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PubMed2003

Linezolid for the treatment of methicillin-resistant Staphylococcus aureus infections in children.

BACKGROUND: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are becoming increasingly prevalent. Linezolid is effective and well-tolerated in the treatment of adults with MRSA infections. OBJECTIVE: To evaluate the clinical efficacy and safety of iv/oral linezolid in children with MRSA infections. METHODS: Data were obtained from two independent clinical trials. In an outpatient trial children (5 to 17 years of age) with uncomplicated skin and skin structure infections (SSSIs) were treated with linezolid or cefadroxil. In an inpatient trial hospitalized children (0 to 11 years of age) with pneumonia, bacteremia or complicated SSSI caused by resistant Gram-positive pathogens were administered iv linezolid with the option to switch to oral suspension (patients >90 days of age) or iv vancomycin. A subset of patients with MRSA infections from the two clinical trials is analyzed herein. RESULTS: In the outpatient trial children with skin infections caused by MRSA were treated with linezolid (15 patients) and cefadroxil (10 patients). In the microbiologically evaluable population, the clinical cure rate was 92.3% in the linezolid group and 85.7% in the cefadroxil group (P = 0.64). The pathogen eradication rate for MRSA was 92.3 and 85.7% in the linezolid and cefadroxil groups, respectively (P = 0.64). There were very few adverse events or drug-related adverse events and no serious adverse events in the outpatient trial. In the inpatient trial 20 children treated with linezolid and 14 treated with vancomycin had infections caused by MRSA. In the microbiologically evaluable population, the clinical cure rate was 94.1% in the linezolid group and 90.0% in the vancomycin group (P = 0.69). Pathogen eradication rates were 88.2 and 90.0% for the linezolid and vancomycin groups, respectively (P = 0.89). Susceptibility patterns of the MRSA isolates showed distinct patterns between the outpatient and inpatient trials. In the inpatient trial fewer patients in the linezolid group had drug-related adverse events than did those in the vancomycin group (20% vs. 43%; P = 0.15). CONCLUSIONS: Intravenous/oral linezolid is effective and well-tolerated in children with MRSA infections.

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PubMed2003

Peritoneal dialysis fluid concentrations of linezolid in the treatment of vancomycin-resistant Enterococcus faecium peritonitis.

OBJECTIVE: To determine linezolid concentrations in peritoneal dialysis fluid after multiple oral doses of the drug in a 46-year-old man with vancomycin-resistant Enterococcus faecium peritonitis who was undergoing peritoneal dialysis. METHODS: After administration of oral linezolid 600 mg twice/day was started, peritoneal dialysis fluid was collected at the end of several 4- and 8-hour dwell times and submitted for analysis of linezolid concentration. Before linezolid therapy was begun, and immediately after several peritoneal dialysis exchanges, 30 ml of expended peritoneal dialysis fluid was collected in a sterile container and immediately frozen at -70 degrees C until analysis by high-performance liquid chromatography. RESULTS: Peritoneal dialysis concentrations of linezolid greater than 4 microg/ml were achieved after the first dose of linezolid and maintained after repeated doses. During the course of therapy, mean linezolid concentrations in peritoneal dialysis fluid tended to increase (mean 7.60 pg/ml, range 3.54-16.2 microg/ml). All assayed peritoneal dialysis samples demonstrated linezolid concentrations greater than 4 microg/ml at the end of 4- or 8-hour dwell times, except for one level after a missed dose on linezolid treatment day 3. Duration of dwell times did not appear to correlate with linezolid concentrations. CONCLUSION: In this patient, linezolid 600 mg twice/day penetrated into peritoneal dialysis fluid at or above the concentrations necessary to treat common gram-positive bacteria. Linezolid therapy is likely to have a role in peritoneal dialysis-associated peritonitis based on its antimicrobial activity, pharmacokinetic properties, ease of administration, and tolerability.

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PubMed2006

Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature.

