Probiotics Decrease Mortality from Stem Cell Transplantation

by Jeffrey Dach MD

We are continually surprised by new studies showing the importance of the microbiome, or “friendly bacteria” colonizing the gut.  One such study was done  by Dr Ying Taur published in the hematology oncology journal, Blood, in 2014.(1)

Bacterial Diversity Associated with Improved Survival

Dr Ying Taur studied the “effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.”  He obtained fecal specimens from 80 allogeneic transplant recipients, at time of engraftment.  He used bacterial 16S rRNA gene sequencing to characterize microbial diversity classified into high, intermediate, and low diversity.   Surprisingly, after three years, over all survival was only 36% for the patients with low diversity, compared to 67% over-all survival for patients with higher microbial diversity. Dr Taur’s conclusion:

In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT. (1) (note allo-HSCT =allogeneic stem cell transplant”

Further Studies on Loss of Diversity in Allogeneic Stem Cell Treansplant

Another 2014 study from Dr Holler in Germany confirms Dr Ying’s findings.(8)  Dr Holler used next generation 16s RNA sequencing to study microbial content of stool samples before and after allogeneic stem cell transplant in 31 patients.(8)  Dr Holler found a considerable shift from commensal bacteria towards enterococci associated with antibiotic treatment of febrile neutropenia.  He found a greater shift in those patients who developed GI tract Graft vs Host Disease:

“At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections.The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD).”(8)

Urinary Indoxyl Sulfate Marker for Bacterial Diversity

Dr Holler found that a simple urinary test for the bacterial metabolite, indoxyl sulfate, was an excellent marker for loss of bacterial diversity in allogeneic transplant patients.  Pre-transplant levels of 42 dropped 11.8 post transplant in all patients probably a consequence of chemotherapy and antibiotics.  However a more profound reduction to 3.5 was found in those patients with active Graft vs. Host Disease.(8)

“As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 μmol/L to 11.8 ± 2.8 μmol/L in all post-transplant samples and to 3.5 ± 3 μmol/L in samples from patients with active GVHD.”(8)

Measuring Urinary Indoxyl Sulfate

In a 2015 study published in Blood, Dr Weber found that a poor outcome after transplantation is associated with a disrupted microbiome detected by low urinary indoxyl sulfate, a metabolic by-product of commensal bacteria which convert L-tryptophan to indole. (2)  Low indoxyl sulfate level indicates loss of micrboial diversity, and increased risk of Graft vs. Host disease.  According to Dr. Weber, early onset of antibiotic treatment, and reduced indole sulfate level was the major risk factor for disrupted microbiome and increased mortality from transplant procedure .(2)  He says:

“Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P = .017) and worse overall survival”(2)

Probiotics Reduce Mortality of Stem Cell Transplantation in Mice

In 2004, Dr Armin Gerbitz and Dr Holler studied the effects of “Probiotics on experimental graft-versus-host disease”.  in a mouse model of stem cell transplantation.   (14)  Oral administration of Lactobacillus rhamnosus GG before and after stem cell transplantation results in improved survival, reduced mortality and reduced Graft vs. Host Disease in the mice.  The authors concluded that lower LPS  serum levels (lower gram negative bacteremia) accounted for the reduced Graft vs Host Disease, “since LPS represents an enormous stimulus in the development of GVHD.”(14)

Retrospective Study of Probiotics in Allogeneic Transplant Patients.

In 2014, Dr Gorshein reported on a retrospective study in 30 patients using probiotics  (lactobacillus GG) following allogeneic hematopoietic stem cell engraftment (HSCT).(12)  Fifty patients not receiving probiotics served as controls.  The authors reported “no untoward events associated with administration of the probiotic”….”  However, this retrospective analysis does not prove that (probiotics) reduces the overall incidence of GVHD in this patient population.” (12)  The authors suggested doing a prospective randomized study next.

What is allogeneic hematopoetic stem cell transplantation?

This is a common treatment for leukemia or lymphoma in which the patient’s bone marrow stem cells are destroyed by an intensive chemotherapy regimen.  Bone marrow stem cells are essential for the immune system and  necessary for life. To restore them, stem cells from a matching sibling are drawn off. and then infused into the cancer patient, called engraftment, this  restores patient’s bone marrow function.   The new bone marrow cells from the matched sibling creates an immune response to the cancer cells, called “Graft Vs. Lymphoma” thus accounting for curative ability of the procedure.

Graft Vs. Host Disease

A common adverse effect of transplantation is Graft Vs. Host Disease in which the donor lymphocytes attack the recipient tissues as foreign.  Graft vs host disease may affect the Liver, Skin, GI tract etc.

Antibiotics Frequently Given for Febrile Neutropenia

After donor stem cell engraftment, it takes a few weeks for the new stem cells to restore the recipient patient’s immune system.  During this period, , the patient is at risk for “febrile neutropenia” caused by gram negative bacteriemia, a major cause of non-relapse mortality.  This is frequently treated in the transplant ward with broad spectrum antibiotics.  The drug of  choice is Zosyn (Pfizer inc) Piperacillin/tazobactam, recommended by the NIH as first line therapy for the treatment of bloodstream infections in neutropenic cancer patients.(24)

Broad Spectrum Antibiotic Increases Graft Vs Host Disease

Dr Shono found increased Graft vs. Host Disease related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in both humans and animal models. (3)  The use of imipenem-cilastatin antibiotics (Primaxin, Tienam and Zienam) in mice with Graft Vs Host Disease led to loss of the protective mucus lining of the colon and compromised intestinal barrier function.(3)

Cautionary Tales for Probiotic Use in Allogeneic Transplantation

A case report submitted by Dr Mehta from U of Alabama in 2013 describes a case of Lactobacillus acidophilus sepsis from yogurt consumption in a patient with mantle cell lymphoma undergoing autologous stem cell transplant.(11)  Because of severe mucositis, the patient was consuming 6-8 cups of yogurt daily, thought to be the cause of his positive blood cultures for lactobacillus.(11)

Lactobacillus Sepsis without Use of Probiotics

Another case report from 2010 by Dr Robin describes Lactobacillus rhamnosus spesis and meningitis after allogeneic transplantation.(16)  There was no history of probiotic use in this case.  This patient was a 10 year old child suffering from lymphoblastic leukemia treated with allogeneic stem cell transplant.  Engraftment was delayed and the patient was immunocompromised with prolonged low white cell count . After discharge home, the patient had febrile neutropenia with 16 positive blood cultures and one positive CSF culture for lactobacillus rhamnosus over a 73 day period.  The authors sate: “This case confirms the risk of Lactobacillus infection in immunocompromised patients, even without probiotic use, and the importance of highly active antibiotics such as clindamycin in limiting recurrence of the infection.”(16)

Conclusion:  The use of probiotics and avoidance of antibiotics improves microbial diversity in microbial flora.  Increased microbial diversity has been found to reduce mortality associated with allogeneic stem cell transplantation.

