The Evaluation of Meropenem Dosing Regimens Against ESBL-Producing Escherichia coli in ICU Patients Using Monte Carlo Simulation

Figures & data

Table 1 Antimicrobial Dosing Regimens for Simulation

Renal Function CLcr (mL/min)	Total Daily Dose		Dosage Regimens		Infusion Time	Non-Vasopressor Receiver	Vasopressor Receiver
81–100	6g		2g q 8hr		30 min^a	/	/
					3hr^d	/	/
	4g		1g q 6hr		30 min^e	/	/
					3hr^e	/	/
	3g		1g q 8hr		30 min^b	/	/
					3hr^e	/	/
	2g		0.5g q6hr		30 min^e	/	/
					3hr^e	/	/
	1.5g		0.5g q 8hr		30min^c	/	/
					3hr^e	/	/
	1g		0.5g q 12hr		30 min^e	-	/
					3hr^e	-	/
	0.75g		0.25g q 8hr		30 min^e	-	/
					3hr^e	-	/
51–80	6g		2g q 8hr		30 min^a	/	/
					3hr^d	/	/
	4g		1g q 6hr		30 min^e	/	-
					3hr^e	/	-
	3g		1g q 8hr		30 min^b	/	/
					3hr^e	/	/
	2g		0.5g q6hr		30 min^e	/	-
					3hr^e	/	-
	1.5g		0.5g q 8hr		30min^c	/	/
					3hr^e	/	/
	1g		0.25g q 6hr		30 min^e	/	-
					3hr^e	/	-
	0.5g		0.5g q 12hr		30 min^e	-	/
					3hr^e	-	/
	0.75g		0.25g q 8hr		30 min^e	/	-
					3hr^e	/	-
	0.5g		0.25g q 12hr		30 min^e	-	/
					3hr^e	-	/
26–50	4g		2g q 12hr		30 min^a	/	/
					3hr^e	/	/
	3g		1g q 8hr		30min^d	/	/
					3hr^e	/	-
	2g		1g q 12hr		30 min^b	/	/
					3hr^e	/	/
	1.5g		0.5g q 8hr		30 min^e	/	-
					3hr^e	/	-
	1g		0.5g q 12hr		30 min^c	/	/
					3hr^e	/	/
	0.75g		0.25g q 8hr		30 min^e	/	-
					3hr^e	/	-
	0.5g		0.25g q 12hr		30 min^e	/	/
					3hr^e	/	/
			0.5g q 24hr		30 min^e	-	/
					3hr^e	-	/
	0.25g		0.125g q 12hr		30 min^e	-	/
					3hr^e	-	/
11–25	2g		1g q 12hr		30 min^a,d	/	/
					3hr^e	/	-
	1g		0.5g q 12hr		30 min^b	/	/
					3hr^e	/	/
	0.5g		0.25g q12hr		30 min^c	/	/
					3hr^e	/	/
			0.5g q 24hr		30 min^e	-	/
					3hr^e	-	/
	0.25g		0.125g q 12hr		30 min^e	/	/
					3hr^e	/	/
			0.25g q 24hr		30 min^e	-	/
					3hr^e	-	/
	0.125g		0.125g q 24hr		30 min^e	-	/
					3hr^e	-	/
1–10	2g		1g q 12hr		30 min^d	/	/
	1g		1g q 24hr		30min^a	/	/
			0.5g q 12hr		30 min^e	/	-
	0.5g		0.5g q 24hr		30min^b	/	/
			0.25g q 12hr		30 min^e	/	-
	0.25g		0.25g q 24hr		30 min^c	/	/
			0.125g q 12hr		30 min^e	/	/
	0.125g		0.125g q 24hr		30 min^e	-	/

Notes: ^aEMA recommended high-dose regimen. ^bUS-FDA recommended high-dose regimens. ^cUS-FDA recommended low-dose regimens. ^dEhmann et al study regimens at CLSI breakpoint. ^eOur study regimens.

Abbreviations: CLcr, creatinine clearance; q 6hr, every 6 hours; q 8hr, every 8 hours; q 12hr, every 12 hours; q 24hr, every 24 hours.

Table 2 Susceptibility Pattern of Antimicrobial Agents for ESBL E. coli

Antibiotics	Sensitive Isolates (n)	MIC Range (μg/mL)	S%
Ampicillin	0	32	0
Aztreonam	20	2–64	21.5
Cefazolin	0	4–64	0
Ceftriaxone	6	1–64	6.5
Cefepime	29	1–64	31.2
Amikacin	90	1–64	96.8
Gentamycin	40	1–16	43
Tetracycline	14	1–16	15.1
Trimethoprim–Sulfamethoxazole	0	20–320	0
Levofloxacin	5	0.12–18	5.4
Ciprofloxacin	10	0.25–4	10.8
Amoxicillin/Clavulanate	25	2–32	26.9
Ampicillin/Sulbactam	8	4–32	8.6
Piperacillin/Tazobactam	70	4–128	75.3
Imipenem	93	0.25–0.5	100
Meropenem	93	0.25–1	100
Ertapenem	93	0.12–0.5	100

Abbreviations: MIC, minimum inhibitory concentration; S, sensitivity; %, percentage.