A 47-year-old woman developed confusion, incoordination, and hypertension after she was given linezolid in addition to sertraline for 5 days. Her symptoms resolved within 4 days of discontinuing linezolid. One and a half months later, she received a second course of linezolid; sertraline was discontinued on day 1 of linezolid therapy. On day 9 of therapy, the patient developed confusion, myoclonus, and incoordination, and cardiopulmonary arrest occurred, leaving the patient in a coma. Diarrhea, hypertension, and tachycardia developed after cardiopulmonary arrest. Linezolid was discontinued on day 10, and cyproheptadine was given. Linezolid is a weak monoamine oxidase inhibitor and has been reported to interact with selective serotonin reuptake inhibitors (SSRIs). Several cases of serotonin syndrome in patients taking linezolid and SSRIs have been reported, including two reports with sertraline, one with paroxetine, four with citalopram, and two with fluoxetine. One abstract of a retrospective analysis reported that serotonin syndrome did not occur in patients who received linezolid and fluoxetine, paroxetine, or sertraline. Because of several limitations, however, no conclusions can be drawn from that retrospective analysis. A drug interaction involving escitalopram and linezolid has not been documented. Caution should be used when linezolid is used in patients receiving an SSRI. Other antibiotic options should be considered first, and linezolid should be reserved as the last resort if possible. If the infection requires linezolid, the SSRI should be discontinued, and the patient should be monitored closely for serotonin syndrome.

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PubMed2005

Surveillance of linezolid resistance in Germany, 2001-2002.

A surveillance study was performed throughout Germany from November 2001 to June 2002 to assess the prevalence of linezolid-resistant isolates among Gram-positive bacteria from routine susceptibility data and to compare the in-vitro activity of linezolid to that of other antibacterial agents. Each of 86 laboratories provided routine susceptibility data for 100 consecutive isolates. Most laboratories (c. 60%) used the disk diffusion test. Laboratories were also requested to send a representative sample of their isolates, as well as all isolates reported as intermediate or resistant to linezolid, to a reference laboratory for MIC determination. Susceptibility data for 8594 isolates were evaluated. Sites of infection were skin and soft tissue (29.9%), upper and lower respiratory tract (19.1%), foreign body or catheter (10.5%), or urinary tract (9.8%). Routine linezolid susceptibility data were reported for 6433 isolates. The prevalence of linezolid resistance, as reported to the clinician, was 0.4% in Staphylococcus aureus, 0.3% in Staphylococcus epidermidis, 2.9% in Enterococcus faecalis, 2.3% in Enterococcus faecium, 1.4% in Streptococcus pyogenes and 2.9% in Streptococcus agalactiae. Linezolid resistance was not detected in Streptococcus pneumoniae or in viridans group streptococci. Sixty-nine of 115 isolates reported as intermediate or resistant to linezolid were retested, but none was resistant to linezolid. Linezolid exhibited excellent in-vitro activity against representative isolates of the six most frequently encountered species (MIC90, 1-2 mg/L). The prevalence of resistance to linezolid was very low in Germany. Organisms reported as linezolid-resistant should be retested, either in the same laboratory with an alternative method or in a reference laboratory.

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PubMed2003

Hospital resource use and cost of treatment with linezolid versus teicoplanin for treatment of serious gram-positive bacterial infections among hospitalized patients from South America and Mexico: results from a multicenter trial.

BACKGROUND: Linezolid is a novel oxazolidinone antibiotic that is effective for the treatment of gram-positive bacterial infections. The oral formulation has the potential to reduce length of stay (LOS) when used as a substitute for parenteral glycopeptide antibiotics. In a recent multinational trial comparing linezolid (i.v. followed by oral administration) with teicoplanin (i.v. alone or switched to i.m. administration), linezolid was found to have better efficacy (P = 0.005) and similar safety for treating serious gram-positive infections. OBJECTIVE: The purpose of this study was to compare hospital resource use (primarily LOS) and cost of treatment between linezolid and teicoplanin for hospitalized patients with serious gram-positive infections in South America and Mexico using data from the multinational trial. METHODS: In a multinational, Phase IIIb, open-label, comparator-controlled trial, data were collected from hospitalized patients in centers in 6 South America can countries and Mexico with suspected or confirmed serious gram-positive infections. Patients were randomly assigned to receive i.v. linezolid 600 mg BID (for the entire treatment period [7-28 days] or switched to oral linezolid 600 mg BID) or i.v. teicoplanin (for the entire treatment period or switched to i.m. teicoplanin) dosed per approved prescription information. Data on direct medical resource utilization were collected for each patient, including duration and doses of study medication, location of hospitalization and LOS, comedications, tests and procedures, and outpatient service usage. Unit costs for the medical resources were obtained from secondary sources. RESULTS: A total of 203 patients (97 treated with linezolid and 106 treated with teicoplanin) were enrolled from these 7 countries. The unadjusted results showed that compared with teicoplanin, patients treated with linezolid had a 3.1-day shorter mean i.v. antibiotic treatment duration (P < 0.001), a 2.0- to 2.2-day shorter median and mean LOS (P = 0.03), and a 311 US dollars lower mean total cost of treatment (P = NS). After controlling for age, race, sex, site of infection, inpatient location when the antibiotic treatment started, number of historical and current comorbidities, and whether the patient had a diagnosis of systemic inflammatory response syndrome or sepsis, the multivariate adjusted results were similar to the unadjusted results. The linezolid group had a 1.6-day shorter adjusted LOS or 66% greater odds of early discharge (P = 0.049) and a 335 US dollars lower adjusted mean total cost of treatment (P = NS). CONCLUSION: Linezolid was associated with shorter LOS and duration of IV antibiotic treatment than teicoplanin for serious gram-positive infections in the population studied. Linezolid therapy has the potential to reduce the total cost of treatment.

