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Linezolid for the Treatment of Multidrug-Resistant, Gram-Positive Infections: Experience from a Compassionate-Use Program

  1. Mary C. Birmingham1,
  2. Craig R. Rayner1,a,
  3. Alison K. Meagher1,
  4. Susan M. Flavin1,
  5. Donald H. Batts3,a, and
  6. Jerome J. Schentag1,2
  1. 1CPL Associates, University at Buffalo, Buffalo, New York
  2. 2School of Pharmacy, University at Buffalo, Buffalo, New York
  3. 3Pharmacia Corporation, Kalamazoo, Michigan
  1. Reprints or correspondence: Dr. Jerome J. Schentag, University at Buffalo Clinical Pharmacokinetics Laboratory, 543 Hochstetter Hall, Amherst Campus, Buffalo, NY 14260 (schentag{at}buffalo.edu).

  • ↵Present affiliations: Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia (C.R.R.); and Michigan State University, Kalamazoo Campus (D.H.B.).

 
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Abstract

Linezolid was provided for treatment of multidrug-resistant, gram-positive infections through a compassionate-use program. Patients (n = 796) received 600 mg of linezolid intravenously or orally every 12 h (828 treatment courses). Bacteremia was present in 46% of infections, endocarditis was present in 10.6%, and line-related infections were present in 31.1%. Other infections included intraabdominal infections (15.1%), complicated skin and skin-structure infections (13.3%), and osteomyelitis (10.7%). Causative pathogens included vancomycin-resistant enterococci (66.3%) and methicillin-resistant staphylococci (22.1%). Clinical intent-to-treat (ITT) outcomes in the evaluable population were as follows: cure, 73.3%; failure, 6.8%; and indeterminate, 19.9%. Microbiological ITT outcomes in evaluable patients were as follows: cure, 82.4%; failure, 14.1%; and indeterminate, 3.5%. At the test of cure assessment, the clinical cure and microbiological success rates were 91.5% and 85.8%, respectively. The most common adverse events possibly related to linezolid use were gastrointestinal disturbances (9.8% of cases), thrombocytopenia (7.4% of cases), decreased hemoglobin/hematocrit levels (4.1% of cases), and cutaneous reactions (4.0% of cases). Linezolid provided high rates of clinical cure and microbiological success in this complicated patient population, with very good overall tolerance.

The prevalence of multidrug resistance in gram-positive bacteria is increasing rapidly. The worldwide prevalence of infections due to methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumoniae is increasingly difficult to manage with currently available therapies [1]. Moreover, reports of S. aureus with intermediate resistance to vancomycin [2, 3] and vancomycin-resistant staphylococci [4] predict future difficulties in the use of vancomycin for treatment.

Linezolid is a synthetic antimicrobial and the first member of the oxazolidinone class to receive approval by the US Food and Drug Administration (FDA). Linezolid has activity against virtually all gram-positive cocci, a few gram-negative anaerobes, and some mycobacteria [5–8]. The drug is not active against typical aerobic gram-negative rods. Linezolid acts against bacteria via the inhibition of ribosomal protein synthesis [9].

As demonstrated in healthy volunteers, linezolid has essentially 100% oral bioavailability, an elimination half-life of 5–7 h, a distribution volume of >0.8 L/kg, good tissue penetration, and a clearance of 140 mL/min [10–12]. Linezolid clearance is not dependent on hepatic enzyme action because it is metabolized by nonenzymatic oxidation of the morpholine ring. Therefore, no dosing adjustments are necessary for patients with renal or hepatic dysfunction [13, 14].

The linezolid compassionate-use program was coordinated by the Clinical Pharmacokinetics Laboratory in Buffalo, NY, and it was designed in collaboration with Pharmacia & UpJohn (Kalamazoo, MI). The goals of this program were to examine the safety, tolerance, and efficacy, pharmacokinetics, and pharmacodynamics of linezolid when administered to patients in need of the drug who could not typically be enrolled in phase 3 trials for various reasons, including their health care institution not being a study site, their severity of illness, presence of multidrug-resistant pathogens, and the presence of certain types of infections (e.g., osteomyelitis, endocarditis, and intra-abdominal infections). Clinical and microbiological outcomes for patients enrolled during the period of October 1997 through May 2000 are reported.

