Tolerability Of Linezolid Research Articles

Linezolid Tolerability in Drug Resistant TB Patients and Its Future use in all Oral Shorter Regimens

Linezolid (Lzd) belongs to group of Oxazolidinones a repurposed drug to treat Drug resistant TB (DR TB). WHO in 2019 placed Lzd in Group A Drugs along with Levofloxacin/Moxifloxacin and Bedaquiline as most effective drugs to treat RR/MDR TB. The RR/MDR TB regimen should be constructed with a combination of at least 4 likely effective drugs. The toxicity profile of Lzd may feature from 22% to 80% and among most common toxicities are myelosuppression and neuropathy and such frequent toxicities lead from temporary interruption to permanent discontinuation of Lzd during RR/MDR TB treatment. The median time to development of toxicity is around 5-6 months of treatment but toxicity may occur even during early weeks of treatment. The Linezolid (Lzd) usual dose of 600 mg OD is also used for <28 days to treat various gram-positive infections. Linezolid toxicity is frequent but relatively easy to detect and manage and is reversible other than complete nerve damage if not detected early and drug interrupted timely. Linezolid (600 mg daily) is also part of WHO recommended BPaLM and BPaL regimens which are safe, shorter, low cost and highly effective as future RR/MDR TB treatment. To ensure safety of patients all TB programs must ensure appropriate adverse drug safety, monitoring and management (DSM) mechanism as essential component of Drug resistance TB treatment.

The Safety and Tolerability of Linezolid in Novel Short-Course Regimens Containing Bedaquiline, Pretomanid, and Linezolid to Treat Rifampicin-Resistant Tuberculosis: An Individual Patient Data Meta-analysis.

Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials. A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid. Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3-4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid. Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.

Efficacy and safety profile of linezolid in the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis: a systematic review and meta-analysis.

BackgroundTreatment options for drug-resistant tuberculosis are still limited. Linezolid has been recommended for treatment of patients with multidrug-resistant (MDR) or extensively-drug-resistant (XDR) tuberculosis, although uncertainties remain regarding its safety and tolerability in these circumstances.ObjectiveTo systematically evaluate the existing evidence regarding the efficacy and tolerability of linezolid in the treatment of MDR or XDR tuberculosis.MethodsWe conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines. Searches were conducted in PubMed, Web of Science and EMBASE followed by direct search of abstracts in the International Journal of Tuberculosis and Lung Disease to retrieve primary studies published between January 2000 and January 2016 assessing linezolid efficacy and safety in the treatment of drug-resistant TB. We evaluated the occurrence of outcomes including culture conversion, treatment success and incidence of adverse events such as myelosuppression and neuropathy.ResultsTwenty-three (23) studies conducted in fourteen (14) countries and involving 507 patients were retrieved. Only 1 randomized controlled trial was identified and none of the identified studies involved participants from Africa. The pooled proportion for treatment success was 77.36 % (95 % CI = 71.38–82.83 %, I2 = 37.6 %) with culture conversion rate determined as 88.45 % (95 % CI = 83.82–92.38 %, I2 = 45.4 %). There was no strong evidence for both culture conversion (p = 0.0948) and treatment success (p = 0.0695) between linezolid daily doses ≤ 600 and > 600 mg. Only myelosuppression showed a strong statistical significance (p < 0.0001) between dose comparisons. The incidence of neuropathy and other adverse events leading to permanent discontinuation of linezolid also showed no significance upon dose comparisons (p = 0.3213, p = 0.9050 respectively).ConclusionAvailable evidence presents Linezolid as a viable option in the treatment of MDR/XDR TB although patients ought to be monitored closely for the incidence of major adverse events such as myelosuppression and neuropathy. Additionally, highly powered randomized controlled trials including participants from endemic regions are urgently needed to better inform the magnitude and significance of Linezolid treatment effect in MDR and XDR TB patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12941-016-0156-y) contains supplementary material, which is available to authorized users.

Bicytopenia, especially thrombocytopenia in hemodialysis and non-hemodialysis patients treated with linezolid therapy.

