Evaluation of Prolonged vs Short Courses of Antibiotic Prophylaxis Following Ear, Nose, Throat, and Oral and Maxillofacial Surgery: A Systematic Review and Meta-analysis | Facial Plastic Surgery | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Figure 1.  Flow Diagram of Literature Search and Article Inclusion
Flow Diagram of Literature Search and Article Inclusion

SSI indicates surgical site infection.

Figure 2.  Risk of Bias in the Included Studies
Risk of Bias in the Included Studies
Figure 3.  Forest Plot of the Results of Meta-analysis
Forest Plot of the Results of Meta-analysis

The included studies and their corresponding numbers of patients, with risk ratios (RRs) and 95% confidence intervals (CIs), are outlined on the left. Results were plotted for ear, nose, throat (ENT), and oral and maxillofacial (OMF) surgery separately, and also for the total results. A relative risk greater than 1 favors the use of short-course antibiotic prophylaxis, while a relative risk less than 1 favors the use of extended-course antibiotic prophylaxis.

Table.  Study Characteristics of Included ENT and OMF Studies
Study Characteristics of Included ENT and OMF Studies
1.
Bratzler  DW, Dellinger  EP, Olsen  KM,  et al; American Society of Health-System Pharmacists (ASHP); Infectious Diseases Society of America (IDSA); Surgical Infection Society (SIS); Society for Healthcare Epidemiology of America (SHEA).  Clinical practice guidelines for antimicrobial prophylaxis in surgery.  Surg Infect (Larchmt). 2013;14(1):73-156. doi:10.1089/sur.2013.9999PubMedGoogle ScholarCrossref
2.
Ottoline  AC, Tomita  S, Marques  MdaP, Felix  F, Ferraiolo  PN, Laurindo  RS.  Antibiotic prophylaxis in otolaryngologic surgery.  Int Arch Otorhinolaryngol. 2013;17(1):85-91.PubMedGoogle Scholar
3.
Simo  R, French  G.  The use of prophylactic antibiotics in head and neck oncological surgery.  Curr Opin Otolaryngol Head Neck Surg. 2006;14(2):55-61. doi:10.1097/01.moo.0000193183.30687.d5PubMedGoogle ScholarCrossref
4.
Zegers  S, Dieleman  J, van der Bruggen  T, Kimpen  J, de Jong-de Vos van Steenwijk  C.  The influence of antibiotic prophylaxis on bacterial resistance in urinary tract infections in children with spina bifida.  BMC Infect Dis. 2017;17(1). doi:10.1186/s12879-016-2166-yGoogle Scholar
5.
Chandra  RK, Conley  DB, Kern  RC.  Prophylactic I.V. antibiotics in functional endoscopic sinus surgery: trends and attitudes of the American Rhinologic Society membership.  Am J Rhinol Allergy. 2009;23(4):448-450. doi:10.2500/ajra.2009.23.3349PubMedGoogle ScholarCrossref
6.
Colgan  SJ, Mc Mullan  C, Davies  GE, Sizeland  AM.  Audit of the use of antimicrobial prophylaxis in nasal surgery at a specialist Australian hospital.  ANZ J Surg. 2005;75(12):1090-1095. doi:10.1111/j.1445-2197.2005.03624.xPubMedGoogle ScholarCrossref
7.
Grunebaum  LD, Reiter  D.  Perioperative antibiotic usage by facial plastic surgeons: national survey results and comparison with evidence-based guidelines.  Arch Facial Plast Surg. 2006;8(2):88-91. doi:10.1001/archfaci.8.2.88PubMedGoogle ScholarCrossref
8.
Higgins  JP, Altman  DG, Gøtzsche  PC,  et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.  BMJ. 2011;343:d5928. doi:10.1136/bmj.d5928PubMedGoogle ScholarCrossref
9.
Effective Practice and Organisation of Care (EPOC).  Data Collection Form: EPOC Resources For Review Authors. Oslo, Norway: Norwegian Knowledge Centre for the Health Services; 2013.
10.
