Promising New Antivirals, Antibacterials but No Blockbusters
Amid continuing concerns about the very real development of antimicrobial resistances, several participants during the symposium ``New and Emerging Therapies'' and at other sessions during the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco, Calif., last September provided glimpses into a promising assortment of new antiviral and antibacterial drug candidates.
If any generalization fits these developments, it is that up-and-coming antimicrobial products no longer seem to qualify as wonder drugs. Instead, developers are portraying these products in more modest terms, noting that many of them are relatively narrow-spectrum therapeutics that seem to offer solid but deliberately limited clinical utility-at least insofar as the target pathogens are concerned. This narrow-spectrum feature of many antimicrobial drugs being developed carries implications for the diagnostic testing that will be needed to determine what agents particular patients should receive.
Consider two types of antiviral drugs that seem headed for wide use. One class consists of viral capsid-targeted inhibitors for treating enteroviruses, including several picornaviruses and rhinoviruses responsible for causing sepsis, meningitis, and respiratory infections, while the other antiviral drug class consists of neuraminidase (NA) inhibitors intended for treating influenza viruses.
Although zanamavir and GS4071 have different pharmacokinetic properties, both compounds are potent inhibitors of NA and thus are effective against both influenza A or B viruses, according to Frederick Hayden of the University of Virginia Health Sciences Center in Charlottesville, Va. Zanamavir, which received approval from the U.S. Food and Drug Administration in mid 1999, is applied topically as an inhalant, whereas GS4071 (oseltamavir) is administered orally as a pro-drug, which then releases an active NA inhibitor component. Another NA inhibitor that is not so far along in its development shows a generally similar profile and ``significant antiviral effects'' in preclinical tests, he notes.
Treatment with either zanamavir or GS4071 can reduce the severity of influenza infections and, if administered in a timely fashion--preferably before or soon after exposure--can prevent the spread of such infections among family members or other close contacts, such as those that occur among residents of nursing homes, according to Hayden. ``The oral drug [GS4071] is an effective treatment and preventative [agent] when used for six weeks against community outbreaks,'' he says.
``Even with prolonged exposure to the drug, there is good tolerance and no safety issues,'' Hayden continues. ``We are getting to a point with flu that we can treat the primary viral infection and reduce the need for antibiotics for treating complications.'' Nonetheless, he adds, ``The first line of defense is still the vaccine.''
Pleconaril is an antiviral compound that inhibits several types of picornaviruses by binding irreversibly to the viral capsid, according to Harley Rotbart of the University of Colorado in Denver, Colo. He says that this agent causes a conformational shift and thus interferes with uncoating of the virus and its attachment to host cells, thereby blocking infectivity at the cellular level.
Viruses belonging to this class, including the enteroviruses and rhinoviruses, cause more than 10 million infections each year in the United States, including life-threatening cases of meningitis and encephlitis, Rotbart says. When evaluated across several clinical trials involving patients with a variety of conditions, including meningitis and viral respiratory infections, pleconaril proved effective at reducing the severity of symptoms, shortened the duration of infections, and in some cases cured the patients of the specific virus being treated, he and his collaborators report.
Like zanamavir and its near relative GS4071, which inhibit the influenza viruses, pleconaril can also be considered a relatively narrow-spectrum antiviral drug. When drugs are so specific to the infections they can treat, proper diagnosis becomes an especially important issue, Rotbart says. Although respiratory infections due to rhinoviruses can be distinguished from flu by clinical signs as well as the seasons in which the two types of virus tend to circulate, precise diagnosis may be needed for many of the likely clinical uses of these new antiviral agents. Thus, along with the current development of such antiviral drugs, ``a parallel effort to develop diagnostics for viral infections'' is also needed, he says.
Meanwhile, some of the recent attention being paid to the development of new antibacterial drugs also focuses on narrow-spectrum agents. For example, researchers at Cubist Pharmaceuticals in Cambridge, Mass., are developing the antibiotic daptomycin for a relatively limited range of clinical applications. In particular, this ``profoundly'' bacteriocidal drug is very effective at disrupting gram-positive bacterial cell membranes, according to Cubist's Frank Tally.
Depending on the outcome of ongoing clinical trials, daptomycin may provide an alternative to vancomycin against some of the pathogens that cause bacteremia as well as skin and soft tissue infections. Tally and his collaborators appear to have found a means for overcoming adverse side effects of this drug with a strategy that entails administering the drug only once daily and strictly controlling its upper-range dosage.
The oxazolidinones, with linazolide as the leading agent in this group, represent a class of antibacterial agents that, although broadly active, are ``strictly useful for treating gram-positive [pathogens],'' says George Eliopoulos of Beth Israel Deaconess Medical Center in Boston, Mass. The oxazolidinones, which are being developed by Pharmacia & Upjohn, inhibit protein synthesis in target bacterial cells, are generally bacteriostatic, and do not seem to be cross-resistant with other widely used antibiotics, he notes.
Linazolide appears to be effective for treating gram-positive infections in a variety of clinical situations, according to Eliopoulos. For instance, this drug was equal to standard treatments for certain skin infections as well as for specific types of pneumonias. In addition, it was more successful than standard treatments for bloodstream infections. Moreover, resistance to this antibiotic has been relatively slow to emerge, and for the most part has been confined to special cases involving use of catheters or other devices that tend to develop biofilms that can provide a harbor in which resistance to ongoing treatment may develop.
Jeffrey L. Fox
December 8, 1999
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