Linezolid: safety and efficacy in special populations.
Gould F Kate
The Journal of antimicrobial chemotherapy
Linezolid has been in general use in the UK since 2000. Although toxicity, particularly haematological and neurological, has been an issue, linezolid has proved to be an effective alternative to glycopeptides in the treatment of Gram-positive infections. Since its original licence for the treatment of skin and soft tissue infections and pneumonia, there have been reports of its successful use in the treatment of bone and joint infections, endocarditis, and other difficult-to-treat infections.
10.1093/jac/dkr071
Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement.
Lovering A M,Zhang J,Bannister G C,Lankester B J A,Brown J H M,Narendra G,MacGowan A P
The Journal of antimicrobial chemotherapy
Twelve patients undergoing total hip replacement were given 600 mg of linezolid as a 20 min iv infusion along with conventional prophylaxis of 1 g of cefamandole immediately before surgery. Routine total hip arthroplasty was carried out, and at timed intervals during surgery samples of bone, fat, muscle and blood were collected for assay by high-performance liquid chromatography analysis. Samples of the haematoma fluid that formed around the operation site and further blood samples for assay were also collected at timed intervals following the operation. The penetration of linezolid into bone was rapid, with mean concentrations of 9.1 mg/L (95% CI 7.7-10.6 mg/L) achieved at 10 min after the infusion, decreasing to 6.3 mg/L (95% CI 3.9-8.6 mg/L) at 30 min. Correction for the simultaneous blood concentrations gave mean values for bone penetration of 51% at 10 min, 60% at 20 min and 47% at 30 min. Although the penetration of linezolid into fat was also rapid, mean concentrations and degree of penetration were c. 60% of those in bone; at 10 min they were 4.5 mg/L (95% CI 3.0-6.1 mg/L; penetration 27%); at 20 min they were 5.2 mg/L (95% CI 4.0-6.4 mg/L; penetration 37%); and at 30 min, 4.1 mg/L (95% CI 3.3-4.8 mg/L; penetration 31%). For muscle the corresponding values were 10.4 mg/L (95% CI 8.1-12.7 mg/L; penetration 58%) at 10 min, 13.4 mg/L (95% CI 10.2-16.5 mg/L; penetration 94%) at 20 min and 12.0 mg/L (95% CI 9.2-14.8 mg/L; penetration 93%) at 30 min. Mean concentrations of linezolid in the haematoma fluid drained from around the operation site were 8.2 mg/L at 6-8 h and 5.6 mg/L at 10-12 h after the infusion, and 7.0 mg/L at 2-4 h following a second 600 mg infusion given 12 h post-operatively. We conclude that linezolid exhibits rapid penetration into bone, fat and muscle of patients undergoing hip arthroplasty, to achieve levels in excess of its MIC for susceptible organisms (< or=4 mg/L); therapeutic concentrations were maintained in the haematoma fluid that surrounds the operation site for >16 h.
10.1093/jac/dkf066
Clinical experience of linezolid in bone marrow transplantation patients.
Hogan Holly L,Hachem Ray Y,Neuhauser Melinda,Raad Issam I,Coyle Elizabeth
Journal of pharmacy practice
Linezolid is an oxazolidinone antibiotic that has been associated with myelosuppression, including leukopenia and thrombocytopenia. Few studies have assessed the use of linezolid in bone marrow transplantation (BMT) patients. The authors evaluated patients who were admitted to the BMT service at their institution from 2001 to 2002 and had undergone ≥3 days of linezolid therapy. These patients (cases) were matched with BMT patients who had not undergone linezolid therapy (controls). Forty-nine patients were evaluated; 25 cases and 24 controls. The authors found no significant differences in the duration of neutropenia or thrombocytopenia, but there was a trend toward a difference in time to engraftment (P = .16). More bleeding episodes were seen and more platelet transfusions were needed in cases than in controls (16% vs 8%; P = .35 and 54.5 ± 55.0 units vs 19.9 ± 20.0 units, respectively). Patients who had undergone linezolid therapy for >10 days (n = 10) had longer thrombocytopenia (102.2 ± 98.0 vs 62.0 ± 61.0 days; P = .27) and time to engraftment (20.5 ± 20.0 vs 10.7 ± 2.0 days; P = .16) and required more platelet transfusions (83.6 ± 76.0 vs 35.1 ± 23.0 units). None of these observations reached statistical significance. The authors conclude that linezolid therapy can be used safely in BMT patients for up to 10 days. However, when therapy is needed for >10 days, monitoring of platelet counts, bleeding time, and time to engraftment are recommended.
