1 Department of Microbiology, Leeds General Infirmary & University of Leeds Teaching Hospitals, Old Medical School, Leeds LS1 3EX; 2 Ninewells Hospital & Medical School, East Block, Dundee; 3 Department of Microbiology, Royal Hampshire County Hospital, Winchester, UK
Received 15 January 2003; returned 19 February 2003; revised 27 November 2003; accepted 27 November 2003
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Abstract |
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Keywords: glycopeptides, Gram-positive bacteria, oxazolidinones
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Introduction |
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Linezolid is the first available oxazolidinone that inhibits bacterial protein synthesis by preventing formation of the 70S initiation complex.11,12 Linezolid has in vitro and in vivo activity against a broad range of antibiotic-susceptible and -resistant Gram-positive bacteria, and it lacks cross-resistance with current antimicrobial therapies owing to its novel mechanism of action. In comparative clinical trials, linezolid was as effective as vancomycin for treating nosocomial pneumonia13 and MRSA,14 and as effective as oxacillin-dicloxacillin for the treatment of complicated skin and soft tissue infections.15 This study compared the clinical efficacy, safety and tolerance of linezolid with that of teicoplanin in patients with suspected or proven Gram-positive infections. Secondary objectives included assessment of the microbiological efficacy of linezolid compared with teicoplanin, and to determine the direct medical costs required to achieve an acceptable clinical outcome in patients with documented Gram-positive infections. The latter economic aspects of this study will be reported elsewhere.
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Materials and methods |
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A Phase IIIb study was conducted from November 1999 to December 2000 at 50 investigator sites in 13 countries in Europe and Latin America. In each country, the Pharmacia market company was asked to nominate centres and indicate approximately how many patients they thought could be recruited from each based on the population. Centres were then chosen for their clinical trial experience and adherence to Good Clinical Practice criteria. The study consisted of baseline screening, a treatment phase of 728 days, an end-of-treatment (EOT) assessment within 72 h of the last dose of study medication, a short-term follow-up (STFU) assessment scheduled 714 days after the EOT visit, and a long-term follow-up (LTFU) assessment, 1521 days after the EOT visit, that was considered to be the test-of-cure (TOC) assessment. The patients were hospitalized for at least the first intravenous (iv) dose of study medication, and received clinical, microbiological and safety assessments daily as inpatients, every 6 days after Day 3 as outpatients, and then again at the EOT, STFU and TOC visits. The protocol was designed to reflect local practice as much as possible. The protocol, informed consent form and all other forms of patient information related to the study were reviewed and approved by each investigators independent ethics committee or institutional review board.
The study was designed in a randomized, open-label, comparator-controlled fashion. The study design was intended to reflect real world clinical practice so that cost comparisons could be more accurately evaluated; the pharmaco-economic assessment of the study will be reported elsewhere. The study was randomized to reduce bias in patient selection. The study was open-label because the complexities involved in blinding patients or investigators to the medications in the two treatment arms (e.g. teicoplanin cannot be administered orally) made double-blinding impractical. Some measurements used to assess efficacy (such as microbiological endpoints at baseline and follow-up, and changes in some vital signs) could be interpreted objectively and were to be evaluated by a blinded, third party in an effort to reduce bias. Pharmacia collected the data and carried out data analysis, as is normal practice for a Phase IIIb study. Further data analysis was carried out by and at the request of the authors, during the write up phase. Author access was provided to all data as required.
