Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

MBI-LCBI and CLABSI: more than scrubbing the line

Introduction

The Hospital-Acquired Conditions Initiative, mandated by Congress and implemented in 2008, was a Centers for Medicare & Medicaid Services (CMS) payment reform intended to improve value and patient safety [1]. The initiative decreased reimbursement rates for patients that developed specific complications during their hospitalization [2]. Central line-associated bloodstream infections (CLABSI) was one of the initial eight hospital-acquired conditions determined to be preventable, based on landmark work showing a reduction of CLABSI by standardization of process and quality improvement. Pronovost et al. showed that adherence with five evidence-based guidelines (hand washing, sterile technique for central line placement, cleaning the skin with chlorhexidine prior to line placement, avoiding femoral site if possible, and discontinuation of unnecessary catheters) was associated with substantial, sustained reductions in CLABSI [3, 4].

Hematopoietic stem cell transplantation (HSCT) is the definitive therapy for many malignancies, marrow failure syndromes, and immune deficiencies in children, adolescents, and adults [5, 6]. Bloodstream infections (BSI) continue to be a significant cause of morbidity and mortality following HSCT, although transplant strategies and supportive care have evolved over the past few decades, resulting in improved overall survival [7,8,9,10,11]. Patients undergoing HSCT are hospitalized for prolonged periods, require complex care, usually have central venous catheters throughout their hospitalization, and are at risk for BSI secondary to contamination of the central line, as well as from translocation of bacteria through a compromised oral and gut mucosa secondary to chemotherapy and radiotherapy [12,13,14]. Shortly after implementation of the Hospital-Acquired Conditions Initiative, physicians caring for oncology and HSCT patients were being held accountable by hospital leadership for CLABSI likely related to treatment-related mucosal barrier injury [15].

In 2013, the Center for Disease Control and Prevention modified the hospital associated infection classification for patients with an infection and a central line (central line-associated bloodstream infection or CLABSI) to include those likely occurring from translocation of bacteria through injured mucosa [16, 17]. This definition, termed mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI), was integrated into National Healthcare Safety Network (NHSN) methods for primary BSI surveillance to help delineate preventable (CLABSI) and non-preventable (MBI-LCBI) infections in oncology and HSCT patients [16].

The healthcare-associated infection classification system is complex. Primary bloodstream infections (BSI) in patients with a central venous catheter (CVC) are defined as a laboratory-confirmed bloodstream infection (i.e., CLABSI) with or without the MBI-LCBI subcategory classification [18, 19]. Bacteria found in the bloodstream that can be directly correlated to a site-specific infection (e.g., bacteremia and urinary tract infection with Escherichia coli) are defined as secondary BSI. Over the past few years, the NHSN has required additional validation steps to categorize a BSI as a secondary infection to decrease the amount of subjectivity in primary and secondary BSI determination [18, 19]. Finally, BSI in patients that have only one positive culture from an organism considered to be a common commensal (e.g., Staphylococcus epidermidis) are classified as a contaminant, whatever the patient’s clinical course [19].

The classification of MBI-LCBI (detailed in Fig. 1) is dependent on several factors, including the offending organism and presence of neutropenia and/or graft versus host disease (GVHD) with associated diarrhea [19]. Unlike CLABSI, MBI-LCBIs are not expected to be prevented by improved central venous catheter maintenance care [16, 20, 21]. There are few data describing the incidence, timing, and outcomes in patients who develop an MBI-LCBI after HSCT, as MBI-LCBI is a recent classification of primary BSI. Moreover, there are limited data on potential prevention strategies to prevent bacteremia secondary to mucosal barrier injury after HSCT.

Fig. 1
figure1

Classification criteria for mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBI). 2019 National Healthcare Safety Network criteria for mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI)19. ANC absolute neutrophil count, MBI-LCBI mucosal barrier injury laboratory-confirmed bloodstream infection

Incidence and risk factors for MBI-LCBI after HSCT

The incidence of BSI in the weeks immediately following HSCT ranges from 20–60% [10, 22,23,24,25,26]. Cappellano et al. demonstrated nearly 21% of patients develop a BSI in the first 30 days post-HSCT and the majority (75%) were from a Gram-positive organism [25]. Wang et al. found nearly 24% of patients undergoing transplant developed a BSI shortly after HSCT despite levofloxacin prophylaxis, and nearly 70% of the infections were related to organisms found in the oral cavity [27]. In a subset analysis of HSCT patients receiving fluoroquinolone prophylaxis who developed bacteremia from Streptococcus viridans (MBI-LCBI organism generally confined to the oral cavity), Kimura et al. found viridans Streptococci alone in 15% of patients. Neutropenia and cord blood stem cell source increased the risk of Streptococcus viridans in this study [28].

