Target site antibiotic concentrations in orthopedic/trauma extremity surgery: is prophylactic cefazolin adequately dosed? A systematic review and meta-analysis

Figures & data

Figure 1. Flow diagram of included studies.

Table 1. Study characteristics. Characteristics are reported for intervention groups (patients receiving cefazolin i.v. only) unless otherwise reported

A	B	C	D	E	F	G	H	I	J	K	L	M
1	Angthong (2015)	PC	18	C 1 g iv (12)	–	70 (5)	25	61 (8)	TKA (18)	Yes	< TQ / incision	30
				C 2 g iv (6)		68 (3)	17	62 (8)
2	Bryan (1988)	DB	97	C 1 g iv (48)	Cefamandole 2 g iv	59 (12)	46		THA (37)/	NR	30–60 min	NR
		RCT			(49)				TKA (11)		< anesthesia
3	Cunha (1977)	PC	71	C 1 g iv (?)	Cephradine 1 g iv (?)	NR	NR	NR	THA	No		NR
					Cephalothin 1 g iv (?)
4	Cunha (1984)	PC	35	C 1 g iv (13)	Cephradine 1 g iv (?)	[61–88]	NR	NR	TKA	Yes	10–225 min	0.5
											< bone removal
5	Deacon (1996)	PC	25	C 1 g iv (25)	–	< 55	NR	NR	Bunion-	Yes	60 min < TQ	0.5–1.0
									ectomy
6	Friedman (1990)	RCT	24	C 1 g	–		52		TKA	Yes	Until 1, 2,	1
				1 min < TQ (8)		67 (8)		94 (18)			or 5 min < TQ
				2 min < TQ (8)		63 (10)		98 (22)
				5 min < TQ (8)		60 (8)		90 (25)
7	Miller (2004)	PC	15	C 1 g iv (7)	Cefazolin 1 g iv	49	57	NR	Shoulder	No	20 min	NR
					+ regional (8)	[29–77]			surgery		< incision
						51 (14)
8	Parsons (1978)	PC	7	C 4 g iv (7)	–	61 (1.3)	57	65 (5)	THA	No	Immediately	0.25–4
											< anesthesia
9	Polk (1983)	PC	20	C 10 mg/kg	Cefazolin 10 mg/kg	[27–82]	65	[51–83]	THA	No	Shortly after	NR
		SR		bolus (9)	infusion (11)						anesthesia
10	Sharareh (2016)	PC	34	C 1 g/2 g	–	67	44	83	THA (12)/	Yes ^d	< 60 min to	2
				< 70 kg/		[38–86]		[50–125]	TKA (22)		incision / < TQ
				> 70 kg (31) ^a		64 (12)		85 (19)
11	Sørensen (1978)	PC	20	C 1 g iv (1) ^b	Erythromycin (8)	75	40 ^c	NR	Fixation	No	< surgery	0.5–3
					Methicillin (6)	[48–92] ^c			femur
						73 (11)			fracture
12	Williams (1983)	PC	125	C 1 g iv (17)	Cephalothin 0.5 g (38)	65	NR	NR	THA (13)/	Yes ^d	30 min < TQ	0.5–7
				C 2 g iv (6)	Cefamandole 2 g (13)	[13–91] ^c			TKA (10)
					Cefoxitin 0.5 g (37)	59 (13)
					Ceforanide 0.5 g (14)
13	Yamada (2011)	PC	43	C 2 g iv (43)	–	75 (8)	16	55 (8)	THA (16)/	Yes ^d	< TQ /incision	1–100
									TKA (27)
14	Young (2013)	RCT	22	C 1 g iv (11)	Cefazolin 1 g io (11)	65	36	BMI 29	TKA	Yes	10–30 min < TQ	0.5–100
						[48–83]		[23–35]
						65 (10)

AReference number

BFirst author (year)

CStudy design

DB = Double-blind

PC = Prospective cohort

RCT = Randomized controlled trial

SR = Semi-randomized

DTotal number

EIntervention (n)

C = cefazolin

^a 3 patients did not receive cefazolin because of allergy, 4 received 1 g, 27 received 2g.

