Atletico are one of a number of top-flight clubs facing difficulties in the cup against lower league opposition along with Levante, Real Betis, Villarreal, Valencia, Espanyol and Real Zaragoza this week.
Nine-times winners Atletico's season is threatening to fall apart with their fans in open revolt against the unpopular Manzano and the board, while the team have been putting in wildly erratic performances.
Local media are speculating on Luis Aragones, Luiz Felipe Scolari or Rafa Benitez as possible replacements while former Arsenal winger Jose Antonio Reyes looks set to be sold to Sevilla to help finance the change.
Atletico's first home defeat of the campaign, 2-0 against promoted Betis on Sunday, left the 2010 cup finalists mid-table in La Liga and with Manzano calling for the fans to get behind the team.
"There is a particular culture here, a sensitivity to slip ups, and it doesn't benefit the team at all," Manzano told reporters.
"Rather than such a hostile atmosphere there needs to be a sense of balance."
Levante, fourth in La Liga, trail second division Deportivo La Coruna 3-1 and Betis are 1-0 down against second division Cordoba. Both play Wednesday.
Valencia return to the Mestalla with the scoreline at 0-0 against third-tier Cadiz on Thursday the same result Espanyol hold when they host second division Celta Vigo on Tuesday.
YELLOW SUBMARINE
Villarreal are at home to third tier Mirandes on Wednesday having drawn 1-1 in the first leg, and coach Juan Carlos Garrido is feeling the heat.
The team known as the 'The Yellow Submarine' are out of Europe, are hovering above the relegation places and are without a win in seven outings.
Zaragoza coach Javier Aguirre is also in the spotlight on Wednesday when La Liga's basement club entertain second division Alcorcon with the scores level at 1-1.
Alcorcon famously dumped Real Madrid out of the Cup two years ago when they were a third-tier side.
There would appear to be little chance of holders Real slipping up this time as they take a 2-0 lead back to the Bernabeu against third tier Ponferradina on Tuesday.
Newly-crowned world club champions Barcelona jet back from Japan in time for their second leg at home to near neighbours Hospitalet on Thursday.
Pep Guardiola's side, who have lifted five trophies in 2011, hold a 1-0 first leg advantage and play the last match before Spain's two week winter break.
