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Mohamed ME, Saqr A, Staley C, Onyeaghala G, Teigen L, Dorr CR, Remmel RP, Guan W, Oetting WS, Matas AJ, Israni AK, Jacobson PA. Pharmacomicrobiomics: Immunosuppressive Drugs and Microbiome Interactions in Transplantation. Transplantation 2024; 108:1895-1910. [PMID: 38361239 PMCID: PMC11327386 DOI: 10.1097/tp.0000000000004926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high.
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Affiliation(s)
- Moataz E Mohamed
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Abdelrahman Saqr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | | | - Guillaume Onyeaghala
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
| | - Levi Teigen
- Department of Food Science and Nutrition, University of Minnesota, St Paul, MN
| | - Casey R Dorr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
- Department of Medicine, Hennepin Healthcare, Minneapolis, MN
| | - Rory P Remmel
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN
| | - William S Oetting
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, MN
| | - Ajay K Israni
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, Hennepin Healthcare, Minneapolis, MN
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
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Weerdenburg H, Lindsay J. Expanding the scope of the infectious diseases pharmacist in HCT: Beyond antimicrobial stewardship. Transpl Infect Dis 2023; 25 Suppl 1:e14094. [PMID: 37418600 DOI: 10.1111/tid.14094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/19/2023] [Accepted: 06/08/2023] [Indexed: 07/09/2023]
Abstract
BACKGROUND Infectious disease (ID) pharmacists and antimicrobial stewardship (AMS) programs are integral to the infection management of hematopoietic cell transplant (HCT) recipients demonstrating effective implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN), allergy assessments, and use of rapid diagnostic testing. The HCT procedure is complex, dynamic, and a high risk for infectious complications. Therefore, there is an important role for an ID and AMS pharmacist to collaborate with the primary treating team, with ongoing care, involving the optimal individual patient prophylactic, pre-emptive and treatment management of infections in this high-risk population. CONCLUSION This review highlights key factors for consideration of ID/AMS Pharmacists in relation to HCT, including important aspects in the evaluation of infection risk prior to transplant, risk from donor sources, length of, and changes in immunosuppression, and potential drug-drug interactions from other essential supportive care therapies.
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Affiliation(s)
- Heather Weerdenburg
- Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Julian Lindsay
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- National Centre for Infections in Cancer and Transplantation (NCICT), Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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Salvadori M, Tsalouchos A. Microbiota, renal disease and renal transplantation. World J Transplant 2021; 11:16-36. [PMID: 33816144 PMCID: PMC8009061 DOI: 10.5500/wjt.v11.i3.16] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/06/2021] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open
Abstract
Aim of this frontier review has been to highlight the role of microbiota in healthy subjects and in patients affected by renal diseases with particular reference to renal transplantation. The microbiota has a relevant role in conditioning the healthy status and the diseases. In particular gut microbiota is essential in the metabolism of food and has a relevant role for its relationship with the immune system. The indigenous microbiota in patients with chronic renal failure is completely different than that of the healthy subjects and pathobionts appear. This abnormality in microbiota composition is called dysbiosis and may cause a rapid deterioration of the renal function both for activating the immune system and producing large quantity of uremic toxins. Similarly, after renal trans-plantation the microbiota changes with the appearance of pathobionts, principally in the first period because of the assumption of immunosuppressive drugs and antibiotics. These changes may deeply interfere with the graft outcome causing acute rejection, renal infections, diarrhea, and renal interstitial fibrosis. In addition, change in the microbiota may modify the metabolism of immuno-suppressive drugs causing in some patients the need of modifying the immunosuppressant dosing. The restoration of the indigenous microbiota after transplantation is important, either to avoiding the complications that impair the normal renal graft, and because recent studies have documented the role of an indigenous microbiota in inducing tolerance towards the graft. The use of prebiotics, probiotics, smart bacteria and diet modification may restore the indigenous microbiota, but these studies are just at their beginning and more data are needed to draw definitive conclusions.
