Pharmacokinetics of Antistaphylococcal Antibiotics in Infants
Phase: PHASE1
Conditions: Systemic Infection
Sponsor: Phillip Brian Smith

 ____________________________________________________________________________________________ 
 
 
Pediatric Trials Network 
 
Pharmacokinetics of Antistaphylococcal Antibiotics in Infants 
 
Phase 1 Trial 
 
Funding Sponsor: 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD) 
 
Funding Mechanism: Task Order 
 
Protocol Number: NICHD-2012-02-Staph Trio 
 
Protocol Date: 
03 February 2014 
Protocol Version: 
4.0 
IND Number: 
115396 
Principal Investigator: 
 
Matthew M. Laughon, MD, MPH 
Associate Professor  
The University of North Carolina at Chapel Hill 
Chapel Hill, NC  27599-7596 
Telephone:  919-966-5063 
Fax:  919-966-3034 
Mobile:  919-824-6373 
Email:  matt_laughon@med.unc.edu 
 
IND Sponsor 
 
P. Brian Smith, MD, MPH, MHS 
Associate Professor of Pediatrics 
Duke University Medical Center 
Duke Clinical Research Institute 
Telephone: 919-668-8951 
Email: brian.smith@duke.edu 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
i 
STATEMENT OF COMPLIANCE 
 
 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP): Consolidated Guideline, and 
the applicable regulatory requirements from the United States Code of Federal Regulations 
(CFR), including 45 CFR 46 (human subjects protection, incorporating Subpart D Additional 
Protections for Children Involved as Subjects in Research), 21 CFR 312 (Investigational New 
Drug [IND]), 21 CFR 50 (Protection of Human Subjects, incorporating Subpart D Additional 
Safeguards for Children in Clinical Investigations), 21 CFR 11 (electronic records and 
signatures), 21 CFR 54 (financial disclosure), and 21 CFR 56 (institutional review board [IRB]). 
 
 
All individuals responsible for the design and/or conduct of this study have completed human 
subjects’ protection training and are qualified to be conducting this research. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 
 ____________________________________________________________________________________________ 
ii 
SITE PRINCIPAL INVESTIGATOR STATEMENT 
 
I have read the protocol, including all appendices and the investigator brochure or product label, 
and I agree that it contains all necessary details for my staff and me to conduct this study as 
described. I personally will oversee the conduct of this study as outlined herein and will make a 
reasonable effort to complete the study within the time designated. I agree to make all 
reasonable efforts to adhere to the attached protocol. I understand and am aware of my 
responsibilities as an investigator as described in the applicable GCP regulations. 
 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by the sponsor or its representative. I will discuss this material with 
them to ensure that they are fully informed about the efficacy and safety parameters and the 
conduct of the study in general. I am aware that, before beginning this study, the institutional 
review board responsible for such matters must approve this protocol in the clinical facility 
where it will be conducted. 
 
I agree to provide all participants with informed consent forms, as required by government and 
International Conference on Harmonisation regulations. I further agree to report to the sponsor 
or its representative any adverse events in accordance with the terms of this protocol and the 
U.S. Code of Federal Regulations, Title 21, part 312.64. 
 
 
 
 
 
Principal Investigator Name (print) 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 
 ____________________________________________________________________________________________ 
iii 
STUDY PRINCIPAL INVESTIGATOR / IND SPONSOR SIGNATURE 
 
The signature below documents the review and approval of this protocol and the attachments 
(e.g., package inserts) and provides the necessary assurances that this clinical study will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality and according to local legal and regulatory requirements and to the principles 
outlined in applicable U.S. federal regulations and ICH guidelines. It is the investigator’s 
responsibility to ensure that, prior to initiating this study; this protocol is reviewed and approved 
by the appropriate local IRB. The composition and conduct of this committee must conform to 
the U.S. CFR, including provisions outlined in 45 CFR 46, subpart D. 
 
 
 
 
 
Pediatric Trials Network Study Principal 
Investigator Name (print) 
 
 
 
 
 
 
 
Signature 
 
Date 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
Table of Contents 
 
 
page 
 ____________________________________________________________________________________________ 
iv 
Statement of Compliance .......................................................................................................... i 
Signature Pages ........................................................................................................................ ii 
List of Abbreviations .............................................................................................................. vii 
Protocol Synopsis ............................................................................................................... …ix 
 
1 
Key Roles
 
 .......................................................................................................................... 9
2 
Background Information and Scientific Rationale
 
 ....................................................... 10
2.1 
Background Information
 
 ........................................................................................ 10
2.2 
Scientific Rationale
 
 ............................................................................................... 13
2.2.1 
Potential Risks
 
 .......................................................................................... 13
3 
Objective
 
 ......................................................................................................................... 16
3.1 
Study Outcome Measures
 
 .................................................................................... 16
3.1.1 
Primary Outcome Measures
 
 ...................................................................... 16
3.1.2 
Secondary Outcome Measures
 
 ................................................................. 16
4 
Study Design
 
 .................................................................................................................. 17
5 
Study Population
 
 ............................................................................................................ 18
5.1 
Selection of the Study Population
 
 ......................................................................... 18
5.2 
Inclusion/Exclusion Criteria
 
 ................................................................................... 18
6 
Study procedures
 
 ........................................................................................................... 19
6.1 
Summary of Procedures
 
 ....................................................................................... 19
6.2 
Screening
 
 ............................................................................................................. 19
6.3 
Enrollment
 
 ............................................................................................................ 20
6.4 
Follow-up
 
 .............................................................................................................. 20
6.5 
Final Study Visit
 
 .................................................................................................... 21
6.6 
Laboratory Evaluations
 
 ......................................................................................... 21
6.6.1 
Clinical Laboratory Evaluations
 
 ................................................................. 21
7 
Study Product Description
 
 ............................................................................................ 23
7.1 
Dosage and Study Drug Information
 
 ..................................................................... 23
7.1.1 
Rationale for Dose Selection
 
 ..................................................................... 23
7.1.2 
Rifampin, ticarcillin-clavulanate, and clindamycin local standard of care 
dosing
 
 ....................................................................................................... 24
7.1.3 
Formulation, Packaging, and Labeling
 
....................................................... 24
7.1.4 
Product Storage and Stability
 
 .................................................................... 24
7.1.5 
Preparation and Administration of Study Intervention/Investigational 
Product
 
 ...................................................................................................... 24
7.2 
Concomitant Medications/Treatments
 
 ................................................................... 25
8 
Assessment of Safety
 
 .................................................................................................... 26
8.1 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
 
26
8.1.1 
Adverse Events
 
 ......................................................................................... 26
8.1.2 
Unexpected Adverse Event Definition
 
 ....................................................... 27

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
Table of Contents - continued 
 
 
page 
 ____________________________________________________________________________________________ 
v 
8.1.3 
Identification of Events and Timeframe for Reporting
 
 ................................ 27
8.1.4 
Interim Safety Analysis
 
 .............................................................................. 27
8.2 
Guidelines for Determining Causality
 
 .................................................................... 28
8.3 
Reporting Procedures
 
 ........................................................................................... 28
8.3.1 
Adverse Event Reporting
 
........................................................................... 28
8.3.2 
Regulatory Reporting
 
 ................................................................................ 28
8.4 
Halting or Discontinuation
 
 ..................................................................................... 28
8.5 
Safety Oversight
 
 ................................................................................................... 29
9 
Clinical Monitoring
 
 ......................................................................................................... 30
10 
Statistical Considerations
 
 ............................................................................................. 31
10.1 
Study Outcome Measures
 
 .................................................................................... 31
10.2 
Sample Size Considerations
 
 ................................................................................. 31
10.3 
Analysis Plan
 
 ........................................................................................................ 31
11 
Participant Confidentiality
 
 ............................................................................................. 33
12 
Informed Consent Process
 
 ............................................................................................ 34
13 
Source Documents and Access to Source Data/Documents
 
 ...................................... 35
14 
Ethics/Protection of Human Participants
 
 ..................................................................... 37
14.1 
Ethical Standard
 
 ................................................................................................... 37
14.2 
Institutional Review Board
 
 .................................................................................... 37
14.3 
Informed Consent
 
 ................................................................................................. 37
14.4 
Study Discontinuation
 
 ........................................................................................... 37
15 
Data Handling and Record Keeping
 
 .............................................................................. 38
15.1 
Data Management Responsibilities
 
 ....................................................................... 38
15.2 
Data Capture Methods
 
 .......................................................................................... 38
15.3 
Types of Data
 
 ....................................................................................................... 39
15.4 
Timing/Reports
 
 ..................................................................................................... 39
15.5 
Study Records Retention
 
 ...................................................................................... 39
15.6 
Protocol Deviations
 
 ............................................................................................... 39
15.7 
Participant Privacy/Authorization
 
 .......................................................................... 39
16 
Publication Policy
 
 .......................................................................................................... 41
17 
Literature References
 
..................................................................................................... 42
 
 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
List of Abbreviations 
 
 ____________________________________________________________________________________________ 
vi 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
AUC
Area Under the Concentration-Time Curve 0–24 hours 
0–24 
AUC
Area Under the Curve at Steady State 
ss 
BPCA 
Best Pharmaceuticals for Children Act 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CL 
Clearance 
C
Maximum Concentration 
max 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CV% 
Coefficient of Variance 
DBS 
Dried Blood Spot 
DCC 
Data Coordinating Center 
DCF 
Data Collection Form 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GA 
Gestational Age 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDES 
Internet Data Entry System 
IEC 
Independent or Institutional Ethics Committee 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
mg 
Milligram 
MRSA 
Methicillin-resistant Staphylococcus aureus  
μg 
Microgram 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NICHD 
National Institute of Child Health and Human Development 
NICU 
Neonatal Intensive Care Unit 
NIH 
National Institutes of Health 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
List of Abbreviations - continued 
 
