Comparison of Prophylactic Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors: A Randomized Clinical Trial | Infectious Diseases | JAMA Oncology | JAMA Network
[Skip to Navigation]
Sign In
Visual Abstract. Comparison of Prophylactic Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors
Comparison of Prophylactic Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors
Figure 1.  Patient Flow Diagram
Patient Flow Diagram

MRSA indicates methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant Enterococcus.

Figure 2.  Kaplan-Meier Estimates of the Duration of Primary Outcome-Free Survival at the Time of Final Assessment
Kaplan-Meier Estimates of the Duration of Primary Outcome-Free Survival at the Time of Final Assessment

SSI indicates surgical site infection.

Figure 3.  Forest Plot for Subgroup Analyses
Forest Plot for Subgroup Analyses

HR indicates hazard ratio.

Table 1.  Baseline Characteristics of the Study Patientsa
Baseline Characteristics of the Study Patientsa
Table 2.  Study Outcomes by Treatment Group (Primary and Secondary)
Study Outcomes by Treatment Group (Primary and Secondary)
1.
Jeys  L, Grimer  R. The long-term risks of infection and amputation with limb salvage surgery using endoprostheses. In: Tunn  PU, ed.  Treatment of Bone and Soft Tissue Sarcomas: Recent Results in Cancer Research. Springer; 2009:75-84. doi:10.1007/978-3-540-77960-5_7
2.
Morii  T, Yabe  H, Morioka  H,  et al.  Postoperative deep infection in tumor endoprosthesis reconstruction around the knee.   J Orthop Sci. 2010;15(3):331-339. doi:10.1007/s00776-010-1467-z PubMedGoogle ScholarCrossref
3.
Jeys  LM, Grimer  RJ, Carter  SR, Tillman  RM.  Risk of amputation following limb salvage surgery with endoprosthetic replacement, in a consecutive series of 1261 patients.   Int Orthop. 2003;27(3):160-163. doi:10.1007/s00264-003-0429-x PubMedGoogle ScholarCrossref
4.
Akahane  T, Shimizu  T, Isobe  K, Yoshimura  Y, Fujioka  F, Kato  H.  Evaluation of postoperative general quality of life for patients with osteosarcoma around the knee joint.   J Pediatr Orthop B. 2007;16(4):269-272. doi:10.1097/BPB.0b013e3280925670 PubMedGoogle ScholarCrossref
5.
Racano  A, Pazionis  T, Farrokhyar  F, Deheshi  B, Ghert  M.  High infection rate outcomes in long-bone tumor surgery with endoprosthetic reconstruction in adults: a systematic review.   Clin Orthop Relat Res. 2013;471(6):2017-2027. doi:10.1007/s11999-013-2842-9 PubMedGoogle ScholarCrossref
6.
Hasan  K, Racano  A, Deheshi  B,  et al.  Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) survey.   BMC Musculoskelet Disord. 2012;13:91. doi:10.1186/1471-2474-13-91 PubMedGoogle ScholarCrossref
7.
Bratzler  DW, Dellinger  EP, Olsen  KM,  et al; American Society of Health-System Pharmacists; Infectious Disease Society of America; Surgical Infection Society; Society for Healthcare Epidemiology of America.  Clinical practice guidelines for antimicrobial prophylaxis in surgery.   Am J Health Syst Pharm. 2013;70(3):195-283. doi:10.2146/ajhp120568 PubMedGoogle ScholarCrossref
8.
Parvizi  J, Gehrke  T, Chen  AF. Proceedings of the International Consensus on Periprosthetic Joint Infection. Bone Joint J. 2013;95-B(11):1450-1452. doi:10.1302/0301-620X.95B11.33135
9.
Costelloe  C, Metcalfe  C, Lovering  A, Mant  D, Hay  AD.  Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis.   BMJ. 2010;340:c2096. doi:10.1136/bmj.c2096 PubMedGoogle ScholarCrossref
10.
Ghert  M, Deheshi  B, Holt  G,  et al; PARITY Investigators.  Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY): protocol for a multicentre randomised controlled study.   BMJ Open. 2012;2(6):e002197. doi:10.1136/bmjopen-2012-002197 PubMedGoogle Scholar
11.
Horan  TC, Gaynes  RP, Martone  WJ, Jarvis  WR, Emori  TG.  CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections.   Infect Control Hosp Epidemiol. 1992;13(10):606-608. doi:10.2307/30148464 PubMedGoogle ScholarCrossref
12.
Tunn  PU, Pomraenke  D, Goerling  U, Hohenberger  P.  Functional outcome after endoprosthetic limb-salvage therapy of primary bone tumours: a comparative analysis using the MSTS score, the TESS and the RNL index.   Int Orthop. 2008;32(5):619-625. doi:10.1007/s00264-007-0388-8 PubMedGoogle ScholarCrossref
13.
Davis  AM, Wright  JG, Williams  JI, Bombardier  C, Griffin  A, Bell  RS.  Development of a measure of physical function for patients with bone and soft tissue sarcoma.   Qual Life Res. 1996;5(5):508-516. doi:10.1007/BF00540024 PubMedGoogle ScholarCrossref
14.
Schreiber  D, Bell  RS, Wunder  JS,  et al.  Evaluating function and health related quality of life in patients treated for extremity soft tissue sarcoma.   Qual Life Res. 2006;15(9):1439-1446. doi:10.1007/s11136-006-0001-4 PubMedGoogle ScholarCrossref
15.
Schneider  P, Heels-Ansdell  D, Thabane  L, Ghert  M; PARITY Investigators.  Prophylactic Antibiotic Regimens In Tumor Surgery (PARITY): a multi-center randomized controlled study comparing alternative antibiotic regimens in patients undergoing tumor resections with endoprosthetic replacements-a statistical analysis plan.   Trials. 2021;22(1):223. doi:10.1186/s13063-021-05147-2 PubMedGoogle ScholarCrossref
16.
PARITY Investigators.  Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY): a pilot multicentre randomised controlled trial.   Bone Joint Res. 2015;4(9):154-162. doi:10.1302/2046-3758.49.2000482 PubMedGoogle ScholarCrossref
17.
Langit  MB, Miwa  S, Yamamoto  N,  et al.  Risk factors for postoperative deep infection after malignant bone tumor surgery of the extremities.   Anticancer Res. 2020;40(6):3551-3557. doi:10.21873/anticanres.14344 PubMedGoogle ScholarCrossref
18.
Illingworth  KD, Mihalko  WM, Parvizi  J,  et al.  How to minimize infection and thereby maximize patient outcomes in total joint arthroplasty: a multicenter approach: AAOS exhibit selection.   J Bone Joint Surg Am. 2013;95(8):e50. doi:10.2106/JBJS.L.00596 PubMedGoogle Scholar
19.
Voigt  J, Mosier  M, Darouiche  R.  Systematic review and meta-analysis of randomized controlled trials of antibiotics and antiseptics for preventing infection in people receiving primary total hip and knee prostheses.   Antimicrob Agents Chemother. 2015;59(11):6696-6707. doi:10.1128/AAC.01331-15 PubMedGoogle ScholarCrossref
20.
AAOS. Information statement: recommendations for the use of intravenous antibiotic prophylaxis in primary total joint arthroplasty. Accessed June 4, 2021. https://www.aaos.org/globalassets/about/bylaws-library/information-statements/1027-recommendations-for-the-use-of-intravenous-antibiotic-prophylaxis-in-primary-total-joint-arthroplasy.pdf
21.
British Orthopaedic Association. Primary total hip replacement: a guide to good practice. Accessed June 4, 2021. https://britishhipsociety.com/wp-content/uploads/2020/12/2012-Nov_BOA-Blue-Book.pdf
22.
New Zealand Orthopaedic Association. Total hip joint arthroplasty good practice guidelines. Accessed June 4, 2021. https://nzoa.org.nz/sites/default/files/Total_Hip_Joint_Arthroplasty_Guidelines_0.pdf
23.
Thornley  P, Evaniew  N, Riediger  M, Winemaker  M, Bhandari  M, Ghert  M.  Postoperative antibiotic prophylaxis in total hip and knee arthroplasty: a systematic review and meta-analysis of randomized controlled trials.   CMAJ Open. 2015;3(3):E338-E343. doi:10.9778/cmajo.20150012 PubMedGoogle ScholarCrossref
24.
Rosenberger  LH, Politano  AD, Sawyer  RG.  The surgical care improvement project and prevention of post-operative infection, including surgical site infection.   Surg Infect (Larchmt). 2011;12(3):163-168. doi:10.1089/sur.2010.083 PubMedGoogle ScholarCrossref
25.
Strony  J, Brown  S, Choong  P, Ghert  M, Jeys  L, O’Donnell  RJ.  Musculoskeletal infection in orthopaedic oncology: assessment of the 2018 International Consensus Meeting on Musculoskeletal Infection.   J Bone Joint Surg Am. 2019;101(20):e107. doi:10.2106/JBJS.19.00182 PubMedGoogle Scholar
26.
Infectious Diseases Society of America (IDSA). Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis. 2011;52(suppl 5):S397-S428. doi:10.1093/cid/cir153
27.
Mullish  BH, Williams  HR.  Clostridium difficile infection and antibiotic-associated diarrhoea.   Clin Med (Lond). 2018;18(3):237-241. doi:10.7861/clinmedicine.18-3-237 PubMedGoogle ScholarCrossref
28.
Aldeyab  MA, Kearney  MP, Scott  MG,  et al.  An evaluation of the impact of antibiotic stewardship on reducing the use of high-risk antibiotics and its effect on the incidence of Clostridium difficile infection in hospital settings.   J Antimicrob Chemother. 2012;67(12):2988-2996. doi:10.1093/jac/dks330 PubMedGoogle ScholarCrossref
29.
Talpaert  MJ, Gopal Rao  G, Cooper  BS, Wade  P.  Impact of guidelines and enhanced antibiotic stewardship on reducing broad-spectrum antibiotic usage and its effect on incidence of Clostridium difficile infection.   J Antimicrob Chemother. 2011;66(9):2168-2174. doi:10.1093/jac/dkr253 PubMedGoogle ScholarCrossref
30.
Al-Obaydi  W, Smith  CD, Foguet  P.  Changing prophylactic antibiotic protocol for reducing Clostridium difficile-associated diarrhoeal infections.   J Orthop Surg (Hong Kong). 2010;18(3):320-323. doi:10.1177/230949901001800312 PubMedGoogle ScholarCrossref
31.
Järvinen  TLN, Sihvonen  R, Bhandari  M,  et al.  Blinded interpretation of study results can feasibly and effectively diminish interpretation bias.   J Clin Epidemiol. 2014;67(7):769-772. doi:10.1016/j.jclinepi.2013.11.011 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    January 6, 2022