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Affiliation(s)
- Maurizio Salvadori
- Department of Transplantation Renal Unit, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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Pouch SM, Friedman-Moraco RJ. Prevention and Treatment of Clostridium difficile-Associated Diarrhea in Solid Organ Transplant Recipients. Infect Dis Clin North Am 2018; 32:733-748. [PMID: 30146033 DOI: 10.1016/j.idc.2018.05.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Clostridium difficile infection is a significant cause of morbidity and mortality in solid organ transplant recipients. Risk factors in this population include frequent hospitalizations, receipt of immunosuppressive agents, and intestinal dysbiosis triggered by several factors, including exposure to broad-spectrum antimicrobials. The incidence and potential for significant adverse outcomes among solid organ transplant recipients with C difficile infection highlight the evolving need for strategic C difficile infection risk factor modification and novel approaches to disease management in this patient population. This review focuses on current concepts related to the prevention and treatment of C difficile infection in solid organ transplant recipients.
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Affiliation(s)
- Stephanie M Pouch
- Division of Infectious Diseases, Emory University School of Medicine, 101 Woodruff Circle, WMB #2101, Atlanta, GA 30322, USA.
| | - Rachel J Friedman-Moraco
- Division of Infectious Diseases, Emory University School of Medicine, 101 Woodruff Circle, WMB #2101, Atlanta, GA 30322, USA
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Preston SH, Choi D, Elo IT, Stokes A. Effect of Diabetes on Life Expectancy in the United States by Race and Ethnicity. BIODEMOGRAPHY AND SOCIAL BIOLOGY 2018; 64:139-151. [PMID: 31178981 PMCID: PMC6550350 DOI: 10.1080/19485565.2018.1542291] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
We investigated the impact of diabetes on US life expectancy by sex and race/ethnicity using a prospective cohort study design. Cohorts were drawn from 1997-2009 waves of the National Health Interview Survey and linked to death records through December 31, 2011. We combined data on the prevalence of diabetes among decedents with estimates of the hazard ratios of individuals diagnosed with diabetes to calculate population attributable fractions (PAFs) by age, sex, and race/ethnicity at ages 30 and above. These estimates were then applied to deaths in the official US life table for 2010 to estimate effects of diabetes on life expectancy. Diabetes was responsible for a reduction of 0.83 years of life expectancy for men at age 30 and 0.89 years for 30-year-old women. The impact was greatest among Black women at 1.05 years. Estimates based on traditional demographic and actuarial methods using the frequency with which a disease appears as an underlying cause of death on death certificates produced a reduction in life expectancy at age 30 of only 0.33 years. We conclude that diabetes is substantially reducing US longevity and that its effect is seriously underestimated when using data on underlying causes of death.
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Affiliation(s)
- Samuel H. Preston
- Department of Sociology and Population Studies Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Daesung Choi
- Department of Sociology and Population Studies Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Irma T. Elo
- Department of Sociology and Population Studies Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew Stokes
- Department of Global Health, Boston University School of Public Health, Boston, MA, USA
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Amaro R, Panagiotarakou M, Alcaraz V, Torres A. The efficacy of inhaled antibiotics in non-cystic fibrosis bronchiectasis. Expert Rev Respir Med 2018; 12:683-691. [DOI: 10.1080/17476348.2018.1500179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Rosanel Amaro
- Department of Pulmonary Medicine, Institut Clinic del Tórax, Hospital Clinic of Barcelona - Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona - Ciber de Enfermedades Respiratorias (Ciberes), Barcelona, Spain
| | - Meropi Panagiotarakou
- Department of Pneumonology, Sotiria General Hospital for Thoracic Diseases, Medical School, University of Athens, Barcelona, Spain
| | - Victoria Alcaraz
- Fundació Clínic per la Recerca Biomèdica, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Antoni Torres
- Department of Pulmonary Medicine, Institut Clinic del Tórax, Hospital Clinic of Barcelona - Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona - Ciber de Enfermedades Respiratorias (Ciberes), Barcelona, Spain
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Nanayakkara D, Nanda N. Clostridium difficile infection in solid organ transplant recipients. Curr Opin Organ Transplant 2017; 22:314-319. [PMID: 28542111 DOI: 10.1097/mot.0000000000000430] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Clostridium difficile infection (CDI) is a major healthcare-associated infection that causes significant morbidity and an economic impact in the United States. In this review, we provide an overview of Clostridium difficile infection in solid organ transplant recipients with an emphasis on recent literature. RECENT FINDINGS C. difficile in solid organ transplant population has unique risk factors. Fecal microbiota transplantation has shown favorable results in treatment of recurrent C. difficile in this population. Preliminary data from animal studies suggests excellent efficacy with immunization against C. difficile toxins. SUMMARY Over the last decade, number of individuals receiving solid organ transplants has increased exponentially making peri-transplant complications a common occurrence.C. difficile is a frequent cause of morbidity in solid organ transplant recipients. Early and accurate diagnosis of C. difficile requires a stepwise approach. Differentiating between asymptomatic carriage and infection is a diagnostic challenge. Microbial diversity is inversely proportional to risk of C. difficile infection. Antimicrobial stewardship programs help to retain microbial diversity in individuals susceptible to CDI. Recurrent or relapsing C. difficile infection require fecal microbiota transplantation for definitive cure.