 ____________________________________________________________________________________________ 
vii 
PNA 
Postnatal Age 
PK 
Pharmacokinetics 
SAE 
Serious Adverse Event 
SGOT 
Serum Aspartate Aminotransferase 
SGPT 
Serum Alanine Aminotransferase 
t
Half-life 
1/2 
TORO 
Transfer of Regulatory Obligations 
V 
Volume 
V
Volume of Distribution at Steady State 
ss 
WHO 
World Health Organization 
 
 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
viii 
 
PROTOCOL SYNOPSIS 
Protocol Title: 
Pharmacokinetics of Antistaphylococcal Antibiotics in Infants 
Phase: 
I 
Product: 
Rifampin, ticarcillin-clavulanate, clindamycin 
Objectives: 
Primary: Describe the pharmacokinetics (PK) of rifampin, ticarcillin-
clavulanate, and clindamycin in infants 
Secondary: Describe the safety profile of rifampin, ticarcillin-clavulanate, and 
clindamycin in infants 
Study Design: 
Multiple center, open-label, PK study 
Study 
Population: 
Hospitalized infants: 
1. Rifampin: <121 days postnatal age (PNA) 
2. Ticarcillin-clavulanate: <91 days PNA AND <30 weeks gestational 
age (GA) 
3. Clindamycin: <121 days PNA AND <30 weeks GA 
Number of 
Participants: 
16–32 evaluable per study drug 
Number of 
Sites: 
Approximately 15 sites 
Duration of 
Participant 
Participation: 
Approximately 30 days 
Dose Duration: Study drug will be administered for 2–4 days  
Estimated 
Start: 
July 2012 
Estimated 
Time to 
Complete 
Enrollment: 
Approximately 24 months 
 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
9 
1 
KEY ROLES 
For questions regarding this protocol, contact: 
 
A) Study Principal Investigator:  
 
Matthew M. Laughon, MD, MPH 
Associate Professor  
 
The University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599-7596 
Telephone: 919-966-5063 
Fax: 919-966-3034 
Mobile: 919-824-6373 
E-mail: matt_laughon@med.unc.edu 
 
 
B) NICHD Contract Officer Technical Representative:  
 
Zhaoxia Ren, MD, PhD 
Medical Officer 
Obstetric and Pediatric Pharmacology Branch 
Center for Research for Mothers and Children 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
National Institutes of Health 
6100 Executive Blvd., Room 4A01D MSC 7510 
Bethesda, MD 20892-7510 
Phone: 301-402-9340 
Fax: 301-480-2897 
Email: zren@mail.nih.gov  
 
 
C) Best Pharmaceuticals for Children Act (BPCA)–Data Coordinating Center (DCC):  
 
The EMMES Corp. 
401 N Washington St., #700 
Rockville, MD 20850 
Phone: 301-251-1161 
Fax: 1-800-784-9044 
Email: antistaph@emmes.com   
Statistician: Ravinder Anand, PhD 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
10 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information  
 
Staphylococcal Infections in Infants 
Seventy percent of late-onset sepsis in the neonatal intensive care unit (NICU) is due to gram-
positive organisms.1 The majority of late-onset bacterial sepsis episodes are due to coagulase-
negative Staphylococcus,1,2 and Staphylococcus aureus is the second most commonly isolated 
pathogen.2–7 Staphylococcus aureus is associated with overwhelming septic shock, severe 
necrotizing pneumonia,2,8–11 and high risk of mortality (up to 40%).12 The majority (95%) of 
coagulase-negative Staphylococcus isolates and 40% of Staphylococcus aureus isolates are 
methicillin-resistant (MRSA).9,10 Infants with these infections have prolonged hospitalizations 
and an increased risk of neurodevelopmental impairment.2,13–15 Rifampin, clindamycin, and 
ticarcillin-clavulanate all have activity against Staphylococcus species.  
 
Rifampin: Rifampin is a semisynthetic derivative of rifamycin SV. Rifampin has a wide spectrum 
of antibacterial activity that includes methicillin-resistant staphylococcal species. Rifampin 
inhibits bacterial RNA polymerase but does not inhibit the mammalian enzyme.16 Rifampin is not 
an option for monotherapy given the high likelihood for development of resistance but is often 
added to facilitate bacterial eradication among infants with persistent staphylococcal (including 
MRSA) bacteremia.17  
 
Food and Drug Administration (FDA) label: Rifampin is approved for the treatment of 
tuberculosis and for the treatment of asymptomatic carriers of Neisseria meningitidis to 
eliminate meningococci from the nasopharynx.16 Rifampin exhibits in vitro activity against 
Staphylococcus aureus (including MRSA) and Staphylococcus epidermidis (coagulase-negative 
Staphylococcus); however, the safety and effectiveness of rifampin in treating clinical infections 
due to these microorganisms have not been established in adequate and well-controlled trials.  
 
Understanding of the PK of rifampin in infants is limited (Table 1). The volume (V) of rifampin is 
larger, and clearance (CL) lower, than in older children or adults.18 In 12 pediatric patients aged 
3 months to 12 years (mean age 4.6 years),the V, clearance (CL), and half-life (t½) of rifampin 
were 0.63 L/kg, 0.16 L/kg/h, and 1.94 h, respectively.19 In 9 pediatric patients aged 1 day to 18 
years (mean age 5.6 years) who received a single dose of intravenous (IV) rifampin (20 mg/kg), 
the V, CL, and t½ of rifampicin were 1.1 L/kg, 0.29 L/kg/h, and 2.8 h, respectively. 20 Data from 
phase I trials in infants suggest that peak rifampin concentrations between 2 and 5 mg/L seem 
to be effective in the treatment of persistent staphylococcal bacteremia.18 Rifampin clinical trials 
in infants are few. In 10 infants with persistent staphylococcal bacteremia, all subsequently 
cleared their infections in approximately 1 day after receiving IV rifampin 2.5–10 mg/kg.21 A PK 
study of rifampin (5–10 mg/kg/day IV) in 21 infants (median gestational age 29 weeks [range 
26–41] and median postnatal age 18 days [range 11–55 days]) found that the mean rifampin 
half-life was 4.9 +/- 1.7 hours, and drug CL increased with increasing postnatal age.18 However, 
there was wide inter-patient variability in drug concentrations. This study was limited by lack of 
inclusion of older infants who may require higher rifampin doses. Differences in extracellular 
fluid volume, plasma protein levels, protein affinity to antimicrobials, rate, and mechanism of 
elimination may account for the PK discrepancies observed between infants and older 
populations.18 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
11 
 
Ticarcillin-clavulanate: Ticarcillin is a semisynthetic penicillin with activity against a wide 
range of gram-negative and gram-positive organisms. Ticarcillin is potentially an excellent 
agent to use in infants because of its broad spectrum of activity and safety profile observed in 
older populations.22 Similar to other beta-lactams, ticarcillin’s main CL route is the renal 
system. Ticarcillin is used in combination with clavulanic acid, which is a beta-lactamase 
inhibitor; this combination is termed ticarcillin-clavulanate. 
 
FDA label: The safety and effectiveness of ticarcillin-clavulanate has not been established in 
infants <3 months of age. Ticarcillin-clavulanate is FDA-approved for patients older than 3 
months of age and is indicated in the treatment of infections caused by susceptible strains of the 
designated microorganisms in the following conditions: septicemia (including bacteremia), lower 
respiratory infections, bone and joint infections, skin and skin structure infections, urinary tract 
infections, gynecologic infections, and intra-abdominal infections. 
 
Understanding of the safety and PK of ticarcillin-clavulanate in preterm infants is extremely 
limited (Table 2). In a study evaluating the PK of single-dose ticarcillin in newborn infants, CL 
and half-life increased and decreased, respectively, with increasing GA at birth, birth weight, 
and chronological age.23 For infants >2500 g at birth, CL increased from 6.0 mL/min to 18.9 
mL/min from birth to the third week of life. Similarly, for infants 1500–2000 g, CL increased 
from 3.1 mL/min to 4.6 mL/min from birth to the third week of life. For term infants, half-life 
decreased from 2.5 hours to 1.5 hours from birth to the third week of life. For infants ≤32 
weeks gestation, half-life decreased from 3.7 hours to 1.1 hours from birth to the third week of 
life. The 54 participants were given 50 mg/kg of ticarcillin intramuscular (IM). Only 14 PK 
samples were obtained from infants <1500 g birth weight, and only 9 infants were <33 weeks 
GA at birth. A second study evaluated the PK of multiple-dose IM ticarcillin in infants.24 Infants 
were enrolled into 3 groups: 1) 6 infants <2000 g and 0–7 days of age (75 mg/kg every 8 
hours); 2) 22 infants >2000 g and 0–7 days of age (75 mg/kg every 6 hours); and 3) 8 infants 
>2000 g and 1–8 weeks of age (75–100 mg/kg every 6 hours). Plasma CL increased with 
increasing PNA and GA. The PK of ticarcillin-clavulanate was studied in 9 preterm (range 30–
36 weeks GA) and 7 full-term infants.25 The smallest infant had a birth weight of 1400 g. 
Infants were dosed as follows: preterm infants were given 83.3 mg/kg ticarcillin/3.3 mg/kg 
clavulanate every 8 hours, and term infants were given 100 mg/kg ticarcillin/4 mg/kg 
clavulanate every 8 hours by IV infusion. The doses were well tolerated. Drug accumulation 
was noted in 1 of the 2 smallest infants in the study. Another study in 11 low-birth-weight 
(<2200 g) infants evaluated the PK of 75 mg/kg of IV ticarcillin-clavulanate.26 The median birth 
weight was 1250 g (range 683, 2110). Based on findings of sub-therapeutic exposures to both 
Table 1. Previous PK Studies of IV Rifampin in Children 
 
Reference 
Term 
Infants 
Preterm 
Infants 
Dose 
Route 
Age 
198619 
12 
0 
74–450 mg/m2 q8h 
IV 
3 mo – 12 yr 
Mean: 4.6 yr 
199020 
9 
0 
20 mg/kg 
IV 
1 day – 18 yr 
Mean: 5.6 yr 
199321 
0 
10 
2.5–10 mg/kg 
IV 
24–32 wks GA 
12–77 days PNA 
200618 
2 
19 
5–10 mg/kg q24h 
IV 
26–41 wks GA 
11–55 days PNA 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
12 
ticarcillin and clavulanate, the authors recommended dosing of 50 mg/kg every 6 hours in this 
population. None of these PK studies in infants, however, included subjects born <29 weeks 
gestation.  
 
