A Phase 2 Multicenter Feasibility Trial to Evaluate Safety and Efficacy in Patients Treated for Hip or Knee Prosthetic Joint Infection (PJI) With Alternating Irrigation of Vancomycin Hydrochloride (HCl) and Tobramycin Sulfate in Two-Stage Exchange Arthroplasty
Phase: PHASE2
Conditions: Prosthetic Joint Infection
Sponsor: Osteal Therapeutics, Inc.

Protocol JPS-001 
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A Phase 2 Multicenter Feasibility Trial to Evaluate Safety and Efficacy in Patients 
Treated for Hip or Knee Prosthetic Joint Infection with Alternating Irrigation of 
Vancomycin HCl and Tobramycin Sulfate in Two-Stage Exchange Arthroplasty 
 
 
 
 
 
Protocol Number: 
JPS-001 
IND Number: 
132585 
Study Phase: 
2 
Funding Organization: 
Joint Purification Systems, Inc. (JPS) 
Address: 
215 S. Hwy 101 #200, Solana Beach, CA 92075 
Principal Investigator: 
Address: 
Bryan Springer, MD 
1915 Randolph Rd, Charlotte, NC 28207 
Date: 
JUN 28, 2019 
 
 
 
 
 
 
 
The information provided in this document is confidential and is intended 
for the use of clinical investigators. The information in this document may 
not be disclosed unless federal or state law or regulations require such 
disclosure. Subject to the foregoing, this information may be disclosed only 
to those persons involved in the study who have a need to know, with the 
obligation not to further disseminate this information. 
 
 
 
 

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Clinical Investigational Plan Approval 
 
A Phase 2 Multicenter Feasibility Trial to Evaluate Safety and Efficacy in Patients Treated 
for Hip or Knee Prosthetic Joint Infection with Alternating Irrigation of Vancomycin HCl 
and Tobramycin Sulfate in Two-Stage Exchange Arthroplasty 
 
 
Sponsor: 
Joint Purification Systems, Inc. 
215 S. Hwy 101 #200, Solana Beach, CA 92075 
 
________SIGNATURE ON FILE WITH CRO___________ 
Date: ___________________ 
Jude Paganelli, Chief Executive Officer 
 
 
 
Principal Investigator: 
 
_________SIGNATURE ON FILE WITH CRO____________ Date: ___________________ 
Bryan Springer, MD 
 
Reference: JUN 28, 2019, Version E 
 
 

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Protocol Agreement 
I, the Investigator of Record, agree to conduct this study in full accordance with the 
provisions of this Protocol, the associated site agreement and in accordance with applicable 
regulations and conditions required by the trial overseeing authorities. I agree to maintain all 
study documentation for a minimum of two years after the study has been completed or for 
longer periods as required by law and regulations. Publication of the results of this study will 
be governed by the conditions stipulated in the Investigational Site Agreement. I agree to 
supervise the use of the Investigational Products at my institution and ensure that the 
informed consent document is obtained prior to subject enrollment. 
I have read and understand the information in this Protocol and will ensure that all associates, 
colleagues and employees assisting in the conduct of the study are informed of the 
obligations incurred by their participation. I will attest to the delegation of any obligation 
under this Protocol to my associates, colleagues and employees by signing such delegation in 
the Study Delegation Log. 
Protocol Number: JPS-001 
Protocol Title: 
A Phase 2 Multicenter Feasibility Trial to Evaluate Safety and 
Efficacy in Patients Treated for Hip or Knee Prosthetic Joint 
Infection with Alternating Irrigation of Vancomycin HCl and 
Tobramycin Sulfate in Two-Stage Exchange Arthroplasty 
Protocol Date: 
JUN 28, 2019 
Version:  
E.0 
 
 
Signature of Site Principal Investigator 
Date 
Name of Site Principal Investigator 
 
 
 

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TABLE OF CONTENTS 
 
Contents 
1 
Background and Purpose of the Investigation ......................................................................... 10 
1.1 
Standard of Care Treatment for PJI .................................................................................. 10 
1.1.1 Inefficacy of Systemic Route of Administration ................................................................... 10 
1.1.2 Inconsistent Local Therapy .................................................................................................... 11 
1.1.3 Failure to Complete Treatment .............................................................................................. 11 
1.1.4 Time to Reimplantation ......................................................................................................... 12 
1.1.5 Interstage Mortality ................................................................................................................ 12 
1.2 
Investigational Products ...................................................................................................... 13 
1.2.1 Name and Intended Use of Investigational Product ............................................................... 13 
1.3 
Other Products ..................................................................................................................... 13 
2 
Study Objectives .......................................................................................................................... 14 
2.1 
Study Type ............................................................................................................................ 14 
2.2 
Study Objective .................................................................................................................... 14 
2.3 
Outcome Measures ............................................................................................................... 14 
2.3.1 Safety Evaluations ................................................................................................................. 14 
2.3.2 Efficacy Evaluations .............................................................................................................. 14 
2.3.3 Exploratory Measures ............................................................................................................ 14 
3 
Follow-up ..................................................................................................................................... 15 
4 
Subject Population and Selection .............................................................................................. 16 
4.1 
Inclusion Criteria ................................................................................................................. 16 
4.2 
Exclusion Criteria ................................................................................................................ 17 
5 
Study Treatment Procedures ..................................................................................................... 19 
5.1 
Treatment Summary............................................................................................................ 19 
5.2 
Stage 1 Preoperative Treatment ......................................................................................... 19 
5.3 
Irrigation, Debridement. and Component Removal ......................................................... 19 
5.4 
Irrigation Line Placement and Closure.............................................................................. 21 
5.5 
Wound Dressing and Antibiotic Therapy Start ................................................................ 22 
5.6 
Interstage Antibiotic Therapy ............................................................................................. 23 
5.7 
Monitoring for Toxicity ....................................................................................................... 26 
5.8 
Stage 2 Revision Arthroplasty ............................................................................................ 27 
5.9 
Stage 2 Postoperative Care .................................................................................................. 28 
5.10 
Postoperative Physical Therapy ......................................................................................... 28 
6 
Schedule of Visits ........................................................................................................................ 30 
6.1 
Treatment and Data Collection Table ................................................................................ 30 

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6.2 
Screening and Baseline Data ............................................................................................... 31 
6.3 
Stage 1 Surgery .................................................................................................................... 31 
6.4 
Interstage Period (Daily Until Stage 2 Surgery) ................................................................ 32 
6.5 
Stage 2 Surgery (7 to 10 Days After Stage 1) ..................................................................... 32 
6.6 
3 Weeks Post-op (After Stage 1) ......................................................................................... 33 
6.7 
6 Weeks Post-op (After Stage 1) ......................................................................................... 33 
6.8 
12 Weeks Post-op (After Stage 1) ....................................................................................... 33 
6.9 
12 Months Post-op (After Stage 1) ...................................................................................... 33 
6.10 
Unscheduled Visits ............................................................................................................... 34 
7 
Statistical and Data Considerations .......................................................................................... 35 
7.1 
Overall Statistical Design .................................................................................................... 35 
7.2 
Study Endpoints ................................................................................................................... 35 
7.3 
Analysis Populations ............................................................................................................ 35 
7.4 
Type I Error ......................................................................................................................... 35 
7.5 
Statistical Approach to Secondary Endpoints ................................................................... 35 
7.6 
Sample Size and Power ........................................................................................................ 35 
7.7 
Statistical Analysis Plan....................................................................................................... 36 
7.8 
Baseline Descriptive Statistics ............................................................................................. 36 
7.9 
Safety Analysis ..................................................................................................................... 36 
8 
Risk Analysis ............................................................................................................................... 37 
9 
Discontinuation of Study, Study Sites, or Subjects .................................................................. 39 
9.1 
Discontinuation of Study Sites ............................................................................................ 39 
9.2 
Discontinuation of the Study ............................................................................................... 39 
9.3 
Discontinuation of Subjects from Study Treatment ......................................................... 39 
9.4 
Subject Completion/Disposition .......................................................................................... 40 
10 Adverse Events ............................................................................................................................ 41 
10.1 
Basis of Adverse Events Management................................................................................ 41 
10.2 
Definitions ............................................................................................................................. 41 
10.3 
Adverse Event Recording .................................................................................................... 42 
10.4 
Adverse Event Assessment .................................................................................................. 42 
10.5 
Adverse Event Reporting .................................................................................................... 43 
11 Drug Accountability ................................................................................................................... 44 
12 Quality Control and Quality Assurance ................................................................................... 45 
12.1 
Selection of Study Sites and Investigators ......................................................................... 45 

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12.2 
Training ................................................................................................................................ 45 
12.2.1 Site Training ......................................................................................................................... 45 
12.3 
Monitor Training ................................................................................................................. 45 
12.4 
Study Monitoring ................................................................................................................. 45 
12.5 
Source Data Verification (SDV) .......................................................................................... 45 
12.5.1 Definition of Source Data .................................................................................................... 46 
12.6 
Direct Access to Source Data/Documents .......................................................................... 46 
12.7 
Protocol Deviations .............................................................................................................. 46 
13 Data Handling and Record Keeping ......................................................................................... 47 
13.1 
Subject Coding ..................................................................................................................... 47 
13.2 
Data Handling and Record Keeping .................................................................................. 47 
13.3 
Electronic Case Report Form Completion ........................................................................ 47 
13.4 
Record Retention ................................................................................................................. 47 
14 Ethical Considerations ............................................................................................................... 49 
14.1 
Informed Consent ................................................................................................................ 49 
14.2 
Institutional Review Boards ................................................................................................ 49 
14.3 
Confidentiality and Protection of Study Files ................................................................... 49 
15 Sponsor and Investigator Reports ............................................................................................. 50 
15.1 
Investigator Reports ............................................................................................................ 50 
15.2 
Sponsor Safety Reports ........................................................................................................ 50 
16 Literature Cited .......................................................................................................................... 52 
 
 
 
 

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List of Tables 
 
Table 1 Reinfection Rate at 12 Months for Various Treatments for PJI ..................................................... 10 
Table 2 Proportion of PJI Patients Who Achieve Reimplantation & Clinical Success .............................. 11 
Table 3 Criteria for Periprosthetic Hip and Knee Infection ........................................................................ 16 
Table 4 Treatment Summary ...................................................................................................................... 19 
Table 5 Tissue/Muscle Viability ................................................................................................................. 20 
Table 6 AORI Bone Defect Types .............................................................................................................. 20 
Table 7 Paprosky Classification of Acetabular Bone Loss ......................................................................... 20 
Table 8 Paprosky Classification of Femoral Bone Loss ............................................................................. 21 
Table 9 Antibiotic Instillation and Monitoring Regimen ............................................................................ 26 
Table 10 Treatment and Data Collection .................................................................................................... 30 
Table 11 Summary Table of Risk Mitigation ............................................................................................. 37 
Table 12 Example of the Subject Code ....................................................................................................... 47 
Table 13 Investigator Reports ..................................................................................................................... 50 
 
 
 

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List of Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse event 
AORI 
Anderson Orthopaedic Research Institute 
BA/BE 
Bioavailability/bioequivalence 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CC 
Completed cases 
CCI 
Charlson Comorbidity Index 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
CRO 
Clinical research organization 
CRP 
C-reactive protein 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESR 
Erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
HgA1C 
Glycated hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus 
I&D 
Incision and drainage 
ICF 
Informed consent form 
IDSA 
Infectious Diseases Society of America 
IMSM 
Independent medical safety monitor 
IND 
Investigational new drug (application) 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization  
ITT 
Intent-to-treat 
IV 
Intravenous 
JPS 
Joint Purification Systems, Inc. 
LE 
Leukocyte esterase 
MBEC 
Minimum biofilm eradication concentration 
MDR 
Multi-drug resistant 
MIC 
Minimum inhibitory concentration 
MSIS 
Musculoskeletal Infection Society 
NPWT 
Negative pressure wound therapy 
NS 
Normal saline 
OR 
Operating room 
PEC 
Primary engineering control 

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PI 
Principal investigator 
PK 
Pharmacokinetic 
PJI 
Prosthetic joint infection 
PMN 
Polymorphonuclear leukocytes 
PP 
Per-protocol 
PSI 
Pounds per square inch 
SAE 
Serious adverse event 
SAL 
Sterility assurance level 
SAP 
Statistical analysis plan 
sCr 
Serum creatinine 
SDV 
Source data verification 
SOC 
Standard of care 
SW 
Source worksheet 
TXA 
Tranexamic acid 
UADE 
Unanticipated adverse device effect 
UAE 
Unanticipated adverse event 
VAC 
Vacuum assisted closure 
VTE 
Venous thromboembolism 
WBC 
White blood cell 