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Patients and Methods

Patient enrollment into this open-label, noncomparative, nonrandomized compassionate-use program was initiated between the clinical site personnel and the coordinating center clinicians at the Clinical Pharmacokinetics Laboratory (Buffalo, NY). Patient eligibility was determined by an interview with use of a checklist. The site investigator was required to complete the regulatory and sponsor-required documents, to obtain local institutional review board approval and written informed consent, and to perform baseline evaluations.

Patients. Patients were required to have documented signs and symptoms of a serious infection, such as fever, shaking chills, and leukocytosis with a prominent shift to the left, or significant changes in vital signs. Patients who were colonized with microorganisms were excluded from enrollment. Patients had to be ⩾28 days old. Any device or prosthesis that was the cause of the infection was expected to be removed. Informed consent was obtained from the patients or their guardians, and guidelines for human experimentation of the US Department of Health and Human Services and/or those of the investigators' institutions were followed in the conduct of this clinical research.

Dosing schedule and duration of treatment. The initial linezolid dosage for all adults, regardless of renal or hepatic function, was 600 mg given intravenously or orally every 12 h. The dosage for children (or adults who weighed <40 kg) was 10 mg/kg per dose given intravenously or orally every 12 h. The expected duration of treatment was 5–28 days. Patients were allowed to be re-treated at any time, provided they met the original entry criteria. Patients were considered to have a new treatment course if they had a new infection or a new causative organism or if they had completed the test-of-cure (TOC) follow-up assessment. Extension of the treatment period for up to 3 months was permitted with prior approval by the sponsor.

Microbiology and culture procedures. Samples were obtained for confirmatory cultures before the first dose of linezolid was administered, every other day for the first 6 days or until culture results were negative, at end of therapy, at the short-term follow-up (STFU) visit, and at the long-term follow-up (LTFU) visit, if obtainable. All isolated causative organisms were tested at baseline and during therapy for linezolid susceptibility at the local microbiology laboratory of the investigator; quality controls were used. In addition, the majority of the isolates were sent to a central laboratory (Covance; Indianapolis, IN) for identification and susceptibility verification and storage.

Assessment of outcomes. In the initial protocol, outcome assessments (defined by the sponsor a priori) were conducted at the end of therapy; at the TOC assessment, defined as the STFU visit, which occurred 7–10 days after the discontinuation of linezolid therapy; and at the LTFU visit, which occurred 15–30 days after the discontinuation of linezolid therapy. If patients received >28 days of therapy, the STFU assessment was performed 1 month after the discontinuation of treatment, and the LTFU assessment was performed 6 months after the discontinuation of treatment. The protocol was amended in August 1999 and only required a single TOC (STFU) assessment at 15–30 days after the discontinuation of treatment. Patients with endocarditis were assessed for TOC at 6 months after the discontinuation of treatment, and patients with osteomyelitis were assessed 6 months to 1 year after the discontinuation of treatment. At each assessment, clinical and microbiological efficacy was characterized as “cure,” “failure,” “indeterminate,” or “nonevaluable.” If an outcome assessment was a failure either during or at the end of therapy but was not evaluable at the STFU visit, the TOC finding was considered a failure.

TOC analyses of clinical and microbiological outcomes were conducted in the intent-to-treat population (i.e., all treated patients who received linezolid for ⩾5 days) and in the evaluable population (i.e., the remaining treated patients after removal of nonevaluable patients). Patients were considered to be clinically nonevaluable if they were lost to follow-up, died, received <5 days of therapy, or received concomitant antibiotics that were active against the infecting gram-positive pathogen. Patients were considered to be microbiologically nonevaluable if they had negative culture results before they started receiving linezolid or were clinically nonevaluable.