The first step at developing mechanisms to decrease infection rates is identification of risk factors associated with MBI-LCBI; however, there are some inherent confounding factors. Neutropenia is inherent in the definition for MBI-LCBI as well as gastrointestinal GVHD [19]. Further, the MBI-LCBI classification is not exact, leading to difficulty in clearly identifying those at risk for developing bacteremia from translocation across the oral and gut mucosal barrier. However, it is possible to evaluate risk factors for MBI-LCBI based on the NHSN criteria, as well as evaluate for BSI from organisms translocating through a compromised mucosa in patients with neutropenia prior to engraftment and those who develop a BSI associated with gastrointestinal GVHD.

Risk factors for MBI-LCBI Using NHSN criteria

We performed a retrospective analysis of 374 consecutive pediatric transplants at our center to evaluate the incidence, risk factors, and outcomes of HSCT recipients with MBI-LCBI. We discovered MBI-LCBIs were diagnosed at a significantly higher rate in allogeneic compared with autologous HSCT patients (18% versus 7%, P = .007). In a multivariate analysis, MBI-LCBI was associated with reduced-intensity conditioning (OR, 1.96; P = .015) and transplant-associated thrombotic microangiopathy (OR, 2.94; P = .0004) [9]. In our clinical practice, reduced-intensity preparative regimens are used for immune deficiency and bone marrow failure patients, likely confounding the association with reduced-intensity conditioning. In a separate cohort of patients, we found a high frequency of transplant-associated thrombotic microangiopathy in patients who develop multiple BSI, the majority being MBI-LCBI [29].

Pre-engraftment bacteremia

Girmenia et al. prospectively evaluated the epidemiology of Gram-negative bacteremia prior to engraftment in 2743 pediatric and adult patients from 52 centers [30]. Gram-negative bacteremia prior to engraftment will be classified as MBI-LCBI nearly all of the time unless the infection is caused by Pseudomonas species (not an MBI-LCBI organism). Pre-engraftment bacteremia with Gram-negative bacteria occurred in 17.3% (140 of 1118) of allogeneic transplant recipients and 9% (146 of 1625) of autologous HSCT recipients. Variables associated with Gram-negative bacteremia in allogeneic recipients were older age, diagnosis of acute leukemia, bone marrow and cord stem cell source, mismatched related as well as mismatched unrelated donor, and nonmyeloablative/reduced-intensity conditioning. In autologous HSCT recipients, older age, diagnosis of lymphoma, and no antibacterial prophylaxis were associated with Gram-negative bacteremia prior to engraftment. Colonization by resistant Gram-negative bacteria was significantly associated with an increased rate of infection prior to engraftment by the same pathogen in both autologous and allogeneic transplants [30]. Contrary to Girmenia’s finding of an association between reduced-intensity conditioning and pre-engraftment infections, Ustun et al. found that patients who developed BSI prior to engraftment were more likely to receive a myeloablative conditioning regimens, with a high percentage of patients receiving regimes that included total body irradiation in a Center for International Blood and Marrow Transplant Research (CIBMTR) analysis [31].

Post-engraftment BSI

Levinson et al. reviewed 264 pediatric allogeneic HSCT recipients to determine the risk factors for bacteremia from enteric organisms [32]. They found a significant increase in infection from enteric organisms in patients with acute gastrointestinal GVHD (0.95 infections/person-year before acute gastrointestinal GVHD vs. 2.7 infections/person-year after acute gastrointestinal GVHD) at day 120 [P = .006) [32]. These data were supported by Mori et al., who evaluated risk factors for BSI in the post-engraftment period [33] and found a significant association of post-engraftment BSI with steroid-refractory acute GVHD and gastrointestinal GVHD [33].

