Inclusion Criteria:

• Thirteen years of age or older, 34 kg (75 lb) or more, either sex, and any race;
• C. immitis or C. posadasii identified by culture or microscopic examination from skeletal disease, chronic active pulmonary disease, or soft tissue disease;
• Coccidioidomycosis score of >=6;
• Clinical laboratory safety tests within normal limits or clinically acceptable to the sponsor;
• Free of any clinically significant disease that would interfere with study evaluations;
• Willing to give written informed consent and able to adhere to study medication dose, mandatory procedures (including HIV testing), and visit schedules;
• Able to swallow food or a nutritional supplement;
• Use of a medically accepted method of contraception;
• Negative serum pregnancy test at Screening and negative urine pregnancy test at Randomization;
• Women of childbearing potential not currently sexually active must agree to use a medically accepted method of contraception should they become sexually active while participating in the study.

Exclusion Criteria:

• Key Exclusion Criteria Excluded Medications at Enrollment

  • Medications that are known to interact with POS or FLU and that may lead to serious or life threatening side effects within 7 days prior to initiating study drug;
  • Medications known to lower the serum concentration/efficacy of azole antifungals within 7 days prior to study drug start;
  • Prior investigational drug use or biologic product administration within 30 days before study drug start;
  • Prior antifungal treatment for the current episode of infection with a total cumulative dose of >=8 g of any azole, >=4 mg/kg of amphotericin B deoxycholate, or >=20 mg/kg of lipid amphotericin B;
  • Antiretrovirals that are substrates of CYP3A4 administered to HIV-positive subjects, as it is not currently known how POS or FLU may affect such drugs or the potential to cause adverse reactions.

• Excluded Concomitant Conditions

  • Immediately life-threatening coccidioidomycosis;
  • Confirmed or suspected meningeal coccidioidomycosis;
  • Pulmonary coccidioidomycosis in HIV-negative subjects for less than 3 months;
  • Any condition requiring use of prohibited drugs;
  • CD4 count of <200 cells/mm3 or any AIDS-defining illness in HIV-positive subjects in the prior 30 days.

• Excluded Baseline Laboratory Studies

  • Moderate or severe liver dysfunction (AST or ALT > 5 times ULN) or a total bilirubin level or direct bilirubin > 3 times ULN plus ALT or AST >2 times ULN (Hy's Rule);
  • Moderate or severe renal dysfunction (CrCl <20 mL/min) or dialysis required or expected to be required within the study period;
  • ECG with a prolonged QTc interval by manual reading: QTc >450 msec for males and QTc >470 msec for females.

• General Exclusion Criteria

  • Prior enrollment in this study or other POS studies;
  • Failed treatment with FLU or POS at any time in the past;
  • History of hypersensitivity or idiosyncratic reactions to azole drug therapy;
  • Women who are pregnant, intend to become pregnant, or are breast-feeding;
  • Situation or condition that may interfere with optimal participation in the study; Part of the staff personnel directly involved with this study;
  • Family member of the investigational study staff.