Adverse events and tolerance. Safety laboratory evaluations included serum creatinine level determinations, liver function tests, and hematology assessments performed every 3 days for the first 21 days of therapy and weekly thereafter. Assessments for adverse drug events were performed daily by the investigative site, and clinically relevant abnormalities were reported, including all serious adverse events. All treated patients were evaluable for adverse events, and the coordinating center clinicians ensured that all serious medical events were reported promptly to the sponsor and the FDA. Adverse and serious medical events were characterized as “definite,” “probable,” “possible,” or “not related” (attributed to diseases or other drugs) to linezolid by the investigator.

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Results

During the period of October 1997 through May 2000, 796 patients were enrolled in the study at 278 sites, for a total of 828 treatment courses; 32 patients were re-treated. Baseline demographic characteristics and characteristics of the patient courses are listed in tables 1 and 2, respectively. The duration of therapy had a range of 1–198 days. A total of 556 treatment courses (67.1%) were ⩽28 days in duration (mean, 14.0 days), and the remaining 272 treatment courses (32.9%) were >28 days in duration (mean, 53.8 days). There was a much greater number of infections that are typically difficult to treat among patients who were treated for >28 days, including osteomyelitis (59 infections), complicated skin and skin-structure infections (55 infections), endocarditis (22 infections), bacteremia (60 infections), intra-abdominal abscesses (39 infections), infected devices (10 infections), and other (27 infections). A total of 46% of patients received oral linezolid at some point during therapy. Patients had numerous serious comorbid conditions (e.g., malignancy, neutropenia, receipt of an organ transplant, and end-stage renal disease, including dialysis). Approximately 25% of the patients had infections that failed to respond to or were intolerant to vancomycin therapy, and 19% of the patients had infections that were intolerant to or failed to respond to quinupristin-dalfopristin therapy.

Table 1
Table 1

Baseline patient demographic characteristics for 828 treatment courses.

Table 2
Table 2

Baseline patient characteristics for 828 treatment courses.

Infection sites and infecting pathogens treated are described in tables 3 and 4, respectively. The most common causative organisms were vancomycin-resistant Enterococcus faecium (VREF; 59.2% of treatment courses) and MRSA (19.4% of treatment courses). The mean baseline MIC of the organisms was 2 μg/mL. Enterococcal isolates generally had MICs of 1–2 μg/mL, and staphylococcal isolates generally had MICs of 2–4 μg/mL. A few Nocardia and Mycobacterium isolates had baseline MICs of 8 μg/mL. Bacteremia was associated with 46% of the infections, and intra-abdominal infections (i.e., peritonitis, biliary tract, and abscesses) were the next most common, at 15.1%.

Table 3
Table 3

Sites of infections in 828 treatment courses.

Table 4
Table 4

Primary pathogens involved in 828 treatment courses.

Intent-to-treat clinical and microbiological outcomes at end of treatment, STFU assessments, TOC assessments, and LTFU assessments are provided in table 5. In the evaluable treatment courses, the overall clinical cure rate at the TOC assessment was 91.5% when indeterminate patient courses were treated as nonevaluable. When the outcome of indeterminate patients was reclassified as “failure,” the overall cure rate was 73.3%. The overall microbiological success rate was 85.8% when indeterminate responses were classified as nonevaluable. When indeterminate outcomes were reclassified as “failures,” the microbiological success rate was 83.6%.

Table 5
Table 5

Clinical and microbiological outcomes for 828 treatment courses.

Clinical and microbiological outcomes, by infection and organism. Clinical and microbiological outcomes at the TOC assessment, according to infection site and the most common organisms, are shown in table 6 for evaluable treatment courses. The evaluable group was the best group to assess the effects of linezolid, given the nature of the patients and the high rate of nonevaluable patients who were enrolled. Overall, in patients with VREF infections, the clinical cure rate was 81.4%; only 5.8% of patients had infections that failed to respond to therapy, and 12.8% of patients had indeterminate outcomes. Similarly, in patients with MRSA infections, the clinical cure rate was 66.1%; 12.8% of MRSA cases failed to respond to therapy, and 21.8% had indeterminate outcomes. Lower clinical cure and microbiological success rates were observed for bone infections, endocarditis, and device-related infections. Patients with endocarditis were categorized with use of Duke's criteria, and the results of intensive evaluation of these patients have been presented elsewhere [15]. There were no clear clinical failures in patients with urinary tract infections, upper respiratory tract infections, or subdural infections, but relatively low numbers of infections were evaluable in these groups.