    Comparison of Prophylactic Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors: A Randomized Clinical Trial

    The Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) Investigators
    JAMA Oncol. Published online January 6, 2022. doi:10.1001/jamaoncol.2021.6628
    Key Points

    Question  Can a 5-day regimen of postoperative, prophylactic, intravenous antibiotics reduce the rate of surgical site infections in patients with a lower extremity bone tumor undergoing complex endoprosthetic reconstruction compared with a 1-day regimen?

    Findings  In this randomized clinical trial including 604 patients in the primary analysis, the 5-day regimen did not reduce the rate of surgical site infection compared with the 1-day regimen, although it resulted in a higher rate of antibiotic-related complications, notably Clostridioides difficile–associated colitis.

    Meaning  The results of this study suggest that prolonging use of postoperative antibiotics beyond 1 day does not reduce the rate of surgical site infection but increases the risk of clinically significant antibiotic-related complications.

    Abstract

    Importance  The use of perioperative, prophylactic, intravenous antibiotics is standard practice to reduce the risk of surgical site infection after oncologic resection and complex endoprosthetic reconstruction for lower extremity bone tumors. However, evidence guiding the duration of prophylactic treatment remains limited.

    Objective  To assess the effect of a 5-day regimen of postoperative, prophylactic, intravenous antibiotics compared with a 1-day regimen on the rate of surgical site infections within 1 year after surgery.

