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ZYVOX® (linezolid) Clinical Studies

14 CLINICAL STUDIES

14.1 Adults

Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multi-center, double-blind trial. Patients were treated for 7 to 21 days. One group received ZYVOX I.V. Injection 600 mg every 12 hours, and the other group received vancomycin 1 g every 12 hours intravenously. Both groups received concomitant aztreonam (1 to 2 g every 8 hours intravenously), which could be continued if clinically indicated. There were 203 linezolid-treated and 193 vancomycin-treated patients enrolled in the study. One hundred twenty-two (60%) linezolid-treated patients and 103 (53%) vancomycin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 57% for linezolid-treated patients and 60% for vancomycin-treated patients. The cure rates in clinically evaluable patients with ventilator-associated pneumonia were 47% for linezolid-treated patients and 40% for vancomycin-treated patients. A modified intent-to-treat (MITT) analysis of 94 linezolid-treated patients and 83 vancomycin-treated patients included subjects who had a pathogen isolated before treatment. The cure rates in the MITT analysis were 57% in linezolid-treated patients and 46% in vancomycin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 12.

Table 12. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Nosocomial Pneumonia
Cured
Pathogen ZYVOX
n/N (%)
Vancomycin
n/N (%)
Staphylococcus aureus 23/38 (61) 14/23 (61)
Methicillin-resistant S. aureus 13/22 (59) 7/10 (70)
Streptococcus pneumoniae 9/9 (100) 9/10 (90)

Complicated Skin and Skin Structure Infections

Adult patients with clinically documented complicated skin and skin structure infections were enrolled in a randomized, multi-center, double-blind, double-dummy trial comparing study medications administered intravenously followed by medications given orally for a total of 10 to 21 days of treatment. One group of patients received ZYVOX I.V. Injection 600 mg every 12 hours followed by ZYVOX Tablets 600 mg every 12 hours; the other group received oxacillin 2 g every 6 hours intravenously followed by dicloxacillin 500 mg every 6 hours orally. Patients could receive concomitant aztreonam if clinically indicated. There were 400 linezolid-treated and 419 oxacillin-treated patients enrolled in the study. Two hundred forty-five (61%) linezolid-treated patients and 242 (58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in linezolid-treated patients and 85% in oxacillin-treated patients. A modified intent-to-treat (MITT) analysis of 316 linezolid-treated patients and 313 oxacillin-treated patients included subjects who met all criteria for study entry. The cure rates in the MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 13.

Table 13. Cure Rates at the Test-of-Cure Visit for MicrobiologicallyEvaluable Adult Patients with Complicated Skin and Skin Structure Infections
Cured
Pathogen ZYVOX
n/N (%)
Oxacillin/Dicloxacillin
n/N (%)
Staphylococcus aureus 73/83 (88) 72/84 (86)
Methicillin-resistant S. aureus 2/3 (67) 0/0 (-)
Streptococcus agalactiae 6/6 (100) 3/6 (50)
Streptococcus pyogenes 18/26 (69) 21/28 (75)

A separate study provided additional experience with the use of ZYVOX in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. This was a randomized, open-label trial in hospitalized adult patients with documented or suspected MRSA infection.

One group of patients received ZYVOX I.V. Injection 600 mg every 12 hours followed by ZYVOX Tablets 600 mg every 12 hours. The other group of patients received vancomycin 1 g every 12 hours intravenously. Both groups were treated for 7 to 28 days, and could receive concomitant aztreonam or gentamicin if clinically indicated. The cure rates in microbiologically evaluable patients with MRSA skin and skin structure infection were 26/33 (79%) for linezolid-treated patients and 24/33 (73%) for vancomycin-treated patients.

Diabetic Foot Infections

Adult diabetic patients with clinically documented complicated skin and skin structure infections ("diabetic foot infections") were enrolled in a randomized (2:1 ratio), multi-center, open-label trial comparing study medications administered intravenously or orally for a total of 14 to 28 days of treatment. One group of patients received ZYVOX 600 mg every 12 hours intravenously or orally; the other group received ampicillin/sulbactam 1.5 to 3 g intravenously or amoxicillin/clavulanate 500 to 875 mg every 8 to 12 hours orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hours was used for the intravenous regimen. Patients in the comparator group could also be treated with vancomycin 1 g every 12 hours intravenously if MRSA was isolated from the foot infection. Patients in either treatment group who had Gram-negative bacilli isolated from the infection site could also receive aztreonam 1 to 2 g every 8–12 hours intravenously. All patients were eligible to receive appropriate adjunctive treatment methods, such as debridement and off-loading, as typically required in the treatment of diabetic foot infections, and most patients received these treatments. There were 241 linezolid-treated and 120 comparator-treated patients in the intent-to-treat (ITT) study population. Two hundred twelve (86%) linezolid-treated patients and 105 (85%) comparator-treated patients were clinically evaluable. In the ITT population, the cure rates were 68.5% (165/241) in linezolid-treated patients and 64% (77/120) in comparator-treated patients, where those with indeterminate and missing outcomes were considered failures. The cure rates in the clinically evaluable patients (excluding those with indeterminate and missing outcomes) were 83% (159/192) and 73% (74/101) in the linezolid- and comparator-treated patients, respectively. A critical post-hoc analysis focused on 121 linezolid-treated and 60 comparator-treated patients who had a Gram-positive pathogen isolated from the site of infection or from blood, who had less evidence of underlying osteomyelitis than the overall study population, and who did not receive prohibited antimicrobials. Based upon that analysis, the cure rates were 71% (86/121) in the linezolid-treated patients and 63% (38/60) in the comparator-treated patients. None of the above analyses were adjusted for the use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 14.

