448
Skin, Soft Tissue, Bone, and Joint Infections
reported in diabetic patients. All the patients had normal numbers of neutrophils at entry. The study included a small number of patients in each group and used GCSF for only a short period of time. Results were generally not statistically significant except in the aggregate for all amputations at both evaluation periods. However, there was a trend toward a better outcome in “improvement,” “early amputation” at 3 weeks, and “failure” at 3 and 9 weeks in the GCSF group compared with controls.
This study stimulates thought about an additional approach to this very frustrating problem—both to the clinician and patient—of diabetic foot infections. It seems reasonable to develop a multicenter, randomized, prospective, and controlled study of a larger number of patients treated for even longer periods of time with GCSF to see if this very expensive addition to our present therapy has a clinical and/ or cost-effective benefit, before the clinician employs this modality in everyday care of the diabetic foot infection.
Linezolid Versus Oxacillin-Dicloxacillin for Treatment of Complicated Skin and Soft Tissue Infections Stevens DL, Smith LG, Bruss JB, et al.: Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2000, 44:3408–3413. Rating: •Of importance. Introduction: Skin and soft tissue infections are one of the most common infections encountered in clinical practice. Complicated infections involve the deeper tissues such as the subcutaneous tissue, fascia, or muscle. Most of these infections are caused by Staphylococcus aureus, Streptococcus pyogenes, or other streptococci. Most of these infections have been treated with β-lactam antibiotics, but there is an increasing resistance to all of these agents. Linezolid is a new antibiotic of the oxazolidinone class that inhibits early protein synthesis. It has broad activity against all gram-positive bacteria, including S. aureus, coagulase-negative staphylococci, streptococci, Streptococcus pneumoniae, and enterococci, including strains resistant to β-lactams and vancomycin. Aims: To compared the efficacy and safety of linezolid with oxacillin-dicloxacillin treatment. Methods: This double-blinded, randomized, prospective, multicenter, and multinational study of complicated skin and soft tissue infections was performed in adults 18 years of age and older. Patients were randomized to receive either linezolid 600 mg every 12 hours intravenously, or oxacillin 2 g every 6 hours. Intravenous placebo doses were used to maintain the blinded nature of the study. Aztreonam could be added to either regimen for gram-negative coverage when necessary. Oral therapy could be initiated whenever clinical improvement allowed it, and included oral linezolid 600 mg every 12 hours with placebo dummy pills, or dicloxacillin 500 mg every 6 hours, respectively. Patients were evaluated for both clinical and microbiologic cure. Toxicity and side effects were also monitored and compared.
Results: Eight hundred twenty-six patients were enrolled initially at 133 multinational centers, with 403 patients in the linezolid group and 423 in the oxacillin-dicloxacillin group. Of these, 600 patients were clinically evaluable (298 in the linezolid and 302 in the oxacillin-dicloxacillin group), and 294 patients were microbiologically evaluable (143 in the linezolid and 151 in the oxacillin-dicloxacillin group). Severity of disease and initial pathogens were similar in both groups. Duration of treatment was 13.4 days in each group with less than 5 days of intravenous treatment in each group. All other demographics at baseline were similar. Clinical cure rates were similar in the two groups: 69.8% in the linezolid group and 64.9% in the oxacillindicloxacillin group. In the microbiologically evaluable group of patients, 88.1% and 86.1% were cured in the linezolid and oxacillin-dicloxacillin groups, respectively. The results were also similar for the initial pathogens isolated. Safety appeared to be similar in the two groups, with 47.3% of the linezolid group and 41.3% of oxacillindicloxacillin group reporting adverse events. Nausea, headache, and vomiting were most common in the linezolid group (5%–6% for each), and nausea, headache, and constipation were common in the oxacillin-dicloxacillin group (3%–6% for each). Serious adverse events occurred in 5.5% of the linezolid group and 4.5% of the oxacillindicloxacillin group. None were considered secondary to linezolid, but four of 19 were considered related to oxacillin-dicloxacillin. Three deaths occurred in the linezolid group and one in the oxacillin-dicloxacillin group, none of which were considered to be drug related. Of interest, 3% of the linezolid group had hypertension, whereas only 0.2% of the oxacillin-dicloxacillin group had hypertension. Further evaluation of these patients failed to definitively prove a relationship to linezolid, though it is a weak monoamine oxidase inhibitor. Significantly, more patients withdrew from the oxacillin-dicloxacillin group due to adverse events related to the drug than did patients in the linezolid group. There were no significant hematologic or chemistry abnormalities in the two groups, and no drug interaction with linezolid and other concomitant medications occurred.
