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PubMed2003

The pharmacokinetics of linezolid are not affected by concomitant intake of the antioxidant vitamins C and E.

In vitro metabolism experiments have suggested a possible role for endogenous reactive oxygen species (ROS) in the in vivo clearance of linezolid, a synthetic antibiotic of the oxazolidinone class. This observation has resulted in the hypothesis that dietary antioxidant supplements might disturb the balance of ROS in vivo and thereby lower the clearance of linezolid. The purpose of this open-label, two-group parallel design study was to investigate whether continuous intake of widely used vitamin C or vitamin E will affect the pharmacokinetics of linezolid. A total of 28 healthy volunteers (27 male and 1 female), including 22 of Chinese origin, were administered a single oral dose of 600 mg linezolid on days 1 and 8. Half of the subjects received daily oral doses of 1000 mg vitamin C on days 2 through 9, whereas the other half were administered daily oral doses of 800 IU vitamin E during the same time period. Serial blood samples for assessment of the pharmacokinetic parameters of linezolid and its two inactive metabolites were collected on days 1 and 8, whereas vitamin concentrations were measured prior to and after the vitamin intake on these days. Urine was collected on days 1 and 8 to assess the fraction of dose excreted as linezolid and its major metabolites. All linezolid samples were analyzed according to validated HPLC/MS/MS methods. Linezolid was well tolerated in both groups with no reported clinically significant adverse events. No significant changes were found between the day 1 and day 8 AUC0- infinity and Cmax values of linezolid in either the vitamin C treatment group (p = 0.55 and p = 0.64, respectively) or the vitamin E treatment group (p = 0.06 and p = 0.49, respectively). Assessment of other pharmacokinetic parameters did not imply any change across the study groups. In conclusion, linezolid pharmacokinetics are not affected by concomitant administration with vitamins C and E. Therefore, no dose adjustment is necessary in patients taking vitamin C or vitamin E. These no-effect drug interaction data are in accord with current literature indicating that antioxidant vitamins have only subtle effects on overall ROS balance in vivo.

Acetamides↗
PubMed2001

Linezolid for the treatment of resistant gram-positive cocci.

OBJECTIVE: To provide a comprehensive review of linezolid, the first of a new class of antibiotics, the oxazolidinones. Therapeutic issues regarding the emergence of multidrug-resistant bacteria and a brief history of the oxazolidinones are also discussed. DATA SOURCES: A MEDLINE search (1966-March 2001) was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Unpublished clinical data, adverse effects, and dosing information were abstracted from product labeling. STUDY SELECTION: Clinical efficacy data were extracted from clinical trials, case reports, and abstracts that mentioned linezolid. Additional information concerning antibiotic resistance, the oxazolidinones, in vitro susceptibility and the pharmacokinetic profile of linezolid also was reviewed. DATA SYNTHESIS: Linezolid exhibits activity against many gram-positive organisms, including vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae. Linezolid inhibits bacterial protein synthesis at an early step in translation and is rapidly and completely absorbed from the gastrointestinal tract following oral administration. Efficacy has been demonstrated in a number of unpublished clinical trials in adults with pneumonia, skin and skin structure infections, and vancomycin-resistant E. faecium infections. The adverse effect profile is similar to that of comparator agents (beta-lactams, clarithrornycin, vancomycin). CONCLUSIONS: Linezolid is the first oral antimicrobial agent approved for the treatment of vancomycin-resistant enterococci. Since the oxazoildinones have a unique mechanism of action and expanded spectrum of activity against virulent and highly resistant gram positive pathogens, linezolid is a valuable alternative to currently available treatment options. Clinical trials evaluating linezolid and other oxazolidinones for antibiotic-resistant gram-positive infections, as well as comparator studies comparing linezolid with other candidate drugs, such as quinupristin/dalfopristin and choramphenicol, will further define the role of linezolid.

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PubMed2006

Successful treatment and cerebrospinal fluid penetration of oral linezolid in a patient with coagulase-negative Staphylococcus ventriculitis.