This article is part two, for part one click here.

Articles with related interest:

Curing Autism with Antibiotics

Depression and Leaky Gut Michael Maes

NSAIDS Small Bowel and Leaky Gut

Links and References

header image human stem cell courtesy of  Microbiology Spring 2011

1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133489/
Taur, Ying, et al. “The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.” Blood 124.7 (2014): 1174-1182.
Highly diverse bacterial populations inhabit the gastrointestinal tract and modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. We examined the impact of intestinal diversity on subsequent mortality outcomes following transplantation. Fecal specimens were collected from 80 recipients of allo-HSCT at the time of stem cell engraftment. Bacterial 16S rRNA gene sequences were characterized, and microbial diversity was estimated using the inverse Simpson index. Subjects were classified into high, intermediate, and low diversity groups and assessed for differences in outcomes. Mortality outcomes were significantly worse in patients with lower intestinal diversity; overall survival at 3 years was 36%, 60%, and 67% for low, intermediate, and high diversity groups, respectively (P = .019, log-rank test). Low diversity showed a strong effect on mortality after multivariate adjustment for other clinical predictors (transplant related mortality: adjusted hazard ratio, 5.25; P = .014). In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT.

2) http://www.bloodjournal.org/content/126/14/1723.long?sso-checked=true
Blood. 2015 Oct 1;126(14):1723-8. doi: 10.1182/blood-2015-04-638858. Epub 2015 Jul 24.  Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome.  Weber D1, Oefner PJ2, Hiergeist A3, Koestler J3, Gessner A3, Weber M4, Hahn J1, Wolff D1, Stämmler F5, Spang R5, Herr W1, Dettmer K2, Holler E1.
Indole, which is produced from l-tryptophan by commensal bacteria expressing tryptophanase, not only is an important intercellular signal in microbial communities, but also modulates mucosal barrier function and expression of pro- and anti-inflammatory genes by intestinal epithelial cells. Here, we hypothesized that decreased urinary excretion of 3-indoxyl sulfate (3-IS), the major conjugate of indole found in humans, may be a marker of gut microbiota disruption and increased risk of developing gastrointestinal (GI) graft-versus-host-disease. Using liquid chromatography/tandem mass spectrometry, 3-IS was determined in urine specimens collected weekly within the first 28 days after allogeneic stem cell transplantation (ASCT) in 131 patients. Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P = .017) and worse overall survival (P = .05) 1 year after ASCT. Least absolute shrinkage and selection operator regression models trained on log-normalized counts of 763 operational taxonomic units derived from next-generation sequencing of the hypervariable V3 region of the 16S ribosomal RNA gene showed members of the families of Lachnospiraceae and Ruminococcaceae of the class of Clostridia to be associated with high urinary 3-IS levels, whereas members of the class of Bacilli were associated with low 3-IS levels. Risk factors of early suppression of 3-IS levels were the type of GI decontamination (P = .01), early onset of antibiotic treatment (P = .001), and recipient NOD2/CARD15 genotype (P = .04). In conclusion, our findings underscore the relevance of microbiota-derived indole and metabolites thereof in mucosal integrity and protection from inflammation.

A significantly higher transplant -related mortality (TRM) was observed in patients with low intestinal microbiome diversity, whereas patients with a microbiome dominated by commensal bacteria showed a better overall survival (OS) within 3 years after transplantation.8

3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991773/
Sci Transl Med. 2016 May 18;8(339):339ra71. doi: 10.1126/scitranslmed.aaf2311.
Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice.
Shono Y1, Docampo MD2, Peled JU3, Perobelli SM2, Velardi E4, Tsai JJ2, Slingerland AE2, Smith OM2, Young LF2, Gupta J2, Lieberman SR2, Jay HV2, Ahr KF2, Porosnicu Rodriguez KA2, Xu K2, Calarfiore M2, Poeck H2, Caballero S2, Devlin SM5, Rapaport F6, Dudakov JA7, Hanash AM8, Gyurkocza B8, Murphy GF9, Gomes C9, Liu C10, Moss EL11, Falconer SB11, Bhatt AS11, Taur Y12, Pamer EG13, van den Brink MR14, Jenq RR15.
Intestinal bacteria may modulate the risk of infection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients often develop neutropenic fever, which is treated with antibiotics that may target anaerobic bacteria in the gut. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam antibiotics was associated with increased GVHD-related mortality at 5 years (21.5% for imipenem-cilastatin-treated patients versus 13.1% for untreated patients, P = 0.025; 19.8% for piperacillin-tazobactam-treated patients versus 11.9% for untreated patients, P = 0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (P = 0.78 and P = 0.98, respectively). Analysis of stool specimens from allo-HSCT recipients showed that piperacillin-tazobactam administration was associated with perturbation of gut microbial composition. Studies in mice demonstrated aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P < 0.01 and P < 0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (P < 0.05), but no difference in the concentration of short-chain fatty acids or numbers of regulatory T cells. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective mucus lining of the colon (P < 0.01) and the compromising of intestinal barrier function (P < 0.05). Sequencing of mouse stool specimens showed an increase in Akkermansia muciniphila (P < 0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation may contribute to murine GVHD. We demonstrate an underappreciated risk for the treatment of allo-HSCT recipients with antibiotics that may exacerbate GVHD in the colon.

