De Bruyne has returned to training but the City boss says he is feeling some discomfort when he plays and is not yet ready to return to first team action.
Of the players that missed the Premier League victory over Southampton on Saturday, Guardiola is not expecting anyone back for the clash at Tottenham Hotspur Stadium for the 20:15 (UK) kick-off.
Asked about when De Bruyne could return, Guardiola said: “I would like to tell you, and especially I would like to know it, but I don’t know right now.
“He feels better in training, but to go to the level we need in competition, when he kicks the ball, sometimes he still has pain.
“He doesn’t feel right, and Kevin has to feel good to express his huge talent that he has.
“He’s feeling better, but not the best.
“It’s for sure that if these guys don’t come back as quick as possible, we’ll struggle, because we cannot sustain it on just 14 or 15 players the whole season.
“We need players to come back, but it is what it is. Hopefully it can happen after the international break.”
As well as De Bruyne, Kyle Walker, Jeremy Doku and Jack Grealish missed the 1-0 win over Southampton as well as long-term absentees Oscar Bobb and Rodri.
Guardiola has said the Spanish midfielder is likely to be out for the season after having knee surgery.
Rodri won the Ballon d’Or on Monday night as the best player in the world and the boss says he’s obviously a big loss but that the team has to cope without him.
“Without Rodri, we are less strong,” he added. “With him, we are better. With Kevin, we are better. And with Kyle Walker, we are better. And with Oscar and all the people without the long injuries, we are better.
“But he has to recover well for next season. We have to handle the team game-by-game and try to win games.
“The challenge is to win tomorrow against Spurs, play a good game, and in the other ones, and we will see at the end of the season what happens.
“Imagine any sport, in basketball, if Golden State Warriors played without Steph Curry, or Barcelona in their prime playing without Messi, things would have been different, they would be less strong.
“It’s the same with us. Rodri is irreplaceable. We know it, and so do the players, but we have to move on and do it.
“Kova is playing there, Gundo is playing there. They were exceptional. And one day we will play Manu [Akanji], we will play John [Stones] in that position, and I know they will play good. It’s what we have to do.”
