Guidance for Industry 

Acute Bacterial Skin and Skin 

Structure Infections: 

Developing Drugs for 

Treatment 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2013 

Clinical/Antimicrobial 
 
 
   
Guidance for Industry 

Acute Bacterial Skin and Skin 

Structure Infections: 

Developing Drugs for 

Treatment 

 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 

Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
10903 New Hampshire Ave., Bldg. 51, rm. 2201 

Silver Spring, MD   20993-0002 

Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2013 

Clinical/Antimicrobial 
 
 
   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   DEVELOPMENT PROGRAM ....................................................................................... 2
  
A.   General Considerations ................................................................................................................. 2
  
1.  Definitions of Acute Bacterial Skin and Skin Structure Infection .................................................... 2 
 
2.  Efficacy Considerations................................................................................................................... 3
  
3.  Safety Considerations ...................................................................................................................... 3
  
B.   Specific Efficacy Trial Considerations ......................................................................................... 4
  
1.  Clinical Trial Designs, Populations, and Entry Criteria ................................................................. 4 
 
2.  General Exclusion Criteria.............................................................................................................. 4
  
3.  Clinical Microbiology Considerations ............................................................................................ 4
  
4.  Prior Antibacterial Drug Therapy ................................................................................................... 5
  
5.  Concurrent Antibacterial Drug Therapy ......................................................................................... 6 
 
6.  Adjunctive Therapy .......................................................................................................................... 6
  
7.  Efficacy Endpoints and Timing of Assessments ............................................................................... 6 
 
a.   Primary efficacy endpoint of lesion response at 48 to 72 hours ............................................... 6
  
b.   Secondary endpoint considerations ........................................................................................... 7 
 
8.  Trial Procedures and Timing of Assessments .................................................................................. 7 
 
a.   Entry visit  .................................................................................................................................. 7 
 
b.   On-therapy  visit at approximately 48 to  72 hours ..................................................................... 7 
 
c.   End-of-therapy visit  .................................................................................................................. 7
  
d.   After-therapy visit ..................................................................................................................... 7
  
9.  Statistical Considerations ................................................................................................................ 8
  
a.   Analysis populations ................................................................................................................. 8 
 
b.   Noninferiority margins .............................................................................................................. 8
  
c.   Sample size ............................................................................................................................... 9 
 
10.   Specific Populations  .................................................................................................................... 9 
 
C.   Other Considerations ..................................................................................................................... 9
  
1.  Pharmacokinetic/Pharmacodynamic Considerations ...................................................................... 9 
 
2.  Dose Selection and Formulation ................................................................................................... 10 
 
3.  Labeling Considerations................................................................................................................ 10 
 
REFERENCES............................................................................................................................ 11
  
APPENDIX:  JUSTIFICATION FOR A NONINFERIORITY MARGIN FOR ACUTE 

BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS ............................................ 13 
 
 
  Contains Nonbinding Recommendations 
1
 
Guidance for Industry  
Acute Bacterial Skin and Skin Structure Infections:   

Developing Drugs for Treatment 

 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
treatment of acute bacterial skin and skin structure infections (ABSSSI).2  Specifically, this 
guidance addresses the Food and Drug Administrations (FDAs) current thinking regarding the 
overall development program and clinical trial designs for systemic drugs to support an 
indication for the treatment of ABSSSI.  This guidance defines ABSSSI as cellulitis/erysipelas, 
wound infection, and major cutanenous abscess. 
 
This guidance does not address less serious skin infections, such as impetigo and minor 
cutaneous abscess,3 as well as infections needing more complex treatment regimens, such as 
infections resulting from animal or human bites, necrotizing fasciitis, diabetic foot infection, 
decubitus ulcer infection, myonecrosis, and ecthyma gangrenosum.  Sponsors interested in 
development of drugs for treatment of skin infections not covered in this guidance should discuss 
clinical development plans with the FDA.   
 
This guidance also does not contain discussion of the general issues of statistical analysis or 
clinical trial design. Those topics are addressed in the ICH guidances for industry E9  Statistical 
                                                 
1 This  guidance has been  prepared by the Division of  Anti-Infective Products in the Center  for Drug Evaluation and  
Research (CDER) at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  unless otherwise specified.  
 