10.1177/0897190009358773
Linezolid for the treatment of adults with bone and joint infections.
Falagas Matthew E,Siempos Ilias I,Papagelopoulos Panayiotis J,Vardakas Konstantinos Z
International journal of antimicrobial agents
We reviewed the available evidence regarding the effectiveness and safety of linezolid administration for the treatment of patients with orthopaedic infections due to multidrug-resistant Gram-positive cocci. Although the reports published to date include promising results for the use of linezolid for bone and joint infections, controlled studies will be needed to reach safe conclusions. Attention should be paid to adverse effects that may be related to linezolid administration, especially bone marrow suppression with prolonged administration of the antibiotic. In addition, early identification of linezolid-induced peripheral neuropathy is necessary because this may be an irreversible event.
10.1016/j.ijantimicag.2006.08.030
Penetration of linezolid into bone tissue 24 h after administration in patients with multidrug-resistant spinal tuberculosis.
Li Yuan,Huang Hairong,Dong Weijie,Lan Tinglong,Fan Jun,Wen Shu'an,Zhang Tingting,Qin Shibing,Guo Ai
PloS one
BACKGROUND:Linezolid has shown strong antimicrobial activity against multidrug-resistant (MDR)/rifampin-resistant strains of Mycobacterium tuberculosis. Linezolid achieves clinical efficacy mainly through area under the concentration time curve/minimum inhibitory concentration ratio in the infected lesion site. Previous studies mainly focused on the relationship between linezolid concentrations in the blood and infected bone tissue when the blood drug concentration reached the peak 2 h after administration. However, we do not know whether linezolid can maintain the same bone/plasma ratio in infected bone tissue when the blood concentration reaches the trough level. Therefore, this study aimed to evaluate the penetrability of linezolid into bone tissue 24 h after administration in patients with MDR spinal tuberculosis (TB). METHODS:Nine MDR spinal TB patients, who received a treatment regimen including linezolid and underwent surgery, were enrolled prospectively from April 2017 to March 2019. Blood and diseased bone tissue specimens were collected simultaneously during operations 24 h after taking 600 mg of linezolid orally. Linezolid concentrations in plasma and diseased bone tissue specimens were determined by high-performance liquid chromatography-tandem mass spectrometry. RESULTS:Following a 600 mg oral administration of linezolid 24 h before surgery, median concentrations of linezolid in plasma and diseased bone tissue for the 9 patients were 1.98 mg/L (range 0.30-3.44 mg/L) and 0.60 mg/L (range 0.18-2.13 mg/L), respectively, at resection time. The median diseased bone/plasma linezolid concentration ratio was 0.48 (range 0.30-0.67). Pearson's correlation analysis showed that linezolid concentrations in the plasma were positively related to those in diseased bone tissue (r = 0.949, p < 0.001). CONCLUSIONS:After 24 h of medication, linezolid still had good penetrability into diseased bone tissue in patients with MDR spinal TB.
10.1371/journal.pone.0223391
Clinical, Bacteriological, and Genetic Characterization of Bone and Joint Infections Involving Linezolid-Resistant Staphylococcus epidermidis: a Retrospective Multicenter Study in French Reference Centers.