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PubMed2004

Risk factors for anaemia in patients on prolonged linezolid therapy for chronic osteomyelitis: a case-control study.

OBJECTIVES: The intrinsic properties of the new antibiotic linezolid make it an attractive candidate for the treatment of chronic osteomyelitis. However, data regarding the tolerance of long-term linezolid administration are still lacking. METHODS: The medical charts of patients given linezolid for >4 weeks were retrospectively analysed, especially their haematology. In a case-control study, we compared the respective characteristics of patients who developed anaemia during linezolid therapy and those who did not. RESULTS: Forty-five adults with chronic osteomyelitis received 600 mg linezolid intravenously twice daily for 7 days, and then orally, for a mean total duration of 15.9 weeks (range, 6-36). Anaemia episodes requiring blood transfusion occurred in 13/45 patients (28.9%). Median time from treatment initiation to anaemia onset was 7.4 weeks (range, 4-16). Anaemia was significantly associated with premature linezolid therapy cessation (P = 0.0012). No linezolid-related thrombocytopenia was observed. By univariate analysis, four variables were associated with the occurrence of anaemia: age >58 years, alcohol abuse, diabetes mellitus and low haemoglobin before linezolid treatment. Logistic regression analysis revealed two independent risk factors for anaemia: age >58 years (OR = 20.5, 95% CI 0.69-599; P = 0.0001) and pre-treatment haemoglobin <10.5 g/dL (OR = 16.49, 95% CI 1.06-255; P = 0.04). CONCLUSIONS: Profound anaemia may occur in adult patients with chronic osteomyelitis on prolonged linezolid therapy, and often necessitates linezolid cessation. These patients are likely to be aged >58 years and to have low pre-treatment haemoglobin. The results for the present series might help physicians to identify patients who should not be given long-term linezolid treatment for chronic osteomyelitis.

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PubMed2003

Linezolid for the treatment of children with bacteremia or nosocomial pneumonia caused by resistant gram-positive bacterial pathogens.

BACKGROUND: Nosocomial infections, particularly hospital-acquired pneumonia (HAP) and bacteremia, are an increasing concern in pediatric hospitals and pediatric intensive care units. Gram-positive pathogens are a leading cause of these infections in children. Linezolid is well-tolerated and as effective as vancomycin in the treatment of these infections in adults. OBJECTIVE: To evaluate the clinical effectiveness and safety of iv/oral linezolid and iv vancomycin in children with resistant Gram-positive HAP or bacteremia. METHODS: Hospitalized children <12 years of age were randomized 2:1 to linezolid or vancomycin. Patients received linezolid 10 mg/kg iv every 8 h with the option to change treatment to oral linezolid suspension 10 mg/kg every 8 h or iv vancomycin 10 to 15 mg/kg every 6 to 24 h. Clinical response was evaluated at follow-up. Results from an analysis of patients with HAP or bacteremia are presented. RESULTS: Thirty-nine patients (linezolid, 23; vancomycin, 16) with HAP and 113 patients with bacteremia (linezolid, 81; vancomycin, 32) were included in the intent-to-treat group. Clinical cure rates for clinically evaluable patients with HAP did not differ between treatment groups (linezolid, 90.0% and vancomycin, 100%; P = 0.305). No significant difference was seen in clinical cure rates in the clinically evaluable population between the linezolid and vancomycin groups for patients with catheter-related bacteremia (84.8 and 80.0%, respectively; P = 0.716) or patients with bacteremia of unknown source (79.2 and 69.2%, respectively; P = 0.501). In this subset fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19.4% vs. 28.3%; P = 0.230). Similar percentages of patients with laboratory abnormalities, including selected hematologic parameters, were seen in both treatment groups. CONCLUSIONS: Intravenous/oral linezolid was well-tolerated and as effective as vancomycin in treating children with resistant Gram-positive HAP or bacteremia.

