Antibiotics are a critical part of modern medicine's arsenal.

Yet antibiotic resistance is rising and patients can suffer a wide range of adverse drug responses which further strain the healthcare system and worsen patient outcomes.

Antibiotics with a short half life in the bloodstream must be perscribed frequently- up to three to four times a day in some cases. These short half lives mean far more antibiotic is administered than needed to maintain the minimum concentration to ward of bacterial infection. This puts a strain on healthcare providers.

MightyMoieties: Albumax Edition

focuses on cephalosporins which are one of the most widely used classes of antibiotics.

Our modeling and research centers around cefepime, a commonly used cephalosporin. We designed albumin binding proteins to link the antibiotic to albumin. Albumin is a common component of blood serum and enables the transfer of many biomolecules through the blood. While the antibiotic is linked to the albumin it won't be cleared from the bloodstream resulting in an extended lifespan. This is because the kidney prevents renal excretion of albumin- which in turn helps keep the albumin linked antibiotic in the blood.

How do we know this works?

Within the cephalosporin class of antibiotics Ceftriaxone is notable for its relatively long half life (around 6-9 hours) is routinely given on a single daily dosing cycle as opposed to the multiple dosings needed for other cephalosporins like Cefepime.

Why is this?

Ceftriaxone binds with high affinity to human serum albumin(HSA) preventing its clearance from the blood while cefepime has a significantly lower affinity for HSA resulting in much faster clearance [1-2]. Using our protein-linker system we hope to enable cefepime dosing once every day instead of three times daily.

Our modeling indicates that this is possible and will actually reduce the overall needed amount of antibiotic as well as its peak concentrations in the bloodstream as compared to the normal delivery process. In addition to reducing the workload for healthcare workers this may help reduce the rate of adverse drug events in patients.

In the US there are

1.5 million visits

to the emergency department(ED) due to an adverse drug response(ADR) [3].

Antibiotics make up 13% of those cases and cephalosporins 12% of that group [3-4]. Many ADRs are dosage dependent. By reducing both the total dose of antibiotic we can reduce the likelihood of a patient experiencing an ADR in many cases.

Our system is applicable to drugs other than cephalosporins. We use the carboxylic acid on the cephalosporin to bind it to the linker and thus the albumin binding protein. Similar carboxylic groups exist in penicillins and carbapenems (two other common classes of antibiotics). Albumin facilitated half life extension may be particularly useful in the case of penicillins which often must be IV administered every 4-6 hours [2]. Penicillins and cephalosporins combined are responsible for more than half of all antibiotic ADRs that lead to an ED visit resulting in approximately 100,000 ED visits each year in the US [3-4].

We believe our Mighty Moities: Albumax Edition can by extending the half life of many antibiotics in the blood stream make a significant contribution to improving therapeutic treatment by saving healthcare providers time and improving patient outcomes.

References

[1.] I. H. Patel and S. A. Kaplan, “Pharmacokinetic profile of ceftriaxone in man,” The American Journal of Medicine, vol. 77, no. 4C, pp. 17–25, Oct. 1984, Available: https://pubmed.ncbi.nlm.nih.gov/6093513/
[2.] “Cephalosporins and neurotoxicity,” Medicines Adverse Reactions Committee, New Zealand, Dec. 2022. Available: https://www.medsafe.govt.nz/committees/marc/reports/192-%20Cephalosporins-and-neurotoxicity.pdf
[3.] CDC, “FastStats: Medication Safety Data,” Medication Safety Program, May 03, 2024. https://www.cdc.gov/medication-safety/data-research/facts-stats/index.html
[4.] N. Shehab, Priti R. Patel, A. Srinivasan, and Daniel S. Budnitz, “Emergency Department Visits for Antibiotic‐Associated Adverse Events,” Clinical Infectious Diseases, vol. 47, no. 6, pp. 735–743, Sep. 2008, doi: https://doi.org/10.1086/591126.
[5.] E. C. Meng et al., “UCSF ChimeraX: Tools for structure building and analysis,” Protein Sci., vol. 32, no. 11, p. e4792, 2023, doi: 10.1002/pro.4792.