Waging the deadliest battle: Against both cancer and Candida

August 5, 2010

As more doctors turn to fluconazole for empirical antifungal therapy, some of the weakest patients--those with hematological malignancies and neutropenia--are most likely to pay the price, succumbing to resistant microorganisms.

Increasingly, for patients with hematological malignancies the enemy is not the cancer but a fungal infection. Those with neutropenia are at the highest risk of having a resistant fungal infection, and of dying because of it.

Thus is Darwin confirmed again. Modern medicine is a continually shifting ecosystem. Ever more fragile patients are treated with invasive methods such as hyperalimentation that are ideal breeding grounds for fungi (particularly Candida). The increased use of antifungals has nurtured resistant, non-C. albicans forms of candidiasis.

Overall, survival from fungal infections appears to be improving, as the identification of candidemia as one of the leading causes of bloodstream infections has led to prompt testing and empirical treatment with newer antifungals such as caspofungin and micafungin. But the prevalence of infections with species other than Candida albicans, and more resistant to traditional antifungals, is increasing. Today C.albicans (which is susceptible to the traditional antifungal, fluconazole) accounts for barely half of all bloodstream infections with Candida in most settings. C. krusei, which is resistant, now causes about one-fourth of all such infections. (Its prevalence varies depending on the clinical setting and the continent.)

But everywhere the outlook for patients with hematological cancers, especially those who require transplants, is troubling.

This month, investigators at Virgen del Rocio University Hospital in Seville, Spain, report in Antimicrobial Agents and Chemotherapy on risk factors for fluconazole resistance among inpatients treated for bloodstream infections between 2004 and 2009. It is apparently the first such study that actually carried out in vitro testing for resistance among all Candida isolates.

The major independent risk factor for resistance was prior exposure to fluconazole, they report. Another was neutropenia.

"The empirical use of fluconazole in febrile patients is a common therapeutic strategy," write Jose Garnacho-Montero et al, because it is the least expensive and best understood antifungal.We should be concerned about a possible shift toward non-albicans species, they add, especially toward C. krusei.

C. krusei, most commonly infects patients with hematological malignancies. More than half are women and 45% have neutropenia, according to data collected between 2004 and 2008 from 23 North American medical centers in the Prospective Antifungal Therapy (PATH) Alliance registry. Most patients infected with C. krusei were treated with caspofungin or micafungin, without good odds of surviving. They had the highest 12-week mortality in the database, at 53%.

The Spanish study confirms findings from a population-based survey of cancer patients published in May by a team at the Royal Melbourne Hospital in Australia. Among 138 candidiasis episodes between 2001 and 2004, the most common factors predicting drug resistance were age over 65 years, gastrointestinal surgery in the previous month, and previous treatment with a triazole drug such as fluconazole. Resistant isolates were associated with an increased risk of mortality, but removing a central venous assist device within 5 days of surgery reduced that risk.

Fungal infections are a particularly vexing problem because the variety of available antifungals is far smaller than that of antibacterials. Also, a surprising synergy between human and fungal biology increases the likelihood that any new formulation will cause side effects.

Most antifungals attack components of the fungal cell wall or the enzymes used to construct or maintain it. Fungi respond to this challenge by increasing production of these molecules or by boosting levels of substances that escort the drugs out of the cell (often not just temporarily after antifungal treatment, but constitutively).

The microbes adapt, and so do we. Researchers at the University of Sydney (Australia) this month report strong antifungal activity of a new class of compounds, bisalkylpyridinium alkanes, which are related, but significantly structurally modified from chemical disinfectants and a topical antifungal. Its potency against 80 Candida species in vitro was at least as great as that of fluconazole. Like the others, these compounds interfere with construction of the cell wall, possibly by interfering with fungal phospholipases, the enzymes that hydrolyze phospholipids into fatty acids. It's too soon to know how these compounds would affect the human beings who took them, of course.