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PubMed2006

Efficacy of linezolid versus vancomycin in the treatment of methicillin-resistant Staphylococcus aureus discitis: a controlled animal model.

STUDY DESIGN: A rabbit model was used to assess the efficacy of linezolid and vancomycin for the treatment of discitis due to methicillin-resistant Staphylococcus aureus (MRSA). Nontreated controls were used for comparison. OBJECTIVE: The purpose of this study was to determine if there was a therapeutic difference between using linezolid and vancomycin in the treatment of MRSA discitis. SUMMARY OF BACKGROUND DATA: Vancomycin is currently the gold standard treatment for medical management of MRSA discitis. Linezolid is a relatively new drug that has been approved for treatment of MRSA infections, but currently there is no research demonstrating its efficacy at treating infections of the disc space. METHODS: Twenty-four rabbits were inoculated with MRSA at two adjacent lumbar disc spaces via an anterior retroperitoneal approach. Six rabbits were to receive only pain medication and to serve as controls. Ten rabbits were assigned to a 5-day course of intravenous vancomycin, and 8 were assigned to a 5-day course of intravenous linezolid. Disc spaces were sent for quantitative culture after the 5-day treatment course. RESULTS: The mean culture growth for the disc spaces was not statistically different between the linezolid treated group and the nontreated controls. While vancomycin treatment did lead to lower bacterial loads when compared with controls, the reduction was not statistically significant. When bacterial counts for the vancomycin group and linezolid group were compared, vancomycin treatment resulted in less bacterial growth. This difference was statistically significant. CONCLUSIONS: Linezolid is a clinically attractive alternative to vancomycin due to its mild side effect profile and oral bioavailability. However, in this MRSA discitis model with a short treatment course, vancomycin was superior to linezolid.

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PubMed2003

Linezolid pharmacokinetics in pediatric patients: an overview.

BACKGROUND: There are a number of physiologic and developmental differences between children and adults that can influence the absorption, distribution, metabolism and elimination of a drug. Therefore it is important to determine the specific pharmacokinetic characteristics for individual drugs in pediatric patients so that appropriate age-specific dosage regimens can be developed and evaluated in clinical trials. This review summarizes the pharmacokinetic parameters of linezolid in pediatric patients and the rationale for the approved dosing recommendations for this population. METHODS: The pharmacokinetics of linezolid in pediatric patients has been evaluated in 4 clinical trials, including >180 patients ranging in age from preterm newborn infants up to 18 years of age. In all of these studies, patients received a single intravenous dose of linezolid. Plasma linezolid concentrations have been determined by validated high performance liquid chromatography (adult studies) or liquid chromatography/mass spectrometry/mass spectrometry (pediatric studies) methods. RESULTS: The pharmacokinetics of linezolid, especially elimination clearance, is age-dependent. Children younger than 12 years of age have a smaller area under the drug concentration-time curve, a faster clearance and a shorter elimination half-life than adults. Although clearance rates in newborn infants are similar to those in adults, clearance increases rapidly during the first week of life, becoming 2- to 3-fold higher than in adults by the seventh day of life. The clearance of linezolid decreases gradually among young children, becoming similar to adult values by adolescence. The pharmacokinetics of linezolid in children age 12 years and older is not significantly different from that of adults. CONCLUSIONS: Because of the higher clearance and lower area under the drug concentration-time curve, a shorter dosing interval for linezolid is required for children younger than 12 years of age to produce adequate drug exposure against target Gram-positive pathogens.

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PubMed2003

Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates.

