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Jo J, Hu C, Begum K, Wang W, Le TM, Agyapong S, Hanson BM, Ayele H, Lancaster C, Jahangir Alam M, Gonzales-Luna AJ, Garey KW. Fecal Pharmacokinetics and Gut Microbiome Effects of Oral Omadacycline Versus Vancomycin in Healthy Volunteers. J Infect Dis 2024; 229:273-281. [PMID: 38051631 PMCID: PMC10786255 DOI: 10.1093/infdis/jiad537] [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] [Received: 09/07/2023] [Revised: 11/21/2023] [Accepted: 11/30/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults. METHODS This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared. RESULTS Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants' mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P < .05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin. CONCLUSIONS Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin. CLINICAL TRIALS REGISTRATION NCT06030219.
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Affiliation(s)
- Jinhee Jo
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Chenlin Hu
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Khurshida Begum
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Weiqun Wang
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Thanh M Le
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Samantha Agyapong
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Blake M Hanson
- UTHealth Houston School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas
| | - Hossaena Ayele
- UTHealth Houston School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas
| | - Chris Lancaster
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - M Jahangir Alam
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Anne J Gonzales-Luna
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
| | - Kevin W Garey
- Department of Pharmacy Practice and Translational Research College of Pharmacy, University of Houston
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2
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Uribe-Herranz M, Beghi S, Ruella M, Parvathaneni K, Salaris S, Kostopoulos N, George SS, Pierini S, Krimitza E, Costabile F, Ghilardi G, Amelsberg KV, Lee YG, Pajarillo R, Markmann C, McGettigan-Croce B, Agarwal D, Frey N, Lacey SF, Scholler J, Gabunia K, Wu G, Chong E, Porter DL, June CH, Schuster SJ, Bhoj V, Facciabene A. Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy. Mol Ther 2023; 31:686-700. [PMID: 36641624 PMCID: PMC10014349 DOI: 10.1016/j.ymthe.2023.01.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 10/20/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Several studies have shown the influence of commensal microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19+-A20 lymphoma and CD19+-B16 melanoma, mice receiving vancomycin in combination with CD19-directed CAR T cell (CART-19) therapy displayed increased tumor control and tumor-associated antigens (TAAs) cross-presentation compared with CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in naive gut microbiota mice. Last, B cell acute lymphoblastic leukemia patients treated with CART-19 and exposed to oral vancomycin showed higher CART-19 peak expansion compared with unexposed patients. These results substantiate the role of the gut microbiota on CAR T cell therapy and suggest that modulation of the gut microbiota using vancomycin may improve outcomes after CAR T cell therapy across tumor types.
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Affiliation(s)
- Mireia Uribe-Herranz
- Division of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Immunology Department, Hospital Clínic of Barcelona, Barcelona 08036, Spain
| | - Silvia Beghi
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Marco Ruella
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kalpana Parvathaneni
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Silvano Salaris
- Unit of Biostatistics, Epidemiology and Public Health, University of Padova, Padova, Italy
| | - Nektarios Kostopoulos
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Subin S George
- Bioinformatics Core, Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Stefano Pierini
- Division of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; The Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Elisavet Krimitza
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Francesca Costabile
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Guido Ghilardi
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kimberly V Amelsberg
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yong Gu Lee
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Raymone Pajarillo
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Caroline Markmann
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Bevin McGettigan-Croce
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Divyansh Agarwal
- Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Noelle Frey
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Simon F Lacey
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - John Scholler
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Khatuna Gabunia
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Gary Wu
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Elise Chong
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - David L Porter
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Carl H June
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Stephen J Schuster
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Vijay Bhoj
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Andrea Facciabene
- Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; The Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Kunishima H, Ohge H, Suzuki H, Nakamura A, Matsumoto K, Mikamo H, Mori N, Morinaga Y, Yanagihara K, Yamagishi Y, Yoshizawa S. Japanese Clinical Practice Guidelines for Management of Clostridioides (Clostridium) difficile infection. J Infect Chemother 2022; 28:1045-1083. [PMID: 35618618 DOI: 10.1016/j.jiac.2021.12.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/16/2021] [Accepted: 12/13/2021] [Indexed: 12/19/2022]
Affiliation(s)
- Hiroyuki Kunishima
- Department of Infectious Diseases, St. Marianna University School of Medicine, Japan.
