Simulating moxalactam dosage for extended-spectrum β-lactamase-producing Enterobacteriaceae using blood antimicrobial surveillance network data

Figures & data

Table 1 The pharmacokinetic parameters used in the Monte Carlo simulation

Drug	Dose	Vd (L)	CLT(L∙h^−1)	fu	Reference
FEP	2 g	13.60±2.40	5.30±0.60	0.80–0.90	^Citation30
MOX	1 g	15.61±6.44	5.99±1.85	0.32±0.02	^Citation27, ^Citation28
	2 g	14.95±2.44	5.85±0.89	0.32±0.02	^Citation27, ^Citation28
CFZ/SBT(2:1)^a	3 g	10.20±1.00	5.70±0.84	0.1	^Citation16

Notes: ^aAs CFZ was regarded as the bactericidal effects against Enterobacteriaceae in CFZ/SBT combinations, the parameters of CFZ were used for MCS. The values were represented as mean ± standard deviation.

Abbreviations: V_d, the volume of distribution in liters at steady state; CL_T, the total body clearance in liters per hour; f_u, the fraction of unbound drug; FEP, cefepime; MOX, moxalactam; CFZ/SBT, cefperazone/sulbactam.

Table 2 The in vitro activities of FEP, MOX and CFZ/SBT against Enterobacteriaceae isolated from BRICS

Isolates	FEP			MOX			CFZ/SBT
	MIC50	MIC90	MIC range	MIC50	MIC90	MIC range	MIC50	MIC90	MIC range
ESBL-Ec (n=875)	8	64	0.015–128	0.5	2	0.06–128	16	64	0.06–128
Non-ESBL-Ec (n=637)	0.06	4	0.015–256	0.25	2	0.0.06–128	1	16	0.0.06–128
Ec (n=1512)	1	32	0.015–256	0.25	2	0.06–128	8	64	0.06–128
ESBL-Kp (n=157)	8	64	0.015–128	0.5	32	0.06–128	16	128	0.06–128
Non-ESBL-Kp (n=363)	0.06	4	0.015–256	0.25	8	0.06–256	0.25	32	0.06–128
Kp (n=520)	0.06	64	0.015–256	0.25	8	0.06–256	1	128	0.06–128
REb (n=371)	0.06	8	0.015–128	0.25	8	0.06–128	2	32	0.06–128
Eb (n=2403)	1	64	0.015–256	0.25	4	0.06–256	4	64	0.06–256

Abbreviations: ESBL-Ec, ESBL-producing E. coli; non-ESBL-Ec, non-ESBL-producing E. coli; Ec, E. coli; ESBL-Kp, ESBL-producing K. pneumoniae; non-ESBL-Kp, non-ESBL-proucing K. pneumoniae; Kp, K. pneumoniae; Other-Eb, other Enterobacteriaceae; Eb, Enterobacteriaceae; ESBL, extended-spectrum β-lactamase; BRICS, Blood Bacterial Resistant Investigation Collaborative System; MIC, minimum inhibitory concentration; CFZ/SBT, cefperazone/sulbactam; FEP, cefepime; MOX, moxalactam.

Figure 1 Distributions of MOX, FEP, and CFZ/SBT (MICs) against Enterobacteriaceae isolated from BRICS. (A–C) Frequency distributions of FEP, MOX, and CFZ/SBT MICs against Enterobacteriaceae, respectively.

Abbreviations: FEP, cefepime; MOX, moxalactam; CFZ/SBT, cefperazone/sulbactam; ESBL-Ec, ESBL-producing Escherichia coli; non-ESBL-Ec, non-ESBL-producing E. coli; Ec, E. coli; ESBL-Kp, ESBL-producing Klebsiella pneumoniae; non-ESBL-Kp, non-ESBL-producing K. pneumoniae; Kp, K. pneumoniae; Other-Eb, other Enterobacteriaceae; Eb, Enterobacteriaceae; BRICS, Blood Bacterial Resistant Investigation Collaborative System; MIC, minimum inhibitory concentration.

Figure 2 Probability of target attainment (PTA) for each dosing regimen to achieve 50% fT >MIC.

Notes: %fT >MIC, a percentage of the dosing interval, that the concentration of the antimicrobial agent remains above the MIC for the microorganism.

Abbreviations: FEP, cefepime; MOX, moxalactam; CFZ/SBT, cefperazone/sulbactam; MIC, minimum inhibitory concentration.

