Acute bacterial skin and skin structure infection facts and statistics

Infections of skin and soft tissues are frequently encountered in acute and ambulatory settings. Skin infections can range in severity from mild, superficial, self-limiting infections to severe, life-threatening infections. Acute bacterial skin and skin structure infection (ABSSSI) is characterized as skin infection with a lesion size of at least 75 cm2. Lesion size can be measured from area of edema, redness, or swelling of skin. Signs of ABSSSIs are fever (>380C/100.40F within 24 hours of baseline), leukocytosis (WBC >12,000 cells/mm3), purulent discharge, tenderness, and warm skin. ABSSSIs are caused by Gram-positive organisms such as Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus agalactiae.

• Bacterial skin infections are the 28th most common diagnosis in hospitalized patients.

• The incidence of ABSSSI from 1993-2005 increased from 1 million to 3.5 million at emergency departments. 

• Community-acquired methicillin resistance staphylococcus aureus (CA-MRSA) is a major cause of ABSSSI. 

• The most prevalent comorbidities associated with ABSSSIs are diabetes and chronic pulmonary disease.

Standard of care for ABSSSIs

Incision and drainage of the infection area is the first step of treatment. Culture and sensitivity tests are used to identify the bacteria. The usual standard of care for severe skin infections is to start empiric therapy with vancomycin, daptomycin, linezolid, telavancin, or ceftaroline. If methicillin resistance staphylococcus aureus (MRSA) is suspected patients continue on the empiric therapy that was initially started. If methicillin susceptible Staphylococcus aureus (MSSA) is confirmed from cultures then nafcillin, cefazolin, or clindamycin are recommended options for treatment.

New antibiotics for ABSSSIs

In 2009 the FDA approved a Vibativ (telavancin), a lipoglycopeptide antibiotic effective for treating ABSSSIs. In 2014 the FDA approved Dalvance (dalbavancin), Orbactiv (oritavancin), and Sivextro (tedizolid phosphate) for treatment of ABSSSIs. These new antibiotics offer therapeutic options for treating ABSSSIs and some advantages over older antibiotics. 

Vibativ, Dalvance, and Orbactiv (Lipoglycopeptide class antibiotic)

Lipoglycopeptides are antibiotics with a lipophilic side chain that is linked to glycopeptides. Cell walls of bacteria are made of peptidoglycan and are necessary for survival of bacteria. Lipoglycopeptides kill bacteria by inhibiting cell wall synthesis. Without cell walls newly formed bacteria cannot survive.

Vibativ (telavancin) is the first FDA approved lipoglycopeptide for treatment of ABSSSIs.  Dalvance (dalbavancin), a two-dosage regimen for ABSSI, was approved by the FDA in May 2014. In August 2014, Orbactiv (oritavancin) single dose regimen was FDA approved. These new dosage regimens are advancements in treatment of ABSSSI. 

Vibativ (telavancin)

Vibativ is a lipoglycopeptide antibiotic that inhibits cell wall synthesis and also binds to bacterial membranes, disrupts the function of the membrane barrier, and increases membrane permeability. It is the first medication that was approved for treatment of ABSSSI. It may also be used for hospital-acquired and ventilator-associated bacterial pneumonia when alternative treatments are not effective. Safety and efficacy of Vibativ for ABSSSI was compared with vancomycin in a randomized, multinational, multi-center, double-blind trial of 1,794 patients with ABSSSIs for 7-14 days. The dose used was 10mg/kg over 60 minutes of intravenous infusion once a day for 7-14 days. Clinical cure rate by the end of trial was 72.5% for the Vibativ group and 71.6% for vancomycin group. 

Side effects of Vibativ include taste disturbance, nausea, vomiting, infusion reactions (pruritus, urticaria, or flushing), and foamy urine. Some of its serious adverse reactions are hypersensitivity reactions and clostridium difficile-associated diarrhea, and QTc prolongation. It should not be used in patients with renal impairment (baseline CrCl ≤ 50ml/min) because the efficacy of Vibativ decreases in patients with renal impairment. The wholesale price of one vial of Vibativ 250 mg is $189.65. Since it is given for 7 to 14 days, Dalvance is more expensive than the other two lipoglycopeptides.

Dalvance (dalbavancin)

Dalvance is the second lipoglycopeptide approved for treatment of ABSSSI. Safety and efficacy of Dalvance was compared with vancomycin/linezolid in a randomized, double-blind clinical trial of 1,312 patients with ABSSSIs for two weeks. Clinical response rate at 48-72 hours after initiation of therapy was 83.3% in Dalvance group compared to 78.3% in the vancomycin/linezolid group. The response rate for reduction in lesion size of 20% or greater was 87.6% for the Dalvance group and 85.9% for vancomycin/linezolid group. Also, the clinical success at follow-up (day 26 to 30) was 88.1% in Dalvance group compared to 84.5% in vancomycin/linezolid group. 

Unlike Vibativ, Dalvance is given weekly. The dose is an intravenous infusion of 1000 mg over 30 minutes for the first week followed by 500 mg during the second week. Only two doses of Dalvance are required because it has a long half-life of 8.5 days (204 hours). 

Its common side effects are nausea, headache, diarrhea, vomiting, infusion reactions (pruritus, urticaria, or flushing), and rash. Its serious adverse reactions are hypersensitivity reactions and clostridium difficile-associated diarrhea. Like other antibiotics Dalvance should only be used to treat infections that are proven or are very likely caused by susceptible bacteria. 