4) http://www.ncbi.nlm.nih.gov/pubmed/26900084
Biol Blood Marrow Transplant. 2016 Jun;22(6):1087-93. doi: 10.1016/j.bbmt.2016.02.009. Epub 2016 Feb 18.
Impact of Gut Colonization by Antibiotic-Resistant Bacteria on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective, Single-Center Study.
Bilinski J1, Robak K1, Peric Z2, Marchel H3, Karakulska-Prystupiuk E1, Halaburda K1, Rusicka P1, Swoboda-Kopec E3, Wroblewska M4, Wiktor-Jedrzejczak W1, Basak GW5.
Gut colonization by antibiotic-resistant bacteria may underlie hard-to-treat systemic infections. There is also accumulating evidence on the immunomodulatory function of gut microbiota after allogeneic stem cell transplantation (alloSCT) and its impact on graft-versus-host disease (GVHD). We investigated the epidemiology and clinical impact of gut colonization after alloSCT and retrospectively analyzed data on 107 alloSCTs performed at a single transplant center. Pretransplant microbiology screening identified colonization in 31% of cases. Colonization had a negative impact on overall survival after alloSCT in univariate (34% versus 74% at 24 months, P < .001) and multivariate (hazard ratio, 3.53; 95% confidence interval, 1.71 to 7.28; P < .001) analyses. Nonrelapse mortality was significantly higher in colonized than in noncolonized patients (42% versus 11% at 24 months, P = .001). Colonized patients more frequently experienced bacteremia (48% versus 24%, P = .01), and more deaths were attributable to infectious causes in the colonized group (42% versus 11% of patients and 67% versus 29% of deaths, P < .05). We observed a significantly higher incidence of grades II to IV acute GVHD in colonized than in noncolonized patients (42% versus 23%, P < .05), especially involving the gastrointestinal system (33% versus 13.5%, P = .07). In summary, we determined that gut colonization by antibiotic-resistant bacteria decreases the overall survival of patients undergoing alloSCT by increasing nonrelapse mortality and the incidences of systemic infection and acute GVHD.

5) Khoruts, Alexander, et al. “Toward revision of antimicrobial therapies in hematopoietic stem cell transplantation: target the pathogens, but protect the indigenous microbiota.” Translational Research (2016).
Host microbiota plays important roles in providing colonization resistance to pathogens and instructing development and function of the immune system. Antibiotic treatments intended to target pathogens further weaken the host defenses and may paradoxically increase the risk of systemic infections. This consequence is especially problematic in patients undergoing hematopoietic stem cell transplantation, where the mucosal defenses are already weakened by the conditioning regimens. This review discusses the roles that indigenous microbiota plays in protecting the host and maintaining immune homeostasis. In addition, we highlight possible strategies that are being developed to allow targeted antimicrobial therapy against pathogens, while minimizing the harm to indigenous microbiota.

6) Andermann, T. M., A. Rezvani, and A. S. Bhatt. “Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation.” Current hematologic malignancy reports 11.1 (2016): 19.
Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota’s contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

7) Vossen, Jaak M., et al. “Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation.” PloS one 9.9 (2014): e105706.

Complete Suppression of the Gut Microbiome Prevents Acute Graft-Versus-Host Disease following Allogeneic Bone Marrow Transplantation
The hypothesis that elimination of facultative and strict anaerobic microorganisms from the gastro-intestinal tract by antimicrobial drugs in the period of time around allogeneic bone marrow transplantation (BMT) prevents acute graft-versus-host disease (GVHD), was examined in a cohort of 112 children grafted between 1989 and 2002 for hematological malignancies. All patients received T-cell replete marrow from human leukocyte antigens (HLA) matched sibling donors under identical transplantation conditions. To eliminate microorganisms from the gastro-intestinal tract, total gastro-intestinal decontamination (GID) was applied by high doses of non-absorbable antimicrobial drugs while the graft recipient was maintained in strict protective isolation. About half of the children (51%) proved to be successfully decontaminated, and about half (49%) unsuccessfully. One recipient got acute GVHD in the first group and 8 in the second group (p = 0.013). The degree of success of total GID was decisive for the occurrence of acute GVHD, irrespective of the presence of other risk factors such as higher age of recipient and/or donor, female donor for male recipient and carriership or reactivation of herpesviruses. Our results demonstrate that successful total GID of the graft recipient prevents moderate to severe acute GVHD. We suppose that substantial translocation of gastro-intestinal microorganisms or parts of these, functioning as microbial-associated molecular patterns (MAMP’s), triggering macrophages/dendritic cells via pattern recognizing receptors (PRR’s) is prohibited. As a consequence the initiation and progression of an inflammatory process leading to acute GVHD is inhibited.

8) Biol Blood Marrow Transplant. 2014 May;20(5):640-5.
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.
Holler E1, Butzhammer P2, Schmid K3, Hundsrucker C2, Koestler J4, Peter K3, Zhu W2, Sporrer D3, Hehlgans T5, Kreutz M3, Holler B3, Wolff D3, Edinger M3, Andreesen R3, Levine JE6, Ferrara JL6, Gessner A4, Spang R2, Oefner PJ2.
next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 μmol/L to 11.8 ± 2.8 μmol/L in all post-transplant samples and to 3.5 ± 3 μmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT.

9) Biol Blood Marrow Transplant. 2015 Aug;21(8):1360-6. doi: 10.1016/j.bbmt.2015.02.016. Epub 2015 Feb 21.
Emerging Influence of the Intestinal Microbiota during Allogeneic Hematopoietic Cell Transplantation: Control the Gut and the Body Will Follow.  Docampo MD1, Auletta JJ2, Jenq RR3.
The intestinal microbiota has many critical roles in maintaining gastrointestinal epithelial and gastrointestinal systemic immune homeostasis. This review provides insight into how allogeneic hematopoietic cell transplantation (HCT) and its associated complications and supportive care therapies affect the microbiota. Additionally, the review discusses how preservation and restoration of the microbiota might be advantageous in decreasing HCT-related morbidity and mortality.