^b 6 patients received cefazolin, 3 excluded because of receiving > 1 dose, 2 no detectable levels.

FComparison (n)

io = intra-osseously administered (ref 14)

GMean age (SD)

When only median [range] are reported, values were transformed into estimated mean and standard deviation by using the calculations

from Hozo et al. (2005), estimations are given in italics.

^c For all patients, not just intervention group.

HMale sex (%)

IWeight

See G for values in italics.

JType of surgery (n)

KTourniquet use

^d in TKA

LTiming of antibiotic administration

< = before

TQ = tourniquet

MMIC reported (µg/mL)

Table 2. Cefazolin dose and site of measurement of included studies

Site	Dose	Reference
Hip	1 g	Bryan et al. (1988)
		Cunha et al. (1977)
		Sharareh et al. (2016)
		Sorensen et al. (1978)
		Williams et al. (1983)
	2 g	Sharareh et al. (2016)
		Williams et al. (1983)
		Yamada et al. (2011)
	Other	Parsons et al. (1978), 4 g cefazolin
		Polk et al. (1983), 10 mg/kg (mean: 684 (108) mg)
Knee	1 g	Angthong et al. (2015)
		Bryan et al. (1988)
		Cunha et al. (1984)
		Friedman et al. (1990)
		Sharareh et al. (2016)
		Williams et al. (1983)
		Young et al. (2013)
	2 g	Angthong et al. (2015
		Sharareh et al. (2016)
		Williams et al. (1983)
		Yamada et al. (2011)
Foot	1 g	Deacon et al. (1996)
Shoulder	1 g	Miller et al. (2004)

Figure 2. Risk of bias analysis, according to Newcastle–Ottawa Scale (NOS) (Wells et al2013).

+: low risk of bias/good quality,

–: high risk of bias/poor quality,

?: unknown risk of bias/unclear or not applicable (e.g., comparability of cohorts in studies where only one group received intravenously administered cefazolin).

A green “+” matches with a star on the NOS.

Table 3. Soft tissue target site cefazolin concentrations

Site Author (year)	n/dose	Time of sample min (SD)	Concentration µg/g (SD)
Hip capsule
Parsons et al. (1978)	6/4 g	64 (26)	35 (24)
Knee
Cunha et al. (1984)	13/1 g	ND	8 mg/L
Friedman et al. (1990)^a	24/1 g	10	75%
		30	57%
		60	54%
Young et al. (2013)	11/1 g	26 (23)	11 (2.4)
Shoulder
Miller et al. (2004)	7/1 g	40	11

a See Table 3. ND = not data

Figure 3. Mean target site concentrations organized according to location of measurements. Mean or maximum target site concentrations of all included studies. When results were reported separately for individual patients or results were given for multiple time-points, these are depicted separately. The bar with the dotted line represents the reported MIC90 of Staphylococcus aureus (0.5–2.0 µg/L).