BACKGROUND: Gram-positive infections caused by susceptible and resistant strains of Staphylococcus aureus, coagulase-negative staphylococci and enterococci are increasing problems in neonates. Linezolid, a new oxazolidinone, is active against these pathogens and has recently been approved by the Food and Drug Administration for treating Gram-positive infections in pediatric patients. OBJECTIVE: To compare the clinical efficacy and safety of intravenous and oral linezolid with vancomycin (10 to 15 mg/kg every 6 to 24 h) in neonates (age 0 to 90 days). METHODS: Hospitalized infants with known or suspected hospital-acquired pneumonia, complicated skin or skin structure infections, bacteremia or other infections (e.g. pyelonephritis, abdominal abscess) were eligible. Test-of-cure clinical response was evaluated at follow-up. RESULTS: Sixty-three neonates, randomized 2:1 to linezolid (n = 43) or vancomycin (n = 20) were included in the intent-to-treat group. Clinical cure rates at follow-up in the intent-to-treat group were higher, but not significantly different, for linezolid vs. vancomycin (78% vs. 61%; P = 0.196). Corresponding cure rates in clinically evaluable patients were 84% vs. 77% (P = 0.553) for linezolid and vancomycin, respectively. Pathogen eradication rates were as follows in the linezolid and vancomycin groups, respectively: S. aureus (67% vs. 60%; P = 0.850); coagulase-negative staphylococci (88% vs. 100%; P = 0.379); and enterococci (71% vs. 0%; P = 0.168). Results for hematology and chemistry assays were similar between treatment groups. Fewer linezolid-treated neonates had drug-related adverse events than vancomycin-treated neonates (12% vs. 32%; P = 0.058). CONCLUSIONS: Linezolid is well-tolerated and as effective as vancomycin in the treatment of resistant Gram-positive infections in neonates.

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PubMed2003

Linezolid for the treatment of complicated skin and skin structure infections in children.

BACKGROUND: Gram-positive pathogens are a major cause of complicated skin and skin structure infections (CSSSIs) in children. Many pathogens are developing decreased susceptibility to currently used antibiotics, increasing the need for new therapies. Linezolid is well-tolerated and effective in the treatment of these infections in adults. OBJECTIVE: To evaluate the clinical efficacy and safety of iv/oral linezolid and iv vancomycin in children with Gram-positive CSSSIs. METHODS: Hospitalized children <12 years of age were randomized (2:1 ratio) to receive either 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 (according to age). Clinical response, tolerance and safety were evaluated at follow-up. The results of a subset analysis of patients with CSSSIs are presented here. RESULTS: One hundred twenty intent-to-treat patients (linezolid 80, vancomycin 40) with CSSSI were included in this analysis. Clinical cure rates for clinically evaluable patients with CSSSI did not differ between treatment groups (linezolid, 93.2% vs. vancomycin, 90.0%; P = 0.594). Significantly fewer linezolid-treated patients experienced drug-related adverse events than did vancomycin-treated patients (23% vs. 48%; P = 0.006). The percentages of patients with laboratory abnormalities, including selected hematologic parameters, were generally low and similar between the treatment groups. CONCLUSIONS: Linezolid given iv or orally was well-tolerated and safe. It was as effective as vancomycin in treating children with Gram-positive CSSSIs.

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PubMed2006

Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients.

Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens commonly responsible for central nervous system (CNS) infections in neurosurgical patients hospitalized in intensive care units. In order to study the penetration of this antimicrobial into the cerebrospinal fluid (CSF) of such patients, the disposition of linezolid in serum and CSF was studied in 14 neurosurgical patients given linezolid at 600 mg twice daily (1-h intravenous infusion) for the treatment of CNS infections caused by gram-positive pathogens or for prophylactic chemotherapy. Serum and CSF linezolid steady-state concentrations were analyzed by high-pressure liquid chromatography, and the concentration-time profiles obtained were analyzed to estimate pharmacokinetic parameters. The mean +/- standard deviation (SD) linezolid maximum and minimum measured concentrations were 18.6 +/- 9.6 microg/ml and 5.6 +/- 5.0 microg/ml, respectively, in serum and 10.8 +/- 5.7 microg/ml and 6.1 +/- 4.2 microg/ml, respectively, in CSF. The mean +/- SD areas under the concentration-time curves (AUCs) were 128.7 +/- 83.9 microg x h/ml for serum and 101.6 +/- 59.6 microg x h/ml for CSF, with a mean penetration ratio for the AUC for CSF to the AUC for serum of 0.66. The mean elimination half-life of linezolid in CSF was longer than that in serum (19.1 +/- 19.0 h and 6.5 +/- 3.6 h, respectively). The serum and CSF linezolid concentrations exceeded the pharmacodynamic breakpoint of 4 microg/ml for susceptible target pathogens for the entire dosing interval in the majority of patients. These findings suggest that linezolid may achieve adequate concentrations in the CSF of patients requiring antibiotics for the management or prophylaxis of CNS infections caused by gram-positive pathogens.