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Affiliation(s)
- Deepa Nanayakkara
- Section of Infectious Diseases, Department of Internal Medicine, University of Southern California, California, USA
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Moiseev IS, Burmina EA, Muslimov AR, Pirogova OV, Bondarenko SN, Darskaya EI, Tarakanova YA, Senina NG, Afanasyev BV. Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis. Ann Hematol 2017; 96:935-942. [PMID: 28343273 DOI: 10.1007/s00277-017-2975-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 03/06/2017] [Indexed: 12/22/2022]
Abstract
A number of studies were published with contradictory results comparing tacrolimus (Tac) and cyclosporine A (CsA) for graft-versus-host disease (GVHD) prophylaxis, but there are only few that accounted for pharmacokinetic (PK) parameters. In this study, we created a model based on median concentrations, variability of concentrations, and failures to maintain target levels that distinguished patients with low, intermediate, and high risks of acute GVHD (hazard ratios (HR) 1.77, 95%CI 1.36-2.32, p < 0.0001). This model was used to compare 95 patients with CsA and 239 with Tac GVHD prophylaxis. In the multivariate analysis, incorporating PK risk, no differences were observed for grade II-IV acute GVHD (HR 0.73, 95%CI 0.48-1.10, p = 0.13), but grade III-IV acute GVHD was lower in the Tac group (HR 0.47, 95%CI 0.28-0.78, p = 0.004). The observed difference was due to patients with high PK risk (HR 0.377, 95%CI 0.19-0.75, p = 0.005), but not with low and intermediate PK risk (p > 0.05). Patients in the Tac group had better GVHD relapse-free survival (HR = 0.659, p = 0.01) and comparable overall survival (p > 0.05). In conclusion, PK risk should be accounted for in comparisons of GVHD prophylaxis regimens with calcineurin inhibitors, and Tac was superior to CsA in patients with high, but not intermediate and low PK risk.
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Affiliation(s)
- Ivan Sergeevich Moiseev
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia.
| | - Ekaterina Andreevna Burmina
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Albert Radikovich Muslimov
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Olga Vladislavovna Pirogova
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Sergey Nikolaevich Bondarenko
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Elena Igorevna Darskaya
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Yuliya Alexandrovna Tarakanova
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Nadegda Georgievna Senina
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
| | - Boris Vladimirovich Afanasyev
- R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
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Early CR, Park JM, Dorsch MP, Pogue KT, Hanigan SM. Effect of metronidazole use on tacrolimus concentrations in transplant patients treated for Clostridium difficile. Transpl Infect Dis 2016; 18:714-720. [PMID: 27501504 DOI: 10.1111/tid.12588] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 05/02/2016] [Accepted: 06/05/2016] [Indexed: 11/28/2022]
Abstract
BACKGROUND Two case reports suggest that metronidazole treatment for Clostridium difficile infections (CDI) increases tacrolimus (TAC) trough levels. The primary objective of this study was to determine the clinical significance of this potential interaction in transplant patients receiving CDI treatment. Currently, no robust literature exists to estimate a magnitude of pharmacokinetic interaction between metronidazole and TAC. METHODS In this retrospective study, the effects of CDI and metronidazole treatment on TAC levels in 52 adult solid organ transplant patients were investigated. The primary outcome was to determine the difference in dose-normalized TAC levels between baseline and symptom resolution in patients treated with metronidazole or vancomycin. The secondary outcome was to determine the difference in dose-normalized TAC levels at baseline and CDI diagnosis. RESULTS The average change in log-transformed dose-normalized TAC levels from baseline to symptom resolution was 0.99 for metronidazole (n = 35) and 1.04 for vancomycin (n = 17) treatment. The mean difference between the groups was 0.96 (95% confidence interval: 0.74-1.24). No significant difference was found between dose-normalized TAC levels at CDI diagnosis and baseline (P = 0.37). CONCLUSION CDI treatment with metronidazole was not associated with a >30% increase in TAC levels compared with vancomycin. Both treatment groups required TAC dose adjustments to maintain goal TAC levels and those treated with metronidazole did not require a significantly greater dose adjustment.