One of the major adverse events associated with linezolid treatment is pancytopenia. However, there are few reports about the tolerability of linezolid among patients undergoing hemodialysis. This study retrospectively investigated the frequency of bicytopenia (thrombocytopenia and erythropenia) secondary to linezolid treatment in patients undergoing and not-undergoing hemodialysis. In total, 181 patients treated with linezolid from January 2010 to July 2012 at Aichi Medical University Hospital were divided into three groups; patients undergoing hemodialysis (HD group), those with creatinine clearance (CLCR) of <50 mL/min (CLCR < 50 group) and those with CLCR of ≥ 50 mL/min (CLCR ≥ 50 group). The incidence of thrombocytopenia, and changes in the platelet (PLT) counts during and after linezolid therapy were compared among three groups. Thrombocytopenia (<75% of the baseline level) occurred in 125 patients (69.1%). PLT reached its nadir 3-4 days after the end of linezolid therapy. In particular, the PLT nadir in HD group occurred earlier than that in non-HD groups (HD, 11.5 days [4-31 days]; CLCR < 50, 14 days [5-43 days]; CLCR ≥ 50, 15.5 days [4-49 days]; p = 0.11). HD group exhibited the greatest rate of reduction of PLT (HD, 24.0% [0.4-93.8%]; CLCR < 50, 23.8% [0.8-92.9%]; CLCR ≥ 50, 22.4% [0.92-92.9%]; p = 0.003). Finally, HD group exhibited the slowest recovery of PLT to its baseline level (HD, 10 days [5-29 days]; CLCR < 50, 9 days [2-16 days]; CLCR ≥ 50, 8 days [3-17 days]; p = 0.09). The incidence of erythropenia was not significantly different among three groups. These results indicate the need to monitor the PLT count during and after linezolid treatment in patients undergoing hemodialysis.

Induction therapy with linezolid/clarithromycin combination for Mycobacterium chelonae skin infections in immunocompromised hosts.

The optimal management of Mycobacterium chelonae disease in immunocompromised patients remains unclear. A combination of antimicrobial agents is recommended as monotherapy with clarithromycin has been associated with clinical failures due to acquired resistance. We aim to report the efficacy and tolerability of linezolid in association with clarithromycin for the treatment of M. chelonae infections in immunocompromised patients. We describe four immunocompromised patients treated by linezolid and clarithromycin for cutaneous M. chelonae disease. This combination was associated with rapid clinical efficacy in all patients with no relapse observed after a median follow-up of 2.25 years (1.4 years). However, this treatment was responsible for frequent adverse events including thrombocytopaenia, myalgia and mitochondrial toxicity. All adverse effects were reversible after linezolid discontinuation. We therefore suggest linezolid/clarithromycin combination as the initial therapeutic strategy for M. chelonae skin infections in immunocompromised patients.

Linezolid to treat extensively drug-resistant TB: retrospective data are confirmed by experimental evidence

To the Editor: Extensively drug-resistant tuberculosis (XDR-TB) (defined as TB caused by Mycobacterium tuberculosis strains with in vitro resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the second-line injectable drugs, amikacin, capreomycin or kanamycin) on top of being a growing public health concern, represents a nightmare for the clinician [1–4]. The crucial therapeutic issue is the difficulty of identifying at least four available “active” anti-TB drugs, to ensure treatment success as well as to prevent the emergence of additional drug resistance [1–4]. After more than 40 years without new anti-TB drugs appearing on the horizon, new chemical compounds ( i.e. bedaquiline, PA-824 and delamanid) seem promising for these difficult-to-treat cases of TB [4, 5]. While the necessary experimental studies will prove how to use them, more and more interest is currently focused on existing antibacterial drugs with new indications for drug-resistant TB, particularly linezolid, meropenem, clofazimine and cotrimoxazole [6–9]. Based on in vitro and pharmacological data, suggesting that linezolid (an oxazolidinone antibiotic) could be efficacious in treating mycobacterial infections, and on anedoctal evidence of its effectiveness in the smallest groups of patients, it was used off-label, despite its high price, to treat multidrug-resistant (MDR) TB cases in several countries. The little scientific supporting data on the efficacy, safety and tolerability of linezolid came from ad hoc randomised, controlled clinical trials, as well as from large observational studies [7]. The European Respiratory Journal recently published a systematic review and a meta-analysis of individual patients focused on the main published epidemiological observational studies (n=12), describing cohorts of TB patients (n=121) treated with linezolid-containing regimens in 11 countries [7 …

