A team of researchers led by Guido Memmi of Dartmouth Medical School has concluded that a combination of oxacillin and cefoxitin is the most viable solution to treat CA-MRSA infections. The finding was reported in the November issue of Antimicrobial Agents and Chemotherapy.
There has been an increase in infections recently caused by community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA). MRSA infections have deviated from hospital acquired MRSA (HA-MRSA), and the CA-MRSA infections have proven to be more virulent, due to differences in their genomic backgrounds. The infections are sometimes minor and confined to the skin, but can become severe and potentially fatal deep tissue infections. According to Memmi, this happens often and progresses very quickly.
In bacteria, penicillin-binding proteins (PBPs) are important components of the cell wall, protecting the organism from environmental osmotic pressure. The antibiotic penicillin destroys bacteria by binding to these PBPs, thereby disrupting the cell wall and causing cell death. However, some bacteria have acquired beta-lactamase, which cleaves the penicillin and creates bacterial resistance. Methicillin, a synthetic form of penicillin, contains a methyl group to avoid being cleaved by beta-lactamase. However, bacteria that produce the protein PBP2A are resistant to methicillin.
Memmi observed that when one of the penecillin binding proteins, PBP4, was mutated in the HA-MRSA strain in previous experiments, there was no observed difference in resistance. Therefore, he created a PBP4 mutant in a CA-MRSA strain, and observed a large decrease in resistance to oxacillin and nafcillin, two other forms of penicillin.
The PBP4 mutation also dramatically altered the transcription of PBP2A. Additionally, when treated with oxacillin, there was a major decrease in peptidoglycan cross-linking, contributing to disruption of the cell wall and cell death. Mutations of PBP3 had no affect on the peptidoglycan cross-linking. Also, in the absence of PBP4, resistance to oxacillin in vitro decreased by 94 percent. Memmi concluded that when combined with the human immune system, the resistance would be even further decreased.
The antibiotic cefoxitin binds irreversibly to PBP4, much more strongly than other beta-lactamase antibiotics. Cefoxitin, in conjunction with oxacillin, works well to destroy CA-MRSA strains, and the combination looks promising for treating CA-MRSA infections.
As of now, CA-MRSA infections are treated by first determining if the strain is methicillin sensitive or resistant. If it is resistant, then drug therapy must be specific to the individual infection. The skin is usually drained and cleaned, which may lead to a full recovery. Otherwise, antibiotics such as vancomycin are used, however this drug is expensive, toxic, and is becoming vulnerable to semi-resistance bacteria strains. Doxymycin has also been used to treat skin and deep tissue infections.
In an effort to spread the new treatment combination of cefoxitin and oxacillin, Memmi has initiated a collaborative project with the Tuck Business School in an attempt to start a small company to commercially market the combination. The company would also attempt to chemically modify cefoxitin to increase its efficacy. Currently, Memmi is focusing on the chemical modification of cefoxitin and on the creation of a test which would use four CA-MRSA-specific genes to determine if an infection is HA-MRSA or CA-MRSA.