
[Federal Register Volume 78, Number 113 (Wednesday, June 12, 2013)]
[Proposed Rules]
[Pages 35155-35173]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-13865]


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 Proposed Rules
                                                 Federal Register
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 This section of the FEDERAL REGISTER contains notices to the public of 
 the proposed issuance of rules and regulations. The purpose of these 
 notices is to give interested persons an opportunity to participate in 
 the rule making prior to the adoption of the final rules.
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  Federal Register / Vol. 78, No. 113 / Wednesday, June 12, 2013 / 
Proposed Rules  

[[Page 35155]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 317

[Docket No. FDA-2012-N-1037]
RIN 0910-AG92


Establishing a List of Qualifying Pathogens Under the Food and 
Drug Administration Safety and Innovation Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is proposing 
a regulation to establish a list of ``qualifying pathogens'' that have 
the potential to pose a serious threat to public health. The proposed 
rule would implement a provision of the Generating Antibiotic 
Incentives Now (GAIN) title of the Food and Drug Administration Safety 
and Innovation Act (FDASIA). GAIN is intended to encourage development 
of new antibacterial and antifungal drugs for the treatment of serious 
or life-threatening infections, and provides incentives such as 
eligibility for designation as a fast-track product and an additional 5 
years of exclusivity to be added to certain exclusivity periods. FDA is 
proposing that the following pathogens comprise the list of 
``qualifying pathogens:'' Acinetobacter species, Aspergillus species, 
Burkholderia cepacia complex, Campylobacter species, Candida species, 
Clostridium difficile, Enterobacteriaceae (e.g., Klebsiella 
pneumoniae), Enterococcus species, Mycobacterium tuberculosis complex, 
Neisseria gonorrhoeae, N. meningitidis, Non-tuberculous mycobacteria 
species, Pseudomonas species, Staphylococcus aureus, Streptococcus 
agalactiae, S. pneumoniae, S. pyogenes, and Vibrio cholerae. The 
preamble to the proposed rule describes the factors we considered and 
the methodology we used to develop this list of qualifying pathogens.

DATES: Submit comments by August 12, 2013.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2012-
N-1037 and/or Regulatory Information Number (RIN) 0910-AG92, by any of 
the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency 
name, Docket No. FDA-2012-N-1037 and RIN 0910-AG92 for this rulemaking. 
All comments received may be posted without change to http://www.regulations.gov, including any personal information provided. For 
additional information on submitting comments, see the ``Comments'' 
heading of the SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number(s), found in brackets in the heading of this document, 
into the ``Search'' box and follow the prompts and/or go to the 
Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, 
MD 20852.

FOR FURTHER INFORMATION CONTACT: Kristiana Brugger, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave. Bldg. 51, Rm. 6262, Silver Spring, MD 20993-0002, 301-
796-3601.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
II. Background
III. Consultation With Infectious Disease and Antibiotic Resistance 
Experts
IV. Factors Considered and Methodology Used for Establishing a List 
of Qualifying Pathogens
    A. The Impact on the Public Health Due to Drug-Resistant 
Organisms in Humans
    B. The Rate of Growth of Drug-Resistant Organisms in Humans and 
the Increase in Resistance Rates in Humans
    C. The Morbidity and Mortality in Humans
V. Proposed Pathogens for Inclusion in the List
    A. Acinetobacter Species
    B. Aspergillus Species
    C. Burkholderia cepacia Complex
    D. Campylobacter SpeciesE. Candida Species
    F. Clostridium difficile
    G. Enterobacteriaceae
    H. Enterococcus Species
    I. Mycobacterium tuberculosis Complex
    J. Neisseria gonorrhoeae
    K. Neisseria meningitidis
    L. Non-tuberculous Mycobacteria Species
    M. Pseudomonas Species
    N. Staphylococcus aureus
    O. Streptococcus agalactiae
    P. Streptococcus pneumoniae
    Q. Streptococcus pyogenes
    R. Vibrio cholerae
VI. Environmental Impact
VII. Analysis of Economic Impact
    A. Preliminary Regulatory Impact Analysis
    B. Background
    C. Need for and Potential Effect of the Regulation
VIII. Paperwork Reduction Act
IX. Federalism
X. Comments
XI. References

I. Executive Summary

Purpose of the Regulatory Action

    Title VIII of FDASIA (Pub. L. 112-144), the GAIN title, is intended 
to encourage development of new antibacterial and antifungal drugs for 
the treatment of serious or life-threatening infections. Among other 
things, it requires that the Secretary of the Department of Health and 
Human Services (and thus FDA, by delegation): (1) Establish and 
maintain a list of ``qualifying pathogens'' that have ``the potential 
to pose a serious threat to public health'' and (2) make public the 
methodology for developing the list (see section 505E(f) of the Federal 
Food, Drug, and Cosmetic Act (the FD&C Act), as amended) (21 U.S.C. 
355E(f)). In establishing and maintaining the list of ``qualifying 
pathogens,'' FDA must consider: The impact on the public health due to 
drug-resistant organisms in humans; the rate of growth of drug-
resistant organisms in humans; the increase in resistance rates in 
humans;

[[Page 35156]]

and the morbidity and mortality in humans. FDA also is required to 
consult with infectious disease and antibiotic resistance experts, 
including those in the medical and clinical research communities, along 
with the Centers for Disease Control and Prevention (CDC). FDA is 
issuing this proposed rule to fulfill these requirements.