OBJECTIVE: To describe a case of coagulase-negative Staphylococcus ventriculitis successfully treated with oral linezolid, for which good cerebrospinal fluid (CSF) penetration was observed. CASE SUMMARY: A 69-year-old man had an extraventricular drain inserted following a right cerebellar infarct. On day 6, the CSF culture was positive for coagulase-negative staphylococci; intravenous vancomycin 1 g daily was initiated to treat ventriculitis. A ventriculoperitoneal shunt, inserted on day 35 to manage communicating hydrocephalus, was subsequently removed as symptoms suggesting infection presented. Coagulase-negative Staphylococcus was isolated from shunt reservoir aspirate, and intrathecal vancomycin 10 mg daily was added to the treatment regimen. On day 61, vancomycin was stopped and oral linezolid 600 mg twice daily was started. Linezolid was discontinued 22 days later, with no evidence of ongoing infection. Four blood samples were collected around the seventh dose of linezolid and 5 CSF samples were collected on separate days during treatment. Linezolid concentrations were measured in plasma and CSF by HPLC. Using an ADAPT II maximum a priori Bayesian estimator module, a 2 compartment pharmacokinetic model was fitted to the plasma linezolid concentration data and CSF:predicted plasma concentration ratios (ranging from 0.27 to 1.02) were derived. All CSF concentrations exceeded the reported 90% minimum inhibitory concentration of 2 mg/L for linezolid against coagulase-negative staphylococci. DISCUSSION: Evidence of the effectiveness of linezolid against central nervous system infections is growing; however, limited data exist describing its CSF penetration. Oral linezolid exhibited good CSF penetration in this patient, which corresponded to positive clinical response. CONCLUSIONS: Oral linezolid may play a valuable role in the treatment of multiresistant gram-positive central nervous system infections.

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PubMed2001

Linezolid: a review of its use in the management of serious gram-positive infections.

UNLABELLED: Linezolid is the first of a new class of antibacterial drugs, the oxazolidinones. It has inhibitory activity against a broad range of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae. The drug also shows activity against certain anaerobes, including Clostridium perfringens, C. difficile, Peptostreptococcus spp. and Bacteroidesfragilis. In controlled phase III studies, linezolid was as effective as vancomycin in the treatment of patients with infections caused by methicillin-resistant staphylococci and also demonstrated efficacy against infections caused by VRE. Further phase III studies have demonstrated that linezolid is an effective treatment for patients with nosocomial pneumonia, for hospitalised patients with community-acquired pneumonia, and for patients with complicated skin or soft tissue infections (SSTIs). In these studies, linezolid was as effective as established treatments, including third-generation cephalosporins in patients with pneumonia, and oxacillin in patients with complicated SSTIs. Oral linezolid 400 or 600mg twice daily was as effective as clarithromycin 250mg twice daily or cefpodoxime proxetil 200mg twice daily in the treatment of patients with uncomplicated SSTIs or community-acquired pneumonia. Linezolid is a generally well tolerated drug. The most frequently reported adverse events in linezolid recipients were diarrhoea, headache, nausea and vomiting. Thrombocytopenia was also documented in a small proportion (about 2%) of patients treated with the drug. CONCLUSIONS: Linezolid has good activity against gram-positive bacteria, particularly multidrug resistant strains of S. aureus (including GISA), Enterococcus faecium and E. faecalis (including VRE). In controlled clinical trials, linezolid was as effective as vancomycin in eradicating infections caused by methicillin-resistant Staphylococcus spp. and has demonstrated efficacy against infections caused by VRE. As the level of resistance to vancomycin increases among S. aureus and enterococci, linezolid is poised to play an important role in the management of serious gram-positive infections.

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PubMed2005

[In vitro activity of linezolid, moxifloxacin, levofloxacin, clindamycin and rifampin, alone and in combination, against Staphylococcus aureus and Staphylococcus epidermidis].