3 Sponsors interested in the development of  drugs for treatment of impetigo or minor cutaneous abscess should 
discuss their development plans with the FDA.  In  general,  such trials should  be designed for a finding of  
superiority; see the transcripts of the discussion at the November 18, 2008, Anti-Infective Drugs Advisory  
Committee (AIDAC) meeting. 
1 
 Contains Nonbinding Recommendations 
Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
Trials.4     
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
This guidance provides information to assist sponsors developing drugs for the treatment of skin 
infections that are termed acute bacterial skin and skin structure infections. 5  ABSSSI include 
cellulitis/erysipelas, wound infection, and major cutanenous abscess and have a minimum lesion 
surface area of approximately 75 cm2 . Common bacterial pathogens causing ABSSSI are 
Streptococcus pyogenes and Staphylococcus aureus including methicillin-resistant S. aureus. 
Less common causes include other Streptococcus species, Enterococcus faecalis, or Gram-
negative bacteria. 
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Definitions of Acute Bacterial Skin and Skin Structure Infection 
 
An ABSSSI is defined as a bacterial infection of the skin with  a lesion size area of at least 75 
cm2 (lesion size measured by the area of redness, edema, or induration).6  The minimum area of 
involvement of 75 cm2 is chosen to select patients with acute bacterial skin infections for which a 
reliable control drug treatment effect can be estimated, given that most drugs for ABSSSI will be 
                                                 
4  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
5 Public discussions, including the AIDAC meeting on November 18, 2008, discussed the  previous characterization 
of skin and skin structure infections into two broad categories:  (1) uncomplicated skin and skin structure infections; 
and (2) complicated skin and  skin structure infections.  In addition to suggestions  for re-characterizing categories of 
skin and skin structure infections, noninferiority clinical trial designs and  endpoints were discussed.  Transcripts and 
briefing information from the AIDAC meeting can be found at the FDA Web site at  
http://www.fda.gov/ohrms/dockets/ac/cder08.html#AntiInfective. 
 
6 For areas of ABSSSI that involve certain body surface sites, such as the face, or for young children when it is 
appropriate to enroll them in a phase 3 clinical trial, sponsors can discuss with the FDA the proposed  definitions of  
ABSSSI that are based on a surface area smaller than 75 cm2 . 
 
2 
 Contains Nonbinding Recommendations 
studied using noninferiority trial designs.7  A sufficiently large lesion size also differentiates 
between minor cutaneous abscess (smaller than approximately 75 cm2) and major cutaneous 
abscess (greater than approximately 75 cm2). This distinction is important because there appears  
to be insufficient information to reliably estimate a quantitative treatment effect of an 
antibacterial drug for patients who have surgical incision and drainage for a minor cutaneous 
abscess (Duong, Markwell, et al. 2010; Lee, Rios, et al. 2004; Llera and Levy 1985; Rajerdran, 
Young, et al. 2007). 
 
Patients with the following infection types can be enrolled in ABSSSI clinical trials:   
 
 	  Cellulitis/erysipelas:  A diffuse skin infection characterized by spreading areas of 
redness, edema, and/or induration  
 
 	  Wound infection:  An infection characterized by purulent drainage from a wound with 
surrounding redness, edema, and/or induration 
 
 	  Major cutaneous abscess:  An infection characterized by a collection of pus within the 
dermis or deeper that is accompanied by redness, edema, and/or induration 
 
The method of measuring lesion size should be the same across all trial sites.  Methods to assess 
lesion size include, but are not limited to, the following:  (1) manual measurement of length 
multiplied by perpendicular width; (2) digital planimetry; and (3) computer-assisted tracings.  
 
2.  Efficacy Considerations  
 
Noninferiority trials are interpretable and acceptable to support approval of a drug for an 
indication of the treatment of ABSSSI.  A showing of superiority to an effective control is also 
readily interpretable and would be acceptable.   
 
If an indication for the treatment of ABSSSI is the sole indication for which the drug has been, or 
is being, developed, then two adequate and well-controlled trials generally are recommended to 
provide evidence of effectiveness.  A single adequate and well-controlled trial supported by other 
independent evidence, such as a trial in another infectious disease indication (e.g., treatment of 
community-acquired bacterial pneumonia), could also provide evidence of effectiveness in the 
treatment of ABSSSI.8  Sponsors should discuss with the FDA other independent confirmation 
that would be used to support the findings from a single trial in ABSSSI. 
 
3.  Safety Considerations  
 
In general, we recommend a preapproval safety database of approximately 700 patients or more.  
If the same or greater dose and duration of therapy for the treatment of ABSSSI were used in 
                                                 
7 See the Appendix and the draft guidance for industry Non-Inferiority Clinical Trials (when  final, this guidance will 
represent the  FDAs current thinking  on this topic). 
 
8 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human  Drug and Biological 
Products. 
3 
 Contains Nonbinding Recommendations 
clinical trials for other infectious disease indications, the safety information from those clinical  
trials can be part of the overall preapproval safety database.  For new drugs that have an 
important clinical benefit compared to existing therapies, depending on the benefit demonstrated, 
a smaller preapproval safety database may be appropriate.  Sponsors should discuss the 
appropriate size of the preapproval safety database with the FDA during clinical development. 
 