| | - Hiroki Ohge
- Department of Infectious Diseases, Hiroshima University Hospital, Japan
| | - Hiromichi Suzuki
- Division of Infectious Diseases, Department of Medicine, Tsukuba Medical Center Hospital, Japan
| | - Atsushi Nakamura
- Division of Infection Control and Prevention, Nagoya City University Hospital, Japan
| | - Kazuaki Matsumoto
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Japan
| | - Hiroshige Mikamo
- Clinical Infectious Diseases, Graduate School of Medicine, Aichi Medical University, Japan
| | - Nobuaki Mori
- Division of General Internal Medicine and Infectious Diseases, National Hospital Organization Tokyo Medical Center, Japan
| | - Yoshitomo Morinaga
- Department of Microbiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Katsunori Yanagihara
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Yuka Yamagishi
- Clinical Infectious Diseases, Graduate School of Medicine, Aichi Medical University, Japan
| | - Sadako Yoshizawa
- Department of Clinical Laboratory/Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Japan
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Fecal concentration of intravenous vancomycin preparation after oral administration in an experimental model: preclinical assay. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2022; 88:85-90. [DOI: 10.1016/j.rgmxen.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/21/2021] [Indexed: 11/20/2022]
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Ereshefsky BJ, Alrahmany D, El Nekidy WS, Pontiggia L, Ghazi IM. Optimal vancomycin dose in the treatment of Clostridium difficile infection, antimicrobial stewardship initiative. J Chemother 2020; 33:165-173. [PMID: 32715951 DOI: 10.1080/1120009x.2020.1790166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
C. difficile infections (CDI) are increasingly recognized as a leading cause of infectious diarrhea, with increasing morbidity and mortality. Treatment primarily centers around oral vancomycin treatment. A wide range of dosing regimens exist in clinical practice, with little evidence to help distinguish the therapeutic benefit between them. This is a retrospective cohort study conducted at an academic medical center that enrolled adult patients admitted with CDI. The primary outcome was a composite of complete or partial cure at the end of treatment and was assessed using a test of equivalency with a 20% equivalency limit. Subjects were divided into low dose (125 mg) or high dose (250 mg or 500 mg) of oral vancomycin dosed every 6 hours. Overall, 78 patients were included who received low dose vancomycin and 33 who received high dose. Generally, the two groups were similar, except the low dose group had significantly more leukocytosis and less ICU admission or hypotension compared to the high dose group. Equivalency between the two treatment groups was demonstrated (Absolute Risk Difference -0.022, 90% confidence interval: -0.13 to 0.18, p = 0.03). A stepwise logistic regression identified gender, baseline albumin, and ICU admission as significant predictors of the chance for complete or partial cure. No differences between groups for the secondary outcomes of 90-day readmission/recurrence, 30-day all-cause mortality, or time to resolution of diarrhea were demonstrated. Low dose oral vancomycin was demonstrated to result in equivalent outcomes compared to high dose vancomycin for the treatment of CDI.
