Santana hit two homers and drove in five runs as the Indians routed Kansas City 15-4 Sunday in their highest-scoring game of the season.
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Santana connected for a two-run shot in the sixth inning off Jake Odorizzi, who lost in his major league debut. Santana added his team-leading 18th homer, a three-run drive during a seven-run ninth.
"Carlos had a great day," Indians manager Manny Acta said. "That two-run homer was huge. It gave us the lead. I'm happy for the day he had. For a moment there, I was thinking we weren't going to have one guy with 75 RBI on the whole team. He did it, and it looks like [Jason] Kipnis with 70 might able to do that, too."
Santana, who has 13 home runs and 45 RBI in 65 games since July 15, matched his career high with five RBI. It was his third career multihomer game.
"It was a very good day for me and the pitchers," Santana said. "The key for us is to finish strong."
The loss officially eliminated the Royals from playoff contention and assured them of another losing record. Kansas City has not made the postseason since winning the 1985 World Series, the longest active playoff drought in the majors.
David Huff (2-0) held the Royals to one run on three hits over 5 2/3 innings.
Santana's first homer put the Indians ahead 3-1. Cleveland added five runs in the seventh and pulled away in the ninth.
The Indians spoiled the day for Odorizzi (0-1), one of four players acquired in the 2010 trade for Zack Greinke.
Odorizzi limited Cleveland to a pair of singles by Shin-Soo Choo for the first five innings. After retiring Choo to lead off the sixth, Odorizzi allowed three runs on four consecutive hits.
"I thought he did an outstanding job for his first start," Royals manager Ned Yost said. "He's got all the intangibles. He fields his position. He commands the baseball. He changes speeds. He's got great composure and a great competitive nature."
Kipnis tripled and scored on Asdrubal Cabrera's single before Santana's homer.
The Indians combined four singles, three walks and two Kansas City errors in the seventh. The Royals used three relief pitchers with Vin Mazzaro retiring none of the four batters he faced.
Casey Kotchman and Jack Hannahan hit RBI singles and Cabrera drove in a run with a groundout. The other two Cleveland runs that inning scored after throwing errors by right fielder Jeff Francoeur and catcher Adam Moore.
The Indians added six of their seven runs in the ninth off Jeremy Jeffress, who threw only 18 strikes in 40 pitches. He walked three, including Choo with the bases loaded.
Moore, who was making his Royals debut, homered in the third. It was his first homer since Sept. 7, 2010 while with Seattle.
Francoeur had three hits and drove in a run. Billy Butler contributed a run-producing double, upping his RBI total to 101.
The Royals have had only one winning season since 1994, going 83-79 in 2003. ... Indians INF Jason Donald, who has not played since being hit in the right wrist on Sept. 14 by pitcher from Justin Verlander pitch, took batting practice. ... The Royals open their final trip of the season with the first four games at Detroit. RHP Luke Hochevar, who has allowed 20 runs in 14 2-3 innings in his past three starts against the Tigers, will start Monday night against Verlander.