Optimal Empiric Treatment for Klebsiella pneumoniae Infections in Short-Stay ICU Patients During Continuous Renal Replacement Therapy: Results from a Population Pharmacokinetic/Pharmacodynamic Analysis

Figures & data

Table 1 MICs of K. pneumoniae Against Tested Agents

Antimicrobial Agent	The Length of ICU Stay	MIC50	MIC90	MIC Range
IMP	<10	0.5	32	0.25–64
	≥10	32	64	0.25–64
	All	1	64	0.25–64
PT	<10	4	128	0.5->128
	≥10	32	>128	1->128
	All	32	>128	1->128

Abbreviations: IMP, imipenem; PT, piperacillin-tazobactam.

Figure 1 The prevalence of carbapenem-resistant or susceptible K. pneumoniae among patients in short-stay ICU patients versus long-term ICU patients. Solid dots represent the length of ICU stay for each isolate, and error bars representing 95% confidence intervals. The chi-square analysis showed short-stay ICU patients was tended to be infected with carbapenem-susceptible K. pneumoniae BSIs (P<0.0001).

Figure 2 Probability of target attainment (PTA) of 50% or 100% fT MIC for the piperacillin dosing regimens of 2g q6h, 4g q12h, 4g q8h and 4g q6h in critically ill virtual patients with the CRRT intensity of 35–45 mL/kg/h. II, intermittent infusion as 0.5-h infusion; EI, extended infusion as 4-h infusion.

Abbreviation: CRRT, continuous renal replacement therapy.

Figure 3 Probability of target attainment of 40% or 100% fT MIC for the imipenem dosing regimens of 0.5g q8h, 0.5g q6h, 1g q8h and 1 g q6h in critically ill virtual patients with the CRRT intensity of 20 mL/kg/h (top) and 40 mL/kg/h (bottom). II, intermittent infusion as 0.5-h infusion.

Abbreviation: CRRT, continuous renal replacement therapy.

Figure 4 Probability of target attainment (PTA) for a MIC of 64 mg/L when efficacy is defined as 100% fT>MIC and toxicity is defined as an Cmin > 150 mg/L for doses administered to critically-ill patients during CRRT: (A) dosing schedule for critically-ill patients weighing 50 kg in CRRT intensity of 35–45 mL/kg/h; (B) dosing schedule for critically-ill patients weighing 75 kg in CRRT intensity of 35–45 mL/kg/h; (C) dosing schedule for critically-ill patients weighing 100 kg in CRRT intensity of 35–45 mL/kg/h.

Figure 5 Probability of target attainment (PTA) for a MIC of 1 mg/L when efficacy is defined as 100% fT>MIC and toxicity is defined as an Cmin > 10 mg/L for imipenem doses administered to critically-ill patients during CRRT: (A) dosing schedule for critically-ill patients weighing 50 kg in CRRT intensity of 20 mL/kg/h; (B) dosing schedule for critically-ill patients weighing 50 kg in CRRT intensity of 40 mL/kg/h; (C) dosing schedule for critically-ill patients weighing 75 kg in CRRT intensity of 20 mL/kg/h; (D) dosing schedule for critically-ill patients weighing 75 kg in CRRT intensity of 40 mL/kg/h; (E) dosing schedule for critically-ill patients weighing 100 kg in CRRT intensity of 20 mL/kg/h; (F) dosing schedule for critically-ill patients weighing 75 kg in CRRT intensity of 40 mL/kg/h.

Table 2 The Simulated C_min of PT and IPM Dosing Regimens in Critically-Ill Patients Requiring CRRT

