Marrow Transplant 2016;22:1671-7.  Back to cited text no. 10
    
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El-Mahallawy H, Samir I, Abdel Fattah R, Kadry D, El-Kholy A. Source, pattern and antibiotic resistance of blood stream infections in hematopoietic stem cell transplant recipients. J Egypt Natl Canc Inst 2014;26:73-7.  Back to cited text no. 11
    
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Liu CY, Lai YC, Huang LJ, Yang YW, Chen TL, Hsiao LT, et al. Impact of bloodstream infections on outcome and the influence of prophylactic oral antibiotic regimens in allogeneic hematopoietic SCT recipients. Bone Marrow Transplant 2011;46:1231-9.  Back to cited text no. 12
    
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McGuire DB, Altomonte V, Peterson DE, Wingard JR, Jones RJ, Grochow LB. Patterns of mucositis and pain in patients receiving preparative chemotherapy and bone marrow transplantation. Oncol Nurs Forum 1993;20:1493-502.  Back to cited text no. 16
    
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