Preventing fungal infections: Worth the risk?
Battling resistance and poor outcomes
Clinically, few things put clinicians in more of a bind than the possibility of fungal infections in immunocompromised patients. On one hand, if patients don’t receive antimicrobial prophylaxis, they risk developing a severe infection such as Pseudomonas. On the other hand, a constant course of antibiotics might allow a dangerous fungal infection to take over especially in organ transplant patients who are taking corticosteroids and cyclosporin to boot.
Is the answer mass antifungal prophylaxis? Some researchers attending the 7th annual Focus on Fungal Infections conference in San Antonio suggest there’s danger with such an approach: namely, that resistance may develop to the few effective antifungal medications available especially the azoles.
Jan Patterson, MD, calls it "azole abuse." Patterson, of the University of Texas Health Science Center in San Antonio, says heavy outpatient use of fluconazole as a prophylaxis against thrush among other forms of "abuse" may be leading us down the road to fungal resistance.
It’s a detour we can ill afford to take. Only a tiny number of drugs work against fungal infections a couple of azoles, fluocytosine, and amphotericin-B and the latter two are highly toxic.
Most troubling, Patterson says, is a pattern of cross-resistance to the azoles that seems to be developing in Candida organisms. "That’s really worrisome. We may have Candida strains resistant to new azoles before they’re even released."
One of those potential products is voriconazole, a highly potent drug that stops fungal growth at a much lower dose than the current standard-bearer, fluconazole.
But Thomas F. Patterson, MD, also of the University of Texas, says Candida resistance is uncommon in seriously ill patients at risk for developing fungal infections including patients undergoing organ transplantation. Patterson says that although it’s true some resistance is beginning to show up, azole therapy still has a strong record of success at curbing fungal infections.
"A targeted population may benefit from prophylaxis," he adds, citing statistics that show continuous suppressive azole therapy works better at preventing relapses than does intermittent drug use. Resistance rates are comparable with the two methods of therapy, Patterson says.
Combination therapy one prospect
With such a small number of effective drugs currently available, any suggestion of fungal resistance is disturbing, given that some of these infections aspergillus, for example often are deadly. And while the pharmaceutical industry is busy trying to develop the antifungal equivalent of a broad-spectrum antibiotic (highly toxic to fungi but not to mammals), clinicians are coming up with their own ways to kill off the stubborn pathogens.
One method is combination therapy. John R. Graybill, MD, of the Audie Murphy VA Medical Center in San Antonio says some heretofore frowned-upon combinations of drugs actually work better than using the drugs separately. A case in point: amphotericin-B and an azole.
Graybill says an in vitro study showed that a combination of amnphotericin-B and miconazole suppressed Candida, whereas the two drugs alone did not. Conversely, ketoconazole seemed to suppress the killing power of amphotericin-B in aspergillus infections. Following up amphotericin-B with itraconazole might work, though.
"I think we can now use fluconazole and fluocytosine [together] for cryptococcal meningitis," Graybill says. "If we use both together, you can reduce the dose of fluocytosine, which is quite toxic." One advantage of this regimen, he says, is that both products are oral. The regimen may be especially effective in HIV patients, Graybill adds.
Improving the antifungal arsenal
Combining the two heaviest-hitters in the antifungal arsenal also appears to work better in cryptococcal meningitis. A recent study showed slightly more patients improved using fluocytosine and amphotericin-B than with amphotericin-B alone.
"I lean toward thinking this is meaningful," Graybill says of the small difference in efficacy. "It’s better not to have cryptococcus growing in your spinal fluid."
One area of emerging interest is immunotherapy. It makes sense, given that fungi tend to colonize in those with impaired immunity. A substance you can safely classify as a broad-spectrum antifungal is gamma-interferon, says David A. Stevens, MD, of the Santa Clara Valley Medical Center/Stanford University in San Jose, CA. Gamma-interferon stimulates tissue, pulmonary macrophages, monocytes, and eutrophils.
One study showed a gamma-interferon/ amphotericin-B combination worked significantly better in animals infected with paracoccidiomycosis than either product alone. The combination even scoured pathogens from the brains of the creatures, Stevens says. The same combination improved survival in animals infected with histoplasmosis.
The effectiveness of fluconazole can be greatly enhanced by adding Interleukin-12 and/or Granulocyte Colony Stimulating Factor. The key to these combinations is activation of effector cells such as polymorphonuclear leukocytes. These work synergistically with fluconazole to kill the fungi.
New drugs in the works
There are, of course, some new drugs in the works for fungal infections and it’s clear that pharmaceutical companies are trying to follow the antibiotic model for success that is, targeting the fungal cell wall.
Echinocandins and pneumocandins are two possibilities. Early research into these compounds yielded Cilofungin, a test product that worked well against fungi but was pulled from consideration after some side effects in test subjects. Newer versions of these compounds are either in or planned for clinical trials. They feature a broad-spectrum of activity with low toxicity.
The Nikkomycin/polymycin group of anti-fungals puts a kink in the synthesis of chitin. Nikkomycin Z is undergoing clinical trials and may be even more effective against deadly fungi such as aspergillus if dosed with an azole or an echinocandin.
Pradimicins got off to a rocky start when the first one to be tested caused a dose-related increase in liver enzyme levels. These com-pounds bind to the cell wall and poke holes in it. Eventually, that leads to lethal disruption.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content