Table 6
Table 6

Outcome of evaluable treatment courses at test-of-cure visit.

Pathogens were eradicated in most patients, as illustrated by the high cure rates. Microbiological outcomes in patients with VREF infections were as follows: cure, 86.4%; failure, 12.7%; and indeterminate, 0.9%. Microbiological outcomes for patients with MRSA were as follows: cure, 78.5%; failure, 18.3%; and indeterminate, 3.2%. Microbiological failures did occur at a higher rate in patients with deep-seated or foreign-body—associated wounds.

Drug resistance. No patient had a pathogen recovered at baseline that was resistant to linezolid. Ten of the 828 treated organisms that infected patients enrolled in the program developed drug resistance while the patient received linezolid therapy. All of the organisms that developed resistance were VRE (10 of 550). Nine were E. faecium and one was Enterococcus faecalis, and they developed a ⩾4-fold increase in the MIC of linezolid. All pathogens had baseline MICs of 1–2 μg/mL, and the last isolates to be recovered had MICs of 8 μg/mL (n = 6), 16 μg/mL (n = 3), and 32 μg/mL (n = 1). All patients but 1 were treated for >28 days, with the mean length of therapy being 38 days. The development of drug resistance resulted in clinical failures in 4 of the cases (3 cases of VRE bacteremia and 1 case of VRE peritonitis). In all cases, patients had deep sites of infection, abscesses that were not drained, or foreign materials that were not able to be removed (i.e., infected grafts, lines, left ventricular assist devices). All isolates were sequenced and were found to contain a G2476U mutation, which is consistent with that previously described [16, 17].

Adverse events and drug interactions. Clinical and laboratory adverse events are summarized in tables 7 and 8, respectively. In the 828 treatment courses, 314 adverse events (157 clinical events and 159 laboratory events) assessed by the investigator as being possibly or probably related to linezolid were recorded in 223 patients. One hundred fifty-four patients experienced 1 event and 69 patients experienced >1 event (48 patients had 2 events, 17 had 3 events, and 4 had 4 events). One hundred sixteen events (14.0%) resulted in drug discontinuation, and 75 events (9.1%), which were reported in 63 patients, were considered to be serious. Linezolid was generally well tolerated with respect to the CNS, liver, kidney, and cardiovascular organ systems. The most common adverse events reported were gastrointestinal in nature (incidence, 9.8%); nausea was the most common, and vomiting or diarrhea occurred less frequently. The most common adverse events that resulted in discontinuation of linezolid therapy included decreased platelet counts (3.9% of treatment courses), gastrointestinal disturbances (2.3% of treatment courses), decreased hemoglobin/hematocrit levels (2.0% of treatment courses), and dermatologic events (1.7% of treatment courses). Two anaphylactoid-type reactions (bullous arm lesions and throat swelling) were reported. Peripheral neuropathy was reported in 3 cases, all of which involved long durations of therapy (mean, 95 days) and underlying diseases and medications that potentially contributed to the event. No cardiovascular events (i.e., hypertensive crises and serotonin-type syndromes) were associated with drug-drug or drug-food interactions due to monoamine oxidase inhibition.

Table 7
Table 7

Clinical adverse events considered by the investigator to be possibly or probably related to linezolid use.

Table 8
Table 8

Laboratory adverse events considered by the investigator to be possibly or probably related to linezolid use.