Table 3 The CFRs for different dosage regimens of FEP, MOX and CFZ/SBT against Enterobacteriaceae isolated from BRICS

Dosage regimens	ESBL-Ec	non-ESBL-Ec	Ec	ESBL-Kp	non-ESBL-Kp	Kp	REb	Eb
	CFR50%	CFR50%	CFR50%	CFR50%	CFR50%	CFR50%	CFR50%	CFR50%
FEP 1 g iv q12h	40.69	91.61	56.69	46.46	90.97	74.63	86.78	64.03
FEP 1 g iv q8h	59.82	94.3	70.32	62.53	91.75	81.71	90.68	76.44
FEP 2 g iv q12h	58.66	93.74	66.92	61.83	91.65	79.67	90.01	73.45
FEP 2 g iv q8h	76.48	94.92	80.53	77.45	92.42	85.22	96.48	84.15
MOX 1 g iv q12h	79.13	87.72	82.65	67.34	85.6	81.37	78.32	80.85
MOX 1 g iv q8h	89.94	91.8	90.55	79.96	88.98	86.61	84.91	88.36
MOX 1 g iv q6h	92.71	92.94	92.88	83.62	89.78	87.75	86.77	90.05
MOX 2 g iv q12h	91.42	92.54	91.52	81.4	89.42	87.14	83.55	89.41
MOX 2 g iv q8h	93.55	93.66	93.53	86.27	90.75	89.61	87.99	92.27
CFZ/SBT 1.5 g iv q12h	3.01	26.62	13.02	5.93	48.09	25.16	23.86	19.43
CFZ/SBT 1.5 g iv q8h	5.68	49.96	24.62	12.93	71.19	52.71	43.06	34.32
CFZ/SBT 3 g iv q12h	4.76	39.58	20.32	9.95	63.11	47.12	36.58	29.11
CFZ/SBT 3 g iv q8h	8.19	65.16	32.15	16.57	78.42	58.38	51.09	40.68
CFZ/SBT 3 g iv q6h	11.61	74.84	37.18	19.48	81.87	62.19	57.97	45.44

Abbreviations: FEP, cefepime; MOX, moxalactam; CFZ/SBT, cefperazone/sulbactam; ESBL-Ec, ESBL-producing E. coli; non-ESBL-Ec, non-ESBL-producing E. coli; Ec, E. coli; ESBL-Kp, ESBL-producing K. pneumoniae; non-ESBL-Kp, non-ESBL-producing K. pneumoniae; Kp, K. pneumoniae; Other-Eb, other Enterobacteriaceae; Eb, Enterobacteriaceae; ESBL, extended-spectrum β-lactamase; BRICS, Blood Bacterial Resistant Investigation Collaborative System; CFR, cumulative fractions of response; CFR_50%, the bactericidal effects defined as achieving 50% fT >MIC; MIC, minimum inhibitory concentration.

Figure S1 (A, B, and C) cumulative distributions of FEP, MOX, and CFZ/SBT MICs against Enterobacteriaceae, respectively. The dotted vertical line indicates the susceptible breakpoint according to the CLSI.

Abbreviations: FEP, cefepime; MOX, moxalactam; CFZ/SBT, cefperazone/sulbactam; ESBL-Ec, ESBL-producing E. coli; non-ESBL-Ec, non-ESBL-producing E. coli; Ec, E. coli; ESBL-Kp, ESBL-producing K. pneumoniae; non-ESBL-Kp, non-ESBL-producing K. pneumoniae; Kp, K. pneumoniae; other-Eb, other Enterobacteriaceae; Eb, Enterobacteriaceae; MIC, minimum inhibitory concentration.

Figure S2 CFRs for different simulated dosage regimens against Enterobacteriaceae.

Notes: The dotted line indicates the value of CFR achieving 90%.

Abbreviations: FEP, cefepime; MOX, moxalactam; CFZ/SBT, cefperazone/sulbactam; ESBL-Ec, ESBL-producing E. coli; Ec, E. coli; ESBL-Kp, ESBL-producing K. pneumoniae; Kp, K. pneumoniae; Other-Eb, other Enterobacteriaceae; Eb, Enterobacteriaceae; CFR, cumulative fraction of response.

Nye KJ, Shi YG, Andrews JM, Wise R. Pharmacokinetics and tissue penetration of cefepime. J Antimicrob Chemother. 1989;24(1):23–28.

 Web of Science ®Google Scholar

Friden M, Ljungqvist H, Middleton B, Bredberg U, Hammarlund-Udenaes M. Improved measurement of drug exposure in the brain using drug-specific correction for residual blood. J Cereb Blood Flow Metab. 2010;30(1):150–161. doi:10.1038/jcbfm.2009.20019756019

 PubMed Web of Science ®Google Scholar

Israel KS, Black HR, Brier GL, Wolny JD, DeSante KA. Single- and multiple-dose pharmacokinetics of moxalactam in normal subjects. Antimicrob Agents Chemother. 1982;22(1):94–102.6214998

 PubMed Web of Science ®Google Scholar

Wang H, Zhang B, Ni Y, et al. Pharmacodynamic target attainment of seven antimicrobials against Gram-negative bacteria collected from China in 2003 and 2004. Int J Antimicrob Agents. 2007;30(5):452–457. doi:10.1016/j.ijantimicag.2007.06.00517646088

 PubMed Web of Science ®Google Scholar