Clinical Trials Report 449
Discussion: Linezolid proved to be equally efficacious in the treatment of complicated skin and soft tissue infections as oxacillin-dicloxacillin. It is well absorbed orally with 100% bioequivalent to the intravenous formulation, so that early conversion to oral therapy is appropriate. Linezolid was also very safe and well tolerated, and its twice-daily dosing is convenient to use.
Editor’s comments Since this study was performed, linezolid has been approved by the Food and Durg Administration and marketed in the United States on April 18, 2000. It is approved for the treatment of nosocomial pneumonia secondary to S. aureus and penicillin-susceptible S. pneumoniae; complicated skin and skin structure infections caused by S. aureus, S. pyogenes, or Streptococcus agalactiae; vancomycin-resistant Enterococcus faecium infections; uncomplicated skin and skin structure infections caused by methicillin-sensitive S. aureus and S. pyogenes; and community-acquired pneumonia by penicillin-susceptible S. pneumoniae or methicillin-susceptible S. aureus.
There are no controlled studies showing the efficacy of this agent for deep-seated infections such as infective endocarditis or osteomyelitis. Therefore, empiric treatment of these infections with linezolid must be done with caution, and other agents such as β-lactams or vancomycin should remain the antibiotics of choice if the organisms are sensitive until more data are available. Linezolid also has known hematologic toxicity, most commonly thrombocytopenia. However, in March, 2001, the Food and Durg Administration advised careful monitoring of all hematologic parameters at weekly intervals while on therapy because of reports of myelosuppression during treatment. Lastly, linezolid pricing makes it the most expensive oral antimicrobial agent on the market, averaging up to $100 to $120 daily for the twice-daily dosing of 600 mg. The intravenous cost is even higher. Therefore, this agent can have a dramatic impact on the formulary budget of the hospital and the personal budget of the outpatients who use it. Resistance is already being seen in the hospital setting in a few strains of vancomycin-resistant enterococci. Therefore, linezolid should be restricted to use in situations where no other reasonable alternative exists.
Skin, Soft Tissue, Bone, and Joint Infections
reported in diabetic patients. All the patients had normal numbers of neutrophils at entry. The study included a small number of patients in each group and used GCSF for only a short period of time. Results were generally not statistically significant except in the aggregate for all amputations at both evaluation periods. However, there was a trend toward a better outcome in “improvement,” “early amputation” at 3 weeks, and “failure” at 3 and 9 weeks in the GCSF group compared with controls.
This study stimulates thought about an additional approach to this very frustrating problem—both to the clinician and patient—of diabetic foot infections. It seems reasonable to develop a multicenter, randomized, prospective, and controlled study of a larger number of patients treated for even longer periods of time with GCSF to see if this very expensive addition to our present therapy has a clinical and/ or cost-effective benefit, before the clinician employs this modality in everyday care of the diabetic foot infection.
Linezolid Versus Oxacillin-Dicloxacillin for Treatment of Complicated Skin and Soft Tissue Infections Stevens DL, Smith LG, Bruss JB, et al.: Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2000, 44:3408–3413. Rating: •Of importance. Introduction: Skin and soft tissue infections are one of the most common infections encountered in clinical practice. Complicated infections involve the deeper tissues such as the subcutaneous tissue, fascia, or muscle. Most of these infections are caused by Staphylococcus aureus, Streptococcus pyogenes, or other streptococci. Most of these infections have been treated with β-lactam antibiotics, but there is an increasing resistance to all of these agents. Linezolid is a new antibiotic of the oxazolidinone class that inhibits early protein synthesis. It has broad activity against all gram-positive bacteria, including S. aureus, coagulase-negative staphylococci, streptococci, Streptococcus pneumoniae, and enterococci, including strains resistant to β-lactams and vancomycin. Aims: To compared the efficacy and safety of linezolid with oxacillin-dicloxacillin treatment. Methods: This double-blinded, randomized, prospective, multicenter, and multinational study of complicated skin and soft tissue infections was performed in adults 18 years of age and older. Patients were randomized to receive either linezolid 600 mg every 12 hours intravenously, or oxacillin 2 g every 6 hours. Intravenous placebo doses were used to maintain the blinded nature of the study. Aztreonam could be added to either regimen for gram-negative coverage when necessary. Oral therapy could be initiated whenever clinical improvement allowed it, and included oral linezolid 600 mg every 12 hours with placebo dummy pills, or dicloxacillin 500 mg every 6 hours, respectively. Patients were evaluated for both clinical and microbiologic cure. Toxicity and side effects were also monitored and compared.
