Southampton's resources will be stretched on Saturday with Morgan Schneiderlin, Victor Wanyama and Florin Gardos all suspended against Everton.
Dusan Tadic and Jake Hesketh have joined a long injury list, while Steven Davis and Graziano Pelle are doubts.
Everton's Kevin Mirallas is out with an ankle injury and Leon Osman is not expected to return from a similar problem this weekend.
Darron Gibson (knee) and James McCarthy (hamstring) will have fitness tests.
Midfielder Gareth Barry returns from suspension.
It hasn't been the best of weeks for Ronald Koeman and there's a chance it might get a little bit worse before it starts to get better.
Unhappy at perceived disrespect on the Bramall Lane touchline and knocked out of the Capital One Cup by League One side Sheffield United, Koeman has now seen his team lose five matches in a row after their brilliant start to the season.
Injuries have started to creep in, or not clear up in the case of long-term absentee Jay Rodriguez, but two suspensions in particular may give him a headache as he prepares to face Everton.
Saints are going to be missing their first-choice central midfield pairing of Morgan Schneiderlin and Victor Wanyama this weekend because both picked up yellow cards on Tuesday to trigger one-match bans for accumulating five bookings.
Defender Florin Gardos is also suspended and the team Koeman sends out looks certain to include a sprinkling of youthful, unfamiliar faces from the St Mary's conveyor belt of talent.
According to the manager, Harrison Reed will "probably" start in the Premier League for the first time, and the matchday squad is set to include five or six of the under-21 side.
Everton had selection issues of their own in central midfield ahead of Monday night's game with QPR, but Roberto Martinez was delighted with how things turned out in a 3-1 win after a sparkling show from both Ross Barkley and Mo Besic, capped off with a superb goal from the former.
At 21 and 22 years of age respectively, the pair showed tactical maturity to go with their undoubted ability and desire on a night when the experience of Gareth Barry, Leon Osman, James McCarthy and Darron Gibson was missing.
Everton haven't enjoyed much success away to Southampton in recent times, winning on only one of their last 15 visits.
Last season's 2-0 defeat at St Mary's at the end of April severely dented their hopes of Champions League football. Everton weren't helped on the day by two first-half own goals while having a couple of decent penalty shouts turned down at the other end.
Roberto Martinez has his eyes on a top-four finish this season and believes it won't take as many points as usual to achieve it. His team are seven points behind fourth-placed West Ham at the moment but will hope to start narrowing the gap with a win on the south coast.
Everton have only won twice in 15 Premier League visits to Southampton (W2, D6, L7)
Southampton won this fixture 2-0 last season, thanks to two Everton own goals.
Southampton have lost their last four Premier League matches - that last happened in their first four matches after returning to the top flight in August-September 2012.
Saints have scored just two goals in their last five league matches, having scored 12 in the previous five fixtures.
They conceded just two goals in their first five league matches of the season, but have have let in eight in the last five.
Everton are aiming to avoid a third consecutive away defeat in the Premier League.
The Toffees have failed to keep a clean sheet in their last six away league matches, and their last six home and away.
Everton have scored seven Premier League goals from outside the penalty area, the joint highest total (with Manchester United) in this season's Premier League.
Steven Naismith has scored four goals from eight shots on target this season.