"a Defined as having two or more symptoms (dysuria, urgency, frequency, suprapubic pain, fever, nausea, vomiting) including one or more urinary tract infection-specific symptoms (dysuria, urgency, frequency, suprapubic pain) with onset/worsening within the previous 7 days. For inclusion, patients were also required to have one or more complicating factor, which could include chronic urinary retention (male patients), obstructive uropathy that was scheduled to be relieved during intravenous therapy, urogenital tract functional or anatomical abnormality, use of intermittent bladder catheterization or the presence of an indwelling bladder catheter for[48 h prior to b diagnosis, or a urogenital procedure within the previous 7 days. The mMITT population consisted of all randomized patients who met minimum disease criteria with C 1 c d qualifying baseline pathogen. Difference (95% CI) between CAZ-AVI and DOR-treated patients. Non-inferiority was demonstrated. Primary endpoint under EMA e guidance; non-inferiority was considered demonstrated if the lower limit of the 95% CI of the treatment difference was above – 12.5%. Co-primary endpoint under US FDA guidance; non-inferiority was considered demonstrated if the lower limit of the 95% CI of the treatment difference was above – 10%.

Indian subset from RECLAIM

For the treatment of resistant infections in the ICU setting, CAZ-AVI plus Metronidazole has shown to be efficacious option to carbapenems for critical patients with 2 Complicated In

Clinical response by visit – (MITT, mMITT, CE Analysis Sets)

Visit	Number (%) of Patients		Difference (%) a (95% CI for Percent Difference)
	CAZ-AVI + Metronidazole	Meropenem
mMITT Analysis Set
	(N=30)	(N=35)
TOC	25 (83.3)	27 (77.1)	6.2 (-14.31, 25.65)b
EOT	26 (86.7)	32 (91.4)	-4.8 (-22.63, 11.52)
CE Analysis Set
	(N=46)	(N=44)
TOC	45 (97.8)	42 (95.5)	2.4 (-7.41, 13.33)
EOT	48 (98.0)	53 (96.4)	1.6 (-7.50, 10.62)

Difference: difference in clinical cure rates (CAZ-AVI + metronidazole group minus meropenem group). For subjects reviewed by the SRP, the clinical response was based a on surgical review evaluation if it was different from the investigator's assessment. Percentages were based on the total number of patients in the treatment group (N). CIs b for group differences were calculated using the unstratified Miettinen and Nurminen method. The mMITT population was the primary analysis population for the FDA. Consistent with the protocol, the sponsor concluded non-inferiority if the lower limit of the 95% CI (corresponding to a 97.5% 1-sided lower bound) at TOC was greater than - c 12.5%. The sponsor accepted that FDA concluded non-inferiority if the lower limit of the 95% CI (corresponding to a 97.5% 1-sided lower bound) was greater than -10%. The MITT and CE populations were the co-primary populations for the ROW. Consistent with the SAP, the sponsor concluded non-inferiority if the lower limit of the 95% CI (corresponding to a 97.5% 1-sided lower bound) was greater than -12.5% for both the MITT and CE analysis sets.

CAZ-AVI-ceftazidime-avibactam; cIAI-complicated intra-abdominal infections; cUTI-complicated urinary tract infections; DOR-doripenem, mMITT-microbiologically modified intent-to-treat; CE-clinically evaluable; CI-confidence interval; MITT-modified intent-to-treat; EOT- end of treatment; TOC-test-of-cure; N-number of patients in treatment group; ROW-rest of the world; SAP-statistical analysis plan; SRP-surgical review panel.

REPROVE III trial

CAZ-AVI vs Meropenem for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia(HAP/VAP): Analyses per US FDA–Specified End Points

CAZ-AVI was noninferior to meropenem for the primary end point (28-day all-cause mortality; ITT) based on the prespecified 10% noninferiority margin

Analysis Population	Patient Deaths		Between-Arm a Difference (95%Cl) %
	CAZ-AVI, n/N (%) [KM%]	Meropenem, n/N (%) [KM%]
ITT	42/436 (9.6) [9.9]	36/434 (8.3) [8.4]	1.5 (-2.4 to 5.3)
Micro-ITT	22/187 (11.8)	19/195 (9.7)	2.1 (-4.1 to 8.4)
CAZ-NS	4/49 (8.2)	5/59 (8.5)	-0.1

a Differences based on the KM estimates of the cumulative survival proportions for each treatment arm up to day 28; CIs for the difference were calculated based on Greenwood's variance estimates.

Clinical cure rates at TOC visits (ITT and micro-ITT populations)

According to the end goals given in the FDA guideline, this trial showed that CAZ-AVI was noninferior to meropenem in the treatment of HAP/VAP. Therefore, CAZ-AVI provides a crucial new therapeutic option and carbapenem substitute for patients with HAP/VAP caused by Gram-negative infections, especially in the presence of known or suspected bacterial resistance.

CAZ-AVI-ceftazidime-avibactam; CAZ-NS-ceftazidime-nonsusceptible; HAP-hospital-acquired pneumonia; CI- confidence interval; ITT-intent to treat; KM-Kaplan-Meier; micro-ITT-microbiological ITT; TOC-test of cure; VAP-ventilator-associated bacterial pneumonia.