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1 
Background and Purpose of the Investigation 
A prosthetic joint infection (PJI) is a rare complication of joint replacement surgery, 
also known as arthroplasty. Arthroplasty is done to help relieve pain and restore 
function in a severely diseased joint, such as a knee, hip or shoulder. Approximately 
0.5 to 1 percent of people with replacement joints develop a PJI. Infections can 
occur early in the course of recovery from joint replacement surgery (within the first 
two months) or much later. Signs and symptoms of PJI include fever, chills, 
drainage from the surgical site, and increasing redness, tenderness, swelling and 
pain of the affected joint. Prosthetic joint infections are often hard to treat because 
of the development of a structure called a biofilm within the joint. [1]. 
1.1 Standard of Care Treatment for PJI 
The standard of care for treatment of chronic PJI in the US is surgical removal of the infected 
implant, aggressive debridement and two-stage exchange arthroplasty with administration of 
systemic antibiotics. Stage 1 of the procedure includes the implantation of a temporary 
antibiotic impregnated cement spacer and administration of systemic antibiotic therapy as 
needed, typically for a period of at least 6 weeks. The second Stage of the procedure is 
performed when patients are considered infection free and includes implantation of a new 
permanent prosthesis. Cochran et al., in their review of 16,622 Medicare patients treated for 
PJI from October 2005 through December 2011 reported that 80.3% of reinfections occurred 
in the first postoperative year, and two-stage revision had the lowest reinfection rate of all 
first line treatment options for PJI other than amputation as shown in Table 1 [2]. 
Table 1 Reinfection Rate at 12 Months for Various Treatments for PJI 
First Line Treatment for PJI 
Reinfection Rate at 12 
Months 
Incision and Drainage (I&D) 
28.2% 
I&D with Polyethylene Exchange 
25.7% 
One-stage Exchange Arthroplasty 
24.6% 
Two-stage Exchange Arthroplasty 
19.0% 
1.1.1 Inefficacy of Systemic Route of Administration  
The intravenous (IV) administration of systemic antibiotics for PJI does not result in 
adequate therapeutic concentrations for eradication of biofilm at the site of infection. Bone 
concentrations of vancomycin hydrochloride (HCl) are typically 10% to 60% of serum and 
those of tobramycin sulfate range from 9% to 13% of serum concentration [3]. Achievement 
of locally therapeutic levels is crucial for clinical success; however, this is difficult or 
impossible due to the fact that most PJI pathogens are biofilm forming. Biofilm-encapsulated 
bacteria require minimum biofilm eradication concentrations (MBEC) of antibiotics that are 
several orders of magnitude (100 to 1000X) above the minimum inhibitory concentrations 
(MIC) sufficient to eradicate planktonic bacteria [4, 5]. Therapeutic target attainment at 
levels greater than the MBEC is impossible via systemic routes of administration without 
significant toxicity to other organ systems. 

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1.1.2 Inconsistent Local Therapy  
The multiple variables influencing the release of antimicrobials in cement spacers presents 
both efficacy limitations and toxicity concerns. For example, antimicrobials contained within 
the center of the matrix are essentially isolated from the joint environment, with only the 
surface cement releasing significant amounts of drug. Mixing techniques, antimicrobial 
concentrations, type of cement, surface area, and movement make for a high degree of 
variability in elution. The amount of antibiotic released from the cement in one study ranged 
from 1.3% to 14.8% [6]. Most of the elution from bone cements comes in the first 48 to 72 
hours, and by day 5, the concentrations are often sub-therapeutic [7]. The sub-therapeutic 
antimicrobial concentrations can lead to the formation and colonization of multi-drug 
resistant (MDR) organisms as evidenced by multiple studies. One study showed the 
formation of pseudomonas biofilms with increasing slime layers in gentamicin-impregnated 
cement versus control, while another study isolated coagulase-negative Staphylococci in 88% 
of cases that used gentamicin loaded cement [8, 9]. The inability to control local elution rate 
also presents risk of systemic toxicity, and without means of cessation outside of a repeat 
surgical procedure, this presents risk of a serious adverse event (SAE). 
1.1.3 Failure to Complete Treatment  
Berend et al. [10] and Gomez et al. [11] authored some of the first retrospective reviews to 
fundamentally reexamine the definition of successful treatment of PJI from 1989 to 2012. 
Berend et al. summarized results of two-stage hip exchanges for PJI from 21 publications 
with an overall reported infection control rate of 88.8%; however, on further examination 
only 91.5% of patients treated at Stage 1 completed Stage 2. The infection control rate 
declined to 81.3% when all Intent-to-Treat (ITT) patients are included in the analysis. 
Because reporting on all patients was not common at the time of these publications, the rate 
of patients who failed to complete treatment is likely much higher. Gomez et al. reported 
81.4% treatment success among 329 knee and hip patients who completed the Stage 2 
treatment and had reached 1-year follow-up; however, they reported that of the 504 PJI 
patients in their review, 60 (11.9%) were re-operated on during the interstage phase to place 
another spacer (range: one to six additional spacers), and 87 (17.3%) retained their spacer 
(failed to complete Stage 2). After a minimum 1-year follow-up, just 285/416 (64.4%) of all 
patients in the retrospective study of the two-stage standard of care (SOC) at the Rothman 
Institute, a leading joint infection treatment center in the US, were considered a treatment 
success. The authors recommend that the success of two-stage arthroplasty be considered 
from the starting point of initial spacer implantation rather than from Stage 2 reimplantation, 
which is described below. 
A summary of the findings from 504 patients in Gomez et al. and from 1,537 hip PJI patients 
in Berend et al is shown in Table 2. Both publications indicate that the percentage of patients 
who never complete the Stage 2 revision procedure is comparable to the percentage of 
patients in whom the Stage 2 procedure is unsuccessful (10% to 20%). 
Table 2 Proportion of PJI Patients Who Achieve Reimplantation & Clinical Success 
Study 
No. of Studies 
Stage 2 
Reimplantation Rate 
Stage 2 Reported 
Success Rate 
Composite 
Success Rate 
Gomez et al. [11] 
1 
417/504 (82.7%) 
268/329 (81.4%) 
67.3% 

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Berend et al. [10] 
21 
1407/1537 (91.5%) 
1250/1407 (88.8%) 
81.3% 
Of the 87 patients who did not complete the Stage 2 reimplantation in the Gomez study, 15 
patients (17.2%) were re-operated on to perform arthrodesis, girdlestone, or amputation 
procedures, 19 (21.8%) were lost to follow-up, and 36 patients (41.4%) died during the study 
period without a revision implant, leaving just 17 (19.5%) of patients with retained spacers 
who were considered treatment successes [11]. 
1.1.4 Time to Reimplantation  
The interstage interval between implantation of the Stage 1 temporary spacer and Stage 2 
reimplantation of a revision prosthesis is critical for the patient. During the interstage period, 
the patient has only limited mobility and partial weight bearing on the affected limb. The risk 
of significant morbidity and permanent disability is high, as are the risks of systemic 
antibiotic-related toxicity and development of resistance to antibiotics [12]. Treatment during 
this period may include inpatient rehabilitation (extended care facility/skilled nursing 
facility) for part or all of the interstage phase, in-home nursing care for infusion services, 
extended physical therapy, long-term antibiotic use, extended opioid use, and ongoing 
monitoring for systemic toxicity. Andersson et al. interviewed 14 PJI patients and reported 
that patients with deep surgical site infections suffer significantly from pain, isolation and 
insecurity, and that it changes physical, emotional, social, and economic aspects of life in 
extremely negative ways, often persistently [13]. 
Gomez et al. reported an average interstage interval of 4.2 months (range: 0.7 to 131.7 
months) and median interval of 2.7 months in 504 patients who received Stage 1 temporary 
spacers at a single institution. This means that only slightly more than half of all patients 
completed the critical Stage 2 surgical procedure by the time of the typical 12-week 
postoperative follow-up. [11]. 
Berend et al. reported on 19 publications on two-stage exchange arthroplasty of the hip with 
interstage intervals of 1.5 to 18 months, with a median interval of 4.5 months, and a weighted 
average interval of 6.5 months in more than 1,000 patients [10]. These intervals are 50% 
longer than that reported by Gomez et al. 
Cancienne et al. reported on 18,533 knee PJI cases and 7,146 hip PJI cases with the ITT as 
two-stage exchange arthroplasty, of which only 61.6% of knee PJI patients and 60.2% of hip 
PJI patients completed the Stage 2 revision within 12 months [14, 15]. 
1.1.5 Interstage Mortality  
Gomez et al. and Berend et al. are also among the first to detail the underreported mortality 
of PJI patients prior to Stage 2 reimplantation. Historically, reports of two-stage exchange 
arthroplasty reported only the clinical results for patients who completed the Stage 2 revision 
procedure and they were completely silent on the results of patients who did not complete the 
procedure. Gomez et al. reported 1.2% mortality (5 of 6 related to infection) in the first 30 
days, 2.6% mortality within 90 days, and 6.5% mortality in the first year, compared to a 
national death rate of 2.0% for the general population of the same age [11]. Berend at al. 
reported on 202 hip PJI patients, 7% of whom died within 90 days of the Stage 1 procedure, 
including 4% who died prior to completing Stage 2 revision [10]. Recent evidence 
demonstrates that patients with PJI have a mortality rate of 25.9% at 5 years, which is 4-fold 

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higher than the mortality of age- and comorbidity-matched patients undergoing revision 
arthroplasty for a non-infected cause [16]. 
1.2 Investigational Products 
The investigational products for local irrigation are relabeled commercial product tobramycin 
injection that contains 40 mg/ml in a 2 ml vial and relabeled commercial product vancomycin 
in three 1 g vials of vancomycin base as a lyophilized powder that requires reconstitution. 
Both products are sold by Hospira, Inc. The products are being administered as per 
Investigational New Drug (IND) application 132585. 
1.2.1 Name and Intended Use of Investigational Product  
Vancomycin HCl and Tobramycin Sulfate for local irrigation are indicated for the treatment 
of periprosthetic joint infection in skeletally mature patients undergoing a two-stage revision 
arthroplasty procedure, where vancomycin HCl and tobramycin sulfate are the most 
appropriate antibiotics for treatment of the infection. The drugs are administered following 
removal of the existing prosthetic components and radical debridement by delivering 
vancomycin HCl and tobramycin sulfate in 0.9% sodium chloride to the affected site. 
Vancomycin HCl and Tobramycin Sulfate for local irrigation are intended for use for no 
more than 10 days, at which time a permanent device must be implanted or another 
appropriate treatment performed. 
Bacterial cultures should be obtained prior to and during treatment to isolate and identify 
etiologic organisms and to test their susceptibility to vancomycin HCl and tobramycin 
sulfate. 
1.3 Other Products 
The V.A.C.® ULTA™ Negative Pressure Wound Therapy (NPWT) system is a 
commercially available device that is used in this clinical study to deliver the investigational 
products. 
 

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2 
Study Objectives  
2.1 
Study Type 
This study is a Phase II prospective, single-arm, open-label, multicenter (3 to 5 sites), interventional trial. 
2.2 
Study Objective 
The primary objective of the study is to determine the safety of local antibiotic 
irrigation with Vancomycin HCl and Tobramycin Sulfate for the treatment of PJI. The 
secondary objectives are to collect preliminary efficacy data.  
2.3 
Outcome Measures 
2.3.1 Safety Evaluations  
The overall safety profile is characterized by assessing the incidence of adverse events 
(AEs), serious adverse events (SAEs), suspected adverse reactions, adverse reactions, 
and unexpected adverse reactions.  
2.3.2 Efficacy Evaluations 
Composite endpoint of overall success at 12 weeks: 
To be considered a success at 12 weeks, subjects must achieve ALL of the following: 
• 
Have a permanent revision prosthesis implanted by 12 weeks post initial surgery; 
• 
Have the same functioning prosthesis at 12 weeks post initial surgery; 
• 
Show no signs of infection, per the Delphi Criteria, between implantation and 12 weeks post 
initial surgery; AND 
• 
Have no surgical intervention for infection between initial surgery and 12 weeks post initial 
surgery. 
Composite endpoint of overall success at 12 months: 
To be considered a success at 12 months, subjects must achieve ALL of the following: 
• 
Have a permanent revision prosthesis implanted by 12 weeks post initial surgery;  
• 
Have the same functioning prosthesis at 12 months post initial surgery;  
• 
Show no signs of infection, per the Delphi Criteria, between implantation and 12 months post 
initial surgery; AND 
• 
Have no surgical intervention for infection between initial surgery and 12 months post initial 
surgery. 
2.3.3 Exploratory Measures 
Changes in erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), serum creatinine (sCr), 
complete blood count (CBC) with differential, and blood urea nitrogen (BUN) will be measured at 
each follow-up visit. Tissue viability, bone defects and bone loss will be assessed intraoperatively for 
the Stage 1 and the Stage 2 surgeries. Serum levels of vancomycin and tobramycin will be measured 
daily during experimental treatment to monitor for toxic systemic levels, as will the volume of 
effluent to determine the net fluid volume removed from the joint space. Opioid and other analgesic 
use will be tracked at each follow-up visit. 