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Affiliation(s)
- Benjamin J Ereshefsky
- Department of Pharmacy Services, Kaweah Delta Health Care District, Visalia, California, USA
| | - Diaa Alrahmany
- Department of Pharmacy Services, Sohar Hospital, Sohar, Oman
| | - Wasim S El Nekidy
- Department of Pharmacy Services, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Laura Pontiggia
- Misher College of Arts and Sciences, University of the Sciences, Philadelphia, Pennsylvania, USA
| | - Islam M Ghazi
- Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania, USA
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6
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Does oral vancomycin use necessitate therapeutic drug monitoring? Infection 2019; 48:173-182. [PMID: 31713055 DOI: 10.1007/s15010-019-01374-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/02/2019] [Indexed: 12/24/2022]
Abstract
PURPOSE Oral vancomycin use has generally increased as a consequence of the need to treat and/or prevent Clostridium (Clostridiodes) difficile-associated disease (CDAD). This review examines the cumulative scientific evidence that guides therapeutic monitoring of oral vancomycin therapy. METHODS The existing publications were reviewed from the time of the drug's inception to July 2019. This review utilized access as available in PubMed, EMBASE, CINAHL Plus, and the Cochrane Library. RESULTS Case reports and small patient series have documented anecdotal-associated elevations in serum levels. Correlation of absorbed vancomycin with subsequent toxicity is difficult to determine, but serum levels approaching those obtained after parenteral administration have raised concern. Prolonged usage and total dosing over 500 mg/day among adult age ranges have been associated with accumulation. In addition, risk factors for vancomycin accumulation systemically after oral dosing include renal compromise, combined oral and other enteral therapy, severe CDAD, other intercurrent bowel inflammation, polypharmacy, and increased patient complexity/morbidity. CONCLUSION Until systemic toxicity from oral vancomycin absorption is better understood, individual considerations should be made for therapeutic serum monitoring during oral vancomycin treatment. Therapeutic drug monitoring is suggested for several high-risk situations in which high blood levels may be anticipated.
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7
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Igarashi Y, Tashiro S, Enoki Y, Taguchi K, Matsumoto K, Ohge H, Suzuki H, Nakamura A, Mori N, Morinaga Y, Yamagishi Y, Yoshizawa S, Yanagihara K, Mikamo H, Kunishima H. Oral vancomycin versus metronidazole for the treatment of Clostridioides difficile infection: Meta-analysis of randomized controlled trials. J Infect Chemother 2018; 24:907-914. [PMID: 30170735 DOI: 10.1016/j.jiac.2018.08.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 07/27/2018] [Accepted: 08/03/2018] [Indexed: 12/17/2022]
Abstract
At present, vancomycin (VCM) and metronidazole (MNZ) are used for the first-line standard treatment of Clostridioides difficile infection (CDI). However, their differential use has not been sufficiently investigated. In this study, a meta-analysis on differences in the efficacy for CDI between VCM and MNZ was performed. Reports of randomized controlled studies using VCM or MNZ to treat CDI were surveyed. Meta-analysis was performed using the Mantel-Haenszel method and random-effects model, and the risk ratio and 95% confidence interval were calculated. Excluding overlapping reports, 1043 reports were extracted and 5 randomized controlled studies were extracted. There was no difference in therapeutic effects for CDI between VCM and MNZ (RR = 1.08, 95% CI (0.99-1.17), p = 0.09, I2 = 37%). On subgroup analysis by the severity, there was no difference in the clinical effects for CDI between VCM and MNZ in non-severe cases (risk ratio: 1.09, 95% confidence interval: 1.00-1.19, p = 0.06), but the clinical effects of VCM were significantly higher than those of MNZ in severe cases (risk ratio: 1.19, 95% confidence interval: 1.02-1.39, p = 0.03). No significant difference was noted in the recurrence rate, incidence of adverse event, time to exhibit therapeutic effects, or judgment of the bacteriological effects. As the therapeutic effects of VCM were superior in severe CDI cases, VCM should be considered first in severe cases.