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PubMed2003

Hematologic effects of linezolid in young children.

BACKGROUND: Linezolid is an effective and well-tolerated antibiotic for the treatment of Gram-positive infections, including hospital and community-acquired pneumonia and complicated and uncomplicated skin and skin structure infections. In adults linezolid treatment for >/=2 weeks has been associated with reversible hematopoietic suppression, primarily thrombocytopenia. OBJECTIVE: To evaluate the occurrence of hematologic effects in children with Gram-positive infections in an open label study of linezolid vs. vancomycin. METHODS: Detailed analyses of hematologic data, including reported hematologic adverse events, complete blood counts, reticulocyte index (RI) and iron studies (serum iron and transferrin saturation), were conducted in both groups at baseline and during and after treatment with the use of an intent-to-treat analysis. RESULTS: Three hundred sixteen patients (median age, 1.65 yr) randomized 2:1 to linezolid (n = 215) or vancomycin (n = 101) were treated. Total treatment durations were similar in the vancomycin group (12.2 +/- 6.4 days; median, 11.0 days) and the linezolid group (11.3 +/- 5.0 days; median, 11.0 days) (P = 0.20). No significant differences were noted in drug-related hematologic events, such as thrombocytopenia (linezolid, 1.9% vs. vancomycin, 0%; P = 0.170), anemia (linezolid, 1.4% vs. vancomycin, 1.0%; P = 0.771) or neutropenia (linezolid, 0% vs. vancomycin, 0%). Hemoglobin values also were similar between treatment groups when assessed by shifts from baseline to lowest recorded value. Frequency of occurrence of any substantially abnormal value for hemoglobin (15.7% vs. 12.4%), platelets (12.9% vs. 13.4%) and neutrophils (5.9% vs. 4.3%) were similar in the linezolid and vancomycin groups. No clinically relevant changes in RI or iron studies were noted between treatment groups, and parallel increases in RI occurred with both linezolid and vancomycin. CONCLUSIONS: No significant differences in hematologic profiles between linezolid and vancomycin occurred in this pediatric population.

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PubMed2003

Concentrations in plasma, urinary excretion, and bactericidal activity of linezolid (600 milligrams) versus those of ciprofloxacin (500 milligrams) in healthy volunteers receiving a single oral dose.

In a randomized crossover study, 12 volunteers (6 males, 6 females) received a single oral dose of 600 mg of linezolid or 500 mg of ciprofloxacin to assess the concentrations in plasma (up to 24 h), urinary excretion (by high-pressure liquid chromatography), and bactericidal titers in urine (UBT) at intervals up to 120 h. The mean maximum concentration of linezolid in plasma was 13.1 mg/liter, and that of ciprofloxacin was 2.46 mg/liter. The median cumulative levels of renal excretion of the administered dose of the parent drug were 44% for linezolid (range, 28 to 47%; mean +/- standard deviation, 40% +/- 7.8%) and 43% for ciprofloxacin (range, 20 to 56%; mean +/- standard deviation, 40% +/- 9.3%). The UBTs, i.e., the highest twofold dilution (with antibiotic-free urine used as the diluent) of urine that was still bactericidal, were determined for a reference strain and five gram-positive clinical uropathogens for which the MICs of linezolid and ciprofloxacin were as follows: Staphylococcus aureus ATCC 27278, 2 and 0.25 mg/liter, respectively; Staphylococcus aureus (methicillin susceptible), 1 and 16 mg/liter, respectively; Staphylococcus aureus (methicillin resistant), 2 and 64 mg/liter, respectively; Staphylococcus saprophyticus (methicillin susceptible), 1 and 0.25 mg/liter, respectively; Enterococcus faecalis, 2 and 1 mg/liter, respectively; and Enterococcus faecium, 2 and 1 mg/liter, respectively. The median UBTs of linezolid measured within the first 6 h were 1:96 for each of the two enterococcal strains and between 1:128 and 1:256 for the four staphylococcal strains. The median UBTs of ciprofloxacin were 1:64 for the two enterococcal strains; between 1:384 and 1:512 for the two ciprofloxacin-susceptible strains; and 1 (bactericidal activity of undiluted urine only) and 1:2 for the two resistant staphylococcal strains, respectively. The areas under the UBT-time curve (AUBT) for linezolid and ciprofloxacin showed no statistically significant (P<0.05) differences except for a better AUBT for linezolid for the two ciprofloxacin-resistant staphylococcal strains. For linezolid there were no statistically significant differences in UBTs or AUBTs for ciprofloxacin-susceptible and -resistant strains. Thus, the bactericidal activities of linezolid and ciprofloxacin against susceptible strains in urine were comparable, whereas linezolid also exhibited the same good bactericidal activity against ciprofloxacin-resistant strains. Therefore, linezolid should be tested for use as empirical treatment for complicated urinary tract infections due to gram-positive uropathogens in an appropriate clinical trial.