Andrews  PJ, East  CA, Jayaraj  SM, Badia  L, Panagamuwa  C, Harding  L.  Prophylactic vs postoperative antibiotic use in complex septorhinoplasty surgery: a prospective, randomized, single-blind trial comparing efficacy.  Arch Facial Plast Surg. 2006;8(2):84-87. doi:10.1001/archfaci.8.2.84PubMedGoogle ScholarCrossref
11.
Bartella  AK, Kamal  M, Teichmann  J,  et al.  Prospective comparison of perioperative antibiotic management protocols in oncological head and neck surgery.  J Craniomaxillofac Surg. 2017;45(7):1078-1082. doi:10.1016/j.jcms.2017.04.001PubMedGoogle ScholarCrossref
12.
Bidkar  VG, Jalisatigi  RR, Naik  AS,  et al.  Perioperative only versus extended antimicrobial usage in tympanomastoid surgery: a randomized trial.  Laryngoscope. 2014;124(6):1459-1463. doi:10.1002/lary.24544PubMedGoogle ScholarCrossref
13.
Carroll  WR, Rosenstiel  D, Fix  JR,  et al.  Three-dose vs extended-course clindamycin prophylaxis for free-flap reconstruction of the head and neck.  Arch Otolaryngol Head Neck Surg. 2003;129(7):771-774. doi:10.1001/archotol.129.7.771PubMedGoogle ScholarCrossref
14.
Liu  SA, Tung  KC, Shiao  JY, Chiu  YT.  Preliminary report of associated factors in wound infection after major head and neck neoplasm operations—does the duration of prophylactic antibiotic matter?  J Laryngol Otol. 2008;122(4):403-408. doi:10.1017/S0022215107007529PubMedGoogle ScholarCrossref
15.
Mustafa  E, Tahsin  A.  Cefotaxime prophylaxis in major non-contaminated head and neck surgery: one-day vs. seven-day therapy.  J Laryngol Otol. 1993;107(1):30-32. doi:10.1017/S0022215100122054PubMedGoogle ScholarCrossref
16.
Rajan  GP, Fergie  N, Fischer  U, Romer  M, Radivojevic  V, Hee  GK.  Antibiotic prophylaxis in septorhinoplasty? A prospective, randomized study.  Plast Reconstr Surg. 2005;116(7):1995-1998. doi:10.1097/01.prs.0000191181.73298.b3PubMedGoogle ScholarCrossref
17.
Righi  M, Manfredi  R, Farneti  G, Pasquini  E, Cenacchi  V.  Short-term versus long-term antimicrobial prophylaxis in oncologic head and neck surgery.  Head Neck. 1996;18(5):399-404. doi:10.1002/(SICI)1097-0347(199609/10)18:5<399::AID-HED2>3.0.CO;2-0PubMedGoogle ScholarCrossref
18.
Abubaker  AO, Rollert  MK.  Postoperative antibiotic prophylaxis in mandibular fractures: a preliminary randomized, double-blind, and placebo-controlled clinical study.  J Oral Maxillofac Surg. 2001;59(12):1415-1419. doi:10.1053/joms.2001.28272PubMedGoogle ScholarCrossref
19.
Baliga  SD, Bose  A, Jain  S.  The evaluation of efficacy of post-operative antibiotics in the open reduction of the zygomatic and mandibular fracture: a prospective trial.  J Maxillofac Oral Surg. 2014;13(2):165-175. doi:10.1007/s12663-013-0492-9PubMedGoogle ScholarCrossref
20.
Bentley  KC, Head  TW, Aiello  GA.  Antibiotic prophylaxis in orthognathic surgery: a 1-day versus 5-day regimen.  J Oral Maxillofac Surg. 1999;57(3):226-230. doi:10.1016/S0278-2391(99)90664-XPubMedGoogle ScholarCrossref
21.
Bhathena  HM, Kavarana  NM.  Prophylactic antibiotics administration head and neck cancer surgery with major flap reconstruction: 1-day cefoperazone versus 5-day cefotaxime.  Acta Chir Plast. 1998;40(2):36-40.PubMedGoogle Scholar
22.
Cioacã  RE, Bucur  A, Coca-Nicolae  C, Coca  CA.  Vergleichende Studie zur klinischen Effizienz der Antibiotikaprophylaxe in der aseptischen Mund-, Kiefer- und Gesichtschirurgie.  Mund Kiefer Gesichtschir. 2002;6(5):356-359. doi:10.1007/s10006-002-0376-5PubMedGoogle ScholarCrossref
23.