10) Taur, Ying, et al. “Intestinal Domination and the Risk of Bacteremia in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.” Clinical Infectious Diseases 55.7 (2012): 905-14.intestinal-domination-and-bacteremia-in-allogeneic-hematopoietic-stem-cell-transplantation-taur-ying-2012

 

11) Letter to the Editor.  Bone Marrow Transplantation (2013) 48, 461–462; doi:10.1038/bmt.2012.153; published online 13 August 2012
A cautionary tale for probiotic use in hematopoietic SCT patients–Lactobacillus acidophilus sepsis in a patient with mantle cell lymphoma undergoing hematopoietic SCT
A Mehta1, S Rangarajan2 and U Borate1
1Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
2Department of Nephrology, University of Alabama at Birmingham,
Birmingham, AL, USA
Correspondence: A Mehta, E-mail: amitkumar.mehta@ccc.uab.edu

12)  Probiotic Enteric Regimen for Easing the Complications of Transplant
Elan Gorshein, Susan Ambrosy, Shanna Budney, Juliana Vivas, Jacqueline Manago, Mary Kate McGrath, Anne Tyno, Roger Strair.  Blood 2014 124:5877;

Since the recognition of the important role the intestinal microbiome is playing in our well being, research of its complex nature is gaining momentum. Early recognition for the potential of dysbiosis may help in taking measures to ward off the microbial imbalance, and thus prevent untoward clinical disorders. Preliminary data in animals has indicated that the administration of probiotics may modify graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplant. In humans, recent research has suggested that probiotics may favorably impact gut related immunity. We performed a pilot study to determine the safety of administering the probiotic lactobacillus GG following hematopoietic engraftment after allogeneic hematopoietic stem cell transplant (HSCT). There were no untoward events associated with administration of the probiotic. This retrospective analysis was designed to analyze the effects of the probiotic on the incidence of intestinal GVHD among patients participating in the study.
Methods
We evaluated eighty patients who underwent an allogeneic HSCT between 1/3/2006 and 9/13/2013 through our bone marrow transplant registry. Patients were classified into two groups. Thirty patients were supplemented with the probiotic lactobacillus GG as part of the pilot study, and fifty patients not receiving probiotic therapy were chosen as historic controls. The primary end point of this retrospective analysis was the development of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Patients were evaluated at three, six and twelve months following HSCT.
Results
Among the thirty patients who were treated with probiotics, at the three-month interval, 14 (47%) developed stage I aGVHD, 6 (20%) developed stage II aGVHD, and 10 (33%) were free of disease. At six months, 12 patients (40%) had limited cGVHD, 5 (17%) had extensive cGVHD, and 13 (43%) were without disease. At 12 months, 12 patients (40%) had limited cGVHD, 7 (23%) had extensive cGVHD, 7 (23%) were free of disease, and 4 (13%) were unverifiable.
For the fifty patients who did not receive probiotics, at the three-month interval, 21 (42%) developed stage I aGVHD, 5 (10%) had stage II, and 6 (12%) had stage III or IV aGVHD. Seventeen (34%) patients were free of disease, and 1 (2%) was unknown. At six months, 17 patients (34%) had limited cGVHD, 10 (20%) had extensive cGVHD, 19 (38%) were without disease, and four patients (8%) were unknown or expired. At the 12-month period, 10 patients (20%) had limited cGVHD, 21 (42%) had extensive cGVHD, 15 (30%) had no evidence of disease, and 4 (8%) were unknown or expired.
Conclusion
Our findings suggest that supplementing therapy with probiotics may modulate risk of GVHD with the potential for lower rates of stage III- IV aGVHD. However, this retrospective analysis does not prove that it reduces the overall incidence of GVHD in this patient population. This study demonstrates the safety and feasibility of administering probiotics in post-allogeneic stem cell transplant patients. A randomized study is now ongoing to determine the efficacy of probiotics with respect to aGVHD and cGVHD.

13) Mercadante, Ana CT, et al. “Oral Combined Therapy with Probiotics and Alloantigen Induces B Cell–Dependent Long-Lasting Specific Tolerance.“ The Journal of Immunology 192.4 (2014): 1928-1937.

Allogeneic hematopietic stem cell transplantation (aHSCT) is widely used for the treatment of hematologic malignancies. Although aHSCT provides a good response against the malignant cells (graft-versus-leukemia [GVL]), it also leads to the development of graft-versus-host disease (GVHD), a severe disease with high mortality and morbidity rates. Therapy for GVHD is commonly based on nonspecific immunosupression of the transplanted recipient, resulting in the concomitant inhibition of the GVL effect. In this
study, we propose an alternative approach to specifically suppress GVHD while sparing the GVL, based on oral treatment of transplant donors with recipient Ags, associated with the intake of probiotic Lactococcus lactis as tolerogenic adjuvant (combined therapy). We show that treatment of C57BL/6 donor mice with combined therapy before the transplant protects the recipients F1 (C57BL/6 3 BAL/c) mice from clinical and pathological manifestations of disease, resulting in 100% survival rate. Importantly,
the animals keep the immunological competence maintaining the GVL response as well as the response to third-party Ags. The protection is specific, long lasting and dependent on donor IL-10–sufficient B cells activity, which induces regulatory T cells in the host. These data suggest that combined therapy is a promising strategy for prevention of GVHD with preservation of GVL, opening new possibilities to treat human patients subjected to transplantation. The Journal of Immunology, 2014, 192: 000–000.

HSCT recipients are subjected to conditioning regimens that require a strict diet in which live or raw food is precluded. Our results suggest that oral tolerance induction by the use of a probiotic bacteria and the recipient protein extract,(from spleen cells) on HSCT donors before transplantation, might prove safe, simple, and effective for preventing GVHD in human patients.

14)  Gerbitz, Armin, et al. “Probiotic effects on experimental graft-versus-host disease: let them eat yogurt.” Blood 103.11 (2004): 4365-4367.
We hypothesized that modifying the enteric flora using the probiotic microorganism Lactobacillus rhamnosus GG, would ameliorate aGVHD. Here we show that oral administration of Lactobacillus rhamnosus GG before and after transplantation results in improved survival and reduced aGVHD.
Treatment of recipient mice with L rhamnosus GG significantly reduced mortality (P < .01) after transplantation (Figure 1A).
Furthermore, animals that had had transplants and were receiving L rhamnosus GG displayed a significantly reduced GVHD score
The authors concluded that lower LPS serum levels account for the reduced GVHD since LPS represents an enormous stimulus in the development of GVHD.