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Affiliation(s)
- Yuki Igarashi
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo, Japan
| | - Sho Tashiro
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo, Japan
| | - Yuki Enoki
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo, Japan.
| | - Kazuaki Taguchi
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo, Japan
| | - Kazuaki Matsumoto
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo, Japan
| | - Hiroki Ohge
- Department of Infectious Diseases, Hiroshima University Hospital, Hiroshima, Japan
| | - Hiromichi Suzuki
- Division of Infectious Diseases, Department of Medicine, Tsukuba Medical Center Hospital, Ibaraki, Japan
| | - Atsushi Nakamura
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Graduate School of Medical Sciences, Nagoya City University, Aichi, Japan
| | - Nobuaki Mori
- Department of General Internal Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Yoshitomo Morinaga
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yuka Yamagishi
- Department of Clinical Infectious Diseases, Aichi Medical University Hospital, Aichi, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Aichi, Japan
| | - Sadako Yoshizawa
- Clinical Research Center, Department of Microbiology and Infectious Diseases, Toho University Faculty of Medicine, Tokyo, Japan
| | - Katsunori Yanagihara
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroshige Mikamo
- Department of Clinical Infectious Diseases, Aichi Medical University Hospital, Aichi, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Aichi, Japan
| | - Hiroyuki Kunishima
- Department of Infectious Diseases, St. Marianna University, Kanagawa, Japan
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Oami T, Hattori N, Matsumura Y, Watanabe E, Abe R, Oshima T, Takahashi W, Yamazaki S, Suzuki T, Oda S. The Effects of Fasting and Massive Diarrhea on Absorption of Enteral Vancomycin in Critically Ill Patients: A Retrospective Observational Study. Front Med (Lausanne) 2017. [PMID: 28642864 PMCID: PMC5462912 DOI: 10.3389/fmed.2017.00070] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Purpose Although vancomycin (VCM) is not absorbed from healthy intestinal mucosa, elevations in the serum VCM concentrations have been reported in some cases. The aims of this study are to evaluate the necessity of therapeutic drug monitoring (TDM) during enteral VCM administration in critically ill patients. Materials and methods In this retrospective study, we enrolled 19 patients admitted to our intensive care unit who were treated with enteral VCM from December 2006 to January 2014. Clinical factors were compared between two groups: Group E whose serum concentrations were detectable, and Group N whose concentrations were below the detection limit of the VCM assay. Results Group E comprises 7 patients, and Group N comprises 12 patients. The fasting duration in Group E was significantly longer compared with that in Group N (17 vs. 8 days, p = 0.023). Furthermore, there was a significant correlation between the serum VCM concentrations and the fasting duration (r = 0.79, p < 0.0001), and the amount of diarrhea (r = 0.46, p = 0.046). No difference was observed in the amount of diarrhea at the time of TDM (Group E; 1,850 mL vs. Group N; 210 mL, p = 0.055) and in the Sequential Organ Failure Assessment subscore for the renal system at the time of TDM (Group E; 4.0 vs. Group N; 1.5, p = 0.068). Conclusion Long durations of fasting and massive diarrhea were associated with elevations in the serum VCM concentrations, which suggested that TDM might be necessary during enteral VCM administration in critically ill patients. Trial registration UMIN Clinical Trials Registry identifier UMIN000016955.