Patient selection
Approximately 474 patients were to be enrolled in this study and randomized in a 1:1 fashion to receive one of two treatment regimens for 728 days. The study pharmacist or equivalent randomized patients 1:1 to one of the two treatment arms upon enrolment after calling the central randomization telephone number and receiving randomization information and confirmation. Each investigator received unique patient numbers that were to be used on all study medication containers, case report forms and to identify all specimens. Pharmacia generated the randomization list and provided the list to the central randomization service. Eligible participants were hospitalized patients (including those in chronic care facilities) at least 13 years of age and 40 kg in weight. Patients were classified according to primary site of infection during screening (a priori). The randomization was not stratified, but patients with one of four possible primary sites of infection were prospectively enrolled. Eligible patients had confirmed or suspected Gram-positive infection for which treatment with glycopeptide was clinically indicated including pneumonia (hospital-acquired or hospitalized after community-acquired), severe skin and soft tissue infections [infections that could involve the deeper levels (fascia, muscle) or extensive surface areas and required significant medical intervention and hospitalization], right-sided endocarditis, or bacteraemia. Patients must have been willing to complete all study-related activities and were expected to survive with effective antibiotic therapy and appropriate supportive care throughout the study. Baseline screening included severity of illness scoring using standard Systemic Inflammatory Response Syndrome (SIRS) criteria.16
Patients were excluded from participating in the study if they met any of the following conditions: treatment with potentially effective antibiotic therapy within 48 h before study entry; concurrent use of another investigational medication; previous enrolment in a linezolid clinical study; hypersensitivity to linezolid, teicoplanin, or any excipients in any of these formulations; infections that were expected to require more than 28 days of treatment; left-sided endocarditis, osteomyelitis, or central nervous system infections; infected devices that were not removed; known pheochromocytoma, carcinoid syndrome, untreated hyperthyroidism, or uncontrolled hypertension; baseline absolute neutrophil count <500 cells/mm3 or total bilirubin >5 times the upper limit of normal in the presence of known liver disease; infective exacerbations of COPD; and HIV positive patients who required prophylaxis for Pneumocystis carinii. In addition, female patients were excluded if they were pregnant, lactating, or unable to practice adequate birth control methods during the study.
The study sample sizes (i.e. numbers of evaluable patients) were estimated based on a test of equivalence.17,18 Using a two-sided test level of 0.05 and a desired statistical power of 80% under the assumption that each treatment group would yield a 90% success rate, the number of evaluable patients required per treatment group for a determination of equivalence between the two treatment groups to within 10%, was 142 patients. Assuming an evaluability rate of 60%, this translated to a requirement of 237 enrolled patients per treatment group.
Treatment
Patients were randomized in a 1:1 ratio to receive one of the following two treatment regimens for 728 days: iv linezolid (600 mg every 12 h) either for the entire treatment period, or for part of the treatment period with oral linezolid (600 mg every 12 h) provided thereafter; or teicoplanin as per approved local prescribing information [iv or intramuscular (im)] at the discretion of the study investigator. A need for administration of loading doses of teicoplanin or for measurement of serum teicoplanin concentration was not stipulated in the study protocol. Selected antibiotics could be administered concomitantly to cover suspected infections with Gram-negative organisms (aztreonam, gentamicin, amikacin, ciprofloxacin, ceftazidime or imipenem) or anaerobes (metronidazole).
Laboratory testing
All testing was conducted at study site laboratories. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines were followed and laboratory certificates were obtained from each site. The following laboratory variables were measured: haematologyfull blood count with differential; chemistryaspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, amylase, bilirubin, urea, creatinine and electrolytes, calcium, creatine phosphokinase, glucose, -glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), lipase, total protein and uric acid; urinalysis (including microscopic examination); pregnancy test (for women of child-bearing potential). Infection site cultures, Gram stains, blood cultures (two sets at baseline) and antibiotic susceptibility testing were carried out according to local methodology. Etest strips and discs were provided to all laboratories by AB Biodisk.
Efficacy and statistical analyses
All study patient case record forms were reviewed prospectively and retrospectively. Monitoring visits to the investigational sites were conducted by the monitors (before study initiation, at regular intervals during the study and at the end of the study), to ensure that complete and accurate data were being obtained and the protocol was being followed. The investigators/institutions guaranteed access to source documents by Pharmacia personnel and appropriate regulatory agencies. Pharmacia was responsible for independent quality assurance audits of the clinical trial processes at company sites worldwide.