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3 
Follow-up 
Subjects will be assessed at the interstage period, stage 2 surgery,, 3 weeks, 6 weeks, 12 
weeks, and 12 months from initial surgery. 

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4 
Subject Population and Selection 
Skeletally mature patients with chronic PJI of the hip or knee who meet all the following 
inclusion and none of the exclusion criteria will be recruited for this study. 
Enrollment is defined as providing informed consent for study participation and receiving at least 
one dose of antibiotic via local irrigation. The estimated total number of subjects enrolled is 
expected to be 15. 
Study subjects will be compensated for certain activities required of them during their 
participation in the clinical study, including travel expenses for each visit. 
4.1 Inclusion Criteria 
• Signed informed consent; 
• Age 18 years or greater; 
• Preoperative diagnosis of PJI of the hip or knee per the 2018 Definition of Periprosthetic 
Hip and Knee Infection [18], which is one of the following two major criteria: 
• 
The presence of a sinus tract communicating with the prosthesis; OR 
• 
2 positive cultures from separate fluid or tissue samples from the affected 
joint; OR 
• 
A pre-Stage 1 score ≥ 6 from all minor criteria listed in Table 3, including 
intraoperative criteria from procedures performed within 8 weeks prior to 
Stage 1. 
Table 3 Criteria for Periprosthetic Hip and Knee Infection 
 
Preoperative Diagnosis: Minor Criteria 
Score 
Decision 
Serum 
≥ 6 Infected 
2-5 Possibly infected* 
0-1 Not infected 
Elevated CRP or D-Dimer 
2 
Elevated ESR 
1 
Synovial 
Elevated synovial WBC or LE 
3 
Positive Alpha-defensin 
3 
Elevated synovial PMN (%) 
2 
Elevated Synovial CRP 
1 
Intraoperative Diagnosis: *Inconclusive 
Pre-op Score or Dry Tap 
Score 
Decision 
Preoperative score 
- 
≥ 6 Infected 
4-5 Inconclusive 
≤ 3 Not infected 
Positive histology 
3 
Positive purulence 
3 
Single positive culture 
2 
Abbreviations: CRP = c-reactive protein; ESR = erythrocyte sedimentation rate; WBC 
= white blood cell; LE = leukocyte esterase; PMN = polymorphonuclear 
leukocytes 

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* Patients with a score ≥ 6 from any preoperative or intraoperative minor criteria obtained 
within 8 weeks prior to Stage 1 meet the Musculoskeletal Infection Society (MSIS) criteria. 
Patients with a score of < 6 prior to Stage 1 surgery do not meet the inclusion criteria for 
this clinical study. 
• Chronic PJI (symptoms lasting at least 4 weeks) per Tsukayama et al. [19]; 
• Medical clearance for surgery; 
• Physical and mental ability to comply with the protocol, including the ability to read 
and complete required forms, and willingness and ability to adhere to the scheduled 
follow-up visits and requirements of the protocol. 
4.2 Exclusion Criteria 
• Late acute hematogenous infection per Tsukayama et al. [19]; 
• Patients for whom a two-stage exchange arthroplasty is not indicated; 
• Sepsis; 
• Previously failed single- or two-stage revision arthroplasty for PJI (aseptic revision, 
polyethylene liner exchange, and/or irrigation and debridement with component retention 
is allowed) 
• Patients with PJI of more than one joint; 
• Patients on chronic antibiotic therapy (≥ 6 months duration); 
• Patients who require therapeutic anticoagulation; 
• Patients on antiplatelet therapy for whom withholding antiplatelet therapy for any amount 
of time is contraindicated; 
• Patients with renal insufficiency/failure (sCr ≥ 2.0 mg/dl); [19].  
• Patients with uncontrolled diabetes, defined as: hemoglobin A1C levels > 8.0%; 
• Patients on immunosuppressive therapy, chemotherapy for malignant disease, 
or glucocorticoid therapy (e.g. prednisone ≥ 10 mg/day); 
• Patients with immunodeficiency (e.g., splenectomy, sickle cell anemia, Stage 3 
human immunodeficiency virus (HIV), primary humoral, bone marrow or other 
transplantation); 
• Anticipated or potential patient relocation that may interfere with follow-up examinations; 
• Allergy to vancomycin HCl or tobramycin sulfate (Note: prior history of Red Man’s 
syndrome is not considered an allergy); 
• Patients who are pregnant or planning to become pregnant; 
• Patients in whom negative pressure wound therapy is contraindicated; 
•  Patients infected with pathogens that are not considered susceptible to vancomycin 
HCl or tobramycin sulfate, as per the Investigator’s opinion. 
• Breastfeeding at screening visit; 
• Patients who are prisoners; 

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• Participation in another clinical trial of another Investigational Drug or Investigational Device 
within the past 30 days 
 
 

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5 
Study Treatment Procedures 
5.1 Treatment Summary 
Subjects considered potential candidates for the study will sign an Institutional Review Board 
(IRB)-approved Informed Consent Form (ICF) and Health Insurance Portability and 
Accountability (HIPAA) Authorization Form (if needed) prior to participating in any study 
activities. The treatment consists of standard of care (SOC) procedures and study procedures. 
(Table 4.)  
Table 4 Treatment Summary 
 
 
Pre- 
operative 
Stage 1 
(Day 0) 
Interstage 
(Stage 1 to 7-10 
Days) 
Stage 2 
(Day 7 -10) 
Post-op 
(Stage 2 
to 6 
weeks 
post-
Stage 1 
Medical treatment per standard 
of care (SOC) 
X 
X 
X 
X 
X 
Resection arthroplasty & 
debridement per SOC 
 
X 
 
 
 
Implantation of irrigation line 
 
X 
 
 
 
Application of NPWT 
 
 
X 
 
per SOC 
Local antibiotic irrigation 
therapy 
 
 
X 
 
 
Revision arthroplasty per SOC 
 
 
 
X 
 
Systemic antibiotic therapy per 
IDSA guidelines & study 
protocol 
 
 
As indicated by 
positive culture 
Start at Stage 2 
Stop Day 42* 
* Total 6 weeks antibiotic therapy post Stage 1 
 
5.2 Stage 1 Preoperative Treatment 
Provide preoperative treatment for all Stage 1 subjects per standard of care. Withholding 
preoperative antibiotics for 14 days pending intraoperative cultures is recommended. 
Administer 1 g of commercially available tranexamic acid (TXA) in 100 ml normal saline (NS) 
intravenously over a period of 10 minutes, prior to the operative procedure per the 
manufacturer’s instructions for use. 
5.3 Irrigation, Debridement. and Component Removal 
After entering the joint, proceed as follows: 
• Collect equal amounts of synovial fluid in two syringes (1 to 3 ml each), one for 
aerobic and one for anaerobic culture. 
• Obtain two synovial tissue samples, each from a different area of the joint, for histological 
evaluation of neutrophil count. 
• Remove all existing implants as per standard of care. 
• For knee subjects, obtain two additional samples for tissue culture, one from the femoral 

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canal and one from the tibial canal or the implant/bone interface. 
• For hip subjects, obtain two additional samples for tissue culture, one each from the 
acetabulum and the femoral canal. 
• If no fluid is obtained, obtain one additional sample from the joint for tissue culture. 
• As per standard of care, perform a radical debridement and total synovectomy, including 
debridement of the inner surface of the entire joint capsule including the posterior 
capsule of knee. 
• As per standard of care, debride all bony surfaces, such as gentle reaming of the femur 
and acetabulum in hips and the femoral and tibial canals in knees, and remove all 
visibly infected bone from all implant/bone interfaces in the knee. 
• Assess and record tissue and muscle viability using the parameters provided in Table 5. 
• Assess and record: (i) any bone defects of the knee using the Anderson Orthopaedic 
Research Institute (AORI) Classification (Table 6), or (ii) any acetabular bone loss 
(Table 7) and (iii) any femoral bone loss (Table 8) using the Paprosky 
Classification system. 
Table 5 
Tissue/Muscle Viability 
Muscle contraction upon stimulation with monopolar pencil? 
Yes/No 
Synovitis? 
Yes/No 
Purulence? 
Yes/No 
Necrosis? 
Yes/No 
Bleeding bone? 
Yes/No 
Signs of poor tissue perfusion? 
Yes/No 
 
Table 6 
AORI Bone Defect Types 
Type 1 defect 
• 
Intact metaphyseal bone 
Good cancellous bone at or near a normal joint-line level 
Type 2 defect 
• 
Damaged metaphyseal bone 
Loss of cancellous bone that requires cement fill, augments, or small 
bone grafts to restore a reasonable joint-line level 
• 
2A-one femoral or tibial condyle 
• 
2B-both femoral or tibial condyles 
Type 3 defect 
• 
(Deficient 
metaphyseal bone) 
Deficient bone that compromises a major portion of either condyle or 
plateau; these defects usually require a large structural allograft, a 
rotating hinged component, or custom component 
AORI = Anderson Orthopaedic Research Institute 
Table 7 
Paprosky Classification of Acetabular Bone Loss 
Type I 
Minimal deformity, intact rim 
Type IIA 
Superior bone lysis with intact superior rim 

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Type IIB 
Absent superior rim, superolateral migration 
Type IIIC 
Localized destruction of medial wall 
Type IIIA 
Bone loss from 10am-2pm around rim, superolateral cup migration 
Table 8 
Paprosky Classification of Femoral Bone Loss 
Classification 
Description 
Type I 
Minimal metaphyseal bone loss 
Type 2 
Extensive metaphyseal bone loss with intact diaphysis 
Type III a 
Extensive metadiaphyseal bone loss, minimum of 4 cm of intact cortical bone 
in the diaphysis 
Type III b 
Extensive metadiaphyseal bone loss, less than 4 cm of intact cortical bone in 
the diaphysis 
Type IV 
Extensive metadiaphyseal bone loss and a non-supportive diaphysis 
 
• After documenting bone defects, irrigate the joint using a short nozzle for surface 
irrigation and an intramedullary water pic in the canals. 
• Per the standard of care, use the following irrigation protocol (lavage pressure not to exceed 15 
psi): 
1. Soak the wound in a 50:50 dilution of 3% hydrogen peroxide and NS for 3 
minutes. For example, add 250 ml of 3% hydrogen peroxide to 250 ml of NS 
for a 50% solution. 
2. Irrigate the wound with approximately 3L NS by pulsatile lavage. 
3. Soak the wound in 0.3% dilute povidone-iodine for 3 minutes. For example, povidone-
iodine typically comes as a 10% solution. To dilute it to 0.3% bring 15 ml of 10% 
povidone iodine up to a total volume of 500 ml with NS. 
4. Irrigate the wound with approximately 3L NS by pulsatile lavage. 
5.4 Irrigation Line Placement and Closure 
• Approximately fifteen minutes prior to release of tourniquet (if used) or wound closure, 
administer 1 g of commercially available TXA in 100 ml NS intravenously over a period 
of 10 minutes per manufacturer’s instructions for use. 
• Use only monofilament suture for wound closure. 
• Cut the instillation disk off the end of the negative pressure wound therapy 
(NPWT) instillation line and place the freshly cut end of the line in the 
intraarticular space. 
• Cut one or more wound vacuum sponges approximately 5 cm wide and slightly longer 
than the length of the surgical wound, and place the sponge into the wound along the 
same path as the catheter, leaving approximately 3 cm of sponge extending out of the 
wound (this provides fluid communication from the joint to the NPWT system and allows 
bedside removal of the sponge if subject is unable to return to surgery). 
• In the knee, partially close the capsule from the distal to the proximal end, leaving 
approximately 5 cm of the proximal capsule open to maintain fluid communication 

