1 CPL Associates, LLC, 3980 Sheridan Drive, Suite 501, Amherst, NY 14226; 2 School of Pharmacy, University at Buffalo, Buffalo, NY, USA
Received 6 March 2002; returned 4 July 2002; revised 25 July 2002; accepted 21 August 2002
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Abstract |
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Methods: Patients received linezolid in a dosage of 600 mg intravenously (iv) and/or orally twice daily. Clinical and bacteriological responses were assessed after a minimum of 7 days and following completion of therapy.
Results: Seven hundred and ninety-six patients who suffered 828 episodes of infection were enrolled in the linezolid compassionate use protocol. Of these, 183 patients received linezolid for 191 infections caused by S. aureus; in 151 cases, patients were intolerant of vancomycin, had a mixed S. aureus/vancomycin-resistant enterococcal infection or had no iv access, and, in 40 cases, patients had failed to respond to treatment with vancomycin. The median age of the patients was 57 years (range 1493 years) and 53.9% were female. The predominant sites of infection were as follows: bone or joint (27.2%); skin and skin structure (25.1%); bloodstream (20.9%); and lower respiratory tract (12.6%). The clinical success rates in the clinically evaluable and all-treated populations were 83.9% and 62.3%, respectively, whereas the bacteriological eradication rates were 76.9% and 70.2% in the bacteriologically evaluable and all-treated populations, respectively. Linezolid was well tolerated. In 76 (39.8%) of the 191 episodes of infection, patients experienced one or more adverse events or exhibited one or more abnormal laboratory results; in 35 (18.3%) of the 191 cases it was necessary to discontinue treatment. Gastrointestinal tract-related symptoms (nausea, vomiting and diarrhoea) were the most common possibly or probably related adverse events and the most common reasons for drug discontinuation.
Conclusions: Linezolid was effective and well tolerated in patients with S. aureus infections who were enrolled in this compassionate use protocol.
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Introduction |
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Vancomycin, although not without its limitations, has been the drug of choice in most American hospitals for patients with MRSA infections, and the increasing incidence of such infections has led to a corresponding increase in its use. Recently, S. aureus strains with reduced susceptibilities to vancomycin have been identified in Europe, Asia and North America.716 This has caused considerable concern as the glycopeptide was regarded as one of the last options for the treatment of patients with MRSA infections. The administration of vancomycin is also associated with adverse events. It has the potential to cause nephrotoxicity17 and haematological abnormalities,18 and the rapid infusion of the drug may cause systemic histamine release, which is manifested clinically as the red man syndrome.19 Because the oral formulation of vancomycin is not absorbed systemically, treatment of patients with S. aureus infections requires intravenous (iv) administration, thereby impacting on the quality of life of those needing prolonged courses of therapy. Few alternatives are available for patients who cannot tolerate long-term iv treatment, have suffered adverse effects or have developed allergic reactions to the limited number of antibiotics currently available.
The identification of patients with MRSA infections who have failed to respond to, or who are intolerant of, vancomycin and/or teicoplanin has resulted in an urgent need to develop alternative therapeutic agents. Several new antimicrobials are undergoing Phase II or III trials as treatment for infections caused by multidrug-resistant Gram-positive bacteria such as MRSA. Included among these agents are lipopeptides (e.g. daptomycin20), glycopeptides (e.g. dalbavancin, oritavancin and LY33332821) and glycylcyclines (e.g. GAR-93622). The streptogramin quinupristin/dalfopristin, which has been approved by the Food and Drug Administration (FDA) in the USA for the treatment of patients with infections caused by vancomycin-resistant Enterococcus faecium also has activity against MRSA.23
Linezolid is the first synthetic oxazolidinone to become available. It has a broad spectrum of in vitro activity against Gram-positive organisms, including MRSA, vancomycin-resistant Enterococcus faecalis and vancomycin-resistant E. faecium.23,24 Linezolid has been approved by the FDA as therapy for patients with Gram-positive infections, including MRSA nosocomial pneumonia and complicated skin and skin structure infections. The drug is available in both iv and oral formulations, the latter exhibiting 100% bioavailability.
Between October 1997 and May 2000 linezolid was evaluated in a compassionate use programme into which were enrolled patients with infections caused by multidrug-resistant Gram-positive organisms or those who were intolerant of, or who had failed to respond to, other potentially effective antimicrobial agents. We report here on the efficacy and safety of linezolid in the subset of patients in whom S. aureus was identified as a pathogen and who failed to respond to, or who were intolerant of, previous treatment.