Microbiology spectrum
The choice of the best probabilistic postoperative antibiotics in bone and joint infections (BJIs) is still challenging. Since the implementation of protocolized postoperative linezolid in six French referral centers, linezolid-resistant multidrug-resistant Staphylococcus epidermidis (LR-MDRSE) strains were isolated in patients with BJI. We aimed here to describe clinical, microbiological, and molecular patterns associated with these strains. All patients with at least one intraoperative specimen positive for LR-MDRSE between 2015 and 2020 were included in this retrospective multicenter study. Clinical presentation, management, and outcome were described. LR-MDRSE strains were investigated by MIC determination for linezolid and other anti-MRSA antibiotics, characterization of genetic determinants of resistance, and phylogenetic analysis. Forty-six patients (colonization = 10, infection = 36) were included in five centers, 45 had prior exposure to linezolid, 33 had foreign devices. Clinical success was achieved for 26/36 patients. Incidence of LR-MDRSE increased over the study period. One hundred percent of the strains were resistant to oxazolidinones, gentamicin, clindamycin, ofloxacin, rifampicin, ceftaroline, and ceftobiprole, and susceptible to cyclins, daptomycin, and dalbavancin. Susceptibility to delafloxacin was bimodal. Molecular analysis was performed for 44 strains, and the main mutation conferring linezolid resistance was the 23S rRNA G2576T mutation. All strains belonged to the sequence type ST2 or its clonal complex, and phylogenetic analysis showed emergence of five populations corresponding geographically to the centers. We showed the emergence of new clonal populations of highly linezolid-resistant S. epidermidis in BJIs. Identifying patients at risk for LR-MDRSE acquisition and proposing alternatives to systematic postoperative linezolid use are essential. The manuscript describes the emergence of clonal linezolid-resistant strains of Staphylococcus epidermidis (LR-MDRSE) isolated from patients presenting with bone and joint infections. Incidence of LR-MDRSE increased over the study period. All strains were highly resistant to oxazolidinones, gentamicin, clindamycin, ofloxacin, rifampicin, ceftaroline, and ceftobiprole, but were susceptible to cyclins, daptomycin, and dalbavancin. Susceptibility to delafloxacin was bimodal. The main mutation conferring linezolid resistance was the 23S rRNA G2576T mutation. All strains belonged to the sequence type ST2 or its clonal complex, and phylogenetic analysis showed emergence of five populations corresponding geographically to the centers. LR-MDRSE bone and joint infections seem to be accompanied by an overall poor prognosis related to comorbidities and therapeutic issues. Identifying patients at risk for LR-MDRSE acquisition and proposing alternatives to systematic postoperative linezolid use become essential, with a preference for parenteral drugs such as lipopeptids or lipoglycopeptids.
10.1128/spectrum.04190-22
Differential distribution of linezolid in diseased and nondiseased bones in patients with spinal tuberculosis.
BMC infectious diseases
BACKGROUND:Linezolid exhibits antibacterial activity against sensitive and drug-resistant strains of Mycobacterium tuberculosis. Knowledge on the distribution of linezolid in different types of bones in patients with spinal tuberculosis (TB) is lacking, which limits the pharmacokinetic and pharmacodynamic studies of linezolid. This study aimed to evaluate the distribution of linezolid in diseased and nondiseased bones in patients with spinal TB. METHODS:Spinal TB patients treated with linezolid-containing regimens and whose diseased and nondiseased bones were collected during surgery were enrolled retrospectively from January 2017 to February 2022. Blood, nondiseased bones, and diseased bones were collected simultaneously during the operation. Linezolid concentrations in the plasma, nondiseased bones, and diseased bones were subjected to high-performance liquid chromatography-tandem mass spectrometry. RESULTS:Seven eligible spinal TB patients, including one rifampicin-resistant case, were enrolled. Following a 600 mg oral administration of linezolid before surgery, the median concentrations of linezolid in plasma, nondiseased bone, and diseased bone of the seven patients were 8.23, 1.01, and 2.13 mg/L, respectively. The mean ratios of linezolid concentration in nondiseased bones/plasma, diseased bones/plasma and diseased bones/nondiseased bones reached 0.26, 0.49, and 2.27, respectively. The diseased bones/plasma presented a higher mean ratio of linezolid concentration than nondiseased bones/plasma, and the difference was statistically significant (t = 2.55, p = 0.025). Pearson's correlation analysis showed the positively correlation of linezolid concentrations in diseased and nondiseased bones (r = 0.810, p = 0.027). CONCLUSIONS:Linezolid exhibits a higher concentration distribution in diseased bones than in nondiseased bones.