Figure 1 Probability of target attainment (PTA) of meropenem dosing regimens in patients who do not receive vasopressors and various degrees of renal functions. (A) CLcr 81–100 mL/min, (B) CLcr 51–80 mL/min, (C) CLcr 26–50 mL/min, (D) CLcr 11–25 mL/min, (E) CLcr 1–10 mL/min.

Abbreviations: US-FDA, The United States Food and Drug Administration; EMA, European Medicines Agency; CLcr, creatinine clearance; MIC, minimum inhibitory concentration; inf, infusion; q 6hr, every 6 hours; q 8hr, every 8 hours; q 12hr, every 12 hours; q 24hr, every 24 hours.

Figure 2 Probability of target attainment (PTA) of meropenem dosing regimens in patients who receive vasopressors and various degrees of renal functions. (A) CLcr 81–100 mL/min, (B) CLcr 51–80 mL/min, (C) CLcr 26–50 mL/min, (D) CLcr 11–25 mL/min, (E) CLcr 1–10 mL/min.

Abbreviations: US-FDA, The United States Food and Drug Administration; EMA, European Medicines Agency; CLcr, creatinine clearance; MIC, minimum inhibitory concentration; inf, infusion; q 6hr, every 6 hours; q 8hr, every 8 hours; q 12hr, every 12 hours; q 24hr, every 24 hours.

Table 3 Cumulative Fraction Response (CFR) Results for All Simulated Meropenem Dosage Regimens Against ESBL E. coli

Renal Function CLcr (mL/min)		Total Daily Dose	Regimens			Infusion Time	CFR
							Non-Vasopressor Receiver		Vasopressor Receiver
81–100		6g	2g q 8hr			30 min^a	80.45		99.41
						3hr^d	99.08		99.98
		4g	1g q 6hr			30 min^e	91.99		99.89
						3hr^e	99.99		99.99
		3g	1g q 8hr			30 min^b	68.86		98.40
						3hr^e	97.53		99.96
		2g	0.5g q6hr			30 min	83.77		99.66
						3hr^e	99.98		99.99
		1.5g	0.5g q 8hr			30min^c	53.40		95.95
						3hr^e	93.09		99.91
		1g	0.5g q 12hr			30 min^e	-		79.17
						3hr^e	-		93.47
		0.75g	0.25g q 8hr			30 min^e	-		91.68
						3hr^e	-		99.53
51-80		6g	2g q 8hr			30 min^a	95.86		99.96
						3hr^d	99.95		99.99
		4g	1g q 6hr			30 min^e	98.86		-
						3hr^e	99.99		-
		3g	1g q 8hr			30 min^b	91.10		99.83
						3hr^e	99.71		99.99
		2g	0.5g q6hr			30 min^e	96.91		-
						3hr^e	99.99		-
		1.5g	0.5g q 8hr			30min^c	83.61		99.63
						3hr^e	98.99		99.99
		1g	0.25g q 6hr			30 min^e	91.92		-
						3hr^e	99.98		-
		0.5g	0.5g q 12hr			30 min^e	-		95.47
						3hr^e	-		99.29
		0.75g	0.25g q 8hr			30 min^e	68.32		-
						3hr^e	96.18		-
		0.5g	0.25g q 12hr			30 min^e	-		89.78
						3hr^e	-		97.77
26-50		4g	2g q 12hr			30 min^a	97.60		99.98
						3 hr^e	99.69		99.99
		3g	1g q 8hr			30 min^d	99.63		99.99
						3hr^e	99.99		-
		2g	1g q 12hr			30 min^b	95.25		99.93
						3hr^e	99.23		99.98
		1.5g	0.5g q 8hr			30 min^e	98.86		-
						3hr^e	99.98		-
		1g	0.5g q 12hr			30 min^c	90.22		99.87
						3hr^e	97.89		99.99
		0.75g	0.25g q 8hr			30 min^e	96.68		-
						3hr^e	99.85		-
11–25		2g	1g q 12hr			30 min^a,d	99.73		99.99
						3hr^e	99.98
		1g	0.5g q 12hr			30 min^b	99.20		99.99
						3hr^e	99.93		99.99
		0.5g	0.25g q12hr			30 min^c	97.62		99.99
						3hr^e	99.66		99.88
			0.5g q 24hr			30 min^e	-		99.09
						3hr^e	-		99.60
		0.25g	0.125g q 12hr			30 min^e	92.60		98.69
						3hr^e	98.34		99.99
			0.25g q 24hr			30 min^e	-		97.63
						3hr^e	-		98.91
		0.125g	0.125g q 24hr			30 min^e	-		93.59
						3hr^e	-		96.50
1–10		2g	1g q 12hr			30 min^d	99.99		99.99
		1g	1g q 24hr			30min^a	94.63		99.97
			0.5g q 12hr			30 min^e	99.98		-
		0.5g	0.5g q 24hr			30min^b	90.26		99.89
			0.25g q 12hr			30 min^e	99.82		-
		0.25g	0.25g q 24hr			30 min^c	81.31		99.55
			0.125g q 12hr			30 min^e	93.30		99.99
		0.125g	0.125g q 24hr			30 min^e	-		98.67