Clinical Efficacy of Oral Linezolid Compared With Intravenous Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus–Complicated Skin and Soft Tissue Infections: A Retrospective, Propensity Score–Matched, Case-Control Analysis

BackgroundLinezolid is 100% bioavailable in oral and intravenous formulations. In a recent prospective, randomized, open-label, comparator-controlled, multicenter, phase 4 clinical trial in adults with complicated skin and soft tissue infections (cSSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA), linezolid achieved clinical and microbiologic success comparable to appropriately dosed intravenous vancomycin. Although patients were randomly assigned to receive linezolid or vancomycin, the protocol allowed patients to start therapy using oral or intravenous linezolid on the basis of investigator discretion and patient ability to tolerate oral medication. ObjectiveThe objective of this study was to assess the efficacy and tolerability of linezolid when administered orally in adults with cSSTI caused by MRSA. In this retrospective analysis, we examined data collected from the aforementioned trial to compare outcomes in patients who received either oral linezolid or intravenous vancomycin therapy. MethodsThis study analyzed outcomes in patients who received treatment for 7 to 14 days with either oral linezolid (600 mg q12h; n = 95) or intravenous vancomycin (15 mg/kg q12h, adjusted for creatinine clearance and trough concentration; n = 210). By design, these groups were not randomized. Propensity score matching on baseline variables was used to balance these groups by identifying a comparable group of patients who received vancomycin therapy and comparing them with patients who received oral linezolid therapy. Clinical and microbiologic success rates at the end of treatment and the end of the study (EOS) were then directly compared between the groups using matched-pair logistic regression. The tolerability of the 2 treatments (within this matched group) was also described. ResultsNinety-two patients with well-matched baseline characteristics were included in each treatment group. At EOS, the odds ratio for clinical success of oral linezolid therapy vs intravenous vancomycin therapy was 4.0 (95% CI, 1.3–12.0; P = 0.01), and the odds ratio for microbiologic success at EOS was 2.7 (95% CI, 1.2–5.7; P = 0.01). Overall rates of adverse events in each group were consistent with reported safety profiles for each drug. ConclusionA favorable clinical cure rate was achieved with oral linezolid therapy when compared with intravenous vancomycin therapy in propensity score–matched patients with cSSTI proved to be caused by MRSA. ClinicalTrials.gov Identifier: NCT00087490.

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21-90) and 61 (29-119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤ 600 mg versus >600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.

Le linézolide en pédiatrie

The spread of multiresistant Gram positive bacteria required the development of new drugs. Linezolid, a new oxazolidinone, is active against these pathogens and is marketed for the treatment of severe glycopeptides-resistant Gram positive-bacteria in adults. Moreover, the availability of intravenous and oral formulation with an excellent bioavailability of the latter, is hoped to facilitate the management of these infections. Most information regarding the pharmacoketic profile, efficacy and tolerability of linezolid in pediatric derived from adults studies. In this review we summarize evidence regarding the uses of linezolid in children focusing on the clinical efficacy data and safety in serious Gram-positive infections and also in compassional uses.

Linezolid in the Treatment of Multidrug‐Resistant Tuberculosis

Linezolid is a new antibiotic with activity against Mycobacterium tuberculosis in vitro and in animal studies. Several small case series suggest that linezolid is poorly tolerated because of the side effects of anemia/thrombocytopenia and peripheral neuropathy. To characterize our clinical experience with linezolid, the California Department of Public Health Tuberculosis Control Branch's Multidrug-Resistant Tuberculosis (MDR-TB) Service reviewed cases in which the MDR-TB treatment regimens included linezolid therapy. Record review was performed for 30 patients treated with linezolid as part of an MDR-TB regimen. Data were collected on clinical and microbiological characteristics, linezolid tolerability, and treatment outcomes. The dosage of linezolid was 600 mg daily. Vitamin B6 at a dosage of 50-100 mg daily was used to mitigate hematologic toxicity. During 2003-2007, 30 patients received linezolid for the treatment of MDR-TB. Patients had isolates resistant to a median of 5 drugs (range, 2-13 drugs). Of the 30 cases, 29 (97%) were pulmonary; of these 29, 21 (72%) had positive results of acid-fast bacilli smear, and 16 (55%) were cavitary. Culture conversion occurred in all pulmonary cases at a median of 7 weeks. At data censure (31 December 2008), 22 (73%) of 30 patients had successfully completed treatment. Five continued to receive treatment. There were no deaths. Three patients had a poor outcome, including 2 defaults and 1 treatment failure. Side effects occurred in 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea. However, only 3 patients stopped linezolid treatment because of side effects. Linezolid was well tolerated, had low rates of discontinuation, and may have efficacy in the treatment of MDR-TB.

