ATLANTA (AP) Four North Carolina patients at a single hospital tested positive for a type of swine flu that is resistant to Tamiflu, health officials said Friday.

The cases reported at 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.

The CDC has sent three disease investigators to North Carolina to help in the investigation there, said Dave Daigle, a CDC spokesman. CDC testing confirmed the Tamiflu-resistant cases.

All four cases at the hospital were very ill patients in an isolated cancer unit on the hospital's ninth floor, and it is believed they all caught the flu while at the hospital, said Dr. Daniel Sexton, professor of medicine and director of the Duke Infection Control Outreach Network.

Three of the four patients died and one is recovering, he said. Flu seems to have been a factor in each death, but they were very sick so it was hard to say that it was the primary cause, he added.

North Carolina health officials did not disclose details about the four patients, other than that three of them including the survivor were women and their flu illnesses occurred last month and this month.

The first patient had been given Tamiflu before becoming ill with the virus, as a preventive measure. The three others were given Tamiflu after developing flu symptoms, Sexton said.

The case is under investigation, but hospital officials said they have no evidence the cases represent a hospital-wide concern.

The North Carolina cluster is unusual, but ``at this time we don't have any information that should raise concerns for the general population,'' said Dr. Alicia Frye, epidemiologist in the CDC's flu division, in a prepared statement.

The only other reported U.S. instance of Tamiflu-resistant swine flu spreading from one person to another occurred about four months ago at a summer camp in western North Carolina, where two teenage girls cabin mates were diagnosed with the same drug-resistant strain. Health officials said at the time that the virus may have spread from one girl to the other, or it's possible that the girls got it from another camper.

Why did both Tamiflu-resistant clusters occur in North Carolina? It could be coincidence, or perhaps North Carolina's disease surveillance is unusually good, said Megan Davies, the state's epidemiologist.

Overall, CDC officials said Friday that swine flu cases appear to be declining throughout most of the U.S., with reports of swine flu illnesses widespread in 43 states last week, down from 46 the week before.

CDC officials also said reports have been increasing in a few states, including Maine and Hawaii. They said it's hard to know whether the epidemic has peaked or not.

Thanksgiving and the holidays may not help matters, said Dr. Anne Schuchat, who heads the CDC's National Center for Immunization and Respiratory Diseases.

``All the kids get together with their grandparents and there's a lot of exchange of warmth and love, but a little exchange of viruses, too,'' she said.

Swine flu has sickened an estimated 22 million Americans, hospitalized about 98,000 and killed 4,000 since it was first identified last April. It has proved to be similar to seasonal flu but a much bigger threat to children and young adults.

Also on Friday, CDC officials said they are aware of a new report from Norway of a distinct form of swine flu seen in three patients that seems to have an unusual ability to settle deep into the lungs and therefore could potentially be more dangerous.

The Norway report isn't the first time that particular mutation has been seen: About 15 others have been reported around the world, including four in the United States. Some cases proved fatal, but others caused only mild illnesses, CDC officials said.

The swine flu vaccine and antiviral drugs like Tamiflu and Relenza all seem to work well against it, CDC officials also said.

(Copyright 2009 by The Associated Press. All Rights Reserved.)