Table 2. Previous PK Studies of IV Ticarcillin-clavulanate in Infants 
 
Reference 
Term 
Infants 
Preterm 
Infants 
Dose 
Route 
Age 
197523 
0 
0 
31 
9 
21 
0 
Ticarcillin only:  
50 mg/kg 
IM 
IM 
IM 
<33 weeks GA 
33–35 GA 
>36 weeks GA 
197824 
0 
0 
0 
6 
22 
8 
Ticarcillin only:  
75 mg/kg q8h 
75 mg/kg q6h 
75–100 mg/kg q6h 
IM 
IM 
IM 
0–7 days PNA 
0–7 days PNA 
1–8 weeks PNA 
198925 
7 
0 
0 
9 
Ticarcillin/clavulanate: 
100/4 mg/kg 
83.3/3.3 mg/kg 
IV 
IV 
36–43 weeks GA 
30–36 weeks GA 
199426 
0 
11 
Ticarcillin/clavulanate:  
92 mg/kg q8h 
3.65 mg/kg q8h 
IV 
29–32 weeks GA 
4–117 days PNA 
 
Clindamycin: Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution 
of the 7(R)-hydroxyl group of the parent compound lincomycin that acts by inhibiting protein 
synthesis in much the same way as erythromycin. It was originally isolated from the soil fungus 
Streptomyces lincolnensis and first synthesized in 1967. It is rapidly absorbed when given by 
mouth and penetrates most tissues well, although cerebrospinal fluid (CSF) penetration is poor. 
Clindamycin has activity against MRSA and Staphylococcus epidermidis (coagulase-negative 
Staphylococcus), as well as a wide range gram-positive and gram-negative anaerobic 
organisms. Clindamycin is potentially an excellent agent to use in infants because of its safety 
profile and broad spectrum observed in older populations.22  
 
FDA label: Clindamycin is approved for the treatment of adult patients with serious infections 
caused by susceptible anaerobic bacteria, infections due to susceptible strains of streptococci, 
pneumococci, and staphylococci, including serious respiratory tract infections, serious skin and 
soft tissue infections, and female pelvis and genital tract infections.  This product contains 
benzyl alcohol as a preservative.  Benzyl alcohol has been associated with a fatal “Gasping 
Syndrome” in premature infants.  The potential for the toxic effect in the pediatric population 
from chemicals that may leach from the single dose premixed IV preparation in plastic has not 
been evaluated. 
 
Published data on the safety and PK of clindamycin in preterm and term infants are extremely 
limited (Table 3). In a study evaluating the PK of 20 mg/kg/day of clindamycin divided q 6–8 
hours in term and preterm infants, CL was directly related to PNA.27 The half-life of clindamycin 
was 8.7 hours for infants <28 days of age and 3.6 hours for infants >4 weeks of life. Serum half-
life in adults and older children are 3.0 and 2.5 hours, respectively.28 CL was not presented by 
body weight but was found to be 1.92 L/hr for infants >3.5 kg and 0.31 L/hr for infants <3.5 kg. 
However, no infant in this study was <28 weeks gestation at birth, and only 1 infant was <1000 
g birth weight. Only 2 term infants <14 days of age were enrolled in the study. Drug 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
13 
accumulation was observed in the 1 infant <1000 g who was administered 15 mg/kg/day every 
8 hours. No safety data were collected in this study. In a second study of 12 infants, no 
correlation between clindamycin CL and renal function, PNA, GA, or postmenstrual age was 
observed.29 However, the assay used in this study could not distinguish between clindamycin or 
its metabolites. CL ranged from 37.8 to 135 mL/kg/hr. Again, no safety data were presented.  
 
Table 3. Previous PK Studies of IV Clindamycin in Infants 
 
Reference 
Term 
Infants 
Preterm 
Infants 
Dose 
Rout
e 
Age 
198427 
5 
0 
0 
19 
0 
16 
3 
0 
5 mg/kg q6h 
6.67 mg/kg q8h 
5 mg/kg q8h 
5 mg/kg q6h 
IV 
IV 
IV 
IV 
2–27 days PNA 
28–40 weeks GA 
28–40 weeks GA 
4–51 weeks PNA 
198629 
2 
10 
3.15-11 mg/kg q6h 
IV 
26–39 weeks GA 
2.2 
Scientific Rationale  
 
Dosing for hepatically cleared therapeutics in preterm and term infants are likely to vary greatly 
from older children and adults due to immaturity of metabolic and renal pathways. 
2.2.1 
Potential Risks 
It is the investigator’s responsibility to ensure that, prior to initiating this study, this protocol is 
reviewed and approved by the appropriate local IRB. The composition and conduct of this 
committee must conform to the U.S. CFR, including provisions outlined in 45 CFR 46 subpart D. 
 
Clindamycin and rifampin are protein-bound drugs. There are theoretical risks of increased 
bilirubin in infants with elevated bilirubin. 
 
Risks of Blood Drawing 
There are small risks to blood sampling, usually some pain/discomfort with the blood stick. We 
will make every effort to avoid additional (to standard of care) sticks for this study and will time 
clinical blood draws to coincide with timed samples, using existing intravenous lines when 
possible.  
 
Risks of Rifampin  
From the FDA label and review of the literature, side effects in patients administered rifampin 
include impacts to: gastrointestinal system (heartburn, anorexia, nausea, vomiting, jaundice, 
flatulence, cramps, and diarrhea); blood (low platelets occurred primarily with high-dose 
intermittent therapy; this effect is reversible if the drug is discontinued as soon as bruising 
occurs); central nervous system (headache, fever, drowsiness, fatigue, trouble walking, 
dizziness, inability to concentrate, mental confusion, behavioral changes, pains in arms or feet, 
and generalized numbness); renal system (elevations in kidney laboratory values [blood urea 
nitrogen {BUN} and serum uric acid] have been reported and are reversible when rifampin is 
discontinued and appropriate therapy instituted); and skin (skin reactions are mild and self-
limiting and do not appear to be allergic reactions). 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
14 
Rifampin has the potential to act as a strong inducer of the metabolism of drugs that are 
CYP450 substrates, and such concomitantly administered drugs should be monitored for 
potential lack of efficacy during concurrent treatment with rifampin and for 1 month after 
discontinuation of rifampin therapy. 
 
Rifampin should not be used as monotherapy. Empirical anti-staphylococcal therapy of an 
appropriate anti-staphylococcal antibiotic should be used in combination with rifampin. 
 
Risks of Ticarcillin-clavulanate 
From the FDA label and review of the literature, side effects of ticarcillin-clavulanate, as with 
other penicillins, include the following adverse reactions: hypersensitivity (skin rash, pruritus, 
urticaria, arthralgia, myalgia, drug fever, chills, chest discomfort, erythema multiforme, toxic 
epidermal necrolysis, Stevens-Johnson syndrome, and anaphylactic reactions); central nervous 
system (headache, giddiness, neuromuscular hyperirritability, or convulsive seizures); 
gastrointestinal disturbances (disturbances of taste and smell, stomatitis, flatulence, nausea, 
vomiting and diarrhea, epigastric pain, and pseudomembranous colitis have been reported; 
onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment); 
hemic and lymphatic systems (thrombocytopenia, leukopenia, neutropenia, eosinophilia, 
reduction of hemoglobin or hematocrit, and prolongation of prothrombin time and bleeding time); 
abnormalities of hepatic function tests (elevation of serum aspartate aminotransferase [SGOT], 
serum alanine aminotransferase [SGPT], serum alkaline phosphatase, serum lactate 
dehydrogenase [LDH], serum bilirubin; there have been reports of transient hepatitis and 
cholestatic jaundice, as with some other penicillins and some cephalosporins); renal and urinary 
effects (hemorrhagic cystitis, elevation of serum creatinine and/or BUN, hypernatremia, 
reduction in serum potassium and uric acid); and local reactions (pain, burning, swelling, and 
induration at the infusion site and thrombophlebitis with intravenous administration). 
 
Available safety data for pediatric patients treated with ticarcillin-clavulanate demonstrate a 
similar adverse event profile to that observed in adult patients. 
 
Ticarcillin-clavulanate should not be used as monotherapy when methicillin-resistant 
Staphylococcus aureus is suspected. 
 
