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Antimicrobial Agents and Chemotherapy, December 2007, p. 4249-4254, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00570-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Phase II, Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial of a Polyclonal Anti-Staphylococcus aureus Capsular Polysaccharide Immune Globulin in Treatment of Staphylococcus aureus Bacteremia

Mark E. Rupp,^1* H. Preston Holley Jr.,² Jon Lutz,³ Peter V. Dicpinigaitis,⁴ Christopher W. Woods,^5,7 Donald P. Levine,⁶ Naomi Veney,² and Vance G. Fowler Jr.⁷

University of Nebraska Medical Center, Omaha, Nebraska,¹ Nabi Biopharmaceuticals, Rockville, Maryland,² St. Agnes Medical Center, Fresno, California,³ Montefiore Medical Center, Bronx, New York,⁴ Durham Veterans Affairs Medical Center, Durham, North Carolina,⁵ Wayne State University, Detroit, Michigan,⁶ Duke University Medical Center, Durham, North Carolina⁷

Received 1 May 2007/ Returned for modification 9 June 2007/ Accepted 13 September 2007

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
New treatment modalities are needed for the treatment of infections due to multidrug-resistant Staphylococcus aureus. S. aureus capsular polysaccharide immune globulin (Altastaph) is a polyclonal immune globulin preparation that is being developed as adjunctive therapy for persons with S. aureus infections complicated by bacteremia. In a phase II, multicenter, randomized, double-blind, placebo-controlled trial, 40 subjects with documented S. aureus bacteremia received standard therapy plus either Altastaph at 200 mg/kg of body weight in each of two infusions 24 h apart or placebo. During the 42-day observation period, antibody pharmacokinetics and safety were the primary characteristics studied. Information regarding the resolution of bacteremia and fever was also analyzed. Anti-type-5 and anti-type-8 capsular antibody levels peaked after the second infusion at 550 µg/ml and 419 µg/ml, respectively, and remained above 100 µg/ml at day 28. A total of 316 adverse events were noted in 39 of 40 subjects. Infusion-related adverse events in Altastaph recipients were infrequent and similar to those among recipients of commercial intravenously administered immunoglobulin G products. Five of 21 (23%) subjects in the Altastaph group died, whereas 2 of 18 (11%) subjects in the placebo group died (P = 0.42). Compared to the control patients, the Altastaph recipients had a shorter median time to the resolution of fever (2 days and 7 days, respectively; P = 0.09) and a shorter length of hospital stay (9 days and 14 days, respectively; P = 0.03). However, these findings are exploratory, and there were few differences in the other variables measured. High levels of opsonizing antibodies were maintained for the initial 4 weeks. Although the study was not powered to show efficacy, these preliminary findings and safety profile suggest that Altastaph may be an effective adjunct to antibiotics and warrants further investigation (ClinicalTrials.gov number NCT00063089).

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Staphylococcus aureus is an increasingly common cause of infection and bacteremia in both the health care and community settings (14, 3, 26). S. aureus infection is reported in 0.8% of all hospitalizations in the United States and results in significant morbidity, mortality, and excess economic costs (17, 21). S. aureus bacteremia is commonly associated with endocarditis, septic arthritis, osteomyelitis, or other complications (6). The rising prevalence rates of methicillin-resistant S. aureus (MRSA) and clinical strains of S. aureus with resistance to multiple antibiotics, including vancomycin (5), linezolid (19), and daptomycin (16), have limited the options for the treatment of infections caused by this serious pathogen. Treatment of S. aureus bacteremia, particularly MRSA bacteremia, is less than optimum, as documented by the high rates of mortality, metastatic seeding, and recurrence (14, 17, 10, 4). Clearly, improved means of treatment of S. aureus bacteremia are needed.