The hematologic events reported by the investigative sites were generally mild to moderate in severity, transient in nature, related to treatment duration, and reversible when therapy was discontinued. For those patients who had decreased platelet count reported as an adverse event and who had serial laboratory evaluations available for analysis (n = 160), the percentage of patients who had a decrease in the platelet count of more than two-thirds from baseline was 15%, as we have reported elsewhere [18]. The mean time to 50% reduction in the platelet count in these patients was 2–3 weeks, and the 2 most common comorbidities of these patients were dialysis and vancomycin allergy or intolerance [18]. When all reported hematologic events were broken down according to the duration of therapy, there were 16 events (1.9%) reported for patients who received ⩽14 days of therapy, 42 (5.1%) for those who received 15–28 days of therapy, and 62 (7.4%) for those who received therapy for >28 days. There were no bleeding sequelae due to these adverse events.

Seventy-one patients (8.9%) died, either due to infection or to other diseases, while receiving linezolid therapy. Eight of these patients had infection that failed to respond clinically and/or microbiologically to therapy with linezolid, and death resulted from a failure to cure the infection. Five of these infections were cases of VREF bacteremia, 1 was vancomycin-resistant E. faecalis endocarditis, 1 was VREF osteomyelitis, and 1 was a lower respiratory tract MRSA infection. All organisms were susceptible to linezolid at baseline, and none developed resistance. The overall mortality rate for gram-positive infections in the enrolled population was 1.0%. A total of 203 patients (25.5%) died before the STFU visit. None of the deaths could be directly attributed to linezolid use.

One hundred eighty patient courses (22%) were only oral linezolid, and 78 courses (9.4%) were initiated in the outpatient setting. In addition, ∼4% of the patients received oral linezolid as sequential therapy following discontinuation of intravenous vancomycin therapy because the patients were not able to tolerate long-term intravenous therapy. There was no difference between patients who received intravenous therapy only (80.7%), intravenous therapy with a switch to oral therapy (86.1%), or oral therapy only (80.4%) with regard to outcome.

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Discussion

The linezolid compassionate-use program captured clinical experience with a variety of infection sites and organisms, including MRSA, VRE (either E. faecium or E. faecalis), methicillin-resistant Staphylococcus epidermidis, Mycobacterium species, and Nocardia species in patients with numerous underlying diseases and comorbid conditions. Data regarding sites of infection, such as osteomyelitis (89 infections) and endocarditis (40 infections), and longer durations of therapy (272 patients were treated for >28 days) are not typically captured in registration clinical trials.

Linezolid (600 mg iv or po q12 h) was effective for the treatment of infections due to multidrug-resistant, gram-positive organisms. A broad range of patients with numerous and various infections were evaluated. In the TOC analysis with indeterminate outcomes being reclassified as nonevaluable, the overall clinical efficacy of linezolid was >90%. With indeterminate outcomes reclassified as failures, the evaluable clinical and microbiological response rates were 73% and 84%, respectively. These numbers represent impressive cure rates in this group of patients.

Overall, linezolid was effective against VREF infection, regardless of source of infection. Linezolid was clinically effective in >90% of evaluable cases of VREF infection when indeterminate cases were excluded. Although the percentage of microbiological outcomes was not as high as the percentage of clinical outcomes, possibly reflecting the tendency of seriously ill patients with complicated infections to remain colonized or to become reinfected with the organism, results are encouraging. The results are also impressive if we consider that many patients were treated with multiple antibiotics before they received linezolid and that the time to drug initiation was often later than normally seen with empirical antibiotics. In addition, although linezolid is considered bacteriostatic against most pathogens, impressive clinical responses and microbiologic eradication of the organisms occurred in patients with less than optimal immune systems. These results establish linezolid as an effective treatment for VRE infections in this patient group.