15)  Jenq, Robert R., et al. “Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation.” The Journal of Experimental Medicine 209.5 (2012): 903.
Despite a growing understanding of the link between intestinal inflammation and resident gut microbes, longitudinal studies of human flora before initial onset of intestinal inflammation have not been reported. Here, we demonstrate in murine and human recipients of allogeneic bone marrow transplantation (BMT) that intestinal inflammation secondary to graft-versus-host disease (GVHD) is associated with major shifts in the composition of the intestinal microbiota. The microbiota, in turn, can modulate the severity of intestinal inflammation. In mouse models of GVHD, we observed loss of overall diversity and expansion of Lactobacillales and loss of Clostridiales. Eliminating Lactobacillales from the flora of mice before BMT aggravated GVHD, whereas reintroducing the predominant species of Lactobacillus mediated significant protection against GVHD. We then characterized gut flora of patients during onset of intestinal inflammation caused by GVHD and found patterns mirroring those in mice. We also identified increased microbial chaos early after allogeneic BMT as a potential risk factor for subsequent GVHD. Together, these data demonstrate regulation of flora by intestinal inflammation and suggest that flora manipulation may reduce intestinal inflammation and improve outcomes for allogeneic BMT recipients.

16)  Robin, Frédéric, et al. “Lactobacillus rhamnosus meningitis following recurrent episodes of bacteremia in a child undergoing allogeneic hematopoietic stem cell transplantation.” Journal of clinical microbiology 48.11 (2010): 4317-4319.
This case confirms the risk of Lactobacillus infection in immunocompromised patients, even without probiotic use, and the importance of highly active antibiotics such as clindamycin in limiting recurrence of the infection.

17) Poutsiaka, Debra D. “Editorial Commentary: The Gut Microbiota Strikes Again.” Clinical Infectious Diseases 61.3 (2015): 358-360.
Debra D. Poutsiaka Division of Geographic Medicine and Infectious Disease, Tufts Medical Center, Boston, Massachusetts

blood stream infection with enteric organisms (EB-BSI)

study of pediatric allogeneic HSCT recipients, EB-BSI developed in almost half of all patients. The strongest predictor of EB-BSI was time to neutrophil engraftment.  The development of EB-BSI was significantly associated with mortality in the entire cohort but not in those who developed aG-GVHD, likely due to the small numbers involved as pointed out by the authors. In their discussion, the authors noted the relationship between antibiotic usage and reduced gut microbial diversity observed by others, the latter of which is associated with mortality after HSCT [6]. They acknowledge that a limitation of their study was the lack of antibiotic data because such information might have had an impact on their analysis of mortality. Based on these data, the authors highlight the seriousness of EB-BSI in HSCT patients and the need for preventive measures. The potential strategy proposed by them was the use of probiotics, presumably by stabilizing or restoring the gut microbiota after HSCT.

is it a good idea to disrupt these homeostatic functions with prophylactic antibiotics used in HSCT? Recent data suggest that it is not. The disarray in the gastrointestinal (GI) microbiota that occurs during HSCT contributes to aGVHD in mice and humans [8]. Microbial diversity, a marker of a healthy microbiota, diminishes during HSCT, in large part due to frequent antibiotic usage, and is associated with increased mortality after HSCT

18) Levinson, Anya, et al. “Acute gastrointestinal graft-vs-host disease is associated with increased enteric bacterial bloodstream infection density in pediatric allogeneic hematopoietic cell transplant recipients.” Clinical Infectious Diseases 61.3 (2015): 350-357.
Bacterial septicemia remains the leading cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (AlloHCT). While murine studies have found acute gastrointestinal graft-vs-host disease (aG-GVHD) to be associated with increased incidence of enteric bacterial bloodstream infections (EB-BSI), this association has not been studied in humans. We hypothesized that in patients who developed aG-GVHD, the EB-BSI density after onset of aG-GVHD would be higher than before onset and higher than in patients without acute GVHD (aGVHD).
METHODS:
We retrospectively reviewed data collected on 264 pediatric AlloHCT recipients with malignant and nonmalignant disease. We calculated and compared EB-BSI densities in the following 3 subgroups: patients without aGVHD and patients with aG-GVHD, both before and after onset of aG-GVHD. We also examined the effect of aG-GVHD onset on the first episode of EB-BSI using Cox proportional hazards models.
RESULTS:
The overall incidence of aG-GVHD was 28.8% (n = 76). Analyses done both at 120 and 180 days post-AlloHCT showed that the EB-BSI density increased after aG-GVHD onset (0.95 infections/person-year before aG-GVHD vs 2.7 infections/person-year after aG-GVHD at day 120 [P = .006]; 0.95 infections/person-year before aG-GVHD vs 2.26 infections/person-year after aG-GVHD at day 180 [P = .033]). On multivariate analysis, the onset of aG-GVHD had a positive hazard ratio of 1.47 (P = .077) on time to first EB-BSI.
CONCLUSIONS:
Our results support the theory that aG-GVHD predisposes pediatric AlloHCT recipients to EB-BSI. Prophylactic agents such as probiotics should be studied prospectively in patients with aG-GVHD.

19) MINI REVIEW ARTICLE Front. Immunol., 18 July 2014 |
The role of pattern-recognition receptors in graft-versus-host disease and graft-versus-leukemia after allogeneic stem cell transplantation
Heidegger1, imageMarcel R. M. van den Brink2, imageTobias Haas1 and imageHendrik Poeck1,2*
1III. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
2Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

C Diff

20)  Prevention of Clostridium difficile infection with Saccharomyces boulardii: A systematic review
Jennifer M Tung, BSc,1 Lisa R Dolovich, BSc MSc,1 and Christine H Lee, MD FRCPC1,2

Clostridium difficile is a major cause of antibiotic associated diarrhea within the hospital setting. The yeast Saccharomyces boulardii has been found to have some effect in reducing the risk of C difficile infection (CDI); however, its role in preventive therapy has yet to be firmly established.
OBJECTIVE:To review the effectiveness of S boulardii in the prevention of primary and recurrent CDI. Benefit was defined as a reduction of diarrhea associated with C difficile. Risk was defined as any adverse effects of S boulardii.
METHODS:A literature search in MEDLINE, EMBASE, CINAHL and the Cochrane Library was performed. Included studies were English language, randomized, double-blind placebo controlled trials evaluating S boulardii in CDI prevention.
RESULTS:Four studies were reviewed. Two studies investigated the prevention of recurrence in populations that were experiencing CDI at baseline. One trial showed a reduction of relapses in patients experiencing recurrent CDI (RR=0.53; P<0.05). The other demonstrated a trend toward reduction of CDI relapse in the recurrent treatment group of patients receiving high-dose vancomycin (RR=0.33; P=0.05). Two other studies examined primary prevention of CDI in populations that had been recently prescribed antibiotics. These studies lacked the power to detect statistically significant differences. Patients on treatment experienced increased risk for thirst and constipation.
CONCLUSION: S boulardii seems to be well tolerated and may be effective for secondary prevention in some specific patient populations with particular concurrent antibiotic treatment. Its role in primary prevention is poorly defined and more research is required before changes in practice are recommended.

