TABLE 1.

Investigational product cohorts (8 subjects/cohort) in COMBINE^a

Cohort	Drug regimen
1	2.5 g CZA i.v. as 2-h infusions every 8 h for 7 days
2	2.5 g CZA i.v. as 2-h infusion × 1, then 0.32 g/h i.v. daily as CI (7.5 g/day) for 7 days
3	2 g ATM i.v. as 2-h infusions every 6 h for 7 days
4	2 g ATM i.v. as a 2-h infusion × 1, then 0.33 g/h i.v. daily as a CI (8 g/day) for 7 days
5b	2.5 g CZA i.v. as 2-h infusions every 8 h for 7 days and 1.5 g ATM i.v. as 2-h infusions every 6 h for 7 days
6b	2.5 g CZA i.v. as 2-h infusions every 8 h for 7 days and 2 g ATM i.v. as 2-h infusions every 6 h for 7 days

^aCZA, ceftazidime-avibactam; i.v., intravenously; CI, continuous infusion; ATM, aztreonam.

^bCohorts 5 and 6 reflect modified treatment regimens following recommendations of the Safety Monitoring Committee (SMC). Initial regimen for cohort 5: 2.5 g CZA i.v. as 2-h infusions every 8 h and 2 g ATM i.v. as 2-h infusions every 6 h for 7 days. Initial regimen for cohort 6: 2.5 g CZA i.v. as a 2-h infusion × 1, 0.32 g/h i.v. daily as CI (7.5 g/day) and 2 g ATM i.v. as 2-h infusion × 1, and then 0.33 g/h i.v. daily as CI (8 g/day) for 7 days. A halting rule was observed in cohort 4 (2 subjects experienced grade 3 elevations in ALT/AST values deemed to be related to the study product), and a SMC meeting was convened. In response to the observed study halt, the SMC recommended that dosing in cohorts 5 and 6 be changed, and additional safeguards were incorporated into the study protocol.