The Aquilotti will arrive at Stadio Giovanni Zini with their hosts even more precariously placed despite drawing with Milan, and defeat for the Grigiorossi would surely mean a swift return to the second tier.
Match preview
After going winless throughout the first half the season, Cremonese's situation has incrementally improved over the past few weeks, but they still need a minor miracle to avoid demotion next month.
The Lombardy side sit second-bottom of Serie A with games running out to save themselves and avoid their long-awaited return to Calcio's top flight being curtailed after only one year.
Having just lost to Fiorentina in the Coppa Italia semi-finals, the Grigiorossi played out a 1-1 draw against relegation rivals Hellas Verona last Sunday, before making the short trip to Milan in midweek.
Remarkably, Davide Ballardini's men led heading into stoppage time, thanks to David Okereke's goal as a second-half substitute, but conceding a heartbreaking equaliser in the 93rd minute deprived them of a first-ever Serie A win over the Rossoneri at San Siro.
Now six points adrift of safety, all Wednesday's hard work will be undone should they lose to Spezia, as facing an almost insurmountable nine-point deficit to their fellow strugglers may cause even renowned miracle-worker Ballardini to throw the towel in.
While Cremonese fought back to secure a 2-2 draw in October's reverse fixture, when Cyriel Dessers and Charles Pickel were both on target in La Spezia, only victory will do this time around.
After losing back-to-back league games for the first time under Leonardo Semplici, Spezia arrive in Cremona occupying 17th place in the standings.
Despite taking the lead through captain Emmanuel Gyasi away to Atalanta in midweek, the Aquilotti then conceded three goals in the space of 22 minutes either side of the interval.
Though they later pulled a goal back and Daniele Verde struck the crossbar in the closing stages, the Ligurians ultimately went down 3-2 and had to leave Bergamo empty-handed.
A run of one victory in 17 matches - under both Semplici and his predecessor Luca Gotti - has led to their current predicament, with an underwhelming away record proving a particular concern.
This season, Spezia have won just twice on the road and lost on no less than 10 occasions, and as they lead 18th-placed Verona only by means of a better head-to-head record between the pair, they cannot afford to continue in that vein this weekend.
Cremonese Serie A form:
L
W
W
L
D
D
Cremonese form (all competitions):
W
W
L
D
D
D
Spezia Serie A form:
D
D
L
D
L
L
Team News
Despite taking a commendable point home from San Siro, Cremonese are counting the cost of Charles Pickel's late lapse of discipline, as the Swiss midfielder must now serve a suspension for punching Sandro Tonali.
Michele Castagnetti is his likeliest replacement against Spezia, while Giacomo Quagliata also misses out as he serves the second game of a two-match ban.
With Frank Tsadjout still injured and Felix Afena-Gyan short of goals, midweek scorer David Okereke should start up front for the hosts, though the vastly experienced Daniel Ciofani provides an alternative option for Davide Ballardini to consider.
Meanwhile, Spezia may again turn to Uzbek striker Eldor Shomurodov to stand in for their first-choice centre-forward M'Bala Nzola, who is still unavailable due to injury.
The Angola international joins Daniel Maldini, Emil Holm, Szymon Zurkowski and Joao Moutinho on the sidelines.
Cremonese possible starting lineup:
Carnesecchi; Sernicola, Vasquez, Lochoshvili, Valeri; Meite, Castagnetti, Galdames; Buonaiuto; Afena-Gyan, Okereke
Spezia possible starting lineup:
Dragowski; Amian, Wisniewski, Nikolaou, Bastoni; Bourabia, Ekdal, Agudelo; Verde, Shomurodov, Gyasi