Intraoperative Redosing of Surgical Antibiotic Prophylaxis in Addition to Preoperative Prophylaxis Versus Single-Dose Prophylaxis for the Prevention of Surgical Site Infection

A Meta-Analysis and GRADE Recommendation

Niels Wolfhagen, MD; Quirine J. J. Boldingh, MD; Mats de Lange, MD; Marja A. Boermeester, MD, PhD; Stijn W. de Jonge, MD

Disclosures

Annals of Surgery. 2022;275(6):1050-1057.

Abstract and Introduction

Abstract

Objective: The aim of this study was to determine the effect of preoperative surgical antibiotic prophylaxis (SAP) with additional intraoperative redosing compared to single-dose preoperative surgical antibiotic prophylaxis on the incidence of surgical site infections (SSI).

Summary Background Data: Preoperative SAP is standard care for the prevention of SSI. During long surgical procedures, additional intraoperative redosing of SAP is advised, but there is great variability in redosing strategies and compliance rates.

Methods: We performed a systematic search of MEDLINE (PubMed), Embase, CINAHL and CENTRAL on June 25^th, 2021 according to PROSPERO registration CRD42021229035. We included studies that compared the effect of preoperative SAP with additional intraoperative redosing to single dose preoperative SAP (no redosing) on SSI incidence in patients undergoing any type of surgery. Two researchers performed data appraisal and extraction of summary data independently. Meta-analyses were stratified per study type. We used a generic inverse variance random-effects model to estimate a pooled odds ratio with corresponding 95% confidence intervals (CIs).

Results: We included 2 randomized controlled trials (RCT) and 8 cohort studies comprising of 9470 patients. Pooled odds ratios for SSI in patients receiving intraoperative redosing compared to those without redosing were 0.47 (95% CI: 0.19–1.16. I ² = 36%) for RCTs and 0.55 (95% CI: 0.38–0.79, I ² = 56%) for observational cohorts. There was considerable clinical heterogeneity among antibiotics used and redosing protocols. GRADE-assessment showed overall low certainty of evidence.

Conclusion: Intraoperative redosing of SAP may reduce incidence of SSI compared to a single dose preoperative SAP in any type of surgery, based on studies with considerable heterogeneity of antibiotic regimens and redosing protocols.

Introduction

Surgical site infections (SSI) are a common postoperative complication associated with increased hospital stay, morbidity and mortality.^[1–4] Surgical antibiotic prophylaxis (SAP) is an effective intervention for the prevention of SSI in indicated procedures.^[5] However, administration of antibiotics also has a dose and duration dependent association with adverse effects including the emergence of antibiotic resistance.^[6] Therefore, SAP strategies aim to be both optimally effective and restrictive on the amount of antibiotics administered. Administration of SAP before incision is advised but postoperative continuation is discouraged.^[7–9]

Evidence of the effect of timely preoperative administration of SAP suggest that adequate tissue concentration is needed at the time of incision and throughout the procedure for SAP to be effective.^[10–12] Similarly, inadequate antibiotic tissue concentration upon wound closure is associated with increased risk of SSI^[13] and the redundancy of postoperative continuation of antibiotics depends on timely preoperatively administration and intraoperative redosing.^[14] Tissue concentration depends on pharmacokinetics, pharmacodynamics, the initial dose, and the time passed since the initial dose.^[15,16] Long procedure duration or excessive blood loss may decrease antibiotic tissue levels, potentially below effective concentrations.^[15,16] Intraoperative redosing of SAP increases tissue concentration and has been suggested during longer procedures or after excessive blood loss to help prevent SSI.^[5] There is some clinical evidence to support this hypothesis.^[17,18]

Recent guidelines have assessed redosing of SAP either as out of scope,^[7] deemed too few randomized trials available for proper analysis and recommendation^[8] or recommend to give a repeat dose if the surgical procedure is longer than the half-life of the antibiotic.^[9] However, the latter recommendation is presented without support of evidence.^[9,19] An earlier guideline on SAP by the American Society of Hospital Pharmacists (ASHP) recommended redosing of SAP in long procedures defined as exceeding 2 half-lives of the antimicrobial agent or procedures with excessive blood loss.^[5] Local SAP protocols, such as the American Surgical Care Improvement Programme, also advise redosing of SAP in surgical procedures lasting longer than 2 times the half-life of the antibiotic given.^[20,21] Unfortunately, reported compliance is low.^[22,23] The conflicting recommendations leave patients and practitioners in uncertainty and inevitably lead to suboptimal care in some cases. To our knowledge no systematic review on the effect of SAP redosing on SSI risk has been performed.

