Pharmacokinetic and Pharmacodynamic Evaluation of a Weight-Based Dosing Regimen of Cefoxitin for Perioperative Surgical Prophylaxis in Obese and Morbidly Obese Patients

Pierre Moine; Scott W. Mueller; Jonathan A. Schoen; Kevin B. Rothchild; Douglas N. Fish

doi:10.1128/AAC.00585-16

DOI: 10.1128/AAC.00585-16

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TABLE 1

Subject demographics

Patient characteristic	Value for^a:			P value^b
Patient characteristic	All patients(n = 30)	Patients with BMIs of <40 kg/m² (n = 5)	Patients with BMIs of ≥40 kg/m² (n = 25)	P value^b
Age (yr)	40.6 ± 11.4	48.8 ± 6.3	38.9 ± 11.6	0.02
Sex (no. of females/no. of males)	26/4	3/2	23/2	0.12
Ht (cm)	166 ± 10	174 ± 8	164 ± 9	0.04
Total body wt (kg)	125.6 ± 22.4	112.4 ± 10.4	128.2 ± 23.4	0.03
Ideal body wt (kg)	58.6 ± 9.4	67.0 ± 8.2	56.9 ± 8.8	0.06
Lean body wt, Hume (kg)	63.6 ± 9.5	64.1 ± 6.3	63.5 ± 10.1	0.87
Lean body wt, LBW2005 (kg)	59.9 ± 9.6	63.6 ± 9.6	59.1 ± 9.6	0.38
Adjusted body wt (kg)	85.4 ± 11.9	85.2 ± 8.2	85.4 ± 12.6	0.96
BMI (kg/m²)	45.9 ± 8.0	37.0 ± 2.2	47.6 ± 7.6	<0.0001
Baseline serum creatinine (mg/dl)	0.86 ± 0.28	0.97 ± 0.13	0.84 ± 0.30	0.14
Surgical procedure (no. of patients)	Laparoscopic Roux-en-y gastric bypass (29)
	Laparoscopic gastric band placement (1)
Dose (mg)	5,020 ± 854	4,500 ± 500	5,124 ± 878	0.06
Duration of infusion (min)	5.1 ± 0.9	5.0 ± 0.7	5.1 ± 1.1	0.80
Time from end of drug infusion to incision (min)	1.2 ± 1.6	1.6 ± 0.9	1.3 ± 1.7	0.58

↵a Values are means ± SDs or numbers.
↵b Comparison of patients with BMIs of <40 kg/m² and those with BMIs of ≥40 kg/m².

TABLE 2

Cefoxitin serum and tissue pharmacokinetic parameters in obese surgical patients with BMIs of >30 kg/m²