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Affiliation(s)
- Takehiko Oami
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Noriyuki Hattori
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yosuke Matsumura
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Eizo Watanabe
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Ryuzo Abe
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Taku Oshima
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Waka Takahashi
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shingo Yamazaki
- Division of Pharmacy, Chiba University Hospital, Chiba, Japan
| | - Tatsuya Suzuki
- Division of Pharmacy, Chiba University Hospital, Chiba, Japan
| | - Shigeto Oda
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
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9
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Antoon JW, Hall M, Metropulos D, Steiner MJ, Jhaveri R, Lohr JA. A Prospective Pilot Study on the Systemic Absorption of Oral Vancomycin in Children With Colitis. J Pediatr Pharmacol Ther 2016; 21:426-431. [PMID: 27877096 DOI: 10.5863/1551-6776-21.5.426] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND: Oral vancomycin is used to treat refractory colitis due to Clostridium dificile infection. Traditionally, oral vancomycin was thought to not be absorbed systemically, but recent adult studies have demonstrated detectable serum levels in over half of patients with severe colitis. This has not been studied in children. OBJECTIVE: To determine the absorption of oral vancomycin and the renal safety profile of oral vancomycin in children hospitalized with colitis. METHODS: We performed a prospective, observational, pilot proof of principle study at the North Carolina Children's Hospital in patients 2 years to 18 years of age receiving oral vancomycin for the treatment of C dificile colitis. Severity of disease was determined using a validated scoring system. Serial serum vancomycin levels and renal function tests were performed during the administration of oral vancomycin. RESULTS: All patients enrolled (n = 8) had mild to moderate C dificile colitis and varying severity of underlying systemic diseases; 7 with inflammatory bowel disease and 1 with acute kidney injury following renal transplantation. No enrolled patients had detectable levels of serum vancomycin. Additionally, no adverse renal outcomes were attributed to oral vancomycin, and no cases of "Red Man" syndrome were observed. CONCLUSIONS: Unlike studies in adult patients, oral vancomycin is likely not absorbed in children with mild to moderate colitis. Further study is needed to determine the pharmacokinetics in severe colitis and those with severe illness in a critical care setting.
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Affiliation(s)
- James W Antoon
- Department of Pediatrics and Adolescent Medicine, Children's Hospital, University of Illinois Hospital & Health Sciences System, Chicago, Illinois
| | - Margaret Hall
- Divisions of General Pediatrics and Adolescent Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Diana Metropulos
- Division of General Pediatrics, Rush University Medical Center, Chicago, Illinois
| | - Michael J Steiner
- Divisions of General Pediatrics and Adolescent Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Ravi Jhaveri
- Pediatric Infectious Diseases, Department of Pediatrics, North Carolina Children's Hospital, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Jacob A Lohr
- Divisions of General Pediatrics and Adolescent Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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10
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Marra F, Ng K. Controversies Around Epidemiology, Diagnosis and Treatment of Clostridium difficile Infection. Drugs 2016; 75:1095-118. [PMID: 26113167 DOI: 10.1007/s40265-015-0422-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Clostridium difficile infection is a major public health problem. However, in recent years the epidemiology, risk factors, diagnosis, and treatment of C. difficile infection have undergone a significant change. The incidence of C. difficile has increased, not only in the healthcare sector but also in the community. Hospital-acquired infection and community-acquired disease have different risk factors, with the latter occurring in children and younger individuals without a history of antibiotic use or previous infections. From a clinician's perspective, a quick efficient diagnosis is required for patient treatment; however, the old method of using enzyme immunoassays is insensitive and not very specific. Recent literature around diagnostic testing for C. difficile infection suggests using PCR or a two-step algorithm to improve sensitivity and specificity. More failures and recurrence with metronidazole have led to treatment algorithms suggesting its use for mild infections and switching to vancomycin if there is no clinical improvement. Alternatively, if signs and symptoms suggest severe infection, then oral vancomycin is recommended as a first-line agent. The addition of a new but costly agent, fidaxomicin, has seen some disparity between the European and North American guidelines with regard to when it should be used. Lastly, rapid developments and good results with fecal microbial transplantation have also left clinicians wondering about its place in therapy. This article reviews the literature around some of the recent controversies in the field of C. difficile infection.
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Affiliation(s)
- Fawziah Marra
- University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada,
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Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2015; 31:431-55. [PMID: 20307191 DOI: 10.1086/651706] [Citation(s) in RCA: 2199] [Impact Index Per Article: 219.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Since publication of the Society for Healthcare Epidemiology of America position paper onClostridium difficileinfection in 1995, significant changes have occurred in the epidemiology and treatment of this infection.C. difficileremains the most important cause of healthcare-associated diarrhea and is increasingly important as a community pathogen. A more virulent strain ofC. difficilehas been identified and has been responsible for more-severe cases of disease worldwide. Data reporting the decreased effectiveness of metronidazole in the treatment of severe disease have been published. Despite the increasing quantity of data available, areas of controversy still exist. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, and infection control and environmental management.