Summary of the Major Provisions of the Regulatory Action

    After holding a public meeting and consulting with CDC and the 
National Institutes of Health (NIH), and considering the factors 
specified in section 505E(f)(2)(B)(i) of the FD&C Act, as amended, FDA 
is proposing that the following pathogens comprise the list of 
``qualifying pathogens:'' Acinetobacter species, Aspergillus species, 
Burkholderia cepacia complex, Campylobacter species, Candida species, 
Clostridium difficile, Enterobacteriaceae (e.g., Klebsiella 
pneumoniae), Enterococcus species, Mycobacterium tuberculosis complex, 
Neisseria gonorrhoeae, N. meningitidis, Non-tuberculous mycobacteria 
species, Pseudomonas species, Staphylococcus aureus, Streptococcus 
agalactiae, S. pneumoniae, S. pyogenes, and Vibrio cholerae. The 
preamble to the proposed rule describes the factors FDA considered and 
the methodology FDA used to develop this list of qualifying pathogens.

Costs and Benefits

    The Agency has determined that this proposed rule is not a 
significant regulatory action as defined by Executive Order 12866.

II. Background

    Title VIII of FDASIA (Pub. L. 112-144), entitled Generating 
Antibiotic Incentives Now, amended the FD&C Act to add section 505E (21 
U.S.C. 355E), among other things. This new section of the FD&C Act is 
intended to encourage development of treatments for serious or life-
threatening infections caused by bacteria or fungi. For certain drugs 
that are designated as ``qualified infectious disease products'' 
(QIDPs) under new section 505E(d) of the FD&C Act, new section 505E(a) 
provides an additional 5 years of exclusivity to be added to the 
exclusivity periods provided by sections 505(c)(3)(E)(ii) to 
(c)(3)(E)(iv) (21 U.S.C. 355(c)(3)(E)(ii) to (c)(3)(E)(iv)), 
505(j)(5)(F)(ii) to (j)(5)(F)(iv) (21 U.S.C. 355(j)(5)(F)(ii) to 
(j)(5)(F)(iv)), and 527 (21 U.S.C. 360cc) of the FD&C Act. In addition, 
an application for a drug designated as a QIDP is eligible for priority 
review and designation as a fast track product (sections 524A and 
506(a)(1) of the FD&C Act, respectively).
    The term ``qualified infectious disease product'' or ``QIDP'' 
refers to an antibacterial or antifungal human drug that is intended to 
treat serious or life-threatening infections (section 505E(g) of the 
FD&C Act). It includes treatments for diseases caused by antibacterial- 
or antifungal-resistant pathogens (including new or emerging 
pathogens), or diseases caused by ``qualifying pathogens.''
    The GAIN title of FDASIA requires that the Secretary of the 
Department of Health and Human Services (and thus FDA, by designation) 
establish and maintain a list of such ``qualifying pathogens,'' and 
make public the methodology for the developing the list. According to 
the statute, the term `qualifying pathogen' means a pathogen identified 
and listed by the Secretary * * * that has the potential to pose a 
serious threat to public health, such as[:] (A) resistant gram positive 
pathogens, including methicillin-resistant Staphylococcus aureus, 
vancomycin-resistant Staphylococcus aureus, and vancomycin-resistant 
[E]nterococcus; (B) multi-drug resistant gram[-]negative bacteria, 
including Acinetobacter, Klebsiella, Pseudomonas, and E. coli species; 
(C) multi-drug resistant tuberculosis; and (D) Clostridium difficile 
(section 505E(f)(1) of the FD&C Act, as amended by FDASIA). FDA is 
required under the law to consider four factors in establishing and 
maintaining the list of qualifying pathogens:
     The impact on the public health due to drug-resistant 
organisms in humans;
     The rate of growth of drug-resistant organisms in humans;
     The increase in resistance rates in humans; and
     The morbidity and mortality in humans (section 
505E(f)(2)(B)(i), as amended by FDASIA).
    Furthermore, in determining which pathogens should be listed, FDA 
is required to consult with infectious disease and antibiotic 
resistance experts, including those in the medical and clinical 
research communities, along with CDC (section 505E(f)(2)(B)(ii) of the 
FD&C Act, as amended by FDASIA). As discussed in the paragraphs that 
follow, FDA has met this requirement by convening a public hearing, and 
opening an associated public docket, to solicit input regarding the 
list of qualifying pathogens, as well as by consulting with infectious 
disease and antibiotic resistance experts at CDC and NIH during the 
development of this proposed rule.
    Significantly, the statutory standard for inclusion on FDA's list 
of qualifying pathogens is different from the statutory standard for 
QIDP designation. QIDP designation, by definition, requires that the 
drug in question be an ``antibacterial or antifungal drug for human use 
intended to treat serious or life-threatening infections'' (section 
505E(g) of the FD&C Act, as amended by FDASIA). ``Qualifying 
pathogens'' are defined according to a different statutory standard; 
the term ``means a pathogen identified and listed by the Secretary . . 
. that has the potential to pose a serious threat to public health'' 
(section 505E(f) of the FD&C Act, as amended by FDASIA) (emphasis 
added). That is, a drug intended to treat a serious or life-threatening 
bacterial or fungal infection caused by a pathogen that is not included 
on the list of ``qualifying pathogens'' may be eligible for designation 
as a QIDP, while a drug that is intended to treat an infection caused 
by a pathogen on the list may not always be eligible for QIDP 
designation.
    FDA intends the list of qualifying pathogens to reflect the 
pathogens that, as determined by the Agency, after consulting with 
other experts and considering the factors set forth in FDASIA (see 
section 505E(f)(2)(B)(i) of the FD&C Act, as amended by FDASIA), have 
the ``potential to pose a serious threat to public health'' (section 
505E(f)(1) of the FD&C Act, as amended by FDASIA). FDA does not intend 
for this list to be used for other purposes, such as the following: (1) 
Allocation of research funding for bacterial or fungal pathogens; (2) 
setting of priorities in research in a particular area pertaining to 
bacterial or fungal pathogens; or (3) direction of epidemiological 
resources to a particular area of research on bacterial or fungal 
pathogens. Furthermore, as section 505E of the FD&C Act makes clear, 
the list of qualifying pathogens includes only bacteria or fungi that 
have the potential to pose a serious threat to public health. Viral 
pathogens or parasites, therefore, were not considered for inclusion 
and are not included as part of this list.