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PubMed2006

Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia.

The objective of the present study was to determine the mitochondrial toxicity mechanisms of linezolid-related hyperlactatemia. Five patients on a long-term schedule of linezolid treatment were studied during the acute phase of hyperlactatemia and after clinical recovery and lactate normalization following linezolid withdrawal. Mitochondrial studies were performed with peripheral blood mononuclear cells and consisted of measurement of mitochondrial mass, mitochondrial protein synthesis homeostasis (cytochrome c oxidase [COX] activity, COX-II subunit expression, COX-II mRNA abundance, and mitochondrial DNA [mtDNA] content), and overall mitochondrial function (mitochondrial membrane potential and intact-cell oxidative capacity). During linezolid-induced hyperlactatemia, we found extremely reduced protein expression (16% of the remaining content compared to control values [100%], P < 0.001) for the mitochondrially coded, transcribed, and translated COX-II subunit. Accordingly, COX activity was also found to be decreased (51% of the remaining activity, P < 0.05). These reductions were observed despite the numbers of COX-II mitochondrial RNA transcripts being abnormally increased (297%, P = 0.10 [not significant]) and the mitochondrial DNA content remaining stable. These abnormalities persisted even after the correction for mitochondrial mass, which was mildly decreased during the hyperlactatemic phase. Most of the mitochondrial abnormalities returned to control ranges after linezolid withdrawal, lactate normalization, and clinical recovery. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related hyperlactatemia, which resolves upon discontinuation of linezolid treatment.

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PubMed2000

Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections.

This randomized, double-blind, multicenter trial compared the efficacy and safety of linezolid, an oxazolidinone, with those of oxacillin-dicloxacillin in patients with complicated skin and soft tissue infections. A total of 826 hospitalized adult patients were randomized to receive linezolid (600 mg intravenously [i.v.]) every 12 h or oxacillin (2 g i.v.) every 6 h; following sufficient clinical improvement, patients were switched to the respective oral agents (linezolid [600 mg orally] every 12 h or dicloxacillin [500 mg orally] every 6 hours). Primary efficacy variables were clinical cure rates in both the intent-to-treat (ITT) population and clinically evaluable (CE) patients and microbiological success rate in microbiologically evaluable (ME) patients. Safety and tolerability were evaluated in the ITT population. Demographics and baseline characteristics were similar across treatment groups in the 819 ITT patients. In the ITT population, the clinical cure rates were 69.8 and 64.9% in the linezolid and oxacillin-dicloxacillin groups, respectively (P = 0.141; 95% confidence interval -1.58 to 11. 25). In 298 CE linezolid-treated patients, the clinical cure rate was 88.6%, compared with a cure rate of 85.8% in 302 CE patients who received oxacillin-dicloxacillin. In 143 ME linezolid-treated patients, the microbiological success rate was 88.1%, compared with a success rate of 86.1% in 151 ME patients who received oxacillin-dicloxacillin. Both agents were well tolerated; most adverse events were of mild-to-moderate intensity. No serious drug-related adverse events were reported in the linezolid group. These data support the use of linezolid for the treatment of adults with complicated skin and soft tissue infections.

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PubMed2002

Intrapulmonary pharmacokinetics of linezolid.