B.  Specific Efficacy Trial Considerations 
 
1.  Clinical Trial Designs, Populations, and Entry Criteria 
 
The clinical trial population for efficacy trials should include male and female patients with a 
mixture of the ABSSSI disease entities (e.g., cellulitis/erysipelas, wound infection, major 
cutaneous abscess) described in section III.A.1., Definitions of Acute Bacterial Skin and Skin 
Structure Infection.  Because surgical incision and drainage might influence treatment outcomes 
among patients with major cutaneous abscesses, patients with major cutaneous abscesses should 
not comprise more than 30 percent of the clinical trial population. 
 
2.  General Exclusion Criteria 
 
Recommended general exclusion criteria include the following: 
 
 	  Patients with medical conditions that would alter the interpretation of a primary endpoint 
(e.g., patients with neutropenia) 
 
 	  Patients with suspected or confirmed osteomyelitis  
 
 	  Patients with suspected or confirmed septic arthritis 
 
 	  Patients who have received more than 24 hours of effective antibacterial drug therapy for 
treatment of the current episode of ABSSSI (see section III.B.4., Prior Antibacterial Drug 
Therapy) 
 
3.  Clinical Microbiology Considerations 
 
Sponsors should obtain an adequate clinical specimen for microbiologic evaluation (e.g., pus 
from a wound or abscess; an aspirate from the leading edge of cellulitis), including culture, Gram  
stain, and in vitro antibacterial susceptibility testing performed on appropriate organisms isolated 
from the specimen.  Specimens should be processed according to recognized methods (e.g., 
American Society for Microbiology 2011).  The specimen for microscopic evaluation and 
culture, as well as blood cultures from two separate venipuncture sites, should be obtained before 
administration of antibacterial therapy, if possible.  This microbiological information is 
important for characterizing the underlying bacterial etiologies of ABSSSI. 
 
Sponsors should save all isolates considered possible pathogens taken from patients enrolled in 
clinical trials in the event that additional testing of an isolate is needed (e.g., pulse field gel 
electrophoresis for strain identification).  
4 
 Contains Nonbinding Recommendations 
 
Rapid diagnostic tests can be used for enrichment of trial populations with specific infections.  In 
addition, the clinical trial of an antibacterial drug may provide an opportunity to contribute to the 
development and evaluation of a new diagnostic test.  Sponsors interested in the development of 
a new diagnostic test should discuss potential approaches with the FDA. 
 
4.  Prior Antibacterial Drug Therapy 
 
Ideally, patients enrolled in an ABSSSI clinical trial would not have received prior antibacterial 
drug therapy because such therapy can have a number of potential consequences for a clinical 
trial. Prior antibacterial drug therapy could: 
 
	   Obscure any potential treatment differences between an investigational drug and control 
drug and therefore bias toward a finding of no difference (i.e., a bias toward 
noninferiority) 
 
	   Influence the evaluation of efficacy findings based on an endpoint earlier in therapy (48 
to 72 hours) 
 
However, a complete ban on prior antibacterial therapy could have adverse consequences, 
including: 
 
	   Exclusion of all patients who received prompt administration of antibacterial drug 
therapy because of the severity of their disease could result in a patient population with 
lesser severity of illness and greater potential for spontaneous recovery; trial results could 
therefore be biased toward a finding of no difference between treatment groups (i.e., a 
bias toward noninferiority) 
 
 	  Certain trial sites may not participate in the clinical trial because of concerns regarding 
standard-of-care treatment. 
 
A pragmatic approach to these concerns is to:  (1) encourage prompt enrollment procedures so 
that patients can receive the clinical trial treatment initially, with no need for other antibacterial 
drug therapy; and (2) allow enrollment of some  patients who have received a single dose of a 
short-acting antibacterial drug within 24 hours of enrollment (e.g., ideally there would be few 
such patients, and they could be limited to 25 percent of the patient population).  This would 
allow patients in the trial to receive prompt antibacterial drug therapy if that was clinically 
necessary, consistent with the standard of care.  The results in the subgroup of patients (i.e., the 
majority of patients) who did not receive prior effective antibacterial drug therapy will be 
important to evaluate and the primary analysis can be stratified by prior therapy to assess the 
consistency of the results across the two subgroups (i.e., patients who received prior therapy and 
those who did not receive prior therapy).   
 