III. Consultation With Infectious Disease and Antibiotic Resistance 
Experts

    GAIN requires FDA to consult with infectious disease and antibiotic 
resistance experts, including those in the medical and clinical 
research communities, along with the CDC, in determining which 
pathogens should be included on the list of ``qualifying pathogens'' 
(section 505E(f)(2)(B)(ii) of the FD&C Act, as amended by FDASIA).

[[Page 35157]]

In order to fulfill this statutory obligation, on December 18, 2012, 
FDA convened a public hearing, at which the Agency solicited input 
regarding the following topics: (1) How FDA should interpret and apply 
the four factors FDASIA requires FDA to ``consider'' in establishing 
and maintaining the list of qualifying pathogens, (2) whether there are 
any other factors FDA should consider when establishing and maintaining 
the list of qualifying pathogens, and (3) which specific pathogens FDA 
should list as qualifying pathogens. The transcript of this hearing, as 
well as comments submitted to the hearing docket, are available at 
www.regulations.gov, docket number FDA-2012-N-1037. FDA has considered 
carefully the input presented at this hearing, as well as the comments 
submitted to the docket, in creating this proposed list of qualifying 
pathogens.\1\ In addition, FDA consulted with experts in infectious 
disease and antibiotic resistance at CDC and NIH during the development 
of this proposed rule.
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    \1\ The public hearing and this proposed rule share docket 
numbers because they are part of the same rulemaking process. 
Accordingly, the documents from the public hearing phase of Docket 
No. FDA-2012-N-1037 are included in the docket for this rulemaking.
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IV. Factors Considered and Methodology Used for Establishing a List of 
Qualifying Pathogens

    As stated previously, section 505E(f)(2)(B)(i) of the FD&C Act (as 
amended by FDASIA) requires FDA to consider the following factors in 
establishing and maintaining the list of qualifying pathogens:
     The impact on the public health due to drug-resistant 
organisms in humans;
     The rate of growth of drug-resistant organisms in humans;
     The increase in resistance rates in humans; and
     The morbidity and mortality in humans.
    The Agency recognizes it is important to take a long-term view of 
the drug resistance problem. For some pathogens, particularly those for 
which increased resistance is newly emerging, FDA recognizes that there 
may be gaps in the available data or evidence pertaining to one or more 
of the four factors described in section 505E(f)(2)(B)(i) of the FD&C 
Act. Thus, consistent with GAIN's purpose of encouraging the 
development of treatments for serious or life-threatening infections 
caused by bacteria or fungi, the Agency intends to consider the 
totality of available evidence for a particular pathogen to determine 
whether that pathogen should be included on the list of qualifying 
pathogens. Therefore, if, after considering the four factors identified 
in section 505E(f)(2)(B)(i) of the FD&C Act, FDA determines that the 
totality of available evidence demonstrates that a pathogen ``has the 
potential to pose a serious threat to public health,'' the Agency may 
designate the pathogen in question as a ``qualifying pathogen.'' More 
detailed explanations of each factor identified in section 
505E(f)(2)(B)(i) are set forth in the paragraphs that follow.

A. The Impact on the Public Health Due to Drug-Resistant Organisms in 
Humans

    This first factor that section 505E(f)(2)(B)(i) requires FDA to 
consider is also the broadest. Many factors associated with infectious 
diseases affect public health directly, such as a pathogen's ease of 
transmission, the length and severity of the illness it causes, the 
risk of mortality associated with its infection, and the number of 
approved products available to treat illnesses it causes. Additionally, 
although the Agency did not consider financial costs in its analyses 
for this proposed list of qualifying pathogens, we note that the 
published literature supports the conclusion that antimicrobial-
resistant infections are associated with higher healthcare costs (see, 
e.g., Refs. 1 and 2; Ref. 3 at pp. 807, 810, 812).
    In considering a proposed pathogen's impact on the public health 
due to drug-resistant organisms in humans, FDA will assess such 
evidence as: (1) The transmissibility of the pathogen and (2) the 
availability of effective therapies for treatment of infections caused 
by the pathogen, including the feasibility of treatment administration 
and associated adverse effects. However, FDA may also assess other 
public health-related evidence, including evidence that may indicate a 
highly prevalent pathogen's ``potential to pose a serious threat to 
public health'' due to the development of drug-resistance in that 
pathogen, even if most documented infections are currently drug-
susceptible.