Table 4. Antibiotic concentrations organized by location of target site

Author (year)	Site	n/dose	Time of sample min (SD)	Concentration µg/g (SD)
Angthong et al. (2015)	Hip	14/1 g	52 (7)	22 (10)
	Hip	7/2 g	63 (23)	40 (16)
Bryan et al. (1988)	Hip	31/1 g	118 (49)	1.6 (1.4)
Cunha et al. (1977)	Hip	ND/1 g	40	30
Parsons et al. (1978)	Hip ^b	6/4 g	61 (31)	10 (2.9)
	Hip ^c	12/4 g	64 (26)	14 (2.3)
	Hip ^d	3/4 g	37 (28)	15 (3.3)
	Hip ^e	14/4 g	74 (30)	88 (23)
Polk et al. (1983)	Hip	9/ ^f	53 (20)	7.7 (4.8)
Sharareh et al. (2016)	Hip	11/1&2 g	ND	12 (6.7)
Sorensen et al. (1978)	Hip	1/1 g	45	12
Williams et al. (1983)	Hip	9/1 g	ND	6.9 (1.3)
		4/2 g	ND	18
Yamada et al. (2011)	Hip	16/2 g	64 (33)	32 (15)
Bryan et al. (1988)	Knee	11/1 g	107 (39)	0.64 (0.57)
Cunha et al. (1984)	Knee	13/1 g	30	11
Friedman et al. (1990) ^a	Knee	24/1 g	10	20%
			30	40%
			60	39%
Sharareh et al. (2016)	Knee	20/1&2 g	ND	6.0 (3.6)
Williams et al. (1983)	Knee	8/1 g	ND	4.7 (2.4)
		2/2 g	ND	7.8
Yamada et al. (2011)	Knee	27/2 g	63 (19)	16 (10)
Young et al. (2013)	Knee	11/1 g	34 (20)	11 (2.5)
Deacon et al. (1996)	Foot	25/1 g	70	2.4
Miller et al. (2004)	Shoulder	7/1 g	40	36

a Multiple samples, results are in percentage of patients achieving a

concentration > 4 µg/g (MIC).

b acetabulum,

c proximal femur,

d cortical shaft,

e hip ground up

f 10 mg/kg

ND = not data

Table 5. Antibiotic bone concentrations organized by dose

Dose Author (year)	Site	n	Time of sample min (SD)	Concentration µg/g (SD)
Cefazolin 1 g
Angthong et al. (2015)	Hip	14	52 (7)	22 (10)
Bryan et al. (1988)	Hip	31	118 (49)	1.6 (1.4)
	Knee	11	107 (39)	0.64 (0.57)
Cunha et al. (1977)	Hip	ND	40	30
Cunha et al. (1984)	Knee	13	30	11
Deacon et al. (1996)	Foot	25	70	2.4
Friedman et al. (1990) ^a	Knee	24	10	20%
			30	40%
			60	39%
Miller et al. (2004)	Shoulder	7	40	36
Sharareh et al. (2016)	H&K	4	ND	5.0 (3.1)
Sorensen et al. (1978)	Hip	1	45	12
Williams et al. (1983)	H&K	17	69	5.9
Young et al. (2013)	Knee	11	34 (20)	11 (2.5)
Cefazolin 2 g
Angthong et al. (2015)	Hip	7	63 (23)	40 (16)
Sharareh et al. (2016)	H&K	27	ND	8.3 (5.6)
Williams et al. (1983)	H&K	6	51	15
Yamada et al. (2011)	H&K	42	63 (25)	22 (15)
Other dose
Polk et al. (1983)^f	Hip	9	53 (20)	7.7 (4.8)
Parsons et al. (1978) ^g	Hip ^b	6	61 (31)	10 (2.9)
	Hip ^c	12	64 (26)	14 (2.3)
	Hip ^d	3	37 (28)	15 (3.3)
	Hip ^e	14	74 (30)	88 (23)

a See Table 3

b acetabulum,

c proximal femur,

d cortical shaft,

e hip ground up

f 10 mg/kg,

g Cefazolin 4 g

H&K = Hip and knee

ND = not data

Figure 4. Mean target site concentrations organized according to dose of cefazolin. Mean or maximum target site concentrations of all included studies. When results were reported separately for individual patients or results were given for multiple time points, these are depicted separately. The bar with the dotted line represents the reported MIC90 of Staphylococcus aureus (0.5–2.0 µg/L).

Figure 5. Pooled results: mean target site concentrations compared by location of measurement.

Figure 6. Pooled results: mean target site bone concentrations compared by dose. Due to the small number of studies for this outcome, no predictive interval was computed

Angthong C, Krajubngern P, Tiyapongpattana W, Pongcharoen B, Pinsornsak P, Tammachote N, Kittisupaluck W. Intraosseous concentration and inhibitory effect of different intravenous cefazolin doses used in preoperative prophylaxis of total knee arthroplasty. J Orthop Traumatol 2015; 16(4): 331–4.