A potential strategy to improve the clinical outcome in patients with S. aureus bacteremia is to target S. aureus virulence determinants via adjunctive therapy. Staphylococcal capsular polysaccharides are virulence factors that act by reducing opsonophagocytic killing by host polymorphonuclear neutrophils (18). Approximately 85% of clinical isolates of S. aureus produce type 5 or type 8 capsular polysaccharide (1). In the former Soviet Union, antistaphylococcal immunoglobulins have been used as adjunctive therapy for years (12, 13). Unfortunately, many of these studies were retrospective, nonrandomized, and poorly designed. Altastaph is a polyclonal human immunoglobulin G (IgG) with high levels of antibody to capsular polysaccharide type 5 and type 8. Altastaph exhibits opsonic activity in in vitro assays of opsonophagocytosis and offers passive protection in various animal models of staphylococcal sepsis (15, 8, 7, 11). In humans, Altastaph has been studied extensively in low-birth-weight and very-low-birth-weight neonates (2). Herein, we report on the safety and pharmacokinetics of Altastaph and offer a preliminary evaluation of efficacy measures in subjects with S. aureus bacteremia.

(This work was presented in abstract form [abstr. LB-6] at the 43rd Annual Meeting of the Infectious Diseases Society of America, San Francisco, CA, 5 October to 9 October 2005 [21a]).

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Setting and study design. The study was a randomized, double-blind, placebo-controlled, phase II clinical trial conducted to evaluate the pharmacokinetics, safety, and efficacy of Altastaph as an adjunct to standard antibiotic treatment in patients with S. aureus bacteremia. The trial was conducted at nine medical centers in the United States from December 2002 to September 2004. The protocol and consent forms were approved by the institutional review board at each participating site. The study was registered at ClinicalTrial.gov (NCT00063089).

Study population. Patients greater than or equal to 7 years of age with documented S. aureus bacteremia from the peripheral bloodstream and fever for greater than 24 h following the acquisition of the index blood sample for culture were eligible for participation. Written informed consent was obtained from the patient or the patient's legal guardian. The first dose of study drug was initiated within 72 h of acquisition of the index blood sample for culture. Patients were excluded from the study if they were pregnant, were nursing, had received an investigational drug within 30 days of study entry, or had any of the following: polymicrobic bacteremia, weight greater than 150 kg, neutropenia (absolute neutrophil count < 500/mm³), known human immunodeficiency virus infection with a CD4 leukocyte count of <200/mm³, hypersensitivity to polysaccharides or polysaccharide vaccines, IgA deficiency, or an anticipated life expectancy that precluded completion of the study.

Randomization and test product administration. The subjects were randomized in a 1:1 ratio via a computer-generated list to receive Altastaph at a dose of 200 mg/kg of body weight or 0.45% normal saline placebo. Drug allocation was concealed; and the patients, study personnel, and all health care workers were unaware of subject assignment. A single pharmacist at each institution was unblinded and performed test product preparation. The active agent and placebo were visually indistinguishable. Two doses of Altastaph or matching placebo were administered intravenously, with 24 h between infusions. The infusion was started at a rate of 0.5 ml/kg/h and was titrated upward to a maximum rate of 4 ml/kg/h over a maximum of 4 h.

Measurements and definitions. At the time of enrollment the following data were recorded: subject demographic characteristics, comorbidities, severity of illness score (Acute Physiology and Chronic Health Evaluation [APACHE II] score), baseline blood chemistry and hematology parameters, and physical examination findings. Antibiotic selection and the duration of treatment were determined by the subject's attending physician. The subjects were monitored closely during the infusion of study drug, with vital signs recorded approximately 15 and 30 min after the initiation of infusion, every 30 min thereafter during the infusion, and 1 and 4 h after completion of the infusion. Samples for pharmacokinetic analysis were taken prior to the infusion of study drug; at 10 min after completion of the infusion; at 4, 12, and 24 h postinfusion; and on days 7, 14, 21, 28, and 42. Blood samples for culture were obtained daily until they were negative for 2 consecutive days. APACHE II scores were calculated daily until discharge from the hospital. Vital signs were recorded every 6 h until the patient was afebrile (temperature, <100.4°F) for 12 consecutive hours and then daily until discharge and on days 7, 14, 21, 28, and 42. Concomitant medications were recorded daily until discharge and at follow-up visits. Adverse events were recorded and were graded as mild, moderate, or severe by the investigators. Safety was also monitored by the use of laboratory parameters.

