The Antifungal Drugs Market

Most antifungal drugs in the market today use outdated or obsolete technology while patents have expired. These drugs have become low cost generic treatments; everybody may produce them freely without patent infringement occurring. Despite the low cost generic character of the drugs, the worldwide turnover of antifungal drugs is expected to grow up to about 8.4 billion US Dollars annually by 2016. This global revenue would evidently be substantially higher if the market would not be saturated with poorly performing low cost generic drugs against the background of an increasing need for new, more effective anti-fungal technologies with superior resistance profiles.

Ergosterol Inhibitors: Azoles and Amphotericin B

Both Amphotericin B and Azole class drugs directly or indirectly target the ergosterol component of the fungal cell membrane. Amphotericin B does this in a crude but effective way. It directly binds to - and thus inhibits - ergosterol and in this way disrupts the cell membrane, ultimately leading to cell death. However, unfortunately Amphotericin B is not specific in its action towards ergosterol. It also binds to mammalian sterols and is as such highly toxic in humans. Since systemic antifungal treatment is typically prescribed in already seriously ill patients with a substantially weakened immune system, the in many cases life threatening toxicity of Amphotericin B is unacceptable in today's level of therapeutic sophistication. Nevertheless, as a direct result of increasing resistance towards Azole class drugs, Amphotericin B has made a remarkable comeback as a last resort salvage treatment against resistant fungal strains.

Like Amphotericin B, Azole class drugs also target the ergosterol compound on the fungal cell membrane, but does this in a more subtle, indirect way. It does not directly bind to it like Amphotericin B. Instead it inhibits its biosynthesis within the fungal cell. Ergosterol is synthesized from lanosterol and Azole class drugs inhibit the enzyme that removes two methyl groups, a crucial step in its biosynthetic pathway. Since this enzyme, called lanosterol 14 α-demethylase, is unique to fungal cells, its inhibition results in a more target specific, and as such a less toxic mechanism of action.

Azoles: resistance mechanism

Since the inhibition of the ergosterol biosynthesis takes place within the fungal cell, it offers the fungal cells biological possibilities to overcome the disrupting effect of the intruding Azole compounds. Eukaryotic cells have a very complex metabolism and are capable of adapting over time by up- or down regulating various biosynthetic pathways. In the case of Azole resistance several mechanisms have been documented, such as overexpression of cellular efflux pumps, overexpression or mutation of the 14 α-demethylase target enzyme, and alteration of other enzymes in the same biosynthetic pathway. These sophisticated resistance mechanisms render an ever growing number of fungal strains completely resistant to Azole class drugs. Since all Azole class drugs rely on the same above described mechanism of action, it will immediately become clear that the development of cross resistance between various Azole compounds and fungal strains was inevitable.

Echinocandins: pros and cons

As mentioned, over the last decades the antifungal drug market was and still is completely dominated by the cell membrane interrupting ergosterol inhibiting Azole and Amphotericin B compounds. The only novel drug class that came on the market are the Echinocandins, which function by inhibiting the 1-3 beta glucan synthase enzyme necessary for the biosynthesis of glucan, a vital component of the fungal outer cell wall. Echinocandins were first developed in the seventies of the last century and are as such relative newcomers when compared to Azoles (first developed during World War II). They offer some advantages, such as far less toxicity than Amphotericin B and no Azole related drug resistance. As such Echinocandins managed to replace Azoles in certain territories as first line therapy for Invasive Candidiasis. Echinocandins also show fungistatic activity against Aspergillosis, although this is less documented. However Echinocandins also have their limits. While there is an eminent need for novel antifungal medications that can effectively target therapy resistant strains, only about 36% of patients refractory to other therapies respond well to Echinocandin therapy. Besides this, just as Azoles, Echinocandins seem to be prone to resistance development over time, with first cases of Candida resistance already having been documented. The main vulnerability most likely being mutations in the gene responsible for the 1-3 beta glucan synthase enzyme. These inherent weaknesses together prevented Echinocandins from taking over the position of the traditional ergosterol inhibiting Azole and Amphotericin compounds.

A Clinical Emergency

In order to understand drug resistance from a clinical point of view it is important to understand that systemic fungal infections are life threatening by nature. Fungi are everywhere around us. They share our living space and peacefully reside in and on the human body. Our immune system is perfectly capable off keeping them at bay. That is to say of course, as long as we are in good health and our immune system is functioning adequately. In case of a weakened immune system, as with many cancer and hiv/aids patients and potentially also as a side effect of less serious illnesses such as a common influenza, fungal colonies are offered the opportunity grow and can expand rapidly within the human body, infecting the blood steam and attacking just about every internal organ, including heart, lungs, kidneys and even our brain. Once fungal cultures overcome a critical mass in the body, organ failure will lead to a complete shutdown of the immune system accelerating the expansion of the fungals even more, leading to an inevitable demise of the patient.

As such, physicians, when confronted with a case of acute systemic fungal infection, must act very quickly and do not have the time to perform cell culture resistance tests or experiment with various treatments hoping that sooner or later they will find one that does not manifest resistance by the fungal pathogens afflicting their patients. For instance; among intensive care patients, today there is a mortality rate of 30 to 50% when systemic candidiasis develops. Ideally physicians should be able to administer a less toxic Azole compound as primary therapy and when confronted with a resistant fungal strain, should have the possibility to fall back to Amphoterisin B as salvage therapy. However in practice by that time the condition of the patient will probably have deteriorated to such an extent that the highly toxic Amphotericin treatment would become life threatening by itself. As such, once the total percentage of treatment resistant strains in life threatening circumstances surpasses a certain threshold, prescription of the treatment in question will introduce unacceptable risks for the life of the patient.

From an epidemiological point of view a certain treatment failure percentage in the range of 20% might be acceptable for a primary therapy as long as a viable salvage therapy is available, but as explained, today this is no longer the case with the combination of Azole class drugs and Amphotericin B, resulting in often desperate situations in which hospitalized patients find an untimely death as a result of insufficient treatment options.