Dihydrophthalazine Antifolates for MRSA

By John Schieszer

Staphylococcus aureus

S aureus

CHICAGO—Several investigational agents in a new class known as dihydrophthalazine antifolates are showing good activity against almost all strains of multidrug-resistant tested, including methicillin-resistant (MRSA) infection, a serious and growing problem both in the community and in the hospital, investigators reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

The compounds, currently known as BAL30543, BAL30544, and BAL30545 (Basilea Pharmaceutica), have shown good oral bioavailability, favorable pharmacologic/toxicologic characteristics, and bactericidal activity.

Multidrug-resistant staphylococci have been a persistent cause of severe hospital-acquired infections. Increasingly, MRSA infection has become the cause of life-threatening infections in otherwise healthy people in the community, in addition to the hospital setting. Some staphylococcal infections, such as those affecting the heart or bone tissue, require extensive periods of therapy to ensure bacterial eradication.

There is a huge unmet need for an oral agent that is capable of overcoming resistance to the currently available antibiotics. This need may finally be met by this new class of antibiotics.

Dihydrophthalazine antifolates target dihydrofolate reductase, an enzyme that is essential for the growth of most pathogenic microorganisms. These compounds have displayed excellent in vitro activities against recently collected MRSA isolates.

The 3 new compounds were compared with vancomycin (Vancoled) and linezolid (Zyvox)—which are regarded as the "gold standard" for treating staphylococcal infections—as well as with the older antifolate trimethoprim (Proloprim).

S aureus

The test panel consisted of 153 recently collected clinical isolates of methicillin-susceptible and MRSA, including vancomycin-intermediate and vancomycin-resistant strains. Only 2 of the isolates were not affected by the 3 new compounds at concentrations ≤0.5 µg/mL. This compared favorably with vancomycin, to which 7 strains were resistant, and to trimethoprim, to which 28 strains were resistant.

"This is really good news for physicians," said lead investigator Lois Ednie, MT(ASCP), who is a researcher at the Penn State Hershey Medical Center, Pa. "Because the staph strains are becoming more and more resistant, to see something that will actually work against these very resistant strains is very promising."

Coinvestigator Stuart Shapiro, PhD, a microbiologist at Basilea Pharmaceutica, Basel, Switzerland, pointed out that all 3 compounds appear to be highly effective, and one of them may advance to human trials soon.