Table 1.

PKPD indices to support breakpoint decision making.

Antibiotic	Year Approved	Labeled Indication(s)	Neutropenic Thigh	Pneumonia	Preclinical Target to Support Breakpoint	Clinical Target to Support Breakpoint
Ceftolozane-Tazobactam [29]	2014, 2019 additional approval for HABP/VABP	cIAI, cUTI, HABP/VABP	%T > MIC Ceftolozane P. aeruginosa Static: 24% 1-log kill: 31.5% 2-log kill: 52.2%		Neutropenic thigh 40%T > MIC	Clinical cure rates at various MICs.
Dalbavancin [21]	2014	ABSSSI	fAUC24/MIC: Static: 265 2-log kill: 332 Protein bound: 93%		Neutropenic thigh fAUC24/MIC static and 2-log kill	AUCavg/MIC of 13,396 where AUCavg is the mean AUC from day 1 and day 8 of treatment. Corresponds to 20% reduction in baseline area by day 4.
Oritavancin [22]	2014	ABSSSI	AUC72/MIC: Static: 3941 1-log kill: 4581		Neutropenic thigh AUC72/MIC stasis and 1-log kill	Comparison of AUC72/MIC for early clinical endpoint, 20% reduction in lesion by day 3 and at post-treatment evaluation.
Tedizolid [23]	2014	ABSSSI	Static AUC24/MIC Neutropenic: 250 Non-neutropenic: 15		Non-neutropenic thigh model bacteriostasis	Flat exposure-response relationship, where higher exposure was not associated with higher clinical response rates, limited the utility of clinical PKPD breakpoint determination.
Ceftazidime-Avibactam [16]	2015	cIAI, cUTI	Avibactam %fT > 1 mg/L Static: 40.2% 1-log kill: 50.3% Protein bound: 5.7–8.2% 50% fT > CAZ-AVI MIC	Avibactam %fT > 1 mg/L Static: 20.2% 1-log kill: 24%	Neutropenic thigh 1-log kill	Exposure-response analyses of individual exposures and microbiologic outcomes in Phase II cIAI and cUTI patients revealed that almost all CAZ %fT > MIC and AVI %fT > 0.5 mg/L values were close to 100% and unfavorable microbiologic outcomes (i.e., treatment failure) were relatively infrequent; thus, formal exposure-response modeling was not feasible.
Delafloxacin [24]	2017	ABSSSI	fAUC24/MIC Stasis: 9.3 1-log kill: 14.3		Neutropenic thigh, stasis and 1-log kill	Due to the limited number of clinical isolates for E coli and P. aeruginosa in Phase 3 clinical studies, clinical evidence appears insufficient to determine the breakpoints for E. coli and P. aeruginosa.
Meropenem-Vaborbactam [17]	2017	cUTI	%fT > MIC Static: 30% 1-log kill: 35% 2-log kill: 45%		Neutropenic thigh 1-log kill and 2-log kill	The rate of overall success in each group was >90%. Therefore, the analysis of outcomes for enterobacteriaceae demonstrated no obvious cutoff in MIC that discriminated between successes and failures.
Omadacycline [25]	2018	CABP, ABSSSI	AUC24/MIC 1-log kill: 33.3 S. pneumo 64.1 E. coli	Neutropenic 1-log kill 13.6 S. pneumo	Neutropenic thigh 1-log kill used to support ABSSSI, Neutropenic pneumonia 1-log kill used to support CABP	No targets derived from clinical data; however, success rates at higher MICs supported breakpoint decision in conjunction with non-clinical PKPD.
Plazomicin [26]	2018	cUTI, cIAI	AUC24/MIC Enterobacteriaceae Static: 24 1-log kill: 73 K. Pneumo Static: 30 1-log kill: 95	AUC24/MIC Enterobacteriaceae Static: 1.6 1-log kill: 6 K. Pneumo Static: 3.6 1-log kill: 9.5	Neutropenic thigh, stasis and 1-log kill	No exposure response was identified for cIAI or cUTI based on clinical data.
Cefiderocol [27]	2019	cUTI, HABP, VABP	%fT > MIC Static: 63.9% 1-log kill: 75.6%	%fT > MIC Static: 57.5% 1-log kill: 66.9%	Neutropenic thigh 1-log kill	Exposure response confirmed trend of efficacy in patients achieving 75% fT > MIC.
Imipenem-Relebactam [30]	2019	cUTI/cIAI	AUC24/MIC Relebactam Stasis: 4.8 1-log kill: 7.5		Neutropenic thigh, stasis and 1-log kill	Clinical PKPD targets were limited by insufficient data in the clinical trials.
Lefamulin [28]	2019	CABP		fAUC24/MIC Plasma 1-log kill: 2.97 2-log kill: 6.96 ELF 1-log kill: 30.4 2-log kill: 71.2	Plasma Neutropenic lung 1-log kill	Stratifying outcomes by MIC supported the breakpoint decision. Limited data at higher MICs.