The efficacy and safety of linezolid as treatment for Staphylococcus aureus infections in compassionate use patients who are intolerant of, or who have failed to respond to, vancomycin

Pamela A. Moise1, Alan Forrest1,2, Mary C. Birmingham1 and Jerome J. Schentag1,2,*

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective: The incidence of infections caused by methicillin-resistant Staphylococcus aureus continues to increase annually. Unfortunately, only a few therapeutic agents are available for the treatment of patients with such infections and all of the existing drugs have limitations. A pressing need exists, therefore, to identify new antibiotics for use in this clinical setting. The efficacy and safety of linezolid were studied in a compassionate use treatment programme and the results of treating a subset of patients with S. aureus infections are presented here.

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 14–93 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.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Gram-positive bacteria, particularly Staphylococcus aureus, are increasingly common causes of nosocomial and community-acquired infections.13 Penicillin was successful therapy for patients with S. aureus infections until the emergence of resistance, mediated by penicillinase production; today, between 70% and 90% of S. aureus isolates are resistant to this drug.4,5 Subsequently, oxacillin, methicillin and other semi-synthetic penicillins were used effectively to treat patients with infections caused by penicillin-resistant strains of S. aureus. In 1975 only 2% of S. aureus isolates in the USA were methicillin resistant.5 By 1998, however, methicillin-resistant S. aureus (MRSA) rates had risen to 54.5% according to data from the National Nosocomial Infections Surveillance System of the Centers for Disease Control and Prevention.6

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design

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 15–17 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 patient’s 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 patient’s 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 Pearson’s {chi}2 or Fisher’s exact test, as appropriate. Continuous variables were compared with the Kruskal–Wallis analysis of variance. P < 0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Altogether, 796 patients who were treated for 828 infections were enrolled in the linezolid compassionate use programme. S. aureus was isolated from 183 patients with 191 infections; 92.7% of the strains were methicillin resistant. Of the 191 infections, 40 patients had failed to respond to vancomycin therapy and 151 were included for the following reasons: history of allergy to vancomycin (n = 19); adverse events developing during treatment with vancomycin, i.e. rash (n = 39), anaphylaxis (n = 15), neutropenia (n = 10), nephrotoxicity (n = 7), exfoliative dermatitis (n = 6), urticaria (n = 6), Stevens’ Johnson syndrome (n = 5), ototoxicity (n = 3) and the ‘red man’ syndrome (n = 2); inability to tolerate long-term iv treatment with vancomycin (n = 28); and concurrent infection with VRE (n = 10) or a vancomycin-dependent enterococcus (VDE) (n = 1).

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 14–93 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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Table 1.  Baseline demographics of patients with S. aureus infections treated with linezolida
 

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Table 2.  Characteristics of patients with S. aureus infections treated with linezolida
 
The types of infection are summarized in Table 3. The predominant indications for treatment were bone or joint infections, skin and skin structure infections, bacteraemias and lower respiratory tract infections.


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Table 3.  Types of infection in patients treated with linezolida
 
The overall median duration of treatment with linezolid was 28 days. The median durations for the individual types of infection were as follows: bone or joint infections, 45.5 days; infected devices, 39 days; upper respiratory tract infections, 30 days; skin and soft tissue infections, 28 days; central nervous system infections, 26.5 days; intra-abdominal infections, 26 days; infective endocarditis, 21 days; urinary tract infections, 17 days; bacteraemias, 16.5 days; and lower respiratory tract infections, 13 days. Eighty-six patients received the drug for >28 days. Sixteen were treated for 3 months, the maximum duration allowable according to the protocol. Of these 16 patients, eight continued therapy outside of the protocol, either through an investigational new drug application (n = 7) or by purchasing linezolid when it became commercially available (n = 1). Eight (4.4%) patients received second courses of therapy owing to recurrences of their infections following the test-of-cure visit. Recurrences were observed in three patients with lower respiratory tract infections, three with skin and skin structure infections, one with osteomyelitis and one with infective endocarditis.