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Affiliation(s)
- C R Early
- Department of Pharmacy, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - J M Park
- Department of Pharmacy, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - M P Dorsch
- Department of Pharmacy, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - K T Pogue
- Department of Pharmacy, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - S M Hanigan
- Department of Pharmacy, University of Michigan Health System, Ann Arbor, Michigan, USA.
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Abstract
PURPOSE OF REVIEW Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, and the threat associated with CDI continues to grow in all patient populations. There is increasing evidence that CDI has a substantial impact on the morbidity and mortality in solid organ transplant (SOT) recipients. Furthermore, new diagnostic and treatment options and strategies for CDI have emerged over the last decade. The purpose of this review is to provide a general understanding of CDI and its evidence-based diagnosis and management strategies, with a focus on SOT recipients. RECENT FINDINGS The incidence and severity of CDI have significantly increased since the year 2000. Studies have identified novel risk factors for CDI, and a new epidemic strain, the NAP1/BI/027, has emerged. Despite the development of newer testing methods and approaches, including nucleic acid amplification tests and testing algorithms, the optimal method for diagnosing CDI is an area of controversy. New agents for treating CDI are being developed, and the use of fecal microbiota transplantation to treat recurrent CDI in SOT recipients is also evolving. SUMMARY CDI is a significant problem for SOT recipients. Further studies on diagnostic and therapeutic strategies with a focus on SOT recipients are needed to further improve patient outcomes.
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Lee JR, Muthukumar T, Dadhania D, Taur Y, Jenq RR, Toussaint NC, Ling L, Pamer E, Suthanthiran M. Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One 2015; 10:e0122399. [PMID: 25815766 PMCID: PMC4376942 DOI: 10.1371/journal.pone.0122399] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 01/13/2015] [Indexed: 12/14/2022] Open
Abstract
Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels.
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Affiliation(s)
- John R. Lee
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America
- Department of Transplantation Medicine, New York Presbyterian Hospital—Weill Cornell Medical Center, New York, New York, United States of America
- * E-mail:
| | - Thangamani Muthukumar
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America
- Department of Transplantation Medicine, New York Presbyterian Hospital—Weill Cornell Medical Center, New York, New York, United States of America
| | - Darshana Dadhania
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America
- Department of Transplantation Medicine, New York Presbyterian Hospital—Weill Cornell Medical Center, New York, New York, United States of America
| | - Ying Taur
- Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Weill Cornell Medical College, New York, New York, United States of America
| | - Robert R. Jenq
- Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Weill Cornell Medical College, New York, New York, United States of America
- Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Nora C. Toussaint
- Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Lilan Ling
- Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Eric Pamer
- Department of Medicine, Infectious Diseases Services, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Weill Cornell Medical College, New York, New York, United States of America
| | - Manikkam Suthanthiran
- Department of Medicine, Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York, United States of America
- Department of Transplantation Medicine, New York Presbyterian Hospital—Weill Cornell Medical Center, New York, New York, United States of America
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Kudo T, Endo Y, Taguchi R, Yatsu M, Ito K. Metronidazole reduces the expression of cytochrome P450 enzymes in HepaRG cells and cryopreserved human hepatocytes. Xenobiotica 2014; 45:413-9. [PMID: 25470432 DOI: 10.3109/00498254.2014.990948] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
1. Blood levels of S-warfarin have been reported to be increased by concomitant administration of metronidazole (MTZ), an antiprotozoal imidazole derivative. 2. To elucidate the mechanism of this interaction and to identify other possible drug-drug interactions, we conducted an in vitro study with the human hepatoma HepaRG cells and cryopreserved human hepatocytes on the ability of MTZ to reduce the expression of cytochrome P450 (CYP) as well as nuclear receptors that regulate the expression of these enzymes. 3. HepaRG cells and cryopreserved human hepatocytes were treated with MTZ (20 to 500 µM) and were then analyzed by real-time RT-PCR to determine mRNA levels of drug-metabolizing enzymes and nuclear receptors. 4. In both cells, the expressions of CYP2C8, CYP2C9, CYP3A4 and constitutive androstane receptor (CAR) were decreased by MTZ treatment. Particularly, in HepaRG cells, their mRNA levels were decreased by MTZ treatment in a concentration-dependent manner. 5. Our findings suggest that the interaction between MTZ and S-warfarin may be due to the MTZ-induced down-regulation of CYP2C9, the primary enzyme responsible for S-warfarin hydroxylation, and CAR, which regulates CYP2C9 expression. We also found that MTZ use may alter the disposition of drugs metabolized by the CYP isozymes investigated.