There are other circumstances in which patients who received prior antibacterial drug therapy 
can be eligible for clinical trial entry:   
 
5 
 Contains Nonbinding Recommendations 
 	  Objective documentation of clinical progression of ABSSSI while on antibacterial drug 
therapy (i.e., not by patient history alone) 
 
	   The patient received an antibacterial drug for surgical prophylaxis and subsequently 
develops ABSSSI  
 
5.  Concurrent Antibacterial Drug Therapy 
 
Ideally, concurrent antibacterial drug therapy should be avoided.  However, certain patients with 
ABSSSI could receive additional empirical antibacterial drug treatment, preferably treatment that 
has no overlapping antibacterial activity with the investigational drug.  For example, a patient 
who has a new diagnosis of ABSSSI while in the hospital (e.g., wound infection) might require 
empirical antibacterial drug therapy that treats both Gram-positive and Gram-negative bacterial 
pathogens; such a patient could enroll in a trial for an investigational drug that has only Gram-
positive antibacterial activity, provided that the concurrent empirical antibacterial drug for Gram-
negative treatment does not have overlapping Gram-positive antibacterial activity with the 
investigational drug. 
 
6.  Adjunctive Therapy 
 
The following adjunctive therapy is often used in ABSSSI treatment: 
 
	   Daily dressing changes 
 
	   Use of topical solutions including nonspecific antimicrobial drugs such as povidone-
iodine 
 
	   Debridement 
 
	   Hyperbaric oxygen treatments  
 
	   Surgical interventions planned at the initiation of treatment 
 
Sponsors should specify which adjunctive therapies are to be permitted in the clinical trials.  
With proper blinding and randomization, both the investigational drug group and control group 
should have comparable use of these adjunctive therapies.  Sponsors should analyze the clinical 
outcomes stratified by the presence or absence of adjunctive therapies (e.g., daily debridement).  
Topical treatments with specific antibacterial activity should not be used as adjunctive therapy in 
ABSSSI clinical trials. 
 
7.  Efficacy Endpoints and Timing of Assessments  
 
a.  Primary efficacy endpoint of lesion response at 48 to 72 hours 
 
Clinical response should be based on the percent reduction in the lesion size at 48 to 72 hours 
compared to baseline, measured in patients who did not receive rescue therapy and are alive.  A 
6 
 Contains Nonbinding Recommendations 
clinical response in a patient generally is defined as a percent reduction in lesion size greater than 
or equal to 20 percent compared to baseline.9  Alternative metrics of lesion response should be 
discussed with the FDA before initiation of clinical trials.  
 
b.  Secondary endpoint considerations 
 
Resolution of ABSSSI evaluated at 7 to 14 days after completion of therapy should be a 
secondary endpoint. 
 
Refinement of the clinical outcome assessments in ABSSSI trials (e.g., lesion size measurements 
other than length times width) can be considered.10  In addition, symptoms, including pain, 
caused by ABSSSI can be important to evaluate.11    
 
8.  Trial Procedures and Timing of Assessments 
 
a.  Entry visit 
 
At this visit, sponsors should collect appropriate demographic information, history and physical 
examination findings, lesion size measurements, microbiological specimens, and safety 
laboratory tests. 
 
b.  On-therapy visit at approximately 48 to 72 hours  
 
At this visit, sponsors should evaluate the lesion size in the same manner as at the entry visit, as 
specified by the protocol. Safety and laboratory tests, as appropriate, should be evaluated.   
 
c.  End-of-therapy visit 
 
At this visit, sponsors should evaluate the lesion size in the same manner as at the entry visit, as 
specified by the protocol. Safety and laboratory tests, as appropriate, should be evaluated.  
Assessment of whether discontinuation of antibacterial drug therapy is appropriate also can be 
made.  
 
d.  After-therapy visit  
 
This visit should correspond to a visit within a window of approximately 7 to 14 days after the 
last day of therapy. Sponsors should assess the maintenance of clinical response and any new 
safety effects or safety laboratory tests, as appropriate, at this visit.  A day-28 all-cause mortality 
assessment is recommended. 
 
                                                 
9 See, for example, Talbot, Powers, et al. 2012. 
 
10 See Talbot, Powers, et al. 2012. 
 
11 For more information, see the guidance for industry  Patient-Reported Outcome Measures:  Use in Medical  
Product Development to Support Labeling Claims. 
7 
 Contains Nonbinding Recommendations 
9.  Statistical Considerations 
 
In general, sponsors should provide a detailed statistical analysis plan stating the trial hypotheses 
and the analysis methods before trial initiation.  The primary efficacy analysis is based on the 
difference in the proportions of patients achieving  a successful clinical response (e.g., at least a 
20 percent reduction in the lesion size at 48 to 72 hours when compared to baseline).  An 
exploratory analysis that compares clinical responses among patients who received prior 
antibacterial drug therapy and patients who did not receive prior antibacterial drug therapy 
should be considered. 
 
a.  Analysis populations 
 
The definitions for the statistical analysis populations are provided as follows: 
 
	   Safety population  All patients who received at least one dose of drug during the trial.  
 
 	  Intent-to-treat (ITT) population  All patients who were randomized.  
 