Information about the in vitro effect of combinations of anti-staphylococcal agents on staphylococci is scarce. The aim of the study was to evaluate the in vitro activity of linezolid, moxifloxacin, levofloxacin, clindamycin and rifampin, alone or in combination, against Staphylococcus spp. Two Staphylococcus aureus and two Staphylococcus epidermidis strains isolated from blood cultures were studied using the killing curve method. The combinations analyzed were linezolid+moxifloxacin, linezolid+levofloxacin, linezolid+clindamycin, linezolid+rifampin, moxifloxacin+rifampin, moxifloxacin+clindamycin, levofloxacin+rifampin and levofloxacin+clindamycin. The following concentrations (mg/l) were used: 8 and 16 for linezolid, 2 for moxifloxacin, 3 for levofloxacin, 2 for clindamycin and 2 and 5 for rifampin. The activity was considered synergistic when a reduction in growth of at least 2 log(10) was produced with the combination in comparison to the most active antibiotic alone; antagonistic when a growth of at least 2 log(10) was produced with the combination in comparison to the most active antibiotic alone; and indifferent if the variation was less than 1 log(10). Linezolid and clindamycin were bacteriostatic, while moxifloxacin and levofloxacin were bactericidal. Rifampin was bacteriostatic against S. aureus and bactericidal against S. epidermidis. Linezolid and clindamycin reduced the bactericidal activity of levofloxacin and moxifloxacin, however an antagonistic effect was only observed against S. aureus. Other combinations of linezolid, rifampin, clindamycin, levofloxacin or moxifloxacin were indifferent. Linezolid and clindamycin antagonize the bactericidal activity of fluorquinolones against staphylococci. There was no difference between any other combinations against either S. aureus or S. epidermidis.

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PubMed2006

[Linezolid in the treatment of antibiotic-resistant gram-positive infections of the musculoskeletal system].

PURPOSE OF THE STUDY: The growing incidence of resistant microorganisms has been responsible for complications associated with treatment of osteomyelitis, infections following joint arthroplasty, as well as septic arthritis. Their therapy often requires a long-term administration of antibiotics to which the bacterial strain is sensitive. Oxazolidinons present a novel group of antibiotics recently adopted in clinical medicine. However, the only member of this group so far approved for clinical use is linezolid. It is effective for Gram-positive bacteria including antibiotic-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), resistant coagulase-negative staphylococci and penicillin-resistant pneumococci. Linezolid is well absorbed in the intestinal system. Oral administration results in serum levels comparable with those following intravenous injection of the same dose. MATERIAL, METHODS AND RESULTS: In the 1st Orthopedic Department of the 1st Faculty of Medicine at Charles University, linezolid was used for treating infections of the musculoskeletal system caused by MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE). Fourteen patients, eight women and six men, were treated in the period from 1999 to 2005. The average age at the time of therapy was 65 years (range, 24-80). The treatment involved infection of 10 joints following arthroplasty (six total hip and four total knee replacements), one osteomyelitis, one septic arthritis, one abscess in the gluteal region and one infected amputation stump. With the exception of one patient, antibiotic therapy was always combined with an appropriate surgical intervention. The average antibiotic course was 27 days, with intravenous administration of linezolid at the beginning (average, 11.4 days; range, 9-14) and oral administration later (average, 15.9 days; range, 14-18). Antibiotic therapy was well tolerated by the patients, and no adverse side-effects were recorded. The success rate of therapy was 93 %. The only failure was in the patient in whom the infection of total knee replacement was treated with mere antibiotics, without any surgical intervention. DISCUSSION: Linezolid is a treatment option for joint infections following arthroplasty that are caused by resistant bacterial strains, such as MRSA, MRSE or VRE. The therapeutic efficiency varies in relation to whether the patients have undergone conservative or surgical treatment and, in the latter case, on the surgical technique used. On the basis of our results we suggest that a radical surgery is necessary, but in agreement with other recent reports we prefer a surgical approach combined with antibiotic therapy. The costs of linezolid treatment are high, but the possibility of its oral administration, with maintenance of the required tissue levels, markedly reduces hospital stay costs and increases patients' comfort during treatment. In our group, the patients received linezolid doses orally for up to 16 days, which means a hospital stay shorter by more than two weeks. The antibiotic course varies and, in relation to the kind of infection, may range from 5 days to 2 months; however, linezolid administration for 4 to 8 weeks is most frequent. The period of 28 days recommended by the manufacturer is thus usually extended. CONCLUSIONS: Infections caused by Gram-positive bacteria resistant to common antibiotics present serous epidemiological, therapeutic and economic problems, which will soon be in the focus of attention in the majority of Czech hospitals. In the patients who, due to allergic reactions, intolerance or bacterial resistance, cannot be treated with vancomycin or other antibiotics, linezolid may be a useful option for treatment of musculoskeletal system infections. The possibility of linezolid administration in oral doses markedly reduces hospital stay costs and increases patients' comfort during treatment.