Risks of Clindamycin 
From the FDA label and review of the literature, the following are adverse reactions of 
clindamycin: antibiotic-associated colitis, pseudomembranous colitis, abdominal pain, nausea, 
and vomiting; hypersensitivity reactions (maculopapular rash and urticaria have been observed 
during drug therapy; generalized mild-to-moderate morbilliform-like skin rashes are the most 
frequently reported of all adverse reactions; rare instances of erythema multiforme, some 
resembling Stevens-Johnson syndrome, have been associated with clindamycin; a few cases of 
anaphylactoid reactions have been reported); skin and mucous membranes (pruritus, vaginitis, 
and rare instances of exfoliative dermatitis have been reported); liver (jaundice and 
abnormalities in liver function tests have been observed during clindamycin therapy); renal 
system (although no direct relationship of clindamycin to renal damage has been established, 
renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria has been observed in 
rare instances); hematopoietic (transient neutropenia [leukopenia] and eosinophilia have been 
reported; reports of agranulocytosis and thrombocytopenia have been made; no direct etiologic 
relationship to concurrent clindamycin therapy could be made in any of these instances); local 
reactions (pain, induration, and sterile abscess have been reported after intramuscular injection 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
15 
and thrombophlebitis after intravenous infusion); musculoskeletal (rare instances of polyarthritis 
have been reported); and cardiovascular (rare instances of cardiopulmonary arrest and 
hypotension have been reported following too-rapid intravenous administration). 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
16 
3 
OBJECTIVE 
The objective of this study is to determine the PK of rifampin, ticarcillin-clavulanate, and 
clindamycin in infants. 
3.1 
Study Outcome Measures 
 
3.1.1 Primary Outcome Measures 
1. Area under the curve 0–24 hours (AUC0–24
2. Area under the curve at steady state (AUC
) 
ss
3. Maximum concentration (C
) 
max
4. Clearance (CL) 
)  
5. Volume of distribution at steady state (Vss
6. Half life (t
) 
1/2
 
) 
3.1.2 Secondary Outcome Measures 
Safety profile of rifampin, ticarcillin-clavulanate, and clindamycin in infants. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
17 
4 
STUDY DESIGN 
Study design: Multiple center, open-label, multiple-dose PK study. 
 
Randomization: None 
 
Study intervention: Each participant will receive study drug over 2–4 days.  
 
Duration of participant participation:  Approximately 30 days: 2–4 days of study drug plus up 
to 30 days of safety monitoring. 
 
PK sampling: PK concentrations in plasma will be measured at a central lab using a validated 
bioanalytical assay. Plasma samples will be drawn according to specific schedules for each 
drug.  
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
18 
5 
Study Population 
5.1 
Selection of the Study Population 
 
Rifampin: 16 to 32 evaluable participants, at least 4 in each group 
 
Group 1: GA <32 weeks, PNA <14 days 
 
Group 2: GA <32 weeks, PNA ≥14 days–120 days 
 
Group 3: GA ≥32 weeks, PNA <14 days 
 
Group 4: GA ≥32 weeks, PNA ≥14 days–120 days 
 
Ticarcillin-clavulanate: 16 to 32 evaluable participants, at least 4 in each group 
 
Group 1: GA <30 weeks, PNA <14 days 
 
Group 2: GA <30 weeks, PNA ≥14 days–45 days 
 
Group 3: GA <30 weeks, PNA >45 days–90 days 
 
Clindamycin: 16 to 32 evaluable participants, at least 4 in each group 
 
Group 1: GA <30 weeks, PNA <14 days 
 
Group 2: GA <30 weeks, PNA ≥14 days–45 days 
 
Group 3: GA <30 weeks, PNA >45 days–120 days 
5.2 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
1. Informed consent from legal guardian  
2. GA/PNA 
i. 
Rifampin: <121 days PNA 
ii. Ticarcillin-clavulanate: <91 days PNA AND <30 weeks GA 
iii. Clindamycin: <121 days PNA AND <30 weeks GA 
3. Sufficient intravascular access 
4. Suspected systemic infection 
 
OR 
 
Receiving 1 of the study drugs per local standard of care 
 
Exclusion Criteria 
2. Allergic reactions: 
i. 
Rifampin: history of allergic reactions to rifampin 
ii. Ticarcillin-clavulanate: history of allergic reaction to any penicillin, cephalosporin, 
or clavulanate 
iii. Clindamycin: history of allergic reaction to clindamycin 
2. Urine output <0.5 mL/hr/kg over the prior 24 hours 
3. Serum creatinine >1.7 mg/dl  
4. Any condition that in the judgment of the investigator precludes participation because it 
could affect participant safety 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
19 
6 
STUDY PROCEDURES 
6.1 
Summary of Procedures 
Table 4. Schedule of Study Procedures and Assessments 
 
1Day 0 refers to time point prior to start of study drug but may be the same calendar date as day 1. 
² Includes urine PK collection. 
3Labs need only to be collected up to 72 hours post last dose of study drug. EOT = end of treatment. 
6.2 
Screening 
 
Infants in the GA and PNA range will be screened for eligibility by the sites. 
 
Screen1 
Therapy1 
Post Therapy (days) 
Time (Day) 
-72 h – Day 0 
Day 1–2/4 
Day 3/5–9/11 
EOT or Early 
Termination 
Visit 
 
1 
2 
3 
Informed consent/assent 
X 
 
 
 
Demographics 
X 
 
 
 
Physical examination 
X 
 
 
 
Medical history 
X 
 
 
 
Serum creatinine 
X 
 
 
 
Chemistry labs 
X 
X 
X3 
X 
Hematology labs 
X 
X 
X3 
X 
Microbiology labs 
X 
X 
X3 
 
Study drug administration 
 
X 
 
 
PK sampling2 
 
X 
 
 
Adverse events 
 
X 
X 
X 
Concomitant medications 
 
X 
X 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
20 
6.3 
Enrollment 
Research staff will obtain written informed consent from the parent/guardian.  
 
Screening/Pre-Dose Assessment 
After the parent or legally authorized representative has signed the IRB-approved informed 
consent form and after it has been determined that the participant satisfies all inclusion and no 
exclusion criteria, the following evaluations will be recorded in the case report form (CRF): 
1. Participant demographics 
2. Medical history (from chart) 
3. Concomitant medications 
4. Physical examination, including weight 
5. Laboratory determinations 
6.4 
Follow-up 
Assessments/Procedures (Day 1–4) 
The following assessments will be conducted each day while the participant is on study: 
1. Date and time of each study drug dose will be recorded 
2. Concomitant medications 
3. PK sampling 
4. Laboratory and microbiologic determinations 
5. Adverse events 
Table 5 below provides the optimal plasma sampling collection windows for the study drug 
according to dosing interval. PK samples can be collected after dose 3, 4, 5, or 6. Every effort 
should be made to collect biological samples within these windows; however, samples obtained 
outside of the sampling windows are acceptable. Sample collection windows are relative to the 
end of the flush. PK samples should not be drawn during infusions or during the flush. The start 
and stop times of the flush will be recorded and will be ≤15 minutes. All study drugs will be 
administered over 30 minutes.  Elimination samples will only be obtained around the last dose 
of study drug. 
 
Table 5. Optimal Plasma Sampling Collection Windows for Study Drug by Dosing Interval 
 
 
Dosing interval (hours) 
Sample # 
6 
8 
12 
24 
1 
0–15 min* 
0–15 min* 
0–15 min* 
0–15 min* 
2 
30–60 min 
30–60 min 
30–60 min 
30–60 min 
3 
1–2 hr 
1–2 hr 
1–2 hr 
1–3 hr 
4 
2–3 hr 
2–3 hr 
2–4 hr 
3–6 hr 
5 
3–4 hr 
3–4 hr 
5–8 hr 
6–12 hr 
6 
4–5 hr 
4–6 hr 
8–10 hr 
12–18 hr 
7 
15 min prior to 
next dose 
15 min prior to 
next dose 
15 min prior to 
next dose 
15 min prior to 
next dose 
8 
(elimination) 
12–18 hr 
16–24 hr 
24–36 hr 
48–72 hr 
*End of flush. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
21 
 
Priority PK samples: At least 3 timed PK plasma samples at different time points should be 
collected per subject. Ideally 5 timed PK plasma samples should be collected per subject. 
Priority samples include # 2, 5, and 7 for each drug (see Table 5). For example, if an infant is 
receiving a drug every 8 hours, after the third dose the study coordinator collects sample #1, 2, 
and 6 and after the fourth dose the study coordinator collects sample #3, 4, 5, and 7. 
 
Flush times: Flush times will be recorded and will occur ≤15 minutes from the end of study 
drug infusion. 
 
Minimizing blood loss: Plasma samples will be collected in 200 µL blood aliquots. To minimize 
the amount of blood sampling, a limited PK sampling scheme will be employed such that no 
more than 8 timed PK samples (1.6 mL of blood) are obtained from each participant for PK 
analysis. 
 
Dried Blood Spots (DBS) PK Sampling:  Collect 2 DBS samples at the same time as 2 of the 
timed plasma PK samples.  If not enough blood is available for both samples, collect only timed 
plasma PK samples.  DBS should be collected from the collected whole blood before spinning 
the samples for the plasma PK samples.  
 
Scavenge PK Sampling:  A maximum of 10 scavenged plasma samples will be collected per 
participant. 
 
CSF PK Measurements:  Collect 100-200 µL of additional CSF into a cryovial tube from infants 
when CSF is obtained as part of clinical care from the time of first dose of study drug until 12 
hours after the last dose.  Alternatively, scavenged CSF samples (samples left over in the 
clinical microbiology lab) may be used. 
 
