Antibiotic dosing recommendations in critically ill patients receiving new innovative kidney replacement therapy

BMC Nephrology

Table 4 Probability of neurotoxicity of MCS-driven piperacillin/tazobactam dosing recommendation in five kidney replacement therapies

	KRT setting	PD target^†	MCS-driven Piperacillin/tazobactam dosing recommendation	Probability of total concentration above neurotoxicity threshold at the end of each day during 1 week of therapy^£
	KRT setting	PD target^†	MCS-driven Piperacillin/tazobactam dosing recommendation	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7
1	4-hour HD on Mon-Wed-Fri	50% fT > MIC	4.5 g q12h post-HD	10.9%	2.0%	22.6%	6.5%	24.7%	29.9%	10.1%
		50% fT > MICx4	4.5 g q8h post-HD	36.8%	15.7%	50.3%	22.5%	51.2%	54.9%	24.9%
		50% fT > MICx4	3.375 g q6h post-HD	41.0%	16.8%	53.5%	22.6%	54.3%	57.8%	25.5%
2	4-hour HD daily	50% fT > MIC	4.5 g q12h post-HD	0.0%	0.3%	1.1%	1.7%	2.3%	2.4%	2.6%
		50% fT > MICx4	4.5 g q8h post-HD	1.3%	9.5%	13.4%	14.6%	15.1%	15.2%	15.3%
		50% fT > MICx4	3.375 g q6h post-HD	1.5%	9.8%	14.1%	15.8%	16.4%	16.6%	16.7%
3	Sequential 4-hour HD & 20-hour UF	50% fT > MIC	4.5 g q12h post-HD	0.0%	0.0%	0.5%	1.0%	1.2%	1.4%	1.6%
		50% fT > MICx4	4.5 g q8h post-HD	0.4%	5.7%	9.2%	10.4%	10.0%	10.7%	11.0%
		50% fT > MICx4	3.375 g q6h post-HD	0.7%	6.6%	10.2%	11.4%	11.9%	12.0%	12.1%
4	Early 9-hour PIKRT^€ daily	50% fT > MIC	4.5 g q12h	3.1%	7.8%	10.5%	11.7%	12.1%	12.3%	12.5%
		50% fT > MICx4	4.5 g q8h	28.6%	40.1%	43.4%	44.2%	44.6%	44.7%	44.8%
		50% fT > MICx4	3.375 g q6h	45.8%	59.1%	61.5%	62.4%	62.6%	62.7%	62.7%
	Late 9-hour PIKRT^€ daily	50% fT > MIC	4.5 g q12h	0.0%	0.2%	0.6%	1.0%	1.4%	1.7%	1.8%
		50% fT > MICx4	4.5 g q8h	1.1%	9.1%	13.2%	14.7%	15.1%	15.0%	15.1%
		50% fT > MICx4	3.375 g q6h	1.7%	9.8%	14.0%	15.6%	15.6%	15.7%	15.7%
5	Extended PIKRT daily	50% fT > MIC	3 g q8h	0.0%	0.3%	0.8%	1.1%	1.2%	1.3%	1.4%
5	Extended PIKRT daily	50% fT > MICx4	4 g q6h	17.4%	28.9%	31.1%	31.5%	31.7%	31.8%	31.8%

KRT: kidney replacement therapy; PD: pharmacodynamic; MCS: Monte Carlo simulation; HD: Hemodialysis at dialysate flow rate (Qd) 300 ml/min; UF: Ultrafiltration at ultrafiltration flow rate of 5 ml/min; PIKRT: Prolonged intermittent kidney replacement therapy (9-hour PIKRT runs at Qd 100 ml/minl and extended PIKRT runs at Qd 50 ml/min for 24 h); LD: loading dose
^†50% fT_> MIC or 50% fT_> MICx4 denotes at least 50% of time during each day of one week of antibiotic therapy that the free plasma piperacillin concentration was greater than the target minimum inhibitory concentration (MIC) or four time of the target MIC of 16 mg/L (susceptibility breakpoint MIC for P. aeruginosa)
^£This indicates the percentage of 5000 simulated patients that were at or above the suggested piperacillin safety threshold (i.e. free plasma concentration ≥ 157 mg/L) at the end of each day during 1 week of therapy
^€ EARLY PIKRT is where the initial piperacillin/tazobactam dose is infused at the beginning of 9-hour PIKRT and late PIKRT where the initial piperacillin/tazobactam dose is given 15 h prior to 9-hour PIKRT
Interestingly, a 4-hour extended infusion strategy, commonly utilized in clinical practice, did not appreciably enhance PTA compared to 0.5-hour intermittent infusion, and did not alter the selection of optimal cefepime and piperacillin/tazobactam doses in our analyses (supplementary materials)

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