We performed a systematic review and meta-analysis to assess the effect of intraoperative redosing in addition to preoperative SAP compared to a single dose of preoperative SAP on the incidence of SSI. We hypothesized that intraoperative redosing of SAP reduces the risk of SSI.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Study Characteristics
Author, Year	No. of patients	Type of Surgery	Minimal Length Surgery	Antibiotic Class	Antibiotic Regimen	Redosing Strategy (RCT) or Analysis Definition of Redosing (OBS) & t1/2*	SAP Timing (Min. pre-incision)	Postoperative SAP	Reported Primary Outcome	Covariates Adjusted For
Randomized controlled trials
Colombo et al, 1998³³	448	Gynecologic surgery	120 min	Penicillin	Ampicillin (2 g) and sulbactam (1 g)	120 min after incision (t1/2: 0.8–1.3)	15	None	C: 32/223 I: 20/225	—
Scher, 1997³⁴	296	Urology, otorhinolaryngology, general, thoracic surgery	180 min	First-generation cephalosporin	Cefazolin (1g)	180 min after initial dose (t1/2: 1.2–2.2)	15–30	None	C: 9/147 I: 2/149	—
Prospective observational cohort studies
de Jonge et al, 2021²³	671	General, orthopedic and gynecologic surgery	240 min	Cephalosporin, quinolone	Cefuroxime and clindamycin, cefuroxime, cefamandole, other	Redose after 2 times t1/2 or >1.5 L blood loss. (t1/2: 1–2)	< 120 (96%)Other (4%)	None	aOR: 0.60 (0.32–1.12)	Diabetes, use immunosuppressant, wound class, implantations
Steinberg et al, 2009²²	512	Cardiac, orthopedic, gynecologic surgery	240 min	Cephalosporin, macrolide, quinolone, glycopeptide	Cephalosporin, cephalosporin and vancomycin, vancomycin, fluoroquinolones	240 min after start but before the end of surgery (t1/2: 1.2–2.2)	< 60	Varying from none up to 48 h	1) aOR: 0.32 (0.08–1.36) 2) aOR: 1.02 (0.23–4.54)	Hospital, period of measurement, group status, procedure type, procedure duration, ASA score
Retrospective observational cohort studies
Bertschi, 2019³⁵	593	Abdominal, vascular and trauma surgery	240 min	Cephalosporin, other	Cefuroxime (1.5 g) with/without metronidazole (0.5 g)^†	Any intraoperative administration before wound closure (t1/2: 1–2)	<120	None	aOR: 0.60 (0.37–0.96)	Wound class, ASA, elective vs emergency
Kasatpibal et al, 2017¹⁷	4001	General surgery	n.a.	First-generation cephalosporin, Macrolide, Quinolone	Cefazolin, cefazolin and metronidazole, ciprofloxacin and metronidazole, clindamycin, other	Redose after 1–2 times t1/2 (t1/2: 1.2–2.2)	<60	None	aRR: 0.22 (0.06–0.75)	Sex, race, in-patient status, origin status, smoking, serum albumin, ASA classification, Emergency surgery, Operative procedure, incision classification, duration of surgery, multiple procedures, antibiotic agent, insulin, crystalloids, colloids, transfusion, blood loss
Morita et al, 2005³⁶	96	Colorectal surgery	240 min after SAP	Cephalosporin	Cephalosporin (1 g)	240 min after initial SAP (t1/2: 1.2–2.2)	<60	Yes, unspecified	aOR: 0.09 (0.02–0.53)	Protocol of administration, DM, procedure, operating time
Zanetti et al, 2001¹⁸	1548	Cardiac surgery	240 min	First-generation cephalosporin	Cefazolin (1 g)	Any intraoperative administration before wound closure (t1/2: 1.2–2.2)	< 90	6 additional gifts	1) aOR: 1.27 (0.80–2.02) 2) aOR: 0.44 (0.23–0.85)	Procedure duration, surgeon
Zhang, 2015³⁷	547	Colorectal or hepatobiliary surgery	240 min	First-generation cephalosporin, macrolide, glyco -peptide, other	Cefazolin (2 g) (and metronidazole [0.5 g]), gentamycin (2 mg/kg), and clindamycin (0.6 g), gentamycin (2 mg/kg), and metronidazole (0.5 g)	Every 3 to 12 ho depending on SAP, based on initial timing of preoperative dose (t1/2: 1.2–2.2)	n.a.	None	aOR: 0.65 (0.35 – 1.22)	Age, operating time
Zhang et al, 2019³⁸	1840	Cardiothoracic, orthopedic, vascular, abdominal, and neurosurgery. All patients had diabetes	240 min	First-generation cephalosporin	Most commonly; cefazolin	240 min After initial dose (t1/2: 1.2–2.2)	< 60	n.a.	aOR: 0.43 (0.24–0.78)	Sex, ASA, operation location, hypertension, blood glucose control, WBC

