Treatment of Methicillin-sensitive Staphylococcus Aureus (MSSA) (CLINDOS)

Treatment of Methicillin-sensitive Staphylococcus Aureus Orthopaedic Infections With Clindamycin in Combination With Rifampin or Levofloxacin: a Randomized Pharmacological and Clinical Study (the CLINDOS Trial)

Background:

One of the leading causes of peri-operative osteoarticular infections (OAI) is Staphylococcus aureus. Treatment usually requires surgical debridement in association with appropriate antibiotic therapy. After surgery, an intravenous (IV) antibiotic therapy is routinely indicated for 10 to 15 days, followed by a minimal one-month oral treatment. In this protocol, the latter includes clindamycin in combination with rifampin or levofloxacin. Clindamycin is considered a good option in staphylococcal infections, because of its action against biofilm formation and bacterial adherence, its high level of joint and bone penetration and its good tolerance. Rifampin, a potent cytochrome P-450 inducer, enhances the elimination of a large number of drugs. Therefore, an influence of rifampin on clindamycin pharmacokinetics must be considered.

Objectives:

The primary objective is to compare the influence of rifampin and levofloxacin respectively on the pharmacokinetics of clindamycin in a randomized series of peri-operative staphylococcal OAI. The investigators then seek to determine the optimal drug association with regard to infection control and drug tolerance.

Study design:

Monocentric, randomized, open label, comparative study

Study period:

From November 2010 to October 2011.

Materials and Methods:

Following surgical debridement and after 10 to 15 days of IV antibiotherapy, patients are randomly assigned either to the "clindamycin/rifampin" arm either to the "clindamycin/levofloxacin" arm, according to the antimicrobial susceptibility testing. Peak and trough serum concentrations of clindamycin are measured at day-1, day-15 and day-30 of oral treatment. Rifampin and levofloxacin serum concentrations are measured at the same intervals to monitor patient compliance.

Study Overview

• Status: Completed
• Conditions: Osteoarticular Infection
• Intervention / Treatment: Drug: association of RIFAMPIN + CLINDAMYCIN; Drug: association of LEVOFLOXACIN+ CLINDAMYCIN

Detailed Description

Background:

One of the leading causes of peri-operative osteoarticular infections (OAI) is Staphylococcus aureus. Treatment usually requires surgical debridement in association with appropriate antibiotic therapy. After surgery, an intravenous (IV) antibiotic therapy is routinely indicated for 10 to 15 days, followed by a minimal one-month oral treatment. In this protocol, the latter includes clindamycin in combination with rifampin or levofloxacin. Clindamycin is considered a good option in staphylococcal infections, because of its action against biofilm formation and bacterial adherence, its high level of joint and bone penetration and its good tolerance. Rifampin, a potent cytochrome P-450 inducer, enhances the elimination of a large number of drugs. Therefore, an influence of rifampin on clindamycin pharmacokinetics must be considered.

Objectives:

The primary objective is to compare the influence of rifampin and levofloxacin respectively on the pharmacokinetics of clindamycin in a randomized series of peri-operative staphylococcal OAI. The investigators then seek to determine the optimal drug association with regard to infection control and drug tolerance. Study design: monocentric, randomized, open label, comparative study

Study period:

From November 2010 to October 2011.

Materials and Methods:

Following surgical debridement and after 10 to 15 days of IV antibiotherapy, patients are randomly assigned either to the "clindamycin/rifampin" arm either to the "clindamycin/levofloxacin" arm, according to the antimicrobial susceptibility testing. Peak and trough serum concentrations of clindamycin are measured at day-1, day-15 and day-30 of oral treatment. Rifampin and levofloxacin serum concentrations are measured at the same intervals to monitor patient compliance. Infection cure is evaluated clinically, with periodic X-rays and CRP dosage in serum.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Assistance Publique Hopitaux de Paris

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• subject over 18 years with a IOA with GERME sensitivity to three antibiotics,
• Patient in orthopedic unit of HEGP,
• Patient who received and understood the information and who signed consent,

Exclusion Criteria:

• Known allergy to one of three antibiotics and / or excipients,
• Pregnancy or during lactation,
• Congenital galactosemia, malabsorption of glucose and galactose, or lactase deficiency,
• History of tendinopathy with fluoroquinolones,
• G6PD deficiency,
• porphyria,
• subject receiving a protease inhibitor,
• subject receiving anticoagulants
• Malabsorption syndrome,
• subject unable to follow the protocol (organizational problem, intellectual disability, ...).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RIFAMPIN; CLINDAMYCIN + RIFAMPIN	Drug: association of RIFAMPIN + CLINDAMYCIN; association of RIFAMPIN + CLINDAMYCIN; Other Names: RIFAMPIN
Active Comparator: LEVOFLOXACIN; CLINDAMYCIN + LEVOFLOXACIN	Drug: association of LEVOFLOXACIN+ CLINDAMYCIN; association of LEVOFLOXACIN+ CLINDAMYCIN; Other Names: LEVOFLOXACIN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of peak and trough serum concentrations of clindamycin	Measurement of peak and trough serum concentrations of clindamycin will be performed at Day 1, Day 15 and Day 30	1 month

Secondary Outcome Measures

Outcome Measure	Time Frame
proportion of patients healing (as determined from absence of fever, absence of pain and favorable aspect of scar).	Day 30

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Director: Brigitte Sabatier, PD, PhD, Department of Pharmacology

Publications and helpful links

General Publications

• Bernard A, Kermarrec G, Parize P, Caruba T, Bouvet A, Mainardi JL, Sabatier B, Nich C. Dramatic reduction of clindamycin serum concentration in staphylococcal osteoarticular infection patients treated with the oral clindamycin-rifampicin combination. J Infect. 2015 Aug;71(2):200-6. doi: 10.1016/j.jinf.2015.03.013. Epub 2015 Apr 30.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: November 28, 2011
• First Submitted That Met QC Criteria: December 28, 2011
• First Posted (Estimate): December 29, 2011

Study Record Updates

• Last Update Posted (Estimate): September 18, 2013
• Last Update Submitted That Met QC Criteria: September 17, 2013
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: Staphylococcus aureus; orthopedic surgery; clindamycin; serum concentration; osteoarticular infection
• Additional Relevant MeSH Terms: Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Protein Synthesis Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Rifampin; Clindamycin; Clindamycin palmitate; Clindamycin phosphate; Levofloxacin; Ofloxacin
• Other Study ID Numbers: K000000