Parameter	Value for^a:			P value^b
Parameter	All patients(n = 30)	Patients with BMIs of <40 kg/m² (n = 5)	Patients with BMIs of ≥40 kg/m² (n = 25)	P value^b
Serum pharmacokinetics
Observed C_max (mg/liter)	216.15 ± 41.80	205.35 ± 27.60	218.31 ± 44.21	0.42
Observed C_max/D (mg/liter/g)	44.29 ± 12.11	46.35 ± 10.14	43.88 ± 12.62	0.65
Observed T_max (min)	12.9 ± 4.6	11.6 ± 2.6	13.1 ± 4.9	0.34
AUC_0-∞ (μg · h/ml)	266.92 ± 97.51	328.30 ± 34.03	254.64 ± 101.75	0.009
CL (ml/min)	349.02 ± 118.22	232.11 ± 48.28	372.40 ± 114.37	<0.001
CL/TBW (ml/min/kg)	2.80 ± 0.91	2.05 ± 0.28	2.94 ± 0.92	<0.001
CL/IBW (ml/min/kg)	6.04 ± 2.09	3.44 ± 0.37	6.56 ± 1.89	<0.001
CL/LBW2005 (ml/min/kg)	5.88 ± 1.99	3.65 ± 0.45	6.33 ± 1.88	<0.001
CL/AdjBW (ml/min/kg)	4.09 ± 1.33	2.70 ± 0.31	4.37 ± 1.28	<0.001
V (liters)	29.28 ± 9.83	21.34 ± 9.12	31.12 ± 9.44	0.08
V/TBW (liters/kg)	0.23 ± 0.07	0.19 ± 0.06	0.24 ± 0.07	0.25
V/IBW (liters/kg)	0.51 ± 0.19	0.32 ± 0.12	0.55 ± 0.18	0.01
V/LBW2005 (liters/kg)	0.49 ± 0.17	0.34 ± 0.14	0.53 ± 0.16	0.05
V/AdjBW (liters/kg)	0.34 ± 0.11	0.25 ± 0.09	0.36 ± 0.11	0.08
t_1/2 (h)	1.05 ± 0.54	1.06 ± 0.38	1.05 ± 0.58	0.96
k_el (h)	0.75 ± 0.20	0.71 ± 0.18	0.75 ± 0.21	0.33
Tissue pharmacokinetics
Observed C_max (mg/liter)	12.62 ± 5.89	11.08 ± 2.35	12.93 ± 6.36	0.28
Observed T_max (min)	16.7 ± 5.9	16.8 ± 6.6	16.7 ± 6.0	0.97
AUC_0-∞ (μg · h/ml)	15.35 ± 6.24	13.09 ± 3.58	15.80 ± 6.61	0.22
t_1/2 (h)	1.73 ± 0.73	1.66 ± 0.65	1.74 ± 0.75	0.81
k_el (h)	0.45 ± 0.15	0.49 ± 0.26	0.44 ± 0.13	0.70
Serum concns
Surgical opening (mg/liter)	174.41 ± 38.07	168.48 ± 36.58	175.60 ± 38.98	0.71
60 min postinfusion (mg/liter)	93.13 ± 23.69	97.31 ± 31.80	92.30 ± 22.48	0.75
180 min postinfusion/surgical closure (mg/liter)	37.62 ± 24.34	50.73 ± 34.25	35.00 ± 21.84	0.38
Tissue concns
Surgical opening (mg/liter)	12.62 ± 5.89	11.08 ± 2.35	12.93 ± 6.36	0.28
60 min postinfusion (mg/liter)	6.33 ± 2.01	6.97 ± 3.26	6.21 ± 1.74	0.64
180 min postinfusion/surgical closure (mg/liter)	4.26 ± 1.80	4.49 ± 2.21	4.22 ± 1.75	0.81
Tissue/serum concn ratios
Surgical opening (mg/liter)	0.08 ± 0.05	0.07 ± 0.02	0.08 ± 0.05	0.37
60 min postinfusion (mg/liter)	0.07 ± 0.02	0.07 ± 0.01	0.07 ± 0.02	1.00
180 min postinfusion/surgical closure (mg/liter)	0.14 ± 0.07	0.10 ± 0.04	0.14 ± 0.07	0.09
Ratio of tissue/blood AUCs from surgical opening to closure	0.08 ± 0.03	0.07 ± 0.05	0.08 ± 0.04	0.28

↵a Values are means ± SDs.
↵b Comparison of patients with BMIs of <40 kg/m² and those with BMIs of ≥40 kg/m².

TABLE 3

MIC frequency distribution for Escherichia coli, Bacteroides fragilis, and Staphylococcus aureus isolates collected from the EUCAST database

Organism	No. of isolates	% of isolates with indicated cefoxitin MIC (mg/liter)^a
Organism	No. of isolates	<0.125	0.125	0.25	0.5	1	2	4	8	16	32	64	>64
E. coli	66,874	0	0	0.1	2.1	6.9	34.3	37.1	12.8	3.8	1.7	1.1	0.1
B. fragilis	1,898	0	0	0.8	0.1	0.2	2.2	27.5	34.4	17.4	8.8	3.6	5.1
S. aureus	856	0	0.1	1.0	7.8	32.4	27.8	19.5	3.4	1.6	1.9	0.8	3.6

↵a Current CLSI susceptibility MIC breakpoints are indicated by distribution percentages that are underlined.