Linezolid was effective for the treatment of MRSA infections, including cases that failed to respond to therapy or infections in patients who did not tolerate vancomycin. In patients who are prone to poor responsiveness and who had received previous vancomycin therapies but whose infections had failed to respond, it is important to note that only 11.8% of these infections failed to respond to linezolid. In addition, many of the clinical successes occurred in patients with difficult-to-treat infections, such as endocarditis, osteomyelitis, and nosocomial pneumonia. Results are also encouraging because they are similar to those of the largest comparator-controlled study of MRSA infections, which evaluated linezolid versus vancomycin [19]. In addition, the pharmacoeconomic results of that study illustrate that the use of an oral agent to treat MRSA infection instead of having to use intravenously administered vancomycin is an attractive and cost-effective option [20]. Even in the compassionate-use program, which was conducted before the drug's approval, clinicians discovered the utility of the orally administered agent, as shown by the large percentage of patients (46.1%) who received orally administered linezolid at some point in their treatment.

There were only 14 evaluable treatment courses for patients with MRSA bacteremia (10 cures and 4 infections that failed to respond to therapy), which makes conclusions difficult for this group of patients. All 4 patients whose infections failed to respond to therapy had received previous therapies of long duration with vancomycin plus rifampin or gentamicin. Three of the 4 patients had also been unsuccessfully treated with quinupristin-dalfopristin before they received linezolid treatment. Many of these sites of infection caused by MRSA were likely from complicated and deep-seated sources of infection, such as osteomyelitis and endocarditis that were not diagnosed, which would make a response to any antibiotic therapy less likely. All baseline S. aureus isolates were susceptible to linezolid, and there were no instances in which posttreatment isolates developed resistance to linezolid.

Linezolid was generally well tolerated. Most reported adverse effects were mild, transient, and reversible upon the cessation of therapy. Common adverse effects included gastrointestinal discomfort (nausea, vomiting, and diarrhea) and dermatologic reactions (rashes and itching). Suppression of the indices of hematologic function, including decreases in the platelet count, hemoglobin level, hematocrit, and WBC count, were rare before day 14 of therapy and appear to be related to longer durations of therapy. In these patients, hematologic events were reported for 1.9% of courses when linezolid was given for ⩽14 days and 12.6% when linezolid was given for >14 days.

In phase 3 studies of linezolid therapy, the definition of a significantly abnormal hematologic value was <75% of the lower limit of normal or of the baseline value, if the baseline value was abnormal. Thrombocytopenia was reported in 2.4% (range, 0.3%–10%) versus 1.5% (range, 0.4%–7.0%) and anemia was reported in 0.7% versus 0.2% of patients who received linezolid and all comparators combined, respectively, for 10–14 days on average [21, 22]. After linezolid was approved, spontaneous postmarketing surveillance included reports of myelosuppression. These reports prompted a change in the package insert to include the postmarketing experience and recommendations for monitoring the complete blood cell count [21]. A summary of these reports concluded that the effects were reversible, mild to moderate in severity, and related to duration of therapy, with a temporal relationship suggesting transient bone marrow suppression [23]; the authors also noted that underlying diseases and concomitant use of medications also could have been related to the hematological findings. In addition, case reports or series have been published on thrombocytopenia and anemia in linezolid-treated patients [24–26]. The incidence rates in some of these small, uncontrolled, observational studies are higher than rates reported elsewhere. In the compassionate-use program, when actual platelet counts were monitored, 15% of the patients had a decrease in the platelet count of more than two-thirds from the baseline value [18]. Of these patients, the investigators reported that approximately one-half had a clinically significant decrease in the platelet count. Finally, the most concerning clinically significant complication of low platelet count and anemia would be bleeding. In this population, one patient experienced gastrointestinal bleeding that was considered possibly or probably related to linezolid use by an investigator (table 7). This patient did not have thrombocytopenia or anemia. In summary, our results indicate that there is a greater risk of myelosuppression when linezolid is given for >14 days. Of greater importance, hematologic indices decreased slowly over time and can be detected with the appropriate monitoring of complete blood cell counts during treatment with linezolid.

There were no reports of serotonin syndrome or any other monoamine oxidase inhibitor interactions in this program. Other studies also found that the incidence of these types of reactions was very low [27–29]. There have been a few case reports on serotonin syndrome and linezolid use in the literature, and the authors of these reports concluded that there is a potential for linezolid to interact with selective serotonin reuptake inhibitors [30, 31], which is similar to what is reported in the package insert [20].