 	  Microbiological intent-to-treat (micro-ITT) population  All patients randomized to 
treatment who have a baseline bacterial pathogen known to cause ABSSSI.  Patients 
should not be excluded from this population based upon events that occur after 
randomization (e.g., lost to follow-up).  
 
 	  Per-protocol, clinically evaluable, or microbiologically evaluable populations  Patients 
who follow important components of the trial can then be defined as part of a per-
protocol or other evaluable population (i.e., ITT patients who follow important 
components of the trial can be defined as the clinically evaluable population, or micro-
ITT patients who follow important components of the trial can be defined as the 
microbiologically evaluable population).  
 
In general, sponsors should consider the ITT population to be the primary analysis population 
because the definitions of ABSSSI described in section III.A.1., Definitions of Acute Bacterial 
Skin and Skin Structure Infection, are most consistent with bacterial infectious diseases even for 
cases in which purulent material is not easily obtained (e.g., cellulitis).  For an antibacterial drug 
with targeted activity against a specific pathogen or class (e.g., a drug with antibacterial activity 
against Gram-negative pathogens), sponsors should discuss the appropriate analysis population 
with the FDA. Generally, it is not appropriate, as a scientific matter, to consider analyses of the 
per-protocol population as primary, because population membership is based on after 
randomization events or characteristics of patients.  However, consistency of the results should 
be evaluated in all populations. 
 
b.  Noninferiority margins 
 
A noninferiority margin of 10 percent for the primary efficacy endpoint based on a reduction in 
lesion size at 48 to72 hours (defined in section III.B.7., Efficacy Endpoints and Timing of 
8 
 Contains Nonbinding Recommendations 
Assessments) is supported by the historical evidence (see the Appendix).12  Sponsors should 
discuss the selection of a noninferiority margin with the FDA in advance of trial initiation, 
particularly for a proposed margin of greater than 10 percent or for a margin using an endpoint 
other than lesion response based on the reduction in lesion size (i.e., the proportion of patients 
achieving at least a 20 percent reduction in lesion size). 
 
c.  Sample size 
 
An estimate of the sample size for a noninferiority trial with 1:1 randomization is approximately 
310 patients per arm based on the following assumptions:  (1) the noninferiority margin is 
selected at 10 percent; (2) the type I error is 0.05; (3) the type II error is 0.10 (90 percent power); 
and (4) 80 percent of patients achieve clinical success with the comparator drug.  
 
10.  Specific Populations 
 
Sponsors should discuss drug development in the pediatric populations as early as is feasible.  
The Pediatric Research Equity Act (PREA), as amended by the Food and Drug Administration 
Safety and Innovation Act, states that initial plans for the conduct of pediatric studies (referred to 
as an initial  pediatric study plan) shall be submitted to the FDA before the date on which 
required pediatric assessments are submitted under PREA and no later than:  (1) 60 days after the  
end-of-phase 2 meeting; or (2) such other time as may be agreed upon by the Secretary and the 
applicant.13  In most situations, the course of the disease and the effects of therapy for ABSSSI 
are sufficiently similar in the adult and pediatric populations.  Accordingly, under those 
circumstances, adult efficacy findings for drugs to treat ABSSSI may be extrapolated to the 
pediatric population. Pharmacokinetic (PK) and safety studies should be conducted to determine 
dosing in the pediatric population that provides exposure similar to exposure that is effective in 
adults and safety information at the identified dose(s).  Drug development programs should 
include a sufficient number of geriatric patients (e.g., older than 65 years of age and older than 
75 years of age) to characterize safety and efficacy in this population.14   
 
C.  Other Considerations 
 
1.  Pharmacokinetic/Pharmacodynamic Considerations 
 
Sponsors should evaluate the PK/pharmacodynamic (PD) characteristics of the drug using in 
vitro models or animal models of infection.  The results from nonclinical PK/PD assessments 
should be integrated with the findings from phase 1 PK assessments to help identify appropriate 
                                                 
12 See the draft guidance for industry Non-Inferiority Clinical Trials.  
 
13 See PREA  (Public Law 108-155;  section 505B of the Federal Food, Drug, and Cosmetic Act; 21  U.S.C. 355c) as 
amended by the Food and Drug Administration  Safety and Innovation  Act of  2012 (Public Law 112-114) and the 
draft guidance  for industry  Pediatric Study Plans:  Content of and Process for Submitting Initial Pediatric Study 
Plans and Amended Pediatric Study Plans. When final, this  guidance will represent the FDAs current thinking  on  
this topic. 
 
