Antifungal Resistance on the Rise in Immunocompromised

Nancy A. Melville

September 04, 2015

ATLANTA ― A troubling increase in treatment-resistant fungal infections in immunocompromised patients has raised concern about the effects of antifungal azole therapies in cancer and transplantation patients, according to data presented here at the International Conference on Emerging Infectious Diseases.

"I find the data coming out of Europe on azole-resistant Aspergillus species to be particularly unnerving," Steven Pergam, MD, from the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance, told Medscape Medical News.

One recent report detailed the extent of the problem in the Netherlands (J Antimicrob Chemother. 2015;70:178-181). Of the 952 Aspergillus fumigatus isolates tested in that country, 364 (38%) had mutations in the cyp51A gene, indicating resistance to azole drugs, including posaconazole (Noxafil, Schering-Plough), itraconazole (multiple brands), and voriconazole (Vfend, Pfizer).

Despite an investigation of trends in the United States conducted by the Center for Disease Control and Prevention (CDC), which revealed no signs of the mutation in samples from 22 states, Dr Pergam said there is nevertheless cause for concern (Emerg Infect Dis. 2014;20:1498-1503).

"I think the resistance probably is here in the United States, but is just not being detected as frequently," he said. "It's something for all of us to watch out for."

Other breakthrough fungal infections have been caused by Fusarium, in particular Fusarium solani. Some F solani strains are multidrug resistant, and therefore associated with high mortality. Although survival rates from these infections have improved in recent years — from 24% to 43% — the infection is still considered very serious, Dr Pergam said.

 
I think the resistance probably is here in the United States, but is just not being detected as frequently.
 

"We've improved survival over time, but outcomes are still dismal." More than 50% of patients diagnosed with invasive fusariosis die, he reported.

"As new cancer treatments become available, we have been seeing more and more patients who fail that first round of chemotherapy offered a second, third, or even fourth round for relapsed disease at centers around the world," said Dr Pergam.

"We're also seeing much more antifungal therapy use in patients moving to transplant, and with more pre-exposure, resistant pathogens are emerging," he explained.

Breakthrough infections caused by Mucorales, a diverse order of fungi with more than 300 species, are also a concern, he pointed out.

"I see these molds as the 'Darth Vader' of transplantation," he said. "They can be very challenging for all of us. Diagnoses can be very difficult, antifungal options are limited, and surgery is often needed for treatment. Thankfully, these infections are still rare."

Breakthrough Infection

One study suggested that breakthrough Mucorales infections are becoming more common in patients receiving posaconazole prophylaxis (J Antimicrob Chemother. 2012;67:2268-2273).

In addition, the extensive use of azoles in agriculture could play a role in antimicrobial resistance, according to Mary Brandt, PhD, chief of the Mycotic Diseases Branch at the CDC in Atlanta.

"It is thought that there is a correlation between the high levels of azole antifungals used to control fungal growth in agriculture in Europe — in particular the flower industry — and the appearance of these resistant Aspergillus fumigatus molds in cancer patients," she told Medscape Medical News.

Another theory suggests that the increase in cases might be the result of patients living longer.

"We don't know whether, or to what extent, prophylaxis with Aspergillus-active azoles, such as voriconazole (to which Mucorales species are resistant), may be contributing to these outbreaks, or whether we are just seeing more patients survive their transplants, neutropenia, cancer therapies, bacterial infections, etc, more easily in order to get sick with mold infections," said Dr Brandt.

As the problem continues to rise in Europe and as cases emerge in Asia and the Middle East, however, the CDC is keeping a close watch on the situation, she reported.

"The CDC is concerned about drug-resistant fungal infections in these vulnerable patients," she explained. "We did not find any azole-resistant Aspergillus organisms in our small study 2 years ago, but we are continuing to ask laboratories to send Aspergillus fumigatus so we can search for resistance in the United States."

Dr Brandt pointed out that the GAIN Act, passed by Congress in 2012, might help by providing incentives for drug companies to develop antifungal therapies to tackle resistant organisms.

But in the meantime, there is a lack of awareness about resistance. "Partly, we don't know how much resistance is occurring and in what patient populations," she said, "and partly, we don't know the reasons for this antifungal resistance."

"Unfortunately, at this time, the CDC does not have any dedicated mold surveillance to collect cases of mold infection and to investigate their causes," she added.

Dr Pergam has served as a consultant for Merck and Cubist, and has been involved in clinical trials with Merck, Cubist, and Chimerix. Dr Brandt has disclosed no relevant financial relationships.

International Conference on Emerging Infectious Diseases (ICEID). Presented August 25, 2015.

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