Since linezolid has been on the market, there have been 2 reports in the literature that have described the development of linezolid resistance (5 cases involving VRE [32] and 1 case involving MRSA [33]). In addition, there have been reports of nosocomial spread of drug-resistant VRE to patients who were ultimately colonized with the organisms [34], illustrating the need for compliance with infection-control practices. Of note, the risk factors for these patients who developed linezolid resistance were very similar to those found in the compassionate-use program: long durations of therapy, unremoved indwelling devices, and undrained abscesses. In the compassionate-use program, 10 patients with VRE infection and no patients with MRSA infection had drug resistance develop while receiving therapy.

The usual linezolid dosage (600 mg q12 h) in the compassionate-use treatment of these patients was well tolerated and resulted in clinical cure and microbiological success in the majority of patients. During the course of this compassionate-use program, considerable experience was gained with difficult-to-treat patients, pathogens, and infections, with only a few reports of development of myelosuppression and drug resistance. Therefore, the compassionate-use program supports the use of linezolid for treating gram-positive infections, even in patients with numerous comorbid conditions.

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Acknowledgments

This program would not have been possible without considerable efforts made by the clinical pharmacists who contributed to the screening and enrollment process (Gabrial S. Zimmer, Jennifer D. Root, Katherine E. Welch, Pamela A. Moise, Patrick F. Smith, James D. Scott, Kristin K. Gilliland, Linda D. Dresser, Tracy R. Perry, Alice M. O'Donnell), research assistant Vaunne Ma, and by the Linezolid Compassionate Use investigators and coordinators (I. Abolnik, J. Abramson, S. Ahrnedt, K. Alston, M. Alvarez-Krizan, A. Anglim, M. Antalek, S. Antony, J. H. Armstrong, S. Aronin, D. Ashkin, I. Avraham, P. Axelrod, P. Azimi, L. Baddour, M. Baer, I. Baird, S. Balter, C. Banerjee, A. Barile, T. Barlam, J. Bartels, S. Bass, D. Batts, G. Bedsole, S. Beeson, A. Belani, D. Benator, V. Bengualid, B. Bernstein, J. Bernstein, R. Betts, M. C. Birmingham, M. Bittner, R. Blinkhorn, E. Blumberg, B. Bock, R. Bolivar, R. Bracis, M. Brown, B. Buggy, M. Butera, D. Cable, J. Campbell, A. Carden, J. Carpenter, P. Carson, J. Cederna, H. Chambers, V. Chundi, M. Climo, P. Colombani, D. Condoluci, D. Connaghan, F. Cook, L. Corey, R. Corey, B. Corigliano, H. Cranston, F. Criddle, S. Crider, B. Cunha, R. D'Aquila, L. Danziger, S. Davies, S. Dolan, E. Dominguez, R. Duncan, M. Eads, T. A. Edell, P. Eder, D. Ehrensaft, M. Enzler, M. Epstein, L. Eron, V. Fainstein, V. Felipa, D. Felsenstein, R. Finberg, M. Finney, S. Fischer, M. Fisher, J. A. Fishman, C. Fogarty, M. Frank, D. Frohnapple, B. Fuhrman, Warren Furey, R. B. Gainer