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with the deep sponge(s). In the hip, no deep fascial closure is necessary. 
• Partially close the skin layer with a running subdermal monofilament suture. Leave 
approximately 5 cm open for communication with the deep sponge(s). 
5.5 Wound Dressing and Antibiotic Therapy Start 
• Cut the incisional vacuum sponge to cover the entire wound, both closed and 
open portions, ensuring contact with the deep sponges for fluid communication. 
• Place a sterile occlusive wound dressing over the incisional vacuum sponge. 
• The infusion line, exiting from the open portion of the wound, requires additional 
attention to prevent leaking. A “basement layer” of occlusive dressing is applied 
directly on the skin under the infusion line. A second layer of occlusive dressing is 
applied over the top of the infusion line, wrapping around it to form a mesentery, which 
then adheres to the basement layer. 
• Create an outflow system by cutting a window approximately 2cm long in the 
occlusive dressing directly over proximal end of the incisional vacuum sponge and 
placing the V.A.C.® ULTA™11 outflow disc with catheter on top of the window cut 
into the occlusive dressing. 
• Place an additional occlusive dressing over the outflow disc and tubing to protect it from 
being accidentally disconnected. 
• Connect the irrigation and vacuum lines to the NPWT cassette and collection cannister, 
respectively, then load the cassette and cannister on the NPWT system. 
• Hang the tobramycin sulfate solution for local irrigation. 
• Select V.A.C.® VeraFlo™ Therapy and program the NPWT settings as follows:  
Fill Assist: (Off) 
Start Phase: Instill 
Instill Volume: 50 ml 
Soak Time: 30 min 
VAC (vacuum assisted closure) Therapy Time: ½  hour Target 
Pressure: -125 mmHg  
Intensity: Low 
• Select “OK” to confirm the settings on the NPWT system, which will then 
automatically check for an intact seal. 
• Once the seal is confirmed, select “OK” on the NPWT system to proceed to the 
programmed instillation of tobramycin sulfate. This is the “Operating Room (OR) 
Therapy Start Time”. RECORD the OR Therapy Start Time. This time will be used 
by nursing to repeat the 24-hour local antibiotic treatment cycles. 
• The first dose of tobramycin sulfate will automatically be instilled into the wound in the 
operating room. Upon completion of the instillation of the tobramycin sulfate solution, 
CLAMP the VACUUM LINE first, then TURN OFF the NPWT system in order to allow 
the tobramycin to soak for 2 hours. The NPWT System must be turned off within 30 
                                                     
1 V.A.C. ULTA is a Trademark of KCI, an Acelity company. 

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minutes of instillation. DO NOT turn off the NPWT system before clamping. If the 
NPWT system is not turned off within 30 minutes of instillation, the system will 
automatically start a vacuum cycle. In this case, immediately turn off the NPWT system. 
Do not administer additional tobramycin sulfate. Wait 2 hours from the OR Therapy 
Start Time and proceed with administration of vancomycin HCl per Section 5.5 below. 
• Finally, for the knee place a blanket inside an immobilizer. Keep the tubing away from 
the skin and on top of the blanket within the immobilizer and close the immobilizer 
while ensuring there are no kinks in the tubing. 
• Do not open the wound dressing (hip or knee) until the day of the Stage 2 operation. 
• Initiate venous thromboembolism (VTE) prophylaxis with low molecular weight heparin 
12 hours post-op, continuing until the last dose is administered the night before Stage 2 
surgery 
5.6 Interstage Antibiotic Therapy 
The total antibiotic dose per 24-hour period reflects current labeling for safe total 24-hour 
systemic dose of 80 mg/day for tobramycin sulfate and up to 3000 mg/day for vancomycin 
HCl. Each day, the pharmacy shall reconstitute tobramycin sulfate and vancomycin HCl as 
specified in Table 9.  
Initial Dose 
NOTE: The first dose of tobramycin sulfate is administered in the operating room. This is the 
start of Interstage therapy. 
• After the tobramycin sulfate solution has been allowed to soak for 2 hours from the OR 
Therapy Start Time recorded in the operating room (and no more than 2.5 hours), hang 
the vancomycin HCl solution, UNCLAMP the vacuum line and TURN ON the NPWT 
system. RECORD the vancomycin HCl hang time. If the soak time exceeds 2.5 hours, 
immediately complete this step and proceed to the next step below. 
• On the NPWT screen, go to Advanced Settings and change the setting for Start Phase 
to “VAC” and select “OK”. DO NOT CHANGE ANY OTHER SETTINGS. 
Confirm the NPWT Settings as follows: 
 
V.A.C.® VeraFlo™ Therapy  
Fill Assist: (Off) 
Start Phase: VAC 
Instill Volume: 50 ml 
Soak Time: 30 min 
VAC Therapy Time: 1/2 hour 
Target Pressure: -125 mmHg 
Intensity: Low 
 
DO NOT CHANGE SETTINGS AGAIN FOR THE DURATION OF THERAPY. 
• Select “OK” to confirm the settings, and the NPWT system will automatically check 
for an intact seal.  
• The NPWT system will then automatically begin with a 30-minute vacuum, 
followed by instillation of vancomycin HCl solution and a 30-minute soak. The 

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NPWT system will follow this programmed cycle until manually stopped.  
• Three to four hours after the OR Therapy Start Time, collect blood for measurement 
of peak serum tobramycin level. If blood is not collected at the specified time, 
collect blood as soon as possible thereafter and continue with therapy and blood 
collection on the schedule described in this protocol. 
• Replace the NPWT collection canister approximately every 12 hours as needed, 
RECORD the total volume of fluid collected in each canister. 
Subsequent Interstage Doses 
During each subsequent 24-hours of Interstage therapy, perform the following: 
• 30 minutes before the OR Therapy Start Time (+/- 30 minutes), press “Stop” on the 
NPWT screen, hang a new bag of tobramycin sulfate solution, then press “Start”. This 
will perform a final 30-minute vacuum cycle and ensure that the daily antibiotic 
treatment cycle begins approximately at the OR Therapy Start Time. RECORD the 
tobramycin sulfate hang time. 
• At the same time as hanging the tobramycin sulfate (30 minutes before the OR Therapy 
Start Time +/- 30 minutes), collect blood for measurement of daily vancomycin serum 
level, tobramycin trough serum level, sCr, complete blood count (CBC) with differential 
and BUN. If blood is not collected at the specified time, collect blood as soon as possible 
thereafter and continue with therapy and blood collection on the schedule described in 
this protocol.  
• Immediately after the tobramycin sulfate solution instillation, CLAMP the VACUUM 
LINE first, then TURN OFF the NPWT system. The NPWT System must be turned off 
within 30 minutes of instillation. DO NOT turn off the NPWT system before clamping. 
If the NPWT system is not turned off within 30 minutes of instillation, the system will 
automatically start a vacuum cycle. In this case, immediately turn off the NPWT system. 
Do not administer additional tobramycin sulfate. Wait 2 hours from tobramycin 
instillation (approximately the OR Therapy Start Time) and proceed to the next step 
below. 
• Two hours after tobramycin sulfate instillation (approximately 2 hours and no more than 
2.5 hours after OR Therapy Start Time), hang the vancomycin HCl solution, UNCLAMP 
the vacuum line and then TURN ON the NPWT system. DO NOT CHANGE THE 
NPWT SETTINGS. RECORD the vancomycin HCl hang time. If the soak time 
exceeds 2.5 hours, immediately complete this step and proceed to the next step below. 
• The NPWT system will then automatically begin with a 30-minute vacuum, 
followed by instillation of vancomycin HCl solution and a 30-minute soak. The 
NPWT system will follow this programmed cycle until manually stopped.  
• Three hours (and no more than 4 hours) after the OR Therapy Start Time, collect 
blood for measurement of peak serum tobramycin level. If blood is not collected at 
the specified time, collect blood as soon as possible thereafter and continue with 
therapy and blood collection on the schedule described in this protocol. 
• Replace the NPWT collection canister every 6 to 8 hours as needed, RECORD the 
total volume of fluid collected in each canister. 
Repeat the 24-hour antibiotic irrigation regimen above until the subject is transferred to surgery for the 

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Stage 2 procedure. The Stage 2 procedure may be scheduled any time on post-operative day 7. It is 
acceptable for the Stage 2 procedure to take place earlier in the day than the previous Stage 1 procedure, 
resulting in less than 24 hours of local antibiotic therapy on day 7. 
Always begin each antibiotic therapy cycle as close as possible to 30 minutes before the OR Therapy 
Start Time. Any deviation in timing of antibiotic therapy or blood collection from a previous day is not 
carried forward to subsequent days. 
During the interstage period, subjects may receive systemic antibiotics as directed by a physician per 
Infectious Diseases Society of America (IDSA) guidelines. However, systemic vancomycin HCl or 
tobramycin sulfate administered simultaneously with local vancomycin HCl and tobramycin sulfate 
should be avoided unless directed by the treating physician, due to the risk of nephrotoxicity or 
ototoxicity. In the event that intravenous vancomycin or aminoglycoside administration is deemed 
appropriate in the interstage period, timing of daily laboratory blood collection may be adjusted on the 
order of the treating physician or pharmacist. See Table 9 for a summary of the local irrigation and 
monitoring protocol. 
Per the standard of care, subjects are non-weight bearing but allowed to stand with toe touch if tolerated. 
Elevation of the extremity should be continuous when in bed to reduce potential for edema and fluid 
retention. 
For further instruction on programming settings on the V.A.C.® ULTA™ Negative Pressure Wound 
Therapy System, see the V.A.C.® ULTA™ Quick Reference Guide. 
 
 

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Table 9 Antibiotic Instillation and Monitoring Regimen 
 
Drug 
Tobramycin 80mg in 50 ml NS 
Vancomycin 3000 mg in 1200 ml NS 
Concentration 
1.6 mg/ml (1600 µg/ml) 
2.5 mg/ml (2500 µg/ml) 
Compounding (In 
ISO Class 7 Clean 
Room with ISO 
Class 5 PEC) 
Remove 8 ml from 50ml NS infusion bag 
to yield 48 ml. Add 2 ml of tobramycin 40 
mg/ml for total of 80 mg tobramycin in 50 
ml NS. 
Reconstitute vancomycin powder to 
concentration of 50 mg/ml. Add 100 ml NS to 
1000 ml (1040 ml total volume) NS infusion 
bag to yield 1140 ml. Add 60 ml of 
vancomycin (50 mg/ml) to yield vancomycin 
3000 mg in 1200 ml NS. 
Stability 
24 hrs (room temperature) / 48 hrs 
(refrigerated) 
24 hrs (room temperature) / 7 days 
(refrigerated) 
Administration 
 
Nursing Administration Instructions: 
**For Irrigation** **Dispense in Bag** 
Irrigate with 50 ml tobramycin sulfate 
solution once every 24 hours via NPWT 
system with a 2-hour soak time, by 
UNCLAMPING the irrigation line, starting 
irrigation, CLAMPING vacuum line 
during soak, and turning pump OFF to 
achieve 2-hour soak time (no more than 
2.5 hours). 
NPWT Settings: 
 V.A.C. VeraFlo Therapy 
 Fill Assist: (Off)  
 Start Phase: Vacuum  
 Instill Volume: 50 ml  
 Soak Time: 30 min 
 VAC Therapy Time: 1/2 hour  
 Target Pressure: -125 mmHg 
 Intensity: Low 
Nursing Administration Instructions: 
**For Irrigation** **Dispense in Bag** 
Irrigate with 50 ml vancomycin HCl 
solution once every hour via NPWT system 
with a 30-minute soak time and 30 minutes 
suction @ -125mmHg. Repeat hourly. Stop 
once daily for administration of tobramycin 
sulfate. Restart upon completion of 
tobramycin sulfate soak. 
NPWT Settings: 
 V.A.C. VeraFlo Therapy 
 Fill Assist: (Off)  
 Start Phase: Vacuum  
 Instill Volume: 50 ml  
 Soak Time: 30 min 
 VAC Therapy Time: 1/2 hour  
 Target Pressure: -125 mmHg 
 Intensity: Low 
Monitoring 
 
Collect blood for daily tobramycin 
serum levels:  
(i) 3-4 hours after the OR Therapy 
Start Time (peak level)  
(ii) 30 minutes (+/- 30 minutes) 
before the OR Therapy Start Time 
(trough level). 
Collect blood for daily CBC with differential, 
BUN, sCr and 
vancomycin serum levels 30 minutes (+/- 30 
minutes) before the OR Therapy Start Time. 
Dose Adjustments 
Maintain tobramycin serum trough levels at 
<1 μg/ml. If serum trough levels are >1 
μg/ml or toxicity is a concern, decrease 
total dose based on serum concentration 
and PK parameters of the drug. Decrease 
total drug administered but not total 
volume. 
Example: 40 mg tobramycin sulfate in 50 
ml NS. 
Maintain vancomycin serum levels at 
<20 μg/ml. If serum levels >20 μg/ml or if 
toxicity is a concern, decrease total dose based 
on serum concentration and PK parameters of 
the drug. Decrease total drug administered but 
not total volume. Example: 1500 mg 
vancomycin HCl in 1200 ml NS. 
 
