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      Clinical use of linezolid in periprosthetic joint infections – a systematic review

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          Abstract

          Introduction: The most common causative organism in periprosthetic joint infections (PJIs) is Gram-positive bacteria that are increasingly drug resistant. In these cases the use of linezolid may be warranted. However, there are conflicting reports regarding its role in antibiotic treatment of PJIs. The aim of this review is to gather and analyze clinical results and treatment details on linezolid in patients with PJIs. Methods: In August 2019, a comprehensive literature search using MEDLINE (Pubmed and Ovid) and Cochrane Library was performed. A total of 504 records were screened, and a total of 16 studies including 372 patients treated with linezolid for a PJI were included in this review based on the PRISMA criteria and after quality analysis using the MINOR score and Newcastle–Ottawa scale, as well as assessing level of evidence. Pooling analysis as well as descriptive analysis was performed. Results: Based on the results from the studies included, infection control was achieved in 80 % (range 30 %–100 %) of patients after a mean follow-up period of 25 (range 2–66) months. The mean duration of treatment was 58 d intravenous and orally at a median dose of 600 mg bis in die (b.i.d.) (range 400–900 b.i.d.). A combination therapy with rifampicin was used in 53 % of patients. MRSA (methicillin-resistant Staphylococcus aureus) infections were present in 29 % and resistant CoNS (coagulase-negative Staphylococcus) in 46 %. Adverse effects occurred in 33 % of cases, mostly anemia, thrombocytopenia and gastrointestinal complaints leading to treatment discontinuation in 9 %. However, great heterogeneity was found with respect to surgical treatment, diagnosis of infection and indication for linezolid. Discussion: Linezolid is an appropriate option for treatment of resistant Gram-positive organisms in PJIs. Most commonly 600 mg b.i.d. is used, and a combination with rifampicin appears feasible although one must consider individual increases in doses in these cases. However, adverse effects are common and there are limited data for long-term use and optimal antibiotic combinations or individual doses.

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          Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients.

          Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid. We performed a retrospective study of patients who had trough (C(min)) and peak (C(max)) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C(min) ≥10 mg/L and/or AUC₂₄ ≥400 mg/L · h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C(min) [3.71 mg/L (1.43-6.38) versus 1.37 mg/L (0.67-2.55), P < 0.001] or AUC₂₄ [212.77 mg/L · h (166.67-278.42) versus 123.33 mg/L · h (97.36-187.94), P < 0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid + rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)-guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of C(min) of 6.53 mg/L and/or of AUC₂₄ of 280.74 mg/L · h. Maintenance over time of C(min) between 2 and 7 mg/L and/or of AUC₂₄ between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.
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            The Role of Rifampin against Staphylococcal Biofilm Infections in Vitro, in Animal Models, and in Orthopedic Device-Related Infections.

            Rifampin has been used as an agent in combination therapy in orthopedic device-related infections (ODRI) for almost three decades. The aim of this review is to provide data regarding the role of rifampin against biofilm infection in vitro , in animal models, and in clinical ODRI. Available data are gathered in order to present the rational use of rifampin combinations in patients with periprosthetic joint infection (PJI). In-vitro data, animal data and available clinical data in the field of staphylococcal PJI will be reviewed. The role of rifampin is well-defined in patients with PJI and is indicated in those who fulfill the Infectious Diseases Society of America criteria for debridement and implant retention or one-stage exchange. It should be used with care because of the danger of rapid emergence of resistance. Potential drug interactions should be considered.
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              Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement)

              Background For the diagnosis of prosthetic joint infection, real evidence-based guidelines to aid clinicians in choosing the most accurate diagnostic strategy are lacking. Aim and Methods To address this need, we performed a multidisciplinary systematic review of relevant nuclear medicine, radiological, orthopaedic, infectious, and microbiological literature to define the diagnostic accuracy of each diagnostic technique and to address and provide evidence-based answers on uniform statements for each topic that was found to be important to develop a commonly agreed upon diagnostic flowchart. Results and Conclusion The approach used to prepare this set of multidisciplinary guidelines was to define statements of interest and follow the procedure indicated by the Oxford Centre for Evidence-based Medicine (OCEBM). Electronic supplementary material The online version of this article (10.1007/s00259-019-4263-9) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Journal
                J Bone Jt Infect
                J Bone Jt Infect
                JBJI
                Journal of Bone and Joint Infection
                Copernicus GmbH
                2206-3552
                13 July 2020
                2020
                : 6
                : 1
                : 7-16
                Affiliations
                [1]Department of Orthopedics and Tumor Orthopedics, Muenster University Hospital, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
                Author notes
                [*] Correspondence: Christoph Theil ( christoph.theil@ 123456ukmuenster.de )
                Article
                01021829
                10.5194/jbji-6-7-2020
                7517662
                32983842
                1c7de3b0-143a-4e56-a6dd-ba3f3c7c9597
                Copyright: © 2020 Christoph Theil et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/

                History
                : 16 March 2020
                : 20 June 2020
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