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 . The initiative decreased reimbursement rates for patients that developed specific complications during their hospitalization . 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 .
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 .
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 .
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 . 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.
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 . 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 . 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 .
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 . 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) . 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 .
Girmenia et al. prospectively evaluated the epidemiology of Gram-negative bacteremia prior to engraftment in 2743 pediatric and adult patients from 52 centers . 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 . 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 .
Levinson et al. reviewed 264 pediatric allogeneic HSCT recipients to determine the risk factors for bacteremia from enteric organisms . 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) . These data were supported by Mori et al., who evaluated risk factors for BSI in the post-engraftment period  and found a significant association of post-engraftment BSI with steroid-refractory acute GVHD and gastrointestinal GVHD .
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) . Additionally, patients who developed early BSI have a two-fold increased risk of developing acute GVHD . 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 . 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 . 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) .
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 . 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 . 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 , empiric antibiotics use, and infections , 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 . Additionally, antibiotics alter the composition of taxa and affect gene expression, protein activity, and the overall metabolism of the gut . 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 . 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], . 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 . 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  and cryotherapy  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 . 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.
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 . 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).
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.
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.
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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
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