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Affiliation(s)
- Toshiyuki Kudo
- Research Institute of Pharmaceutical Sciences, Musashino University , Tokyo , Japan
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Interactions between Tacrolimus and Metronidazole in a renal transplant patient. Open Med (Wars) 2012. [DOI: 10.2478/s11536-012-0035-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractWe present a case which reports the occurrence of a potential elevation of Tacrolimus (Tac) plasma levels to toxic values in a renal transplant recipient after adding Metronidazole (Met) to the medication regimen. A 30-year old female, status post living-related renal transplant, who was stabilized on Tac 4.5 mg, twice daily, for 4 months, presented to the clinic with diarrhea. We used Microparticle Enzyme Immunoassay (MEIA) to determine Tac trough concentration (trough concentrations 5–10 ng/ml). After 6 days of Met therapy on 1.5 g/d, Tac trough concentration and serum creatinine (sCr) increased to 20.2 ng/ml and 7.8 mg/dl respectively. Met therapy was discontinued, also one dose of Tac was withheld, while daily dose was decreased to 2 mg/d. Four days after Met discontinuation, Tac concentration dropped to 8.7 ng/ml, sCr to 2.1 mg/dl, warranting Tac dose increase to 3 mg/d. Co-administration of Tac with Met may result in elevated Tac concentrations, possibly leading to tacrolimus nephrotoxicity. Clinicians should be aware of this potential interaction and closely monitor Tac concentration and renal function.
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Cervera C, Linares L, Bou G, Moreno A. Multidrug-resistant bacterial infection in solid organ transplant recipients. Enferm Infecc Microbiol Clin 2012; 30 Suppl 2:40-8. [PMID: 22542034 DOI: 10.1016/s0213-005x(12)70081-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The most frequent complication from infection after solid organ transplantation is bacterial infection. This complication is more frequent in organ transplantation involving the abdominal cavity, such as liver or pancreas transplantation, and less frequent in heart transplant recipients. The sources, clinical characteristics, antibiotic resistance and clinical outcomes vary according to the time of onset after transplantation. Most bacterial infections during the first month post-transplantation are hospital acquired, and there is usually a high incidence of multidrug-resistant bacterial infections. The higher incidence of complications from bacterial infection in the first month post-transplantation may be associated with high morbidity. Of special interest due to their frequency are infections by S. aureus, enterococci, Gram-negative enteric and non-fermentative bacilli. Opportunistic bacterial infections may occur at any time on the posttransplant timeline, but are more frequent between months two and six, the period in which immunosuppression is higher. The most frequent bacterial species causing opportunistic infections in organ transplant recipients are Listeria monocytogenes and Nocardia spp. After month six, posttransplantation solid organ transplant patients usually develop conventional community-acquired bacterial infections, especially urinary tract infections by E. coli and S. pneumoniae pneumonia. In this article we review the clinical characteristics, epidemiology, diagnosis and prognosis of bacterial infections in solid organ transplant patients.