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PubMed2000

Linezolid, critical characteristics

In spite of a constantly expanding information base with the oxazolidinones generally and linezolid specifically, we have elected here to focus on the key characteristics of linezolid. Linezolid is the first member of a new class of antimicrobial agents, the oxazolidinones, to be tested in humans in Phase I, Phase II and Phase III clinical trials. The oxazolidinones have a novel mechanism of action in that they inhibit initiation complex formation in bacterial protein synthesis and, consistent with a novel mechanism of action, they do not exhibit cross-resistance with existing antibacterial agents. Importantly, resistance development as measured in the laboratory occurs very slowly, there is no evidence of rapid resistance development. The spectrum of oxazolidinone activity is principally gram-positive and in vitro studies demonstrate that linezolid is equivalent to vancomycin in vitro. Linezolid is orally as well as intravenously active and orally administered linezolid is as efficacious in mouse models of bacterial disease as is subcutanously administered vancomycin against appropriate pathogens. The exceptional oral behavior of linezolid in mouse models is readily explained by the observation that oral linezolid is 100% bioavilable and that administration of 400- and 600-mg doses of linezolid in humans results in blood level curves which predict that linezolid will be very well suited for bid dosing. Additionally, the blood level concentrations are in significant and very comfortable excess of the MIC90 concentrations for the important gram-positive pathogens for the bulk of the dosing interval.

Journal Article↗
PubMed2005

Possibly linezolid-induced peripheral and central neurotoxicity: report of four cases.

BACKGROUND: Linezolid is the first member of the new synthetic class of antibacterial agents that prevent the formation of the 70S ribosomal subunit. It represents an attractive choice in the therapeutic arsenal because it is effective against methicillin-resistant strains of Staphylococcus spp. Adverse hematological events have been reported. They are rapidly reversible after discontinuation of treatment and usually occur during treatment courses of more than 2 weeks. The advised duration of linezolid use is 28 days and the consequences of prolonged use are unknown. In addition, this drug has some dopaminergic properties that can induce the serotonin syndrome if a monoamine oxidase inhibitor is used simultaneously. PATIENTS AND METHODS: Since linezolid became available for use in 2002, four cases of probable central and peripheral linezolid-induced neurotoxicity have been recorded in our unit. RESULTS: Two de novo peripheral neuropathies and one worsening of a preexisting toxic neuropathy have been observed. In each case, linezolid therapy was used during a prolonged duration of 8, 23, and 24 weeks, respectively. First neurological signs appeared in one case during the 2nd week of treatment and beyond the 1st month in the other cases. To date, all cases of peripheral neuropathy resulted in persistent neurological damage after discontinuation of linezolid. Assessments did not reveal any other explanation for these neurological impairments. Another case concerned a patient who developed transient encephalopathy attributed to linezolid during a coadministration with hydroxyzine. CONCLUSION: Linezolid may induce persistent peripheral neuropathy after prolonged use and may cause a transient central neurotoxicity in combination with an anticholinergic agent, such as an antihistamine. Close neurological monitoring should be recommended in prolonged linezolid therapy and coadministration of a serotonin reuptake inhibitor or antihistamine should be avoided to limit neurological adverse events.

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PubMed2006

Cost-effectiveness analysis of linezolid compared with vancomycin for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus.

OBJECTIVE: This study compared the cost-effectiveness of linezolid and vancomycin in the treatment of patients with nosocomial pneumonia (NP) caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: A retrospective decision-analytic model was applied to pooled data from 2 prospective, randomized, controlled, double-blind studies, and claims data from a large health plan (3.3 million members) located in the Mid-Atlantic region. Using hospital claims for patients in the health plan with suspected NP, we then determined their daily billed (submitted) hospital charges for 4 mutually exclusive potential health outcomes of linezolid or vancomycin treatment: survival with bacteremia, survival without bacteremia, nonsurvival with bacteremia, and nonsurvival without bacteremia. To generate the expected total daily billed hospital charge for each drug-treatment group, we weighted the determined daily billed hospital charges by the probabilities of each outcome developing in each treatment arm, as derived from the clinical-trial data. Drug acquisition costs were then incorporated, and the difference in expected total costs relative to the difference in rates of survival between the linezolid and vancomycin arms was used to calculate the incremental cost-effectiveness ratio (ICER) for linezolid. RESULTS: Costs were higher for nonsurviving patients compared with surviving patients. Estimated median daily billed treatment charges were $2888 for linezolid and $2993 for vancomycin. Based on Monte Carlo simulations, the respective 95% CIs were $2671 to $3106 and $2615 to $3372. Using mean treatment durations of 11.3 and 10.7 days, respectively, we obtained expected total hospitalization charges of $32,636 for linezolid treatment (95% CI, $30,182-$35,098), compared with $32,024 for vancomycin treatment (95% CI, $27,978-$36,078). The ICER for linezolid per life saved was $3600. CONCLUSIONS: The higher acquisition cost of linezolid was almost completely offset by improved survival and a reduction in health care costs associated with improved survival. As a result, linezolid was almost cost-neutral compared with vancomycin in the treatment of NP caused by MRSA.