Davis  CM, Gregoire  CE, Davis  I, Steeves  TW.  Prevalence of surgical site infections following orthognathic surgery: a double-blind, randomized controlled trial on a 3-day vs 1-day postoperative antibiotic regimen.  J Oral Maxillofac Surg. 2017;75(4):796-804. doi:10.1016/j.joms.2016.09.038PubMedGoogle ScholarCrossref
24.
Johnson  JT, Schuller  DE, Silver  F,  et al.  Antibiotic prophylaxis in high-risk head and neck surgery: one-day vs. five-day therapy.  Otolaryngol Head Neck Surg. 1986;95(5):554-557. doi:10.1177/019459988609500506PubMedGoogle ScholarCrossref
25.
Kang  SH, Yoo  JH, Yi  CK.  The efficacy of postoperative prophylactic antibiotics in orthognathic surgery: a prospective study in Le Fort I osteotomy and bilateral intraoral vertical ramus osteotomy.  Yonsei Med J. 2009;50(1):55-59. doi:10.3349/ymj.2009.50.1.55PubMedGoogle ScholarCrossref
26.
López-Cedrún  JL, Pijoan  JI, Fernández  S, Santamaria  J, Hernandez  G.  Efficacy of amoxicillin treatment in preventing postoperative complications in patients undergoing third molar surgery: a prospective, randomized, double-blind controlled study.  J Oral Maxillofac Surg. 2011;69(6):e5-e14. doi:10.1016/j.joms.2011.01.019PubMedGoogle ScholarCrossref
27.
Miles  BA, Potter  JK, Ellis  E  III.  The efficacy of postoperative antibiotic regimens in the open treatment of mandibular fractures: a prospective randomized trial.  J Oral Maxillofac Surg. 2006;64(4):576-582. doi:10.1016/j.joms.2006.01.003PubMedGoogle ScholarCrossref
28.
Schaller  B, Soong  PL, Zix  J, Iizuka  T, Lieger  O.  The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomized, double-blind, placebo-controlled pilot clinical study: part 2, mandibular fractures in 59 patients.  Br J Oral Maxillofac Surg. 2013;51(8):803-807. doi:10.1016/j.bjoms.2013.08.008PubMedGoogle ScholarCrossref
29.
Soong  PL, Schaller  B, Zix  J, Iizuka  T, Mottini  M, Lieger  O.  The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomised, double-blind, placebo-controlled pilot clinical study: part 3, Le Fort and zygomatic fractures in 94 patients.  Br J Oral Maxillofac Surg. 2014;52(4):329-333. doi:10.1016/j.bjoms.2014.01.010PubMedGoogle ScholarCrossref
30.
Zix  J, Schaller  B, Iizuka  T, Lieger  O.  The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomised, double-blind, placebo-controlled pilot clinical study: part 1, orbital fractures in 62 patients.  Br J Oral Maxillofac Surg. 2013;51(4):332-336. doi:10.1016/j.bjoms.2012.08.008PubMedGoogle ScholarCrossref
31.
Valent  A, DeArmond  C, Houston  J,  et al.  Effect of post–cesarean delivery oral cephalexin and metronidazole on surgical site infection among obese women.  Obstet Gynecol Surv. 2018;73(2):85-87. doi:10.1097/01.ogx.0000530381.99105.a9Google ScholarCrossref
32.
Vila  PM, Zenga  J, Jackson  RS.  Antibiotic prophylaxis in clean-contaminated head and neck surgery: a systematic review and meta-analysis.  Otolaryngol Head Neck Surg. 2017;157(4):580-588. doi:10.1177/0194599817712215PubMedGoogle ScholarCrossref
33.
Haidar  YM, Tripathi  PB, Tjoa  T,  et al.  Antibiotic prophylaxis in clean-contaminated head and neck cases with microvascular free flap reconstruction: a systematic review and meta-analysis.  Head Neck. 2018;40(2):417-427. doi:10.1002/hed.24988PubMedGoogle ScholarCrossref
34.
Blair  EA, Johnson  JT, Wagner  RL, Carrau  RL, Bizakis  JG.  Cost analysis of antibiotic prophylaxis in clean head and neck surgery.  Arch Otolaryngol Head Neck Surg. 1995;121(3):269-271. doi:10.1001/archotol.1995.01890030011002PubMedGoogle ScholarCrossref
Original Investigation
May 9, 2019