B. The Rate of Growth of Drug-Resistant Organisms in Humans and the 
Increase in Resistance Rates in Humans

    The second and third factors that FDA must consider overlap 
substantially with one another, and for the most part are assessed 
using the same trends and information. Therefore, the Agency will 
analyze these factors together.
    In considering these factors with respect to a proposed pathogen, 
FDA will assess such evidence as: (1) The proportion of patients whose 
illness is caused by a drug-resistant isolate of a pathogen (compared 
with those whose illness is caused by more widely drug-susceptible 
pathogens); (2) number of resistant clinical isolates of a particular 
pathogen (e.g., the known incidence or prevalence of infection with a 
particular resistant pathogen); and (3) the ease and frequency with 
which a proposed pathogen can transfer and receive resistance-
conferring elements (e.g., plasmids encoding relevant enzymes, etc.). 
Given the temporal limitations on infectious disease data, FDA also 
will consider evidence that a given pathogen currently has a strong 
potential for a meaningful increase in resistance rates. Evidence of 
the potential for increased resistance may include, for example, 
projected (rather than observed) rates of drug resistance for a given 
pathogen, and current and projected geographic distribution of a drug-
resistant pathogen. Furthermore, in acknowledgement of the growing 
problem of drug resistance, FDA may also assess other available 
evidence demonstrating either existing or potential increases in drug 
resistance rates.

C. The Morbidity and Mortality in Humans

    Patients infected with drug-resistant pathogens are inherently more 
challenging to treat than those infected with drug-susceptible 
pathogens. For example, in some cases, a patient infected with a drug-
resistant pathogen may have a delay in the initiation of effective drug 
therapy that can result in poor outcomes for such patients. 
Consequently, in determining whether a pathogen should be included in 
the list, FDA will consider the rates of mortality and morbidity (the 
latter as measured by, e.g., duration of illness, severity of illness, 
and risk and extent of sequelae from infections caused by the pathogen, 
and risk associated with existing treatments for such infections) 
associated with infection by that pathogen generally--and particularly 
by drug-resistant strains of that pathogen.
    Setting quantitative thresholds for inclusion on the list based on 
any pre-specified endpoint would be inconsistent with FDA's approach of 
considering a totality of the evidence related to a given pathogen, as 
well as infeasible given the variety of pathogens under consideration. 
Instead, in considering whether this factor weighs in favor of 
including a given pathogen, the Agency will look for evidence of a 
meaningful increase in morbidity and mortality rates when infection 
with a drug-resistant strain of a pathogen is compared to infection 
with a more drug-

[[Page 35158]]

susceptible strain of that pathogen. The Agency may also assess other 
evidence, such as overall morbidity and mortality rates for infection 
with either resistant or susceptible strains of a pathogen to determine 
whether that pathogen has the potential to pose a serious threat to 
public health, in particular if drug-resistant isolates of the pathogen 
were to become more prevalent in the future.

V. Proposed Pathogens for Inclusion in the List

    FDA is proposing to include the following pathogens in its list of 
qualifying pathogens based on the data described in the paragraphs that 
follow. FDA expects that the inclusion of any additional pathogens in 
the list would be supported by similar data.

A. Acinetobacter Species

    Members of the genus Acinetobacter are gram-negative bacteria that 
can cause hospital-acquired infections such as pneumonia, bacteremia 
(i.e., bloodstream infections), meningitis, genitourinary infections, 
or soft tissue infections (e.g., cellulitis) (Ref. 4 at pp. 2881-2883 
(internal citation omitted)). A total of 1,490 healthcare-associated 
infections with Acinetobacter species, the majority of which were 
resistant to at least one class of antibacterial drugs, were reported 
to CDC's National Healthcare Safety Network (NHSN) in 2009-2010 (Ref. 
132, Table 7). Thus, Acinetobacter resistance is a well-recognized and 
growing problem (see generally, e.g., Ref. 5), and most hospital-
acquired A. baumannii are now resistant to multiple classes of 
antibacterial agents (Ref. 4 at p. 2884 (internal citation omitted)). 
Indeed, in recognition of this problem, in 2008, the Infectious 
Diseases Society of America (IDSA) designated Acinetobacter species to 
be among six highly problematic drug-resistant organisms identified as 
the so-called ``ESKAPE'' pathogens, which ``currently cause the 
majority of U.S. hospital infections and effectively `escape' the 
effects of antibacterial drugs.'' \2\ (Refs. 5 and 6). Acinetobacter 
species can survive for prolonged periods in the environment and on the 
hands of healthcare workers, and as such are well-recognized as 
transmissible nosocomial pathogens (see, e.g., Ref. 7). Several 
independent resistance mechanisms, such as those mediated by 
cephalosporinases, beta-lactamases, or carbapenemases, have been 
identified in Acinetobacter species, and some resistance mechanisms 
(e.g., genes encoding resistance-mediating enzymes) can be readily 
transferred from one bacteria to another on highly ambulatory genetic 
cassettes (Ref. 9). In addition, the pool of available effective 
treatments for Acinetobacter infections is shrinking (see, e.g., Ref. 5 
at p. 7; Ref. 6).
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    \2\ The ``ESKAPE'' pathogens are: Enterococcus faecium, S. 
aureus, Klebsiella pneumoniae, A. baumanni, Pseudomonas aeruginosa, 
and Enterobacter species (Ref. 6).
---------------------------------------------------------------------------