The primary measures of biologic activity were (i) the time to resolution of the S. aureus bacteremia, defined as the number of days from the first infusion of study drug to the first day of 2 consecutive days of sterile blood cultures, and (ii) the time to resolution of fever, defined as the time between the first infusion of study drug to the first of two consecutive temperature measurements at least 6 h apart that were less than 100.4°F. Additional measures included the time to the durable resolution of fever, defined as the time between the first infusion of study drug to the first day of an afebrile interval of 7 days, and the time to hospital discharge, defined as the number of days from the first infusion of study drug to the day of discharge from the hospital. Relapse was defined as one or more blood cultures positive for the growth of an S. aureus isolate with the same serotype as the index blood isolate occurring after the definition of resolution of bacteremia had been met, and recurrence was defined as having one or more blood cultures positive for the growth of an S. aureus isolate with the same serotype as the index blood isolate occurring greater than 7 days after the definition of resolution of bacteremia had been met.

Statistical methods. All analyses were performed by using SAS software (SAS, Cary, NC). An exponential distribution for time-to-event outcomes was assumed. A sample size of 20 in each treatment arm was chosen, as a hazard ratio of 2.45 would be detectable by using a two-sided test with 5% type I error and 80% power. All subjects who received study drug were included in the modified intent-to-treat (mITT) population and were included in the safety analysis. The mITT population was used for analysis of the mortality data and analysis of other possible indicators of biologic activity. Two-sided P values of 0.05 or less were considered statistically significant, and multiple-comparison adjustments were not used. The geometric mean concentrations of type 5 and type 8 antibodies were calculated for the groups with the use of the log-transformed values from all subjects. The geometric mean antibody concentration was taken as the antilog of the mean of the transformed values. Ninety-five percent confidence intervals for the ratio of the geometric mean antibody concentrations were calculated, with intervals that excluded 1.0 indicating possible differences between treatment groups. Continuous outcome measures were analyzed by Student's t test and the median test, time-to-event variables were analyzed by the log-rank test, and categorical variables were analyzed by Fisher's exact test. Some of the statistical techniques that were used required a normal distribution of the data. This assumption of normality was checked for validity by use of the Shapiro-Wilk statistic and by visual inspection of the relevant normal probability plot. If the assumption of normality was not tenable, then a nonparametric procedure (the median test) was used to complement the normal theory procedures (22).

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Patient characteristics. A total of 40 patients were enrolled in the trial (Fig. 1). The 39 subjects who received at least some study drug made up the mITT population. In addition to standard antibiotic therapy, 21 patients received Altastaph and 18 received placebo. Thirty patients (75%) completed all follow-up clinical and laboratory procedures. Table 1 documents the baseline characteristics of the study population. The demographic parameters were similar between the two groups. In comparison to the control group, the Altastaph group had a higher rate of bacteremia due to unknown origin (24% versus 0% for the control group) and a larger number of subjects with bacteremia due to hemodialysis vascular access (24% versus 11% for the control group). The laboratory parameters were similar between the groups, with the exception of the baseline creatinine level, which was higher in the Altastaph group (4.1 mg/dl ± 4.0 mg/dl versus 1.9 mg/dl ± 1.7 mg/dl for the control group). Seventeen subjects had MRSA bacteremia (7 in the Altastaph group, 10 in the placebo group). Serotype studies revealed that 29 of the 39 (74%) subjects experienced bacteremia with capsular serotype 5 or 8 (16 in the Altastaph group, 13 in the placebo group). Capsular serotype 5 was the most common serotype observed (41%), followed by serotype 8 (33%) and serotype 336 (23%). The S. aureus bloodstream isolate from one patient in the Altastaph group was unavailable for serotyping. Antibiotic use was comparable between the groups. All patients received at least two different antibiotics. Nearly all subjects initially received vancomycin (20/21 [95%] for the Altastaph group, 17/18 [94%] for the placebo group), and similar numbers of subjects received combination therapy with gentamicin (9/21 [43%] for the Altastaph group, 7/18 [39%] for the placebo group) or rifampin (6/21 [29%] for the Altastaph group, 6/18 [33%] for the placebo group).

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FIG. 1. Subject disposition. Forty patients were enrolled in the study. One patient did not receive study drug and was excluded from further analysis. Among the subjects receiving Altastaph, 5 subjects died, 2 were noncompliant, and 1 withdrew consent, resulting in 13 per protocol subjects. Among the subjects in the placebo arm of the study, one subject died, resulting in 17 per protocol subjects (1 additional subject died 1 day after the 42-day follow-up period). All subjects in the mITT population were included in the safety analysis.