Evaluation of Prolonged vs Short Courses of Antibiotic Prophylaxis Following Ear, Nose, Throat, and Oral and Maxillofacial Surgery: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Division of Medical Microbiology and Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
  • 2Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 3Division of Ear, Nose, and Throat Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 4Division of Oral and Maxillofacial Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
JAMA Otolaryngol Head Neck Surg. 2019;145(7):610-616. doi:10.1001/jamaoto.2019.0879
Key Points

Question  Is there a difference in outcome associated with a short course of antibiotic prophylaxis (≤24 hours) vs an extended course of antibiotic prophylaxis (≥72 hours) for preventing surgical site infections after ear, nose, throat (ENT), and oral and maxillofacial (OMF) surgery?

Findings  In this systematic review and meta-analysis, which included 21 articles and 1974 patients, no significant differences were found in the relative risks of developing surgical site infections after receiving short-course antibiotic prophylaxis vs extended-course antibiotic prophylaxis.

Meaning  These findings suggest that short-course antibiotic prophylaxis should be used for standard ENT and OMF surgery, unless there are documented conditions that would be best treated with an extended course.

Abstract

Importance  Antibiotic prophylaxis is widely used after surgical procedures operating on the mucosal tissues of the aerodigestive tract, but the optimal duration of these prophylactic therapies is often unclear.

Objective  To compare short-course antibiotic prophylaxis (≤24 hours) vs extended-course antibiotic prophylaxis (≥72 hours) after ear, nose, throat, and oral and maxillofacial surgery.

Data Sources and Study Selection  Literature searches of PubMed were completed in October 2017 and included prospective trials that compared antibiotic prophylaxis courses of 24 hours or less vs 72 hours or more after ear, nose, throat, and oral and maxillofacial surgery. Some studies were also handpicked from reference lists of studies found with the initial search terms. All analysis was performed between September 2017 and October 2018.

Data Extraction and Synthesis  All review stages were conducted in consensus by 2 reviewers. Data extraction and study quality assessment were performed with the Cochrane data extraction form and the Cochrane risk of bias tool. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for reporting. The fixed-effects Mantel-Haenszel method was used for meta-analysis.

Main Outcomes and Measures  Relative risk (RR) of surgical site infections, microbial origins of surgical site infections, adverse events, duration of hospital stay, and treatment costs.

Results  Included in the meta-analysis were 21 articles with a cumulative 1974 patients. In patients receiving 24 hours or shorter vs 72 hours or longer antibiotic prophylaxis regimens, no significant difference was found in the occurrence of postoperative infections in the pooled population (RR, 0.90; 95% CI, 0.67-1.19), or in the ear, nose, throat (RR, 0.89; 95% CI, 0.54-1.45), and oral and maxillofacial populations (RR, 0.88; 95% CI, 0.63-1.21), separately. No heterogeneity was observed overall or in the subgroups. Patients receiving extended-course antibiotic prophylaxis were significantly more likely to develop adverse events unrelated to the surgical site (RR, 2.40; 95% CI, 1.20-3.54).

Conclusions and Relevance  No difference was found in the occurrence of postoperative infections between short-course and extended-course antibiotic prophylaxis after ear, nose, throat, and oral and maxillofacial surgery. Therefore, a short course of antibiotic prophylaxis is recommended unless documented conditions are present that would be best treated with an extended course. Using short-course antibiotics could avoid additional adverse events, antibiotic resistance development, and higher hospital costs. Future research should focus on identifying risk groups that might benefit from prolonged prophylaxis.

Introduction

To prevent surgical site infections (SSIs), antibiotic prophylaxis is used in most surgical interventions where the surgical site is either clean-contaminated or contaminated.1,2 This is the case in most otorhinolaryngologic (ENT) and oral and maxillofacial (OMF) surgical procedures because of the involvement of the mucosal tissues of the aerodigestive tract, which are covered with high loads of both aerobic and anaerobic bacteria, with the exclusion of tonsillectomies and adenoidectomies. This makes surgery in ENT and OMF sites prone to postoperative wound infections.1,2

Presently, existing evidence favors short-course postoperative prophylaxis (<24 hours) over prolonged prophylaxis (>72 hours), since little to no additional antiinfective benefits have been observed after prolonging the postoperative antibiotic prophylaxis period.1-3 In the clinical practice guideline for antimicrobial prophylaxis in surgery published by the Surgical Infection Society, most recommendations concerning surgical antibiotic prophylaxis in the head and neck region were graded with much lower evidence than the recommendations for urology, vascular surgery, neurosurgery, cardiac surgery, and gastroduodenal surgery.1 This contrast highlights the lack of evidence on the postoperative use of antimicrobial prophylaxis in the field of ENT and OMF surgery, especially after those procedures that invade contaminated tissues.