Dosage adjustment is not recommended for patients with renal impairment or are receiving  hemodialysis. Also for mild hepatic impairments no dosage adjustment is necessary. Caution is advised when used in patients with moderate to severe hepatic impairment. Since this is a newly approved medication no drug interactions have been reported. The wholesale price of one 500 mg vial is $1490 and the cost for a complete course of therapy is $4,470.

Orbactiv (oritavancin)

Like Vibativ, Orbactiv has a multiple mechanisms of action. It inhibits 2 steps in bacterial cell wall synthesis and it also binds to bacterial membranes, disrupts the function of the membrane barrier, and increases membrane permeability. Safety and efficacy of Orbactiv 1200 mg single dose was compared with vancomycin given twice daily for 7 to 10 days in a randomized, double-blind, multi-center, multinational trial of 1,987 patients with ABSSSIs. Clinical response rate at 48-72 hours after treatment was 82.3% in Orbactiv group compare to 78.9% in vancomycin group and response rate for reduction in lesion size of 20% or greater for Orbactiv group was 86.9% and for vancomycin group was 82.9%. Also, the clinical success rate at follow-up (7-14 days after end of therapy) was 82.7% for Orbactiv and 80.5% for vancomycin.

The recommended Orbactiv dose is one 3 hour intravenous infusion of 1200 mg. A single dose of Orbactiv is effective for treating ABSSSI because Orbactiv has a half-life of 245 hours (10 days). 

The most common side effects are headache, nausea, vomiting, infusion reactions (pruritus, urticaria, or flushing), and diarrhea. Serious adverse reactions are hypersensitivity reactions and clostridium difficile-associated diarrhea. In clinical trials more cases of osteomyelitis were reported in the Orbactiv treated group than in the vancomycin-treated group. Orbactiv is a week inhibitor of CYP2CP and CYP2C19 and an inducer of CYP3A4 and CYP2D6. Drugs (e.g., warfarin) that are metabolized by these enzymes should be monitored when combined with Orbactiv, Orbactiv interferes with coagulation tests because it may artificially prolong aPTT, PT and INR for up to 24 hours.

Dosage adjustment is not necessary in patients with mild to moderate renal or hepatic impairment. Patients with severe renal or hepatic impairment were not studied. The wholesale price for 3 vials of 400 mg (1200 mg), which is a single dose of Orbactiv, is $2900. Based on average whole sale price a complete course of Orbactiv is cheaper than a course of Dalvance or Vibativ for treatment of ABSSSI.   

Sivextro (Oxazolidinone- Class Antibiotic)

Sivextro (tedizolid phosphate) is the prodrug (inactive form) of tedizolid, an oxazolidinone type antibiotic. After oral or intravenous administration it is converted to its active form by enzymes. Cells require vital cellular proteins for survival. Tedizolid, the active form of Sivextro, binds to cell structures that produce these essential proteins that allow bacterial cells to function and inactivates them. Because its mechanism of action differs from non-oxazolidinone class antibacterials, bacterial cross-resistance is unlikely. Tedizolid is active against gram-positive organisms. 

Oxazolidinones are also used for treatment of ABSSSIs. Zyvox (linezolid) that was the first Oxazolidinone and it was approved in 2000. Sivextro is the second antibiotic in this class and it was FDA approved in June 2014 for treatment of ABSSSI.

In a multicenter, double-blind, randomized, non-inferior trial, Sivextro for 6 days was compared with linezolid for 10 days in 1,315 patients with ABSSSIs. Clinical response in reduction of lesion size 20% or greater was 78% in Sivextro group and 75.5% in linezolid group. Also, clinical response rate at post therapy evaluation was the 85.8% in both groups. Sivextro was not inferior to linezolid for treatment of ABSSSIs and the duration of Sivextro treatment is shorter.

Unlike Zyvox which is administered twice a day for 10-14 days, Sivextro 200 mg is given orally or infused over 1 hour once daily for 6 days. The most common side effects are nausea, headache, diarrhea, vomiting, and dizziness. Serious adverse reactions are tachycardia (increase heartbeat), clostridium difficile-associated diarrhea, neutropenia, optic nerve disorder, and peripheral nerve disease. Dosage adjustment is not necessary in patients with renal or hepatic impairment. Sivextro can be  given orally for treatment ABSSSIs. The wholesale price for one 200 mg vial is $235 and the price for one 200 mg tablet price is $295.  

Conclusion

Acute bacterial skin and skin structure infections are common. New antibiotics that are as effective as vancomycin were recently approved for treatment ABSSIs. These newer medications offer advantages of less frequent dosing or may be administered orally. Given the prevalence of MRSA, these new medications increase the options for treatment of ABSSIs. 

Reference

Vibativ, Prescribing Information, Theravance Inc.

Dalvance, Prescribing Information, Durata Therapeutics

Orbactiv, Prescribing Information, The Medicines Company

Sivextro, Prescribing Information, Cubist Pharmaceuticals

Diagnosis and Management of Skin and Soft Tissue Infection Guideline, 2014

Dalvance for Treatment of ABSSSI, US Food and Drug Administration, March 2014

Stulberg Daniel, et al. Common Bacterial Skin Infection, 2002 July1, 66;119-125

RedBook Online, Truven Health Analytics, Inc.; 2014