Prognosis of patients with MBI-LCBI

MBI-LCBI are associated with poor outcome

Development of Gram-negative bacteremia before engraftment is independently associated with increased mortality at four months both in allogeneic HSCT recipients (HR, 2.13; 95% CI, 1.45–3.13; P < .001) and autologous HSCT recipients (2.43; 1.22–4.84; P = .01) [30]. Additionally, patients who developed early BSI have a two-fold increased risk of developing acute GVHD [32]. Using multivariate analysis, we showed a significant risk of non-relapsed mortality at one year in patients who developed at least one MBI-LCBI, but CLABSIs was not associated with non-relapsed mortality [9]. Further, 46% of patients who developed MBI-LCBI developed septic shock within 24 h of infection, 39% required central line removal with 7 days, and 23% were transferred to the intensive care unit within 48 h of the infection [9]. These results demonstrate that BSI not only cause significant harm to HSCT patients, increasing their risk for adverse outcomes as well as acute GVHD, but also prolong hospitalization and potentially increased hospital resource utilization. Additionally, Ustun et al. found that non-relapsed mortality is significantly increased in patients with bacteremia prior to engraftment, (RR 1.82 95% CI 1.63–2.04) compared with those without BSI, and overall survival is significantly lower in those who develop a BSI prior to engraftment (RR 1.36, 95% CI 1.26–1.47) [31].

Prevention of MBI-LCBI

Maintaining a healthy orogastrointestinal microbiome

Over the past few years, there has been an explosion of data about the human microbiome [34]. The gastrointestinal microbiome is essential for food and nutrient digestion, host immune response, protection against translocation of toxins, pathogenic bacteria, and fungus into the bloodstream, and participates in metabolic regulation [35]. Microbiome diversity has been used to describe the general health of the gastrointestinal system and has been used in studies as a simple indicator of overall “health” of the microbiome. Transplant leads to loss of host-microbiome diversity from chemotherapy and radiation [36], empiric antibiotics use, and infections [37], as well as diet and nutrition changes [38,39,40]. Loss of microbiome diversity along with mucosal barrier injury allows translocation of bacteria into the bloodstream.

Fever is often the first and only sign of infection in HSCT patients. Empiric use of broad-spectrum antimicrobial agents to manage fever and neutropenia in oncology and HSCT patients is the standard of care shown to improve survival [41,42,43,44]. However, bacteremia is not the only cause of fever in febrile neutropenic patients. Inflammation secondary to chemotherapy or engraftment are frequent causes of fever in patients undergoing HSCT [45,46,47]. Several lines of evidence confirm that antibiotic administration can result in gastrointestinal microbiome dysbiosis, i.e., disturbance in composition and function and potentially an increase of potentially pathogenic bacteria [48, 49]. Broad-spectrum antibiotics can affect the abundance of 30% of the bacteria in the gut community, causing rapid and significant drops in taxonomic richness, diversity, and evenness [49]. Additionally, antibiotics alter the composition of taxa and affect gene expression, protein activity, and the overall metabolism of the gut [50]. Antibiotic use prior to neutrophil engraftment has been shown to be particularly associated with loss of microbiome diversity and bacteremia from MBI-LCBI organisms [51,52,53]. Loss of microbiome diversity that leads to domination of MBI-LCBI pathogens in the gut was associated with subsequent systemic infection with the corresponding pathogen in blood [53]. These data provided confirmation that BSI during neutropenia arise primarily from a gastrointestinal source, and that translocation of bacteria is preceded by a transformative process in the gastrointestinal microbiome, in which colonization resistance is lost, leading to overgrowth by a single species.

There are no known strategies to reduce/prevent BSI from oral organisms

Mucositis has a profound negative effect on nutritional status, oral intake of food and medications, and quality of life in HSCT patients, although the exact pathophysiology is unclear [13, 54], [54]. Chemotherapy and irradiation directly damage the oral and gastrointestinal tract, allowing pathogen-associated molecules and intact bacteria to enter the systemic circulation (i.e., organism transmigration and subsequent BSI). Acute GVHD causes further insult to the epithelium, further increasing the risk of translocation of organisms and BSI [55]. Surprisingly, mucositis severity itself does not correlate with the incidence of BSI. For example, prospective studies evaluating interventions that are effective in reducing mucositis like keratinocyte growth factor [56] and cryotherapy [57] have not shown a beneficial effect in reducing BSI rates. Oral rinses have been used to enhance oral hygiene and to decrease oral mucositis in HSCT patients. Bland rinses, such as 0.9% saline or sodium bicarbonate/saline as well as analgesics, mucosal coating agents, and topical anesthetic solutions like viscous lidocaine and diphenhydramine solutions, have been studied [58, 59]. Chlorhexidine has also been widely used as a bactericidal agent to reduce bacterial colony-forming units but has not been shown to reduce BSI from oral flora [60, 61]. Finally, our own data demonstrate that gingivitis and dental plaque are common after HSCT, despite oral care [62]. Additional studies are needed to evaluate the association of bacteremia from oral organisms with oral gingivitis and dental plaque, ascertain methods that decrease plaque and gingivitis post-transplant, and determine the influence of oral microbiome diversity on BSI.