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PubMed2003

Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children.

BACKGROUND: Pediatric infections caused by resistant Gram-positive infections are an increasing concern with limited treatment options. Linezolid, a new oxazolidinone, is active against staphylococci, streptococci and enterococci. OBJECTIVE: To assess clinical efficacy and safety of linezolid vs.vancomycin in antibiotic-resistant Gram-positive infections in children. DESIGN Hospitalized children (birth to 12 years of age) with nosocomial pneumonia, complicated skin/skin structure infections, catheter-related bacteremia, bacteremia of unknown source or other infections caused by Gram-positive bacteria were randomized 2:1 to receive linezolid intravenously followed by oral linezolid or vancomycin and then by an appropriate oral agent. Treatment duration was 10 to 28 days. RESULTS: There were 321 patients enrolled (linezolid 219, vancomycin 102). Clinical cure rates were 79% vs.74% (P = 0.36) and 89% vs.85% (P = 0.31) for linezolid and vancomycin in intent-to-treat and clinically evaluable patients, respectively. Cure rates were similar by age and infection diagnosis. Pathogen eradication rates in microbiologically evaluable patients were high for linezolid and vancomycin, respectively, for methicillin-susceptible S. aureus (95% vs.94%; P = 0.82), methicillin-resistant S. aureus (88% vs.90%; P = 0.89) and methicillin-resistant coagulase-negative staphylococci (85% vs.83%, P = 0.87). In clinically evaluable patients, linezolid-treated patients required significantly fewer days of intravenous therapy compared with vancomycin-treated patients (8.0 +/- 4.8; 10.9 +/- 5.8 days, respectively; P < 0.001). In addition significantly fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19% vs.34%, respectively; P = 0.003). Hematologic events were uncommon and similar between treatment groups. CONCLUSIONS: Linezolid was well-tolerated and as effective as vancomycin in treating serious Gram-positive infections in children.

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PubMed2005

Trends in linezolid susceptibility patterns: report from the 2002-2003 worldwide Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) Program.

Linezolid is an important oxazolidinone antimicrobial for the treatment of infections caused by Gram-positive cocci, especially vancomycin-resistant enterococci and oxacillin-resistant Staphylococcus aureus (ORSA). Since its introduction, however, ribosomal mutations have been detected that produce resistance; thus, longitudinal surveillance remains necessary to monitor for emerging resistance in all geographic areas of oxazolidinone use. The 2003 Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) Program compared linezolid minimum inhibitory concentration (MIC) results with 13-15 comparator antimicrobial agents (8089 isolates) and also with results from an earlier surveillance period (2002). Sampling institutions in the United States of America (USA), Canada, Europe (seven nations), South America (three nations) and the Asia-Pacific (three nations) referred 200 Gram-positive cocci to the central laboratory for MIC processing and identification confirmation. Linezolid resistance (MIC > or = 8 mg/L) was established by alternative susceptibility testing methods as well as by ribosomal target characterisation. Concurrent drug use data were collected. Linezolid activity against the six major organism groups did not vary between years or geographic areas. In contrast, penicillin resistance increased 2% in Streptococcus pneumoniae; macrolide resistance was stable among beta-haemolytic streptococci (19-21%), but increased in S. pneumoniae (+2%); ORSA rates increased 4%; and vancomycin resistance in enterococci was present, but varied markedly by region. Non-clonal linezolid-resistant isolates were detected, each having the same G2576U 23S rRNA target mutation. Furthermore, the first linezolid-resistant, non-USA isolate (S. aureus in Greece) was observed, apparently related to linezolid use. In 2003, near complete activity for linezolid against Gram-positive isolates was again documented (99.93% susceptible) in the ZAAPS Program. Rare linezolid-resistant isolates were identified among enterococci, limited to USA strains. Limited correlations of linezolid resistance to drug use continues, with an average consumption rate of 0.63DDD/100 patient days (a 50% increase since 2002), and indicates the important role of hospital hygiene practice in preventing the dissemination of oxazolidinone resistances, should they be detected.