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PubMed2001

Economic evaluation of linezolid, flucloxacillin and vancomycin in the empirical treatment of cellulitis in UK hospitals: a decision analytical model.

Standard antibiotic treatment of infections has become more difficult and costly due to treatment failure associated with the rise in bacterial resistance. New antibiotics that can overcome such resistant pathogens have the potential for great clinical and economic impact. Linezolid is a new antibiotic that is effective in the treatment of both antibiotic-susceptible and antibiotic-resistant Gram-positive bacterial infections, including those resistant to other available antibiotics. This breadth of activity is unique in existing antibiotics for Gram-positive bacteria and serves as the rationale for exploring the hypothesis that linezolid is an appropriate choice when considering empirical treatment of cellulitis in complicated or compromised patients in the nosocomial setting. A decision-modelling approach was used to compare the predicted first-line treatment efficacy and direct medical costs of linezolid with standard treatment of cellulitis among hospitalized patients. For the purposes of this analysis, standard care is defined along two main pathways: (1) initiating care with intravenous (iv) flucloxacillin, switching to vancomycin if the pathogen is found to be resistant to flucloxacillin, or maintaining flucloxacillin if the pathogen is found susceptible, or when culture and sensitivity analysis is inconclusive; or (2) initiating care with vancomycin, switching to iv flucloxacillin if the pathogen is found susceptible to flucloxacillin, maintaining vancomycin if the infection is found resistant, or when culture and sensitivity are inconclusive. For those patients taking iv flucloxacillin, a switch to oral flucloxacillin was allowed when clinically appropriate. We hypothesized that the cost of care of initiating treatment with linezolid would be less than that for both vancomycin and flucloxacillin in resistance risk ranges typically encountered in UK hospitals. In addition, while the registration trials showed equivalence of linezolid with the comparators in known or suspected methicillin-resistant Staphylococcus aureus (MRSA) and in known or suspected methicillin-susceptible Staphylococcus aureus (MSSA) (vancomycin and oxacillin) respectively, we hypothesized that first-line success rates would be higher in empiric treatment with linezolid. Efficacy data were obtained from recent clinical trials with linezolid and standard treatment, and medical resource utilization was obtained from an expert panel of clinicians who were questioned regarding resistant and susceptible infections separately. UK hospital direct medical costs of treatment were determined using standard costing techniques. Base case analyses assumed a residual 80% unknown pathogen rate after culture and susceptibility based on a physician survey and supported in the literature. The analysis in this model predicts that initiating empirical treatment of cellulitis with linezolid will (1) result in higher overall success rates than flucloxacillin for first-line treatment, regardless of resistance risk and (2) be less costly than initiating treatment with flucloxacillin when the likelihood of a patient being infected by a resistant pathogen is greater than 24.1%. Furthermore, initiating treatment with linezolid is predicted to result in higher overall success rates and be less costly than vancomycin across the entire spectrum of the patients' risk of being infected by a resistant pathogen.

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PubMed2003

Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers.