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Patients and methods |
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This open-label, non-comparative, non-randomized multicentre study was conducted in the USA. Patients received linezolid in the context of a compassionate use programme if they were diagnosed as having infections caused by Gram-positive bacterial pathogens, such as S. aureus or vancomycin-resistant enterococci (VRE), that were not otherwise treatable with vancomycin. Patients were included in the subset that formed the basis of the current analysis if they had culture-proven S. aureus infections.
The site of infection was determined by the principal investigator according to clinical signs and symptoms and microbiology culture results. Patients were eligible for enrolment if they exhibited signs and symptoms of serious infectious disease, such as fever, rigors, leucocytosis with a prominent shift to the left or marked changes in vital signs. To be included in the subset, they were also required to fulfil one or more of the following criteria: isolation of a strain of S. aureus that exhibited resistance or intermediate susceptibility to currently available antibiotics, including vancomycin; clinical intolerance of licensed antimicrobial agents conventionally used to treat patients with infections caused by S. aureus; inability to tolerate long-term iv treatment; and a documented failure to respond to initial therapy. Patients were considered to have failed treatment with vancomycin if they had received the drug at appropriate dosages for at least 5 days, if specimens from the sites of infection continued to yield the putative pathogens and if they exhibited one or more of the following: persistence of signs and/or symptoms of infection present at baseline; appearance of new signs and/or symptoms; or exacerbation of one or more signs or symptoms present at baseline. Vancomycin intolerance was defined as an adverse event, such as exfoliative dermatitis, anaphylaxis or neutropenia, which necessitated discontinuation of treatment.
Males and females of all ages, including term and preterm neonates, were eligible for inclusion. Patients were excluded from enrolment if they exhibited hypersensitivity to oxazolidinones or one of the excipients in either the iv or oral formulation, but not because of the presence of underlying disease, including impairment of renal or hepatic function. If a foreign body, such as a prosthesis, was deemed to be the source of infection its removal was required. Adult patients were given linezolid 600 mg iv or orally twice a day. Paediatric patients and adults weighing <40 kg received the drug at a dosage of 10 mg/kg iv or per os twice a day.
The duration of treatment was anticipated to be between 5 and 28 days and retreatment was permitted. Patients were classified as requiring retreatment, and hence new patient cases, if they had attended the test-of-cure visit following a previous course of therapy and had developed recurrent or new infections. An interruption of therapy was not classified as a retreatment. It was possible to extend the treatment period to a maximum of 3 months, subject to the approval of the Clinical Pharmacokinetics Laboratory (CPL) monitor.
The antimicrobial susceptibility to linezolid of each S. aureus isolate was determined by the disc diffusion method in the laboratory of the hospital in which the patient was being treated; most isolates were also referred to a central laboratory (Covance, Indianapolis, IN, USA). Susceptibility testing was carried out in accordance with NCCLS guidelines, but the breakpoints used to characterize susceptibility to linezolid were defined by the sponsor. Patients were permitted to receive or continue to receive therapy if diameters of zones of inhibition were 18 mm (susceptible) or 1517 mm (intermediate susceptibility). Isolates for which the diameters were
14 mm (resistant) were excluded or linezolid treatment was discontinued.
Clinicians were required to contact the CPL in Buffalo, NY via a 24 h telephone line in order to discuss each patients condition and to obtain approval before initiating treatment with linezolid. After giving approval, CPL maintained frequent contact with the parental clinical team in order to monitor the clinical response to treatment and to assess tolerability and safety.
Clinical and bacteriological responses were assessed following completion of therapy and at the test-of-cure (follow-up) visit between 7 and 30 days after completing treatment or, in the case of patients with infective endocarditis or bone or joint infections, 6 months and 1 year, respectively, after discontinuing treatment. Clinicians were requested to obtain specimens for culture from the relevant sites on alternate days for the first 6 days or until cultures were negative. Safety assessments were carried out weekly while patients were receiving treatment and following completion of therapy.