In this study, our objective was to determine the steady-state intrapulmonary concentrations and pharmacokinetic parameters of orally administered linezolid in healthy volunteers. Linezolid (600 mg every 12 h for a total of five doses) was administered orally to 25 healthy adult male subjects. Each subgroup contained five subjects, who underwent bronchoscopy and bronchoalveolar lavage (BAL) 4, 8, 12, 24, or 48 h after administration of the last dose. Blood was obtained for drug assay prior to administration of the first dose and fifth dose and at the completion of bronchoscopy and BAL. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method, and the total number of alveolar cells (AC) was counted in a hemocytometer after cytocentrifugation. Linezolid was measured in plasma by a high-pressure liquid chromatography (HPLC) technique and in BAL specimens and AC by a combined HPLC-mass spectrometry technique. Areas under the concentration-time curves (AUCs) for linezolid in plasma, ELF, and AC were derived by noncompartmental analysis. Half-lives for linezolid in plasma, ELF, and AC were calculated from the elimination rate constants derived from a monoexponential fit of the means of the observed concentrations at each time point. Concentrations (means +/- standard deviations) in plasma, ELF, and AC, respectively, were 7.3 +/- 4.9, 64.3 +/- 33.1, and 2.2 +/- 0.6 microg/ml at the 4-h BAL time point and 7.6 +/- 1.7, 24.3 +/- 13.3, and 1.4 +/- 1.3 microg/ml at the 12-h BAL time point. Linezolid concentrations in plasma, ELF, and AC declined monoexponentially, with half-lives of 6.9, 7.0, and 5.7 h, respectively. For a MIC of 4, the 12-h plasma AUC/MIC and maximum concentration/MIC ratios were 34.6 and 3.9, respectively, and the percentage of time the drug remained above the MIC for the 12-h dosing interval was 100%; the corresponding ratios in ELF were 120 and 16.1, respectively, and the percentage of time the drug remained above the MIC was 100%. The long plasma and intrapulmonary linezolid half-lives and the percentage of time spent above the MIC of 100% of the dosing interval provide a pharmacokinetic rationale for drug administration every 12 h and indicate that linezolid is likely to be an effective agent for the treatment of pulmonary infections.

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PubMed2003

Pharmacokinetics and efficacy of linezolid in a gerbil model of Streptococcus pneumoniae-induced acute otitis media.

The oxazolidinone linezolid represents a new antibacterial class of potential benefit in managing multidrug-resistant gram-positive infections, including those caused by Streptococcus pneumoniae. In a gerbil model of acute otitis media (AOM) induced by either penicillin-resistant S. pneumoniae (PRSP; amoxicillin MIC = 8 micro g/ml, linezolid MIC = 1 micro g/ml) or penicillin-susceptible S. pneumoniae (PSSP; amoxicillin MIC = 0.015 micro g/ml, linezolid MIC = 1 micro g/ml), we explored the plasma and ear fluid levels of linezolid required to demonstrate efficacy. Threshold pathogen doses required to induce bilateral AOM (1,500 CFU/ear with PRSP; 30 CFU/ear with PSSP) were administered to gerbils by intrabullar injection on day 0. At peak infection ( approximately 10(6) to 10(7) CFU/ear flush; day 2 for PRSP-AOM and day 3 for PSSP-AOM), twice-a-day oral doses of linezolid, amoxicillin, or vehicle were administered over 4.5 days prior to collection and assay of middle ear effluents for S. pneumoniae content. Linezolid doses of >/=10 mg/kg of body weight induced significant cure rates of >/=72% versus both PRSP and PSSP infections, whereas amoxicillin at </=100 mg/kg was consistently effective only versus PSSP-AOM. Plasma and ear fluid levels of linezolid necessary to elicit pneumococcal eradication from the middle ear were measured by high-performance liquid chromatography-tandem mass spectrometry and found to be similar both within and between each infection protocol. The plasma-ear fluid pharmacodynamic profile associated with linezolid efficacy was a T>MIC of >/=42%, a C(max)/MIC ratio of >/=3.1, and a (24-h area under the curve)/MIC ratio of >/=30 h. Application of this model will be useful in defining preclinical pharmacodynamic relationships of novel antibiotics necessary to cure S. pneumoniae-induced AOM.

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PubMed2005

In vitro activity of linezolid against key gram-positive organisms isolated in the united states: results of the LEADER 2004 surveillance program.