In general, patients were deemed to be evaluable if they fulfilled entry criteria, received at least 80% of the prescribed study medication and returned for follow-up visits. The primary efficacy variable in this study was patient clinical outcome assessed by investigators (IACO) at the EOT and TOC visits, and the Sponsors Assessment of Clinical Outcome (SACO) at the TOC visit. At the EOT and TOC visits, all patients were to be assessed for clinical outcome by the investigator according to the following criteria. Cured: resolution of clinical signs and symptoms of Gram-positive infection, when compared with baseline (e.g. body temperature, white blood cell count). Improvement or lack of progression of infection-related radiographic abnormalities. Improved: improvement in two or more, but not all, of clinical signs and symptoms of Gram-positive infection, when compared with baseline. Improvement or lack of progression of infection-related radiographic abnormalities. This outcome category was only to be used at the EOT evaluation. Failed: Persistence or progression of baseline clinical signs and symptoms of Gram-positive infection; progression of baseline infection-related radiographic abnormalities; development of new clinical findings consistent with active infection. For IACO, a clinical success was defined as a patient who was classified by the investigator as either cured or improved at the EOT assessment. A clinical failure was defined as a patient the investigator classified as failed.
The Sponsors Assessment of Clinical Outcome (SACO) was a more rigorous analysis of clinical outcome in the intent-to-treat (ITT) popu-lation based primarily on the global evaluation by the investigator at both the EOT and TOC (LTFU) visits. The Pharmacia medical and biostatistical teams developed the SACO algorithm/matrix to address the potential influence of confounding variables and duration of treatment on clinical outcome. A two-step procedure initially selected the clinically evaluable patients from the ITT population and then assigned an outcome (success, failed, indeterminate) based on their clinical responses during follow-up. The SACO encompassed the IACO and also took into consideration the concomitant and/or post-treatment use of other antibiotics with significant Gram-positive activity, significant loss to follow-up of patients deemed failures by the investigator at the EOT visit and duration of treatment with study medication regimen. As defined in the protocol, inclusion into the ITT population required only the receipt of one dose of study medication. For the SACO analysis, clinically evaluable ITT patients were required to satisfy all eligibility criteria and have an IACO at both the EOT and TOC assessment. SACO eligible patients were classified as a success if they had not received any prohibited antibiotic therapy during the study (between first dose date of study medication and TOC date), were compliant with study medication for a minimum of 5 days, in addition to being considered a clinical success by the investigator.
The secondary efficacy variables included microbiological outcome. For each of these, the proportions of patients in each outcome category were summarized for each treatment group at follow-up. In addition, for all primary efficacy variables, 95% confidence intervals (CI) for the differences in success rates between the treatment groups were calculated. IACO and SACO analyses were done separately for ITT and modified ITT (MITT) patient populations. The ITT population included all randomized patients who received at least one dose of study medication, and the MITT population included all ITT patients who also had a Gram-positive pathogen isolated at baseline. The microbiologically evaluable population was the MITT population that met the SACO criteria for evaluation.
Safety assessment
All patients who received at least one dose of study medication were included in the safety analysis. Laboratory safety results and vital signs were summarized as change from baseline to each post-baseline visit within treatment groups. Treatment-emergent adverse events, changes in vital signs, physical examinations, laboratory test results and concomitant medication therapy were used to evaluate safety.
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Results |
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Study enrolment was terminated after 438 patients were randomized (Table 1): 219 patients randomized to linezolid and 219 patients randomized to teicoplanin. Of these enrolled patients, 215 patients received at least one dose of linezolid and 215 received at least one dose of teicoplanin, forming the final group of 430 ITT patients that was followed for clinical outcomes and safety. Of the 215 ITT patients in each treatment group, 172 (80%) and 162 (75%) who received linezolid and teicoplanin, respectively, completed both the treatment and follow-up phases of the study. A total of 96 ITT patients (22%) did not complete the required course of treatment (43 linezolid and 53 teicoplanin) and/or return for at least one follow-up visit. The MITT patients comprised 115 and 106 patients treated with linezolid and teicoplanin, respectively. Patient demographics and baseline characteristics are shown in Table 2. Severity of illness at baseline was similarly distributed in the two treatment groups, i.e. numbers of patients with SIRS, sepsis, severe sepsis and septic shock were 118 (113), 51 (55), 4 (6) and 2 (0) in the linezolid (teicoplanin) treatment groups, respectively. In 40 (41) patients, severity of illness was not reported. The distribution of illness severity was very similar between the two treatment groups in each of the infection types (data not shown). Only 34 patients (8%) entered the study with an infected device; 30 of these patients were bacteraemic. Most (30/34) of these patients had the infected device removed before treatment.