NS = normal saline; ISO = International Organization for Standardization; PEC = primary engineering control; NPWT = negative 
pressure wound therapy; VAC = vacuum assisted closure; HCl = hydrochloride; OR = operating room; CBC = complete blood 
count; BUN = blood urea nitrogen; sCr = serum creatinine; PK = pharmacokinetic 
5.7 Monitoring for Toxicity 
The subject and the surgical site around the NPWT dressing shall be monitored for unexpected 
increase in: 

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• edema; 
• local tissue redness (erythema) and induration; 
• local tissue temperature; 
• local itching/pruritus; 
• surgical site pain; 
• discoloration or worsening appearance of NPWT drainage; and 
• frequency of NPWT drainage volume of less than 50 cc per hour. 
Moderate increases of the conditions listed above are routinely encountered post-operative to a resection 
arthroplasty procedure. Should these conditions persist or exceed post-operative clinical expectations, 
local toxicity should be considered as a possible cause. 
Serum levels of each antibiotic are monitored daily during local irrigation therapy. Vancomycin HCl 
serum levels in this study are not true trough or peak levels, because of the near-continuous irrigation 
regimen. Serum levels will slowly increase toward a steady state level.  
If toxicity is suspected prior to completion of the local antibiotic irrigation therapy, the dose of local 
antibiotic irrigation may be adjusted, or local antibiotic irrigation may be withheld at the direction of the 
treating physicians. The subject may also be returned to the operating room for replacement of the NPWT 
dressing, including all sponges, at which time the local tissue may be examined and debrided if necessary. 
All additional treatments, surgical procedures, and deviations from the clinical protocol shall be recorded 
and reported to the Sponsor as appropriate. 
5.8 Stage 2 Revision Arthroplasty 
Administer preoperative antibiotics per IDSA guidelines and 1 g of commercially available TXA in 100 
ml NS intravenously over a period of 10 minutes, prior to the operative procedure per manufacturer’s 
instructions for use. 
Upon entering the joint proceed as follows: 
• Collect equal amounts of any available fluid in two syringes (1 to 3 ml each), one for anerobic 
culture and one for aerobic culture. 
• Obtain two synovial tissue samples, each from a different area of the joint, for 
histopathological evaluation of neutrophil count and complete histological evaluation for 
toxicity. 
• For knee subjects, obtain two additional samples for tissue culture, one from the femoral canal 
and one from the tibial canal or the implant/bone interface. 
• For hip subjects, obtain two additional samples for tissue culture, one each from the 
acetabulum and the femoral canal. 
• If no fluid is obtained, obtain one additional sample for tissue culture from the joint. 
• Debride any necrotic tissue, ream the intramedullary canals and lavage at surgeon’s discretion 
to prepare the joint for implant placement. 
• Assess and record tissue and muscle viability using the parameters provided in Table 5. 
• Assess and record: (i) any bone defects of the knee using the AORI Classification System 

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(Table 6), or, for hip defects (ii) any acetabular bone loss (Table 7) and (iii) any femoral bone 
loss (Table 8) using the Paprosky Classification system. 
• Repair any bony defects and prepare the bone for implant revision at surgeon’s discretion. 
• Implant the revision prosthesis using bone cement premixed with 1 gram of vancomycin per 
package of cement. 
• After reimplantation, use the following irrigation protocol (lavage pressure not to exceed 15 
psi): 
o Soak the wound in a 50:50 dilution of 3% hydrogen peroxide and NS for 3 minutes. 
For example, add 250 ml of 3% hydrogen peroxide to 250 ml of NS for a 50% 
solution. 
o Irrigate the wound with approximately 3L NS by pulsatile lavage. 
o Soak the wound in 0.3% dilute povidone-iodine, while continuing to mechanically 
debride wound with scrub brushes and sponges for three minutes. For example, 
povidone-iodine typically comes as a 10% solution. To dilute it to 0.3% bring 15 ml of 
10% povidone iodine up to a total volume of 500 ml with NS. 
o Irrigate the wound with approximately 3L NS by pulsatile lavage. 
• Approximately fifteen minutes prior to release of tourniquet (if used) or wound closure, 
administer 1 g of commercially available TXA in 100 ml NS intravenously over a period of 10 
minutes per manufacturer’s instructions for use. 
• Use only monofilament suture for wound closure. 
• Apply a commercially available incisional vacuum system at closing and use postoperatively 
as indicated and directed by the treating physician. 
5.9 Stage 2 Postoperative Care 
• Per the standard of care, initiate VTE prophylaxis on aspirin 12 hours post-op and 
continue until the 6-week follow-up visit. 
• Per the standard of care, allow weight bearing following Stage 2 at surgeon’s discretion. 
• Administer postoperative intravenous (IV) antibiotics as follows: 
o Culture-negative subjects receive IV vancomycin and cefepime; and culture-
positive subjects receive organism-specific IV or oral antibiotics per IDSA 
guidelines for approximately 5 weeks, ending 6 weeks after Stage 1 surgery 
(+/- 3 days). 
o Selection of vancomycin and/or cefepime may be modified for clinical reasons, 
such as subject allergies, as directed by the treating physicians. 
o Antibiotic therapy is expected to end 6 weeks after Stage 1 surgery unless 
otherwise directed by the treating physicians. If additional antibiotic therapy is 
required, RECORD the subject’s PJI status per the Delphi criteria and the 
reason for continued antibiotic therapy. 
5.10 Postoperative Physical Therapy 
There is no standard physical therapy regimen for subjects undergoing resection arthroplasty. 

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Numerous factors influence the physical therapy protocol. Thus, physical therapy will be 
individualized for each subject according to the clinical judgment of the operating surgeon. 

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6 
Schedule of Visits 
6.1 Treatment and Data Collection Table 
The study treatment and data collection for each scheduled visit are summarized in Table 10. 
Table 10 Treatment and Data Collection 
Events 
Visit 1 
Baselin 
e    
Screen 
Visit 2 
Stage 1 
Visit 3 
Interstage 
period 
Daily 
Visit 4 
Stage 2 
Visit 5 
3-week 
± 1 week 
follow-up 
Visit 6 
6-week 
± 1 week 
follow-up 
Visit 7 
12-week 
follow-up 
± 2 weeks 
Visit 8 
1-year 
follow-up 
± 4 weeks 
Time range permitted 
for logistical purposes 
Pre-op 
Day 0 
Days 1-7 
Max. 10 
Day 7 
Max. 10♦ 
Day 14- 
28 
Day 35- 
49 
Day 70-98 
Day 337- 
Day 393 
Inclusion/Exclusion 
X 
Informed Consent 
(& HIPAA) 
X 
Confirm 
Urine pregnancy test 
X 
2 synovial fluid cultures 
X 
X 
Medical history, vital 
signs, therapy, CCI score 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Administer 1g IV TXA 
pre-op and intraop 
X 
X 
2-3 tissue cultures 
X 
X 
2 samples for pathology 
X 
X 
Muscle/bone (AORI) 
viability assessment 
X 
X 
Operative time 
X 
X 
Place irrigation line & 
NPWT sponges 
X 
Program NPWT pump 
X 
X 
Document implant and 
local antibiotics/cement 
X 
*Administer 
local tobramycin 
& vancomycin 
Start 
intra-op 
Stage 1 
ongoing 
Stop 
pre-op 
Stage 2 
**Administer tailored 
IV or oral antibiotics 
per IDSA, if culture + 
Start 
post-op 
Stage 1 
ongoing 
ongoing 
ongoing 
Stop 
Day 42 
If culture -, administer IV 
vancomycin & cefepime 
Start post- 
op Stage 2 
ongoing 
Stop 
Day 42 
Tobramycin 
(peak/trough)/ 
vancomycin serum levels 
X 
daily 
X 
Vancomycin and 
aminoglycosides serum 
levels, if administered 
X 
X 
Transfusion record 
X 
X 
X 
X 
X 
sCR and BUN 
X 
Xb 
daily 
X 
X 
X 
X 
Complete Blood Count 
with differential & 
absolute neutrophils 
X 
Xb 
daily 
daily until 
discharge 
X 
X 
X 
X 
ESR, non-Cardiac CRP 
X 
Xb 
daily 
X 
X 
X 
X 
X 
Concomitant medications, 
including opioid use 
X 
X 
X 
X 
X 
X 
X 
X 
AE’s and complications 
X 
X 
X 
X 
X 
X 
X 
Wound check 
/joint 
assessment/Delphi 
No leak. 
Do not 
open 
X 
X 
X 
X 
X 
 
 

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HIPAA = Health Insurance Portability and Accountability Act; CCI = Charlson Comorbidity Index; AEs = adverse events; 
HgA1C = glycated hemoglobin; AORI = Anderson Orthopaedic Research Institute; NPWT = Negative Pressure Wound 
Therapy; IV = intravenous; IDSA = Infectious Diseases Society of America; sCr = serum creatinine; BUN = blood urea 
nitrogen; CBC = complete blood count; ESR = erythrocyte sedimentation rate; CRP = c-reactive protein; AE = adverse event 
All study time-points, follow-up visits and time-based outcomes are defined from the day of Stage 1. 
* The interstage period shall be completed on the seventh day after Stage 1 whenever possible, and no later than the 
10th day, to account for scheduling of Stage 2. The last instillation of antibiotics should be given the day of the Stage 
2 surgery. Administer tobramycin first (before vancomycin) so that at least 7 days of both tobramycin and 
vancomycin are administered.  Vancomycin may be administered for less than a full day on the seventh day if 
needed to accommodate a Stage 2 surgery time that is earlier than the Stage 1 surgery time. 
** Subjects may have positive cultures from previous aspirations or early in the interstage period. In either of these 
cases non-nephrotoxic IV or highly bioavailable oral antibiotics safe for use with vancomycin and tobramycin, are 
allowed at any time, including during the interstage period for ancillary treatment of specific organisms according to 
IDSA recommendations. Rifampin is not allowed during the interstage period, due to interaction with anesthetic in 
Stage 2. Non-nephrotoxic oral companion therapy of rifampin for Staphylococci or fluoroquinolones per IDSA 
recommendations for gram negative infections may be added during post-Stage 2 systemic antibiotic therapy. 
a Abbreviated medical history, vital signs, change in medical therapy, no CCI score. Vital signs do not need to be collected at 
Visits 5, 6, 7, and 8. 
b If baseline blood tests are taken within 48 hours of Stage 1 surgery and new blood tests are not performed day of Stage 1 
surgery 
The Delphi Criteria as used in this study are defined as: (1) infection eradication, characterized by a 
healed wound without fistula, drainage, or pain, and no infection recurrence caused by the same organism 
strain; (2) no subsequent surgical intervention after reimplantation surgery owing to infection; and (3) no 
occurrence of PJI-related mortality (by causes such as sepsis, necrotizing fasciitis) [17]. 
Ensure that the subject meets all inclusion/exclusion criteria and document in file. Collect signed 
informed consent, HIPAA form, screening and baseline data. Subjects found to not meet one or more 
inclusion/exclusion criteria are documented as screening failures, notified as such and treated outside of 
the study as directed by the physician. Perform the following activities for all other subjects, starting with 
Stage 1 surgery and at each subject visit for one year. 
6.2 Screening and Baseline Data 
o Administer Informed Consent Form 
o Confirm that the patient meets all inclusion criteria and none of the exclusion criteria 
o Administer pregnancy test (only women of childbearing potential) 
o Collect blood for tests in Table 10  and record results 
o Record demographics, CCI score, medical history, and current therapy 
o Confirm physician’s evaluation for chronic PJI diagnostic criteria per MSIS and check all diagnostic 
criteria on the source worksheet (SW) 
o Document infecting organism, if known 
o Record dose of all concomitant medications, including opioid use 
o Record vital signs: height, weight, heart rate, respiration rate, blood pressure, and temperature 
 
See Section 9.3 for procedures to follow if the subject is unfit for surgery on days 7-10. 
6.3 Stage 1 Surgery 
o Record date of surgery 
o Update medical history, changes in therapy, and preoperative and postoperative vital signs 