21)   Therap Adv Gastroenterol. 2011 May; 4(3): 185–197.
Probiotics in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection  Mary Hickson
Diarrhoea, as a common side effect of antibiotics, increases treatment costs and length of stay in acute healthcare facilities. One potential strategy to prevent this side effect is the concurrent use of probiotic bacteria or yeast. This review discusses the evidence for the efficacy of probiotics in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection; the potential mechanisms by which probiotics may work; their safety; what future research is required; and recommendations for use in clinical practice.

Kefir

22) Lett Appl Microbiol. 2002;35(2):136-40.
Dietary influence of kefir on microbial activities in the mouse bowel.
Marquina D1, Santos A, Corpas I, Muñoz J, Zazo J, Peinado JM.
In this work the microflora present in kefir, a fermented milk product, was studied together with the effect of kefir administration on different groups of indigenous bacteria of mouse bowel.
METHODS AND RESULTS: Kefir microflora was composed of lactic acid bacteria, acetic acid bacteria and yeasts. Yeast population was composed of Saccharomyces cerevisiae, S. unisporus, Candida kefir, Kluyveromyces marxianus and K. lactis. The streptococci levels in kefir treated mice increased by 10-fold and the levels of sulfite-reducing clostridia decreased by 100-fold. The number of lactic acid bacteria increased significantly.
CONCLUSIONS: The administration of kefir significantly increased the lactic acid bacteria counts in the mucosa of the bowel. Ingestion of kefir specifically lowered microbial populations of Enterobacteriaceae and clostridia.
SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first long-term study about the effects of the kefir administration on the intestinal microflora of mice.

23) Antitumor Activity of Milk Kefir and Soy Milk Kefir in Tumor-Bearing Mice
Je-Ruei Liu , Sheng-Yao Wang , Yuh-Yih Lin & Chin-Wen Lin
Pages 183-187 | Published online: 18 Nov 2009
Abstract: The effects of oral administration of milk and soy milk kefirs on tumor growth in tumor-bearing mice and the mucosal immunoglobulin A response in mice were studied. Oral administration of milk and soy milk kefirs to mice inoculated with sarcoma 180 tumor cells resulted in 64.8% and 70.9% inhibition of tumor growth, respectively, compared with controls. In addition, oral administration of the two kefir types induced apoptotic tumor cell lysis. Total immunoglobulin A levels for tissue extracts from the wall of the small intestine were also significantly higher for mice fed a milk kefir or a soy milk kefir regimen for 30 days. These results suggest that milk and soy milk kefirs may be considered among the more promising food components in terms of cancer prevention and enhancement of mucosal resistance to gastrointestinal infection.

— — — Antibiotics for febrile neutropenia in the chmotherapy patient.

24) Zosyn (U.S., by Pfizer inc) Piperacillin/tazobactam
Pipercillin-tazobactam is recommended by the National Institute for Health and Care Excellence as first line therapy for the treatment of bloodstream infections in neutropenic cancer patients.[1] piperacillin/tazobactam is a combination antibiotic containing the extended-spectrum penicillin antibiotic piperacillin and the β-lactamase inhibitor tazobactam. It is commercially available as Tazocin (Canada, UK, Australia and New Zealand, Italy, marketed by Pfizer), and Zosyn (U.S., by Pfizer inc) as well as a generic drug. The combination has activity against many Gram-positive and Gram-negative pathogens and Pseudomonas aeruginosa.
Its main uses are in intensive care medicine (pneumonia, peritonitis), some diabetes-related foot infections, and empirical therapy in febrile neutropenia (e.g., after chemotherapy). The drug is administered intravenously every 6 or 8 hr, typically over 3-30 min. It may also be administered by continuous infusion over four hours. Prolonged infusions are thought to maximize the time that serum concentrations are above the minimum inhibitory concentration (MIC) of the bacteria implicated in infection.

Niclosamide for Clostridia

25) Gooyit, Major, and Kim D. Janda. “Reprofiled anthelmintics abate hypervirulent stationary-phase Clostridium difficile.” Scientific Reports 6 (2016): 33642.

Prolonged use of broad-spectrum antibiotics disrupts the indigenous gut microbiota, which consequently enables toxigenic Clostridium difficile species to proliferate and cause infection. The burden of C. difficile infections was exacerbated with the outbreak of hypervirulent strains that produce copious amounts of enterotoxins and spores. In recent past, membrane-active agents have generated a surge of interest due to their bactericidal property with a low propensity for resistance. In this study, we capitalized on the antimicrobial property and low oral bioavailability of salicylanilide anthelmintics (closantel, rafoxanide, niclosamide, oxyclozanide) to target the gut pathogen. By broth microdilution techniques, we determined the MIC values of the anthelmintics against 16 C. difficile isolates of defined PCR-ribotype. The anthelmintics broadly inhibited C. difficile growth in vitro via a membrane depolarization mechanism. Interestingly, the salicylanilides were bactericidal against logarithmic- and stationary-phase cultures of the BI/NAP1/027 strain 4118. The salicylanilides were poorly active against select gut commensals (Bacteroides, Bifidobacterium and Lactobacillus species), and were non-hemolytic and non-toxic to mammalian cell lines HepG2 and HEK 293T/17 within the range of their in vitro MICs and MBCs. The salicylanilide anthelmintics exhibit desirable properties for repositioning as anti-C. difficile agents.