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More patients (56%) entered the study with skin and soft tissue infections (123 received linezolid, 117 received teicoplanin) than any other primary infection site. Corresponding figures for pneumonia and bacteraemia were 27% (57, 59) and 15% (32, 33); 83% of the skin/soft tissue lesions in SSTI patients were characterized as deep/extensive lesions. In the ITT patient population, the median size of the lesion was comparable between the linezolid (180 cm2, range: 32310 cm2) and teicoplanin (160 cm2, range: 185 800 cm2) groups. Treatment groups were similar with respect to overall assessment of X-rays and incidence of abnormalities noted; an abnormal X-ray was noted in 55% (154/281) of patients with a baseline radiograph. All pneumonia patients in the study had an abnormal chest X-ray at baseline.
Antibiotic treatment
Approximately 90% of patients in each treatment group received treatment for at least 7 days; median duration was 12 days for the linezolid group and 10 days for the teicoplanin group. Most (82%) linezolid patients were switched to oral dosing during the study. Linezolid patients tended to be dosed iv for shorter periods of time and were more likely to be switched from iv dosing than teicoplanin patients (Table 3). In the ITT population, 66% (141/215) of patients in the linezolid treatment group and 30% (64/215) of patients in the teicoplanin treatment group received iv treatment for <7 days (2 = 55.3, P < 0.001). Eighty-two percent (177/215) of linezolid patients received oral administration of their study medication for a median duration of 8 days. A total of 185 linezolid patients switched at least once between iv and oral administration during the study, with a median time of 4 days until first switch. The median daily dose for all ITT patients receiving teicoplanin was 400 mg (range 200800 mg). The mean daily iv and/or im teicoplanin dose was 355.9, 388.9 and 396.4 mg, in ITT patients with pneumonia, SSTI and bacteraemia, respectively. In bacteraemic patients, the median daily dose of teicoplanin was 6.2 mg/kg body weight (range 3.410.9) in patients treated successfully, and was 6.5 mg/kg (5.99.8) in those who failed. Seventy-one teicoplanin patients switched at least once between iv and im administration during the study, with a median time of 6 days until first switch. The median number of im doses received by teicoplanin patients was 7 (range 127 doses).
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Clinical outcome success rates for linezolid-treated patients exceeded success rates for teicoplanin-treated patients when all infections were combined (ITT and MITT patients), and for the subset of patients with bacteraemia (ITT patients at EOT) (Figure 1and Table 4). IACO assessment of clinical efficacy in the ITT group at EOT demonstrated overall treatment success in 95.5% of the 199 linezolid patients and 87.6% of the 202 teicoplanin patients. The clinical success advantage of linezolid over teicoplanin in treating all infections combined was statistically significant (2 = 7.97, P = 0.005; 95% CI: 2.5, 13.2). IACO success rates by site of infection were: pneumonia 96.2% (51/53) versus 92.9% (52/56) (95% CI: 5.1, 11.8); skin and soft tissue 96.6% (113/117) versus 92.8% (103/111) (95% CI: 2.0, 9.6); and bacteraemia 88.5% (23/26) versus 56.7% (17/30) (95% CI: 10.2, 53.4), at the EOT assessment for the linezolid and teicoplanin groups, respectively. The 31.8% treatment advantage for bacteraemia observed for linezolid-treated patients was statistically significant (
2 = 6.90, P = 0.009; 95% CI: 10.2, 53.4).
