In people who do not require hospitalization and live in an area where there is a low prevalence of antibiotic-resistant bacteria, an fluoroquinolone by mouth such as ciprofloxacin or levofloxacin is an appropriate initial choice for therapy. In areas where there is a higher prevalence of fluoroquinolone resistance, it is useful to initiate treatment with a single intravenous dose of a long-acting antibiotic such as ceftriaxone or an aminoglycoside, and then continuing treatment with a fluoroquinolone. Oral trimethoprim/sulfamethoxazole is an appropriate choice for therapy if the bacteria is known to be susceptible. If trimethoprim/sulfamethoxazole is used when the susceptibility is not known, it is useful to initiate treatment with a single intravenous dose of a long-acting antibiotic such as ceftriaxone or an aminoglycoside. Oral beta-lactam antibiotics are less effective than other available agents for treatment of pyelonephritis. Improvement is expected in 48 to 72 hours.

In people suspected of having pyelonephritis, a urine culture and antibiotic sensitivity test is performed, so therapy can eventually be tailored on the basis of the infecting organism. As most cases of pyelonephritis are due to bacterial infections, antibiotics are the mainstay of treatment. The choice of antibiotic depends on the species and antibiotic sensitivity profile of the infecting organism, and may include fluoroquinolones, cephalosporins, aminoglycosides, or trimethoprim/sulfamethoxazole, either alone or in combination.