AIMS: To determine the pharmacokinetics and tolerance of oral and intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers following single- and multiple-dose administration. METHODS: In two randomized, double-blind, placebo-controlled, dose-escalating trials, subjects were exposed either to oral (375, 500 or 625 mg) or intravenous (500 or 625 mg) linezolid or placebo twice daily. Serial blood and urine samples were obtained after the first- and multiple-dose administrations for up to 18 days. Non-compartmental pharmacokinetic analyses were used to describe the disposition of linezolid. RESULTS: Plasma linezolid concentrations and area under the concentration-time curves increased proportionally with dose irrespective of the route of administration. Plasma linezolid concentrations remained above the MIC90 for susceptible target pathogens (4.0 mg/L) for the majority of the 12 h dosing interval. Mean clearance, half-life and volume of distribution were similar irrespective of dose for both the oral and intravenous routes. Linezolid was well tolerated and the frequency of drug-related adverse events was similar between the linezolid and placebo groups. CONCLUSIONS: Oral and intravenous linezolid exhibit linear pharmacokinetics, with concentrations remaining above the target MIC90 for most of the dosing interval. These results support a twice-daily schedule for linezolid and demonstrate the feasibility of converting from intravenous to oral dosing without a dose adjustment.

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PubMed2003

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.

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PubMed2006

Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis.

OBJECTIVES: Although linezolid has good in vitro activity against Mycobacterium tuberculosis, its long-term use in the treatment of multidrug-resistant tuberculosis (MDR-TB) may be limited by its cost and serious adverse reactions. We therefore evaluated the efficacy and tolerability of a reduced dose of linezolid, in combination with other anti-TB drugs, in patients with intractable or extensive MDR-TB. METHODS: MDR-TB patients unresponsive to at least three cycles of treatment were treated with daily-half doses of linezolid (600 mg once per day) plus at least four companion drugs. RESULTS: As of March 2006, eight patients, all HIV-negative, had been treated with linezolid for 3-18 months. Cultures became negative in all patients in an average of 82 days. Four patients developed peripheral neuropathy, two developed optic neuropathy and one developed anaemia. Although optic neuropathy resolved after cessation of linezolid therapy, peripheral neuropathy continued. One patient completed 18 months of linezolid therapy. Two patients, who have taken linezolid for 15-17 months, are still on treatment and remain in culture conversion. Three patients stopped linezolid after 7-9 months, two because of side effects and one for economic reasons, but remain on treatment with other second-line drugs with culture conversion. Two patients died from severe respiratory failure, but both previously had shown culture conversion. CONCLUSIONS: Although daily-half doses of linezolid were effective in patients with intractable or extensive MDR-TB, this dosage regimen did not reduce long-term use-related side effects, such as peripheral and optic neuropathy.

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PubMedDate not supplied

Quality assurance assessment of the use of linezolid in the treatment of thermal injury patients at a community teaching hospital.

We sought to evaluate the adverse effect profile of linezolid among thermal injury patients requiring treatment for Enterococcus species or other Gram-positive infection warranting treatment with linezolid. Seventy-six inhalation injury and/or thermal injury patients experiencing 94 exposures to linezolid for 48 hours or longer (range, 2-83 days) were included. We evaluated leukocyte count and platelet count for the time period preceding, during, and after therapy with linezolid based on specified time periods of exposure for evaluation of specific adverse effects. Sixty-three of 76 (83%) patient admissions were complicated by inhalation injury. The average TBSA involvement was 34.4% (range, 0-98%). The onset of thrombocytopenia before linezolid therapy was noted in 21 of 57 patients (36.8%), which was attributable to fluid resuscitation and acute platelet consumption. After they were exposure to linezolid, 12 patients developed thrombocytopenia. Platelet counts recovered in 7 of these 12 patients with continued exposure to linezolid; however, thrombocytopenia persisted for more than 9 days after therapy in 9 patients, of whom 6 patients succumbed to sepsis. On average, thrombocytes increased by 102,000/mm3 during linezolid treatment. Leucopenia was rare in thermal injury patients, and persisting thrombocytopenia in this population was associated with sepsis and mortality. Continuing linezolid therapy after the onset of thrombocytopenia among survivors almost always resulted in recovery from thrombocytopenia.

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PubMed2003

Linezolid versus cefadroxil in the treatment of skin and skin structure infections in children.

