De Bruyne went off with a knee injury against Tottenham on Saturday, and will miss the game at Old Trafford, though Guardiola is hopeful the playmaker will still be able to feature before the season is out.
The injury is the latest in a string of set-backs for the 27-year-old, who has been restricted to 30 appearances in all competitions for City this term, making just 11 Premier League starts.
And manager Guardiola confirmed that City will reassess how they treat De Bruyne moving forward, in order to ensure he avoids a repeat of his injury hit campaign next season.
"It is a muscular problem, and we will see in the next days how it is," Guardiola told a news conference. "It's getting better but he is not available [for Wednesday].
"Unfortunately it was one injury and then another one and another one. Before in the past he was safe, especially from muscular problems, but now he has had two or three as a consequence of his knee.
"But with all the competitions we have in England, we don't have time to make preparation when they come back from injury. That is not the best way.
"Now we have to pay more attention in the little details, see if he can play one, two more games before the end of the season, then next season have a good pre-season and take care of himself.
"He has a lovely family, his life is organised in training, rest, prepare for the next game. We are going to speak with the doctors, everybody, to make the problem go and for him to be safe and fit. That's what we are trying to do from now on."
De Bruyne's absence has been felt by City over the course of the season, as the Premier League title race with Liverpool promises to run to the wire.
Victory at Old Trafford would see City move back above their rivals with three games to play, and Guardiola did not downplay the magnitude of Wednesday's fixture.
"Four games left, we have to win all four games to keep the title," he said.
"It is not an easy place to go, but at the same time a nice place to go. We know exactly what we need to do, they are fighting for top four and we are fighting for the title. We will go there to play a good game."