Notes: ^aEMA recommended high-dose regimen. ^bUS-FDA recommended high-dose regimens. ^cUS-FDA recommended low-dose regimens. ^dEhmann et al study regimens at CLSI breakpoint. ^eOur study regimens.

Abbreviations: CLcr, creatinine clearance; q 6hr, every 6 hours; q 8hr, every 8 hours; q 12hr, every 12 hours; q 24hr, every 24 hours.

Table 4 Recommendation for MIC 2 μg/mL (EUCAST Breakpoint)

Renal Function CLcr (mL/min)	Non-Vasopressor Receiving Patients			Vasopressor Receiving Patients
	Regimens	TDD	Alternative Regimens	Regimens	TDD	Alternative Regimens
81–100	1g q 6hr (3hr)	4g		0.5g q 6hr (3hr)	2g
51–80	0.5g q 6hr (3hr)	2g		0.5g q 8hr (3hr)	1.5g
25–50	0.5g q 8hr (3hr)	1.5g		0.25g q 12hr (3hr)	0.5g
11–25	0.5g q 12hr (3hr)	1g		0.25g q 12hr (30 min)	0.5g
1–10	0.5g q 12hr (30 min)	1g		0.125g q 12hr (30 min)	0.25	0.5g q 24hr (30 min)

Abbreviations: MIC, minimum inhibitory concentration; CLcr, creatinine clearance; EUCAST, European Committee on Antimicrobial Susceptibility Testing; TDD, total daily dose; q 6hr, every 6 hours; q 8hr, every 8 hours; q 12hr, every 12 hours; q 24hr, every 24 hours.

Table 5 Recommendation for MIC 1μg/mL (CLSI Breakpoint)

Renal Function CLcr (mL/min)	Non-Vasopressor Receiving Patients			Vasopressor Receiving Patients
	Regimens	TDD	Alternative Regimens	Regimens	TDD	Alternative Regimens
81–100	0.5g q 6hr (3hr)	2g		0.5g q 8hr (3hr)	1.5g
51–80	0.25g q 6hr (3hr)	1g		0.5g q 12hr (3hr)	1g
25–50	0.25g q 8hr (3hr)	0.75g		0.25g q 12hr (30 min)	0.5g
11–25	0.25g q 12hr (3hr)	0.5g		0.125g q 12hr (30 min)	0.25g	0.5g q 24hr (30 min/3hr)
1–10	0.25g q 12hr (30 min)	0.5g		0.125g q 12hr (30 min)	0.25g	0.25g q 24hr (30 min)

Abbreviations: MIC, minimum inhibitory concentration; CLcr, creatinine clearance; CLSI, Clinical and Laboratory Standards Institute; TDD, total daily dose; q 6hr, every 6 hours; q 8hr, every 8 hours; q 12hr, every 12 hours; q 24hr, every 24 hours.

Table 6 Recommendation for MIC 0.25 μg/mL (MIC_50/90 of Myanmar Population)

Renal Function CLcr (mL/min)	Non-Vasopressor Receiving Patients			Vasopressor Receiving Patients
	Regimens	TDD	Alternative Regimens	Regimens	TDD	Alternative Regimens
81–100	0.5g q 8hr (3hr)	1.5g		0.25g q 8hr (3hr)	1g
51–80	0.25g q 8hr (3hr)	0.75g		0.25g q12hr (30 min)	0.5g
25–50	0.25g q 12hr (3hr)	0.5g		0.125g q 12hr (30 min)	0.25g
11–25	0.125g q 12hr (30 min)	0.25g		0.125g q 24hr (30 min)	0.125g
1–10	0.125g q 12hr (30 min)	0.25g	0.5g q 24hr (30 min)	0.125g q 24hr (30 min)	0.125g

Abbreviations: MIC, minimum inhibitory concentration; MIC_50/90, MIC for 50% and 90% of isolates tested; CLcr, creatinine clearance; TDD, total daily dose; q 6hr, every 6 hours; q 8hr, every 8 hours; q 12hr, every 12 hours; q 24hr, every 24 hours.