Urine Samples:  During one dosing interval when the timed multiple dose blood samples are 
obtained (after 3rd, 4th, or 5th), collect urine from the beginning of infusion to the next scheduled 
infusion. 
6.5 
Final Study Visit 
 
Follow-up Assessment (Day 11) 
For 7 days following the last dose of study drug, participants will be followed for the 
development of adverse reactions. These will be recorded on the CRF.  
6.6 
Laboratory Evaluations 
6.6.1 
Clinical Laboratory Evaluations 
 
Laboratory Determinations 
1. Any hematology values obtained within 72 hours prior to the first dose of study drug, 
while the participant is on study drug, and 72 hours after the last dose of study drug 
should be recorded. These include: hematocrit, white blood cell count, platelet count, 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
22 
and differential. If multiple values for a laboratory are obtained in the 72 hours prior to 
first dose, record the value closest to enrollment. 
2. Any serum chemistry values obtained within 72 hours prior to the first dose of study 
drug, while the participant is on therapy, and 72 hours after the last dose of study drug 
should be recorded. These include: BUN, calcium, potassium, sodium, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total 
bilirubin, albumin, magnesium, chloride, and bicarbonate. If multiple values for a 
laboratory are obtained in the 72 hours prior to first dose, record the value closest to 
enrollment. The participant must have a baseline serum creatinine within 72 hours prior 
to first dose of study drug. 
 
Microbiological Determinations 
We will record the results of all blood cultures that are obtained within 72 hours before the first 
dose of study drug and up to 72 hours after the last dose of study drug. If CSF or urine 
(obtained by catheterization or suprapubic tap) is collected as part of the sepsis work-up, these 
results will be recorded on the CRF. 
 
Special instructions for the collection, labeling, preparation, handling, and storage of specimens 
will be clearly detailed in the Manual of Procedures (MOP). 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
23 
7 
STUDY PRODUCT DESCRIPTION 
7.1 
Dosage and Study Drug Information  
7.1.1 
Rationale for Dose Selection 
Rifampin: Infants receiving rifampin 5–10 mg/kg/day demonstrate wide inter-patient variability 
in rifampin concentrations, with some patients demonstrating low peak and trough plasma 
concentrations.18 
 
A higher dose might provide higher therapeutic exposure without adverse 
effects. In addition, high inter-patient variability may lead to the need for rifampin therapeutic 
drug monitoring. 
Record all doses of Rifampin, Ticarcillin-clavulante, or Clindamycin for up to 6 SOC doses prior 
to and including the first on-study dose after the informed consent is signed and any subsequent 
SOC doses through last dose.  The last dose of study drug dosing is defined as the fourth dose 
for rifampin, and the sixth dose of clindamycin or ticarcillin-clavulanate after enrollment, even if 
the clinicians continue the study drug. 
 
Table 5. Rifampin Dosing 
 
Cohort 
GA  
PNA 
Dose 
1 
<32 weeks 
<14 days 
10 mg/kg Q 24 hours x  
4 doses 
2 
<32 weeks 
≥14 days–120 days 
15 mg/kg Q 24 hours x 
4 doses 
3 
≥32 weeks 
<14 days 
15 mg/kg Q 24 hours x  
4 doses 
4 
≥32 weeks 
≥14 days–120 days 
20 mg/kg Q 24 hours x  
4 doses 
 
Ticarcillin-clavulanate (based on ticarcillin component): Older infants receiving ticarcillin-
clavulanate 50–100 mg (based on ticarcillin component) every 8 hours demonstrated wide 
variability in ticarcillin concentrations, with some patients demonstrating low peak and trough 
plasma concentrations. Premature infants will likely need a longer interval because of a lower 
CL. 
 
Table 6. Ticarcillin Dosing 
 
Cohort 
GA  
PNA 
Dose 
1 
<30 weeks 
<14 days 
75 mg/kg Q12 hours x 
6 doses 
2 
<30 weeks 
≥14 days–45 days 
75 mg/kg Q 8 hours x 
6 doses 
3 
<30 weeks 
>45 days–90 days 
75 mg/kg Q 6 hours x  
6 doses 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
24 
All dosing regimens are similar to alternative published regimens.  
 
Clindamycin: In adults, clindamycin is extensively metabolized by the liver cytochrome P450 
system and subsequently eliminated by the kidneys.30 Clindamycin inhibits cytochrome P450 
2C9, which suggests this enzyme may be responsible for its metabolism. In a clindamycin PK 
study of newborns, term infants during the first 3 days of life had reduced clindamycin 
elimination with a weight-adjusted CL that was approximately one quarter of adult CL and an 
elimination half-life 3 times that of the adult value.31 Infants born at 28–30 weeks gestation had 
further reduced CL to a third of that seen in term infants, with an associated half-life 3 times 
longer than term infants.31 This large difference between term and preterm infants suggests 
rapid maturation of clindamycin elimination pathways. Thus, we propose to decrease the dosing 
interval.  
 
Table 7. Clindamycin Dosing 
 
Cohort 
GA  
PNA 
Dose 
1 
<30 weeks 
<14 days 
10 mg/kg Q 12 hours x 
6 doses 
2 
<30 weeks 
≥14 days–45 days 
10 mg/kg Q 8 hours x 
6 doses 
3 
<30 weeks 
>45 days–120 days 
10 mg/kg Q 6 hours x  
6 doses 
7.1.2 
Rifampin, ticarcillin-clavulanate, and clindamycin local standard of care 
dosing 
If the site Principal Investigator deems it appropriate for the infant to receive the local standard 
of care dose, this SOC dose may be selected and administered as the study dose throughout 
the on-study dosing period. 
7.1.3 
Formulation, Packaging, and Labeling  
All study drugs will be standard intravenous formulations. This protocol will not specify the brand 
of product. Each product will be “off the shelf” as determined by the site. Detailed information 
will be part of the MOP. 
7.1.4 
Product Storage and Stability  
Detailed information will be part of the MOP.  
7.1.5 
Preparation and Administration of Study Intervention/Investigational 
Product  
The pharmacist at each site will prepare and dispense the study drug. IV study drug will be 
dispensed by the pharmacy in appropriately sized syringes. If the infant receives study drug as 
part of clinical care, the dose and frequency will be recorded. 
 
Detailed information will be part of the MOP. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
25 
7.2 
Concomitant Medications/Treatments 
 
All drugs and/or treatments are permitted while on study and will be recorded on the CRF. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
26 
8 
ASSESSMENT OF SAFETY 
8.1 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
 
Safety will be assessed from the time of informed consent through 72 hours after last study 
dose (adverse events) and 7 days after last study dose (serious adverse events, serious 
suspected adverse reactions, serious adverse reactions, suspected adverse reaction, adverse 
reactions). The last dose of study drug dosing is defined as the 4th dose of rifampin and the 6th 
dose of clindamycin or ticarcillin-clavulanate after enrollment, even if the clinicians continue the 
study drug. Safety will be assessed by frequency and incidence of adverse events (AEs) and 
serious AEs (SAEs). The BPCA data monitoring committee (DMC) convened by NICHD will 
review data and safety information from study participants on a quarterly basis. 
8.1.1 
Adverse Events 
An adverse event is any untoward medical occurrence in humans, whether or not considered 
drug-related, that occurs during the conduct of a clinical trial. Any change in clinical status 
(routine labs, physical examinations, etc.) that is considered clinically significant by the study 
investigator is considered an AE. 
 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. A reasonable possibility implies that there is evidence 
to suggest that the drug caused the event. 
 
Adverse reaction is any adverse event caused by the drug. 
 
A serious adverse event or serious suspected adverse reaction or serious adverse 
reaction as determined by the investigator or the IND sponsor is any event that results in any of 
the following outcomes: 
1. Death 
2. Life-threatening AE (life-threatening means that the study participant was, in the opinion 
of the investigator or IND sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention)  
3. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
4. Inpatient hospitalization or prolongation of existing hospitalization 
5. Important medical event that may not result in 1 of the above outcomes but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent 1 of the outcomes listed in the above definition of serious event  
Guidelines for Assessing Severity of an Adverse Event 
The investigator should use the following definitions when assessing intensity of an adverse 
event: 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
27 
1. MILD: Participant is aware of symptoms or has minor findings, but tolerates them well 
and no or minimal intervention required 
2. MODERATE: Participant experiences enough symptoms or findings to require 
intervention  
3. SEVERE: Participant experiences symptoms or findings that require significant 
intervention 
8.1.2 
Unexpected Adverse Event Definition 
Any AE, the specificity or severity of which is not consistent with the package insert or 
investigational brochure. 
8.1.3 
Identification of Events and Timeframe for Reporting  
As all participants in this study will have pre-existing medical conditions and will be currently 
hospitalized, those pre-existing conditions will not be considered as adverse events. New 
events that occur or worsening through frequency or intensity of pre-existing conditions will be 
reported as adverse events. All reportable events as defined above, determined to be an AE 
based on physical examination, laboratory findings, or other means, will be recorded in the 
source documents and entered in the electronic CRF (eCRF). Each event will be recorded on 
an AE case report form starting after consent has been obtained. The investigator will provide 
date of onset and resolution, severity, action(s) taken, changes in study drug dosing, causality 
to study drug, and outcome. 
  
Follow-up of AEs 
Reportable events that are identified at the last assessment (or the early termination visit) must 
be recorded on the AE CRF with the status of the AE noted and followed until resolution. All 
serious suspected adverse reactions will be followed until resolution. All other events that 
cannot be resolved by 30 days after last study contact will be considered resolved by 
convention and entered in the electronic data capture (EDC) system as such. Any event 
beginning more than 7 days after the last dose of study drug will not be captured.  
8.1.4 
Interim Safety Analysis 
Rifampin: The study team will evaluate safety after 3 participants are enrolled in each cohort 
and receive the protocol dose. The safety review will be performed within 1 week after all data 
on the third participant in each cohort are entered and there are no pending queries. Enrollment 
in the cohort will be halted if there are any safety concerns.  
 