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TABLE 1. Baseline characteristics of patients

Antibody pharmacokinetics. Figure 2 illustrates the mean antibody concentrations over the 42-day course of the study. Among subjects receiving Altastaph, the geometric mean anti-type 5 and anti-type 8 levels peaked on day 2 at 550 µg/ml and 419 µg/ml, respectively. On day 7, the anti-type 5 and anti-type 8 levels were 244 µg/ml and 199 µg/ml, respectively. The anti-type 5 and anti-type 8 levels remained greater than 100 µg/ml on day 28 and were 111 µg/ml and 75 µg/ml, respectively, on day 42. The concentrations of anti-type 5 and anti-type 8 antibodies in the subjects receiving placebo were low and did not change substantially over the course of the study.

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FIG. 2. Pharmacokinetics of Altastaph. The geometric mean concentration (µg/ml) of anti-type 5 antibodies (A) and the mean concentration (µg/ml) of anti-type 8 antibodies (B) for Altastaph recipients versus time over the 42-day course of the study are indicated. The 95% upper and lower confidence (Conf.) intervals are also shown. The interrupted dashed line indicates the antibody levels for the placebo recipients.

Safety. A total of 316 adverse events involving 39 of the study subjects were reported by the investigators. Nineteen of these were considered to be study drug related. Eighteen of these 19 study drug-related adverse events were in Altastaph recipients. All study drug-related events were regarded as mild or moderate by the investigators. The most common study-related adverse events were infusion associated events and consisted of fever (n = 3), rigors (n = 4), exacerbation of dyspnea (n = 1), wheezing (n = 1), chest tightness (n = 1), and tachycardia (n = 1). Other study drug-related adverse events consisted of nausea (n = 1), vomiting (n = 1), peripheral edema (n = 1), infusion site erythema (n = 1), back pain (n = 1), headache (n = 1), and rash (n = 1). The only study drug-related adverse event in the placebo group consisted of leukocytosis (n = 1). Table 2 summarizes all adverse events reported in greater than 10% of the subjects in either arm of the study.

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TABLE 2. Adverse events reported in >10% of study subjects in either treatment group arranged in descending order of incidence in the Altastaph group

Seven subjects (18%) died prior to the 42-day follow-up or shortly thereafter (5/21 [23%] in the Altastaph group, 2/18 [11%] in the placebo group) (P = 0.42). None of the deaths were considered by the investigators to be study drug related. A total of nine subjects (five in the Altastaph group, four in the placebo group) experienced 21 serious adverse events. None of the serious adverse events were considered by the investigators to be study drug related. The serious adverse events noted in the Altastaph group consisted of hypoxemia, respiratory failure, myocardial infarction (n = 2), cardiac arrest, febrile neutropenia, pneumonia, pleural effusion, pneumothorax (twice in one subject), renal failure, and staphylococcal sepsis. In the placebo group, the serious adverse events consisted of respiratory distress, muscle abscess, empyema, endocarditis, staphylococcal bacteremia, central venous catheter infection, fungemia, and catheter-related sepsis (twice in one subject). All of the subjects who died were in the group of patients with serious adverse events.

Response measures. In the mITT population, 15 patients in each group had complete follow-up blood cultures that allowed assessment of the response (Fig. 1). The median time to clearance of bacteremia was 2 days (range, 0 to 7 days) in the placebo group and 1 day (range, 0 to 10 days) in the Altastaph group (P = 0.58). Among the patients with MRSA bacteremia (n = 14; 8 in the placebo group, 6 in Altastaph group), the median times to resolution of bacteremia were 2 days (range, 0 to 6 days) in the placebo group and 0 days (range, 0 to 6 days) in the Altastaph-treated patients (P = 0.3). The median times to resolution of fever were 3 days and 2 days in the placebo group and the Altastaph group, respectively (P = 0.3). The times to the durable resolution of fever were 7 days in the placebo group and 2 days in the Altastaph group (P = 0.09). There was a substantial reduction in the time to hospital discharge from the time of the first study drug infusion: 14 days (range, 3 to 53 days) for the placebo group and 9 days (range, 2 to 41 days) for the Altastaph group (P = 0.03). Two subjects in each group experienced a relapse or a recurrence of S. aureus bacteremia.

