MRSA
Zyvox® More Effective than Vancomycin in Treating Complicated Soft Tissue Infections
By Pfizer
Jun 6, 2005 - 10:16:00 AM

Pfizer's antibiotic ZYVOX® (linezolid injection, tablets, and for oral suspension) is more effective than vancomycin for the treatment of complicated skin and soft tissue infections (cSSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA), according to the largest MRSA cSSTIs study to date published in Antimicrobial Agents and Chemotherapy. Of the total study population, including those treated for methicillin-susceptible infections, the number of patients cured with ZYVOX was comparable to those cured with vancomycin.

In addition, patients taking ZYVOX spent up to five fewer days on IV treatment because of its availability as a pill. Available in interchangeable IV and oral formulations, ZYVOX is the only oral medicine approved by the U.S. Food and Drug Administration for MRSA infections.

This study involved 1,180 patients with cSSTIs, 361 of whom had confirmed MRSA infections. MRSA is a serious, multidrug-resistant infection, which is on the rise and can lead to prolonged hospitalization, along with increased morbidity, mortality and cost. Patients in the microbiologically evaluable MRSA subgroup treated with ZYVOX had better microbiologic cure rates: 88.6 percent for ZYVOX patients vs. 66.9 percent for vancomycin patients.

"In this study, ZYVOX was shown to be better than traditional vancomycin therapy in improving outcomes for patients with serious MRSA infections," said Dr. John Weigelt, lead investigator of the study, and professor and vice chairman of the department of surgery at the Medical College of Wisconsin. "These data also reinforce the value of having a pill for patients which may allow patients to leave the hospital sooner on oral therapy."

Because of the oral availability of ZYVOX, patients in the ZYVOX arm had up to five fewer days on IV therapy than patients treated with vancomycin. More than half of study participants ( 52 percent ) treated with ZYVOX began treatment on the oral formulation. The U.S. Centers for Disease Control and Prevention recommends getting the catheters out and using an IV only when essential since these and other invasive devices are a frequent cause of hospital-acquired infections.

Skin and soft tissue infections are a common cause of morbidity in the community and hospital. Those at risk for cSSTIs include surgical patients, patients with diabetes and those who are immunocompromised, such as patients with cancer. These infections are increasingly caused by resistant bacteria such as MRSA. According to a previous study, the rate of MRSA among cSSTI isolates is approximately 30 percent. Thirty years ago, only two percent of hospital-acquired Staph infections in intensive care units were resistant to antibiotics, but today physicians are seeing rates of approximately 60 percent.

"The rapid emergence of MRSA is an increasing public health problem, especially among hospitalized patients where skin and soft tissue infections caused by MRSA can be fatal," said Dr. Weigelt. "ZYVOX has been shown to have excellent skin and tissue penetration which I believe is important when treating complicated SSTIs to ensure the treatment reaches the infection site. ZYVOX is a critical option for patients with risk factors for MRSA, such as an acute illness, a compromised immune system or previous antibiotic use."

Study Results

In the intent-to-treat ( ITT ) population, ZYVOX had clinical cure rates of 92.2 percent vs. 88.5 percent for patients on vancomycin. In the MRSA subgroup ( microbiologically evaluable population ), patients treated with ZYVOX had better microbiologic cure rates of 88.6 percent compared with 66.9 percent for patients on vancomycin. In the ITT population, patients in the ZYVOX group had fewer days of IV therapy than those in the vancomycin group ( 4.0 + 2.6 days vs. 9.0 + 5.3 days, respectively ). The overall mean treatment duration was significantly longer in the ZYVOX group vs. the vancomycin group ( 11.8 + 4.9 days vs. 10.9 + 5.3, respectively ).

Study Background

This randomized, open-label, comparator-controlled, multicenter, multinational study evaluated 1,180 patients' response to treatment with ZYVOX and vancomycin. The most common types of cSSTIs seen in study patients were cellulitis ( spreading infection of the skin and subcutaneous tissues ), a major skin abscess ( pus and infected material build up in the skin ) and an infected surgical incision. Clinical efficacy outcomes ( e.g., cured, failed or indeterminate ) were measured by resolution of the signs and symptoms of infection compared with baseline. Microbiologic cure rates were defined as presumed or documented eradication. The study also compared the mean IV duration of each treatment and the total number of days that patients received antibiotic therapy. Patients who received vancomycin did not have the option to start on or switch to an oral agent because vancomycin is only available intravenously.

Patients were randomly assigned in a 1:1 ratio to receive either IV or oral ZYVOX 600 mg every 12 hours ( 592 patients ) or IV vancomycin 1 g every 12 hours ( 588 patients ) for seven to 14 days. The minimal treatment period was four days, but no longer than 21 days. Of the 592 patients treated with ZYVOX, 308 were started on oral therapy. Test-of-cure assessment was planned to be performed seven days after the end of treatment.

The incidence of drug-related adverse events appeared similar between treatment arms. Most adverse events in both groups were classified as mild to moderate. Drug-related adverse events in the ZYVOX-treated patients were noted more often in the digestive system and in lab tests documenting thrombocytopenia. Rash, anaphylaxis, drug-related allergic reaction and phlebitis were reported more often by patients in the vancomycin treatment group.

About ZYVOX

ZYVOX was initially approved in the United States in April 2000 for the treatment of complicated skin and skin structure infections ( cSSSIs ) and nosocomial pneumonia, including those caused by MRSA. In December 2002, ZYVOX was approved for use in pediatric patients and subsequently received approval for diabetic foot infections in July 2003. Since its introduction, ZYVOX has proven to be an important treatment option for designated infections known or suspected to be caused by MRSA. To date, nearly one million patients worldwide have been treated with ZYVOX for its approved indications.

ZYVOX is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms:

-- Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus ( methicillin-susceptible and -resistant strains ), Streptococcus pyogenes, or Streptococcus agalactiae. ZYVOX has not been studied in the treatment of decubitus ulcers. Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram-negative organisms.

-- Nosocomial pneumonia caused by Staphylococcus aureus ( methicillin-susceptible and -resistant strains ) or Streptococcus pneumoniae ( including multidrug-resistant strains [MDRSP]* ). Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram-negative organisms.

ZYVOX formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.

Myelosuppression ( including anemia, leukopenia, pancytopenia, and thrombocytopenia ) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than 2 weeks, those with preexisting myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.

Lactic acidosis has been reported with the use of ZYVOX. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving ZYVOX should receive immediate medical evaluation.

Spontaneous reports of serotonin syndrome associated with co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors ( SSRIs ), have been reported. Patients who are treated with ZYVOX and concomitant serotonergic agents should be closely observed for signs and symptoms of serotonin syndrome ( e.g., cognitive dysfunction, hyperpyrexia, hyperreflexia, incoordination ). If any signs or symptoms occur physicians should consider discontinuation of either one or both agents ( ZYVOX or concomitant serotonergic agents ).

Peripheral and optic neuropathy have been reported in patients treated with ZYVOX, primarily those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with ZYVOX for less than 28 days.

If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking ZYVOX for extended periods ( =3 months ) and in all patients reporting new visual symptoms regardless of length of therapy with ZYVOX. If peripheral or optic neuropathy occurs, the continued use of ZYVOX in these patients should be weighed against the potential risks.

The most commonly reported adverse events in adults across clinical trials were nausea, headache, and diarrhea.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZYVOX and other antibacterial drugs, ZYVOX should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

As with nearly all antibacterial agents, pseudomembranous colitis has been reported with ZYVOX. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of ZYVOX.

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