Despite the current lack of evidence, the fear of SSIs is still considerably larger than the fear of possible adverse effects or antimicrobial resistance resulting from prolonged antibiotic administration.3-7 As a result, antibiotic prophylaxis regimens are often prolonged when they might not be necessary.3-7 However, in light of the antimicrobial resistance issue, the increased risk of serious postoperative adverse effects, and additional pharmaceutical costs, it is becoming extremely difficult to ignore the need for solid evidence on the ideal duration of postoperative antibiotic prophylaxis. The aim of this study is to systematically review the literature and perform a meta-analysis focused on the association of SSIs with use of short-course antibiotic prophylaxis (≤24 hours) vs extended-course antibiotic prophylaxis (≥72 hours) after ENT and OMF surgery.

Methods
Search Strategy and Study Selection

A systematic literature PubMed search was conducted using the search terms listed in eAppendix 1 in the Supplement and was completed on October 9, 2017. All analysis was conducted between September 2017 and October 2018. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines checklist was used during the process of systematic review and meta-analysis (eTable 1 in the Supplement). Additionally, eligible articles were handpicked from the reference lists of studies during the initial search. Publications were included if they met the following inclusion criteria: (1) the study was a prospective clinical trial; (2) postsurgical infections were reported as a dichotomous outcome measure; and (3) the comparison of short-course antibiotic prophylaxis vs extended-course antibiotic prophylaxis was made. Short-course antibiotic prophylaxis was defined as a perioperative regimen of no longer than 24 hours, and extended-course antibiotic prophylaxis was defined as a perioperative regimen of at least 3 days. The type of antibiotic used was not a selection criterion.

Studies were excluded if they were written in a language other than English, Dutch, German, or French, or if full text was not available. The articles were screened for eligibility by the first 2 authors (M.C.O. and C.Z.).

Outcomes of Interest

The primary outcome of interest was SSI, defined according to the original study’s criteria and expressed as a relative risk (RR). Secondary outcome measures were the microbial origins of SSIs, differences in adverse events (expressed as RR), duration of hospital stay, and treatment costs for the 2 regimens. Postoperative complications and adverse events were defined as any adverse event not confined to the surgical site and included, among others, pruritus, nausea, diarrhea, and even death. Only studies that reported frequencies and types of adverse events for both their short- and long-course antibiotic regimens were included in this secondary analysis.

Risk of Bias Assessment

The Cochrane collaboration tool for assessing risk of bias in randomized trials8 was used for assessing the methodological quality of the included studies. The risk of bias assessment included randomization, allocation concealment, blinding of participants, personnel involved in the trials (ie, nursing staff, pharmacists, physicians, and outcome assessors), and incomplete outcome data. Bias assessment was performed by the first 2 coauthors separately (M.C.O. and C.Z.).

Data Extraction

Data extraction was performed by the first 2 coauthors independently (M.C.O. and C.Z.). To minimize bias, data from included studies were extracted using the 2013 Data Extraction Form9 provided by Cochrane. All relevant data for the present study can be extracted with this form, including information on study characteristics, participants, antibiotic regimens, and outcomes.

Statistical Analysis

Once data extraction was completed, the RRs of SSI and secondary outcomes were calculated from the data reported in the included studies. The RRs from each study were pooled using the Mantel-Haenszel method and visualized in a forest plot using the Microsoft Excel add-in MetaXL from EpiGear, version 5.3. Heterogeneity was assessed by the same software using the Cochrane Q test and I2 statistics. Heterogeneity was decided to be present if P < .10, or if the I2 value was 40% or greater.