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PubMed2001

Determination of linezolid in human plasma by LC-MS-MS.

A rapid, sensitive and selective LC-atmospheric pressure-chemical ionization-MS-MS method for the determination of the new antimicrobial agent, linezolid, in human plasma using selected reaction monitoring (SRM) was developed. Linezolid and the internal standard were extracted from the biological samples by solid phase extraction (SPE) and analyzed on a reversed-phase Shim Pack CLC-CN, C18 column with the mobile phase of acetonitrile and 20 mM ammonium acetate solution (4 + 1 v/v). Detection was accomplished using an LCQ mass spectrometer (Finnigan), which was programmed in positive MS-MS mode to permit measurement of the fragment ions of linezolid and internal standard at m/z 296.2 and 223.2, respectively. The assay run-time was less than 3.5 min. Quantitative analysis was based on peak area ratio of linezolid to the internal standard. Calibration plots were established over the concentration range of 0.1-20 micrograms ml-1 of linezolid with the lowest detection limit of 0.05 microgram ml-1 using 10 microliters sample volume. The SPE technique quantitatively recovered linezolid and the internal standard from the plasma samples at a percentage range of 89.1-93.7%. Determination of control samples of linezolid in plasma validated the LC-MS-MS-SRM method. Intra-assay and inter-assay precision were in the range of 5.1-11.4% relative standard deviation, whereas the intra- and inter-accuracy were in the range of 97.5-114.0% of the nominal concentrations of linezolid added. The data confirmed that the plasma samples of linezolid were stable at room temperature and when stored at -20 degrees C for at least 10 d. The developed LC-MS-MS-SRM method is recommended for the determination of linezolid in human plasma.

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PubMed2006

Linezolid and serotonergic drug interactions: a retrospective survey.

BACKGROUND: Linezolid is a reversible, nonselective monoamine oxidase inhibitor. There are currently 11 published case reports of serotonin syndrome being associated with linezolid and selective serotonin reuptake inhibitors (SSRIs). Controversy exists regarding whether linezolid and SSRIs can be given concomitantly. The purpose of this study was to report the incidence of serotonin syndrome in patients receiving linezolid and SSRIs. METHODS: This study was a retrospective chart review of inpatients at the Mayo Clinic (Rochester, MN) with concomitant orders or therapy within 14 days for linezolid and an SSRI from 2000 to 2004. The Sternbach criteria and Boyer criteria for diagnosis of serotonin syndrome were used to identify clinical features of serotonin syndrome. RESULTS: Seventy-two patients received linezolid and an SSRI or venlafaxine within 14 days of each other. Fifty-two patients (72%) received concomitant therapy with linezolid and an SSRI or venlafaxine, and 20 patients (28%) did not receive concomitant therapy but received linezolid and an SSRI within a 14-day period. Overall, only 2 patients (3%) had a high probability of serotonin syndrome. In both patients with high probability, symptoms reversed rapidly on discontinuation of serotonergic therapy. The Boyer criteria were much more specific than the Sternbach criteria for identification of serotonin syndrome. CONCLUSIONS: On the basis of our experience, we suggest that, if the clinical situation warrants use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with SSRIs, without a 14-day washout period and with careful monitoring for signs and symptoms of serotonin syndrome. Serotonergic agents should be promptly discontinued if serotonin syndrome is suspected.

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PubMed2004

Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study.