Table 14. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Diabetic Foot Infections
Cured
Pathogen ZYVOX
n/N (%)
Comparator
n/N (%)
Staphylococcus aureus 49/63 (78) 20/29 (69)
Methicillin-resistant S. aureus 12/17 (71) 2/3 (67)
Streptococcus agalactiae 25/29 (86) 9/16 (56)

Vancomycin-Resistant Enterococcal Infections

Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multi-center, double-blind trial comparing a high dose of ZYVOX (600 mg) with a low dose of ZYVOX (200 mg) given every 12 hours either intravenously (IV) or orally for 7 to 28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose linezolid and 66 to low-dose linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 in the low-dose arm.

The cure rates for the ITT population with documented vancomycin-resistant enterococcal infection at baseline are presented in Table 15 by source of infection. These cure rates do not include patients with missing or indeterminate outcomes. The cure rate was higher in the high-dose arm than in the low-dose arm, although the difference was not statistically significant at the 0.05 level.

Table 15. Cure Rates at the Test-of-Cure Visit for ITT Adult Patients with Documented Vancomycin-Resistant Enterococcal Infections at Baseline
Cured
Source of Infection ZYVOX
600 mg every 12 hours
n/N (%)
ZYVOX
200 mg every 12 hours
n/N (%)
*
Includes sources of infection such as hepatic abscess, biliary sepsis, necrotic gall bladder, pericolonic abscess, pancreatitis, and catheter-related infection.
Any site 39/58 (67) 24/46 (52)
Any site with associated bacteremia 10/17 (59) 4/14 (29)
Bacteremia of unknown origin 5/10 (50) 2/7 (29)
Skin and skin structure 9/13 (69) 5/5 (100)
Urinary tract 12/19 (63) 12/20 (60)
Pneumonia 2/3 (67) 0/1 (0)
Other* 11/13 (85) 5/13 (39)

14.2 Pediatric Patients

Infections due to Gram-positive Bacteria

A safety and efficacy study provided experience on the use of ZYVOX in pediatric patients for the treatment of nosocomial pneumonia, complicated skin and skin structure infections, and other infections due to Gram-positive bacterial pathogens, including methicillin-resistant and -susceptible Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Pediatric patients ranging in age from birth through 11 years with infections caused by the documented or suspected Gram-positive bacteria were enrolled in a randomized, open-label, comparator-controlled trial. One group of patients received ZYVOX I.V. Injection 10 mg/kg every 8 hours followed by ZYVOX for Oral Suspension 10 mg/kg every 8 hours. A second group received vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance. Patients who had confirmed VRE infections were placed in a third arm of the study and received ZYVOX 10 mg/kg every 8 hours intravenously and/or orally. All patients were treated for a total of 10 to 28 days and could receive concomitant Gram-negative antibiotics if clinically indicated. In the intent-to-treat (ITT) population, there were 206 patients randomized to linezolid and 102 patients randomized to vancomycin. The cure rates for ITT, MITT, and clinically evaluable patients are presented in Table 16. After the study was completed, 13 additional patients ranging from 4 days through 16 years of age were enrolled in an open-label extension of the VRE arm of the study. Table 17 provides clinical cure rates by pathogen for microbiologically evaluable patients including microbiologically evaluable patients with vancomycin-resistant Enterococcus faecium from the extension of this study.

Table 16. Cure Rates at the Test-of-Cure Visit for Intent-to-Treat, Modified Intent-to-Treat, and Clinically Evaluable Pediatric Patients for the Overall Population and by Select Baseline Diagnosis
ITT MITT* Clinically Evaluable
Population ZYVOX
n/N (%)
Vancomycin
n/N (%)
ZYVOX
n/N (%)
Vancomycin
n/N (%)
ZYVOX
n/N (%)
Vancomycin
n/N (%)
*
MITT = ITT patients with an isolated Gram-positive pathogen at baseline
Any diagnosis
150/186 (81) 69/83 (83) 86/108 (80) 44/49 (90) 106/117 (91) 49/54 (91)
Complicated skin and skin structure infections 61/72 (85) 31/34 (91) 37/43 (86) 22/23 (96) 46/49 (94) 26/27 (96)
Nosocomial pneumonia 13/18 (72) 11/12 (92) 5/6 (83) 4/4 (100) 7/7 (100) 5/5 (100)
Table 17. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Pediatric Patients with Infections due to Gram-positive Pathogens
Microbiologically Evaluable
Pathogen ZYVOX
n/N (%)
Vancomycin
n/N (%)
*
Includes data from 7 patients enrolled in the open-label extension of this study.
Vancomycin-resistant Enterococcus faecium 6/8 (75)* 0/0 (-)
Staphylococcus aureus 36/38 (95) 23/24 (96)
Methicillin-resistant S. aureus 16/17 (94) 9/9 (100)
Streptococcus pyogenes 2/2 (100) 1/2 (50)

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