Results
Identification of Eligible Studies

The flow diagram of the literature search for meta-analysis is shown in Figure 1. The initial search yielded 2318 potentially eligible articles. These articles were all evaluated based on the established inclusion and exclusion criteria. A total of 2301 were excluded. Four handpicked articles were added, totaling 21 articles for the meta-analysis.

Study Characteristics
Patients and Surgical Procedures

In total, 21 articles with 1974 cumulative participants were included in the meta-analysis, of which 1776 (90%) underwent surgery involving the mucosa of the aerodigestive tract (Table).10-30

Eight of the 21 articles concerned ENT surgery, and 13 articles concerned OMF surgery (Table).10-30 The combined 8 ENT surgery studies included a total of 841 patients (range, 50-200), of which 703 (84%) underwent surgery involving the aerodigestive tract. Two studies concerned tympanomastoid surgery,12 and major head and neck surgery explicitly without involvement of the aerodigestive tract15 (Table). In total, 1133 patients who underwent OMF surgery (range, 30-181) were included, and just 60 patients30 did not undergo surgery involving the aerodigestive tract (Table). The included OMF studies mainly concerned mandibular fracture and flap reconstruction. Eight of the 13 included trials studied mandibular fracture repairs; 2 of the 13 trials studied flap reconstruction procedures21,24; 1 trial studied orbital blowout fracture repairs30; another studied third molar surgical procedures26; and the final trial studied intraoral and extraoral orthognathic surgical procedures20 (Table).

Short- and Extended-Course Regimens

Short-course antibiotic regimens were similar for all included ENT and OMF studies. In both arms, most studies used a short-course regimen of 24 hours (ENT, 5 of 8; OMF, 8 of 13).10-30 Other short-course regimens were defined as 12 hours,10 intraoperatively only,11,20 or preoperatively only16,19,22,26,27 (Table). In contrast, differences in extended-course lengths existed between the OMF and ENT studies. Whereas most OMF studies (9 of 13) used an extended course of 5 days, half of the ENT studies (4 of 8) used an extended-course length of 7 or 8 days (Table).10-30

Short-course antibiotic prophylaxis regimens in both the OMF and ENT subgroups were administered preoperatively in all studies. However, Baliga et al19 and Miles et al27 did not specify when their short-course antibiotic regimens began.19,27 All but 1 study started administration of their extended antibiotic prophylaxis regimen at the same time as the short course.10 Andrews et al10 decided to only administer antibiotics postoperatively in the extended arm, whereas antibiotic prophylaxis was started at induction of anesthesia in the short arm.

Antibiotics Used

Generally, in both the ENT and OMF studies, β-lactams were the preferred antimicrobial agents of choice (ENT, 5 of 8; OMF, 13 of 13).10-30 The 3 studies that did not use β-lactam antibiotics each used clindamycin.13,14,17 Most studies used the same doses and routes of administration for their short- and extended-course regimens. The study by Miles et al27 did not mandate in their study protocol which antimicrobial agents had to be used for the preoperative period. Instead, preoperative antibiotics used during their trial varied between penicillin G with or without metronidazole, cephalosporins, or clindamycin.27 Finally, it should be noted that Cioacã et al22 performed 2 separate trials in their study, 1 trial in which they administered intravenous amoxicillin-clavulanic acid in both their short and extended treatment arms, and 1 trial in which they administered intravenous cefazolin in both short and extended treatment arms. A detailed overview of the antimicrobial agents used in all included studies can be found in eTable 2 in the Supplement.

Risk of Bias Assessment

After performing the risk of bias assessment, 1 study was marked as having a high risk of bias (Davis,23 2017) for risk of incomplete outcome data, owing to analyzing the number actually treated after a considerable loss to follow-up. In 1 study,26 no risk of bias was found. The other studies did not clearly report or perform a part of their randomization sequence generation, allocation concealment, or blinding protocols (Figure 2).10-30 A more detailed description of the risk of bias assessment can be found in eAppendix 2 of the Supplement.