OBJECTIVES: Linezolid, the only commercially available oxazolidinone, is indicated for the treatment of Gram-positive infections, although little has been published specifically on its use in the critically ill. A randomized, prospective study was therefore performed to compare linezolid with the glycopeptide antibiotic, teicoplanin, for the treatment of suspected or proven Gram-positive infections in an intensive care population. METHODS: Using a double-blind, double-dummy, prospective design, patients were randomized to (i) intravenous linezolid (600 mg/12 h) plus teicoplanin dummy [one dose/12 h for three doses then every 24 h intravenously (iv)] or (ii) teicoplanin (400 mg/12 h for three doses then 400 mg/24 h iv) plus linezolid dummy (one dose/12 h iv). Other antibiotics were used in combination with the trial agents in empirical treatment. Clinical and microbiological assessments were made daily in the first week, and at 8 and 21 days after treatment. RESULTS: One hundred patients received linezolid plus placebo-teicoplanin, whereas 102 received teicoplanin plus placebo-linezolid. Population baseline characteristics were similar in both groups. At end of treatment, clinical success [71 (78.9%) linezolid versus 67 (72.8%) teicoplanin] and microbiological success [49 (70.0%) versus 45 (66.2%)] rates were similar, as were adverse effects, intensive care unit mortality, and success rates at short- and long-term follow-up. Linezolid was superior at initial clearance of methicillin-resistant Staphylococcus aureus (MRSA) colonization (end of treatment, 51.1% versus 18.6%, P = 0.002). Two MRSA isolates showed reduced susceptibility to teicoplanin. CONCLUSIONS: Linezolid has similar safety and efficacy to teicoplanin in treating Gram-positive infections in the critically ill. Short-term MRSA clearance achieved with linezolid suggests better skin and mucosal penetration.

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PubMed2004

Linezolid compared with teicoplanin for the treatment of suspected or proven Gram-positive infections.

The efficacy, safety and tolerability of linezolid was compared with teicoplanin in a randomized, controlled, open-label, multicentre study of 430 patients with suspected or proven Gram-positive infection. Patients received intravenous (iv) +/- oral linezolid 600 mg every 12 h (n = 215) or iv or intramuscular teicoplanin (n = 215) for up to 28 days. Clinical outcomes in the intent-to-treat (ITT) and clinically-evaluable populations and microbiological success rates in microbiologically evaluable patients were assessed at follow-up (test of cure). Investigator assessed clinical cure rates at end of treatment (EOT) in ITT patients treated with linezolid (95.5%) were superior to those of teicoplanin (87.6%) for all infections combined, indicating a 7.9% statistically significant treatment advantage for linezolid (P = 0.005, 95% CI: 2.5, 13.2). Clinical cure rates by baseline diagnosis were consistently higher at EOT for the linezolid versus teicoplanin groups with skin and soft tissue infection (96.6% versus 92.8%), pneumonia (96.2% versus 92.9%) and bacteraemia (88.5% versus 56.7%). The 31.8% treatment advantage in bacteraemic patients (but not for those seen in the other infection categories) for linezolid-treated patients was statistically significant (P = 0.009, 95% CI: 10.2, 53.4). Bacterial eradication rates for linezolid exceeded those of teicoplanin for all infection sites combined but this did not reach statistical significance (81.9% versus 69.8%, respectively; P = 0.056). Adverse event rates were similar between the treatment groups, were mild to moderate in severity, and resolved quickly following treatment. The linezolid group experienced a higher incidence of drug related adverse events (30% versus 17%; P = 0.002), and notably of gastrointestinal effects (13.0% versus 1.9%, P = 0.001). However, antibiotic discontinuation rates as a result of drug related adverse events were similar (4.7% in the linezolid group versus 3.7%). Linezolid was clinically superior to teicoplanin in the treatment of Gram-positive infections.

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PubMed2005

Linezolid for the treatment of multidrug-resistant tuberculosis.

OBJECTIVES: In vitro studies have shown good activity of linezolid against Mycobacterium tuberculosis, including multidrug-resistant strains. However, clinical experience with linezolid in tuberculosis is scarce. METHODS: We report our clinical experience with five consecutive patients with multidrug-resistant tuberculosis infection treated with combination regimens that included linezolid. RESULTS: Two patients had multidrug-resistant Mycobacterium bovis infection, with resistance to 12 antituberculous agents (one of them with HIV co-infection and <50 CD4 cells/mm(3)). The other three patients were infected by multidrug-resistant M. tuberculosis strains, with resistance to all first-line drugs and other second-line drugs. All patients received linezolid in combination with thiacetazone, clofazimine or amoxicillin/clavulanate. Susceptibility tests showed linezolid MIC values < or =0.5 mg/L against all tuberculosis strains tested (standard proportion method, Middlebrook agar 7H10). In all cases, tuberculosis cultures from respiratory samples were sterile after 6 weeks of therapy. Three patients have clinical and microbiological cure of tuberculosis with a combination regimen with linezolid (range: 5-24 months). One patient was lost to follow-up at month 5. The remaining patient has completed 11 months of therapy and is still on treatment. Four patients developed anaemia and needed blood transfusions. In two of these patients, the linezolid daily-dose (600 mg twice a day) was successfully reduced to 50% (300 mg twice a day) to decrease toxicity while maintaining efficacy. Peripheral neuropathy (two patients) and pancreatitis (one patient) were other adverse events observed during linezolid treatment. CONCLUSIONS: In our experience, linezolid has been a valid alternative drug in the management of multidrug-resistant tuberculosis. The prolonged use of linezolid is frequently associated with toxicity, mainly anaemia and peripheral neuropathy, that requires special management.