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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Table 4.  Clinical and bacteriological success rates for linezolid according to reason for enrolment
 

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Table 5.  Clinical success rates for linezolid treatment episodes according to type of infection
 
Classification and regression tree modelling was used to identify factors associated with the clinical response. This produced a tree with three subgroups or terminal nodes. One hundred and twelve cases were clinically evaluable for classification and regression tree analysis. The overall clinical success rate for this population was 83.9%. Site of infection and reason for enrolment correlated with the clinical response. The success rates for patients with infections at sites other than bones and joints who were enrolled because they were intolerant of vancomycin were higher than those for patients with the same infections who were enrolled because of vancomycin treatment failure (P = 0.02).

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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Table 6.  Adverse events, including abnormal laboratory results, possibly or probably related to linezolid in patients who received at least one dose
 
The incidence of adverse events and abnormal laboratory results among the 828 patient episodes during which at least one dose of linezolid was administered were not statistically different from those among the 191 episodes of S. aureus infection, with the exception of the incidence of gastrointestinal tract disturbances, i.e. the incidence was significantly higher (P = 0.0004) among patients given linezolid specifically for S. aureus infections than among the total patient population enrolled in the linezolid compassionate use programme.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with S. aureus infections who were entered into the linezolid compassionate use programme were debilitated and had multiple underlying medical problems. Even then, the clinical and bacteriological success rates among patients in the evaluable population were 83.9% and 76.9%, respectively. The observation that success rates for patients in the evaluable population were higher than those in the all-treated population reflects the decision to classify patients with indeterminate responses as failures and to include them in the latter category. Furthermore, 70% of patients who had failed to respond to treatment with vancomycin responded favourably to linezolid. Clinical success following treatment with linezolid was also observed in 93.8% of patients who were unable to tolerate long-term iv vancomycin therapy. The lowest clinical success rate was seen in patients with bone or joint infections. This is not altogether surprising as some of these patients will have had chronic osteomyelitis, a disease requiring surgical intervention which they may not have received.

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.


    Acknowledgements
 
This programme would not have been possible without the considerable efforts of the following clinical pharmacists who contributed to the screening and enrolment processes: Gabrial S. Zimmer, Jennifer D. Root, Katherine E. Welch, Alison K. Meagher, Patrick F. Smith, James D. Scott, Kristin K. Gilliland, Linda D. Dresser, Tracy R. Perry, Alice M. O’Donnell, research assistants Sue Flavin and Vaunne Ma, and the Linezolid Compassionate Use investigators and coordinators. The assistance of Wendy A. Callen, Denise M. Knapp and Jenna L. Sunderlin at CPL Associates, LLC is also greatly appreciated. The authors thank the staff at the investigative sites. Participating investigators in the Linezolid Compassionate Use Study were as follows: S. Antony; S. Aronin; S. Balter; C. Banerjee; D. H. Batts; G. Bedsole; A. Belani; R. Betts; M. C. Birmingham; R. Blinkhorn; E. Blumberg; B. Bock; R. Bracis; B. P. Buggy; F. Cook; R. Corey; B. Corigliano; H. Cranston; S. S. Crider; S. F. Davies; P. Eder; L. Eron; R. W. Finberg; M. Finney; D. Frohnapple; M. Ganapathy; M. Gareca; J. Garner; M. Golden; C. Gonzalez; R. P. Goodman; D. Graham; C. Ham; M. Harrison; J. Havlik; D. Herr; R. Holman; M. Holodniy; B. Hotchkiss; L. Jauregui; P. Katona; C. Kauffman; R. Klein; S. Klotz; T. Kuberski; A. Lentnek; J. R. Little; H. Malech; R. Marosok; D. McClain; S. McQuone; K. Mullane; F. K. Murphy; A. R. Murry; R. Murthy; D. Nafziger; R. Nahass; R. Nieman; P. E. Nolan; J. Patterson; D. Reece; D. Regier; L. S. Rusakow; R. Salata; M. Schlachter; H. Schrager; J. Schwebke; C. Singer; P. Sioson; J. Sivalingam; J. Slim; J. S. Smith; R. Snepar; A. Srbinoska; D. Stevens; R. Stiller; J. Stone; Z. Temesgen; L. Thielen; J. Tomayko; L. Veach; E. Walsh; C. Watkins; G. Wortmann; and B. A. Yirinec. This study was supported in part by a grant from Pharmacia and was presented in part at the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 17–20 September 2000.


    Footnotes
 
* Corresponding author. Tel: +1-716-839-4931; Fax: +1-716-839-5138; E-mail: schentag{at}buffalo.edu Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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