    Design, Setting, and Participants  This randomized clinical superiority trial was performed at 48 clinical sites in 12 countries from January 1, 2013, to October 29, 2019. The trial included patients with a primary bone tumor or a soft tissue sarcoma that had invaded the femur or tibia or oligometastatic bone disease of the femur or tibia with expected survival of at least 1 year who required surgical management by excision and endoprosthetic reconstruction. A total of 611 patients were enrolled, and 7 were excluded for ineligibility.

    Interventions  A 1- or 5-day regimen of postoperative prophylactic intravenous cephalosporin (cefazolin or cefuroxime) that began within 8 hours after skin closure and was administered every 8 hours thereafter. Those randomized to the 1-day regimen received identical saline doses every 8 hours for the remaining 4 days; patients, care providers, and outcomes assessors were blinded to treatment regimen.

    Main Outcomes and Measures  The primary outcome in this superiority trial was a surgical site infection (superficial incisional, deep incisional, or organ space) classified according to the criteria established by the Centers for Disease Control and Prevention within 1 year after surgery. Secondary outcomes included antibiotic-related complications, unplanned additional operations, oncologic and functional outcomes, and mortality.

    Results  Of the 604 patients included in the final analysis (mean [SD] age, 41.2 [21.9] years; 361 [59.8%] male; 114 [18.9%] Asian, 43 [7.1%] Black, 34 [5.6%] Hispanic, 15 [2.5%] Indigenous, 384 [63.8%] White, and 12 [2.0%] other), 293 were randomized to a 5-day regimen and 311 to a 1-day regimen. A surgical site infection occurred in 44 patients (15.0%) allocated to the 5-day regimen and in 52 patients (16.7%) allocated to the 1-day regimen (hazard ratio, 0.93; 95% CI, 0.62-1.40; P = .73). Antibiotic-related complications occurred in 15 patients (5.1%) in the 5-day regimen and in 5 patients (1.6%) allocated to the 1-day regimen (hazard ratio, 3.24; 95% CI, 1.17-8.98; P = .02). Other secondary outcomes did not differ significantly between treatment groups.

    Conclusions and Relevance  This randomized clinical trial did not confirm the superiority of a 5-day regimen of postoperative intravenous antibiotics over a 1-day regimen in preventing surgical site infections after surgery for lower extremity bone tumors that required an endoprosthesis. The 5-day regimen group had significantly more antibiotic-related complications.

    Trial Registration  ClinicalTrials.gov Identifier: NCT01479283

    Introduction

    Operations to remove malignant tumors of the femur or tibia involve the resection of the affected bone and surrounding soft tissue followed by complex reconstruction of the limb. The most common reconstruction involves the use of modular metallic and polyethylene endoprostheses to replace surgically resected bones and joints. Because of the length and intricacies of these procedures and the medical complexity of these patients, the risk of a surgical site infection is high.1-3 Attempts to eradicate the organism often fail and result in the eventual need for amputation in nearly 50% of patients, thereby strongly affecting patient function and quality of life and delaying the administration of adjuvant cancer therapies.1-4

    Strategies to minimize surgical site infections in this population include the administration of perioperative intravenous antibiotics. The most effective antibiotic regimen to prevent surgical site infections remains uncertain and current clinical practice is highly varied, particularly with respect to antibiotic duration. Approximately 2 of every 3 surgeons prescribe prolonged courses well beyond the 24-hour recommended duration for standard total joint replacement operations.5-8 However, overuse of antibiotics can lead to antibiotic-related complications and antibiotic resistance; antibiotic stewardship, therefore, remains a salient issue.9 We conducted the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial to inform the effect of a 5-day regimen of postoperative, prophylactic, intravenous antibiotics compared with a 1-day regimen on the prevention of surgical site infections and on antibiotic adverse effects in patients requiring surgical resection and endoprosthetic reconstruction for a lower extremity bone tumor.

    Methods
    Trial Design and Oversight

    This intention-to-treat study was an investigator-initiated, international, blinded (patients, surgeons, outcomes assessors, and data analysts), parallel, superiority randomized clinical trial. The rationale, design, and methods of the trial have been previously published.10 Written informed consent was required to participate in the study, and all data were deidentified. Supplement 1 (the Trial Protocol) and Supplement 2 provide information on eligibility criteria, interventions, blinding, follow-up, outcomes definitions, and statistical analysis. The Hamilton Integrated Research Ethics Board as well as the relevant local ethics committee at each participating site approved the trial protocol and its amendments before local study initiation. In addition, the following regulatory bodies also approved the trial protocol and its amendments: Health Canada, the Brazilian National Health Surveillance Agency, the European Medicines Agency (including the competent authorities in Austria and Spain), the Indian Council of Medical Research, and the Republic of South Africa’s Department of Health. The PARITY Data and Safety Monitoring Board, composed of 2 orthopedic oncologists and 1 statistician who were independent of the study team, reviewed the trial outcomes. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Patients

    From January 1, 2013, to October 29, 2019, investigators at 48 clinical sites across Canada, the US, Argentina, Australia, Austria, Brazil, Egypt, India, the Netherlands, Singapore, South Africa, and Spain recruited patients for the study. Eligible patients included all individuals 12 years or older with a primary bone tumor or a soft tissue sarcoma that had invaded the femur or tibia or oligometastatic bone disease of the femur or tibia with expected survival of at least 1 year who required surgical management by excision and endoprosthetic reconstruction. Patients with previous infections at the surgical site or who were known to be colonized with methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus were excluded. A total of 895 patients were screened for eligibility, and 7 patients were adjudicated to be ineligible at the time of randomization; thus, of the 611 patients randomized, 604 were included in the final analyses. The final 1-year assessments were completed in March 2021. Details on the eligibility criteria are available in the eAppendix in Supplement 2.