Evaluability assessment
Patients were considered clinically evaluable if they fulfilled the following criteria: linezolid had been administered for at least 5 days; the clinical response was classified as either success or failure; a test-of-cure assessment was carried out after linezolid treatment had been discontinued; there were no protocol violations precluding assessment of clinical outcome; and the patients outcome was not classified as indeterminate (e.g. the patient had received treatment for an insufficient duration to enable the outcome to be determined, the patient died from an underlying disease before the response to treatment could be determined, the clinical outcome was associated with a pathogen other than S. aureus, the patient died before the response to infection could be evaluated or other reasons that precluded determination of the clinical outcome). All of the patients who were clinically evaluable, together with those whose clinical responses were classified as indeterminate, were included in the all-treated group. Patients were considered bacteriologically evaluable if a pathogen was isolated within 72 h of receiving the first dose of linezolid; in the case of patients with osteomyelitis, pathogens could be identified up to 7 days before initiating treatment. Patients who received linezolid for <5 days were not included in the clinical or bacteriological efficacy analyses. In addition, patients were excluded from evaluation of bacteriological efficacy if baseline cultures obtained within 24 h of commencing therapy failed to yield S. aureus. However, all patients who received at least one dose of linezolid were included in the safety assessment.
Efficacy assessment
Clinical outcome was categorized by the principal investigator in terms of the global clinical response on completion of therapy with linezolid and at short-term follow-up visits as follows: cure (resolution of the baseline clinical signs and/or symptoms of infection); failure (persistence of the presenting signs and/or symptoms and/or the appearance of new signs and/or symptoms following entry into the study); and indeterminate (inability to assign classification to one of the other categories owing to extenuating circumstances).
The bacteriological outcome in respect of each S. aureus isolate and each indication was also determined at the end of therapy and at the follow-up visits. Bacteriological responses were classified as follows: documented or presumed eradication of the baseline pathogen; documented or presumed persistence of the baseline pathogen; and indeterminate (confounding circumstances precluded classification to one of the other categories).
Safety assessment
Throughout the treatment and post-treatment periods, changes in physical findings, clinical signs and symptoms and laboratory values consistent with serious and non-serious adverse events were documented. A causal relationship between linezolid and an adverse event was determined by the principal investigator and classified as not related, possibly related, probably related or indeterminate (confounding circumstances precluded classification to one of the other categories).
Statistical analysis
Outcomes were calculated according to the total number of patient cases, patients who were retreated being considered new cases. Categorical variables were compared with the Pearsons 2 or Fishers exact test, as appropriate. Continuous variables were compared with the KruskalWallis analysis of variance. P < 0.05 was considered statistically significant.
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Results |
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Baseline demographics and characteristics of all patients according to the reasons for which they were enrolled are shown in Tables 1 and 2. The median age of the patients comprising the 191 cases was 57 years (range 1493 years) and 53.9% were female. The patients enrolled in the study were generally quite ill and exhibited a high prevalence of underlying diseases, including diabetes mellitus, chronic renal failure, a requirement for mechanical ventilation and malignancy. In addition, four patients (one with AIDS) were HIV-positive. More than 50% had life expectancies of <5 years.
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Efficacy
One hundred and ninety-one patient episodes of S. aureus infection were included in the subset analysis. Of these, 40 were not clinically evaluable, most commonly because they received treatment with linezolid for <5 days. The clinical outcome was classified as indeterminate in respect of 39 cases, predominantly because the patients were given linezolid for insufficient duration to enable the outcome to be assessed or because they died from underlying diseases before the response to infection could be determined. The clinical success rates in the clinically evaluable and all-treated populations were 83.9% and 62.3%, respectively (P = 0.0001) (Table 4). The rate was lower for patients who failed to respond to vancomycin than for those who were intolerant of the drug, although the difference was not statistically significant. The clinical success rate varied according to the site of infection, significantly lower rates (69.2%) being observed in patients with bone or joint infections, compared with the rest of the population (P = 0.02) (Table 5). Response rates for patients with bacteraemias and skin and skin structure infections were 85.7% and 91.4%, respectively.
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The bacteriological eradication rate was 76.9% in the bacteriologically evaluable population and 70.2% in the all-treated population (P = 0.3) (Table 4). In common with the clinical success rate, the bacteriological eradication rate was lower among patients who had failed to respond to vancomycin treatment, compared with those who had been enrolled because of intolerance to this drug, although the difference was not statistically significant. The strains isolated from 113 patients were referred to the central laboratory where it was confirmed that all were susceptible to linezolid (MICs 4 mg/L and zone diameters
18 mm).