14 See the ICH guidances for industry E7 Studies in Support of  Special Populations:  Geriatrics and E7 Studies in  
Support of  Special Populations:  Geriatrics; Questions and Answers.  
9 
 Contains Nonbinding Recommendations 
dose and dosing regimens for evaluation in phase 2 and phase 3 clinical trials.  Plasma drug 
concentrations should be determined from patients in phase 2 clinical trials.  Using the plasma  
concentration data, the sponsor should assess the relationship between antibacterial PK/PD 
indices and observed clinical and microbiological outcomes.  Antibacterial PK/PD indices 
include maximal unbound drug concentration [fCmax]/minimum inhibitory concentration (MIC) 
ratio, area under the unbound drug concentration-time curve [fAUC]/MIC ratio, or the 
percentage of the dosage interval that the unbound drug concentration exceeds the MIC 
[fT>MIC].  The evaluation of exposure-response relationships (efficacy and safety) in phase 2 
helps determine the best dose for evaluation in phase 3 trials.  PK samples can be obtained by 
various approaches, such as rich or sparse sampling obtained from specific subsets of patients 
and/or at specific trial sites. 
 
Sponsors may want to consider obtaining plasma drug concentrations from patients in phase 3 
clinical trials. The concentration data are most important when the population studied in phase 3 
differs from the population studied in phase 2 (e.g., the phase 3 population has more severe 
illness).  If phase 3 trials include a previously unstudied specific population, such as patients 
with renal or hepatic impairment, collection of plasma drug concentrations from those specific 
populations can aid in determining necessary dose adjustments.  The concentration data can also 
help with the interpretation of any unexpected safety or efficacy findings. 
 
2.  Dose Selection and Formulation 
 
Sponsors should integrate the findings from nonclinical toxicology studies, animal models of 
infection, pharmacokinetics, pharmacodynamics, in vitro susceptibility profiles of target 
pathogens, safety and tolerability information from phase 1 trials, and safety and antibacterial 
activity information from phase 2 dose-ranging trials for purposes of selection of appropriate 
doses, dosing regimens, and duration of therapy to be evaluated in phase 3 clinical trials.  
 
For drugs that only have an intravenous (IV) formulation available, we recommend that patients 
receive the IV formulation alone until the assessment of the primary efficacy endpoint (e.g., at 48  
to 72 hours), without a switch to an FDA-approved oral antibacterial drug, if feasible. 
 
For drugs that have both an IV and oral formulation, a switch to the oral drug may be appropriate 
before the primary efficacy outcome assessment at 48 to 72 hours provided that 
pharmacokinetics of the oral formulation have been evaluated to ensure adequate exposure and 
to determine an appropriate dosing regimen.  
 
3.  Labeling Considerations 
 
The labeled indication for a drug approved for the treatment of ABSSSI should be for the 
treatment of ABSSSI caused by specific bacteria identified in patients in the clinical trials.  For 
example: 
 
Drug X is indicated for the treatment of acute bacterial skin and skin structure 
infections due to ... [list genus and species of bacteria].  
 
10 
  Contains Nonbinding Recommendations 
REFERENCES 
 
 
American Society for Microbiology, 2011, Manual of Clinical Microbiology, ASM Press, 
Washington DC, 10th edition. 
 
Corwin P, Toop L, McGoech G et al., 2005, Randomized Controlled Trial of Intravenous 
Antibiotic Treatment for Cellulitis at Home  Compared With Hospital, BMJ, 330(7483):129.  
(Epub 2004 Dec 16.) 
 
Duong M, Markwell S, Peter J, and Barenkamp S, 2010, Randomized, Controlled Trial of 
Antibiotics in the Management of Community-Acquired Skin Abscesses in the Pediatric Patient, 
Ann Emerg Med, 55(5):401-7. 
 
Florey ME and Williams RE, 1944, Hand Infections Treated With Penicillin, Lancet, January 
15;1(6281):73-81. 
 
Lavender HJ and Goldman L, 1935, Evaluation and Comparison of Specific Antiserum and 
Ultraviolet Therapy, JAMA, 105:401-403. 
 
Lee MC, Rios AM, Aten MF et al., 2004, Management and Outcome of Children With Skin and 
Soft Tissue Abscesses Caused By Community-Acquired Methicillin-Resistant Staphylococcus 
aureus, Pediatric Infectious Disease Journal, 23:123-127. 
 
Llera JL and Levy RC, 1985, Treatment of Cutaneous Abscess:  A Double-Blind Clinical Study, 
Annals of Emergency Medicine, 14:15-19. 
 
Rajendran PM, Young D, Maurer T et al., 2007, Randomized, Double-Blind Placebo-Controlled 
Trial of Cephalexin for Treatment of Uncomplicated Skin Abscesses in a Population at Risk for 
Community-Acquired Methicillin-Resistant  Staphylococcus aureus Infection, Antimicrob 
Agents and Chemother, 51:4044-4048. 
 
Skinner D and Keefer CS, 1941, Significance of Bacteremia Caused By Staphylococcus aureus, 
Archives of Internal Medicine, 68:851-875. 
 