    Trial Interventions and Procedures

    Surgical procedures were performed according to the standard practices at each clinical site. All patients received standardized preoperative and intraoperative prophylactic intravenous antibiotics. Patients were randomly allocated perioperatively in a 1-to-1 ratio to receive a 1- or 5-day postoperative prophylactic regimen of an intravenous cephalosporin (cefazolin or cefuroxime); they were blinded to the treatment regimen. Those randomized to the 1-day regimen received identical saline (placebo) doses for the remaining 4 days. Randomization, stratified according to tumor location (femur or tibia) and clinical site, was centralized through an internet-based, computer-generated platform that concealed allocation and used randomly permuted blocks of 2 or 4. An unblinded member of the local investigational pharmacy performed the randomization. Patients began their randomly allocated, postoperative, prophylactic antibiotic regimen within 8 hours after skin closure, and the doses were intravenously administered every 8 hours. Clinical sites used their own inventory to prepare the study antibiotics or placebo. Preparation, blinding of study antibiotics or placebo, and storage and administration of the study antibiotics were conducted as per local procedures established at each clinical site and the relevant manufacturers’ labels. Further details on the intravenous antibiotic regimens are available in the eAppendix in Supplement 2.

    Outcome Measures

    The primary outcome was the development of a surgical site infection (superficial incisional, deep incisional, or organ space [deep prosthetic infection]) within 1 year of the date of surgery. Surgical site infections were classified according to the criteria established by the Centers for Disease Control and Prevention.11 Secondary outcomes included antibiotic-related complications, unplanned additional operations, death, and oncologic and functional outcomes within 1 year after surgical resection and endoprosthetic reconstruction. Validated functional assessments included the Musculoskeletal Tumor Society 1987 (MSTS-87) (range, 0-35, with higher scores indicating better function) and 1993 (MSTS-93) (range, 0-100, with higher scores indicating better function) scores and the Toronto Extremity Salvage Score (TESS) (range, 0-100, with higher scores indicating better function).12-14

    Patients were assessed for study events by their treating surgeon at 2 and 6 weeks, 3, 6, and 9 months, and 1 year postoperatively. The functional assessments were completed before surgery and at the 1-year follow-up visit. The blinded Central Adjudication Committee adjudicated all primary and key secondary outcome events identified during the 1-year study follow-up as well as all instances when eligibility was in doubt.

    Statistical Analysis

    The justification for the PARITY trial sample size has been previously published.10,15 At the trial’s onset, we calculated that the definitive sample size would require a total of 920 patients based on a between-group comparison of deep prosthetic infection. The sample size was calculated as a noninferiority trial under the assumption of an overall 10% event rate with an absolute difference of 5% in the risk of deep surgical site infection within 1 year to define noninferiority. After initiating enrollment and then transitioning from the vanguard to the definitive phase of the trial, we expanded the trial’s primary outcome from deep to any surgical site infection and changed the study’s design to a superiority trial to increase the expected event rate and feasibility without compromising clinical importance. The expanded definition of the primary outcome resulted in an overall vanguard phase event rate of 14%.16 Therefore, with a presumed 50% or greater reduction in the relative risk of deep surgical site infection within 1 year and with a 2-sided α of .05 and study power of 80%, we planned the definitive trial’s sample size to include 300 patients per arm, for a total of 600 patients.

    When conducting the final analyses, we adhered to the published statistical analysis plan.15 Briefly, for the primary analysis, we used a Cox proportional hazards regression model with time from surgery to the surgical site infection as the primary outcome. The analysis included all patients in the groups to which they were randomly allocated. Postoperative antibiotic duration (treatment group) was the independent variable, and the Cox proportional hazards regression included tumor location and clinical site as stratification variables. Patients who did not experience the primary outcome were censored at 1 year or at the time of last study visit. We tested the proportional hazards assumption of the Cox proportional hazards regression model by examining Schoenfeld residuals. We also performed several sensitivity analyses for the primary outcome, including a competing risks analysis that accounted for deaths and amputation as competing risks. We identified the following 5 subgroups a priori, which we analyzed in the primary model to assess for possible effect modification: tumor type, tumor location, sex, age, and preoperative chemotherapy.

    We assessed the effect of postoperative antibiotic duration on the secondary outcomes using Cox proportional hazards regressions with treatment group as the independent variable and tumor location and clinical site as stratification variables. We also estimated the effect of postoperative antibiotic duration on functional outcomes at 1 year using multiple linear regression models that included treatment group, tumor location, clinical site, and baseline score as independent variables. We used multiple imputation to address missing functional outcome data.

    The results are presented as hazard ratios (HRs) for time-to-event outcomes and mean difference for continuous outcomes, with corresponding 95% CIs and associated 2-sided P values. No adjustments were made for multiple testing. Kaplan-Meier curves were constructed for the primary outcome. These analyses were first completed using blinded treatment groups by the data analyst (D.H.-A.). Interpretations for the effect of antibiotic duration were developed and documented based on blinded group A vs B. The randomization code was then broken, the correct a priori interpretation selected, and the manuscript drafted. All analyses were conducted using SAS software, version 9.4 (SAS Institute Inc).

    Results
    Study Patients

    Of the 604 patients included in the final analysis (mean [SD] age, 41.2 [21.9] years; 361 [59.8%] male; 114 [18.9%] Asian, 43 [7.1%] Black, 34 [5.6%] Hispanic, 15 [2.5%] Indigenous, 384 [63.8%] White, and 12 [2.0%] other [3 Middle Eastern, 5 mixed race, 2 North African, 1 Polynesian, and 1 Turkish]), 293 were randomized to a 5-day regimen and 311 to a 1-day regimen. Of the 527 patients alive at 1 year, 496 (94%) had 1-year follow-up data available. Figure 1 and the eAppendix (Section 5.0) and eTables 1 and 2 in Supplement 2 provide details regarding patient flow and the reasons for exclusion.

    Table 1 and eTables 3 to 5 in Supplement 2 present patient characteristics and demonstrate similar characteristics in the 2 groups. The most common tumor type was a primary bone tumor located predominantly in the femur. A total of 290 patients (48.0%) received preoperative chemotherapy; 22 (3.6%) received preoperative radiotherapy. There was an imbalance between treatment groups, with 129 of 293 patients (44.0%) allocated to the 5-day regimen having received preoperative chemotherapy compared with 161 of 311 patients (51.8%) allocated to the 1-day regimen.

