Four North Carolina patients at a single hospital tested positive for a type of swine flu that is resistant to the medication Tamiflu, said health officials on Friday.

The cases reported at the Duke University Medical Center over six weeks make up the biggest cluster seen so far in the U.S.

Tamiflu — made by Switzerland’s Roche Group — is one of two flu medicines that help against swine flu, and health officials have been closely watching for signs that the virus is mutating, making the drugs ineffective.

More than 50 resistant cases have been reported in the world since April, including 21 in the U.S. Almost all in the U.S. were isolated, said officials with the U.S. Centers for Disease Control and Prevention.

The BBC reported another cluster of five Tamiflu-resistant cases this week in Wales, in the United Kingdom.

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