TABLE 4

PTA of single-dose cefoxitin regimens in obese patients with BMIs of >30 kg/m² against Escherichia coli, Bacteroides fragilis, and Staphylococcus aureus

Compartment and pharmacodynamic target	Cefoxitin dose	PTA by pathogen (%)^a
		E. coli at indicated time after dose (h)				B. fragilis at indicated time after dose (h)				S. aureus at indicated time after dose (h)
		1	2	3	4	1	2	3	4	1	2	3	4
Serum
fT>MIC of 100%	40 mg/kg	97	95	76	46	92	79	47	18	100	100	78	36
	2 g	89	68	37	14	74	36	10	2	100	68	19	3
	2 g in nonobese patients (from reference 34)	98	35	12	4	69	13	3	0	98	35	12	4
fT>MIC of 70%	40 mg/kg	98	95	91	80	94	90	77	54	100	100	99	84
	2 g	92	84	66	42	82	60	32	13	100	95	62	26
Tissue
fT>MIC of 100%	40 mg/kg	27	7	2	1	0	0	0	0	55	26	8	2
	2 g	4	1	0	0	0	0	0	0	17	3	1	0
fT>MIC of 70%	40 mg/kg	38	16	6	3	0	0	0	0	63	44	26	10
	2 g	6	2	0	0	0	0	0	0	25	10	3	0

↵a Values meeting the desired goal of PTA of ≥90% at each time point are in bold.

TABLE 5

PTA at fT>MIC of 100% of single-dose cefoxitin regimens in obese patients with BMIs of <40 kg/m² and ≥40 kg/m² against Escherichia coli, Bacteroides fragilis, and Staphylococcus aureus using EUCAST susceptibility data

Compartment and BMI	Cefoxitin dose	PTA by pathogen (%)^a
		E. coli at indicated time after dose (h)				B. fragilis at indicated time after dose (h)				S. aureus at indicated time after dose (h)
		1	2	3	4	1	2	3	4	1	2	3	4
Serum
BMI < 40 kg/m²	40 mg/kg	98	95	88	68	85	75	53	28	94	93	92	82
BMI ≥ 40 kg/m²	40 mg/kg	97	94	82	65	86	72	51	31	94	93	87	77
BMI < 40 kg/m²	2 g	95	85	62	34	70	45	20	6	92	89	79	59
BMI ≥ 40 kg/m²	2 g	91	76	50	31	61	34	16	7	92	86	69	50
Tissue
BMI < 40 kg/m²	40 mg/kg	37	13	0	0	4	1	0	0	63	39	16	0
BMI ≥ 40 kg/m²	40 mg/kg	35	15	3	2	0	0	0	0	64	38	19	8
BMI < 40 kg/m²	2 g	7	2	0	0	0	0	0	0	30	9	0	0
BMI ≥ 40 kg/m²	2 g	5	1	0	0	0	0	0	0	19	7	0	0

↵a Values meeting the desired goal of PTA of ≥90% at each time point are in bold.

TABLE 6

PTA of single-dose cefoxitin surgical prophylaxis regimens according to pathogen MIC at different time points after dosing in obese patients with BMIs of >30 kg/m²

fT>MIC and cefoxitin dose	Time (h)	PTA (%) at indicated MIC (mg/liter)^a
fT>MIC and cefoxitin dose	Time (h)	0.5	1	2	4	8^b	16^c	32	64	128
fT>MIC of 100%
40 mg/kg	1	100	100	100	100	100	90	25	0
	2	100	100	100	100	82	25	1	0
	3	100	100	97	75	30	2	0
	4	99	92	71	34	5	0
2 g	1	100	100	100	100	73	9	0
	2	100	100	97	67	12	0
	3	100	93	64	17	0
	4	87	61	22	2	0
fT>MIC of 70%
40 mg/kg	1	100	100	100	100	100	98	45	1	0
	2	100	100	100	100	99	65	9	0
	3	100	100	100	99	77	23	1	0
	4	100	100	99	84	40	4	0
2 g	1	100	100	100	100	91	22	0
	2	100	100	100	95	41	2	0
	3	100	100	96	60	10	0
	4	100	96	72	25	1	0

↵a Values meeting the desired goal of PTA of ≥90% at each time point are in bold.
↵b Current CLSI breakpoints = 8 mg/liter for E. coli and S. aureus.
↵c Current CLSI breakpoint = 16 mg/liter for B. fragilis.

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Pharmacokinetic and Pharmacodynamic Evaluation of a Weight-Based Dosing Regimen of Cefoxitin for Perioperative Surgical Prophylaxis in Obese and Morbidly Obese Patients

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