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Affiliation(s)
- Stuart H Cohen
- Department of Internal Medicine, Division of Infectious and Immunologic Diseases, University of California Davis Medical Center, Sacramento, California, USA
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Wilcox MH. Editorial Commentary: The Trials and Tribulations of Treating Clostridium difficile Infection--One Step Backward, One Step Forward, but Still Progress. Clin Infect Dis 2014; 59:355-7. [DOI: 10.1093/cid/ciu316] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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IV ECO, III ECO, Johnson DA. Clinical update for the diagnosis and treatment of Clostridium difficile infection. World J Gastrointest Pharmacol Ther 2014; 5:1-26. [PMID: 24729930 PMCID: PMC3951810 DOI: 10.4292/wjgpt.v5.i1.1] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Revised: 10/06/2013] [Accepted: 12/09/2013] [Indexed: 02/06/2023] Open
Abstract
Clostridium difficile infection (CDI) presents a rapidly evolving challenge in the battle against hospital-acquired infections. Recent advances in CDI diagnosis and management include rapid changes in diagnostic approach with the introduction of newer tests, such as detection of glutamate dehydrogenase in stool and polymerase chain reaction to detect the gene for toxin production, which will soon revolutionize the diagnostic approach to CDI. New medications and multiple medical society guidelines have introduced changing concepts in the definitions of severity of CDI and the choice of therapeutic agents, while rapid expansion of data on the efficacy of fecal microbiota transplantation heralds a revolutionary change in the management of patients suffering multiple relapses of CDI. Through a comprehensive review of current medical literature, this article aims to offer an intensive review of the current state of CDI diagnosis, discuss the strengths and limitations of available laboratory tests, compare both current and future treatments options and offer recommendations for best practice strategies.
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Lam SW, Bass SN, Neuner EA, Bauer SR. Effect of vancomycin dose on treatment outcomes in severe Clostridium difficile infection. Int J Antimicrob Agents 2013; 42:553-8. [DOI: 10.1016/j.ijantimicag.2013.08.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 08/07/2013] [Accepted: 08/09/2013] [Indexed: 12/27/2022]
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Erikstrup LT, Danielsen TKL, Hall V, Olsen KEP, Kristensen B, Kahlmeter G, Fuursted K, Justesen US. Antimicrobial susceptibility testing of Clostridium difficile using EUCAST epidemiological cut-off values and disk diffusion correlates. Clin Microbiol Infect 2012; 18:E266-72. [PMID: 22672504 DOI: 10.1111/j.1469-0691.2012.03907.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
With the emergence of reduced susceptibility of Clostridium difficile to metronidazole and vancomycin the value of antimicrobial susceptibility testing has increased. The aim of our study was to evaluate disk diffusion for susceptibility testing of C. difficile by comparing disk diffusion results with MICs from gradient tests and to propose zone diameter breakpoint correlates for the EUCAST epidemiological cut-off values (ECOFFs) recently published. We tested 211 clinical isolates of C. difficile, from patients with diarrhoea hospitalized at Aarhus and Odense University Hospitals, Denmark. Furthermore, ten clinical isolates of C. difficile from the Anaerobe Reference Laboratory, University Hospital of Wales, with known reduced susceptibility to either metronidazole or vancomycin, were included. Isolates were tested with Etest gradient strips and disk diffusion towards metronidazole, vancomycin and moxifloxacin on Brucella Blood Agar supplemented with hemin and vitamin K. We found an excellent agreement between inhibition zone diameter and MICs. For each MIC value, the inhibition zones varied from 0 to 8 mm, with 93% of values within 6 mm for metronidazole, 95% of values within 4 mm for vancomycin, and 98% of values within 4 mm for moxifloxacin. With proposed zone diameter breakpoints for metronidazole, vancomycin and moxifloxacin of WT ≥ 23 mm, WT ≥ 19 and WT ≥ 20 mm, respectively, we found no very major errors and only major errors below 2%. In conclusion, we suggest that disk diffusion is an option for antimicrobial susceptibility testing of C. difficile.