*Agent with shortest t1/2.
†Both antibiotics double dosage if patients weigh >80 kg, In cases of known or suspected allergies to these antibiotics, vancomycin (1 g), gentamicin (4 mg/Kg), and metronidazole or clindamycin (300 mg) with or without ciprofloxacin (400 mg) were used as alternative treatments.
^‡Time between closure and first gift.
aOR indicates adjusted odds ratio; aRR, adjusted relative risk; C, control; I, intervention; min, minutes; n.a., not available; t1/2, half-life.

Table 2. Half-Life of Antibiotics in Adults With a Normal Renal Function ⁵
Antibiotic	Antibiotic Class	Recommended Dose	Half–Life, h
Ampicillin + sulbactam	Penicillin	3 g	0.8–1.3
Cefazolin	First-generation cephalosporin	2 g	1.2–2.2
Cefuroxime	Second-generation cephalosporin	1.5 g	1–2
Cefotaxime	Third-generation cephalosporin	1 g	0.9–1.7
Cefoxitin	Second-generation cephalosporin	2 g	0.7–1.1
Clindamycin	Macrolide	900 mg	2–4
Ciprofloxacin	Quinolone	400 mg	3–7
Levofloxacin	Quinolone	500 mg	6–8
Piperacillin-tazobactam	Penicillin	3.375 g	0.7–1.2
Vancomycin	Glycopeptide	15 mg/kg	4–8
Metronidazole	Other	1 g	6–8

Table 3. GRADE Summary of Findings Table
Certainty Assessment							no of Participant		Effect		Certainty of Evidence (GRADE)	Importance
No. of studies	Study Design	Risk of Bias	Inconsistency	Indirectness	Imprecision	Other Biases	SSI Additional Intraoperative Redosing of SAP	SSI Preoperative Single-dose Prophylaxis	Relative Effect (95% CI)	Absolute Effect (95% CI)	Certainty of Evidence (GRADE)	Importance
Surgical site infections—randomized controlled trials
2	Randomized controlled trials	Serious	No	No	Serious	No other biases	22/372 (5.9%)	41/270 (15.2%)	OR 0.47 (0.19–1.16)	74 Fewer per 1.000 (119 fewer to 20 more)	⊕⊕ LOW	CRUCIAL
Surgical site infections—observational cohort studies
8	Observational cohort studies	Serious	No	No	No	Publication bias suspected; residual confounding may cause underestimation	NA	NA	OR 0.55 (0.38–0.79)	NA	⊕ VERY LOW	CRUCIAL