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Affiliation(s)
- Carlos Cervera
- Department of Infectious Diseases, Hospital Clínic-IDIBAPS, Universidad de Barcelona, Barcelona, Spain
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Tan SY, Kan E, Lim WY, Chay G, Law JHK, Soo GW, Bukhari NI, Segarra I. Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice. J Pharm Pharmacol 2011; 63:918-25. [DOI: 10.1111/j.2042-7158.2011.01296.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Abstract
Objectives
The pharmacokinetic interaction between metronidazole, an antibiotic–antiparasitic drug used to treat anaerobic bacterial and protozoal infections, and imatinib, a CYP3A4, P-glycoprotein substrate kinase inhibitor anticancer drug, was evaluated.
Methods
Male imprinting control region mice were given 50 mg/kg imatinib PO (control group) or 50 mg/kg imatinib PO, 15 min after 40 mg/kg PO metronidazole (study group). Imatinib plasma, brain, kidney and liver concentrations were measured by HPLC and non-compartmental pharmacokinetic parameters estimated.
Key findings
Metronidazole coadministration resulted in a double-peak imatinib disposition profile. The maximum concentration (Cmax) decreased by 38%, the area under the curve (AUC0–∞) decreased by 14% and the time to Cmax (Tmax) was earlier (50%) in plasma. Apparent volume of distribution (VSS/F) and oral clearance (Cl/F) increased by 21% and 17%, respectively. Imatinib tissue penetration was higher after metronidazole coadministration, with 1.7 and 2.1-fold AUC0–∞ increases in liver and kidney, respectively. Metronidazole increased imatinib's tissue-to-plasma AUC0–∞ ratio in liver from 2.29 to 4.53 and in kidney from 3.04 to 7.57, suggesting higher uptake efficiency. Brain Cmax was 3.9-fold higher than control and AUC0–t last was 2.3-fold greater than plasma (3.5% in control group). No tissue-plasma concentration correlation was found.
Conclusions
Metronidazole slightly decreased imatinib systemic exposure but enhanced liver, kidney and brain penetration, probably due to metronidazole-mediated inhibition of P-glycoprotein and other efflux transporters. The high brain exposure opens possibilities for treatment of glioma and glioblastoma. Renal and hepatic functions may need to be monitored due to potential renal and hepatic toxicity.
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Affiliation(s)
- Shin Yee Tan
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Elaine Kan
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Wei Yin Lim
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Grace Chay
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Jason H K Law
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Gian Wan Soo
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Nadeem Irfan Bukhari
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Ignacio Segarra
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia
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Effect of metronidazole on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy male volunteers. Eur J Clin Pharmacol 2010; 66:721-5. [DOI: 10.1007/s00228-010-0797-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Accepted: 01/28/2010] [Indexed: 01/12/2023]
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Abstract
PURPOSE OF REVIEW To provide a general understanding of Clostridium difficile infection with a focus on recent publications that evaluate the disease in solid organ transplant recipients. RECENT FINDINGS The incidence of C. difficile infection is increasing worldwide. Epidemics due to a hypervirulent C. difficile strain are associated with an escalating severity of disease. New evidence further supports basing initial treatment choice on disease severity. SUMMARY C. difficile is a significant pathogen in solid organ transplant recipients. Multiple risk factors are found in this population that may result in more severe disease. A high index of suspicion is necessary for the early diagnosis and treatment of C. difficile infection in transplant recipients. Metronidazole and vancomycin show equivalent efficacy in the treatment for mild-to-moderate disease, but vancomycin has demonstrated superiority in the treatment of severe disease. Surgical intervention is also an important consideration in the treatment of solid organ transplant recipients with severe colitis. Rigorous infection control practices are essential for preventing the spread of C. difficile within the hospital environment.
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Abstract
Adverse drug reactions (ADRs) occur frequently in modern medical practice, increasing morbidity and mortality and inflating the cost of care. Patients with cardiovascular disease are particularly vulnerable to ADRs due to their advanced age, polypharmacy, and the influence of heart disease on drug metabolism. The ADR potential for a particular cardiovascular drug varies with the individual, the disease being treated, and the extent of exposure to other drugs. Knowledge of this complex interplay between patient, drug, and disease is a critical component of safe and effective cardiovascular disease management. The majority of significant ADRs involving cardiovascular drugs are predictable and therefore preventable. Better patient education, avoidance of polypharmacy, and clear communication between physicians, pharmacists, and patients, particularly during the transition between the inpatient to outpatient settings, can substantially reduce ADR risk.