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Microbiological efficacy
The proportion of patients who had at least one pathogen isolated at baseline, and the total number of pathogens, was similar in each treatment group. Overall, 261 (61%) of the 430 ITT patients had at least one pathogen isolated at baseline, of which 84.7% had a Gram-positive pathogen. Thus, 51.4% of the ITT population had a Gram-positive pathogen at baseline and comprised the MITT population. The predominant baseline pathogen in both treatment groups was S. aureus (isolated from infection sites in 58% and 50% of linezolid and teicoplanin patients, respectively, who had at least one baseline pathogen). In the linezolid group, other pathogens isolated at baseline included S. pneumoniae (12/133), S. epidermidis (10/133) and/or other coagulase-negative staphylococci (7/133). In the teicoplanin group, other pathogens isolated at baseline included S. epidermidis (14/128), E. faecalis (10/128), S. pneumoniae (9/128) and/or coagulase-negative staphylococci. S. pneumoniae was the most frequently isolated baseline pathogen in pneumonia patients.
Pathogen eradication rates for linezolid exceeded those for teicoplanin for all pathogens and infection sites except for S. pneumoniae and pneumonia, although these differences were not statistically significant (Table 5). For all infection sites combined, the pathogen eradication rate for linezolid was 81.9% (77/94) versus 69.8% (60/86) for teicoplanin (95% CI: 0.3, 24.6; 2 = 3.64, P = 0.056). For pathogens isolated from patients with Gram-positive bacteraemia, linezolid therapy demonstrated a non-significant 21.9% (95% CI: 7.0, 50.9;
2 = 2.00, P = 0.157) pathogen eradication advantage over teicoplanin [76.5% (13/17) versus 54.5% (12/22)] (Table 6).
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Safety
The proportions of patients for whom one or more treatment-related adverse events (AEs) were reported were not significantly different in the two treatment groups: 56.3% (121) of linezolid-treated patients and 51.2% (110) of teicoplanin-treated patients. In general, AEs were rated as mild to moderate in severity, did not result in discontinuation of study medication and resolved quickly after treatment was completed. There were significantly more study emergent AEs of the digestive (22% versus 14%, P = 0.046) and nervous (9% versus 4%, P = 0.03) systems reported in the linezolid group than in the teicoplanin group.
The percentage of patients who experienced drug-related AEs resulting in the discontinuation of study medication was comparable between treatment groups: 4.7% of patients in the linezolid group (10/215) and 3.7% in the teicoplanin group (8/215). More linezolid-treated patients discontinued study participation as a result of digestive AEs (four versus one); more teicoplanin-treated patients discontinued because of AEs associated with the skin system (four versus nil). Of the 23.7% (102) of patients for whom drug-related AEs were reported, linezolid-treated patients (30.2%, n = 65) had AEs more frequently than teicoplanin-treated patients (17.2%, n = 37) (P = 0.002). This difference between treatment groups was most evident for drug-related AEs related to the digestive system (13.0% versus 1.9%, P = 0.001), the body as a whole (11.6% versus 6.0%, P = 0.06) and the metabolic and nutritional system (5.6% versus 0.9%, P = 0.006). The reported rates for haematological AEs were low (less than 3% for all adverse effects combined) for both treatment groups. The mean changes for all haematological assays were comparable between the linezolid and teicoplanin treatment groups. Five linezolid patients (haemolysis, anaemia, leucopenia and thrombocytopaenia, leucopenia, and worsening of anaemia and thrombocytopaenia present at study entry) and three teicoplanin patients (leucopenia, and two patients with anaemia) were reported to have haematological adverse effects rated as moderate or severe. Three patients treated with linezolid had haematological adverse effects (which were one each of haemolysis, anaemia and leucopenia) that resulted in treatment discontinuation.
There were 33 deaths reported among the study patients, 15 and 18 patients treated with linezolid and teicoplanin, respectively. Half of these deaths occurred in bacteraemia patients, who accounted for 15% of the total population. Septic shock (38%) was the most common cause of death overall. Only one death was reported to be related to the study medication, but a review of the clinical records indicated that this relationship was indirect or not related. The patient received both linezolid and later teicoplanin before suffering a cardiac arrest.
