The Emergence of Treatment-Resistant Fungus

It is hard to kill fungus. Well, not really. They can't handle being burned and chlorine does them in and lots of other chemicals are bad for hem. But when a fungus infects a person ... like with Aspergillos, an infection with Aspergillus in the lungs, fungi are tricky. To kill an infectious agent, one typically poisons it somehow, but to ingest, inject, inhale, or even topically apply a chemical may also affect the person. The reason it is relatively easy to kill an infecting bacterium than it is to kill an infecting fungus is, in part, because fungi are phylogenetically more closely related to human than are bacteria, and share more of their basic cellular process. Therefore a treatment that might kill the infecting cell by interfering with a basic process may also interfere with the health of the human in the case of a fungal infection. With bacteria, there is a wider range of possible poisons that will affect the bacterium but not the humans.

By the way, a common side effect of anti-bacterials is disruption of normal digestive process in humans. This is because some of our digestive process requires a healthy flora of bacteria. Some bacteria are an extension of our digestive organs, and they are negatively affected when we try to kill a bacterial infection elsewhere in our bodies.

This is an evolutionary explanation for this important biological pattern which, in turn, is an important context in which infectious disease is better understood. Evolution is important in understanding medical physiology although, astonishingly, many medical physiologists don't seem to get this (Indeed, the word "evolution" does not appear in this paper except in the bibliography). But I digress.

The point of this post is to highlight some resent research (Published in PLoS) indicating that resistant strains have merged of Aspergillus fumigatus, which is species of Aspergillus that causes one nasty form of lung infection.

Aspergillosis is a group of lung diseases caused by infection with Aspergillus, [which] grows on decaying plant matter. Because Aspergillus is widespread in the environment, people often breathe in its spores. For most people, this is not a problem--their immune system rapidly kills the fungal spores. However, people with asthma or cystic fibrosis sometimes develop allergic bronchopulmonary aspergillosis, a condition in which the spores trigger an allergic reaction in the lungs that causes coughing, wheezing. and breathlessness. Other people can develop an aspergilloma--a fungus ball that grows in cavities in the lung caused by other illnesses such as tuberculosis. However, the most serious form of aspergillosis is invasive aspergillosis. This pneumonia-like infection, which is fatal if left untreated, affects people who have a weakened immune system (for example, people with leukemia) and can spread from the lungs into the heart, brain, and other parts of the body. Aspergillosis is usually treated with triazole drugs, which inhibit an enzyme that the fungus needs to make its cell membranes; this enzyme is encoded by a gene called cyp51A. Voriconazole is the first-line therapy for aspergillosis but itraconazole and posaconazole are also sometimes used and ravuconazole is in clinical development.

About half of patients with invasive aspergillosis recover if they are given triazoles. Worryingly, however, strains of Aspergillus fumigatus ... with resistance to several triazoles have recently been isolated from some patients in The Netherlands. ... However, no one knows what proportion of A. fumigatus strains isolated from patients with aspergillosis are resistant to several azole drugs. That is, no one knows the "prevalence" of multi-azole resistance. In this study, the researchers investigate the prevalence and development of azole resistance in A. fumigatus.

All of the fungi found to infect pations at the Radboud University Nijmegen Medical Center in the Netherlands have been stored since 1994. This study used these samples to identify resistant strains. A small percentage of the samples showed resistance to anti-fungal agents, and all of these strains were collected after 1999, indicating that they entered the study population ... or evolved within it ... recently.

These findings indicate that azole resistance is emerging in A. fumigatus and may already be more prevalent than generally thought. Given the dominance of the TR/L98H genetic alteration in the azole-resistant clinical isolates, the researchers suggest that A. fumigatus isolates harboring this alteration might be present and spreading in the environment rather than being selected for during azole treatment of patients. Why azole resistance should develop in A. fumigatus in the environment is unclear but might be caused by the use of azole-containing fungicides. Further studies are now urgently needed to find out if this is the case, to measure the international prevalence and spread of A. fumigatus isolates harboring the TR/L98H genetic alteration, and, most importantly, to develop alternative treatments for patients with azole-resistant aspergillosis.

By the way Aspergillus is not named after Asperger (as in Hans, as in Asperger's Syndrome). This is a much older name, applied by Pier Antonio Micheli, an Italian biologist and priest, who thought the fungi looked like Aspergilli. Having been an altar boy, I don't see it, but may be they had a different method of spreading holy water around back in the early 18th century.

Eveline Snelders, Henrich A. L. van der Lee, Judith Kuijpers, Anthonius J. M. M. Rijs, János Varga, Robert A. Samson, Emilia Mellado, A. Rogier T. Donders, Willem J. G. Melchers, Paul E. Verweij (2008). Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism PLoS Medicine, 5 (11) DOI: 10.1371/journal.pmed.0050219