Since the approval of linezolid in 2000, sporadic reports of resistance have been given and a greater understanding of the underlying mechanisms of resistance has been gained. However, since these developments, an updated status of the in vitro activity of linezolid against gram-positive organisms from the United States has not been reported. The LEADER 2004 surveillance initiative was undertaken to obtain current and representative data on the activity of linezolid against key species, including isolates with significant resistance phenotypes. Organisms were isolated during 2004 and included 2,872 Staphylococcus aureus, 496 coagulase-negative staphylococcus (CNS), 428 Enterococcus faecalis, 196 Enterococcus faecium, and 422 Streptococcus pneumoniae isolates. All S. aureus isolates (54.2% oxacillin resistant) were susceptible to linezolid (MIC90 = 2 microg/ml); MIC distributions were consistent, regardless of oxacillin or multidrug resistance status. For CNS, one nonsusceptible isolate was encountered (Staphylococcus epidermidis; MIC = 32 microg/ml), but overall, the MIC(90) (1 microg/ml) was lower than that obtained with S. aureus. For E. faecalis and E. faecium, 99.5% and 96.4% of isolates, respectively, were linezolid susceptible. Both species had an MIC90 of 2 microg/ml, and MIC distributions did not vary with the vancomycin susceptibility status of the populations analyzed. Linezolid nonsusceptibility was not encountered among the S. pneumoniae isolates. These findings indicate that linezolid nonsusceptibility has remained rare among staphylococci and uncommon and sporadic among enterococci. Nonetheless, careful and ongoing monitoring of the in vitro effectiveness of linezolid will be needed so that any changes to the current status may be detected as soon as possible.

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PubMed2006

Linezolid in prophylaxis against experimental aortic valve endocarditis due to Streptococcus oralis or Enterococcus faecalis.

There are no experimental studies regarding the prophylactic efficacy of linezolid against infective endocarditis. Nonbacterial thrombotic endocarditis of the aortic valve was induced in rabbits by the insertion of a polyethylene catheter. Twenty-four hours later, animals were randomly assigned to a control group, and groups receiving either ampicillin (two doses of 40 mg/kg of body weight each, given intravenously, 2 h apart) or linezolid (a single per os dose of 75 mg/kg). The first dose of ampicillin and the single dose of linezolid were administered 0.5 and 1 h, respectively, prior to the intravenous inoculation of approximately 10(7) CFU of Streptococcus oralis or Enterococcus faecalis. Linezolid peak levels in rabbit serum were similar to the peak serum levels in humans following a 600-mg oral dose of linezolid. Linezolid prevented endocarditis in 87% of S. oralis-challenged rabbits (P < 0.001 versus controls; P = 0.026 versus ampicillin). In rabbits challenged with E. faecalis, linezolid prevented endocarditis in 73% (P = 0.003 versus controls; P = 0.049 versus ampicillin). Ampicillin prevented endocarditis due to S. oralis or due to E. faecalis in 47% (P = 0.005 versus controls) and in 30% (P = not significant versus controls) of the challenged animals, respectively. In conclusion, linezolid was effective as prophylaxis against endocarditis caused by a strain of S. oralis and to a lesser degree against that caused by a strain of E. faecalis. Its prophylactic efficacy was superior to that of ampicillin.

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PubMed2005

Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis.

BACKGROUND: Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens. OBJECTIVE: To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients. METHODS: We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 microg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 microg/mL), Bacteroides fragilis (MIC 2.0 microg/mL), and Peptostreptococcus magnus (MIC 1.0 microg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated. RESULTS: Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 microg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 microg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (> or =6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 microg/mL) as well as the strain of VRE and P. magnus. CONCLUSIONS: Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC > or =4.0 microg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.

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PubMed2002

Multicenter assessment of the linezolid spectrum and activity using the disk diffusion and Etest methods: report of the Zyvox(R) antimicrobial potency study in Latin America (LA-ZAPS).

Linezolid was the first clinically applied member of the new antimicrobial class called the oxazolidinones. These agents have a powerful spectrum of activity focussed against Gram-positive organisms including strains with documented resistances to other antimicrobial classes. We conducted a multicenter surveillance (Zyvox Antimicrobial Potency Study; ZAPS) trial of qualifying Gram-positive isolates from 24 medical centers in eight countries in Latin America. The activity and spectrum of linezolid was compared to numerous agents including glycopeptides, quinupristin/dalfopristin, beta-lactams and fluoroquinolones when testing 2,640 strains by the standardized disk diffusion method or Etest (AB BIODISK, Solna, Sweden). The linezolid spectrum was complete against staphylococci (median zone diameter, 29 - 32 mm), as was the spectrum of vancomycin and quinupristin/dalfopristin. Among the enterococci, no linezolid resistance was detected, and the susceptibility rate was 93.1 - 96.4%. Only the vancomycin-susceptible Enterococcus faecium strains remained susceptible (92.8%) to quinupristin/dalfopristin. Marked differences in the glycopeptide resistance patterns (van A versus van B) were noted for the 22 isolates of VRE, thus requiring local susceptibility testing to direct therapy. Streptococcus pneumoniae and other species were very susceptible (100.0%) to linezolid, MIC(90) at 0.75 microg/ml. Penicillin non-susceptible rate was 27.7% and erythromycin resistance was at 17.4%. Other streptococci were also completely susceptible to linezolid (MIC(90), 1 microg/ml). These results provide the initial benchmark of potency and spectrum for linezolid in Latin American medical centers. Future comparisons should recognize that the oxazolidinones possess essentially a complete spectrum coverage of the monitored staphylococci, enterococci and streptococcal isolates in 2000-2001. This positions linezolid as the widest spectrum empiric choice against multi-resistant Gram-positive cocci, a spectrum of activity greater than available glycopeptides and the streptogramin combination.