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Discussion |
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This is the first randomized, controlled trial comparing linezolid and teicoplanin for the treatment of Gram-positive infection. Clinical cure rates in ITT patients treated with linezolid (95.5%) were superior to those of teicoplanin (87.6%) for all infections combined (P = 0.005; treatment difference 7.9%, 95% CI: 2.5, 13.2). Clinical cure rates by baseline diagnosis were consistently higher for linezolid versus teicoplanin for skin and soft tissue infections, pneumonia, and most notably for patients with bacteraemia (88.5% versus 56.7%; P = 0.009; treatment difference 31.8%, 95% CI: 10.2, 53.4). Although there were relatively few patients with bacteraemia enrolled, it is difficult to explain the apparent marked superiority of linezolid for the treatment of Gram-positive bacteraemia. Firstly, dosing issues are worthy of consideration. The dosage of teicoplanin, including the decision of whether or not to use loading doses, was left to the discretion of the prescribing clinician in this study. The median teicoplanin dosage was 400 mg daily (i.e. approximately 6 mg/kg per day), which is consistent with data sheet recommendations. This recommended dosing schedule usually achieves trough serum concentrations of at least 10 mg/L and appears to correlate with good outcomes in patients with staphylococcal bacteraemia.21 Some clinicians use higher teicoplanin dosaging, particularly in patients with severe sepsis and notably those with endocarditis.22,23 To the best of our knowledge, patients with endocarditis were not included in the study, and indeed left-sided endocarditis was a specific exclusion criterion. Interestingly, the median daily teicoplanin dose in bacteraemic patients who were clinically cured (6.2 mg/kg) was very similar to that in individuals who failed to respond (6.5 mg/kg), suggesting that the difference in observed outcome between these groups was not associated with teicoplanin dosage.
Monitoring of serum teicoplanin concentrations was not required for the study protocol and such data are thus unavailable. However, the relationships between dose and/or serum concentrations of glycopeptides and their efficacy are not well understood. For example, doses resulting in vancomycin trough serum concentrations of 1520 mg/L, well in excess of the MIC, have been associated with persistent MRSA bacteraemia.24 It is also well documented that very high dosages of teicoplanin (1020 mg/kg per day), associated with serum concentrations approximately 10-fold higher than MIC,25 have been found necessary to treat successfully some, but not all cases of staphylococcal endocarditis.22,23,26 The reasons why apparently acceptable serum concentrations of teicoplanin can be associated with therapeutic failure are unknown, and thus uncertainties over what constitutes the correct dosage remain. Furthermore, as the dosages used in this study were at the discretion of the clinician, they reflect current clinical prescribing of teicoplanin. Pea et al.27 have recently highlighted the importance of using loading doses of teicoplanin in critically ill patients to achieve adequate serum concentrations. Data on whether or not loading doses of teicoplanin were used are not available for patients in this study.
Secondly, results of antibiotic susceptibility testing did not indicate that pathogen resistance to teicoplanin or linezolid was an explanation for treatment failure. It is likely that where apparent in vitro resistance was recorded, the disc zone sizes represented a misinterpretation of disc zone reading, or variations in laboratory techniques that resulted in smaller than expected disc zone sizes. The available data do not support the conclusion that such isolates represented true baseline resistance to the study medications. For pathogens isolated from patients with Gram-positive bacteraemia, linezolid therapy was associated with a non-significant 21.9% pathogen eradication advantage over teicoplanin (76.5% versus 54.5%, P = 0.157), although patient numbers in these groups were small. The majority (9/13) of teicoplanin treatment failures in bacteraemic patients were in S. aureus infections, and of these, almost all (8/9) were associated with methicillin-susceptible strains. MIC results where available did not indicate that teicoplanin resistance in vitro was an explanation for such treatment failure.