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o Record name and dose of all concomitant medications, including opioid use 
o Document type and quantity of NPWT products used 
o Collect intraoperative samples for histopathology and cultures and record results 
o Record results of blood tests in Table 10  (if time between baseline visit and stage 1 surgery is 
greater than 48 hours)  
o Record use of cell savers, transfusions, and volume transfused 
o Record assessment of muscle and bone viability 
o Record assessment of AORI bone defect type 
o Record assessment of Paprosky Classification of Bone Loss 
o Document tourniquet time and surgery time (skin to skin) 
o Record blood loss and all clinical laboratory results 
o Document all adverse events (AEs)/serious adverse events (SAEs) 
o Record time of first tobramycin sulfate instillation (OR Therapy Start Time) 
6.4 Interstage Period (Daily Until Stage 2 Surgery) 
o Record lot number of all irrigation antibiotics and diluents in the pharmacy. 
o Record date and time when tobramycin sulfate and vancomycin HCl is hung. 
o Record V.A.C.® ULTA™ settings on Day 1. DO NOT CHANGE after first dose of vancomycin 
HCl. 
o Record fluid volume in effluent (daily total of all cannister volumes) 
o Record daily dose of all concomitant medications, including opioid use 
o Record changes in therapy, and vital signs 
o Collect blood for tests in Table 10  and record results 
o  Document all AEs/SAEs 
o Record transfusion events and volume transfused (including packed cells) 
6.5 Stage 2 Surgery (7 to 10 Days After Stage 1) 
o Record date and time of surgery 
o Record abbreviated medical history, changes in therapy, and preoperative and postoperative vital 
signs 
o Download electronic Therapy Log from NPWT system.  
o Record implanted device-identifying data 
o Document type and amount of bone cement and antibiotics used for implant fixation 
o Record wound assessment 
o Collect blood for tests in Table 10  and record results 
o Collect intraoperative samples for histopathology and cultures and record results 
o Record assessment of muscle and bone viability 
o Record assessment of AORI bone defect type 
o Record assessment of Paprosky Classification of Bone Loss 
o Document tourniquet time and surgery time (skin to skin) 

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o Record blood loss and all clinical laboratory results 
o Document all AEs/SAEs 
o Record dose of all concomitant medications, including opioid use 
o Record transfusion events and volume transfused (including packed cells) 
o Record date of discharge from hospital 
o Document results of all cultures 
6.6 3 Weeks Post-op (After Stage 1) 
o Collect blood for tests in Table 10  and record results 
o Record changes in therapy, and vital signs 
o Document clinical observations of wound and PJI (per Delphi criteria) 
o Record dose of all concomitant medications, including opioid use 
o Document all AEs/SAEs 
o Record transfusion events and volume transfused (including packed cells) 
o Document any change to organism-specific antibiotics based upon positive culture results per study 
protocol 
6.7 6 Weeks Post-op (After Stage 1) 
o Collect blood for tests in Table 10  and record results 
o Document clinical observations of wound and PJI (per Delphi criteria) 
o Record dose of all concomitant medications, including opioid use 
o Record changes in therapy and vital signs 
o Document all AEs/SAEs 
o Record transfusion events and volume transfused (including packed cells) 
o Determine and document if the subject is to be taken off systemic antibiotics 
If the subject cannot be taken off antibiotic therapy, document reason and schedule additional follow-up 
as needed. 
6.8 12 Weeks Post-op (After Stage 1) 
o Collect blood for tests in Table 10 and record results 
o Document clinical observations of wound and PJI (per Delphi criteria)  
o Record dose of all concomitant medications, including opioid use  
o Record changes in therapy, and vital signs 
o Document all AEs/SAEs 
6.9 12 Months Post-op (After Stage 1) 
o Collect blood for tests in Table 10 and record results 
o Document clinical observations of wound and PJI (per Delphi criteria)  
o Record dose of all concomitant medications, including opioid use  
o Record changes in therapy, and vital signs 
o Document all AEs/SAEs 
 

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6.10 Unscheduled Visits 
Visits made to the site’s Emergency Department or to the operating surgeon’s office for the medical 
condition related to the index joint surgery are considered Unscheduled Visits, and should be documented 
on the relevant form provided by the clinical research organization (CRO) and in the electronic data 
capture (EDC) system. 
o Document clinical observations of wound and PJI (per Delphi criteria) 
o Record dose of all concomitant medications, including opioid use 
o Record changes in therapy 
o Document all AEs/SAEs 

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7 
Statistical and Data Considerations 
7.1 Overall Statistical Design 
This is a single-arm, prospective, multi-center Phase 2 feasibility study. Details of the statistical analysis 
and handling of missing values will be described in the Statistical Analysis Plan (SAP). This section 
provides key elements of the statistical approaches. 
7.2 Study Endpoints 
The study endpoints are: 
• Safety endpoints; 
• Composite endpoint of overall success at 12 weeks and 12 months; 
• Clinical laboratory values; 
• Vitals; 
• Procedural outcomes (operative time; time between Stage 1 and Stage 2 surgeries) 
• Use of pain medications 
• Pharmacokinetics of local irrigation route of administration for study drugs 
7.3 Analysis Populations  
The following analysis populations are defined for the study: Safety, Intent-to-Treat (ITT), Per-Protocol 
(PP) and Completed Cases (CC). The safety will be evaluated on the Safety population. The primary 
analysis of the efficacy will be performed on PP population. The ITT and CC populations will be used in 
a sensitivity analysis of the efficacy endpoints. 
• 
The ITT population includes all enrolled subjects. 
• 
Safety Population includes all ITT subjects who receive at least one dose of investigational medication 
• 
The Per-Protocol population is a subset of the ITT population and includes all subjects who receive the 
study investigational treatment and do not have major protocol violations.  
• 
The Completed Cases population includes all subjects in the PP population who have the 12-month 
follow-up visit.  
7.4 Type I Error 
The alpha level will be set to 0.05 based on the two-sided testing and 0.025 for the one-sided approach, if 
not explicitly stated otherwise. Unless otherwise indicated, all statistical inferences will be based on two-
sided 95% confidence intervals and p-values less than or equal to 0.05 will be considered significant.  
7.5 Statistical Approach to Secondary Endpoints 
This is a feasibility and safety study. No statistical hypotheses are associated with study endpoints. 
Endpoints will be described by means and proportions as appropriate. Confidence intervals will be 
constructed.  
7.6 Sample Size and Power 
This is a feasibility and safety study and safety. A total of 15 subjects are expected to be 
enrolled. The sample size for this study was selected based on practical and not on 

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statistical considerations.  
7.7 Statistical Analysis Plan  
Data will be summarized by the number, mean, median, standard deviation and range for continuous 
variables and by number and relative frequency for categorical variables. Summaries will be presented by 
visit as appropriate. A summary of the subjects combined will be provided for the baseline information 
only.  
7.8  Baseline Descriptive Statistics 
The number of subjects in each study population will be summarized. In addition, the number of subjects 
completing the study and withdrawing from the study will be presented along with reasons for 
withdrawal. 
Descriptive summaries of baseline and demographic characteristics will be presented. 
7.9 Safety Analysis 
The safety analyses will be performed using the ITT Population. An overall summary of AEs will be 
provided including the number of events and percent of subjects with any AEs, SAEs, Suspected Adverse 
Reactions, Adverse Reactions, and Unexpected Adverse Reaction. For each type of event, the number of 
events and number and percent of subjects with the event will be provided in a table. AEs will be coded 
using MedDRA medical dictionary. 

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8 
Risk Analysis 
Anticipated risks associated with this clinical study are summarized in Table 11, along with potential 
causes of risk and associated mitigations. 
Table 11 Summary Table of Risk Mitigation 
 
Risk to Health 
Potential Causes 
Current Mitigation 
Secondary 
infection 
Device introduces additional 
pathogens. 
Device is sterile packed with a sterility assurance level 
(SAL) of 10-6 
The concentrations of tobramycin sulfate and vancomycin 
HCl being delivered to the joint exceed MBEC for the 
most common PJI pathogens. 
• 
Additional pathogens 
migrate down the catheter 
through the opening in the 
skin. 
• 
The NPWT sponge is left 
in or on the wound 
without power and 
irrigation 
Catheter entry and surrounding area is covered and sealed 
with sterile occlusive dressing that is not removed until 
stage 2 surgery. 
NPWT is programmed to operate 30 minutes per hour, 22 
hours per day until stage 2 surgery. 
The concentrations of tobramycin sulfate and vancomycin 
HCl being flushed hourly over the catheter and through 
the sponge during NPWT exceed MBEC for the most 
common PJI pathogens. 
Local adverse 
tissue reaction 
Treatment concentrations of 
vancomycin cause tissue 
reaction. 
History of use of vancomycin in bone cement and 
antibiotic impregnated spacers without adverse local 
tissue reaction 
History of use of vancomycin in allograft and other bone 
substitutes without adverse local tissue reaction 
History of use of vancomycin in direct intra-articular 
instillation without adverse local tissue reaction 
Treatment concentrations of 
tobramycin cause tissue 
reaction. 
History of use of tobramycin in bone cement and 
antibiotic impregnated spacers without adverse local 
tissue reaction 
History of use of tobramycin in direct intra-articular 
instillation without adverse local tissue reaction 
Local irrigation concentrations are below the 
concentrations reported as toxic to bone in literature. 
Implant materials causes 
tissue reaction 
All materials selected are commonly used in short term 
implants with a long history of safe clinical use. 
Testing of temporarily implanted devices has been 
performed by the NPWT manufacturer 

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Reaction between antibiotics 
and implant materials cause 
tissue reaction. 
History of the proposed local antibiotic regimen and 
identical devices without adverse local tissue reaction 
Reaction between 
vancomycin and tobramycin 
cause tissue reaction 
History of use of tobramycin and vancomycin combined 
in bone cement and temporary cement spacers without 
adverse local tissue reaction 
History of use of tobramycin and vancomycin combined 
in direct intra-articular instillation at identical dosing and 
duration without adverse local tissue reaction 
Nephrotoxicity 
and ototoxicity 
Systemic levels of tobramycin 
causing nephrotoxicity 
Peak systemic concentrations are <2μg/ml, due to once 
daily dose and short serum half-life, and history of 
identical dosing and duration without nephrotoxicity or 
ototoxicity complications 
Systemic levels of 
vancomycin causing 
nephrotoxicity 
Average systemic concentration 3-10 μg/ml and 
history of identical dosing and duration without 
nephrotoxicity or ototoxicity complications 
The combination of the 
systemic levels of 
vancomycin and tobramycin 
are high enough to cause 
nephrotoxicity 
Studies using the same intra-articular antibiotic protocol 
showed no signs of nephrotoxicity or ototoxicity 
Fracture of bone 
Debridement and/or bone 
removal weakens bone 
Amount of debridement and bone removal identical to 
other standard of care in PJI 
Embolism 
The pressure created in the 
medullary canal from the 
delivery of the antibiotics 
creates a fat embolism. 
The maximum pressure of the irrigation system is 5 psi. 
The NPWT system removes more fluid than delivered to 
the joint between each irrigation cycle. 
There is no temporary spacer to close the medullary 
canal, eliminating the risk of locally excessive pressure. 
Dissemination of 
infection 
Local irrigation of antibiotics 
drives infection into 
surrounding uninfected tissue 
The maximum pressure of the irrigation system is 5 psi, 
which is well below the pulsatile lavage pressure of 15-25 
psi. 
Bleeding or 
hemorrhage 
NPWT 
Subjects are given TXA prior to NPWT therapy. The 
NPWT dressing is not applied directly over 
an exposed blood vessel. Subjects with contraindications 
for NPWT are expressly excluded 
Loss of protein/ 
malnutrition 
NPWT 
Intra-stage NPWT duration is short (7-10 days). 
Subjects remain in hospital in proposed feasibility study 
Compartment 
syndrome 
Build-up of fluid gets trapped 
in joint capsule. 
Joint capsule is not closed during irrigation treatment. 
NPWT removes excess fluid hourly, 22 hours per day. 
HCl = hydrochloride; MBEC = minimum biofilm eradication concentration; PJI = prosthetic joint infection;  
NPWT = negative pressure wound therapy; psi = pounds/square inch; TXA = transexamic acid  
 
 