Safety
All 191 patient episodes were evaluated for safety. Of these, 76 (39.8%) patients reported at least one adverse event or exhibited at least one abnormal laboratory result. Events reported as possibly or probably related to treatment with linezolid are summarized in Table 6. Gastrointestinal tract disturbances (nausea, vomiting and diarrhoea) were the most frequently reported adverse events, as well as being the most common reasons for discontinuing treatment. Gastrointestinal tract symptoms were reported by 19 of 76 (25%) patients, 12 of 59 (20.7%) patients and five of 57 (8.8%) patients receiving the oral formulation of linezolid only, both iv and oral formulations and the iv formulation only, respectively. Of the patients who reported gastrointestinal tract disturbances, a significantly higher percentage received the oral formulation (31 of 134; 23.1%), compared with those who received only the iv formulation (five of 57; 8.8%) (P = 0.02). A reduction in the platelet count was reported in respect of 20 patients, eight of whom were excluded from analysis in the belief that the relationship between the linezolid and the thrombocytopenia was causal; other explanations for thrombocytopenia were not considered grounds for exclusion.
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Discussion |
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The overall median duration of administration of linezolid in the present study was 28 days. This may seem unduly long, considering that only 27.2% of patients had bone or joint infections and only 4.7% had infective endocarditis. The median durations of treatment for patients with bacteraemias and lower respiratory tract infections were 16.5 and 13 days, respectively, these figures representing more typical courses of therapy for infections caused by S. aureus. Many of the skin and skin structure infections were actually deep wound infections, several of which developed in patients with severe peripheral vascular disease; in other cases, the patients may also have been suffering with osteomyelitis, although this diagnosis had not been confirmed. As many of these patients had failed to respond to previous therapy, the parental clinicians, who retained responsibility for the duration of therapy, were reluctant to discontinue treatment with linezolid until they were confident that patients had been cured; hence the prolonged courses.
Linezolid was well tolerated, although mild gastrointestinal tract disturbances were reported in almost 20% of patient episodes. A fall in the platelet count was observed in 10.5% of patient episodes. In every case, however, the adverse events resolved following discontinuation of the drug. In a majority of patients, assessment of the relationship between haematological side-effects and linezolid was confounded by the presence of other potential causes of thrombocytopenia; difficulty in ascribing a causal relationship has been observed previously in emergency and compassionate use trials.25,26 Moreover, unlike traditional patients enrolled in Phase II or III clinical trials, some of the patients in the present study had underlying illnesses that precluded accurate assessment.
This study suffered from methodological limitations arising from the uncontrolled, non-randomized design. Whereas the efficacy and safety of linezolid as treatment for patients with S. aureus infections have previously been investigated in randomized controlled trials,2729 these trials did not evaluate efficacy and safety in patients with S. aureus infections who had failed to respond to vancomycin therapy or who were intolerant of the drug. In this context, our work adds to the collective experience with linezolid.
Osteomyelitis and infective endocarditis caused by S. aureus represent infections that typically require prolonged courses of iv therapy, as well as surgical intervention in some cases, in order to maximize the potential for a successful outcome. The excellent oral bioavailability of linezolid makes the drug an attractive therapeutic option for patients with these infections. Lovering et al.30 reported that linezolid penetrates rapidly into bone, that the drug achieves concentrations in bone that exceed the MIC90s for susceptible organisms (4 mg/L) and that therapeutic concentrations in the drainage fluid surrounding the operative site are maintained for >16 h. There have also been case reports describing successful treatment of patients with osteomyelitis31 or infective endocarditis32 with linezolid. However, randomized controlled trials studying the efficacy of linezolid as treatment for patients with osteomyelitis and infective endocarditis are lacking.
Recently, there have been a small number of reports of the isolation of linezolid-resistant strains of S. aureus33 and VRE.34 Resistant strains were recovered during courses of therapy of five patients with infections caused by VRE34 and of one patient with continuous ambulatory peritoneal dialysis-related peritonitis caused by MRSA.33 All of the patients had received prolonged treatment courses and four of the five who were infected with VRE were transplant recipients. The frequency of resistance to linezolid among strains of MRSA and VRE is, in general, extremely low. Nonetheless, linezolid should be prescribed appropriately in order to minimize the potential for the emergence of resistance.
In conclusion, we have demonstrated the efficacy and safety of linezolid as treatment for patients with S. aureus infections who are intolerant of, or who have failed to respond to therapy with, vancomycin, and who received the drug as part of a compassionate use treatment programme. Linezolid was associated with high clinical and bacteriological response rates, particularly among patients with skin and skin structure infections, bacteraemias and lower respiratory tract infections who were drawn from a patient population for which there were limited treatment options. Linezolid can be administered either orally or by the iv route to patients with a broad range of S. aureus infections and represents a considerable advance over the paucity of alternative drugs currently available as therapy for patients with serious Gram-positive infections.
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Acknowledgements |
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Footnotes |
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References |
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