Meta-analysis
Primary Outcome

No heterogeneity was found in the overall results (Q= 23.78; P= .30; I2 = 12%), either in the subgroups of ENT (Q = 9.35; P = .23; I2 = 25%) or OMF (Q = 15.40; P = .42; I2 = 3%). Therefore, RRs were pooled to perform the overall meta-analysis. Figure 3 presents these results visualized in a forest plot. The pooled RR of SSI for short-course regimens vs extended-course regimens was 0.90 (95% CI, 0.67-1.19), indicating that there was no difference in SSI between short-course and extended-course prophylaxis. Similar results were obtained for ENT and OMT operations: 0.89 (95% CI, 0.54-1.45) and 0.88 (95% CI, 0.63-1.21), respectively.

Secondary Outcomes
Microbial Etiology

Four ENT surgery studies10,11,14,15 (Andrews, 2006; Bartella, 2017; Liu, 2007; Mustafa, 1993) reported outcomes of microbiology analysis. Not enough data were available to compare protocol groups. Overall, Staphylococcus aureus (16 of 76; 21%) was the most common SSI-causing pathogen in the field of ENT, followed by Pseudomonas aeruginosa (11 of 76; 14%), Escherichia coli (9 of 76; 12%), and Klebsiella pneumoniae (8 of 76; 11%). Rarely reported species consisted of Branhamella catarrhalis, Salmonella, Morganella morganii, Citrobacter koseri, Acinetobacter baumannii, Haemophilus influenzae, and α-hemolytic streptococcus. A complete overview of the reported pathogens isolated from SSIs can be found in eTable 3 of the Supplement. One ENT study by Liu et al14 isolated multiple pathogens from the surgical site in almost half of the SSIs (6 of 14; 46.2%). Most of the SSIs in the study by Liu et al14 contained at least P aeruginosa (9 of 13; 69.2%). The 1 OMF surgery study mostly found Pseudomonas, Acinetobacter, and Enterococcus species, but did not clarify in what frequencies these pathogens were found.21

Adverse Events

In total, 9 studies reported on adverse events: 5 OMF studies22,26,28-30 and 4 ENT studies.12,13,16,17 This analysis therefore included a total of 920 patients, of which 32 who were given short-course prophylaxis developed adverse events compared with 77 patients in the extended-course prophylaxis groups (RR, 2.40; 95% CI, 1.20-3.54). The most common distant adverse event in the extended course was diarrhea (14 of 77; 18%), followed by nausea (11 of 77; 14%) and rash (8 of 77; 10%). In the short course, rash (5 of 32; 16%), gastric pain (3 of 32; 9%), and hyperpyrexia without localization (3 of 32; 9%) were the most commonly reported adverse events.

Some studies reported adverse effects other than SSI without clearly reporting their nature or location. In a separate sensitivity analysis of adverse events, these particular studies were excluded to ensure that the RR adequately represents distant adverse events and not surgical site issues. In this analysis (842 patients), 22 of 420 short course participants developed distant adverse effects, compared with 51 of 422 of participants in the long course (RR, 2.31; 95% CI, 1.43-3.73).

Other Secondary Outcomes

Other reported secondary outcomes included length of hospital stay, treatment costs, and pain scores. Five studies11,12,14,22,23 included length of hospital stay as a secondary outcome in their study, of which 4 did not find a significant difference in the length of hospital stay between the different regimens.11,14,22,23 The study by Bidkar et al12 found that the participants receiving the extended-course regimen were hospitalized significantly longer (mean days [SD], 3.05 [0.72]) than participants in the short-course regimen (2.36 [0.49]; P < .001).12 The study by Rajan et al16 reported treatment costs as a secondary outcome, and found that extended-course participants had significantly higher treatment costs per participant than the short-course participants ($93.45 Australian dollars vs $14.50; P = .04).16 These costs included the cost of treating adverse events.16

Discussion

This meta-analysis of 21 studies is, to our knowledge, the largest to date that has assessed SSI outcomes in short-course antibiotic prophylaxis (<24 hours) vs extended-course antibiotic prophylaxis (>72 hours) in a broad range of ENT and OMF surgical procedures. We found that short-course antibiotic prophylaxis was associated with similar rates of SSI as extended prophylaxis. However, an extended course of prophylactic antibiotics was associated with more than 2-fold increased risk of adverse events.