The other important consideration when considering treatment failures is the intrinsic effectiveness of different agents in serious infection. For example, Gonzalez et al.28 found a marked difference in mortality in bacteraemic patients with pneumonia caused by methicillin-susceptible S. aureus treated with vancomycin (47%) as opposed to cloxacillin (0%). It is possible that the reduced bactericidal activity of glycopeptides compared with ß-lactams against S. aureus may explain such differences. Markedly higher mortality in MRSA bacteraemia was observed in patients treated with vancomycin, as opposed to vancomycin and rifampicin,29 and others have similarly found that clinical cure is only effected in some cases after addition of a second agent to glycopeptide monotherapy.24,30 However, Levine et al.31 found that the median durations of bacteraemia in patients with MRSA endocarditis treated with either vancomycin or vancomycin and rifampicin were both 9 days. Interestingly, linezolid has been shown to be as effective as oxacillin-dicloxacillin for the treatment of SSTI. In those patients with S. aureus SSTI, the bacterial eradication rate was 91.4% compared with 84.5% (P = 0.139) in linezolid and oxacillin-dicloxacillin treated cases, respectively.15
Adverse event rates were similar between the two treatment groups, were mild to moderate in severity, and generally resolved quickly following treatment. Patients in the linezolid group experienced a higher incidence (30% versus 17%) of headache and gastrointestinal effects (nausea, vomiting, diarrhoea), probably reflecting the increased use of oral antibiotic administration in this treatment group. Haematological suppression, and particularly thrombocytopaenia associated with therapy longer than 2 weeks, has been reported in patients treated with linezolid,32,33 and is also associated with high dosage teicoplanin.34 In this study, where the median duration of linezolid treatment was 12 days, thrombocytopaenia was documented in two linezolid-treated patients.
Excellent tissue penetration and 100% oral bioavailability are notable attributes of linezolid.12 It is possible that efficacy differences between glycopeptides and linezolid might be related to superior pharmacokinetic properties of the latter. We have shown that the duration of iv therapy with linezolid was significantly shorter than with teicoplanin. For example, in the ITT population, 66% of patients in the linezolid group versus 30% in the teicoplanin treatment group received iv treatment for <7 days (P < 0.001). Most (82%) linezolid patients were switched to oral dosing during the study, whereas only 33% of teicoplanin patients switched at least once between iv and im administration. These observations are consistent with those seen in comparative studies of linezolid and vancomycin, switching to oral dosing facilitated a shorter hospital stay in linezolid-treated patients.35,36 Such observations should be considered with the findings of this study, when defining the place of linezolid for the management of Gram-positive sepsis. We have shown that linezolid was well tolerated and was clinically superior to teicoplanin in the treatment of Gram-positive infections, but most notably in bacteraemic patients. The reasons for this efficacy difference are worthy of further study.
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Acknowledgements |