Challenges with the current classification system

Although the NHSN has decreased some of the scrutiny placed upon centers for CLABSI, there are still significant gaps in the NHSN classification system. The NHSN classification is dependent on multiple factors, that often make determining the etiology of infection somewhat subjective. As demonstrated in Fig. 2, BSI classification can vary depending on subtle changes in the ANC, the presence of a site-specific culture, or even the timing that the blood culture was taken. Moreover, the classification of the BSI can be variable, despite the patient developing septic shock.

Fig. 2
figure2

Same patient, organism, and outcome: five different classifications? Case study of a bloodstream infection in a single patient. Classification is not based on the etiology of the bloodstream infection, but the healthcare processes performed at the time of fever. Classification of bloodstream infection based on 2019 National Healthcare Safety Network criteria19. AML acute myelogenous leukemia, ANC absolute neutrophil count, BSI bloodstream infection, CLABSI central line-associated bloodstream infection, ICU intensive care unit, MBI-LCBI mucosal barrier injury laboratory-confirmed bloodstream infections, NHSN National Healthcare Safety Network

Further, it is likely that the list of organisms classified as MBI-LCBI organisms utilized by the NHSN is too limited. Tamburini et al. found patients with Escherichia coli and Klebsiella pneumoniae BSI have concomitant intestinal colonization with these organisms, regardless of neutrophil count and graft versus host disease status, suggesting that the gut may be the primary source of these infections [63]. Tamburini also found cases of non-enteric pathogens, such as Pseudomonas aeruginosa and Staphylococcus epidermidis, in the intestinal microbiome, thereby challenging the current CLABSI prevention belief that these infections originate from the environment, skin sources, or other mechanisms of central venous catheter contamination.

Seeing the forest through the trees

Current hospital infection control practices frequently do not take into account the complexities of the oral and gastrointestinal microbiome and are informed by assumptions about the source of various specific pathogens, such as those that are believed to only arise from central venous catheter contamination. It is the opinion of the authors that these assumptions are importantly flawed. On one end, they increase scrutiny on nursing staff and lead to the further implementation of nursing interventions that likely do not influence BSI rates. Current quality improvement CLABSI prevention strategies are centralized on catheter contamination alone and focus (and blame) directed towards nursing care detracts from collaborations between physicians, clinicians, scientists, infection control teams, and frontline nursing staff. Although we have made significant progress in reducing infections from line contamination, this can no longer be the sole focus of prevention efforts.

Significant efforts are undertaken to determine the root cause of the infection when BSI are classified as CLABSI at most institutions. However, once an MBI-LCBI or secondary BSI classification is reached, the impetus to learn from these infections is relieved, reducing pressure to understand, decrease, and improve rates. Ideally, centers would follow all infection rates, tie the organism to the mode of infection (if possible), and evaluate gaps in knowledge through clinical and translational research. Multidisciplinary collaboration between nursing, physicians, and subspecialists can help bring light to MBI-LCBI; institutional, divisions, and research funding organizations should make comprehensive understanding of MBI-LCBI in high-risk populations a priority. MBI-LCBI and all BSI can be reduced through multidisciplinary work using translational studies and improvement science (Figure 3).

Fig. 3
figure3

Multidisciplinary collaboration to decrease bloodstream infections after hematopoietic stem cell transplant. CLABSI central line-associated bloodstream infection, MBI-LCBI mucosal barrier injury laboratory-confirmed bloodstream infection

Delineating the source of the BSI will assist in more accurate tracking and prevention of hospital-acquired infections. This knowledge will complement the growing body of research on therapies to improve oral and gastrointestinal microbiome diversity and inform attempts to bolster colonization resistance against pathogens.

