How do we know the effective dose of antibiotics? Despite considering factors such as infection site, body weight, and age, there is a bit of unknown with each administration, since each individual reacts differently through the complexity of so many interacting variables. Additionally, each infection site is unique, with various oxygen levels, antimicrobial peptide production, and immune cell infiltrate affecting the host-microbe interactions. Finally, factors unique to each drug must be considered, including half-life, toxicity, and specificity.
In new research published in Antimicrobial Agents and Chemotherapy, Drs. Petros Ioannou and Georgios Chamilos have published another host factor that may affect effective antifungal drug dose: albumin. Albumin is a substance carried in everyone’s blood that acts as a major carrier protein of the circulatory system. It is highly charged, and therefore adheres easily to other molecules in the blood, such as triglycerides, bilirubin, retinol, uremic toxins, and transition metal ions. Albumin will absorb some of these molecules and deliver them to the liver or kidneys, where they can be digested or excreted.
Albumin’s antifungal effects have been demonstrated on the fungus Blastomyces dermatitidis. Ioannou predicted that a host factor may affect the low activity of caspofungin on Aspergillus nidulans. Caspofungin is a member of the echinocandin class of antifungals, which block activity of β-1,3-glucan synthase enzymes, part of the fungal cell wall-building machinery. To test in a more systematic way, the researchers looked at in vitro effectivity of caspofungin, as well as other antifungal drugs, on A. nidulans grown in tissue culture conditions.
What Ioannou observed is a consistent caspofungin-specific boost of antifungal activity in the presence of albumin. Albumin presence had no effect on voriconazole (a member of the triazole antifungal class) activity, and only an erratic effect on amphotericin B (in the polyene antifungal class) activity. The activity increase was limited to caspofungin – other echinocandins tested, micafungin and anidulafungin, showed no change in activity with the addition of albumin.
One possible explanation is that serum affects overall growth of the fungus, similar to Blastomyces. The authors tested this and showed no albumin-specific growth effects. By fluorescently labeling albumin, the authors observed heavy interactions between it and germinating hyphae – more interaction than resting or swollen conidial cells (see figure, right). Albumin is also able to bind echinocandins, including caspofungin, and this binding may be important in learning the mechanism of drug synergism.
How could albumin have specificity toward enhancing caspofungin activity among the echinocandins tested? This interesting question is a clear direction for future research from this paper. Albumin assists efficacy of other drugs, such as macrolides, but the mechanism for any drug enhancement remains unknown. Even without understanding albumin’s actions, scientists can now use the available data to determine drug pharmacokinetics with consideration of this additional important factor.
-- Julie Wolf