Efficacy and Tolerability of Linezolid in Chronic Osteomyelitis and Prosthetic Joint Infections: A Case-Control Study

Clinical experience of prolonged use of linezolid in patients with bone infections is accumulating. However more efficacy and safety data are required. This is a case-control study of patients who received linezolid for difficult-to-treat, intolerant or resist-ant-to-other-antibiotics bone infections. Linezolid was administered i.v. or orally in 34 patients. Results concerning efficacy and safety were compared to a group of well-matched controls. The clinical arrest rate was 74% in the linezolid group and 68% in the control group (p=NS). Treatment was discontinued in 14 (44%) patients of the linezolid group and in 2 (6%) patients of the control group due to adverse events. In the linezolid group 11 (33%) patients developed anemia and 3 (9%) developed thrombocytopenia that led to discontinuation of treatment. Linezolid is effective in a substantial proportion of patients, but the incidence of hematologic adverse events makes close follow-up and laboratory monitoring mandatory.

A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis

Linezolid is used to treat patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-tuberculosis (TB) cases, although clinical data on its safety, tolerability and efficacy are lacking. We performed a retrospective, nonrandomised, unblinded observational study evaluating the safety and tolerability of linezolid at 600 mg q.d. or b.i.d. in MDR/XDR-TB treatment in four European countries. Efficacy evaluation compared end-points of 45 linezolid-treated against 110 linezolid-nontreated cases. Out of 195 MDR/XDR-TB patients, 85 were treated with linezolid for a mean of 221 days. Of these, 35 (41.2%) out of 85 experienced major side-effects attributed to linezolid (anaemia, thrombocytopenia and/or polyneuropathy), requiring discontinuation in 27 (77%) cases. Most side-effects occurred after 60 days of treatment. Twice-daily administration produced more major side-effects than once-daily dosing (p = 0.0004), with no difference in efficacy found. Outcomes were similar in patients treated with/without linezolid (p = 0.8), although linezolid-treated cases had more first-line (p = 0.002) and second-line (p = 0.02) drug resistance and a higher number of previous treatment regimens (4.5 versus 2.3; p = 0.07). Linezolid 600 mg q.d. added to an individualised multidrug regimen may improve the chance of bacteriological conversion, providing a better chance of treatment success in only the most complicated MDR/XDR-TB cases. Its safety profile does not warrant use in cases for which there are other, safer, alternatives.

Efficacy and tolerability of prolonged linezolid therapy in the treatment of orthopedic implant infections

The aim of the study presented here was to assess the efficacy and tolerability of linezolid in the treatment of orthopedic implant infections (OII). Eighty-five patients with an OII treated with linezolid were prospectively followed up for a minimum of 12 months from the end of antibiotic therapy. Outcome was evaluated in relation to the duration and type of symptoms (acute or chronic) and the retention or removal of the implant. For acute and chronic infections, the respective success rates were 100 and 92.3% when the implant was removed and 72.2 and 42.8% when it was not. The median length of linezolid treatment in acute and chronic infections was 47 and 60 days, respectively. Thrombocytopenia was observed in four (4.7%) patients and anemia in five (5.8%). The results suggest oral linezolid is an effective and well-tolerated alternative for treating OII.