    Patients who acquire a drug-resistant Acinetobacter bloodstream 
infection appear more likely than those with drug-susceptible 
infections to suffer deleterious effects from the illness. For example, 
in a study of patients with A. baumannii bloodstream infections in 
European intensive care units (ICUs), 74 percent of A. baumannii 
bloodstream infections were resistant to a commonly used antibacterial 
drug (Ref. 10 at p. 33, Table 3).\3\ Patients with resistant A. 
baumannii bloodstream infections became infected sooner after admission 
than patients with drug-susceptible A. baumannii (9 days vs. 19 days) 
(Ref. 10 at p. 33, Table 3). For those who survived, patients infected 
with resistant bacteria remained in the hospital longer than those 
infected with susceptible bacteria (20 days vs. 9 days), and, for those 
who died,\4\ patients infected with resistant bacteria died sooner 
after infection than those with susceptible bacteria (5 days vs. 16 
days) (Ref. 10 at p. 33, Table 3). In addition, ``recent studies of 
patients in the [ICU] who had [bloodstream infection] and burn 
infection due to [drug]-resistant Acinetobacter species demonstrate an 
increased mortality (crude mortality, 26 to 68 percent), as well as 
increased morbidity and length of stay in the [ICU]'' (Ref. 5 at p. 7). 
Similar trends have been seen for A. baumannii pneumonia in terms of: 
Prevalence of drug-resistant infection; time from admission to 
infection; and time from infection to death (Ref. 10).\5\ In one study 
of Pakistani newborns with infections caused by Acinetobacter species, 
57 of 122 Acinetobacter-positive cultures (from 78 newborns) showed 
infection in the bloodstream (Ref. 133). Approximately 71 percent of 
all Acinetobacter infections in the study were susceptible to only one 
antibacterial drug (polymyxin), and were labeled as a ``pan-resistant'' 
(i.e., resistant to many drugs) Acinetobacter; 47 percent of the 
newborns in the study with Acinetobacter infections died (Ref. 133).
---------------------------------------------------------------------------

    \3\ All figures represent data for those strains of A. baumannii 
whose resistance status was known, which was approximately 29 
percent of all patients with A. baumannii bloodstream infections 
(Ref. 10). Numbers indicate median values (id.).
    \4\ The point estimate of the case fatality rate for A. 
baumannii bloodstream infections among patients in which the results 
of in vitro antibacterial susceptibility testing were not available 
for most isolates, was very high at 48 percent (68/142). The point 
estimate of the case fatality rate was slightly lower for known 
resistant infections (13/30 or 43 percent), compared to known 
susceptible infections (6/11 or 55 percent) (Ref. 10 at pp. 33-34). 
The small denominator of patients with known susceptible A. 
baumannii bloodstream infections makes it difficult to draw 
conclusions about a difference in mortality rates based on the in 
vitro susceptibility profiles; therefore any A. baumannii 
bloodstream infection, the majority of which appear to be resistant 
to many antibacterial drugs, is associated with a high mortality 
rate.
    \5\ For A. baumannii pneumonia, results of in vitro 
susceptibility was known for only 34 percent of patients (Ref. 10).
---------------------------------------------------------------------------

    For the reasons described previously, FDA believes that 
Acinetobacter species have the potential to pose a serious threat to 
the public health, particularly for hospitalized patients and, FDA is 
proposing to include Acinetobacter species in its list of qualifying 
pathogens.

B. Aspergillus Species

    Members of the Aspergillus genus are fungi (specifically, hyaline 
molds) that have potential to cause serious infections, typically in 
immunocompromised people. Aspergillus can cause invasive infections of 
the lungs, skin, sinuses, bone, or brain, or be disseminated throughout 
the body. It frequently colonizes airway passages, creating the 
potential for invasive disease among patients who become 
immunocompromised, such as patients who receive lung transplantation 
(Ref. 11). In one center, for example, Aspergillus infection (i.e., 
colonization or evidence of invasive disease) was reported in 
approximately 30 percent of patients who received lung transplantation 
(Ref. 11). These fungi also may cause an allergic reaction, which may 
result in allergic bronchopulmonary aspergillosis, particularly in 
those with cystic fibrosis (CF) (Ref. 4 at pp. 3241, 3244-3249).
    Invasive aspergillosis often responds poorly to antifungal therapy, 
even when Aspergillus infections are susceptible to antifungal drugs 
(Ref. 4 at p. 3250). Therefore, the existence throughout the world of 
azole-resistant A. fumigatus (i.e., A. fumigatus isolates resistant to 
the class of drugs comprising several different antifungal drugs in the 
family of ``azole antifungal drugs''), and reports that azole resistant 
A. fumigatus may be spreading in the environment (see Ref. 12 at pp. 
1635-1636) is of great concern--as are the reports of multiple-drug 
resistant A. fumigatus in Europe

[[Page 35159]]