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The countries, principal investigators and patient enrolling sites (number of patients enrolled) were: UKDr P. Wilson, Dept of Microbiology UCH London (14); Dr R. Davidson, Dept of Infectious Diseases Northwick Park Hospital London(22); Dr C. Kibbler, Dept of Microbiology Royal Free Hospital London (1); Prof. G. French, Dept of Microbiology St Thomas Hospital London (10); Dr C. Johnson, University Surgical Unit Southampton General Hospital (1); Dr M. Dryden, Dept of Microbiology Royal Hampshire County Hospital (31); Dr M. Wood, Dept of Infectious Diseases Birmingham Heartlands Hospital (1); Dr M. Wilcox, Dept of Microbiology Leeds General Infirmary (12); Dr D. Nathwani, Infection Unit (Ward 42), East Block, Ninewells Hospital and Medical School, Dundee (10); Dr R. Lain, Infectious Unit Aberdeen General Infirmary (3); Dr C. Leen, Ward 41 Edinburgh Western General (10); Dr K. Gould, Dept of Microbiology Newcastle Freeman Hospital (7); Dr. M Morgan, Dept of Microbiology Queen Elizabeth Queen Mother Hospital, Margate (1). ItalyProf. S. Esposito, Clinica Malattie Infettive Seconda Università degli Studi di Napoli (5); Prof. F. De Lalla, Divisione Malattie Infettive Ospedale S.Bortolo Vicenza (7); Prof. G. Martinelli, Istituto di Anestesia e Rianimazione Ospedale S. Orsola Bologna (2); Prof. R. De Gaudio, Istituto di Anestesia e Rianimazione Policlinico Careggi Firenze (3); Prof. P. Ruju; Istituto di Anestesia Rianimazione e Terapia Intensiva Università degli Studi di Sassari (3); Prof. R. Urciuoli, II° Servizio Universitario di Anestesia e Rianimazione Azienda Ospedaliera S.Giovanni Battista di Torino (2). GermanyProf. B. Ruf, Klinikum St. Georg, 2. Innere Med. Leipzig (13); Prof. N. Suttorp, Infectious Diseases Virchow University Hospital Berlin (20); Prof. E. Reisinger, Dept of Tropical & Infectious Diseases University Hospital Rostock (6); Dr C. Spies, Dept of Anaesthesiologie Charite University Hospital, Berlin (10); Dr M. Quintel, Dept of Anaestesiologie & Intensiv Care, University Hospital Mannheim (3). SpainDr X. Garau, Hospital Mutua de Terrassa Servicio de Medicina Interna Planta 15 Barcelona (1); Dr M. De Gorgolas, Fundación Jiménez Díaz Servicio de Enfermedades Infecciosas Madrid (4); Dr J. Capdevilla, Hospital Vall dHebron Servicio de Enfermedades infecciosas Barcelona (2); Dr C. Farinas, Hospital Marqués de Valdecilla Avda Santander (3). BelgiumProf. Clumeck, Service du Maladies Infectieeuses C.H.U Saint-Pierre Brussels (1). SwedenDr T. Holmdahl, Universitetssjukhuset MAS Infektionskliniken Malmö (10); Dr B.M. Eriksson, Akademiska sjukhuset Infektionskliniken Uppsala (9); Dr G. Günther, Centrallasarettet Infektionskliniken Västerås (3). BrazilDr J. Mendonça, Hospital do Servidor Público Estadual Setor Moléstias Infecciosas, São Paulo (12); Dr C. Starling, Hospital Felicio Rocho SCIH Belo Horizonte (10); Dr R. Badaró, Universidade Federal da Bahia Hospital Universitário Salvador (12). ArgentinaDr J. Altclas, Sanatorio Mitre Bartolomé Mitre Buenos Aires (8); Dr J. San Juan, Hospital Muñíz Buenos Aires (9); Dr E. Effron, Hospital Britanico Buenos Aires (10); Dr G. Ambasch, Sanatorio Mayo Cordoba (10); Dr G. Benchetrit, Centro Gallego Buenos Aires (10). MexicoE.R. Noriega MD, Av. Las Americas 620 Sector Hidalgo Guadalajara (22); R. Ariza MD, Seeris y Zaachila s/n Col. La Raza (2); G. Castro MD, Gabriel Mancera 222 Col. Del Valle (8); C. Rivera MD, Monterrey 240-C Col. Roma (18). VenezuelaDr B. Gallegos; Hospital Chiquinquirá Maracaibo-Estado Zulia (10). ColombiaJ.M. Gomez MD, Jefe Sección Enfermedades Infecciosas Departamento de Medicina Interna Fundacion Santafe de Bogota (4). ChileDr L. Bavestrello, Unidad de Infectologia Hospital Gustavo Fricke Viña del Mar (2); Dr L.M. Noriega, Hospital Sótero del Rio Santiago (11). PeruDr J. Caballero, Hospital Nacional Arzobispo Loayza Lima (23); C.R. Sea, Hospital Nacional Cayetano Heredia Instituto de Medicina Tropical Lima (23).
Declaration of interest
Mark Wilcox is currently a member of the UK and Global Pfizer (Pharmacia) Advisory Boards for linezolid. Dilip Nathwani is currently a member of the UK Pfizer (Pharmacia) Advisory Board. Matthew Dryden was an investigator on this trial and other Phase II and III linezolid studies, and is also a member of the UK linezolid Advisory Board. Matthew Dryden has no financial interest in linezolid or in Pfizer. None of the authors received any financial reward specifically for authoring this paper.
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