The victories in Wisconsin, Maryland and Washington, DC will increase appeals from Republican party leaders for Santorum to quit so that Romney can gird for a difficult fight against President Barack Obama in the November 6 election.
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In his victory speech in Milwaukee, Romney ignored Santorum and gave voters a sense of what the general election campaign will be like, sharply criticizing Obama for his handling of the US economy and high gasoline prices.
"It's enough to make you think that years of flying around on Air Force One, surrounded by an adoring staff of true believers telling you what a great job you are doing, well, that might be enough to make you a little out of touch," Romney said.
In a clear sign that Obama sees Romney as his chief obstacle to re-election, the president singled him out by name and criticized him in a speech with a sharp partisan tone on Tuesday.
The trio of defeats puts conservative Santorum's campaign in serious trouble. He is badly trailing Romney in both delegates and fundraising.
"I think it's lights out for Santorum," said Republican strategist Ron Bonjean. "He can run a sideshow campaign for the next couple of months, but the spotlight is shining on Romney."
Santorum, a former Senator, vowed to stay in the race at least until April 24 when his home state of Pennsylvania votes and where he is hanging on to a lead in the polls over Romney.
That date looms as a potentially decisive one, with Romney likely to win five states that hold contests then and planning a big challenge to Santorum in Pennsylvania.
Tuesday's victories widened Romney's lead over Santorum in delegates to an estimated 640-264, according to CNN. Romney now has more than half of the 1,144 delegates he needs to clinch the nomination at the Republican convention in August.
Santorum wants to win enough delegates to deny his opponent an outright victory before the convention in Tampa.
"Who's ready to charge out of the locker room in Pennsylvania for a strong second half?" Santorum said to cheers in a speech after Tuesday's result. "This isn't half time. We're hitting the field. The clock starts tonight."
"We don't win by moving to the middle. We win by getting people in the middle to move to us and move this country forward," Santorum said.
A Quinnipiac University poll showed Santorum ahead of Romney in Pennsylvania by 41 to 35 percent, but the former private equity executive's campaign and its allies are likely to spend big on negative ads against Santorum in the coming weeks.
Obama hit out at Romney on Tuesday for backing a controversial Republican budget plan authored by a key Wisconsin backer of Romney, Congressman Paul Ryan.
"He said that he's very supportive of this new budget and he even called it 'marvelous,' which is a word you don't often hear when it comes to describing a budget," Obama said in a speech.
Romney fired back that Obama was trying to deflect blame for high gasoline prices that are hitting American wallets hard and could make Obama's re-election tougher to achieve.
"So the president put an ad out yesterday, talking about gasoline prices and how high they are. And guess who he blamed? Me!" Romney said in Waukesha, Wisconsin.
"Maybe after I'm president I can take responsibility for things I might have done wrong. But this president doesn't want to take responsibility for his mistakes."
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