Conclusions

MBI-LCBI are associated with poor outcomes after HSCT and are associated with significant healthcare resource utilization. We have made significant progress in the past with a lone focus on central venous catheter care; however, at this time we need diversify efforts to include the understanding and prevention of BSI secondary for translocation of bacteria across injured oral and gut mucosa (MBI-LCBI) through comprehensive teams. Reduction in the frequency of MBI-LCBIs should be a major public health and scientific priority.

References

  1. 1.

    Centers for Medicare & Medicaid Services (CMS) HHS. Medicare program: changes to the hospital outpatient prospective payment system and CY 2008 payment rates, the ambulatory surgical center payment system and CY 2008 payment rates, the hospital inpatient prospective payment system and FY 2008 payment rates; and payments for graduate medical education for affiliated teaching hospitals in certain emergency situations Medicare and Medicaid programs: hospital conditions of participation; necessary provider designations of critical access hospitals. Interim Final Rule Comment Period Fed Regist. 2007;72:66579–7226.

  2. 2.

    Waters TM, Daniels MJ, Bazzoli GJ, Perencevich E, Dunton N, Staggs VS, et al. Effect of Medicare's nonpayment for Hospital-Acquired Conditions: lessons for future policy. JAMA Intern Med. 2015;175:347–54.

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Pronovost PJ, Goeschel CA, Colantuoni E, Watson S, Lubomski LH, Berenholtz SM, et al. Sustaining reductions in catheter related bloodstream infections in Michigan intensive care units: observational study. BMJ. 2010;340:c309.

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006;355:2725–32.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Barriga F, Ramírez P, Wietstruck A, Rojas N. Hematopoietic stem cell transplantation: clinical use and perspectives. Biol Res. 2012;45:307–16.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813–26.

    CAS  Article  Google Scholar 

  7. 7.

    Remberger M, Ackefors M, Berglund S, Blennow O, Dahllöf G, Dlugosz A, et al. Improved survival after allogeneic hematopoietic stem cell transplantation in recent years. A single-center study. Biol Blood Marrow Transplant. 2011;17:1688–97.

    PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Dandoy CE, Ardura MI, Papanicolaou GA, Auletta JJ. Bacterial bloodstream infections in the allogeneic hematopoietic cell transplant patient: new considerations for a persistent nemesis. Bone Marrow Transplant. 2017;52:1091–106.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    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.

    PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Poutsiaka DD, Price LL, Ucuzian A, Chan GW, Miller KB, Snydman DR. Blood stream infection after hematopoietic stem cell transplantation is associated with increased mortality. Bone Marrow Transplant. 2007;40:63–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Mitchell AE, Derrington P, Turner P, Hunt LP, Oakhill A, Marks DI. Gram-negative bacteraemia (GNB) after 428 unrelated donor bone marrow transplants (UD-BMT): risk factors, prophylaxis, therapy and outcome. Bone Marrow Transplant. 2004;33:303–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Dandoy CE, Hausfeld J, Flesch L, Hawkins D, Demmel K, Best D, et al. Rapid cycle development of a multifactorial intervention achieved sustained reductions in central line-associated bloodstream infections in haematology oncology units at a children's hospital: a time series analysis. BMJ Qual Saf. 2016;25:633–43.

    PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Wardill HR, Bowen JM. Chemotherapy-induced mucosal barrier dysfunction: an updated review on the role of intestinal tight junctions. Curr Opin Support Palliat Care. 2013;7:155–61.

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Mikulska M, Del Bono V, Raiola AM, Bruno B, Gualandi F, Occhini D, et al. Blood stream infections in allogeneic hematopoietic stem cell transplant recipients: reemergence of Gram-negative rods and increasing antibiotic resistance. Biol Blood Marrow Transplant. 2009;15:47–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Fraser TG, Gordon SM. CLABSI rates in immunocompromised patients: a valuable patient centered outcome? Clin Infect Dis. 2011;52:1446–50.

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    See I, Iwamoto M, Allen-Bridson K, Horan T, Magill SS, Thompson ND. Mucosal barrier injury laboratory-confirmed bloodstream infection: results from a field test of a new National Healthcare Safety Network definition. Infect Control Hosp Epidemiol. 2013;34:769–76.

    PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Freeman JT, Elinder-Camburn A, McClymont C, Anderson DJ, Bilkey M, Williamson DA, et al. Central line-associated bloodstream infections in adult hematology patients with febrile neutropenia: an evaluation of surveillance definitions using differential time to blood culture positivity. Infect Control Hosp Epidemiol. 2013;34:89–92.

    PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Center for Disease Control and Prevention: Bloodstream Infection Event (Central Line-Associated Bloodstream Infection and Non-central line-associated Bloodstream Infection). http://www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf (2016).

  19. 19.

    Identifying Healthcare-associated Infections (HAI) for NHSN Surveillance. https://www.cdc.gov/nhsn/pdfs/pscmanual/pcsmanual_current.pdf (2019).

  20. 20.

    Metzger KE, Rucker Y, Callaghan M, Churchill M, Jovanovic BD, Zembower TR, et al. The burden of mucosal barrier injury laboratory-confirmed bloodstream infection among hematology, oncology, and stem cell transplant patients. Infect Control Hosp Epidemiol. 2015;36:119–24.

    PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Epstein L, See I, Edwards JR, Magill SS, Thompson ND. Mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBI): descriptive analysis of data reported to National Healthcare Safety Network (NHSN), 2013. Infect Control Hosp Epidemiol. 2016;37:2–7.

    Article  Google Scholar 

  22. 22.

    Ballen K, Woo Ahn K, Chen M, Abdel-Azim H, Ahmed I, Aljurf M, et al. Infection rates among acute leukemia patients receiving alternative donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:1636–45.

    PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    El-Bietar J, Nelson A, Wallace G, Dandoy C, Jodele S, Myers KC, et al. RSV infection without ribavirin treatment in pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant. 2016;51:1382–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Castagnola E, Faraci M, Moroni C, Bandettini R, Caruso S, Bagnasco F, et al. Bacteremias in children receiving hemopoietic SCT. Bone Marrow Transplant. 2008;41(Suppl 2):S104–6.

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Cappellano P, Viscoli C, Bruzzi P, Van Lint MT, Pereira CA, Bacigalupo A. Epidemiology and risk factors for bloodstream infections after allogeneic hematopoietic stem cell transplantion. New Microbiol. 2007;30:89–99.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Poutsiaka DD, Munson D, Price LL, Chan GW, Snydman DR. Blood stream infection (BSI) and acute GVHD after hematopoietic SCT (HSCT) are associated. Bone Marrow Transplant. 2011;46:300–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Wang CH, Chang FY, Chao TY, Kao WY, Ho CL, Chen YC, et al. Characteristics comparisons of bacteremia in allogeneic and autologous hematopoietic stem cell-transplant recipients with levofloxacin prophylaxis and influence on resistant bacteria emergence. J Microbiol Immunol Infect. 2018;51:123–31.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Kimura M, Araoka H, Yoshida A, Yamamoto H, Abe M, Okamoto Y, et al. Breakthrough viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients receiving levofloxacin prophylaxis in a Japanese hospital. BMC Infect Dis. 2016;16:372.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Grossmann L, Alonso PB, Nelson A, El-Bietar J, Myers KC, Lane A, et al. Multiple bloodstream infections in pediatric stem cell transplant recipients: A case series. Pediatr Blood Cancer. 2018;65:e27388.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  30. 30.

    Girmenia C, Bertaina A, Piciocchi A, Perruccio K, Algarotti A, Busca A, et al. Incidence, risk factors and outcome of pre-engraftment Gram-negative bacteremia after allogeneic and autologous hematopoietic stem cell transplantation: an Italian Prospective Multicenter Survey. Clin Infect Dis. 2017;65:1884–96.

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Ustun C, Young JH, Papanicolaou GA, Kim S, Ahn KW, Chen M, et al. Bacterial blood stream infections (BSIs), particularly post-engraftment BSIs, are associated with increased mortality after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2018. https://doi.org/10.1038/s41409-018-0401-4.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Levinson A, Pinkney K, Jin Z, Bhatia M, Kung AL, Foca MD, et al. Acute gastrointestinal graft-vs-host disease is associated with increased enteric bacterial bloodstream infection density in pediatric allogeneic hematopoietic cell transplant recipients. Clin Infect Dis. 2015;61:350–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Mori Y, Yoshimoto G, Nishida R, Sugio T, Miyawaki K, Shima T, et al. Gastrointestinal graft-versus-host disease is a risk factor for postengraftment bloodstream infection in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2018;24:2302–9.

    PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold G, et al. The gut microbiota and host health: a new clinical frontier. Gut. 2016;65:330–9.