    Adherence to the Allocated Intervention

    Two patients (0.6%) who had originally been allocated to a 1-day regimen received a 5-day regimen; no patients originally allocated to a 5-day regimen crossed over to a 1-day regimen. Protocol deviations primarily resulted from inpatient hospital discharge earlier than 5 days postoperatively and were similar between groups. Of those allocated to the 5-day regimen, 248 patients (84.6%) received all but the final 3 doses of intravenous infusions as did 256 patients (82.6%) allocated to the 1-day regimen. eTable 6 in Supplement 2 provides details regarding the administration of the antibiotics.

    Primary Outcome

    A surgical site infection occurred within 1 year in 44 of 293 patients (15.0%) allocated to the 5-day regimen and in 52 of 311 patients (16.7%) allocated to the 1-day regimen (HR, 0.93; 95% CI, 0.62-1.40; P = .73) (Figure 2 and Table 2). The Schoenfeld residuals demonstrate that the assumption of proportional hazards for the primary outcome was not violated. Table 2 presents the incidence of superficial incisional, deep incisional, and organ space surgical site infections for each group. The most common causative organisms of surgical site infections were S aureus and coagulase-negative staphylococci.

    The results were similar in the sensitivity analyses that accounted for deaths and amputation as competing risks. Adjusted analyses yielded similar results to those in the primary analysis. Subgroup analyses did not show any effect modification, including when adjusted for preoperative chemotherapy. Figure 3 and eTables 7 and 8 in Supplement 2 provide details regarding the sensitivity and subgroup analyses.

    Secondary Outcomes
    Antibiotic-Related Complications, Unplanned Additional Operations, Oncologic Events, and Mortality

    Study-related antibiotic-related complications occurred in 15 patients (5.1%) allocated to the 5-day regimen and in 5 patients (1.6%) allocated to the 1-day regimen (HR, 3.24; 95% CI, 1.17-8.98; P = .02) (Table 2). The most common antibiotic-related complication was Clostridioides difficile–associated colitis (Table 2). Unplanned additional operations occurred in 75 patients (25.6%) allocated to the 5-day regimen and in 80 patients (25.7%) allocated to the 1-day regimen (HR, 1.06; 95% CI, 0.77-1.46) (eTable 9 in Supplement 2). The most common types of additional operations were irrigation and debridement and implant exchange, most of which were to treat a deep incisional or organ space surgical site infection. Oncologic events (HR, 1.02; 95% CI, 0.75-1.39) and mortality (HR, 1.01; 95% CI, 0.64-1.58) proved similar between the treatment groups (Table 2 and eTable 9 in Supplement 2).

    Functional Outcomes

    Surgeon-reported function was similar between the treatment groups as measured by the MSTS-87 scores (mean difference, −0.49; P = .41) and MSTS-93 scores (mean difference, −1.89; P = .34) as was patient-reported function between the 2 groups as measured by the TESS (mean difference, 0.10; P = .96) (eTable 10 in Supplement 2).

    Discussion

    The PARITY randomized clinical trial failed to demonstrate a benefit of a 5-day prophylactic antibiotic regimen of intravenous cephalosporins compared with a 1-day regimen in reducing surgical site infections after surgical resection and endoprosthetic reconstruction for a lower extremity bone tumor. However, 3 times as many patients allocated to the 5-day regimen experienced serious antibiotic-related complications.

    Our overall primary event rate is higher than previously published studies in the field.5,17 In a meta-analysis5 of retrospective data, the surgical site infection rate after lower extremity endoprosthetic reconstruction was 10% (95% CI, 8%-11%). This meta-analysis5 suggested that antibiotic prophylaxis for longer than 24 hours postoperatively decreases the risk of infection, but the biases of observational research leave only low-quality evidence. Our event rate may be higher than previously reported because of our broader definition of a surgical site infection and the careful prospective collection of study event data.

    Perioperative antibiotic prophylaxis is considered essential in minimizing surgical site infections in total joint arthroplasty, in which the infection rate is much lower.18-22 A meta-analysis23 of randomized clinical trials that compared only preoperative antibiotics with both preoperative and postoperative antibiotics in joint replacement surgery did not show efficacy of postoperative antibiotic prophylaxis. Because there is no evidence of additional benefit to a lengthened course, the Surgical Infection Prevention Project recommends the discontinuation of use of prophylactic antibiotics 24 hours postoperatively for all surgical cases.24 However, lower limb oncologic reconstructions are unique in their complexity and the immunocompromised state of the affected patient population; therefore, these recommendations may not be applicable in this particular setting. The second International Consensus Meeting on Musculoskeletal Infection recently identified whether prolonging use of postoperative antibiotics would prevent surgical site infections in patients with bone tumors undergoing endoprosthetic reconstruction as 1 of the most critical orthopedic oncology clinical questions.25 Their recommendation acknowledged that although more than half of orthopedic oncologists prescribe prophylactic antibiotics for longer than 24 hours postoperatively, there is insufficient evidence to support this practice.25

    The overuse of antibiotics is a major public health concern associated with increased health care costs from antibiotic-related complications and antibiotic resistance.26 The increase in antibiotic-resistant organisms, particularly in a nosocomial setting, is outpacing the development of new antimicrobial agents. Antibiotic use often results in antibiotic-associated diarrhea, not infrequently caused by C difficile. Although antibiotic-associated diarrhea is generally mild and self-limiting, gut infection with C difficile is universally severe and may lead to toxic megacolon, organ failure, or even death.27 Our study found a significant increase in antibiotic-related complications in the 5-day regimen group, with most complications reported to be C difficile–associated colitis. To avoid this complication, hospital antibiotic stewardship programs in the UK have restricted the use of high-risk antibiotics, including cephalosporins, with a subsequent clear reduction of nosocomial C difficile infections.28-30

    Strengths and Limitations

    Our trial has several strengths. Safeguards against potential bias included concealed randomization and blinding of treatment allocation from patients, caregivers, outcomes assessors, and data analysts. The diagnosis of surgical site infection was independently adjudicated using well-established definitions, thus ensuring objective decision-making and minimizing outcome assessment bias. By documenting our interpretations based on blinded results before breaking the randomization code, we safeguarded against interpretation bias.31 After accounting for the nearly 10% mortality rate, true loss to follow-up was only 5%. Close clinical surveillance and rigorous study monitoring procedures resulted in this relatively small loss to follow-up. Our study’s broad eligibility criteria and conduct in many health care systems strengthens its generalizability. Several of the study outcomes are of unequivocal importance to both patients and health care systems. Finally, answering clinical questions in rare conditions requires an immense international, collaborative effort. To our knowledge, this trial was the first-ever collaborative, interventional trial initiated and led by orthopedic oncologists.