Clindamycin: The study team will evaluate safety after 3 participants ≤26 weeks gestation are 
enrolled in cohort 1. The safety review will be performed within 1 week after all data on the third 
participant ≤26 weeks gestation in cohort 1 are entered and there are no pending queries. 
Enrollment for infants ≤26 weeks gestation in cohort 1 will be halted if there are any safety 
concerns. During the safety review, enrollment in this cohort will continue except for infants ≤26 
weeks gestational age at birth.  
 
 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
28 
8.2 
Guidelines for Determining Causality 
 
The investigator will use the following question when assessing causality of an adverse event to 
study drug where an affirmative answer designates the event as a suspected adverse reaction: 
Is there a reasonable possibility that the drug caused the event? ‘‘Reasonable possibility’’ 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event. 
8.3 
Reporting Procedures 
 
Relevant clinical and safety laboratory data will be entered into the data coordinating center 
(DCC) AdvantageEDCSM at the study site within 7 business days of data acquisition. The DCC 
data management personnel will monitor the occurrence of the events listed below and notify 
the DMC, safety monitors, investigators, NIH/NICHD, and PTN staff if any of the halting criteria 
are met. A decision to proceed or to terminate the trial will be made by the sponsor and the 
NIH/NICHD. The DMC may request review of the data if deemed necessary. 
8.3.1 
Adverse Event Reporting 
All AEs will be entered into the safety data system within 7 days of identification. SAEs will be 
entered into the data system within 24 hours of identification. If there are any technical 
difficulties, the SAE will be reported to the DCC by telephone or fax communication. At the 
earliest, the SAE should also be entered into the EDC. Any SAE entered in the EDC will 
generate an automatic email notification to the DCC, IND sponsor, and funding sponsor. The 
BPCA medical monitor will review all SAEs at the time they are reported. Investigators must 
also submit safety reports locally as required by their IRB. 
8.3.2 
Regulatory Reporting  
Any event that requires expedited reporting based on federal regulations will be forwarded to 
the IND sponsor. The IND sponsor or its representative will submit expedited safety reports 
(IND safety reports) to the FDA and other regulatory agencies as necessary, and will inform the 
investigators of such regulatory reports. Site investigators must submit IND safety reports as 
required by their IRB. Documentation of the submission and receipt by the IRB must be retained 
for each IND safety report. All serious events designated as “not related” to study product(s) will 
be reported to the FDA at least annually in a summary format. 
8.4 
Halting or Discontinuation 
 
A participant’s parent/guardian may voluntarily discontinue participation in this study at any time. 
The participant’s parent/guardian is not obligated to state the reason for withdrawal. The 
reasons for withdrawal, or failure to provide a reason, must be documented by the investigator 
on the completion/withdrawal section of the CRF. 
 
Participant safety data will be reviewed on an ongoing basis to monitor for halting criteria. 
The study enrollment and dosing will be halted for 1 or more of the drugs in this study for a 
safety review if serious suspected adverse reactions or serious adverse reactions occur in 2 or 
more participants within each drug group. Enrollment to any remaining drug(s) will continue. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
29 
This information will be submitted to the BPCA DMC, NICHD, and FDA along with an analysis 
and future plans for the study. 
 
Furthermore, the NICHD, the IND sponsor, the DMC, and the investigator shall have the right to 
recommend termination of 1 or more of the drugs in this study at their discretion. Enrollment to 
any remaining drug(s) will continue. Possible reasons for termination of the study include, but 
are not limited to: 
1. Adverse events 
2. Unsatisfactory enrollment with respect to quantity or quality 
3. Inaccurate or incomplete data collection 
4. Falsification of records 
5. Failure to adhere to the protocol 
 
Note: Participants withdrawn from the study due to an AE, whether serious or non-serious, must 
be followed by the investigator until the clinical outcome from the AE is determined. The AE(s) 
should be noted on the appropriate eCRFs, and the participant’s progress should be followed 
until the AE is resolved or considered stable. The medical monitor or study PI must be notified if 
the AE may relate to overdose of study treatment; the package insert should be consulted for 
details of any specific actions to be taken. 
8.5 
Safety Oversight  
 
A qualified and experienced physician not otherwise associated with this protocol will serve as 
the medical monitor. The medical monitor will review all SAEs at the time they are reported. If 
safety concerns are identified, the medical monitor may request a meeting of the DMC to review 
safety data. At a minimum, the medical monitor will comment on the outcomes of the SAE and 
causal relationship of the SAE to the study product. The medical monitor will also indicate 
whether he/she concurs with the details of the report provided by the study investigator. If no 
SAEs prompt review at an earlier time point, the DMC will review AEs and SAEs quarterly. The 
DMC will convene and make recommendations on termination of the study based on review of 
safety reports and halting rules. The safety data will be compiled by the DCC. Based on the 
recommendations of the DMC, PTN, and NIH/NICHD, the IND sponsor will make a decision to 
terminate or continue the study. 
 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
30 
9 
CLINICAL MONITORING 
Site monitoring will be conducted to ensure that human participant protection, study procedures, 
laboratory procedures, study intervention administration, and data collection processes are of 
high quality and meet sponsor, GCP/ICH, and regulatory guidelines, and that the study is 
conducted in accordance with the protocol and DCC or DCRI sponsor standard operating 
procedures. The IND sponsor, or as detailed in the Transfer of Regulatory Obligations (TORO), 
the DCC, NIH/NICHD, or its designee will conduct site-monitoring visits as detailed in the 
monitoring plan or in the manual of procedures.  
 
Site visits will be made at standard intervals as defined by the site monitoring plans and may be 
made more frequently as directed by the IND sponsor and NIH/NICHD. Monitoring visits will 
include, but are not limited to, review of regulatory files, accountability records, data collection 
forms (DCFs), informed consent forms, medical and laboratory reports, and protocol 
compliance. Study monitors will meet with investigators to discuss any problems and actions to 
be taken and document visit findings and discussions. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
31 
10 
STATISTICAL CONSIDERATIONS 
10.1 Study Outcome Measures 
PK of these 3 antimicrobials. 
10.2 Sample Size Considerations 
 
The sample size is based on the ability to observe a serious toxicity rate and to describe the PK. 
A sample size of 32 participants will provide adequate precision in the PK parameter estimates 
(i.e., CL) that will be dependent on the underlying variability of the parameter (see table below). 
For example, assuming an inter-individual coefficient of variance (CV%) of 40% in the 
population CL parameter estimate after weight-based allometric and maturation scaling, a 
sample size of 32 participants would provide a margin of error of ±14% in the 95% confidence 
interval (CI) of the CL estimate. 
 
The sample size is sufficient to describe the PK of these 3 antimicrobials.  
 
PK Parameter CV% 
95% CI Margin of Error 
40% 
± 14% 
50% 
± 17% 
60% 
± 21% 
80% 
± 28% 
 
Replacement Participants  
If participants have <3 evaluable PK samples (not scavenged or dried blood spots), additional 
participants may be enrolled to ensure appropriate analysis. Evaluable samples are defined as 
samples with adequate volume and integrity to generate accurate concentration results as well 
as their associated dosing and sample times data. 
 
Population for Analysis 
All participants who receive at least 1 dose of study drug will be evaluable for safety profile 
analysis. All participants that provide at least 1 PK sample will be included in the PK analysis. 
 
Pharmacokinetic data from premature infants collected in the Pharmacokinetics of Understudied 
Drugs Administered to Children per Standard of Care (POPS) trial will be combined and co-
modeled with data from the Staph Trio trial. Inclusion of POPS data will increase the sample 
size across all cohorts, allow for model evaluation/validation using data from an independent 
trial and likely result in more precise estimation of model parameters. 
10.3 Analysis Plan 
 
Descriptive statistics such as number of observations, mean, median, 95% confidence interval, 
standard deviation, standard error, minimum, and maximum will be presented by gestational 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
32 
age and postnatal age group for continuous variables (such as age, weight, etc.). Other 
descriptive statistics such as counts, proportions, and/or percentages will be presented by 
gestational age and postnatal age group to summarize discrete variables (such as race, sex, 
etc.). 
 
Demographic and Baseline Characteristics 
The number of participants completed and discontinued early from study and the reasons for 
discontinuation will be summarized. Demographic and baseline characteristics will also be 
summarized. Variables include race, age, sex, and selected clinical variables recorded prior to 
initiation of study drug. Study drug administration will be summarized in terms of number of days 
of dosing and reasons for final discontinuation of study drug. 
 
Safety and Clinical Laboratory Analyses 
The number of AEs, suspected adverse reactions, and adverse reactions will be summarized 
overall, by severity, and by each Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class and preferred term. Prior and concomitant medications will be summarized by 
World Health Organization (WHO) drug class. Laboratory data, such as hematology and serum 
chemistry data, will be tabulated by GA and PNA group. Summary statistics for changes from 
baseline will be presented. Continuous laboratory measurements will be described at each visit 
using univariable descriptive statistics (mean, median, etc.); observed values and changes from 
baseline will be summarized. Lab tests reflective of liver toxicity (e.g., ALT, AST) will be further 
summarized in terms of the most extreme values and largest changes from baseline (in the 
appropriate direction) observed from start of study drug through the end of therapy.  
 