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9 
Discontinuation of Study, Study Sites, or Subjects 
9.1 Discontinuation of Study Sites 
Study site participation may be discontinued if the Sponsor, the investigator, or the IRB judges it 
necessary for any reason. 
9.2 Discontinuation of the Study 
The study will be discontinued if the Sponsor judges it necessary for medical, safety, regulatory or other 
reasons consistent with applicable laws, regulations, and good clinical practice or for no reason. 
9.3 Discontinuation of Subjects from Study Treatment 
The criteria for enrollment must be followed explicitly.  
If a subject is medically unfit for surgery for any reason on days 7-10 post-initial surgery, on day 10 local 
antibiotic irrigation shall be discontinued, the NPWT system shall be removed, and culture-specific or 
institutional-specific systemic antimicrobial therapy shall be provided as follows: 
o Remove the NPWT dressing, using a sterile bedside technique. 
o Completely close the wound with dermal layer approximation using suture or staples, 
followed by incisional VAC over the closed wound. 
o Maintain incisional VAC dressing per manufacturer’s instructions for use. 
o Administer systemic antibiotics per institutional standard of care at the direction of the 
treating physicians for a period of at least 5 weeks (minimum 6 weeks antibiotic therapy). 
o Continue non-weight bearing status until the subject undergoes additional surgery. 
In addition to discontinuation of local antibiotic irrigation, a subject who is medically unfit for surgery on 
days 7-10 post-initial surgery shall be treated for underlying medical conditions, as directed by the 
treating physicians, until fit for surgery. At the time of subsequent surgery, the subject shall be assessed 
clinically for signs of PJI. If based on clinical data available at the time of surgery, the treating physician 
determines that the joint is no longer infected, the subject may undergo stage 2 surgery with a permanent 
implant. In the event of ongoing clinical signs/symptoms of infection, the subject shall be managed at the 
direction of the treating physicians as appropriate for the severity of the infection, including any of the 
following: continuation of systemic antibiotic therapy, repeat debridement with subsequent placement of 
an antibiotic-impregnated spacer, amputation, arthrodesis, or girdlestone procedure. 
All additional treatments, surgical procedures and deviations from the clinical protocol shall be recorded 
and reported to the Sponsor as appropriate. 
In addition, subject will be discontinued from study treatment in the following circumstances: 
• The investigator decides that the subject should be withdrawn from study treatment. If this 
decision is made because of toxicity, an SAE (defined in Section 10), or a clinically significant 
laboratory value, the study drug(s) are to be discontinued, and appropriate measures are to be 
taken. 
• The subject requests to be discontinued from study treatment. 
• The subject becomes pregnant (for subjects who are able to conceive). 
• The subject is significantly noncompliant with study procedures, as determined by the 
investigator. 

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• The subject meets Safety Stopping Rules as determined by the Investigator in consultation with 
the Independent Medical Safety Officer (IMSO) and/or Sponsor. 
9.4 Subject Completion/Disposition 
Every possible effort must be made by the study site personnel to contact the subject, obtain 
assessments, and determine the reason for discontinuation. Each subject who fails to attend the 
follow-up visit will first be contacted by phone. Three phone contact attempts will be made 
during a 2-week period. If phone contact attempts fail, a letter sent via registered mail will be 
sent to the subject’s last known address. If there is no response to the registered letter, the subject 
will be declared as lost to follow-up. 
The measures taken to ensure follow-up must be documented. For each case of premature 
termination, detailed information will be obtained explaining circumstances leading to the 
termination. This will be recorded on the Subject Withdrawal Form. Any subject prematurely 
withdrawn from the study will not be replaced. 
If a subject is discontinued from study treatment for any reason, the Sponsor or its designee is to be 
notified immediately. Subjects discontinued from study treatment will be followed up as required for 
monitoring of safety events, and they will be included in the ITT population.

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10 Adverse Events 
 
10.1 Basis of Adverse Events Management  
 
The definitions, recording, assessment and reporting of AEs required in this protocol is based requirement 
from 21CFR312.32(Revised as of April 1, 2018), 21CFR821 (Revised as of April 1, 2018), and Guidance for 
Industry and Investigators: Safety Reporting Requirements for Investigational New Drug (IND) and 
Bioavailability/Bioequivalence (BA/BE) Studies (FDA, December 2012, Drug Safety). 
 
10.2 Definitions 
 
Adverse Event (AE): Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. It can be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, and does not imply any 
judgment about causality.  
 
Suspected Adverse Reaction: Any AE for which there is a reasonable possibility that the drug caused the 
AE. Reasonable possibility means there is evidence to suggest a causal relationship between the drug and the 
AE. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any AE caused by a drug. 
 
Adverse Reaction: Any AE caused by a drug. Adverse reactions are a subset of all suspected adverse 
reactions where there is reason to conclude that the drug caused the event 
 
Unexpected Adverse Reaction: An AE or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has been observed. For 
investigational drugs under this study, because they are marketed and approved in the United States, 
ordinarily FDA-approved prescription drug labeling is used as the basis for determining whether an event is 
unexpected for reporting purposes.  
 
Unanticipated Adverse Device Effect (UADE): any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. 
 
Serious Adverse Event (SAE): An AE or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes:  
− Leads to death 
− Is life threatening, or places the participant at immediate risk of death 
− Requires inpatient hospitalization or prolongation of existing hospitalization,  
− A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect.  

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• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
10.3 Adverse Event Recording 
 
AE information will be collected throughout the study and all AEs will be captured. The Investigator or 
Research Coordinator will record all AEs on the appropriate Source Worksheet (SW) and entered on an 
electronic CRF (eCRF). The applicable SW will capture the event term, date of onset, duration, seriousness, 
severity, actions taken, outcome and causality to the investigational drug, the investigational procedure and 
the NPWT device. The Investigator is responsible for determination of severity and causality.  
 
The Investigator will assess subjects at each study visit for the occurrence of AEs. In order to avoid bias in 
eliciting AEs, subjects should be asked non-leading questions. All AEs reported by the subject or found on 
examination or laboratory report, must be recorded.  
 
All AEs must be followed until resolution or a stable clinical endpoint is reached. All treatments and 
outcomes of the AE must be recorded.  
 
All AEs and SAEs must be followed until: 
− AE is resolved (i.e. return to normal/baseline values)  
− AE is declared clinically insignificant 
− AE has stabilized 
− Subject is lost to follow-up or withdraws consent 
− Subject completes study, including required follow-up visits 
− Study closure 
The Investigator must, following Good Clinical Practice (GCP) guidelines, continue to treat (or refer subject 
to an appropriate practitioner for continuing treatment) any AE that remains unresolved after the subject has 
completed study participation.  
 
10.4 Adverse Event Assessment 
 
The Principal Investigator (PI) is responsible to identify and report all AEs reported from his/her site. The PI 
is responsible for determination of severity, seriousness and causality for each event reported.  
 
The Sponsor or Sponsor’s designee will review promptly all AE information reported by the PI. The Sponsor 
or Sponsor’s designee is responsible to make judgement for serious and causality, and to determine whether 
the event is “unexpected” for IND safety reporting purposes or to determine whether the event meets the 
definition of UADE. 
 
In the case of the PI and Sponsor has different assessment in terms of seriousness and life-threatening of an 
event, for IND safety report purpose, if either the sponsor or investigator believes that the event is serious, the 

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event must be considered serious and evaluated by the sponsor for possible expedited reporting. 
 
In the case of the PI and Sponsor has different assessment in term of causality of an event, for IND safety 
report purpose, the Sponsor’ judgement will overwrite PI’s judgement.  
 
The causality assessment is defined below: 
• Unrelated: known consequences of the underlying disease or condition under investigation or 
other events that commonly occur in the study population independent of investigational drug 
therapy or procedure. 
• Reasonable possibility: there is evidence to suggest a causal relationship between the 
investigational drug, the NPWT device and study procedure to the AE.  
• Definitely Related: there is reason to conclude that the investigational drug, NPWT device and/or 
study procedure caused the event 
10.5 Adverse Event Reporting 
 
The investigator is responsible for the collection and submission of AE and SAE data to the Sponsor/CRO.  
AE data will be collected to Source Worksheet (SW) and entered into the electronic data capture (EDC).  
 
The investigator must report to the Sponsor/CRO ANY SAE within 24 hours of the investigator becoming 
aware of the SAE, whether or not considered drug or NPWT device related, including those listed in the 
protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility 
that the drug or NPWT device caused the event. SAE data will be entered into the EDC and submitted on a 
Serious Adverse Event Report to the Sponsor/CRO. 
 
The Investigator is responsible for all reporting required as per IRB. The Sponsor/CRO is responsible to 
advise the Investigator if an AE is an unanticipated problem that needs to be reported to IRB. In general, an 
AE observed during the conduct of a study should be considered an unanticipated problem involving risk to 
human subjects, and reported to the IRB, only if it were unexpected, serious, and would have implications for 
the conduct of the study. (Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting 
to IRBs — Improving Human Subject Protection, FDA, January 2009, Procedural).  

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11 Drug Accountability 
The study site will maintain an inventory of the investigational products. This will include: 
• Name of person designated as responsible for the inventory of the investigational products 
• Amount received including date, and lot number 
• Amount currently in inventory 
• Amounts dispensed to each subject, identified by subject initials and a unique subject study number 
• Amount destroyed, if applicable – this should not occur without prior notification to Sponsor/CRO 
• Non-study disposition (e.g. wasted, broken) 
• Amount returned to Sponsor or designee, if applicable 
Sponsor, or its designee, will provide forms to facilitate investigational product inventory control. All 
investigational product accountability forms and treatment logs must be retained in the site’s regulatory 
binder. These records must be available for inspection by the Sponsor, its designees or by regulatory 
agencies at any time. 
Investigational drug shipment to sites will be accompanied by a Drug Shipment Form which must be 
signed and dated upon receipt and copy sent back to the Sponsor/CRO. This form must be filed in the site 
regulatory binder.  

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12 Quality Control and Quality Assurance 
12.1 Selection of Study Sites and Investigators 
The Sponsor will select Investigators who are qualified by training and experience to perform clinical 
research in this field and to participate in the clinical investigation. Sites will be selected based upon an 
assessment of the qualifications of the Primary Investigator and the facilities at each site. All Investigators 
will be trained on the investigational treatment, the protocol and all study procedures prior to enrolling 
subjects. 
A site initiation visit will be conducted at each study site to assure that the Investigator and the study staff 
understand the obligations for using and managing the investigational product, following the study 
protocol, obtaining informed consent, adhering to FDA and IRB regulations, and conducting clinical 
research.  
12.2 Training 
12.2.1 Site Training 
All Investigators/study personnel are required to attend Sponsor training sessions, which may be 
conducted at an Investigator's meeting, a site initiation visit or other appropriate training sessions. Remote 
over-the-phone or web-based training will take place as necessary. Training of Investigators/study 
personnel will include, but is not limited to, the study protocol, enrollment (including review of inclusion 
and exclusion criteria), subject retention, investigational drug usage, SW/electronic case report form 
(eCRF) completion, and study personnel responsibilities. All Investigators/study personnel that are trained 
must sign a training log (or an equivalent) upon completion of the training.  
12.3 Monitor Training 
The Sponsor or designee will engage monitors that are qualified by appropriate training and experience to 
review the conduct and quality of the study. Prior to working on the study, monitors will be trained to the 
investigational plan, SWs/eCRFs, and the drug/procedure knowledge. Such training will be documented. 
12.4 Study Monitoring 
Sponsor and/or a designee (e.g., a CRO), will monitor the clinical study in a manner consistent with FDA 
regulations and the Good Clinical Practice (GCP) standards.  
The Investigator is required to ensure compliance with all procedures required by the Investigational plan 
and by study procedures provided by the Sponsor. The Investigator agrees to provide reliable data and all 
information requested by the Investigational Plan including eCRFs, Data Clarification Forms or other 
appropriate instrument according to the instructions provided, and to ensure direct access to source 
documents to Sponsor designees. 
A risk-based approach will be used to determine the site monitoring frequency and the data sampling for source 
verification. Monitoring and data verification may be performed remotely or onsite.  
The Investigator and his/her staff will be expected to cooperate with Sponsor’s personnel or designee and to be 
available during the monitoring visits to answer questions sufficiently and to provide any missing information. 
12.5 Source Data Verification (SDV) 
Source data verification ensures accuracy and credibility of the data obtained. During SDV, reported data 
are reviewed with regard to being accurate, complete, and verifiable from source documents. 