26) Sci Rep. 2016 Sep 16;6:33642. doi: 10.1038/srep33642.
Reprofiled anthelmintics abate hypervirulent stationary-phase Clostridium difficile.  Gooyit M1, Janda KD1.
Prolonged use of broad-spectrum antibiotics disrupts the indigenous gut microbiota, which consequently enables toxigenic Clostridium difficile species to proliferate and cause infection. The burden of C. difficile infections was exacerbated with the outbreak of hypervirulent strains that produce copious amounts of enterotoxins and spores. In recent past, membrane-active agents have generated a surge of interest due to their bactericidal property with a low propensity for resistance. In this study, we capitalized on the antimicrobial property and low oral bioavailability of salicylanilide anthelmintics (closantel, rafoxanide, niclosamide, oxyclozanide) to target the gut pathogen. By broth microdilution techniques, we determined the MIC values of the anthelmintics against 16 C. difficile isolates of defined PCR-ribotype. The anthelmintics broadly inhibited C. difficile growth in vitro via a membrane depolarization mechanism. Interestingly, the salicylanilides were bactericidal against logarithmic- and stationary-phase cultures of the BI/NAP1/027 strain 4118. The salicylanilides were poorly active against select gut commensals (Bacteroides, Bifidobacterium and Lactobacillus species), and were non-hemolytic and non-toxic to mammalian cell lines HepG2 and HEK 293T/17 within the range of their in vitro MICs and MBCs. The salicylanilide anthelmintics exhibit desirable properties for repositioning as anti-C. difficile agents.

27) Di Bella, Stefano, Theodore Gouliouris, and Nicola Petrosillo. “Fecal microbiota transplantation (FMT) for Clostridium difficile infection: Focus on immunocompromised patients.” Journal of Infection and Chemotherapy 21.4 (2015): 230-237.

Clostridium difficile infection (CDI) is an emerging problem worldwide associated with significant morbidity, mortality, recurrence rates and healthcare costs. Immunosuppressed patients, including HIV-seropositive individuals, solid organ transplant recipients, patients with malignancies, hematopoietic stem cell transplant recipients, and patients with inflammatory bowel disease are increasingly recognized as being at higher risk of developing CDI where it may be associated with significant complications, recurrence, and mortality. Fecal microbiota transplantation (FMT) has proven to be an effective and safe procedure for the treatment of recurrent or refractory CDI in immunocompetent patients by restoring the gut microbiota and resistance to further recurrences. During the last two years the first data on FMT in immunocompromised patients began to appear in the medical literature. Herein we summarize the use of FMT for the treatment of CDI with a focus on immunocompromised patients.

28) Alonso, Carolyn D., and Kieren A. Marr. “Clostridium difficile infection among hematopoietic stem cell transplant recipients: beyond colitis.” Current opinion in infectious diseases 26.4 (2013): 326.

29)  Curr Hematol Malig Rep. 2014 Mar;9(1):85-90.
Clostridium difficile: deleterious impact on hematopoietic stem cell transplantation. Callejas-Díaz A1, Gea-Banacloche JC.
C. difficile infection (CDI), the most common cause of hospital-acquired diarrhea, is very frequent after hematopoietic stem cell transplantation (HSCT). Recent publications suggest it affects between 6 % and 20 % of HSCT recipients during the first year and is more common following allogeneic transplant (allo-HSCT). The best diagnostic strategy remains to be defined, but molecular testing for the toxin genes by polymerase chain reaction (PCR) seems to be replacing the traditional enzyme immunoassays (EIA).

The higher sensitivity of the PCR may result in increased measured incidence of disease. C. difficile infection typically occurs during the first month after HSCT. Although the course of CDI after HSCT does not seem to be different than in other hospitalized patients, it may result in worsening of bowel graft versus host disease (GVHD) after allo-HSCT. Current evidence suggests a reciprocal effect by which GVHD may increase the risk of CDI and C. difficile disease may increase the risk of GVHD. Metronidazole was the treatment most commonly used in all recent series, followed by the combination metronidazole and oral vancomycin. There is minimal information on the use of fidaxomicin in HSCT recipients. Regarding stool transplant, there is one case report of successful use of this modality in an HSCT recipient. These two newer approaches will certainly be investigated in the future.

30)  Infect Control Hosp Epidemiol. 2016 Jan; 37(1): 8–15.
Transmission of Clostridium difficile During Hospitalization for Allogeneic Stem Cell Transplant  Mini Kamboj, MD,1,2,3 Anna Sheahan, PhD,1 Janet Sun, BS,1 Ying Taur, MD, MPH,2,3 Elizabeth Robilotti, MD, MPH,1,2,3 Esther Babady, PhD,4 Genovefa Papanicolaou, MD,2,3 Ann Jakubowski, MD, PhD,3,5 Eric Pamer, MD,2,3 and Kent Sepkowitz, MD1,2,3
1Infection Control, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York  2Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York  3Department of Medicine, Weill Cornell Medical College, New York, New York  4Department of Clinical Laboratories, Memorial Sloan Kettering Cancer Center, New York, New York  5Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

Most cases of CDI after stem cell transplant represent delayed onset disease in nonsymptomatic carriers. Transmission on stem cell transplant unit was confirmed in 19% of early CDI cases in our cohort with a probable donor source established in half of the cases.

---

32)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390201/
Clostridium difficile-Associated Disease in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Risk Associations, Protective Associations, and Outcomes
Erik R. Dubberke, MD, Kimberly A. Reske, MPH, Anand Srivastava, BA, Justin Sadhu, MD, Robert Gatti, BA, Rebecca M. Young, BS, Lauren C. Rakes, BA, Brian Dieckgraefe, MD, PhD, John DiPersio, MD, PhD, and Victoria J. Fraser, MD

32)  Transpl Infect Dis. 2012 Dec;14(6):E161-5.
Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient.
Neemann K1, Eichele DD, Smith PW, Bociek R, Akhtari M, Freifeld A.
1Infectious Diseases Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA. kneemann@unmc.edu
We present a case of severe Clostridium difficile infection (CDI) in a non-neutropenic allogeneic hematopoietic stem cell transplant recipient who was treated successfully with fecal microbiota therapy after standard pharmacologic therapy had failed. Following naso-jejunal instillation of donor stool, the patient’s symptoms resolved within 48 h. Bowel resection was averted. This is the first case in the literature, to our knowledge, to describe fecal microbiota therapy in a profoundly immunocompromised host with severe CDI. We propose that fecal microbiota therapy be considered as a therapeutic option in immunosuppressed patients with refractory severe CDI.