    Our trial also has limitations. The large number of participating clinical sites, combined with the rarity of bone tumors, resulted in low enrollment at some sites. More patients in the shorter duration group received preoperative chemotherapy, which may have increased their risk of a surgical site infection. However, our subgroup and adjusted analyses yielded results similar to our primary analysis. Protocol deviations, particularly doses not administered because of early hospital discharge, were not uncommon. Although the deviations were balanced between groups, they would have affected the 5-day regimen group more than the 1-day regimen. However, the discontinuation of antibiotics at hospital discharge is standard procedure; thus, our results are applicable to actual clinical practice. The impact of the postoperative prophylactic antibiotic regimens on late infections that present after the 1-year postsurgery timepoint cannot be inferred from this study; however, these infections are not considered surgical site infections according to the definitions established by the Centers for Disease Control and Prevention. The diagnosis of a surgical site infection is challenging because of the complexities of surgery and wound healing, a concern ameliorated by the rigor and blinding of the adjudication process. Finally, the lack of a statistically significant difference observed may be the result of insufficient study power. However, the observed absolute difference between the 2 treatment groups was small, and the increased sample size needed to show statistical significance would likely not be considered necessary by surgeons in the field.

    Conclusions

    In this randomized clinical trial, the 5-day regimen did not reduce the rate of surgical site infection compared with the 1-day regimen. Although the results of this randomized clinical trial do not definitively exclude an important benefit of postoperative prophylactic antibiotic therapy longer than 24 hours, the significantly higher risk of antibiotic-related complications in the 5-day regimen represents a critical finding. Clinicians should consider the uncertainty of the benefits and the relative confidence in findings of harm to make an informed decision on antibiotic duration after surgical resection and endoprosthetic reconstruction for lower extremity bone tumors.

    Back to top
    Article Information

    Accepted for Publication: October 7, 2021.

    Published Online: January 6, 2022. doi:10.1001/jamaoncol.2021.6628

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 The Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) Investigators. JAMA Oncology.

    Corresponding Author: Michelle Ghert, MD, Division of Orthopaedic Surgery, Department of Surgery, McMaster University, 711 Concession St, Section B, Level 3, Room 169A, Hamilton, ON L8V 1C3, Canada (ghertm@mcmaster.ca).

    The Writing Committee for the PARITY Investigators: Michelle Ghert, MD; Patricia Schneider, BSc; Gordon Guyatt, MD, MSc; Lehana Thabane, PhD; Roberto Vélez, MD, PhD; Timothy O’Shea, MD, MPH; R. Lor Randall, MD; Robert Turcotte, MD; David Wilson, MD, MASc; Jay S. Wunder, MD; André Mathias Baptista, MD, PhD; Edward Y. Cheng, MD; Yee-Cheen Doung, MD; Peter C. Ferguson, MD; Victoria Giglio, MSc; James Hayden, MD, PhD; Diane Heels-Ansdell, MSc; Shah Alam Khan, MS (Ortho); Venkatesan Sampath Kumar, MS (Ortho); Paula McKay, BSc; Benjamin Miller, MD, MS; Michiel van de Sande, MD, PhD; Juan P. Zumárraga, MD, PhD; Mohit Bhandari, MD, PhD.

    Affiliations of The Writing Committee for the PARITY Investigators: Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada (Ghert, Schneider, Wilson, Giglio, McKay, Bhandari); Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Guyatt, O’Shea); Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada (Guyatt, Thabane, Heels-Ansdell, Bhandari); Hospital Vall d’Hebron, Vall d’Hebron Institut de Recerca, Barcelona, Spain (Vélez); Department of Orthopaedic Surgery, University of California Davis Health, Sacramento (Randall); Division of Orthopaedic Surgery, Department of Surgery, McGill University, Montreal, Quebec, Canada (Turcotte); University of Toronto Musculoskeletal Oncology Unit, Mount Sinai Hospital, Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada (Wunder, Ferguson); Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil (Baptista, Zumárraga); Department of Orthopaedic Surgery, University of Minnesota, Minneapolis (Cheng); Department of Orthopaedics and Rehabilitation, Oregon Health & Science University, Portland (Doung, Hayden); Department of Orthopaedics, All India Institute of Medical Sciences, Delhi, India (Khan, Sampath Kumar); Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City (Miller); Department of Orthopaedic Surgery, Leids Universitair Medisch Centrum, Leiden, the Netherlands (van de Sande).

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

    Concept and design: Ghert, Guyatt, Thabane, Vélez, O’Shea, Randall, Turcotte, Wunder, Ferguson, McKay, Bhandari.

    Acquisition, analysis, or interpretation of data: Ghert, Schneider, Guyatt, Thabane, Vélez, O’Shea, Randall, Turcotte, Wilson, Wunder, Baptista, Cheng, Doung, Ferguson, Giglio, Hayden, Heels-Ansdell, Khan, Sampath Kumar, McKay, Miller, van de Sande, Zumárraga, Bhandari.

    Drafting of the manuscript: Ghert, Schneider.

    Critical revision of the manuscript for important intellectual content: Ghert, Guyatt, Thabane, Vélez, O’Shea, Randall, Turcotte, Wilson, Wunder, Baptista, Cheng, Doung, Ferguson, Giglio, Hayden, Heels-Ansdell, Khan, Sampath Kumar, McKay, Miller, van de Sande, Zumárraga, Bhandari.

    Statistical analysis: Thabane, Heels-Ansdell.

    Obtained funding: Ghert, Schneider, McKay, Bhandari.

    Administrative, technical, or material support: Schneider, Vélez, O’Shea, Randall, Turcotte, Wilson, Giglio, McKay, Zumárraga, Bhandari.

    Supervision: Ghert, Schneider, Guyatt, Thabane, Vélez, McKay, Bhandari.