Snodgrass WR and Anderson T, 1937(a), Prontosil in the Treatment of Erysipelas; A Controlled 
Series of 312 Cases, BMJ, 2:101-104 (July 17). 
 
Snodgrass WR and Anderson T, 1937(b), Sulfanilamide in the Treatment of Erysipelas; A 
Controlled Series of 270 Cases, BMJ, 2:1167-1159 (Dec 11). 
 
Spellberg B, Talbot GH, Boucher HW, Bradley JS, Gilbert D, Scheld WM, Edwards J, Bartlett 
JG, and Antimicrobial Availability Task Force of the Infectious Diseases Society of America, 
2009, Antimicrobial Agents for Complicated Skin and Skin-Structure Infections:  Justification of 
Noninferiority Margins in the Absence of Placebo-Controlled Trials, Clin Infect Dis, Aug 
1;49(3):383-91. 
 
11 
  Contains Nonbinding Recommendations 
Sutherland DS and Day FM, 1935, The Ultra-Violet Light Treatment of Erysipelas, The Medical 
Officer, Nov 2;185-186. 
 
Symmers D, 1928, The Antitoxin Treatment of Erysipelas, Journal of the American Medical 
Association, 91(5):535-538. 
 
Talbot GH, Powers JH, Fleming TR et al., 2012, Progress on Developing Endpoints for 
Registrational Clinical Trials of Community-Acquired Pneumonia and Acute Bacterial Skin and 
Skin Structure Infections: Update From the Biomarkers Consortium of the Foundation for the 
National Institutes of Health, Clin Infect Dis;55:1114-1121. 
 
Titus NE, 1934, The Treatment of Erysipelas By Ultra-Violet Light, Br. J of Physical Medicine, 
150-152. 
 
Ude WH and Platou ES, 1930, Erysipelas; A Comparative Study of the More Recent Methods of  
Treatment, JAMA, 95(1):1-4. 
 
Ude WH, 1931, Erysipelas; Further Comparative Studies of the More Recent Methods of 
Treatment, Archives of Physical Therapy, x-ray, radium, 16-18. 
 
 
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APPENDIX: 

JUSTIFICATION FOR A NONINFERIORITY MARGIN FOR ACUTE BACTERIAL 

SKIN AND SKIN STRUCTURE INFECTIONS 
 
 
Background 
 
The first step in the consideration for a noninferiority trial design is determining the treatment 
effect of the active-comparator drug that can be reliably distinguished from placebo (M ). This 
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margin is based on evidence from previously conducted trials using reliable efficacy endpoints.15   
For ABSSSI, there were no placebo-controlled trials reported in the historical literature.  
However, two controlled trials evaluated antibacterial drugs versus nonantibacterial treatments in 
patients with cellulitis/erysipelas.  These two studies can be used to estimate the treatment 
difference for antibacterial drugs in the treatment of ABSSSI for the endpoint based on lesion 
size assessment.  
 
Controlled Studies in Cellulitis/Erysipelas  
 
Two controlled studies were identified in the scientific literature that compared outcomes in 
patients with cellulitis/erysipelas treated with an  antibacterial drug versus ultraviolet (UV) light 
therapy (Snodgrass and Anderson 1937(a); Snodgrass and Anderson 1937(b)).  During the 
1930s, UV light was routinely used because previous studies published in the mid-1930s showed 
potential benefit in erysipelas when compared to other nonantibacterial therapies.  UV light 
therapy was the control group in these studies.   
 
Both studies enrolled patients with clinically documented erysipelas; however, the identification 
of a bacterial pathogen was not reported among study patients.  Erysipelas and cellulitis can be 
difficult to distinguish clinically and physicians use both terms to describe skin infections of the 
upper dermis or subcutaneous tissues.  We inferred that these two studies enrolled patients with 
cellulitis/erysipelas (ABSSSI) caused by either  S. pyogenes or  S. aureus.  
 
In the first study (Snodgrass and Anderson 1937(a)), 312 patients admitted from May 1936 to 
February 1937 received one of four open-label treatments for erysipelas: 
 
   UV light 
   Prontosil (a sulfonamide antibacterial drug that is metabolized to sulphanilamide)  
   UV light plus Prontosil 
   Scarlet fever antitoxin  
 
In the second study (Snodgrass and Anderson 1937(b)), 270 patients admitted from February 
1937 to August 1937 received one of two open-label treatments for erysipelas: 
 
   UV light 

   Sulphanilamide (a sulfonamide antibacterial drug) 

 
                                                 
15 See the draft guidance for industry Non-Inferiority Clinical Trials.  
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The efficacy endpoints were prespecified as clinical observations of whether the lesion continues 
to spread, the temperature has become normal, and the patient continues in a toxic condition. 
The largest treatment difference in lesion spread was the evaluation at 2 days; a smaller 
treatment difference was noted at day 3 and there was no difference in cessation of lesion spread 
at the day 4 time point.  Because the authors described cessation of lesion spread at day 0, then at 
day 1, followed by day 2, and so forth, we assumed that the evaluation at day 2 represented an 
evaluation at approximately 48 to 72 hours of therapy (i.e., day 0 represented the assessment of 
the patients lesions after some amount of time on therapy during the first day of hospitalization). 
 
