Staphylococcus aureus, also called Staph or S. aureus, has long been seen as one of the most important infections in human disease. Some scholars feel the sixth plague of Egypt as described in Exodus may refer to this organism. In this ancient story, before the exodus of the Jewish people from the bondage of Egypt, Moses took soot from a fireplace and scattered the ashes into the air. Egyptian men and livestock then developed boils.
In 1881, Sir Alexander Ogston of Scotland found this organism to be a cause of “acute suppuration” and named it Staphylococcus pyogenes aureus, taking its name from the grapelike clusters it forms, as seen under the microscope; the purulent nature of the infections it causes; and the golden colored colonies it forms on plates of growth media. It can cause abscesses, furuncles, cellulitis, pneumonia, bone and joint infections, and bloodstream infections. It is a common cause of postsurgical infections.
The miracle drug penicillin produced a remarkable decrease in mortality rates, but the reduction was short-lived as the bacteria rapidly became resistant to the penicillin molecule by producing an enzyme called beta-lactamase. Vancomycin, an effective drug with problematic adverse events, was introduced in 1956 and was soon followed by a semisynthetic form of penicillin, methicillin, which became the mainstay of therapy because of its safety profile.
But the 1990s saw a rapid rise in the presence of methicillin-resistant S. aureus (MRSA), which now makes up about 60% of all hospital cases of S. aureus infections. Partly because of MRSA, the U.S. government passed the Generating Antibiotic Incentives Now (GAIN) Act of 2012. This act allows certain novel antimicrobial drugs to be given the designation of Qualified Infectious Disease Product (QIDP) that, in turn, grants incentives to the development of new antibiotics. Basically, the FDA can now approve therapies for serious infections as soon as it can be concluded that the benefits justify their risks. And pharmaceutical companies have responded.
In early August, the FDA approved the latest, oritavancin, a semisynthetic lipoglycopeptide. The Medicines Co. will launch it under the brand Orbactiv in the fourth quarter of this year. Orbactiv is the first antibiotic approved by the FDA to treat acute bacterial skin and skin structure infections (ABSSSIs) with a single, once-only intravenous administration.
Orbactiv was approved based on the results of two randomized, double-blind, multicenter clinical trials named SOLO I and SOLO II, consisting of 1,987 patients including 405 with proven MRSA infections. Orbactiv, given as a once-only, three-hour infusion of 1,200 mg, was administered to 976 subjects. The comparator, vancomycin, 1 gram or 15 mg/kg, administered intravenously twice daily for 7 to 10 days, was administered to 983 subjects in a “noninferiority” trial design.
Orbactiv has a number of interesting characteristics. It is not metabolized but excreted slowly in the feces and urine. Its half-life is approximately 245 hours, which allows for the once-only dosing — virtually unheard of among antibiotic treatments. There are also no dosage adjustments required for patients with mild to severe renal or mild to moderate liver impairment and no adjustment in dosage for age, gender, race or weight — making it a simple choice. It has not been studied in anyone younger than age 18.
There are cautions with drug-to-drug interactions. Orbactiv inhibits actions of a number of cytochrome 450 enzymes. Use of unfractionated heparin sodium is contraindicated for 48 hours after Orbactiv administration because of the false elevation of the activated partial thromboplastin time (aPTT) test. The prescribing information contains a warning that the prothrombin ratio (PR) and international normalized ratio (INR) tests to determine proper dosage of warfarin are artificially prolonged and concomitant use of both Orbactiv and warfarin may result in higher levels of warfarin and therefore risk of bleeding. Essentially, it renders the monitoring test for warfarin unreliable and may increase the levels of warfarin.
Rates of serious adverse reactions were virtually identical between the Orbactiv and vancomycin groups (5.8% vs. 5.9%), with the most serious reaction being cellulitis in both groups (1.1 and 1.2%). The most common adverse events in the Orbactiv (and vancomycin) group were headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea.
Orbactiv provides a concentration-dependent bactericidal action against S. aureus, S. pyogenes, E. faecalis by way of three mechanisms of action: inhibition of both the polymerization and crosslinking step of cell wall biosynthesis and disruption of bacterial membrane integrity; basically, these three processes cause the walls around the cell to fall apart.
In two clinical trials, response rates were reported as: 82.3% and 80.1% in the Orbactiv groups versus 78.9% and 82.9% in the Vancomycin patients, allowing Orbactiv to meet the primary endpoint of the studies and the desired noninferiority designation. The studies included a secondary efficacy endpoint of “investigator-assessed” clinical success at Day 14–24, defined as “complete or nearly complete resolution of baseline signs and symptoms related to ABSSI such that no further treatment with antibacterial drugs was needed.” Both drugs achieved nearly the same results, but the PI was clear to point out that because of a variety of reasons, “comparisons of Orbactiv to vancomycin based on clinical success rates could not be utilized to establish noninferiority.”
Orbactiv is available in 400 mg sterile vials, meaning that three vials need to be reconstituted and administered in one liter of D5W. Normal saline cannot be used, as it is incompatible with Orbactiv and will cause it to precipitate.
Orbactiv is “noninferior” to the mainstay of MRSA therapy, vancomycin. But it offers a once-only administration approach to serious infections, something that managed care may find attractive if it can lead to outpatient therapy after one infusion. Other potential advantages are the assurance of compliance, reduced hospital-acquired infections, lack of need for continuous IV access, and improved patient satisfaction.
Remember that these are serious infections typically treated in the hospital, not just because the current drug requires twice-daily infusions. If these patients are treated as outpatients, physicians will still need to carefully monitor these patients, perhaps via telemedicine, which has often carried less-than-adequate reimbursement.
Orbactiv’s price has not been announced, so managed care companies and integrated risk-bearing systems cannot do an adequate cost-benefit analysis. But this drug certainly demonstrates some unique advantages, something common to Tomorrow’s Medicine.