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PubMed2003

Linezolid clearance during continuous venovenous hemodiafiltration: a case report.

OBJECTIVE: To determine the linezolid clearance and serum concentrations in a critically ill man receiving continuous venovenous hemodiafiltration (CVVHDF). METHODS: Intravenous linezolid 600 mg every 12 hours was administered to a critically ill, 85-year-old man with anuria who was receiving CVVHDF at a dialysate flow rate of 2000 ml/hour and a mean ultrafiltrate production rate of 775 ml/hour. Samples of blood and spent dialysate and ultrafiltrate were obtained at the time of linezolid peaks and troughs, and linezolid concentrations were determined. RESULTS: The CVVHDF yielded a mean linezolid clearance of 36.5 ml/minute and an elimination half-life of 7.5 hours. The linezolid saturation coefficient ranged from 0.77-0.81. Administration of intravenous linezolid 600 mg every 12 hours yielded suitable serum trough concentrations. CONCLUSION: Administration of intravenous linezolid 600 mg every 12 hours maintained therapeutic serum trough concentrations in this critically ill patient receiving CVVHDF.

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PubMed2004

Linezolid therapy for orthopedic infections.

OBJECTIVE: To assess the clinical and bacteriological efficacy and the safety and tolerability profile of linezolid when used as the primary component of a combined surgical and antimicrobial treatment strategy for orthopedic infections. PATIENTS AND METHODS: We retrospectively reviewed medical records to obtain clinical, bacteriological, and safety outcomes of 20 consecutive patients who took linezolid for the treatment of orthopedic infections between April 1, 2000, and November 30, 2002. RESULTS: Twenty patients received linezolid therapy for microbiologically confirmed orthopedic infections due to gram-positive cocci during the 32-month study period. Fifteen patients (75%) had infections involving orthopedic hardware; in 10 of these patients, the hardware was removed. All 20 patients underwent surgical débridement. At a mean follow-up of 276 days, 11 patients (55%) achieved clinical cure, 7 (35%) had clinical improvement but received long-term antimicrobial suppressive therapy, 1 (5%) had clinical relapse after discontinuing linezolid treatment, and 1 (5%) died of a cause unrelated to linezolid treatment. Bacterial persistence was documented in 3 patients (15%), all of whom were Infected with methicillin-resistant Staphylococcus aureus. Eight patients (40%) developed reversible myelosuppression, 1 (5%) had irreversible peripheral neuropathy, and 2 (10%) discontinued linezolid treatment because of pancytopenia or urticaria. CONCLUSION: Oral linezolid may be an effective alternative therapy for orthopedic infections due to linezolid-susceptible gram-positive bacteria in patients who are unable to take other antimicrobial drugs because of drug allergy or Intolerance or antimicrobial resistance.

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PubMed2006

Possible macular exanthema associated with linezolid therapy.