Results: Eight hundred twenty-six patients were enrolled initially at 133 multinational centers, with 403 patients in the linezolid group and 423 in the oxacillin-dicloxacillin group. Of these, 600 patients were clinically evaluable (298 in the linezolid and 302 in the oxacillin-dicloxacillin group), and 294 patients were microbiologically evaluable (143 in the linezolid and 151 in the oxacillin-dicloxacillin group). Severity of disease and initial pathogens were similar in both groups. Duration of treatment was 13.4 days in each group with less than 5 days of intravenous treatment in each group. All other demographics at baseline were similar. Clinical cure rates were similar in the two groups: 69.8% in the linezolid group and 64.9% in the oxacillindicloxacillin group. In the microbiologically evaluable group of patients, 88.1% and 86.1% were cured in the linezolid and oxacillin-dicloxacillin groups, respectively. The results were also similar for the initial pathogens isolated. Safety appeared to be similar in the two groups, with 47.3% of the linezolid group and 41.3% of oxacillindicloxacillin group reporting adverse events. Nausea, headache, and vomiting were most common in the linezolid group (5%–6% for each), and nausea, headache, and constipation were common in the oxacillin-dicloxacillin group (3%–6% for each). Serious adverse events occurred in 5.5% of the linezolid group and 4.5% of the oxacillindicloxacillin group. None were considered secondary to linezolid, but four of 19 were considered related to oxacillin-dicloxacillin. Three deaths occurred in the linezolid group and one in the oxacillin-dicloxacillin group, none of which were considered to be drug related. Of interest, 3% of the linezolid group had hypertension, whereas only 0.2% of the oxacillin-dicloxacillin group had hypertension. Further evaluation of these patients failed to definitively prove a relationship to linezolid, though it is a weak monoamine oxidase inhibitor. Significantly, more patients withdrew from the oxacillin-dicloxacillin group due to adverse events related to the drug than did patients in the linezolid group. There were no significant hematologic or chemistry abnormalities in the two groups, and no drug interaction with linezolid and other concomitant medications occurred.
Clinical Trials Report 449
Discussion: Linezolid proved to be equally efficacious in the treatment of complicated skin and soft tissue infections as oxacillin-dicloxacillin. It is well absorbed orally with 100% bioequivalent to the intravenous formulation, so that early conversion to oral therapy is appropriate. Linezolid was also very safe and well tolerated, and its twice-daily dosing is convenient to use.
Editor’s comments Since this study was performed, linezolid has been approved by the Food and Durg Administration and marketed in the United States on April 18, 2000. It is approved for the treatment of nosocomial pneumonia secondary to S. aureus and penicillin-susceptible S. pneumoniae; complicated skin and skin structure infections caused by S. aureus, S. pyogenes, or Streptococcus agalactiae; vancomycin-resistant Enterococcus faecium infections; uncomplicated skin and skin structure infections caused by methicillin-sensitive S. aureus and S. pyogenes; and community-acquired pneumonia by penicillin-susceptible S. pneumoniae or methicillin-susceptible S. aureus.
There are no controlled studies showing the efficacy of this agent for deep-seated infections such as infective endocarditis or osteomyelitis. Therefore, empiric treatment of these infections with linezolid must be done with caution, and other agents such as β-lactams or vancomycin should remain the antibiotics of choice if the organisms are sensitive until more data are available. Linezolid also has known hematologic toxicity, most commonly thrombocytopenia. However, in March, 2001, the Food and Durg Administration advised careful monitoring of all hematologic parameters at weekly intervals while on therapy because of reports of myelosuppression during treatment. Lastly, linezolid pricing makes it the most expensive oral antimicrobial agent on the market, averaging up to $100 to $120 daily for the twice-daily dosing of 600 mg. The intravenous cost is even higher. Therefore, this agent can have a dramatic impact on the formulary budget of the hospital and the personal budget of the outpatients who use it. Resistance is already being seen in the hospital setting in a few strains of vancomycin-resistant enterococci. Therefore, linezolid should be restricted to use in situations where no other reasonable alternative exists.