To estimate a treatment effect of an antibacterial drug, we evaluated the results of the cessation 
of spread of the lesion after 2 days of therapy.  Table A provides summary information about the 
results of cessation of the spread of the lesion. Figure A shows the results of a random effects 
meta-analysis. 
 
Table A. Results of Studies 1 and 2 as Reported in the Articles 
  Study (a)  Study (b) 
  UV light  Prontosil  UV light  Sulphanilamide 
N  104  106  135  135 
Deaths  6  4  4  5 
Treatment discontinuations  0  0  9   0 
N evaluable for cessation of spread  98  102  122  130 
of lesion 
Cessation of spread of lesion at 2  75/98  100/102  89/122  129/130 
days (i.e., 48-72 hours)  (76.5%)   (98%)  (73%)  (99.2%)  
 
Figure A. Meta-Analysis for Cessation of Spread of Lesion at 2 Days 
   
Study name  Statistics for each study  Treatment  difference and 95%  CI 
 
Treatment Standard  Lower  Upper  

   
difference  error  limit  limit
 
     
Prontosil  0.215  0.045  0.127  0.303 
     
Sulphanilamide  0.263  0.041  0.183  0.343 
   
Overall  0.241  0.030  0.182  0.300 
 
-0.40  -0.20  0.00  0.20  0.40 
Favors UV  Favors Antibacterial 
 
 
The results of the random effects meta-analysis in patients with erysipelas demonstrate that there 
is a statistically significant treatment difference for the endpoint of cessation of the spread of 
cellulitis/erysipelas in favor of sulfonamides compared to UV light.  The treatment effect of 
sulfonamides compared to UV light in cellulitis/erysipelas was estimated to be approximately 24 
percent with a lower 95 percent confidence bound of approximately 18 percent based on the 
meta-analysis of the two studies.   
 
An early on-therapy clinical evaluation as a primary efficacy endpoint in ABSSSI has support 
from other publications: 
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 	  Skin infections of the hand caused by S. aureus or S. pyogenes that involved underlying 
tendon-sheaths showed a mean time to resolution of fever at 3.7 days for patients that 
received penicillin and at 12.0 days for patients that did not receive an antibacterial drug 
(Florey and Williams 1944) 
 
	   A primary endpoint of days to no advancement of cellulitis found that approximately 85 
percent of all patients in the trial had no advancement of cellulitis at a day 2 time point 
regardless of whether the patient received the antibacterial drug therapy in a hospital or at 
home (Corwin, Toop, et al. 2005) 
 
	   Before the availability of antibacterial drugs in 1928, 142 patients with erysipelas were 
treated with nonantibacterial therapies (intramuscular administration of horse serum  
antitoxin) and 78.1 percent were considered cured at day 7 (Symmers 1928), suggesting 
that an efficacy evaluation for antibacterial drugs much earlier than day 7 is appropriate 
for the noninferiority trial design in ABSSSI  
 
The treatment difference estimated from the two studies cited above  is probably a conservative 
estimate for the following reasons: 
 
	   UV light therapy appeared to result in more favorable outcomes among patients with 
cellulitis/erysipelas (Lavender and Goldman 1935; Titus 1934; Ude and Platou 1930; Ude 
1931; Sutherland and Day 1935) 
 
	   Before the availability of antibacterial drug therapy, morbidity (bacteremia) and mortality 
were observed in patients with skin abscesses caused by S. aureus (Skinner and Keefer 
1941) 
 
	   In comparison to a sulfonamide antibacterial drug, antibacterial drugs available today are 
probably more effective therapies for ABSSSI (Spellberg, Talbot, et al. 2009) 
 
Summary and Selection of Noninferiority Margin for ABSSSI  
 
The overall data support the treatment difference to be conservatively estimated at 18 percent for 
antibacterial drugs in the treatment of ABSSSI for the endpoint based on lesion size assessment.  
Because this appears to be a conservative estimate, further discounting of the treatment effect 
may not be necessary and thus M  is estimated to be 18 percent.  These scientific data provide 
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support for the selection of a noninferiority margin of 10 percent that preserves some of M  
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based on an endpoint of lesion size assessment.  Sponsors should discuss the selection of a 
noninferiority margin greater than 10 percent with the FDA in advance of trial initiation. 
 
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