OBJECTIVE: To report a case of macular exanthema associated with linezolid therapy. CASE SUMMARY: A 54-year-old white man diagnosed as having laryngeal epidermoid carcinoma attended our emergency department because of fatigue, fever, neck pain and a fistulized fixed mass in the right side of the neck with purulent exudation. Treatment with amoxicillin/clavulanic acid 875 mg/125 mg p.o. every 8 hours as empirical therapy was started. Cultures of the exudates from the fistula confirmed the presence of methicillin-resistant Staphylococcus aureus (MRSA). Amoxicillin/clavulanic acid was discontinued and therapy was started with linezolid 600 mg p.o. every 12 hours but 5 days after commencing linezolid the patient came to our emergency room because of generalized erythematous macular eruptions. A diagnosis of severe and generalized macular exanthema induced by linezolid was made. Administration of linezolid was suspended and there was an improvement in the skin lesions and general state of health. The patient was discharged without further symptoms. DISCUSSION: In this case, there was a close temporal correlation between drug exposure and the onset of symptoms. When linezolid was discontinued, the skin lesions resolved quickly and the general condition of the patient improved. Furthermore, linezolid was the only drug added before the cutaneous lesions appeared. It is possible that the adverse reaction was associated with administration of amoxicillin/clavulanic acid. However, the patient had been treated with this antibiotic previously without appearance of any cutaneous reaction. An objective causality assessment revealed that an adverse effect was possible. CONCLUSION: Based on our observations, we conclude that linezolid was the most likely cause of the adverse reaction. Clinicians should be aware of this infrequent but severe reaction.

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PubMed2003

[The first clinical experiences in Hungary with a new effective antibiotic (linezolid) effective against Gram-positive infections].

INTRODUCTION: The occurrence of gram-positive infections caused by multiresistant organisms has increased significantly in general, particularly among the surgical patients, and only a few effective antibiotics are available. A new and effective, synthetic antibiotic, against gram-positives is the oxazolidinon group, that electively inhibits bacterial protein synthesis in the early phase. Linezolid, the first member of this group to be used in clinical practice is the linezolid was studied. AIMS: The purpose of this study was to evaluate the effectiveness and safety of linezolid in the gram-positive infections of surgical patients. METHODS: A 3rd phase, clinical trial was conducted at the Semmelweis University Ist Surgical Department in the period of 1999-2001. Twenty-one patients with gram-positive infections were enrolled to this study. The mean of age was 57 years. Patients were selected for linezolid treatment in whom the conventional anti-gram-positive antibiotic therapy caused difficulties. RESULTS: Sixteen patients out of 21 recovered, one patient was cured clinically, but not microbiologically, and one case showed microbiological cure with clinical failure. In one case the methicillin resistant Staphylococcus aureus carriership was cured. Two cases had a fatal outcome. The causes of death were mediastinitis plus pneumonia in one case, and diffuse peritonitis with renal insufficiency in the other. Withdrawal from the study occurred in one case, due to drug intolerance. CONCLUSIONS: The linezolid administration proved to be safe and effective even in those cases, in which either hypacusis or decreased renal function persisted, or oral intake was advantagous. Contraindication of linezolid therapy did not occur. Few side effects were observed. If the infection was polymicrobial, the linezolid could be combined with other antibiotics. Further investigations are mandatory to evaluate the role of linezolid in the treatment of methicillin resistant Staphylococcus aureus carriership.

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PubMed1999

Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center.

Oxazolidinones represent a novel class of antibiotics that inhibit protein synthesis in sensitive bacteria. The mechanism of action and location of the binding site of these drugs is not clear. A new representative of oxazolidinone antibiotics, linezolid, was found to be active against bacteria and against the halophilic archaeon Halobacterium halobium. The use of H. halobium, which possess only one chromosomal copy of rRNA operon, allowed isolation of a number of linezolid-resistance mutations in rRNA. Four types of linezolid-resistant mutants were isolated by direct plating of H. halobium cells on agar medium containing antibiotic. In addition, three more linezolid-resistant mutants were identified among the previously isolated mutants of H. halobium containing mutations in either 16 S or 23 S rRNA genes. All the isolated mutants were found to contain single-point mutations in 23 S rRNA. Seven mutations affecting six different positions in the central loop of domain V of 23 S rRNA were found to confer resistance to linezolid. Domain V of 23 S rRNA is known to be a component of the ribosomal peptidyl transferase center. Clustering of linezolid-resistance mutations within this region strongly suggests that the binding site of the drug is located in the immediate vicinity of the peptidyl transferase center. However, the antibiotic failed to inhibit peptidyl transferase activity of the H. halobium ribosome, supporting the previous conclusion that linezolid inhibits translation at a step different from the catalysis of the peptide bond formation.

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