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12.5.1 Definition of Source Data 
Source data includes all information in source documents (original records, certified copies of original 
records, appointment books, original laboratory records, and original data recorded on customized 
worksheets) and includes all original recordings or copies of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. Certain data may 
be directly entered into SW. In this case, the SW serves as source document. 
12.6 Direct Access to Source Data/Documents 
The Investigator(s)/institution(s) will permit direct access to source data/documents for study-related 
monitoring, audits, IRB and regulatory inspection(s). 
Consenting subjects are agreeing to allow the Sponsor or designee access and copying rights to pertinent 
information in their medical records relevant to study participation. As part of the informed consent, the 
Investigator or designee will obtain permission for regulatory authorities to review any records identifying 
subjects in this study. Sponsor will not otherwise release any personal information  
12.7 Protocol Deviations 
It is the Investigator's responsibility to ensure that there are no deviations from the protocol except in 
cases of medical emergencies, when the deviation is necessary to protect the life or physical well-being of 
the subject. In the event of any deviation from the protocol, a Protocol Deviation Report Form will be 
completed. The occurrence of protocol deviations will be monitored by the Sponsor for evaluation of 
Investigator compliance to the protocol, Good Clinical Practice (GCP), and regulatory requirements. The 
Investigator will inform the IRB of protocol deviations according to requirements of each reviewing IRB.  
A protocol deviation for this protocol consists of, but is not limited to, the following:  
• 
Failure to obtain subject’s informed consent prior to enrolling subject into the study  
• 
Enrollment of subjects who do not meet all eligibility requirements 
• 
Failure to conduct protocol required clinical follow-ups  
• 
Failure to report SAEs according to protocol requirements  
In the event of any deviation from the protocol, the Investigator will be notified of the site’s non-
compliance. Corrective actions will be advised if necessary and the methods, plan or other activities put in 
place to ensure non-recurrence will be documented by the Investigator and forwarded to the sponsor or 
their designee. Continued protocol deviations despite re-education of study site personnel and/or 
persistent protocol deviations may result in termination of the site’s study participation. Subjects already 
enrolled at these sites will continue to be followed per protocol guidelines. 

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13 Data Handling and Record Keeping 
13.1 Subject Coding 
The eCRFs and all other documents sent to the Sponsor will not contain identifying study subject 
information. Each subject will be assigned a unique subject code that reflects the site number and 
subject number. The subject code will consist of 8 characters in an alphanumeric combination. 
The site will maintain a log that links the subject code to the name of each subject. An example 
is shown in Table 12. 
Table 12 Example of the Subject Code 
 
Site Code 
Connector 
Subject Study Number 
A 
B 
C 
- 
1 
0 
0 
1 
13.2 Data Handling and Record Keeping 
For the study duration, the Investigator will maintain complete and accurate regulatory documentation as 
required per ICH GCP E6 r2 (8). Source Documentation. 
The following materials should be included in the subject record:  
• Signed Informed Consent Form 
• SWs including but not limited to dated and signed notes from each subject’s visit (for specific 
results of procedures and exams and study drug dosing and accountability data)  
• Medical records for subject medical history/physical condition prior to study involvement, study 
progress records, laboratory reports and medication record, device using record. 
• AEs reported and their outcome including supporting documents  
• Subject’s condition upon study completion or withdrawal and information regarding the subject’s 
discontinuation or completion 
13.3 Electronic Case Report Form Completion 
Accurate primary data collection will be performed by site staff trained on the protocol and eCRF 
completion. All data fields will be completed where appropriate. However, if data are not available (i.e., 
missed visit, etc.), the site will receive instruction regarding electronic documentation.  
Appropriate error messages will be generated, allowing for the modification and/or verification of the 
entered data. Queries will generally be sent to the investigational site using an electronic data query 
system that includes an automated audit trail of the corrections. The Investigator, will certify that the data 
are complete and accurate by applying an electronic signature to the eCRF. Any subsequent alterations, 
corrections, or additions will be reviewed and electronically signed by the Investigator prior to the 
database lock. 
The Sponsor or designee will provide clinical monitoring to include eCRF review and parity checks with 
the source documentation. 
13.4 Record Retention 
The Investigator/Site will maintain all records pertaining to this study for the later of (a) five years 
following study completion, or (b) five years after the study has been terminated by the Sponsor, or (c) as 

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otherwise instructed by the Sponsor. Investigator will be notified by Sponsor of the date of completion or 
discontinuation of the study.  
To comply with these requirements, the Investigator will not dispose of or transfer any records relevant to 
this study without either (1) written permission from the Sponsor, or (2) providing an opportunity for the 
Sponsor to archive the records with an external vendor.  

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14 Ethical Considerations 
14.1 Informed Consent 
Written informed consent will be obtained from each subject before any study-specific procedures or 
assessments are done and after the aims, methods, anticipated benefits and potential hazards are 
explained. The subject’s willingness to participate in the study will be documented in writing in the ICF, 
which will be signed by the investigator or designee and the subject with the date of that signature 
indicated. The Investigator will keep the original consent forms and copies will be given to the subjects. It 
will also be explained to the subjects that they are free to refuse entry into the study and free to withdraw 
from the study at any time without prejudice to future treatment. Written and/or oral information about the 
study will be provided in understandable language to all subjects. 
14.2 Institutional Review Boards 
IRB approval for the protocol and informed consent form will be obtained prior to study participation by 
subjects. The approval letter must be obtained prior to beginning this study and a copy must be provided 
to the Sponsor. No changes will be made to the protocol or informed consent form without appropriate 
approval from the IRB, the Sponsor and/or the regulatory agencies.  
As per responsible IRB requirements, the Investigator will report study progress until it is completed. 
Further, any protocol amendments as well as associated informed consent changes will be submitted to 
the IRB and written approval must be obtained prior to implementation. 
14.3 Confidentiality and Protection of Study Files 
The identity of subjects enrolled in the study and the information contained in their study records will be 
kept confidential by Sponsor.  
Each subject will be assigned a study identification number to be used on eCRFs and other study records 
sent to the Sponsor or its designee.  
Confidentiality will be protected as much as possible throughout the study. Medical records will be 
reviewed by designees of Sponsor and/or its designee and will be made available for review as required 
by the IRB and regulatory authorities. Results of data collected will be reported as statistical information 
only. The subject’s name will not be used or otherwise disclosed unless required by US law or regulation.  

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15 Sponsor and Investigator Reports 
15.1 Investigator Reports 
The reports in Table 13 are required of each investigator as described. 
Table 13 Investigator Reports 
 
Report 
Submit to 
Submission Schedule 
Screening & 
Enrollment 
CRO 
Weekly 
All study data 
EDC (CRO) Baseline data: within 48 hours, all others: no later than 14days 
Serious adverse 
events (SAEs) 
CRO/IRB 
Report to CRO within 24 hours after the Investigator first learns 
of the event. Reporting to IRB acceding to IRB’s reporting roles, 
or if notified by the Sponsor/CRO that the SAE meets FDA’s IND 
safety report criteria.  
Study Deviations 
and Subject 
withdrawal  
CRO/IRB 
Report to CRO and IRB within 48 hours if the deviation affects 
the subject’s safety and wellbeing. Otherwise, report to CRO no 
later than 14 days; reporting to IRB acceding to IRB’s reporting 
roles.  
IRB submission for 
continued approval  
IRB/CRO 
Submit to IRB annually or as required during and at the end of the 
study. Submit IRB’s approval document to CRO within 5 working 
days.  
15.2 Sponsor Safety Reports 
The Sponsor is responsible for timely reviewing and making determination of safety information submitted 
from the investigational sites meets the IND safety reporting criteria as defined in 21 CFR 321.32:  
• Suspected adverse reaction 
• Serious  
• Unexpected 
The Sponsor is responsible to ensure the serious and unexpected suspected adverse reaction is reported to the 
FDA in an IND safety reporting format and all participating investigators as soon as possible, but in no case 
later than 15 calendar days after the sponsor determines that the information qualifies for reporting according 
to 21 CFR 321.32 (c) (1) (i). For any unexpected fatal or life-threatening suspected adverse reaction, the 
sponsor must also notify FDA as soon as possible but in no case later than 7 calendar days after the sponsor's 
initial receipt of the information. 21 CFR 321.32 (c) (2).  
 
The Sponsor will notify the central IRB and advise all participating investigational sites to notify the local 
IRBs for the aforementioned IND safety report.  
 
In addition, the sponsors will report the results of an evaluation of an UADE to FDA and all reviewing IRBs 
and investigators within 10 working days after the sponsor first receives notice of the adverse effect. Per 21 
CFR 812.150 (b)(1).  
 
If the sponsor determines that an UADE presents an unreasonable risk to subjects, the sponsor will terminate 
all investigations or parts of investigations presenting that risk as soon as possible. Termination shall occur 

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not later than 5 working days after the sponsor makes this determination and not later than 15 working days 
after the sponsor first received notice of the effect as defined in 21 CFR 812.46(b)(2).  
 

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16 Literature Cited 
 
1. 
Genetic and Rare Diseases Information Center. Prosthetic Joint Infection; Available 
from: https://rarediseases.info.nih.gov/diseases/11977/prosthetic-joint-infection 
2. 
Cochran AR, Ong KL, Lau E, et al. Risk of reinfection after treatment of infected total 
knee arthroplasty. J Arthroplasty. 2016;31(9 Suppl):156-161. 
3. 
Landersdorfer CB, Bulitta JB, Kinzig M, et al. Penetration of antibacterials into bone: 
pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clin 
Pharmacokinet. 2009;48(2):89-124. 
4. 
Ceri H, Olson ME, Stremick C, et al. The Calgary biofilm device: new technology for 
rapid determination of antibiotic susceptibilities of bacterial biofilms. J Clin Microbiol. 
1999;37(6):1771-1776. 
5. 
Laverty G, Alkawareek MY, Gilmore BF. The in vitro susceptibility of biofilm forming 
medical device related pathogens to conventional antibiotics. Data Set Papers in Science, 
2014. 
6. 
Neut D, van de Belt H, van Horn J, et al. The effect of mixing on gentamicin release from 
polymethylmethacrylate bone cements. Acta Orthop Scand. 2003;74(6):670-676. 
7. 
Kuechle DK, Landon GC, Musher DM, et al. Elution of Vancomycin, daptomycin, and 
amikacin from acrylic bone cement. Clin Orthop Relat Res. 1991;(264):302-308. 
8. 
Neut D, Hendriks JGE, van Horn JR, et al. Pseudomonas aeruginosa biofilm formation 
and slime excretion on antibiotic-loaded bone cement. Acta Orthop. 2005;76(1):109-114. 
9. 
Tunney MM, Ramage G, Patrick S, et al. Antimicrobial susceptibility of bacteria isolated 
from orthopedic implants following revision hip surgery. Antimicrob Agents Chemother. 
1998;42(11):3002-3005. 
10. 
Berend KR, Lombardi AV, Morris MJ, et al. Two-stage treatment of hip periprosthetic 
joint infection is associated with a high rate of infection control but high mortality. Clin 
Orthop Relat Res. 2013;471(2):510-518. 
11. 
Gomez MM, Tan TL, Manrique J, et al. The fate of spacers in the treatment of 
periprosthetic joint infection. J Bone Joint Surg Am. 2015;97(18):1495-1502. 
12. 
van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of 
vancomycin-induced nephrotoxicity associated with dosing schedules that maintain 
troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 
2013;57(2):734-744. 
13. 
Andersson AE, Bergh I, Karlsson J, et al. Patients' experiences of acquiring a deep 
surgical site infection: an interview study. Am J Infect Control. 2010;38(9):711-717. 
14. 
Cancienne JM, Werner BC, Bolarinwa SA, et al. Removal of an infected total hip 
arthroplasty: risk factors for repeat debridement, long-term spacer retention, and 
mortality. J Arthroplasty. 2017;32(8): 2519-2522. 

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15. 
Cancienne JM, Granadillo VA, Patel KJ, et al. Risk factors for repeat debridement, spacer 
retention, amputation, arthrodesis and mortality after removal of an infected total knee 
arthroplasty with spacer placement. J Arthroplasty. 2018;33:515-520. 
16. 
Zmistowski B, Karam JA, Durinka JB, et al. Periprosthetic joint infection increases the 
risk of one-year mortality. J Bone Joint Surg Am. 2013;95:2177–84. 
17. 
Diaz-Ledezma C, Higuera CA, Parvizi J. Success after treatment of peri-prosthetic joint 
infection: a Delphi-based international multidisciplinary consensus. Clin Orthop Relat 
Res, 2013;471(7):2374-2382. 
18. 
Parvizi J, Tan T, Goswami K, et al. The 2018 definition of periprosthetic hip and knee 
infection: an evidence-based and validated criteria. J Arthroplasty. 2018;33:1309-1314. 
19. 
Tsukayama DT, Estrada R, Gustilo RB, Infection after total hip arthroplasty. A study of 
the treatment of one hundred and six infections. J Bone Joint Surg Am. 1996;78:512–523. 
20. 
Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin 
Pract. 2012;120:179–184.