Isner in upset second-round loss at Sydney
American qualifier Ryan Harrison upstaged his top-seeded countryman John Isner 6-4, 6-4 in a second-round match at the Sydney International on Wednesday.
The exit of Isner, who was promoted to the No 1 seeding after Jo-Wilfried Tsonga and Richard Gasquet withdrew, followed two more injury withdrawals: No 2 and 2011 Sydney champion Giles Simon (neck) and No 6 Radek Stepanek (back).
Isner, who withdrew from the Hopman Cup mixed team competition in Perth last week with a right knee injury, lasted 71 minutes against No 64th-ranked Harrison.
The Australian Open starts Monday, leaving injured players little time to prepare for the season's first major.
In other matches, third-seeded Andreas Seppi of Italy beat John Millman of Australia 6-2, 3-6, 6-3, Australian Bernard Tomic, who beat No 1-ranked Novak Djokovic last week at the Hopman Cup, advanced with a 7-6 (4), 6-2 win over fifth-seeded Florian Mayer of Germany and Denis Istomin of Uzbekistan beat fourth-seeded Fernando Verdasco of Spain 6-3, 6-3.