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Clindamycin-rifampin Drug Interaction in the Treatment of Bone and Joint Infections (CLIRIFA)

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ClinicalTrials.gov Identifier: NCT02629770
Recruitment Status : Recruiting
First Posted : December 14, 2015
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
Fondation Ophtalmologique Adolphe de Rothschild
Information provided by (Responsible Party):
Groupe Hospitalier Diaconesses Croix Saint-Simon

Brief Summary:
Treatment of bone and joint infections remains difficult and variable according to centres and countries. Clindamycin given intravenously and followed by an oral route is recommended for the treatment of staphylococcal, streptococcal and anaerobes bone and joint infections by the French Society for Infectious Diseases. For staphylococcal bone and implant infections, rifampin is a major drug, as it remains active in bacterial biofilm and on quiescent staphylococci. For that reasons, clindamycin-rifampin combination therapy is frequently used in these infections.Clindamycin is metabolized by the P450 3A4 cytochrome, an enzyme strongly inducible by rifampin. A retrospective study published in 2010 on 70 patients treated for bone and joint infections showed that clindamycin serum concentrations were significantly lower when clindamycin was combined with rifampin (5.3 mg/liter vs 8.9 mg/liter; p<0.02). This drug interaction could even be stronger with the oral route, because of hepatic first-past effect, ending up with very low clindamycin serum concentration, a risk of selecting resistant microorganisms and treatment failure. This latter point is an important issue, because clindamycin has an excellent oral bioavailability and is frequently used in oral regimens. In the above study, a wide variability of clindamycin serum concentration was observed in the group of patients treated with combination therapy (1-12mg/l) suggesting interindividual variability. Rifampin induction of CYP 450 3A4/A5 depends on different receptor (PXR, RXR, LXRalpha) submitted to genetic polymorphism. Hypothesis: Plasma clearance of clindamycin (CLclin) combined with rifampicin (CLclinrif) is higher when clindamycin is administered by the oral route (CLclinrif OR) compared with IV administration (CLclinrif IV).

Condition or disease Intervention/treatment
Arthritis, Infectious Bone Diseases, Infectious Drug: usual antibiotic treatment

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Study Type : Observational
Estimated Enrollment : 40 participants
Observational Model: Ecologic or Community
Time Perspective: Cross-Sectional
Official Title: Clindamycin-Rifampin Interactions: Effect of Rifampin's Enzyme-induction (Cytochrome P450 3A4/3A5) on Plasma Clindamycin Concentrations, With Clindamycin Given Intravenously and Orally to Treat Bone-and-joint Infections
Actual Study Start Date : December 2015
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions


Intervention Details:
  • Drug: usual antibiotic treatment
    pharmacological studies in patients treated with usual antibiotics, for different types of joint and bone infections


Primary Outcome Measures :
  1. mean clearances of clindamycin [ Time Frame: 3 weeks ]
    The principal evaluation criterion is the mean clearances of clindamycin with and without administration of rifampin (intravenous or oral administration)

  2. mean clearances of clindamycin [ Time Frame: 5 weeks ]
    The principal evaluation criterion is the mean clearances of clindamycin with and without administration of rifampin (intravenous or oral administration)


Secondary Outcome Measures :
  1. plasma concentrations of IV- or PO-administered clindamycin, combined or not with rifampin. [ Time Frame: 3 weeks ]
  2. plasma concentrations of IV- or PO-administered clindamycin, combined or not [ Time Frame: 5 weeks ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
patients hospitalized for medical-surgical management of OAIs in the Department of Trauma and Bone Surgery
Criteria

Inclusion Criteria:

  • age ≥18 years
  • surgical management of OAI
  • Postoperative IV antibiotic therapy for 10±2 days
  • Chronic bone and/or joint infection (evolving for >4 weeks) with bacteriologically documented staphylococci, streptococci or susceptible anaerobes in skin flora susceptible to clindamycin and rifampin
  • Continuation of IV administration possible for a maximum of 25 days
  • Patient consent to participate in the study
  • Patients entitled enrolled to a French National Health Insurance

Exclusion Criteria:

  • Allergy or intolerance to the family of antibiotics used, i.e. lincosamides (clindamycin, lincomycin) and rifamycins (rifampin), or to one of their constituents
  • Taking active products able to induce CYP3A4/3A5: alcohol (chronic intake), anti-seizure drugs (carbamazepine, phenobarbital, phenytoin), anti-infectious agents (rifabutin, efavirenz, nevirapine, griseofulvin), anti-fungals (ketoconazole, itraconazole, voriconazole, posaconazole, fluconazole, miconazole), calcium channel blockers (diltiazem, verapamil), macrolides (erythromycin, clarithromycin, josamycin, telithromycin)
  • Being treated with one of the following: cyclosporine and/or tacrolimus (immunosuppressants) ; midazolam (psychotropic agents)
  • Human immunodeficiency virus-positive patient being treated with protease inhibitors (ritonavir, amprenavir, atazanavir, indinavir, nelfinavir, lopinavir, saquinavir) or delavirdine
  • Cirrhosis, hepatocellular insufficiency
  • Creatinine clearance < 30 mL/min (according to the cockcroft and gault formula)
  • Severe sepsis (systolic blood pressure (SBP) <90 mm Hg; O2 saturation <90%, encephalopathy, oligo-anuria, creatininemia >176 mmol/L, platelets <100,000/mm3, INR >1.5, Glasgow coma score <13) or septic shock (persistent hypotension despite volumetric filling) at arrival in the unit
  • Porphyria
  • Congenital galactosemia, glucose and galactose malabsorption syndrome, lactase deficit because of the presence of lactose in the dalacin® capsules
  • Intolerance of fructose, glucose and galactose malabsorption syndrome, sucrase-isomaltase deficit because of the presence of saccharose in the rifadin® capsules
  • Major cognitive disorders, according to the DSM IV-TR (Diagnostic and Statistical Manual of Mental Disorders) definition (36)
  • Weight >100 kg or <50 kg
  • Woman of childbearing age using estrogen-progestin contraception and not wanting to switch to an effective mechanical-type contraceptive method
  • Pregnancy or breast-feeding
  • Patient under guardianship

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02629770


Contacts
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Contact: Valerie ZELLER, MD vzeller@hopital-dcss.org

Locations
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France
GH Diaconesses Croix Saint Simon Recruiting
Paris, Ile De France, France, 75012
Contact: Valerie ZELLER, MD       vzeller@hopital-dcss.org   
Sponsors and Collaborators
Groupe Hospitalier Diaconesses Croix Saint-Simon
Fondation Ophtalmologique Adolphe de Rothschild

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Responsible Party: Groupe Hospitalier Diaconesses Croix Saint-Simon
ClinicalTrials.gov Identifier: NCT02629770     History of Changes
Other Study ID Numbers: VZR_2014-3
First Posted: December 14, 2015    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Additional relevant MeSH terms:
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Clindamycin
Clindamycin palmitate
Clindamycin phosphate
Infection
Communicable Diseases
Bone Diseases, Infectious
Arthritis, Infectious
Bone Diseases
Arthritis
Joint Diseases
Musculoskeletal Diseases
Anti-Bacterial Agents
Rifampin
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Protein Synthesis Inhibitors