The First Years of Linezolid Experience in Clinical Practice: A Balance and Future Implications

Multi-antibiotic resistant Gram-positive cocci, which include Staphylococcus aureus, the coagulase-negative staphylococcal group, Enterococcus faecalis and Enterococcus faecium, and other streptococci, represent emerging pathogens especially in the setting of the immunocompromised, hospitalized patients, in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are to be considered, and broad-spectrum antibiotics or immunosuppressive drugs are needed for prolonged administration. During the recent years, the phenomenon of multi-resistant Gram-positive cocci is spreading from the Hospital into the community, where the retrieval of such microorganism is progressively increasing. The spectrum of available antimicrobial compounds for an effective management of these relevant infections is significantly impaired in selection and clinical efficacy by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant Gram-positive microbial strains. The first oxazolidinone derivative linezolid, together with the recently licensed quinupristin-dalfopristin, daptomycin and tigecycline, followed by a number of glycopeptides, fluoroquinolones, and other experimental compounds on the pipeline or approaching the market in the year 2006, represent an effective response to the great majority of these concerns. Because of their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic-pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also when compromised patients are of concern. The main problems related to the epidemiological and clinical features of multiresistant Gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of linezolid as the golden standard compound for vancomycinresistant Gram-positive cocci in multiple clinical situations, are outlined and updated on the ground of an extensive review of all the available. Recent evidences are commented from the international literature. Keywords: Linezolid, oxazolidinones, resistant gram-positive organisms, staphylococci, enterococci

Update on the appropriate use of linezolid in clinical practice

Multi-antibiotic resistant Gram-positive cocci, which include Staphylococcus aureus, the coagulase-negative staphylococcal group, Enterococcus faecalis and Enterococcus faecium, and other streptococci, represent emerging pathogens especially in the setting of the immunocompromised, hospitalized patients, in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are of concern, and broad-spectrum antibiotics or immunosuppressive drugs are widely administered. During the recent years, the phenomenon of multiresistant Gram-positive cocci is spreading to the community, where the retrieval of such microorganism is progressively increasing. The spectrum of available antimicrobial compounds for an effective management of these relevant infections is significantly impaired in selection and clinical efficacy by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant Gram-positive microbial strains. The first oxazolidinone derivative linezolid, together with the recently licensed quinupristin-dalfopristin, daptomycin, and tigecycline, followed by a number of glycopeptides, fluoroquinolones, and other experimental compounds on the pipeline, represent an effective response to the great majority of these concerns, due to their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic/pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also when compromised patients are of concern. The main problems related to the epidemiological and clinical features of multiresistant Gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of linezolid as the golden standard compound for vancomycin-resistant Gram-positive cocci in multiple clinical situations, are outlined and updated on the ground of an extensive review of all the available, recent evidences coming from the international literature.

Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: A retrospective study

Background:Linezolid is an oxazolidinone agent which is apparently well designed for treating chronic osteomyelitis, but data on effectiveness and tolerability as prolonged therapy is currently lacking. Objective:The purpose of this study was to assess the effectiveness and tolerability of linezolid in the treatment of chronic osteomyelitis. Methods:The charts of hospitalized patients who had been treated with linezolid for >4 weeks because of chronic osteomyelitis and were followed up for ≥12 months after the end of treatment were retrospectively reviewed for clinical outcome and tolerability. Cure was defined as the absence of clinical, biological, or radiological evidence of infection throughout the posttreatment follow-up. Linezolid tolerability was assessed on the basis of hematologic properties during treatment. Results:Of the 66 patients included, all were white (mean [SD] age, 67.7 [18.1] years; 41 men and 25 women; mean [SD] weight, 80.7 [18.6] kg). Thirty-seven (56.1%) patients had infection due to implants including 27 prosthetic joints. Pathogens were predominantly methicillin-resistant staphylococci (49/72 strains, 68.1 %). Every patient was administered N linezolid (600 mg BID) treatment for 6 to 8 days as inpatients, and then, as outpatients, they were switched to PO treatment. Fifty (75.8%) patients received a combination of linezolid and other antimicrobial agents, including rifampin (32 [48.5%]). Surgery was performed in 52 (78.8%) patients. The median hospital stay was 14 days (mean [SD], 19 [11.4] days [range, 7–70 days] ). The median duration of treatment was 13 weeks (mean [SD], 14.3 [8.2] weeks [range, 5–36 weeks]). At the end of treatment, 56 (84.8%) patients were cured, and during the post-treatment follow-up (median duration, 15 months [range, 12–36 months]), 4 relapses occurred, resulting in an overall successful cure for 52 (78.8%) patients.Reversible anemia was reported in 21 patients (31.8%), of whom 16 (24.2%) required blood transfusions. Median time from treatment initiation to anemia onset was 7.3 weeks (range, 4–12 weeks). Peripheral neuropathy was reported in 6 (9.1%) patients, of whom 4 remained symptomatic for up to 24 months after linezolid discontinuation. Other reported adverse events included nausea (6 [9.1%]), diarrhea (1 [1.5%]), and headache (2 [3.0%]), although none of these patients discontinued treatment. Conclusions:In this retrospective chart review, treatment with linezolid as monotherapy or in combination with antimicrobials and/or surgery was associated with cure of chronic osteomyelitis in 84.8% of subjects at 12 weeks after the end of treatment and 78.8% at follow-up. Adverse events were reported in 51.5% of subjects, and 34.8% of subjects discontinued the study because of adverse events. The potential for severe complications justifies close monitoring of these patients.