BACKGROUND: Skin and skin structure infections are common reasons for visits to pediatricians, accounting for up to 18%. Staphylococcus aureus and Streptococcus pyogenes are the most frequently isolated Gram-positive pathogens in uncomplicated skin infections. Increasingly outpatient infections involve antibiotic-resistant Gram-positive pathogens including methicillin-resistant S. aureus. METHODS: This randomized, blinded, comparator-controlled, multinational trial compared the efficacy and safety of linezolid and cefadroxil for treatment of uncomplicated skin/skin structure infections in pediatric patients. Children ages 5 to 11 years were to receive linezolid suspension [10 mg/kg (up to 600 mg)] or cefadroxil suspension [15 mg/kg (up to 500 mg)] every 12 h. Patients ages 12 to 17 years were to receive linezolid tablets (600 mg) or cefadroxil capsules (500 mg) every 12 h. Therapy lasted 10 to 21 consecutive days with a follow-up visit 10 to 21 days posttherapy. RESULTS: Linezolid and cefadroxil were consistently effective treatments across all primary and secondary efficacy assessments. At follow-up cure rates were 88.7% (205 of 231) for linezolid-treated and 86.2% (193 of 224) for cefadroxil-treated intent-to-treat patients; cure rates were 91.0% (201 of 221) for linezolid-treated and 90.0% (189 of 210) for cefadroxil-treated clinically evaluable patients. S. aureus was eradicated in 89.6% (120 of 134) linezolid-treated and 88.8% (111 of 125) cefadroxil-treated microbiologically evaluable patients. Gastrointestinal complaints were the most common adverse events reported, without significant differences between treatment groups, and myelosuppression was not observed in this study. CONCLUSIONS: Linezolid is well-tolerated and as effective as cefadroxil in treating uncomplicated skin infections in pediatric patients. Linezolid effectively treated infections caused by S. aureus, methicillin-resistant S. aureus and S. pyogenes.

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PubMed2003

Efficacy of linezolid plus rifampin in an experimental model of methicillin-susceptible Staphylococcus aureus endocarditis.

The efficacy of linezolid, alone or in combination with rifampin, against methicillin-susceptible Staphylococcus aureus in rabbits with experimental endocarditis was investigated. Linezolid (50 or 75 mg/kg of body weight), rifampin, and linezolid (25, 50, or 75 mg/kg) plus rifampin produced statistically significant reductions in bacterial counts compared with those in untreated controls. Plasma or valvular vegetation levels of linezolid in the groups treated with the linezolid-rifampin combination were similar to those in the respective linezolid-only treatment groups. At therapeutic levels of linezolid, rifampin resistance was not observed. The results from this experimental model of endocarditis suggest that while rifampin did not provide synergy to the linezolid dosing, it did not antagonize the efficacy of linezolid.

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PubMed2006

Lack of pharmacokinetic interaction between linezolid and antacid in healthy volunteers.

Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. Coadministration with antacids did not change the pharmacokinetics of linezolid. The ratios (90% confidence intervals) of the individual values of the area under the concentration-time curve and the maximum concentration in plasma (C(max)) (linezolid plus antacid versus linezolid alone) were 1.01 (0.99 to 1.02) and 0.99 (0.96 to 1.02), respectively. Likewise, no significant difference in any of the other pharmacokinetic parameters was observed between the treatment groups (the time to C(max), lag time, volume of distribution [V/F], and clearance [CL/F]). However, a significant sex difference was observed for AUC, C(max), V/F, and CL/F; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.

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PubMed2006

Treatment of post-traumatic hand Staphylococcus aureus osteomyelitis with oral linezolid.

The Authors report on the use of linezolid for the treatment of three patients with osteomyelitis. All three patients had post-traumatic multisensitive hand bone methicillin-susceptible Staphylococcus aureus osteomyelitis, which did not respond to antimicrobial regimens including drugs in vitro active against the isolated strains. Clinical cure and microbiologic eradication was obtained with oral linezolid in all three patients. Linezolid was well tolerated. Mild thrombocytopenia was observed in one patient at the end of the third week of treatment and it was promptly resolved after the discontinuation of linezolid. Linezolid minimum inhibitory concentrations (MICs) consisted of 2 mg/l for all three S. aureus isolates while the bactericidal activity in vitro was not present up to the linezolid concentration of 32 mg/l. In spite of a lack of in vitro bactericidal activity, linezolid was effective in curing the patients and eradicating the infection. Trough and peak plasma concentrations of linezolid were above the MICs of the isolates. These values ranged from 3.93 to 14.95 mg/l at trough and 5.03 to 25.91 mg/l at peak. The oral bioavailability, pharmacokinetic profile and antibacterial spectrum of linezolid make this oxazolidonone antimicrobial an attractive drug for the treatment of chronic osteomyelitis. Prolonged administration requires careful surveillance for side effects, until these complications are better understood.

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