(Refs. 12 and 13). The predominant resistance mechanism in A. fumigatus 
is thought to be a chromosomally encoded mutation in the target enzyme, 
although alternative resistance mechanisms have been observed (see, 
e.g., Ref. 13). In some cases antifungal drugs are recommended as 
chemical prophylaxis to prevent invasive infections in high-risk 
patients (Ref. 4 at p. 3253), including some asthmatics (see Ref. 13). 
However, the use of prophylactic antifungal drugs creates selective 
pressure on these organisms, thus increasing the risk of drug-resistant 
Aspergillus colonization and infection. Moreover, European studies have 
found that many patients who had not received antifungal therapy 
nevertheless were colonized with resistant strains of A. fumigatus 
(Ref. 13 (internal citations omitted)).
    Many patients with Aspergillus infections are vulnerable already, 
due to concomitant conditions such as cystic fibrosis or some level of 
immunodeficiency. Should Aspergillus resistance further diminish the 
already low efficacy of existing treatments and prophylaxis, patient 
outcomes would, similarly, be expected to worsen. For the reasons 
described above, FDA believes that Aspergillus species have the 
potential to pose a serious threat to the public health, and FDA is 
proposing to include Aspergillus species in its list of qualifying 
pathogens.

C. Burkholderia cepacia Complex

    The Burkholderia cepacia complex (Bcc) comprises about 10 species 
of gram-negative bacteria (Ref. 4 at p. 2861). The Burkholderia genus 
was established relatively recently, however, and species are being 
identified and added to the Bcc on an ongoing basis (Ref. 4 at p. 
2861). Bcc can cause pneumonia, particularly in patients with CF and 
patients with chronic granulomatous disease (Ref. 4 at pp. 2862, 2865 
(internal citation omitted)). Bcc can also cause life-threatening 
bacteremia among hospitalized patients who are immunocompromised, 
resulting in a mortality rate of 33 percent of hematology patients with 
Bcc bacteremia in one academic medical center (Ref. 14). Other 
outbreaks of serious bacterial infections caused by Bcc have been 
documented due to nosocomial transmission, indicating the potential for 
an ease of transmissibility in the hospital setting in patients without 
CF (see, e.g., Ref. 15).
    Bcc infections cause noteworthy levels of morbidity and mortality, 
particularly in patients with CF (see, e.g., Ref. 14), although 
outbreaks among patients without CF also have been reported (see, e.g., 
Ref. 16). ``Increased mortality has been observed in CF patients after 
colonization with Bcc,'' (Ref. 4 at p. 2865 (internal citations 
omitted); Ref. 17) and, in one study, survival rates for patients with 
CF who were infected with B. cenocepacia (a Bcc species) were markedly 
worse than rates for patients with CF who were infected with P. 
aeruginosa (not a Bcc species) (Ref. 150; see also Ref. 4 at p. 2862, 
Fig. 220-1 (internal citation omitted)). Because patients with CF often 
require repeated or chronic administration of antibacterial drugs, 
antibacterial drug resistance among Bcc isolates can develop through 
these selective pressures (see Ref. 18 (noting that an increase in 
antibacterial resistance was observed among patients with CF who 
received a chronically inhaled antibacterial drug)). In fact, a pan-
resistant isolate of Bcc already has been documented in patients with 
CF (Ref. 19). Although there appear to be limited data on the exact 
incidence and prevalence of Bcc infection in the CF population, because 
the average life-span for patients with CF has been steadily increasing 
over the past few decades (Ref. 20 at p. 789, Fig. 1), it stands to 
reason that Bcc colonization and infection in patients with CF likely 
will increase. Furthermore, although data comparing outcomes of drug-
resistant infections with outcomes of drug-susceptible infections also 
are limited, it stands to reason that decreasing susceptibility and 
resistance patterns in Bcc likely will be observed during the life span 
of a patient with CF based on selective pressures caused by appropriate 
use of antibacterial drugs.
    For the reasons described previously, FDA believes that these 
pathogens have the potential to pose a serious threat to the public 
health--particularly for patients with CF--and FDA is proposing to 
include Bcc species in its list of qualifying pathogens.