PK Analysis Plan 
PK parameters will be estimated by non-compartmental analysis using WinNonlin software. The 
plasma concentrations-time profiles of each study drug will be presented in figure form by 
participant and cohort. The appropriate non-compartmental pharmacokinetic parameters will be 
computed, including AUC0–24, AUCss, Cmax, CL, Vss, and t1/2
 
. PK parameters will be summarized 
by age cohort. The influence of covariates on PK parameters will be explored. If not enough 
samples are obtained per subject to allow for noncompartmental analysis, a population PK 
analysis approach will be used. 
Interim PK analysis 
Rifampin: An interim PK analysis will be performed after enrollment of 3 participants in each 
cohort for rifampin. If the interim analysis suggests the PK data are sufficient to describe 
rifampin disposition in this patient population, enrollment will stop after 8 participants are 
enrolled in each cohort. If additional participants are required, the interim PK data will be used to 
determine the number of additional participants. 
 
Clindamycin: An interim PK analysis will be performed after enrollment of 3 participants in 
cohort 1 for participants ≤26 weeks gestational age. If the interim analysis suggests the PK data 
are sufficient to describe clindamycin disposition in this patient population, enrollment will stop 
after 8 participants are enrolled in each cohort. If additional participants are required, the interim 
PK data will be used to determine the number of additional participants. 
 
For both analyses, if the PK analysis suggests that drug exposure is below the maximum 
tolerated exposure in adults, no dosing modifications will be made.  

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
33 
11 
PARTICIPANT CONFIDENTIALITY  
Participants will be assigned unique code numbers and will not be identified by name. 
Participant confidentiality is held strictly in trust by the participating investigators, their staff, the 
sponsor(s), and their agents. This confidentiality extends to genetic and biological sample tests, 
in addition to the clinical information relating to participating participants. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
 
The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator. This documentation includes, but is 
not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. Clinical study sites will permit access to such records. 
 
The principal investigator will ensure that the use and disclosure of protected health information 
obtained during this research study complies with the Health Insurance Portability and 
Accountability Act (HIPAA) Privacy Rule. The rule provides U.S. federal protection for the 
privacy of protected health information by implementing standards to protect and guard against 
the misuse of individually identifiable health information of participants participating in clinical 
trials. “Authorization” is required from each research participant (i.e., specific permission granted 
by an individual to a covered entity for the use or disclosure of an individual’s protected health 
information). A valid authorization must meet the implementation specifications under the 
HIPAA Privacy Rule. Authorization will be combined in the informed consent document 
(approved by the IRB). 
 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
34 
12 
INFORMED CONSENT PROCESS 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation in this study will be provided to the participants’ 
families. Consent forms describing in detail the study procedures and risks are given to the 
participant’s legal guardian, and written documentation of informed consent is required prior to 
enrolling in the study. Consent forms will be IRB-approved, and the participant’s legal guardian 
will be asked to read and review the document. Once the legal guardian has reviewed the 
document, the investigator will explain the research study to the participant’s legal guardian and 
answer any questions that may arise. The participant’s legal guardian will sign and date the 
informed consent document prior to the participant being enrolled in the study. The participant’s 
legal guardian may withdraw consent at any time throughout the course of the study. A copy of 
the informed consent document will be given to the participants’ legal guardians for their 
records. The rights and welfare of the participants will be protected by emphasizing to their legal 
guardians that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
 
The IND sponsor or designee will provide the investigator, in writing, any new information that 
bears significantly on the participants' risk to receive the investigational product. This new 
information will be communicated by the investigator to participants’ legal guardians who 
consent to participate in the trial in accordance with IRB requirements. The informed consent 
document will be updated, and participants’ legal guardians will be re-consented, if necessary. 
 
Site staff may employ IRB-approved recruitment efforts prior to the participant consenting; 
however, before any protocol-specific procedures are performed to determine protocol eligibility, 
an informed consent form must be signed.  
 
By signing the informed consent form, the participant’s legal guardian agrees that the participant 
will complete all evaluations required by the trial, unless the participant is withdrawn voluntarily 
or is terminated from the trial for any reason. 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
35 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
A case report form (CRF) will be used to record participant data. The CRF will be used for the 
recording of all historical participant information and study data as specified by this protocol. 
The CRF must be completed by designated and trained study personnel. The CRF will be 
signed off (certified) by the principal investigator or designee. 
 
According to ICH E6, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). Source documents are defined as original 
documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-
rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical trial).  
 
It will be the responsibility of the investigator(s) to ensure that the regulatory binder at the site is 
maintained. The study file will contain, but will not be limited to: 
• 
Current package inserts, and all previous versions 
• 
Final study protocol 
• 
Protocol amendments (if applicable) 
• 
Manual of operations (if applicable) 
• 
Informed consent form (blank) 
• 
Signed informed consent forms 
• 
Revised informed consent forms and/or all addenda (blank) 
• 
DHHS number for IRB or other documentation of IRB compliance with FDA regulations 
(if applicable) 
• 
Documentation of IRB approval of protocol, consent form, any protocol amendments, 
and any consent form revisions. 
• 
Annual IRB updates and approvals 
• 
All correspondence between the investigator and IRB 
The Manual of Procedures (MOP) describes all the components of the study file in detail. 
 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6, Section 4.9, and regulatory and institutional requirements for the 
protection of confidentiality of participants. Each site will permit authorized representatives of 
the sponsor, its designees, and appropriate regulatory agencies to examine (and, when required 
by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 
and evaluation of the study safety and progress. These representatives will be permitted access 
to all source data, which include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, participants’ memory aid or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
36 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial.  
 
Quality Control and Quality Assurance  
The principal investigator will provide direct access to all trial-related sites, source 
data/documents, data collection forms, and reports for the purpose of monitoring and auditing 
by the sponsor and inspection by local and regulatory authorities. The principal investigator will 
ensure all study personnel are appropriately trained and applicable documentations are 
maintained on site. 
 
DCC-designated clinical monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, Good Clinical 
Practice, and the applicable regulatory requirements. Clinical monitoring reports will be 
submitted to the principal investigator, PTN, and NIH/NICHD. 
 
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for prompt clarification and resolution. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
37 
14 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS  
14.1 Ethical Standard 
 
The investigator will ensure that the study will be conducted in accordance with the protocol, the 
ethical principles of Good Clinical Practice (ICH E6) that have their origin in the Declaration of 
Helsinki, and all applicable local regulations. The investigator will ensure the study is conducted 
in accordance with the provisions as stated and will comply with the prevailing local laws and 
customs. 
14.2 Institutional Review Board 
 
Prior to enrollment of participants into this trial, the protocol, the informed consent form, and any 
materials or advertisements presented to participants will be reviewed and approved by the 
appropriate IRB.  
 
The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to the 
start of this trial and a copy will be provided to the DCC. Notification of the IRB's composition 
and the institution’s Federal-Wide Assurance number will be provided to the DCC. 
 
Should amendments to the protocol be required, the amendments will be written by the sponsor 
and provided to the investigator for submission to the IRB. 
14.3 Informed Consent  
 
The investigator will choose participants in accordance with the eligibility criteria detailed 
previously. The investigator will not exercise selectivity so that bias is prevented. In this study, a 
participant’s parent/legal guardian will sign an informed consent for study enrollment. All 
participants must sign an informed consent form that complies with the requirements of both 21 
CFR Part 50 and the Health Insurance Portability and Accountability Act (HIPAA) before 
entering the trial. A consent form that complies with the requirements of 21 CFR Part 50 and a 
separate HIPAA-compliant authorization form for the use and disclosure of the participant’s 
protected health information may be used instead, per institutional standard operating 
procedures. For details regarding the informed consent process, see section 12. 
14.4 Study Discontinuation 
 
If the study is discontinued, enrolled participants will continue to be followed for safety 
assessments for 7 days.  All adverse events must be followed through resolution. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
38 
15 
DATA HANDLING AND RECORD KEEPING 
The investigator is obligated to conduct this study in accordance with U.S. Federal Regulation 
21 CFR 312.60-69 as specified on the signed form FDA 1572, applicable state laws, and the 
International Conference on Harmonization: Good Clinical Practice: Consolidation Guideline. 
The investigator is responsible for informing the IRB of any safety issues related to the study 
and the study drug, including reports of serious adverse events, if required, and all IND safety 
reports.  
 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  
 
Data collection forms will be derived from the eCRFs and provided by the DCC to the sites to 
record and maintain data for each participant enrolled in the study. All source documents should 
be completed in a neat, legible manner to ensure accurate interpretation of data. Permanent ink 
is required to ensure clarity of reproduced copies. When making a change or correction, the 
original entry should be crossed out with a single line, and the change should be initialed and 
dated. Do not erase, overwrite, or use correction fluid or tape on the original.  
 
Data reported in the eCRF should be consistent with the data collection form/source documents, 
or the discrepancies should be documented.  
 
The sponsor and/or its designee will provide guidance to investigators on making corrections to 
the data collection forms and eCRFs. 
15.1 Data Management Responsibilities 
 
All data collection forms and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete. Adverse events must be 
assessed for severity and causality, and reviewed by the site principal investigator or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site principal investigator. During the study, the investigator must maintain complete and 
accurate documentation for the study. The DCC will be responsible for data management, 
quality review, analysis, and reporting of the study data. 
15.2 Data Capture Methods 
 
Clinical data (including AEs and concomitant medications) will be entered into a 21 CFR Part 
11-compliant internet data entry system provided by the DCC. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the data collection forms/source documents. 
 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
39 
15.3 Types of Data 
 
Data for this study will include safety, laboratory, and outcome measures (e.g., PK data). 
15.4 Timing/Reports 
 
The DMC will convene and make recommendations on study continuation based on the safety 
data collected quarterly. 
15.5 Study Records Retention 
 
Records and documents pertaining to the conduct of this study, including data collection forms, 
source documents, consent forms, laboratory test results, and medication inventory records, 
must be retained by the investigator for at least 10 years after the end of the study or per 
local/state regulations or until subjects reach 21 years, whichever is longer. No study records 
will be destroyed without prior authorization from the sponsor. 
15.6 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or manual of 
procedures requirements. The noncompliance may be on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with Good Clinical Practice: 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1 and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation or within 5 working days of the 
scheduled protocol-required activity. All deviations must be promptly reported to the sponsor, 
via the DCC’s Internet Data Entry System (IDES). 
 