10.1186/s12879-023-08970-x
Prolonged use of linezolid in bone and joint infections: a retrospective analysis of adverse effects.
The Journal of antimicrobial chemotherapy
OBJECTIVES:Antibiotic treatment for bone and joint infections generally lasts for 6 weeks or longer. Linezolid may be a good option for treating bone and joint infections, but there is an increased risk of potential serious adverse drug events (ADEs) when used for more than 28 days. The aim of this study was to obtain detailed information on the type and time to occurrence of the patient-reported ADEs, the dynamics of haematopoiesis over time, and the reasons for early discontinuation of linezolid when used for an intended maximum duration of 12 weeks. METHODS:This single-centre retrospective study was conducted at the Sint Maartenskliniek in The Netherlands. Patients were included if they were planned to use linezolid for more than 28 days. The main reason for discontinuation of linezolid, the ADE according to the Naranjo score, and the time to occurrence of ADEs were analysed. RESULTS:Among 78 patients, drug toxicity led to early discontinuation of linezolid in 11 (14%) patients before and nine (12%) after 28 days of therapy. The median treatment duration was 42 days. Gastrointestinal intolerance (42%) and malaise (32%) were the most common ADEs. In 75% of the cases the ADE occurred within 28 days of therapy. Sixty-seven patients were able to continue linezolid beyond 28 days, 87% of whom completed therapy as scheduled. Severe cytopenia, according to the Common Terminology Criteria for Adverse events (CTCA), was observed in four patients and was reversible after discontinuation of linezolid. One patient suffered optic neuropathy related to linezolid use. CONCLUSIONS:Linezolid could be considered an alternative option to the current standard of IV glycopeptides for the treatment of bone and joint infection for up to 12 weeks. If patients pass the first 28 days of therapy, the likelihood of successful completion of therapy is high with a low risk of serious ADEs.
10.1093/jac/dkad276
Safety and clinical efficacy of linezolid in children: a systematic review and meta-analysis.
World journal of pediatrics : WJP
BACKGROUND:We aimed to evaluate the tolerability and efficacy of linezolid in children for treating suspected and diagnosed Gram-positive bacterial infections. METHODS:A systematic literature search was conducted up to April 23, 2021, using linezolid and its synonyms as search terms. Two reviewers independently identified and extracted relevant randomized controlled trials and prospective cohort studies. The extracted studies were included in a single-rate meta-analysis of adverse events and clinical outcomes using random-effects models. RESULTS:A total of 1082 articles were identified, and nine studies involving 758 children were included in the meta-analysis. The overall proportion of adverse events was 8.91% [95% confidence interval (CI) = 1.64%-36.52%], with diarrhea (2.24%), vomiting (2.05%), and rash (1.72%) being the most common. The incidences of thrombocytopenia and anemia were 0.68% and 0.16%, respectively. Some specific adverse events, including rash and gastrointestinal events, were more frequent in the oral administration subgroup. In terms of efficacy, the overall proportion of clinical improvement was 88.80% (95% CI = 81.31%-93.52%). Children with a history of specific bacteriological diagnosis or concomitant antibiotic therapy had a 1.13-fold higher clinical improvement than children without such histories. The proportion of microbial eradication was 92.68% (95% CI = 84.66%-96.68%). The proportion of all-cause mortality was 0.16% (95% CI = 0.00%-7.75%). CONCLUSIONS:Linezolid was well-tolerated in pediatric patients and was associated with a low frequency of adverse events, such as anemia, thrombocytopenia, and neutropenia. Moreover, linezolid was effective in children with diagnosed and suspected Gram-positive infections.
10.1007/s12519-022-00650-1