    Article  Google Scholar 

  35. 35.

    Tuddenham S, Sears CL. The intestinal microbiome and health. Curr Opin Infect Dis. 2015;28:464–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Wang W, Xu S, Ren Z, Jiang J, Zheng S. Gut microbiota and allogeneic transplantation. J Transl Med. 2015;13:275.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8:339ra71.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, et al. Influence of diet on the gut microbiome and implications for human health. J Transl Med. 2017;15:73.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124:1174–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Taur Y, Pamer EG. The intestinal microbiota and susceptibility to infection in immunocompromised patients. Curr Opin Infect Dis. 2013;26:332–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Schimpff S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med. 1971;284:1061–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011;52:e56–93.

    Article  Google Scholar 

  43. 43.

    Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:794–810.

    PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Wright JD, Neugut AI, Ananth CV, Lewin SN, Wilde ET, Lu YS, et al. Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. JAMA Intern Med. 2013;173:559–68.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    van der Velden WJ, Herbers AH, Netea MG, Blijlevens NM. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol. 2014;167:441–52.

    PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Winter SE, Lopez CA, Bäumler AJ. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep. 2013;14:319–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27:893–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Consortium HMP. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207–14.

    Article  CAS  Google Scholar 

  49. 49.

    Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci Usa. 2011;108 Suppl 1:4554–61.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Franzosa EA, Hsu T, Sirota-Madi A, Shafquat A, Abu-Ali G, Morgan XC, et al. Sequencing and beyond: integrating molecular ‘omics' for microbial community profiling. Nat Rev Microbiol. 2015;13:360–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Galloway-Peña J, Smith D, Sahasrabhojane P, Ajami N, Wadsworth W, Daver N, et al. The role of the gastrointestinal microbiome in infectious complications during induction chemotherapy for acute myeloid leukemia. Cancer . 2016;122:2186–96.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:640–5.

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55:905–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Al-Dasooqi N, Sonis ST, Bowen JM, Bateman E, Blijlevens N, Gibson RJ, et al. Emerging evidence on the pathobiology of mucositis. Support Care Cancer. 2013;21:3233–41.

    PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan WJ, Patnaik MS, et al. The incidence and severity of oral mucositis among allogeneic hematopoietic stem cell transplantation patients: a systematic review. Biol Blood Marrow Transplant. 2016;22:605–16.

    PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Vadhan-Raj S, Trent J, Patel S, Zhou X, Johnson MM, Araujo D, et al. Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial. Ann Intern Med. 2010;153:358–67.

    PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Svanberg A, Ohrn K, Birgegård G. Oral cryotherapy reduces mucositis and improves nutrition—a randomised controlled trial. J Clin Nurs. 2010;19:2146–51.

    PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Peterson DE, Bensadoun RJ, Roila F, Group EGW. Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines. Ann Oncol. 2010;21 Suppl 5:v261–5.

    PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Best D, Osterkamp E, Demmel K, Kiniyalocts S, Mock S, Mulligan K, et al. Increasing activities of daily living is as easy as 1-2-3. J Pediatr Oncol Nurs. 2016;33:345–52.

    PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Bortoluzzi MC, Santos FA. Amoxicillin and 0.12% chlorhexidine mouthwash may not be better than placebo for reducing bacteremia in third molar extractions. J Evid Based Dent Pract. 2014;14:34–5.

    PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Smith K, Robertson DP, Lappin DF, Ramage G. Commercial mouthwashes are ineffective against oral MRSA biofilms. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115:624–9.

    PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Doss LM, Dandoy CE, Kramer K, Pate A, Flesch L, El-Bietar J, et al. Oral health and hematopoietic stem cell transplantation: a longitudinal evaluation of the first 28 days. Pediatr Blood Cancer. 2018;65. https://doi.org/10.1002/pbc.26773.

    Article  Google Scholar 

  63. 63.

    Tamburini FB, Andermann TM, Tkachenko E, Senchyna F, Banaei N, Bhatt AS. Precision identification of diverse bloodstream pathogens in the gut microbiome. Nat Med. 2018;24:1809–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Christopher E. Dandoy.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dandoy, C.E., Alonso, P.B. MBI-LCBI and CLABSI: more than scrubbing the line. Bone Marrow Transplant 54, 1932–1939 (2019). https://doi.org/10.1038/s41409-019-0489-1

Download citation

Further reading

Search

Quick links