    Conflict of Interest Disclosures: Dr Ghert reported receiving grants from Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Orthopaedic Research and Education Foundation, Physician Services Incorporated, and Musculoskeletal Tumor Society during the conduct of the study and consulting and speaker fees from Wright Medical outside the submitted work. Dr O’Shea reported receiving grants from the Canadian Cancer Society, Canadian Institutes of Health Research, and Physicians Services Inc during the conduct of the study. Dr Cheng reported serving as editor for the Journal of Bone and Joint Surgery Essential Surgical Techniques. Ms McKay reported receiving personal fees from Global Research Solutions Inc and Platform Life Sciences outside the submitted work. Dr Miller reported receiving grants from Canadian Institutes of Health Research during the conduct of the study. Dr Bhandari reported receiving grants from Canadian Institutes of Health Research, National Institutes of Health, Michael G. DeGroote Institute for Pain Research and Care, and Physicians’ Services Inc Foundation, personal fees from Pendopharm, Bioventus, and Acumed, and nonfinancial support from Canadian Orthopaedic Association and Mayo Clinic Core Center for Clinical Research outside the submitted work. No other disclosures were reported.

    Funding/Support: This research was supported by operating grant 137104 from the Canadian Institutes of Health Research, innovation grant 701639 and innovation to impact grant 703398 from the Canadian Cancer Society Research Institute, the Canadian Orthopaedic Foundation 2018 J. Édouard Samson Award, the Orthopaedic Research and Education Foundation in conjunction with the Musculoskeletal Tumor Society (Clinical Research Grant in Orthopaedic Oncology 2011), and the Physicians’ Services Incorporated (Clinical Research Grant 2012). This study was also funded, in part, by generous donations from the Silverhearts Association and private donors.

    Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Group Information: The PARITY Investigators are listed in Supplement 3.

    Data Sharing Statement: See Supplement 4.

    Additional Information: The PARITY Steering Committee designed the trial and prespecified the statistical analysis plan. The members of the PARITY Steering Committee vouch for the completeness and accuracy of the data and analyses reported and for the fidelity of the trial to the protocol. The Methods Center at McMaster University in Hamilton, Ontario, Canada, was responsible for the trial randomization system, the maintenance, validation, and analysis of the data and the coordination of all clinical sites. The Central Adjudication Committee adjudicated all suspected primary outcome events, as well as key secondary outcome events and eligibility when in doubt.