WT	Regimens	Infusion Time (h)	CRRT Intensity (mL/kg/h)	Cmin		Regimens	Infusion Time (h)	CRRT Intensity (mL/kg/h)	Cmin
	PT			Median (mg/L)	Range (mg/L)	IMP			Median (mg/L)	Range (mg/L)
50kg	2g q6h	0.5	35–45	74.4	67.4–81.9	0.5g q8h	0.5	20	3.6	0.002–17.6
		4	35–45	100.1	88.9–107.6	0.5g q6h	0.5	20	6.2	0.026–25.0
	4g q12h	0.5	35–45	41.3	33.5–49.2	1g q8h	0.5	20	7.3	0.004–35.3
		4	35–45	55.5	47.7–63.4	1g q6h	0.5	20	12.4	0.050–50.1
	4g q8h	0.5	35–45	92.4	81.6–103.5	0.5g q8h	0.5	20	3.2	0.002–14.3
		4	35–45	124.3	113.2–135.9	0.5g q6h	0.5	20	5.5	0.021–20.6
	4g q6h	0.5	35–45	148.8	134.8–163.9	1g q8h	0.5	20	6.4	0.003–28.7
		4	35–45	200.3	177.9–215.2	1g q6h	0.5	20	11.0	0.043–41.2
75kg	2g q6h	0.5	35–45	50.2	45.2–55.6	0.5g q8h	0.5	20	2.8	0.001–11.9
		4	35–45	71.2	63.4–76.7	0.5g q6h	0.5	20	5.0	0.010–17.4
	4g q12h	0.5	35–45	24.8	19.9–29.9	1g q8h	0.5	20	5.6	0.003–23.9
		4	35–45	35.2	30.0–40.6	1g q6h	0.5	20	9.9	0.035–34.7
	4g q8h	0.5	35–45	60.2	53.1–67.8	0.5g q8h	0.5	40	2.8	0.001–11.9
		4	35–45	85.2	77.4–93.6	0.5g q6h	0.5	40	5.0	0.020–17.4
	4g q6h	0.5	35–45	100.4	90.9–111	1g q8h	0.5	40	5.6	0.002–23.9
		4	35–45	142.5	126.8–153.3	1g q6h	0.5	40	9.9	0.034–34.7
100kg	2g q6h	0.5	35–45	38.3	34.2–42.5	0.5g q8h	0.5	40	2.2	0.001–8.7
		4	35–45	56.2	50.5–60.5	0.5g q6h	0.5	40	4.0	0.011–12.9
	4g q12h	0.5	35–45	17.5	14.1–21.3	1g q8h	0.5	40	4.4	0.001–17.3
		4	35–45	25.7	21.9–29.7	1g q6h	0.5	40	8.0	0.020–25.8
	4g q8h	0.5	35–45	44.8	39.5–50.6	0.5g q8h	0.5	40	1.7	0.001–6.5
		4	35–45	65.7	59.7–72.1	0.5g q6h	0.5	40	3.3	0.006–10.0
	4g q6h	0.5	35–45	76.6	69.5–84.9	1g q8h	0.5	40	3.5	0.001–13.1
		4	35–45	112.5	100.9–121.1	1g q6h	0.5	40	6.6	0.012–20.0

Abbreviations: IMP, imipenem; PT, piperacillin-tazobactam; CRRT, continuous renal replacement therapy.

Table 3 Cumulative Fraction of Response (CFR) to IPM and PT Against the Tested K. pneumoniae Isolated from ICU Patients

Drug	CRRT Intensity (mL/kg/h)	Dosing Regimens	CFR Based on %f>MIC
			40%	100%	40%	100%
IPM	20	0.5g q8h II	62.39	43.36	86.51	61.42
		0.5g q6h II	60.32	51.21	87.6	77.05
		1g q8h II	59.25	48.21	87.05	72.68
		1g q6h II	62.13	58.19	87.36	82.24
	40	0.5g q8h II	57.95	47.04	84.55	51.11
		0.5g q6h II	61.23	49.31	86.96	70.06
		1g q8h II	59.56	45.13	85.31	65.62
		1g q6h II	61.74	53.96	86.55	78.07
PT			50%	100%	50%	100%
	35–45	2g q6h II	48.9	45.1	71.7	67.1
		4g q12h II	53.8	48.2	71.9	67
		4g q8h II	55.9	52.3	73.5	70.4
		4g q6h II	56.2	53.8	74	71.9
	35–45	2g q6h EI	50.5	47	72	67.5
		4g q12h EI	54.3	48.8	72.8	67.4
		4g q8h EI	55.9	53.6	74.2	72
		4g q6h EI	56.1	54.3	74.4	72.8

Note: Bold indicates 80% to 90% CFR.

Abbreviations: IMP, imipenem; PT, piperacillin-tazobactam; II, II, intermittent infusion as 0.5-h infusion; EI, extended infusion as 4-h infusion; CRRT, continuous renal replacement therapy.