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Muñoz P, Giannella M, Alcalá L, Sarmiento E, Fernandez Yañez J, Palomo J, Catalán P, Carbone J, Bouza E. Clostridium difficile–associated Diarrhea in Heart Transplant Recipients: Is Hypogammaglobulinemia the Answer? J Heart Lung Transplant 2007; 26:907-14. [PMID: 17845929 DOI: 10.1016/j.healun.2007.07.010] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2007] [Revised: 07/03/2007] [Accepted: 07/03/2007] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Information regarding Clostridium difficile-associated diarrhea (CDAD) after solid-organ transplantation (SOT) is scarce, particularly after heart transplantation (HT). Although host immune response to C. difficile plays a substantial role in the outcome of this infection, the responsibility of hypogammaglobulinemia (HGG) as a predisposing condition for CDAD has not been studied in SOT. We analyzed the incidence, clinical presentation, outcome and risk factors, including HGG, of CDAD after HT. METHODS Two hundred thirty-five patients who underwent HT (1993 to 2005) were included. Transplantation procedure and immunosuppression were standard. From January 1999 HGG was systematically searched and corrected when IgG levels were <400 mg/dl or severe infection was present. Toxin-producing C. difficile was detected by means of cytotoxin assay and culture of stool samples. Patients with and without CDAD were compared for identification of risk factors. RESULTS CDAD was detected in 35 patients (14.9%). Incidence decreased significantly since HGG was sought and treated: 29 (20.6%) in the first period, and 6 (6.4%) in the second (p = 0.003). CDAD appeared a mean of 32 days (range 5 to 3,300 days) after HT. No related death or episode of fulminant colitis was detected. At least one episode of recurrence was noted in 28.6% of patients. Severe HGG was found to be the only independent risk factor for CDAD after HT (RR 5.8; 95% CI: 1.05 to 32.1; p = 0.04). CONCLUSIONS C. difficile is a significant cause of diarrhea in HT recipients and post-transplant HGG is independently associated with an increased risk. The potential role of immunoglobulin administration in this population requires further study.
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Affiliation(s)
- Patricia Muñoz
- Division of Clinical Microbiology and Infectious Diseases, Clinical Immunology Unit, Department of Cardiology, Hospital General Universitario Gregorio Marañón, University of Madrid, Madrid, Spain.
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Roedler R, Neuhauser MM, Penzak SR. Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered? Ann Pharmacother 2007; 41:653-8. [PMID: 17374625 DOI: 10.1345/aph.1h401] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE To explore whether CYP3A inhibition by metronidazole is the primary mechanism by which metronidazole interacts with coadministered CYP3A substrates. DATA SOURCES Literature was accessed using the MEDLINE database (1966-February 2007). Search terms included metronidazole, cytochrome P450, CYP3A4, CYP3A5, drug interactions, and P-glycoprotein. References from pertinent articles, as well as from tertiary sources, were also considered. STUDY SELECTION AND DATA EXTRACTION All articles identified from the data sources that were published in English were evaluated. Case reports and pharmacokinetic evaluations were included. DATA SYNTHESIS Elevated plasma concentrations and toxicities have been reported for a number of CYP3A substrates including amiodarone, carbamazepine, quinidine, tacrolimus, and cyclosporine when administered with metronidazole. This has led to the widespread belief that metronidazole is a significant inhibitor of CYP3A4. However, 4 pharmacokinetic studies conducted in humans showed that metronidazole did not increase plasma concentrations of the CYP3A substrates midazolam, erythromycin, cyclosporine, and alprazolam, thereby refuting the suggestion that metronidazole is a CYP3A4/5 inhibitor. CONCLUSIONS Drug interactions between metronidazole and certain CYP3A substrates do not appear to result from CYP3A4/5 inhibition by metronidazole. Until any mechanism is identified by which metronidazole alters the disposition of certain CYP3A substrates, drug interactions with this agent should be assessed on a case-by-case basis, taking into account the safety index of the coadministered drug and the availability of equally effective substitutes for either metronidazole or the drug with which it putatively interacts.
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John Wiley & Sons, Ltd.. Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2005. [DOI: 10.1002/pds.1034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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