D. Campylobacter Species

    The Campylobacter genus comprises several species of gram-negative 
bacteria, some of which are causative agents of diarrheal and systemic 
diseases in humans (Ref. 4 at pp. 2793-2796). These are common 
infections: Campylobacter is estimated to cause over 1.3 million cases 
of enteric infection in the United States each year (Ref. 42). It is 
believed that most human infections are caused by consuming 
contaminated food (e.g., meat) or water (Ref. 4 at p. 2794), though 
person to person transmission of C. jejuni has been reported to occur 
through the fecal-oral route, and other routes (Ref. 4 at p. 2795). 
Transmissibility is readily apparent, with clinical disease that can be 
caused by just 500 Campylobacter organisms (Ref. 4 at p. 2795), so, for 
example, ``[e]ven one drop of juice from raw chicken meat can infect a 
person'' (Ref. 21).
    The following indicates the potential for Campylobacter infections 
to result in enhanced morbidity and mortality, regardless of whether 
the bacterium is fully susceptible or is resistant to antibacterial 
drugs: C. jejuni infections have been linked to reactive arthritis in a 
certain subset of patients (Ref. 4 at p. 2797), C. jejuni infections 
are a major cause of Guillain-Barr[eacute] syndrome (1 case per 2,000 
C. jejuni infections, accounting for 20 to50 percent of all cases of 
Guillain-Barr[eacute] syndrome (id.)), and C. fetus infections ``may be 
lethal to patients with chronic compensated diseases such as cirrhosis 
or diabetes mellitus or may hasten the demise of seriously compromised 
patients'' (Ref. 4 at p. 2799). Although many people recover from 
enteric Campylobacter infections without the need for drug treatment, a 
variety of antibacterial drugs, including azithromycin, erythromycin, 
or ciprofloxacin, may be prescribed to treat severe Campylobacter 
infections (Ref. 21; Ref. 4 at p. 2799).
    Drug resistance in Campylobacter species, particularly resistance 
to fluoroquinolones, has been increasing rapidly (Ref. 4 at p. 2799 
(internal citation omitted); see Ref. 22; see also Ref. 134). Indeed, 
in human Campylobacter infections, resistance has been observed to many 
different classes of antibacterial drugs (see, e.g., Ref. 22 (internal 
citations omitted); Ref. 23), and resistance mechanisms can be readily 
transferred from bacteria to bacteria (Ref. 22). ``Infection with C. 
jejuni strains resistant to erythromycin or fluoroquinolones is more 
likely to result in prolonged or invasive illness or death'' (Ref. 4 at 
p. 2799), and it stands to reason that drug-resistant strains of other 
pathogenic Campylobacter species are likely to be similarly 
problematic. One survey of Campylobacter isolates indicated increasing 
and high levels of resistance to antibacterial drugs in several 
classes, with some of the resistance encoded on transferable plasmids 
(Ref. 24). Because Campylobacter infections are common, any increase in 
resistance rates may translate quickly into a threat to the public 
health.
    For the foregoing reasons, FDA believes that Campylobacter species 
have the potential to pose a serious threat to public health, and FDA 
is proposing to include bacteria from the

[[Page 35160]]

genus Campylobacter in the list of qualifying pathogens.

E. Candida Species

    Candida species are fungi (specifically, yeast) that are part of 
the normal human flora, and thus Candida species can easily be 
transmitted and can cause invasive disease, particularly among 
immunocompromised patients (see, e.g., Ref. 4 at pp. 3225-3226; Ref. 
25). Candida can infect almost any part of the body to which they are 
introduced (so-called invasive candidiasis), including the central 
nervous system, respiratory tract, urinary tract, gastro-intestinal 
tract, or heart (see Ref. 4 at pp. 3227-3235).
    Those who are already fragile are at higher risk of invasive 
disease (e.g., between 5 percent and 20 percent of neonates weighing 
less than 2.2 pounds will develop some form of invasive candidiasis 
(Ref. 26)), and the risk is particularly high in those who are 
immunocompromised. For example, before the availability of highly-
active antiretroviral therapy for the treatment of human 
immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), 
invasive candidiasis (such as esophageal candidiasis) was a common 
infection in this patient population, with a well-documented increase 
in the rates of antifungal resistance (Ref. 27). Many patients with 
HIV/AIDS did not respond to standard antifungal therapy and required 
administration of parenteral antifungal drugs, which limited 
therapeutic options and was directly associated with the development of 
resistance (Ref. 27). Today, infections caused by Candida species rank 
as the fourth most common bloodstream infection in the United States 
(Ref. 25). Candida bloodstream infections are associated with high 
mortality rates, with approximately 35 to 40 percent of infected 
patients dying of Candida infections in a study involving patients in 
one tertiary-care center (Ref. 28).
    Although the problem of invasive candidiasis has diminished in the 
population of patients with HIV/AIDS due to advances in antiretroviral 
therapy, the number of patients receiving solid organ transplants, and 
therefore on immunosuppressive therapy, is increasing (Ref. 29). 
Experts are now concerned about antifungal-resistant invasive 
candidiasis in this patient population, echoing the concerns previously 
borne out in the population of patients with HIV/AIDS (see, e.g., Refs. 
27 and 30). Transplant patients often take prophylactic antifungal 
drugs, which exert selective pressure on the Candida organisms and make 
it more likely that these patients will be colonized by, or develop 
infections with, drug-resistant fungi. Indeed, it has been noted that 
Candida species with antifungal resistance patterns are emerging as a 
common fungal infection in this population (Refs. 28 and 30).
    Resistance genes in Candida species tend to proliferate in 
localized populations, though they occasionally may be transferred 
through mating (Ref. 31). Some reports have documented continued 
selective pressures of oral antifungal drugs administered as 
prophylaxis in certain populations, resulting in an increasing rate of 
infection caused by Candida species resistant to ``azole antifungal 
drugs'' (e.g., Candida glabrata and Candida krusei) (see, e.g., Refs. 
32 and 33). Selective pressures from the use of oral azole antifungal 
drugs can shift infections from C. albicans to certain other Candida 
species, such as Candida glabrata and Candida krusei, which both have 
intrinsic resistance to azole antifungal drugs and eliminates any 
possibility of treatment with an oral azole antifungal drug. Thus, some 
patients with invasive candidiasis already have treatment options 
limited to only intravenously-administered antifungal drugs (Ref. 34).
    For the foregoing reasons, FDA believes that Candida species have 
the potential to pose a serious threat to the public health, and FDA 
proposes that Candida species be included in the list of qualifying 
pathogens.