II, M. Ganapathy, M. Gareca, J. Garner, D. Gilbert, J. Gimbel, M. Golden, E. Goldstein, N. Golshan, C. Gonzalez, R. Goodman, K. V. Gopalakrishna, R. Gordon, S. Gordon, L. Gottlieb, D. Graham, J. Griebel, J. Gugliotta, M. Gupta, C. Ham, G. Harrington, M. Harrison, R. Hasbun, K. Hauer, J. Havlik, M. Heerema, A. Henson, D. Herr, P. Hibberd, D. Hickey, J. Hofflin, M. Holidniy, S. Holland, R. Holman, S. Homann, D. Hopper, M. Hori, B. Hotchkiss, S. Houston, A. Hoven, C. Hsiao, A. Huang, W. Huang, R. Husni, D. Hutt, P. Hyams, C. Isada, M. Iseman, G. Iverson, R. Jacobs, A. Jandourek, L. Jauregui, J. Jernigan, R. Jones, R. Kapila, P. Katona, C. Kauffman, G. Kearns, S. Kemmerly, N. Khardori, L. W. Kirkegaard, R. Klein, S. Klotz, S. Kohl, T. Kuberski, M. Lamacchia, A. Lentnek, C. Lerner, M. Levin, A. Licht, P. Linden, J. Liquete, R. Little, R. Lodato, N. Madinger, D. Maki, H. Malech, V. Mani, F. Manian, D. Marcus, R. Marosok, H. Martin, G. Mathisen, D. Matzke, T. McAndrew, D. McClain, J. J. McClelland, G. McLeod, S. McQuone, T. Meyer, A. Mian, G. Miller, L. Miller, T. Monson, J. Montoya, G. Moss, M. Mullen, S. Munsiff, J. Murillo, K. Murphy, T. Murphy, A. Murry, R. Murthy, S. Nachman, D. Nafziger, R. Nahass, R. Nathan, S. Nelson, M. Nguyen, R. Nieman, P. Nolan, G. Noskin, J. Nussbaum, P. J. O'Keefe, S. Olewiler, N. Olson, A. Ortega, J. Ortiz, M. Otto, S. Pacheco, K. Parayath, D. Parenti, M. Pasternack, J. Patterson, L. Pelletier, J. Penico, J. Perkins, D. Peterson, D. Petreccia, R. Pinsky, R. Pontzer, G. Poporad, R. Porwancher, R. Prier, J. Rabkin, K. Ramsey, D. Reece, D. Regier, L. Rice, L. Robinson, W. Robinson, J. Rogers, S. Ross, L. Rusakow, L. Sabath, R. Salata, C. Sanchez, A. Sanders, N. Sawhney, R. Sawyer, M. Schlachter, R. Schmitt, H. Schrager, D. Schroeder, J. Schwebke, A. Scribner, B. Segal, S. Seidenfeld, P. Sen, S. Shulman, R. Silibovsky, C. Singer, N. Singh, P. Sioson, J. Sivalingam, D. Skiest, L. Slater, T. Sleweon, J. Slim, L. Sloan, S. Smith, G. Smulian, R. Snepar, R. Soave, R. Sokolov, C. Spooner, A. Srbinoska, T. Stalder, H. Standiford, D. Steffensen, J. Steingrub, D. L. Stevens, R. Stiller, J. Stone, J. Streit, D. Strike, M. Suarez, B. Suh, R. Sullivan, C. Teague, Z. Temesgen, S. Tessler, L. Thielen, J. Tomayko, A. Valenti, B. Van Uitert, L. Veach, E. Visconti, B. Wade, D. Waitley, R.Wallace, E. Waller, E. Walsh, C.Watkins, G. Weaver, B. Wenglin, C. White, J. Wolf, G. Wortmann, B. Yirinec, M. Zaman, N. Zide, and D. Zimmerman).

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Footnotes

  • Financial support: M.C.B. was the principal coordinator of the program while at the Clinical Pharmacokinetics Laboratory (Buffalo, NY) until January 2001, and she received support for completion of this article in manuscript as part of her current duties as a consultant to Pharmacia Corporation. D.H.B. currently serves as a consultant to Pharmacia Corporation (Kalamazoo, Michigan) and has Pharmacia Corporation stock options as a retired Pharmacia Corporation employee. C.R.R., A.K.M., and J.J.S. currently serve as consultants to Pharmacia Corporation. The Clinical Pharmacokinetics Laboratory received support for the conduct of the program by Pharmacia & UpJohn (Kalamazoo).

  • Received April 11, 2002.
  • Revision received September 8, 2002.
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  1. Clin Infect Dis. (2003) 36 (2): 159-168. doi: 10.1086/345744
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