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Affiliation(s)
- L T Erikstrup
- Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark.
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Cribb JL, O'Brien K, DeRemer CE. Rifaximin in Combination with Metronidazole and Oral Vancomycin for the Treatment of an Initial Episode of Clostridium difficile–Associated Diarrhea: Case Report and Literature Review. Hosp Pharm 2012. [DOI: 10.1310/hpj4703-206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Purpose Example of successful use of rifaximin in the treatment of an apparent Clostridium difficile infection refractory to vancomycin and metronidazole with literature review. Case Summary A 69-year-old Caucasian female developed C. difficile infectious diarrhea, confirmed by enzyme immunoassay (EIA) test. Following diagnosis, the patient was initiated on a treatment regimen of intravenous (IV) metronidazole and oral vancomycin. The patient sought additional medical treatment 3 days after initiating this treatment regimen. She presented with continued symptoms of diarrhea, bloating, anorexia, weakness, and leukocytosis nonresponsive to metronidazole and vancomycin. After a total of 7 days of treatment with metronidazole and vancomycin, the patient remained symptomatic with loose stools occurring approximately every 2 hours. Oral rifaximin 400 mg 3 times a day was added to the regimen, after which the patient's symptoms improved rapidly. Conclusion A patient with presumed C. difficile–associated diarrhea refractory to metronidazole and vancomycin was successfully treated after the addition of oral rifaximin 400 mg 3 times a day. Based on current literature and this case, rifaximin should not replace metronidazole or vancomycin as primary therapy for presumed or diagnosed C. difficile but should be retained as a useful alternative, especially in light of limited alternatives.
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Affiliation(s)
| | - Karly O'Brien
- Critical Care, Shands at the University of Florida, Gainesville, Florida
| | - Christina E. DeRemer
- Department of Pharmacy, Georgia Health Sciences Medical Center, Augusta, Georgia
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Rao S, Kupfer Y, Pagala M, Chapnick E, Tessler S. Systemic absorption of oral vancomycin in patients with Clostridium difficile infection. ACTA ACUST UNITED AC 2011; 43:386-8. [DOI: 10.3109/00365548.2010.544671] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Gonzales M, Pepin J, Frost EH, Carrier JC, Sirard S, Fortier LC, Valiquette L. Faecal pharmacokinetics of orally administered vancomycin in patients with suspected Clostridium difficile infection. BMC Infect Dis 2010; 10:363. [PMID: 21192802 PMCID: PMC3022836 DOI: 10.1186/1471-2334-10-363] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 12/30/2010] [Indexed: 12/17/2022] Open
Abstract
Background Oral vancomycin (125 mg qid) is recommended as treatment of severe Clostridium difficile infection (CDI). Higher doses (250 or 500 mg qid) are sometimes recommended for patients with very severe CDI, without supporting clinical evidence. We wished to determine to what extent faecal levels of vancomycin vary according to diarrhoea severity and dosage, and whether it is rational to administer high-dose vancomycin to selected patients. Methods We recruited hospitalized adults suspected to have CDI for whom oral vancomycin (125, 250 or 500 mg qid) had been initiated. Faeces were collected up to 3 times/day and levels were measured with the AxSYM fluorescence polarization immunoassay. Results Fifteen patients (9 with confirmed CDI) were treated with oral vancomycin. Patients with ≥4 stools daily presented lower faecal vancomycin levels than those with a lower frequency. Higher doses of oral vancomycin (250 mg or 500 mg qid) led to consistently higher faecal levels (> 2000 mg/L), which were 3 orders of magnitude higher than the MIC90 of vancomycin against C. difficile. One patient receiving 125 mg qid had levels below 50 mg/L during the first day of treatment. Conclusions Faecal levels of vancomycin are proportional to the dosage administered and, even in patients with increased stool frequency, much higher than the MIC90. Patients given the standard 125 mg qid dosage might have low faecal levels during the first day of treatment. A loading dose of 250 mg or 500 mg qid during the first 24-48 hours followed by the standard dosage should be evaluated in larger studies, since it might be less disruptive to the colonic flora and save unnecessary costs.