The similar SSI outcomes when using extended prophylaxis vs short-course prophylaxis in OMF and ENT patients is in line with other studies in this field and other fields of surgery. Nevertheless, risk groups may exist that substantially benefit from prolonged antibiotic prophylaxis where the general population does not. This has, for example, been found in women with obesity undergoing cesarean section.31 However, to date, such a subgroup has not been identified among patients undergoing OMF/ENT surgery, despite 2 meta-analyses addressing this question in more complex operations. The study by Vila et al32 compared the efficacy of prolonged prophylaxis with short prophylaxis in adults undergoing ENT oncology surgery in a meta-analysis of 4 studies, but found no differences.

Another recent meta-analysis by Haidar et al33 included studies on antibiotic prophylaxis in head and neck microvascular free-flap reconstruction, and showed an increased risk in patients receiving antibiotics for over 24 hours. However, after post hoc correcting for antibiotic type, this outcome proved to be caused by antibiotic choice (clindamycin) rather than duration.33 This illustrates the fact that the antibiotic should match the susceptibility profiles of the pathogens causing SSI, and that the choice of antibiotics besides dose and duration need careful consideration for every type of surgery.

Additional results showed that in patients undergoing an antibiotic prophylaxis regimen of more than 72 hours, an increased risk of adverse events was found as compared to those undergoing a regimen of (less than) 24 hours. Furthermore, the use of more antibiotics inherently leads to increased hospital costs, even costs unrelated to increased adverse events.34 Furthermore, it has widely been recognized that inappropriate use of antibiotics leads to antibiotic resistance, and needlessly prolonging antibiotic prophylaxis therefore contributes to the current antimicrobial resistance crisis.

Limitations

One limitation of this study was the sole use of the PubMed library for article extraction. However, since PubMed extracts references from MEDLINE, PMC, and NCBI, and the search term was not limited to MeSH controlled vocabulary, it is doubtful whether this has affected any outcomes. Furthermore, even though only the PubMed library was used, this meta-analysis is at present the largest in this field of surgery, to our knowledge. Another limitation of this meta-analysis is the lack of appropriate reporting or conducting randomization and blinding in the included studies. This might introduce bias, but it can be argued that randomization and blinding does not actually influence SSI development, so these studies were included. Moreover, there is a large amount of interest in this particular aspect of surgery as it relates to the use of implants; however, no articles comparing antibiotic prophylaxis regimens in implant surgery fit our inclusion criteria, so our findings cannot be extrapolated to these interventions. Finally, a limitation of the present study was the differences between included studies; every trial used different short-course and prolonged-course prophylaxis regimens and used different classes of antibiotics, which might have influenced the outcome of this literature study. However, most of the included studies reported an insignificant association between SSI and the different courses, and the studies that did find a significant association did not seem to be related to the same antibiotic agent, but this was not tested.

Conclusions

No association was found between SSI and antibiotic prophylaxis for 24 hours or less vs 72 hours or more after ENT and OMF surgery. However, administering antibiotic prophylaxis for an extended period was associated with significantly more adverse events compared with administering antibiotic prophylaxis up to 24 hours. These results suggest that short-course antibiotic prophylaxis is recommended unless risk groups are found to benefit from an extended course. In the future, placebo-controlled randomized clinical trials need to be conducted to identify these risk groups who might benefit from different protocols.

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Article Information

Accepted for Publication: March 21, 2019.

Corresponding Author: Heiman F. L. Wertheim, MD, PhD, Division of Medical Microbiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands (heiman.wertheim@radboudumc.nl).

Published Online: May 9, 2019. doi:10.1001/jamaoto.2019.0879

Author Contributions: Dr Wertheim had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: Oppelaar, Zijtveld, Kuipers, Oever, Wertheim.

Drafting of the manuscript: Oppelaar, Zijtveld, Wertheim.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Oppelaar, Zijtveld.

Administrative, technical, or material support: Oppelaar, Zijtveld, Oever, Weijs, Wertheim.

Study supervision: Kuipers, Oever, Honings, Weijs, Wertheim.

Conflict of Interest Disclosures: None reported.

Additional Contributions: This research was part of the Antimicrobial Stewardship activities of the Radboud University Medical Center, in collaboration with the department of Medical Microbiology, Otolaryngology and Oral and Maxillofacial surgery. The authors would like to thank F.F. Stelma, MD, PhD, and A. Tostmann, PhD, for their aid and insights during this study. No supporters received compensation for their contributions. This study was conducted without any form of third-party benefactors, funding, or financial relationships.

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