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PubMed2001

Efficacy of linezolid in treatment of experimental endocarditis caused by methicillin-resistant Staphylococcus aureus.

The efficacies of orally (p.o.) dosed linezolid and intravenously (i.v.) dosed vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in rabbits with experimental aortic-valve endocarditis were investigated. After endocarditis was established with a recent clinical MRSA isolate, rabbits were dosed for 5 days with linezolid (p.o., three times a day) at either 25, 50, or 75 mg/kg of body weight or vancomycin (i.v., twice a day) at 25 mg/kg. The 25-mg/kg linezolid group had a high mortality rate and bacterial counts in the valve vegetations that were not different from those of the controls. Linezolid dosed p.o. at 50 and 75 mg/kg and i.v. vancomycin produced statistically significant reductions in bacterial counts compared to those of the untreated controls. The reduced bacterial counts and culture-negative valve rates for the animals treated with linezolid at 75 mg/kg were similar to those for the vancomycin-treated animals. Concentrations of linezolid in plasma were determined at several points in the dosing regimen. These results suggest that the efficacy of linezolid in this infection model is related to trough levels in plasma that remain above the MIC for this microorganism. At the ineffective dose of linezolid (25 mg/kg) the concentration at sacrifice was 0.045 times the MIC, whereas the concentrations of linezolid in plasma in the 50- and 75-mg/kg groups were 2 and 5 times the MIC at sacrifice, respectively. The results from this experimental model suggest that the oxazolidinone linezolid may be effective for the treatment of serious staphylococcal infections when resistance to other antimicrobials is present.

Acetamides↗
PubMed2002

Pharmacodynamic activity and efficacy of linezolid in a rat model of pneumococcal pneumonia.

Linezolid is a new oxazolidinone antibiotic with potent activity against gram-positive bacteria, including Streptococcus pneumoniae. The pharmacodynamic activity and in vivo efficacy of linezolid were compared to those of ceftriaxone in an immunocompetent rat model of pneumococcal pneumonia. Rats infected intratracheally with 8 x 10(7) CFU of a penicillin-sensitive (MIC, 0.032 microg/ml) strain of S. pneumoniae were treated for 5 days beginning 18 h postinfection. Groups of rats were sham treated with oral phosphate-buffered saline or received oral liquid linezolid at 25 or 50 mg/kg of body weight twice a day (b.i.d.) or subcutaneous ceftriaxone at 100 mg/kg once daily. Mortality was monitored for 10 days postinfection; blood culturing was performed on day 1 (pretreatment) and on days 3, 5, and 10 postinfection for the determination of bacteremia. Serum also was collected for the determination of pharmacokinetic and pharmacodynamic parameters at 30 min and at 3, 5, and 12 h (linezolid) or 3, 5, and 24 h (ceftriaxone) postdose. The cumulative mortality rates were 100% for the sham-treated group, 58.3% for the low-dose linezolid group, 8.3% for the high-dose linezolid group, and 0% for the ceftriaxone group. Rats in each of the antibiotic treatment groups had significantly fewer bacteria (P < 0.00001) in their bronchoalveolar lavage fluid (BALF) on day 3 postinfection than sham-treated rats. There also were significantly fewer organisms in the BALF of rats treated with ceftriaxone than in the BALF of rats treated with either dose of linezolid. Oral linezolid at 50 mg/kg b.i.d. therefore was as effective as ceftriaxone in experimental pneumococcal pneumonia, whereas the 25-mg/kg b.i.d. dose was significantly less effective. All pharmacodynamic parameters reflected efficacy and were significantly different for the two dosage regimens of linezolid (P < 0.01). However, the free-fraction pharmacodynamic parameters predictive of outcome were a value of >39% for the percentage of time in the experimental dosing interval during which the linezolid concentration exceeded the MIC and a value of >147 for the ratio of the area under the serum concentration-time curve to the MIC.

Acetamides↗