MELBOURNE, Australia (AP) — Novak Djokovic showed the first signs of vulnerability at the Australian Open before holding off Lleyton Hewitt and reaching the quarterfinals in the last match of a day that had featured a stunning loss for Serena Williams.

The defending champion held his composure and survived to win 6-1, 6-3, 4-6, 6-3 late Monday night, ensuring all of the top five men reached the quarterfinals.

“It’s obviously the first match that I’ve been tested,” Djokovic said. “It was against the player that I expected to be tested.”

Numbers told the surprising story for Williams in her fourth-round loss: seven double-faults, including four in one game; 37 unforced errors, and a first-serve percentage of just over 50 per cent had her convinced “maybe I should have started serving lefty”.

Some other numbers indicated why her 6-2, 6-3 loss to Ekaterina Makarova of Russia on what she admitted was a still-sore left ankle was more of a shock.

She has played 43 singles matches at Melbourne Park since she won the first of her five Australian Open titles in 2003, and Monday’s loss was just her third. She’s 54-7 since playing at the Australian Open for the first time in 1998, and she hasn’t gone out this early since 2006.

“I’m not physically 100 per cent, so I can’t be so angry at myself, even though I’m very unhappy,” Williams said. “I know that I can play a hundred times better than I did this whole tournament.”

Without Williams, who injured her left ankle in Brisbane two weeks ago, the only major winners still in contention were Maria Sharapova, defending champion Kim Clijsters and Wimbledon winner Petra Kvitova.

Sharapova earned the right to play Makarova in the quarterfinals when she beat Sabine Lisicki of Germany 3-6, 6-2, 6-3 in a night match. The 2008 champion blew a 3-0 lead in the opening set, needed three set points to win the second and advanced on her second match point despite making 47 unforced errors and eight double-faults.

Top-seeded Caroline Wozniacki, still in search of her first Grand Slam title, was to play Clijsters in the quarterfinals on Tuesday.

Kvitova had some trouble late before beating former top-ranked Ana Ivanovic 6-2, 7-6 (2) Monday and will next play Sara Errani of Italy, who beat 2008 semi-finalist Zheng Jie 6-2, 6-1.

In the late-finishing night match, Djokovic reached the quarterfinals for the fifth straight year with the win over Hewitt, ending Australia’s participation in the singles draws.

Djokovic is aiming to become only the fifth man in the Open era to win three consecutive majors after collecting the Wimbledon and U.S. Open titles last year.

Nobody had taken more than three games in a set off Djokovic in the opening three rounds. He was leading by two sets and a break before Hewitt, who was playing on a wild-card entry after his ranking plummeted in an injury-plagued 2011, ended that streak by winning six straight games to force a fourth set.

But Djokovic regained his cool, cut out the loose shots and advanced to the quarterfinals against No. 5 David Ferrer, who had a 6-4, 6-4, 6-1 victory over Richard Gasquet of France.

The loss for former U.S. Open and Wimbledon champion Hewitt ended his 16th campaign at the Australian Open.

Earlier, two-time runner-up Andy Murray was leading 6-1, 6-1, 1-0 when Mikhail Kukushkin retired from their fourth-round match with a left hip injury, giving Murray an easy path into the quarterfinals.

Murray will next play Kei Nishikori, who had a 2-6, 6-2, 6-1, 3-6, 6-3 win over sixth-seeded Jo-Wilfried Tsonga, the 2008 finalist.

The 22-year-old Nishikori became the first Japanese man in the last eight at the Australian Open in 80 years, and only the second man from his country to reach a Grand Slam quarterfinal since the Open era started in 1968. Shuzo Matsuoka reached the 1995 Wimbledon quarterfinals.