All deviations from the protocol must be addressed in study data collection forms. A completed 
copy of the protocol deviation form must be maintained in the regulatory file. Protocol deviations 
must be submitted to the local IRB/IEC per their guidelines. The site principal investigator/study 
staff is responsible for knowing and adhering to their IRB requirements. 
15.7 Participant Privacy/Authorization 
 
The principal investigator will ensure that the use and disclosure of protected health information 
obtained during a research study complies with the HIPAA Privacy Rule. The rule provides U.S. 
federal protection for the privacy of protected health information by implementing standards to 
protect and guard against the misuse of individually identifiable health information of participants 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
40 
participating in clinical trials. “Authorization” is required from each research participant (i.e., 
specific permission granted by an individual to a covered entity for the use or disclosure of an 
individual’s protected health information). A valid authorization must meet the implementation 
specifications under the HIPAA Privacy Rule. Authorization will be combined in the informed 
consent document (approved by the IRB). 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
41 
16 
PUBLICATION POLICY  
Following completion of the study, the investigator may publish the results of this research in a 
scientific journal under the oversight by the Publication Committee of the Pediatric Trials 
Network. The PTN Publication Committee comprises representatives of the network cores, 
thought leaders, DCC, and PTN and is responsible for generation and coordination of the 
publications that report scientific findings of the network. All public presentations (abstracts, 
manuscripts, slides and text of oral or other presentations, and text of any transmission through 
any electronic media) by participating investigators, participating institutions, DCC, and PTN that 
use PTN data, are intended to represent the PTN, or are supported by the PTN will be reviewed 
by the Publication Committee per the Publication Committee charter.  
 
The Publication Committee guarantees that the study results are presented by experts in the 
field that have working knowledge of the study design, implementation, data synthesis/analysis, 
and interpretation. The committee goals are to ensure that any confidential or proprietary 
information is protected and that all appropriate statistical analyses have been included.  
 
The PTN Publication Committee will adhere to the trials registration policy adopted by the 
International Committee of Medical Journal Editors (ICMJE) member journals. This policy 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, 
which is sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. It is the responsibility of the IND holder to register this trial 
in an acceptable registry.  
 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
participants to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome. Studies designed for other purposes, 
such as to study pharmacokinetics or major toxicity (e.g., phase I trials), would be exempt from 
this policy. 
 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central an electronic version of their final, peer-reviewed 
manuscripts upon acceptance for publication, to be made publicly available no later than 12 
months after the official date of publication. The NIH Public Access Policy ensures the public 
has access to the published results of NIH-funded research. It requires investigators to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. Further, the policy stipulates that these papers must be 
accessible to the public on PubMed Central no later than 12 months after publication. Refer to: 
http://publicaccess.nih.gov/ and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-
033.html. 
 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
42 
17 
LITERATURE REFERENCES 
1. Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research 
Network. Semin Perinatol 2003;27:293-301. 
2. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: 
the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110:285-91. 
3. Denniston S, Riordan FAI. Staphylococcus aureus bacteraemia in children and neonates: a 
10 year retrospective review. J Infect 2006;53:387-93. 
4. Jeong IS, Jeong JS, Choi EO. Nosocomial infection in a newborn intensive care unit (NICU), 
South Korea. BMC Infect Dis 2006;6:103. 
5. Sohn AH, Garrett DO, Sinkowitz-Cochran RL, et al. Prevalence of nosocomial infections in 
neonatal intensive care unit patients: Results from the first national point-prevalence survey. 
J Pediatr 2001;139:821-7. 
6. Usukura Y, Igarashi T. Examination of severe, hospital acquired infections affecting 
extremely low birthweight (ELBW) infants. Pediatr Int 2003;45:230-2. 
7. Drews MB, Ludwig AC, Leititis JU, Daschner FD. Low birth weight and nosocomial infection 
of neonates in a neonatal intensive care unit. J Hosp Infect 1995;30:65-72. 
8. Remington J, Klein J, Wilson C, Baker C. Infectious Diseases of the Fetus and Newborn 
Infant. 6th ed. Philadelphia, PA: Elsevier Saunders; 2006. 
9. Healy CM, Hulten KG, Palazzi DL, Campbell JR, Baker CJ. Emergence of new strains of 
methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit. Clin Infect Dis 
2004;39:1460-6. 
10. Healy CM, Palazzi DL, Edwards MS, Campbell JR, Baker CJ. Features of invasive 
staphylococcal disease in neonates. Pediatrics 2004;114:953-61. 
11. Karlowicz MG, Buescher ES, Surka AE. Fulminant late-onset sepsis in a neonatal intensive 
care unit, 1988-1997, and the impact of avoiding empiric vancomycin therapy. Pediatrics 
2000;106:1387-90. 
12. Fowler VG, Jr., Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for 
bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 
2006;355:653-65. 
13. Payne NR, Carpenter JH, Badger GJ, Horbar JD, Rogowski J. Marginal increase in cost and 
excess length of stay associated with nosocomial bloodstream infections in surviving very 
low birth weight infants. Pediatrics 2004;114:348-55. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
43 
14. Fanaroff AA, Korones SB, Wright LL, et al. Incidence, presenting features, risk factors and 
significance of late onset septicemia in very low birth weight infants. The National Institute of 
Child Health and Human Development Neonatal Research Network. Pediatr Infect Dis J 
1998;17:593-8. 
15. Deulofeut R, Critz A, Adams-Chapman I, Sola A. Avoiding hyperoxia in infants < or = 1250 g 
is associated with improved short- and long-term outcomes. J Perinatol 2006;26:700-5. 
16. DailyMed. 2010. (Accessed at 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7821#nlm34090-1.) 
17. Cohen-Wolkowiez M, Benjamin DK, Jr., Fowler VG, Jr., et al. Mortality and 
neurodevelopmental outcome after Staphylococcus aureus bacteremia in infants. Pediatr 
Infect Dis J 2007;26:1159-61. 
18. Pullen J, Stolk LM, Degraeuwe PL, van Tiel FH, Neef C, Zimmermann LJ. Pharmacokinetics 
of intravenous rifampicin (rifampin) in neonates. Ther Drug Monit 2006;28:654-61. 
19. Koup JR, Williams-Warren J, Weber A, Smith AL. Pharmacokinetics of rifampin in children. I. 
Multiple dose intravenous infusion. Ther Drug Monit 1986;8:11-6. 
20. Nahata MC, Fan-Havard P, Barson WJ, Bartkowski HM, Kosnik EJ. Pharmacokinetics, 
cerebrospinal fluid concentration, and safety of intravenous rifampin in pediatric patients 
undergoing shunt placements. Eur J Clin Pharmacol 1990;38:515-7. 
21. Tan TQ, Mason EO, Jr., Ou CN, Kaplan SL. Use of intravenous rifampin in neonates with 
persistent staphylococcal bacteremia. Antimicrob Agents Chemother 1993;37:2401-6. 
22. Tan JS, Wishnow RM, Talan DA, Duncanson FP, Norden CW. Treatment of hospitalized 
patients with complicated skin and skin structure infections: double-blind, randomized, 
multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. The 
Piperacillin/Tazobactam Skin and Skin Structure Study Group. Antimicrob Agents 
Chemother 1993;37:1580-6. 
23. Nelson JD, Shelton S, Kusmiesz H. Clinical pharmacology of ticarcillin in the newborn infant: 
relation to age, gestational age, and weight. J Pediatr 1975;87:474-9. 
24. Nelson JD, Kusmiesz H, Shelton S, Woodman E. Clinical pharmacology and efficacy of 
ticarcillin in infants and children. Pediatrics 1978;61:858-63. 
25. Fricke G, Doerck M, Hafner D, Horton R, Kresken M. The pharmacokinetics of 
ticarcillin/clavulanate acid in neonates. J Antimicrob Chemother 1989;24 Suppl B:111-20. 
26. Burstein AH, Wyble LE, Gal P, et al. Ticarcillin-clavulanic acid pharmacokinetics in preterm 
neonates with presumed sepsis. Antimicrob Agents Chemother 1994;38:2024-8. 
27. Bell MJ, Shackelford P, Smith R, Schroeder K. Pharmacokinetics of clindamycin phosphate 
in the first year of life. J Pediatr 1984;105:482-6. 

Anti-Staphylococcal Trial 
 
Version 4.0 
IND #115396 
03 February 2014 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
44 
28. DeHaan RM, Metzler CM, Schellenberg D, Vandenbosch WD. Pharmacokinetic studies of 
clindamycin phosphate. J Clin Pharmacol 1973;13:190-209. 
29. Koren G, Zarfin Y, Maresky D, Spiro TE, MacLeod SM. Pharmacokinetics of intravenous 
clindamycin in newborn infants. Pediatr Pharmacol (New York) 1986;5:287-92. 
30. Jensen JC, Gugler R. Single- and multiple-dose metronidazole kinetics. Clin Pharmacol 
Ther 1983;34:481-7. 
31. Jager-Roman E, Doyle PE, Baird-Lambert J, Cvejic M, Buchanan N. Pharmacokinetics and 
tissue distribution of metronidazole in the new born infant. J Pediatr 1982;100:651-4.