World No 1 Novak Djokovic and Serena Williams advanced safely to the next round of the US Open on Saturday but the women's draw saw yet another big upset as Wimbledon winner Petra Kvitova was sent packing by a 145th-ranked qualifier.
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Five-time US Open champion Williams played her part in the American demise, dispatching three of her compatriots in rapid succession.
After dismissing Taylor Townsend in the opening round and Vania King in the second, Williams chased the 52nd ranked Lepchenko with a 6-3, 6-3 victory.
Williams, who has failed to reach the quarter-finals of any of the previous three grand slams this year, was just happy not to be one of the US casualties.
"I've been a casualty this whole year at Grand Slams," said Williams, who will next face Kaia Kanepi of Estonia, a 7-5, 6-0 upset winner over 15th seed Carla Suarez Navarro. "I'm just hoping to keep staying in there.
"I just treat every round as if it's your last. Do the best that I can. Just stay positive, you know, because I want to continue to do the best I can."
Djokovic eases into Fourth Round
Djokovic, a US Open finalist the last four years and winner in 2011, has also done his part to spoil America's Grand Slam party.
The Serb squashed another American hope on Saturday, pounding Querrey 6-3, 6-2, 6-2 to reach the fourth round for the eighth straight year while improving his record to a perfect 8-0 when facing US opponents at Flushing Meadows.
Third-seed Kvitova fell victim to 21-year-old Serbian Aleksandra Krunic, leaving only three of the top eight women's seeds still in the tournament. Simona Halep (2nd), Agnieszka Radwanska (4th), Angelique Kerber (6th) and Ana Ivanovic (8th) have already been shown the door.
While the women's draw has been ravaged by upsets the top 10 men are still in the hunt, with No 3 Stanislas Wawrinka, No 5 Milos Raonic, eighth seed Andy Murray and No 8 Jo-Wilfried Tsonga all moving on.
Eugenie Bouchard digs deep
Twice Australian Open winner Azarenka secured her spot in the last 16 with a 6-1, 6-1 win over Russian Elena Vesnina.
Eugenie Bouchard, a semi-finalist in the previous three Slams, including a runner-up finish at Wimbledon, had to fight to keep from joining the list of upsets, the seventh-seeded Canadian holding her nerve to earn a 6-2, 7-6(2), 6-4 win over Czech Barbora Zahlavova Strycova.
Williams, the last American standing
Williams is the last American standing at the US Open after the remaining home-grown hopefuls said goodbye to Flushing Meadows on Saturday.
A total of 29 Americans (12 men, 17 women) started the year's final grand slam on Monday and by the time the gates to the US National Tennis Centre closed on Saturday only the world number one was still in the hunt for a singles title.
The last two hopes of the men's draw, 13th seed John Isner and Sam Querrey, both bowed out in the third round, while Nicole Gibbs and Varvara Lepchenko also made third-round exits, leaving home fans pinning their hopes on Williams heading into the second week.
Isner bombarded Philipp Kohlschreiber with 42 aces and never lost his serve but still dropped a 7-6(4), 4-6, 7-6(2), 7-6(4) decision to the German.
Murray sets up clash against Tsonga
Briton Murray, the 2012 Open champion and 2013 Wimbledon winner, double-faulted to send his match to a fourth set, then swiftly took charge in a 6-1, 7-5, 4-6, 6-2 win over Russian Andrey Kuznetsov.
That set up a clash against Tsonga, a 6-4, 6-4, 6-4 winner against Pablo Carreno Busta of Spain.
Raonic won three tiebreakers in a straight-sets win against Dominican Victor Estrella Burgos to set up a fourth-round duel with Japanese 10th seed Kei Nishikori, who beat 23rd seed Leonardo Mayer of Argentina in straight sets.
Australian Open winner Wawrinka was given a walkover into the fourth round when Blaz Kavcic of Slovenia defaulted because of a right foot injury.