33) Dig Dis Sci. 2015 Jan;60(1):181-5.
Intestinal microbiota transplantation, a simple and effective treatment for severe and refractory Clostridium difficile infection.
Zainah H1, Hassan M, Shiekh-Sroujieh L, Hassan S, Alangaden G, Ramesh M.
Restoring normal fecal flora through intestinal microbiota transplantation (IMT) was successful in curing recurrent Clostridium difficile infection (CDI). However, only a few cases have been reported of IMT being utilized for the treatment of severe or fulminant CDI.
AIM:Is IMT a simple and effective treatment for severe and recurrent CDI?
METHODS:In this retrospective study, we report 14 patients with severe CDI refractory to conventional medical therapy, who underwent IMT. Fresh donor stool specimen was manually homogenized with warm tap water, filtered through gauze and then instilled through nasogastric tube (NGT). The primary outcome was clinical cure, defined as less than 3 loose bowel movements a day on day 7 after IMT and no need for further CDI therapy. The secondary outcomes were recurrence of CDI within 100 days of IMT and 30-day mortality after IMT. Descriptive statistics were done.
RESULTS:Fourteen patients with severe and refractory CDI received IMT. Mean age was 73.4 ± 11.9 years (range 52-92). IMT was given via NGT in 13 of the 14 patients. Eleven patients (79 %) achieved cure after IMT. No recurrence was seen in the patients who responded to IMT and were alive within the 100 day follow-up period. IMT was well tolerated. The 30-day all-cause mortality was 29 %, all 4 patients died as a result of their underlying cancer. No patients died as a result of CDI or IMT.
CONCLUSIONS:IMT performed at the bedside via NGT is effective and safe for the treatment of severe and refractory CDI, and prevents recurrence.

34)  Am J Gastroenterol. 2014 Jul;109(7):1065-71.
Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients.
Kelly CR1, Ihunnah C1, Fischer M2, Khoruts A3, Surawicz C4, Afzali A4, Aroniadis O5, Barto A6, Borody T7, Giovanelli A8, Gordon S9, Gluck M10, Hohmann EL11, Kao D12, Kao JY13, McQuillen DP6, Mellow M14, Rank KM3, Rao K13, Ray A15, Schwartz MA10, Singh N16, Stollman N8, Suskind DL16, Vindigni SM4, Youngster I11, Brandt L5.
Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients.
METHODS:A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT.
RESULTS:Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3-46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT.
CONCLUSIONS:This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.

==========================================================35)   Antimicrob Agents Chemother. 2015 Jul;59(7):3726-35. doi: 10.1128/AAC.04794-14. Epub 2015 Mar 30.
Berberine blocks the relapse of Clostridium difficile infection in C57BL/6 mice after standard vancomycin treatment.
Lv Z1, Peng G2, Liu W3, Xu H4, Su J5.
Vancomycin is a preferred antibiotic for treating Clostridium difficile infection (CDI) and has been associated with a rate of recurrence of CDI of as high as 20% in treated patients. Recent studies have suggested that berberine, an alternative medical therapy for gastroenteritis and diarrhea, exhibits several beneficial effects, including induction of anti-inflammatory responses and restoration of the intestinal barrier function. This study investigated the therapeutic effects of berberine on preventing CDI relapse and restoring the gut microbiota in a mouse model. Berberine was administered through gavage to C57BL/6 mice with established CDI-induced intestinal injury and colitis. The disease activity index (DAI), mean relative weight, histopathology scores, and levels of toxins A and B in fecal samples were measured. An Illumina sequencing-based analysis of 16S rRNA genes was used to determine the overall structural change in the microbiota in the mouse ileocecum. Berberine administration significantly promoted the restoration of the intestinal microbiota by inhibiting the expansion of members of the family Enterobacteriaceae and counteracting the side effects of vancomycin treatment. Therapy consisting of vancomycin and berberine combined prevented weight loss, improved the DAI and the histopathology scores, and effectively decreased the mortality rate. Berberine prevented CDIs from relapsing and significantly improved survival in the mouse model of CDI. Our data indicate that a combination of berberine and vancomycin is more effective than vancomycin alone for treating CDI. One of the possible mechanisms by which berberine prevents a CDI relapse is through modulation of the gut microbiota. Although this conclusion was generated in the case of the mouse model, use of the combination of vancomycin and berberine and represent a novel therapeutic approach targeting CDI.

36) Natural Antimicrobials. Certain herbs and nutrients have the ability to kill bacteria and treat bacterial infections. Dr. Morstein uses an encapsulated blend of caprylic acid, quebracho tannins, berberine sulfate, garlic, and uva ursi. She may also use allicin capsules (allicin is a component of garlic extract) and/or freeze-dried uva ursi capsules.
Probiotics. As discussed above, probiotics have been proven to be effective for prevention of antibiotic-associated diarrhea and to be useful with other antimicrobials for treatment of C. difficile disease. Dr. Morstein recommends a mixture of Lactobacillus, Bifidobacillus, and Saccharomyces boulardii (200 billion live bacteria a day).

37) Ann Hematol. 2008 Sep;87(9):727-34.
Prolonged haematological toxicity from the hyper-CVAD regimen: manifestations, frequency, and natural history in a cohort of 125 consecutive patients. Gill S1, Lane SW, Crawford J, Cull G, Joske D, Marlton P, Mollee PN, Prince HM, Seymour JF.
The hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) regimen has impressive efficacy in several haematological malignancies but is associated with considerable short-term haematological toxicity. Secondary myelodysplasia (MDS) or acute myeloid leukaemia (AML) also occurs. In this retrospective study, we also describe other prolonged haematological sequelae of this regimen. One hundred and twenty-five patients were treated with a median of six hyper-CVAD cycles and followed for a median of 28 months. Follow-up for cytopenias was censored at the next cytotoxic therapy. At 3 months post-therapy, 77 patients were evaluable. Cytopenias persisted in 59% of patients. Requirement for dose attenuation was the only factor significantly associated with persisting cytopenias (p<0.05). The median time to normalisation of counts for those with post-treatment cytopenias in the respective lineages was 9 months (range, 6-12) for anaemia, 6 months (range, 6-30) for neutropenia and 9 months (range, 6-30) for thrombocytopenia. MDS/AML was diagnosed in four patients at 4, 21, 24 and 37 months after therapy with a cumulative incidence rate of 4.43% at 4 years. These results indicate a considerable rate of prolonged haematological toxicity after hyper-CVAD and a modest rate of MDS at this limited follow-up. These findings likely reflect cumulative damage to haematopoietic stem cells.

–  – – – – – – – –

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