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Serious infection due to S. aureus is an important medical problem that is increasing in incidence (17, 24). Unfortunately, despite standard antibiotic and supportive therapy, morbidity and mortality remain substantial. Fowler et al. documented an overall mortality rate of 22% in patients with S. aureus bacteremia (10). Recently, a mortality rate of 11% was noted in a prospective study of antimicrobial therapy of S. aureus bacteremia (9). Therefore, it is imperative that we continue efforts to develop improved modalities of therapy for staphylococcal infections.

In the prior Soviet Union, adjunctive therapy with antistaphylococcal immunoglobulins was common practice (12). Also, the findings from initial studies of an S. aureus capsular polysaccharide conjugate vaccine appeared to be promising (23). For these reasons, interest in passive immunization with specific antistaphylococcal capsular polysaccharide IgG is warranted. The goals of this study were to assess the pharmacokinetics and safety of Altastaph and evaluate initial evidence of its clinical activity in patients with S. aureus bacteremia.

Passive immunization with two doses of Altastaph produced high concentrations of anti-type 5 and anti-type 8 capsular antibodies that were maintained at levels of greater than 100 µg/ml for longer than 28 days. Although it is unknown what levels of anticapsular antibodies are required for a therapeutic effect in patients with S. aureus bacteremia, in vivo data indicate that the prevention of S. aureus bacteremia is achieved with type 5 and type 8 antibody levels of about 80 µg/ml (7, 23).

Safety data were carefully analyzed. As expected for persons with serious S. aureus infections, nearly all subjects experienced at least one adverse event. However, all adverse events that were deemed likely to be study drug related were regarded as mild to moderate in severity by the investigators. The majority of potentially study drug-related adverse events appeared to be infusion associated and consisted of fevers, rigors, dyspnea, wheezing, or chest tightness; and further evaluation of these adverse events is required in a larger study. Similar allergic reactions are known to occur with infusion of other immunoglobulin products (6). The high patient mortality in this investigation reaffirms the serious nature of S. aureus bacteremia and the need for improved therapeutic modalities. Although the mortality rate was higher among subjects receiving Altastaph, this may have been due to the disproportionate distribution of patients with underlying endocarditis/bacteremia of unknown origin and renal dysfunction. These differences in underlying risk factors for complicated disease may have also been reflected in the higher APACHE II scores (mean scores, 11.2 for the Altastaph group and 9.2 for the placebo group). Clearly, potential infusion-related adverse events and mortality rates will need to be carefully scrutinized in larger studies powered to better assess efficacy and safety.

Although the study sample size in this phase II trial was not powered to examine questions of efficacy, several observations warrant closer scrutiny. The time to resolution of bacteremia or defervescence was longer in the placebo group, and after correction for mortality, the time to hospital discharge was significantly shorter for the group receiving Altastaph. However, a number of potential confounding variables must be emphasized in considering these favorable trends. First, antibiotic use was not controlled and was left to the discretion of the subject's treating physicians. However, the antibiotic treatments appeared to be comparable between the groups. In addition, the need for and the timing of surgical intervention or intravascular catheter removal were not assessed.

A potential limitation to passive or active immunization directed against S. aureus type 5 and type 8 capsular polysaccharides is the possibility of infection with S. aureus strains with non-type 5 or non-type 8 capsular types. The literature suggests that approximately 85% of S. aureus strains causing bacteremia are type 5 or type 8 capsular types (1). This study found that approximately 25% of persons experiencing S. aureus bacteremia had strains recovered from the bloodstream that were not type 5 or type 8 capsular types and thus would not be expected to derive potential benefit from the test product, which is directed at the type 5 and the type 8 capsular polysaccharides. A rapid diagnostic test to define persons with S. aureus bacteremia due to capsular type 5 or 8 would help to focus this treatment for those most likely to accrue benefit.

The results of the current clinical trial are similar to those of another recently published phase II randomized, double-blind, placebo-controlled trial evaluating immunotherapy as an adjunctive treatment for S. aureus bacteremia (25). The previous trial evaluated tefibazumab, a humanized monoclonal antibody that binds to surface-expressed adhesion protein clumping factor A. The rates of treatment failure, defined as the development of a new S. aureus-related complication, microbiologically confirmed relapse, or death, were similar in the tefibazumab and placebo recipients (6.7% and 13.3%, respectively; P = 0.455). Post-hoc analysis found a shorter time to baseline complication resolution in the tefibazumab recipients (P = 0.079). Taken together with the findings presented in the current report, the findings further support the potential role of immunotherapeutic agents as adjunctive therapies for S. aureus bacteremia.