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Affiliation(s)
- Milagros Gonzales
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, 3001 12ème Avenue Nord, Sherbrooke, Quebec, Canada
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Kuijper E, Wilcox M. Editorial Commentary:Decreased Effectiveness of Metronidazole for the Treatment ofClostridium difficileInfection? Clin Infect Dis 2008; 47:63-5. [DOI: 10.1086/588294] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
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Pépin J, Valiquette L, Gagnon S, Routhier S, Brazeau I. Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027. Am J Gastroenterol 2007; 102:2781-8. [PMID: 17900327 DOI: 10.1111/j.1572-0241.2007.01539.x] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To reassess the comparative efficacy of vancomycin versus metronidazole in the treatment of Clostridium difficile-associated disease (CDAD) after the emergence in 2003 of the hypervirulent NAP1/027 strain. METHODS A retrospective cohort study was conducted in a tertiary-care Canadian hospital among 1,616 patients treated initially with metronidazole (N=1,360), vancomycin (N=219), or both (N=37), between 1991 and 2006, and followed for 60 days after diagnosis. Primary outcome was severe/complicated CDAD (SC-CDAD) defined as any of: (a) death within 30 days, (b) septic shock, (c) megacolon, (d) perforation, or (e) emergency colectomy. Adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were calculated, stratifying into pre-epidemic (1991-2002) and epidemic (2003-2006) periods. Secondary outcome was recurrence within 60 days. RESULTS Risk factors for SC-CDAD were the same in both periods: age>or=65 yr, male sex, immunosuppression, hospital acquisition, tube feeding, short duration of diarrhea, fever, elevated leukocytosis, or creatinine. Adjusting for confounders and using metronidazole therapy as baseline, vancomycin therapy was associated with a lower probability of developing SC-CDAD in 1991-2002 (AOR 0.21, 95% CI 0.05-0.99, P=0.048) but not during 2003-2006 (AOR 0.90, 95% CI 0.53-1.55, P=0.71). For both metronidazole and vancomycin, risk of recurrence increased in 2003-2004 but decreased in 2005-2006. CONCLUSIONS Loss of superiority of vancomycin over metronidazole coincided with the emergence of NAP1/027. Toxin hyperproduction by NAP1/027 might be such that the disease follows its natural course. Novel therapeutic approaches are needed. The higher risk of recurrence in 2003-2004 probably reflected reinfections rather than relapses.
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Affiliation(s)
- Jacques Pépin
- Department of Microbiology and Infectious Diseases, University of Sherbrooke, Sherbrooke, Quebec, Canada
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Affiliation(s)
- Paul R. Chadwick
- Department of Microbiology, Salford Royal Hospitals NHS Trust, Hope Hospital, Salford M6 8HD, UK
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Abstract
Clostridium difficile infection is a common and potentially lethal complication of antibiotic usage. Since the aetiology of antibiotic-associated colitis was discovered 14 years ago, two antibiotics in particular, metronidazole and vancomycin, have been used to treat C. difficile infection. Studies comparing the efficacy of these antibiotics are reviewed. It is now apparent that many of the so-called 'relapses' of C. difficile infection following antibiotic treatment are, in fact, re-infections. Such findings have major infection control implications.
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Affiliation(s)
- M H Wilcox
- Department of Experimental and Clinical Microbiology, University of Sheffield Medical School, UK
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