Safety and tolerability of linezolid.

Clinical trials have shown that linezolid (600 mg twice daily in adults) is safe and generally well tolerated for up to 28 days. Drug-related adverse events, which are typically mild to moderate in intensity and of limited duration, include diarrhoea, nausea and headache in adults, and diarrhoea, loose stools and vomiting in children. Clostridium difficile-related complications with linezolid are uncommon. Linezolid is a weak, reversible monoamine oxidase inhibitor: foods containing high concentrations of tyramine should be avoided, and linezolid should be used with caution in patients taking adrenergic or serotonergic agents or in those with uncontrolled hypertension. In the majority of patients, linezolid has minimal adverse effects on blood chemistry or haematology. There have been case reports of reversible thrombocytopenia, anaemia and neutropenia associated with linezolid therapy. In Phase III studies, 2.4% of patients treated with linezolid and 1.5% of patients treated with comparator drugs developed reversible thrombocytopenia (P = 0.066), but there was no evidence of an increased risk of agranulocytosis, aplastic anaemia or other irreversible blood dyscrasias. Reduced platelet counts were associated with linezolid treatment for >/=2 weeks; complete blood counts should be monitored weekly in patients receiving linezolid for more than 14 days and treatment should be discontinued if there is evidence of myelosuppression.

Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia

Background: The clinical efficacy and tolerability of linezolid were demonstrated in a previously published, randomized, double-blind, registration study comparing linezolid with vancomycin for the empiric treatment of 396 patients with nosocomial pneumonia. Objectives: The aims of this study were to obtain additional experience with linezolid and vancomycin in patients with nosocomial pneumonia and to satisfy international regulatory requirements. Methods: Patients with pneumonia acquired after 48 hours in an inpatient facility were randomly assigned to receive either IV linezolid 600 mg or IV vancomycin 1 g every 12 hours for 7 to 21 consecutive days. Patients also received IV aztreonam 1 to 2 g every 8 hours, which could be discontinued if gram-negative pathogens were not identified. The primary efficacy variables were clinical and microbiologic outcomes in evaluable patients at the follow-up visit 15 to 21 days after the end of therapy. Results from the continuation study were analyzed separately and did not include patients from the previously reported study. Results: A total of 623 patients were enrolled: 321 in the linezolid group and 302 in the vancomycin group. Mean (SD) ages were 63.1 (19.1) years and 61.9 (19.3) years, respectively. Mean (SD) Acute Physiology and Chronic Health Evaluation II scores were 14.1 (5.8) and 14.1 (6.2), respectively. There were no significant differences between the linezolid and vancomycin groups at the follow-up visit in clinical cure rates ( 114 168 ) [67.9%] and 111 171 [64.9%]) or microbiologic success rates ( 47 76 [61.8%] and 42 79 [53.2%]) in evaluable patients (excluding those who had indeterminate or missing outcomes). There were also no significant differences in the rates of all drug-related adverse events (14.0% and 14.0%) or those that occurred in >1% of patients, including diarrhea (3.7% and 3.0%), nausea (0.3% and 1.3%), and rash (0.6% and 1.7%) in the linezolid and vancomycin groups, respectively. Conclusion: In the population studied, linezolid appeared to be as well tolerated and as effective as vancomycin, each in combination with aztreonam.