Subsequent to the completion of this Altastaph study, the results of a large, double-blind, placebo-controlled trial of active immunization with an S. aureus capsular polysaccharide conjugate vaccine in hemodialysis patients was announced (20). Contrary to prior observations, no reduction in S. aureus infections due to capsular type 5 or 8 was observed, and pending additional analysis, the sponsor suspended further efforts in the development of active or passive immunization directed against S. aureus capsular polysaccharides. However, because the trial described in this report was directed at the treatment of bacteremia in a different patient population, there remains the distinct possibility that specific S. aureus anticapsular antibody therapy might offer merit as adjunctive therapy in subjects with S. aureus bacteremia.

In conclusion, this study demonstrated that, compared to placebo, passive immunization with Altastaph resulted in elevated levels of anti-type 5 and anti-type 8 capsular antibodies for up to 6 weeks. Altastaph recipients experienced minor infusion-associated adverse events. The significance of elevated anti-type 5 and anti-type 8 capsular antibody levels on the clinical course of S. aureus bacteremia remains unknown and warrants further consideration.

 
We thank the study coordinators at the study sites, Enoch Bortey for statistical analyses, and Camilla Rasmussen for assistance with manuscript preparation.

The Altastaph Adult Clinical Trials Group consisted of the following persons: Alan S. Cross (University of Maryland, Baltimore), Peter V. Dicpinigaitis (Montefiore Medical Center, Bronx, NY), Vance Fowler (Duke University Medical Center, Durham, NC), Donald P. Levine (Wayne State University, Detroit, MI), Jon Lutz (St. Agnes Medical Center, Fresno, CA), Mark E. Rupp (University of Nebraska, Omaha, NE), Amar Safdar and Kenneth Rolston (M. D. Anderson Cancer Center, University of Texas, Houston), Priya Sampathkumar (St. Mary's Hospital, Rochester, MN), and Christopher Woods (Durham VA Medical Center, Durham, NC).

Potential conflicts of interest are as follows. M.E.R. received research funding from Becton Dickinson, Cubist Pharmaceuticals, and 3 M; serves on advisory boards for Cubist Pharmaceuticals and Wyeth Pharmaceuticals; and is on the Speaker's Bureaus for Becton Dickinson and Cubist Pharmaceuticals. H.P.H. and N.V. are employees of Nabi Biopharmaceuticals. P.V.D. has stock ownership in Nabi Biopharmaceuticals. C.W.W. received research funding from Cubist Pharmaceuticals and Roche Diagnostics, serves on advisory boards for Biomerieux and Sanofi-Aventis, and is on the Speaker's Bureau for Sanofi Aventis. D.P.L. received research funding, served as a consultant, and is on the Speaker's Bureau for Cubist Pharmaceuticals. V.G.F. received grant funding from Cubist, Inhibitex, Merck, Nabi, and Theravance; is a consultant for Biosynexus, Cerexa, Cubist, Inhibitex, Johnson & Johnson, and Merck; and is on the Speaker's Bureaus of Pfizer and Cubist. No other potential conflicts of interest relevant to this paper were reported.

This study was funded by Nabi Biopharmaceuticals, through individual research contracts with participating institutions. Several of the authors formulated the study design in conjunction with personnel from Nabi Biopharmaceuticals. The investigators performed the study independently, but the sponsor collected and initially analyzed the data. All data in the study were source documented. Preparation and approval of the manuscript were done by the authors. The authors had full independence in decisions regarding the reporting of results and the content of this paper.

 
* Corresponding author. Mailing address: Division of Infectious Diseases, University of Nebraska Medical Center, 984031 Nebraska Medical Center, Omaha, NE 68198-4031. Phone: (402) 559-5276. Fax: (402) 559-8300. E-mail: merupp{at}unmc.edu

Published ahead of print on 24 September 2007.

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Antimicrobial Agents and Chemotherapy, December 2007, p. 4249-4254, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00570-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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