Manning’s Broncos swamp 49ers 42-17

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DENVER — The 49ers had several factors working against them Sunday night: a slew of injuries, a short workweek and a game against the defending AFC champions in mile-high altitude.

Oh, yeah, they also had to deal with this rather significant obstacle: Peyton Williams Manning.

Even if well-rested, at full strength and at home, the 49ers might not have been a match for the Broncos’ quarterback, who broke Brett Favre’s record for career passing touchdowns en route to leading Denver to a 42-17 win at Sports Authority Field.

“You can blame whatever you want to blame it on,” safety Eric Reid said. “At the end of day, we’re all professional athletes. We play for the San Francisco 49ers. We’re expected to do a job and we didn’t execute. Especially on the defensive side of the ball.”

And the opposing quarterback had plenty do with that.

In yet another virtuoso performance, Manning, 38, feasted on a banged-up defense missing All-Pro linebacker Patrick Willis, starting cornerback Chris Culliver and nickel corner Jimmie Ward. The 49ers began the game with four healthy corners, although Tramaine Brock was at less than full strength in his first game back from a turf-toe injury he suffered in Week 1. They were down to three cornerbacks early in the third quarter when Chris Cook exited with a hamstring injury.

The results were predictable: Manning completed of 22 of 26 passes for 318 yards and four touchdowns before he exited with the Broncos leading by 32 after three quarters.

After his 23rd career start, Reid laughed when asked if Manning is the best quarterback he’d faced.

Denver Broncos quarterback Peyton Manning (18) throws his first touchdown of the game as San Francisco 49ers linebacker Aaron Lynch (59) defends during the first half of an NFL football game Sunday, Oct. 19, 2014, in Denver. (AP Photo/Jack Dempsey) less Denver Broncos quarterback Peyton Manning (18) throws his first touchdown of the game as San Francisco 49ers linebacker Aaron Lynch (59) defends during the first half of an NFL football game Sunday, Oct. 19, ... more Photo: Jack Dempsey, Associated Press Photo: Jack Dempsey, Associated Press Image 1 of / 37 Caption Close Manning’s Broncos swamp 49ers 42-17 1 / 37 Back to Gallery

“Yeah, that’s pretty easy to say,” Reid said. “I’m not sure what their coaches do, but they probably don’t have to do much. He’s out there on the field, he recognizes the defense, he makes audibles. He does it all. You’re playing against a coordinator when you’re out there.”

On Sunday, Manning’s passer rating (157.2) was just short of perfection (158.3), and he required less than 27 minutes to collect the three touchdowns he needed to eclipse Favre’s record of 508. With the flashes of cell-phone cameras filling the stands, Manning surpassed Favre with an 8-yard strike to Demaryius Thomas with 3:09 left in the second quarter to give the Broncos a 21-3 lead.

After the score, 49ers rookie linebacker Aaron Lynch, who was 5 when Manning entered the NFL, was the first to congratulate him. Manning then tried to retrieve the record-breaking ball, but three of his pass-catchers — Emmanuel Sanders, Wes Welker and Julius Thomas — played keep-away from the quarterback.

It was, indeed, a laugher. In fact, in a sign that the famously intense and exacting Manning was in complete command, he smiled in the huddle after he tripped over left guard Orlando Franklin and was sacked on the play before his record-breaking pass.

Manning acknowledged that the Broncos took advantage of a defense operating at less than full strength. Denver had 405 yards in the first three quarters and had five plays of 32-plus yards.

“They had some injuries that, I think, put some pressure on their defense,” Manning said. “And we were able to take advantage of that.”

It was a grim evening for the 49ers, who allowed six sacks, dropped four passes, allowed their longest run (37 yards) since 2010 and endured more attrition.

With San Francisco already playing without All-Pro left guard Mike Iupati (concussion), center Daniel Kilgore was carted off the field in the third quarter with his left leg in an air cast. Kilgore immediately beckoned for medical assistance after linebacker Brandon Marshall crashed into the side of his leg at the end of a run by Frank Gore.

The ugliness began early.

Manning threw TD passes of 3 yards to Sanders and 39 yards to Welker to give the Broncos a 14-0 first-quarter lead.

Trailing 21-3, the 49ers had a must-have touchdown 11 seconds before halftime when Colin Kaepernick threw a 4-yard pass to Stevie Johnson in the back of the end zone.

On the 49ers’ first drive of the third quarter, though, Kaepernick threw an interception, which set the stage for the other quarterback.

One play after Kaepernick’s pick, Manning fired a perfectly placed 40-yard pass to Demaryius Thomas to give the Broncos a 28-10 lead.

Linebacker Ahmad Brooks said the man with the most passing touchdowns in NFL history doubles as the best quarterback he’s ever faced.

“Yeah,” Brooks said. “By far. By far. By far.”

Eric Branch is a San Francisco Chronicle staff writer. E-mail: ebranch@sfchronicle.com Twitter: @Eric_Branch

Most TD passes

Peyton Manning broke Brett Favre’s all-time touchdown record with his third scoring pass of the first half (he finished with four).

510: Peyton Manning

508: Brett Favre

420: Dan Marino

372: Tom Brady, Drew Brees

3 notables

LB Chris Borland: The rookie third-round pick filled in capably for All-Pro Patrick Willis. Borland matched a game high with eight tackles and had one of the 49ers’ two sacks.

TE Vernon Davis: Davis acknowledged the obvious: He still isn’t fully recovered from the back injury he suffered Oct. 5. He had two drops — bringing his total to four in the past two games — and managed two catches for 21 yards.

RB Frank Gore: Gore wasn’t part of the plan after the 49ers fell behind early. He finished with 20 yards on nine carries, with just four carries coming after the first quarter.

— Eric Branch