Spain sealed their place in the 2018 World Cup as Group G winners after storming to a 3-0 win over Albania on Friday with a ruthless first half display, while nearest challengers Italy were held to a draw by Macedonia.
Valencia forward Rodrigo Moreno marked his first international start by opening the scoring in the 16th minute, chesting down an outrageously stylish pass from Isco to swivel and fire into the top corner.
Real Madrid midfielder Isco then shot high into the net in the 23rd to complete an equally impressive move of short floor passes between David Silva and Koke, while Thiago Alcantara scored the third three minutes later with a thumping header from a pinpoint cross from debutant Alvaro Odriozola.
The only downside for Spain was a shaky performance from Gerard Pique, who was booed by large sections of the Alicante crowd every time he touched the ball following his support for last Sunday's referendum on Catalan independence and was substituted by Lopetegui after an hour was up.
Italy's hopes of qualifying directly for next year's World Cup ended as they produced another lacklustre performance and were jeered off the field after a 1-1 draw at home to eliminated Macedonia.
The result, coupled with Spain's 3-0 win over Albania, ensured that Italy will finish second in Group G although they are not yet certain of making the playoff round.
Italy, under fire since their comprehensive 3-0 defeat by Spain last month, seemed to have done the hard part when Giorgio Chiellini scored to break down the visitors' defence five minutes before halftime.
But the goal failed to inspire the four-times world champions and they were stunned when Aleksandar Trajkovski, who plays for Palermo in the Italian league's second tier, equalised in the 77th minute.
Italy have 20 points in Group G and their hopes of reaching Russia now rest on finishing as one of the best eight runners-up who progress to the playoff round from the nine European groups. The group winners all qualify directly.
However, the prospect of deciding their fate in a two-leg tie has made the Italian media and fans jittery and recent performances have added to fears that the unthinkable may happen and Italy could fail to qualify for the first time since 1958.
Coach Giampiero Ventura blamed Italy's poor fitness levels for their dismal second half.
"That made a big difference and when that drops, the sharpness goes," he said.
“I think Italy should never be jeered, as the team represents all of us," he added. "I thought the first half was positive, the second was not, but when you run out of gas, that's what happens."
Italy visit Albania in their final game on Monday.