 PubMed Web of Science ®Google Scholar

Bryan C S, Morgan S L, Caton R J, Lunceford E M. Cefazolin versus cefamandole for prophylaxis during total joint arthroplasty. Clin Orthop Relat Res 1988; (228): 117–22.

 Google Scholar

Cunha B A, Gossling H R, Pasternak H S, Nightingale C H, Quintiliani R. The penetration characteristics of cefazolin, cephalothin, and cephradine into bone in patients undergoing total hip replacement. J Bone Joint Surg Am 1977; 59(7): 856–9.

 PubMed Web of Science ®Google Scholar

Cunha B A, Gossling H R, Pasternak H S, Nightingale C H, Quintiliani R. Penetration of cephalosporins into bone. Infection 1984; 12(2): 80–4.

 PubMed Web of Science ®Google Scholar

Deacon J S, Wertheimer S J, Washington J A. Antibiotic prophylaxis and tourniquet application in podiatric surgery. J Foot Ankle Surg 1996; 35(4): 344–9.

 PubMedGoogle Scholar

Friedman R J, Friedrich L, White R L, Kays M B, Brundage D M, Graham J. Antibiotic prophylaxis and tourniquet inflation in total knee arthroplasty. Clin Orthop Relat Res 1990; (260): 17–23.

 PubMed Web of Science ®Google Scholar

Miller B S, Harper W P, Hughes J S, Sonnabend D H, Walsh W R. Regional antibiotic prophylaxis in elbow surgery. J Shoulder Elb Surg 2004; 13(1): 57–9.

 PubMed Web of Science ®Google Scholar

Parsons R L, Beavis J P, David J A, Paddock G M, Trounce J R. Plasma, bone, hip capsule, and drain fluid concentrations of cephazolin during total hip replacement. Br J Clin Pharmac 1978; 5: 331–6.

 Web of Science ®Google Scholar

Polk R, Hume A, Kline B J, Cardea J. Penetration of moxalactam and cefazolin into bone following simultaneous bolus or infusion. Clin Orthop Relat Res 1983; 177(7): 216–21.

 Google Scholar

Sharareh B, Sutherland C, Pourmand D, Molina N, Nicolau D P, Schwarzkopf R. Effect of body weight on cefazolin and vancomycin trabecular bone concentrations in patients undergoing total joint arthroplasty. Surg Infect (Larchmt) 2016; 17(1): 71–7.

 PubMed Web of Science ®Google Scholar

Sørensen T S, Colding H, Schroeder E, Rosdahl V T. The penetration of cefazolin, erythromycin and methicillin into human bone tissue. Acta Orthop 1978; 49(6): 549–53.

 Web of Science ®Google Scholar

Williams D N, Gustilo R B, Beverly R, Kind A C. Bone and serum concentrations of five cephalosporin drugs: relevance to prophylaxis and treatment in orthopedic surgery. Clin Orthop Relat Res 1983; (179): 253–65.

 PubMed Web of Science ®Google Scholar

Yamada K, Matsumoto K, Tokimura F, Okazaki H, Tanaka S. Are bone and serum cefazolin concentrations adequate for antimicrobial prophylaxis? Clin Orthop Relat Res 2011; 469(12): 3486–94.

 PubMed Web of Science ®Google Scholar

Young S W, Zhang M, Freeman J T, Vince K G, Coleman B. Higher cefazolin concentrations with intraosseous regional prophylaxis in TKA knee. Clin Orthop Relat Res 2013; 471(1): 244–9.

 PubMed Web of Science ®Google Scholar

Hozo S P, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005; 5: 13.

 PubMedGoogle Scholar

Wells G A, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa Hosp Res Inst 2013; (3): 1–4.

 Google Scholar