Newly approved drugs in 2003

December 2003

This year-end column will review new anti-infective drugs approved by the FDA in 2003. Some products represent new dosage forms or new indications of drugs previously available, while another represents the first of a new class of antibacterial agents. Several products indicated for HIV infection were also approved in 2003, but will not be discussed in this month’s column.

Daptomycin

Perhaps the most interesting newly approved agent for 2003 is daptomycin. Daptomycin (Cubicin, Cubist) represents the first approved product of a new class of anti-infectives, cyclic lipopeptides. Daptomycin is indicated for the treatment of complicated skin and skin structure infections caused by Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp equisimillis and Enterococcus faecalis (vancomycin-susceptible strains only). Daptomycin has no activity toward gram-negative bacterial pathogens. Cyclic lipopeptides’ unique mechanism of action results from binding to bacterial membranes, with a resultant depolarization of membrane potential. This leads to protein, DNA and RNA synthesis inhibition and bacterial cell death.

Clinical studies that led to daptomycin’s FDA approval included two randomized, multicenter, single-blind trials comparing daptomycin to vancomycin or a semi-synthetic penicillin (eg, nafcillin) for the treatment of complicated skin and skin structure infections in adults. Clinical success rates did not differ among patients receiving daptomycin or the comparative antibiotic. Study patients infected with MRSA who were microbiologically evaluable also had similar treatment success rates: 21/28 (75%) and 25/36 (69.4%) for daptomycin and vancomycin, respectively (P values not given). The most commonly reported adverse effects of daptomycin therapy in clinical trials included constipation, nausea, injection site reactions and rash. An uncommon (2.8%) but unique adverse effect reported in these trials was an elevation of serum creatine phosphokinase (CPK). The package insert states that patients should be monitored for muscle pain or weakness (especially of the distal extremities) and CPK should be monitored weekly while receiving daptomycin. Therapy should be halted if CPK levels reach five-fold increases with symptoms of myopathy or 10-fold increases without symptoms. Most patients with daptomycin-induced CPK increases did not have related symptoms, and CPK levels returned to normal upon therapy discontinuance. Thus, the availability of daptomycin represents another treatment option for complicated skin infections. The relatively few studies to date indicate it is equally effective as current therapies. Daptomycin’s unique pharmacologic mechanism may afford this agent’s usefulness for treating serious infections when the bacterial pathogens display resistance to current treatments, although considerably more study data need to be assessed to understand the clinical significance of this. While daptomycin appears to be generally well tolerated, its potential for a drug-induced myopathy requires careful monitoring. The cost of using daptomycin is likely higher than comparative drugs — about $135 for one day’s therapy — not including the additional laboratory monitoring for adverse effects.

Valacyclovir

Valacyclovir (Valtrex, GlaxoSmith- Kline) is not new, but it has received a new indication — suppression and reduction of heterosexual transmission of genital herpes in immunocompetent individuals. No other antiviral agent shares this indication. FDA approval was based upon a double blind, placebo-controlled eight-month trial (unpublished) of 1,484 monogamous, heterosexual adult couples (discordant for HSV-2 infection). All couples were counseled on safe sex practices and condom use. Symptomatic acquisition of HSV-2 in susceptible partners was the primary study endpoint; HSV-2 seroconversion in the susceptible partner was also evaluated. Overall HSV-2 acquisition (symptomatic and/or seroconversion) was 1.9% (14/743) and 3.6% (27/741) in the valacyclovir and placebo groups, respectively (P values not given). This equates to a 48% reduction in overall HSV-2 acquisition. Symptomatic HSV-2 acquisition was reduced by 75% (0.5% for valacyclovir vs. 2.2% for placebo). While the results of this study are encouraging, its limitations should be considered. Study patients were counseled on safe sex practices and use of a condom; how this non-drug therapy, while optimal, compares with “real world” sexual practices and the implications for HSV-2 transmission reduction remain to be delineated. Additionally, study results may not be applicable to homosexual couples or individuals with multiple sexual partners.

Moxifloxacin, gatifloxacin ophthalmic

Moxifloxacin (Vigamox, Alcon) ophthalmic and gatifloxacin (Zymar, Allergan) ophthalmic are new fluoroquinolone antibiotic ophthalmic solution products indicated for the treatment of bacterial conjunctivitis in ages 1 year and older.

Moxifloxacin ophthalmic and gatifloxacin ophthalmic are fourth-generation fluoroquinolones with antimicrobial activity toward Haemophilus influenzae, S. pneumoniae and S. aureus, among other potential bacterial pathogens. Gatifloxacin’s approved dosing schedule includes one drop every two hours while awake on days one and two and QID dosing on days three through seven. Moxifloxacin is dosed as one drop TID for seven days.

Numerous other products are currently available for the treatment of bacterial conjunctivitis, many as generic (and thus less costly) formulations. Antibiotics and classes available include erythromycin, aminoglycosides (gentamicin, tobramycin), bacitracin, sulfonamides, and combination products (eg, polymixin B+neomycin+bacitracin). Several products additionally contain corticosteroids. Other fluoroquinolone products include ciprofloxacin (Ciloxan, Alcon), norfloxacin (Chibroxin, Merck), ofloxacin (Ocuflox, Allergan), and levofloxacin (Quixin, Santen). While moxifloxacin and gatifloxacin are more broad in their antibacterial spectrum as compared with available fluoroquinolone ophthalmic products, how this may translate into a clinical advantage, if at all, has yet to be determined. Cost may be an issue for consideration by clinicians, as several other broad-spectrum products are available generically (eg, polymixin B+neomycin+gramicidin). Several products are also available as ointments (eg, tobramycin, ciprofloxacin, others), which may be useful in some patients. As with the above otic products, newer ophthalmic products have higher costs than products available generically – Ciloxin ($48, AWP), Quixin ($40, AWP), gentamicin generic ($8, AWP). Costs for moxifloxacin and gatifloxacin will likely be competitive to other ophthalmic fluoroquinolone products.

For more information:

• Cubist Pharmaceuticals. Product information – Cubicin. 2003.
• Campanaro ES. Comparison of efficacy and safety of daptomycin (DAP) vs. semisynthetic penicillin (SSP) and vancomycin (VAN) in patients with complicated skin and skin structure infections (cSSSIs). Poster L-737. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Sept. 14-17, 2003. Chicago.
• GlaxoSmith Kline. Product information – Valtrex. 2003.
• Ranbaxy Laboratories Ltd. Product information – DisperMox, Panixine. 2003.
• Bell EA. Tastes of liquid medications: pediatric implications. The Journal of Pediatric Pharmacy Practice. 1999;4:43-50.
• Alcon Inc. Product information – Ciprodex. 2003
• Morden NE. Topical fluoroquinolones for eye and ear. Am Fam Physician. 2000;62:1870-1876.
• Alcon Inc. Product information – Vigamox. 2003.
• Dalhoff A. In vitro antibacterial activity and pharmacodynamics of new quinolones. European Journal of Clinical Microbiology and Infectious Diseases. 2003;22:203-221.
• Allergan Inc. Product information – Zymar. 2003.