    References
    1.
    Jeys  L, Grimer  R. The long-term risks of infection and amputation with limb salvage surgery using endoprostheses. In: Tunn  PU, ed.  Treatment of Bone and Soft Tissue Sarcomas: Recent Results in Cancer Research. Springer; 2009:75-84. doi:10.1007/978-3-540-77960-5_7
    2.
    Morii  T, Yabe  H, Morioka  H,  et al.  Postoperative deep infection in tumor endoprosthesis reconstruction around the knee.   J Orthop Sci. 2010;15(3):331-339. doi:10.1007/s00776-010-1467-z PubMedGoogle ScholarCrossref
    3.
    Jeys  LM, Grimer  RJ, Carter  SR, Tillman  RM.  Risk of amputation following limb salvage surgery with endoprosthetic replacement, in a consecutive series of 1261 patients.   Int Orthop. 2003;27(3):160-163. doi:10.1007/s00264-003-0429-x PubMedGoogle ScholarCrossref
    4.
    Akahane  T, Shimizu  T, Isobe  K, Yoshimura  Y, Fujioka  F, Kato  H.  Evaluation of postoperative general quality of life for patients with osteosarcoma around the knee joint.   J Pediatr Orthop B. 2007;16(4):269-272. doi:10.1097/BPB.0b013e3280925670 PubMedGoogle ScholarCrossref
    5.
    Racano  A, Pazionis  T, Farrokhyar  F, Deheshi  B, Ghert  M.  High infection rate outcomes in long-bone tumor surgery with endoprosthetic reconstruction in adults: a systematic review.   Clin Orthop Relat Res. 2013;471(6):2017-2027. doi:10.1007/s11999-013-2842-9 PubMedGoogle ScholarCrossref
    6.
    Hasan  K, Racano  A, Deheshi  B,  et al.  Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) survey.   BMC Musculoskelet Disord. 2012;13:91. doi:10.1186/1471-2474-13-91 PubMedGoogle ScholarCrossref
    7.
    Bratzler  DW, Dellinger  EP, Olsen  KM,  et al; American Society of Health-System Pharmacists; Infectious Disease Society of America; Surgical Infection Society; Society for Healthcare Epidemiology of America.  Clinical practice guidelines for antimicrobial prophylaxis in surgery.   Am J Health Syst Pharm. 2013;70(3):195-283. doi:10.2146/ajhp120568 PubMedGoogle ScholarCrossref
    8.
    Parvizi  J, Gehrke  T, Chen  AF. Proceedings of the International Consensus on Periprosthetic Joint Infection. Bone Joint J. 2013;95-B(11):1450-1452. doi:10.1302/0301-620X.95B11.33135
    9.
    Costelloe  C, Metcalfe  C, Lovering  A, Mant  D, Hay  AD.  Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis.   BMJ. 2010;340:c2096. doi:10.1136/bmj.c2096 PubMedGoogle ScholarCrossref
    10.
    Ghert  M, Deheshi  B, Holt  G,  et al; PARITY Investigators.  Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY): protocol for a multicentre randomised controlled study.   BMJ Open. 2012;2(6):e002197. doi:10.1136/bmjopen-2012-002197 PubMedGoogle Scholar
    11.
    Horan  TC, Gaynes  RP, Martone  WJ, Jarvis  WR, Emori  TG.  CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections.   Infect Control Hosp Epidemiol. 1992;13(10):606-608. doi:10.2307/30148464 PubMedGoogle ScholarCrossref
    12.
    Tunn  PU, Pomraenke  D, Goerling  U, Hohenberger  P.  Functional outcome after endoprosthetic limb-salvage therapy of primary bone tumours: a comparative analysis using the MSTS score, the TESS and the RNL index.   Int Orthop. 2008;32(5):619-625. doi:10.1007/s00264-007-0388-8 PubMedGoogle ScholarCrossref
    13.
    Davis  AM, Wright  JG, Williams  JI, Bombardier  C, Griffin  A, Bell  RS.  Development of a measure of physical function for patients with bone and soft tissue sarcoma.   Qual Life Res. 1996;5(5):508-516. doi:10.1007/BF00540024 PubMedGoogle ScholarCrossref
    14.
    Schreiber  D, Bell  RS, Wunder  JS,  et al.  Evaluating function and health related quality of life in patients treated for extremity soft tissue sarcoma.   Qual Life Res. 2006;15(9):1439-1446. doi:10.1007/s11136-006-0001-4 PubMedGoogle ScholarCrossref
    15.
    Schneider  P, Heels-Ansdell  D, Thabane  L, Ghert  M; PARITY Investigators.  Prophylactic Antibiotic Regimens In Tumor Surgery (PARITY): a multi-center randomized controlled study comparing alternative antibiotic regimens in patients undergoing tumor resections with endoprosthetic replacements-a statistical analysis plan.   Trials. 2021;22(1):223. doi:10.1186/s13063-021-05147-2 PubMedGoogle ScholarCrossref
    16.
    PARITY Investigators.  Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY): a pilot multicentre randomised controlled trial.   Bone Joint Res. 2015;4(9):154-162. doi:10.1302/2046-3758.49.2000482 PubMedGoogle ScholarCrossref
    17.
    Langit  MB, Miwa  S, Yamamoto  N,  et al.  Risk factors for postoperative deep infection after malignant bone tumor surgery of the extremities.   Anticancer Res. 2020;40(6):3551-3557. doi:10.21873/anticanres.14344 PubMedGoogle ScholarCrossref
    18.
    Illingworth  KD, Mihalko  WM, Parvizi  J,  et al.  How to minimize infection and thereby maximize patient outcomes in total joint arthroplasty: a multicenter approach: AAOS exhibit selection.   J Bone Joint Surg Am. 2013;95(8):e50. doi:10.2106/JBJS.L.00596 PubMedGoogle Scholar
    19.
    Voigt  J, Mosier  M, Darouiche  R.  Systematic review and meta-analysis of randomized controlled trials of antibiotics and antiseptics for preventing infection in people receiving primary total hip and knee prostheses.   Antimicrob Agents Chemother. 2015;59(11):6696-6707. doi:10.1128/AAC.01331-15 PubMedGoogle ScholarCrossref
    20.
    AAOS. Information statement: recommendations for the use of intravenous antibiotic prophylaxis in primary total joint arthroplasty. Accessed June 4, 2021. https://www.aaos.org/globalassets/about/bylaws-library/information-statements/1027-recommendations-for-the-use-of-intravenous-antibiotic-prophylaxis-in-primary-total-joint-arthroplasy.pdf
    21.
    British Orthopaedic Association. Primary total hip replacement: a guide to good practice. Accessed June 4, 2021. https://britishhipsociety.com/wp-content/uploads/2020/12/2012-Nov_BOA-Blue-Book.pdf
    22.
    New Zealand Orthopaedic Association. Total hip joint arthroplasty good practice guidelines. Accessed June 4, 2021. https://nzoa.org.nz/sites/default/files/Total_Hip_Joint_Arthroplasty_Guidelines_0.pdf
    23.
    Thornley  P, Evaniew  N, Riediger  M, Winemaker  M, Bhandari  M, Ghert  M.  Postoperative antibiotic prophylaxis in total hip and knee arthroplasty: a systematic review and meta-analysis of randomized controlled trials.   CMAJ Open. 2015;3(3):E338-E343. doi:10.9778/cmajo.20150012 PubMedGoogle ScholarCrossref
    24.
    Rosenberger  LH, Politano  AD, Sawyer  RG.  The surgical care improvement project and prevention of post-operative infection, including surgical site infection.   Surg Infect (Larchmt). 2011;12(3):163-168. doi:10.1089/sur.2010.083 PubMedGoogle ScholarCrossref
    25.
    Strony  J, Brown  S, Choong  P, Ghert  M, Jeys  L, O’Donnell  RJ.  Musculoskeletal infection in orthopaedic oncology: assessment of the 2018 International Consensus Meeting on Musculoskeletal Infection.   J Bone Joint Surg Am. 2019;101(20):e107. doi:10.2106/JBJS.19.00182 PubMedGoogle Scholar
    26.
    Infectious Diseases Society of America (IDSA). Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis. 2011;52(suppl 5):S397-S428. doi:10.1093/cid/cir153
    27.
    Mullish  BH, Williams  HR.  Clostridium difficile infection and antibiotic-associated diarrhoea.   Clin Med (Lond). 2018;18(3):237-241. doi:10.7861/clinmedicine.18-3-237 PubMedGoogle ScholarCrossref
    28.
    Aldeyab  MA, Kearney  MP, Scott  MG,  et al.  An evaluation of the impact of antibiotic stewardship on reducing the use of high-risk antibiotics and its effect on the incidence of Clostridium difficile infection in hospital settings.   J Antimicrob Chemother. 2012;67(12):2988-2996. doi:10.1093/jac/dks330 PubMedGoogle ScholarCrossref
    29.
    Talpaert  MJ, Gopal Rao  G, Cooper  BS, Wade  P.  Impact of guidelines and enhanced antibiotic stewardship on reducing broad-spectrum antibiotic usage and its effect on incidence of Clostridium difficile infection.   J Antimicrob Chemother. 2011;66(9):2168-2174. doi:10.1093/jac/dkr253 PubMedGoogle ScholarCrossref
    30.
    Al-Obaydi  W, Smith  CD, Foguet  P.  Changing prophylactic antibiotic protocol for reducing Clostridium difficile-associated diarrhoeal infections.   J Orthop Surg (Hong Kong). 2010;18(3):320-323. doi:10.1177/230949901001800312 PubMedGoogle ScholarCrossref
    31.
    Järvinen  TLN, Sihvonen  R, Bhandari  M,  et al.  Blinded interpretation of study results can feasibly and effectively diminish interpretation bias.   J Clin Epidemiol. 2014;67(7):769-772. doi:10.1016/j.jclinepi.2013.11.011 PubMedGoogle ScholarCrossref
    ×