Expect strong formulary restraints on use of new-generation antibiotics
Newest antibiotics aren't cure for resistant strains
The upcoming availability of Synercid, touted as the cure for vancomycin resistance - along with the recent approval of Trovan, the most potent drug of the quinolone class - means new regimens of antibiotics must be learned. For pharmacists, physicians, and hospital administrators, these new antibiotic power drugs pose additional compliance problems in formularies already rife with vancomycin overuse and drugs no longer effective against resistant infections.
Luckily, new tools for dealing with these issues are emerging, allowing pharmacy directors to track and document antibiotic resistance and prescribing habits better. Doubtless, such tools will be needed if physicians embrace the new wonder drugs as quickly as they did the old.
Approved Feb. 19 by the U.S. Food and Drug Administration's Anti-Infective Drugs Advisory Committee, Synercid (quinupristin/dalfopristin), an intravenous injectable streptogramin, is the debutante of the first new class of antibiotics to come to market in the United States in a decade to treat severe gram-positive bacterial infections, including resistant strains. This is true even though Synercid has been used in Europe for a number of years.
The antimicrobial's ability to attack bacteria resistant to vancomycin has generated great enthusiasm, but the fears of overuse are just as great and were realized during the initial approval process. "That's a biggie in terms of FDA approval. The company wanted three to four indications but were restricted," says William Jarvis, an epidemiologist with the Centers for Disease Control and Prevention in Atlanta.
Synercid is made by Rhone-Poulenc Rorer. Company spokeswoman Maureen Early confirms that of the four indications being sought, only three were approved: vancomycin-resistant Enterococcus faecium (VRE), complicated skin and skin structure infections, and nosocomial pneumonia. Left off the roster was community-acquired pneumonia (CAP), a condition already indicated for a host of antibiotics, she says.
Rhone expects Synercid to gain final approval this summer, and Early says it will come in 7.5 mg/kg doses, given as Q8-hour dosing for VRE and nosocomial pneumonia, Q12 for skin infections.
The combination of quinupristin and dalfopristin gives Synercid its potency and its "synergy" namesake, as the elements together disrupt protein synthesis in bacteria cells.
The drug has performed as expected in trials for VRE, but some patients have developed E. faecalis during Synercid therapy, although that species itself was susceptible to vancomycin and ampicillin treatment. Still, the cases point out that E. faecalis itself may be resistant to Synercid and provides a telling caution against its overuse.
"Usually for VRE infection one sees 5% to 10% [of a patient population] cases of E. faecalis," says Peter Linden, MD, associate professor of medicine at the University of Pittsburgh Medical Center. But based on effective treatment with available antibiotics, "it hasn't been a major problem, and there haven't been any resistant Staphylococcus aureus strains develop on [Synercid] therapy."
Synercid also has been studied as a treatment for methicillin-resistant S. aureus (MRSA) and has been found comparable to success rates of vancomycin for the approved indications of nosoco mial pneumonia and skin infections. Researchers point out, however, that Synercid could be used best in these situations only when patients develop an allergic reaction to vancomycin or if vancomycin resistance is assured. Again, the point is to avoid overuse.
Linden says the drug's specific indications, the general consensus that Synercid is too precious to prescribe lightly, and a tangible limitation on its administration will combine to keep it squarely on formulary restrictions and tight protocols. With an IV-only availability, the drug is uniformly given via central lines, as high rates of phlebitis occur when peripheral IV lines have been used, making it unlikely physicians will pursue central line administration when unnecessary or for anything like drug cycling.
Says Linden, "There are some natural impediments toward using it empirically, before we even get to the resistance issue."
Along with its broad spectrum of indications, really the broadest so far for a fluoroquinolone, what has clinicians more excited about Pfizer's Trovan (trovafloxacin) is its achievement as the first quinolone antibiotic to show efficacy against anaerobics such as Bacteroides fragilis, Peptostrepto coccus and Prevotella and its success with gram-negative, gram-positive, and atypical bacteria.
Recently approved and on the market in tab and IV form (as alatrofloxacin), Trovan's broad range of indications also is making it a frontline treatment for community acquired pneumonia - just one of its many indications - based on the equally broad range of typical or atypical pathogens that can cause CAP.
Along with approval as a surgical prophylaxis, Trovan is indicated in adults for:
· uncomplicated urinary tract infections;
· chronic bacterial prostatitis;
· complicated abdominal infections;
· complicated and uncomplicated skin or skin structure infections;
· acute bacterial exacerbations of chronic bronchitis;
· acute sinusitis;
· chlamydial cervicitis;
· gonorrhea;
· pelvic inflammatory disease;
· pelvic and gynecological infections;
· nosocomial pneumonia;
· CAP.
For treating ailments such as community-acquired pneumonia, the drug's ability to replace combination regimens of a beta-lactam and macro lide, for instance, also is being studied. Clinical trials leading to FDA approval included a CAP study combining IV and oral Trovan with combinations of IV ciprofloxacin and IV ampicillin, as well as oral ciprofloxacin and oral amoxicillin, all with equally successful results.
Side effects associated with Trovan include some dizziness, nausea, diarrhea, and headache. More specifically in terms of cautions, the drug's labeling notes that liver function tests can cause elevations in cases of prolonged use, leading to a recommendation that hepatic function be monitored regularly. Studies also showed the drug's systemic potency is decreased if oral Trovan is taken with aluminum-, iron-, or magnesium-based products or with some citric acids, meaning only that the drug should not be taken within two hours' time of these other products, although the drug can be taken without regard to meals.
Both formulations are recommended for once-daily dosage, with Trovan packaged in 100 mg and 200 mg trovafloxacin tabs, or 40 ml and 60 ml IV alatrofloxacin vials, equivalent to 5 mg of trovafloxacin/1 ml.
FDA expands applicationPart of the macrolide group of antibiotics, the dirithromycin tablet marketed as Dynabac by San ofi Pharmaceuticals and Eli Lilly is indicated to treat acute bacterial exacerbations, secondary bacterial infections of chronic bronchitis, and community acquired pneumonia, pharyngitis, and tonsillitis.
On March 3, the FDA approved a Supple mental New Drug Application to include the drug's use for acute bacterial exacerbations of chronic bronchitis due to Haemophilus influenzae, along with uncomplicated skin infections brought by Streptococcus pyogenes. Treatment therapy for the new indications is five days, with once a day administration for all old and new indications.
The agency also has granted pediatric indications for SmithKline Beecham's Timentin (ticarcillin disodium/clavulanate potassium) for patients 3 months to 16 years, along with its previous use in adults. The drug is commonly used for abdominal, respiratory, bone, joint, skin, urinary, and gynecological infections.
Another beta-lactamase inhibitor, Wyeth-Ayerst's Zosyn (piperacillin sodium/tazobactam sodium), has received FDA approval to package the IV antibiotic as a frozen premix, used with Baxter's line of premix IV systems.
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