F. Clostridium difficile

    C. difficile is a toxin-producing gram-positive bacterium (Ref. 35) 
that can cause serious, sometimes fatal, gastrointestinal disease 
(e.g., toxic megacolon) (see, e.g., Ref. 4 at p. 3104 (internal 
citation omitted)). The spores of the C. difficile bacteria (see Ref. 
36) are difficult to eliminate from the environment, even after 
disinfection by hand-washing or cleansing, and individuals can acquire 
the pathogen via contact with either contaminated surfaces or other 
individuals (see, e.g., Ref. 4 at p. 3104 (internal citation omitted)). 
CDC estimates that the vast majority of patients with C. difficile 
infection have had recent contact with healthcare providers, either in 
an inpatient or outpatient setting (Ref. 37). Because spores of the 
bacteria are difficult to eliminate from the environment, it is not 
surprising that transmission of C. difficile infection in the hospital 
environment has been noted (Ref. 37).
    Risk of infection with C. difficile increases with both a patient's 
age and recent antibacterial drug use (Ref. 37). Incidence of C. 
difficile-associated illness has increased significantly over the past 
several years. For example, ``[t]here was an 117% increase in the 
listing of [C. difficile-associated disease] on hospital discharges in 
the Healthcare Costs and Utilization Project Net Web site from 2000 to 
2005'' (Ref. 4 at p. 3106 (internal citation omitted)), and currently, 
``C. difficile infections are at an all-time high'' (Ref. 37). 
Mortality has been increasing along with infection incidence. One study 
showed that from 1999 to 2004 in the United States (Ref. 63) there was 
a 35 percent increase in mortality for which C. difficile infection was 
listed as a contributing factor. CDC has estimated a 400 percent 
increase in deaths between 2000 and 2007 in which C. difficile was a 
contributing factor (Ref. 37). Currently, based on a review of death 
certificates, about 14,000 American deaths each year list C. difficile 
infection as a contributing factor; the majority of deaths occur in 
patients over 65 years of age (Ref. 135).
    The use of antibacterial drugs in hospitals has been identified as 
an important risk factor for C. difficile infections because C. 
difficile is naturally resistant to many commonly used antibacterial 
drugs. However, the prevalence of C. difficile infections is increasing 
and that has been associated with an increased prevalence of strains 
with new resistance to fluoroquinolones (see, e.g., Ref. 38). North 
American epidemiological data have shown the emergence of high levels 
of resistance to fluoroquinolone antibacterial drugs--and this 
resistance emerged quickly (see, e.g., Ref. 39). As noted by CDC, 
``even a modest decrease in [drug] susceptibility might be clinically 
relevant'' to the epidemiology of C. difficile infections (Ref. 38 at 
p. 446). Newly acquired resistance by C. difficile to commonly used 
antibacterials, as in the case of the fluoroquinolones, facilitates the 
emergence of hyper-virulent strains that increase the burden of 
infections and deaths caused by C. difficile (Refs. 39 and 156).
    C. difficile causes serious infections but there are a limited 
number of effective antibacterial drugs used to treat C. difficile 
infection, and treatment often lasts for an extended period of time 
(Ref. 38). Furthermore, relapse or recurrence of C. difficile is 
common, and often necessitates re-treatment with antibacterial drugs 
(Ref. 38). In light of these considerations, the increased prevalence 
of C. difficile infections constitutes a serious threat to the public 
health (Ref. 39).
    Thus, FDA believes that C. difficile has the potential to pose a 
serious threat

[[Page 35161]]

to public health. For the reasons described previously--particularly 
the high prevalence of C. difficile infections, the fact that acquired 
resistance leads to increased infections and deaths via the emergence 
of hypervirulent strains, and the very limited treatment options--FDA 
is proposing to include C. difficile in its list of qualifying 
pathogens.

G. Enterobacteriaceae

    The Enterobacteriaceae are a family of gram-negative bacteria and 
include species in the genera Escherichia (e.g., E. coli), Klebsiella, 
Enterobacter, Shigella, and Salmonella (see Ref. 4 at pp. 2815-2816). 
Most Enterobacteriaceae are toxin-secreting, and they can cause a 
variety of serious and life-threatening bacterial diseases (see Ref. 4 
at pp. 2819-2829). For example, bloodstream infections, urinary tract 
infections, pneumonia, and complicated intra-abdominal infections are 
commonly caused by Enterobacteriaceae, and increasingly these 
infections are resistant to antibacterial drugs (see, e.g., Refs. 40 
and 41). In the United States, there were 1.2 million cases of 
Salmonella infection each year (Ref. 42). In addition, the rate of 
hospitalization due to bloodstream infections--many of which are caused 
by Enterobacteriaceae--doubled from the years 2000 to 2008 (Ref. 43).
    Antimicrobial resistance is already a problem for many genera in 
this family. For example, enteropathic E. coli strains ``are often 
resistant to multiple antibiotics'' (Ref. 4 at p. 2824 (internal 
citation omitted)) and ``resistant mutants are already present in most 
patients with Enterobacter infections before initiation of therapy'' 
(Ref. 4 at p. 2827). Increased resistance in Shigella strains has been 
documented in the United States (Refs. 45 and 154) and abroad (Ref. 
44), as has increased resistance in Salmonella (Refs. 42 and 155). ``In 
addition, nosocomial isolates [of Klebsiella pneumoniae] are frequently 
resistant to numerous `antibacterial drugs' as a result of the 
acquisition of multidrug-resistant plasmids. For example, K. pneumoniae 
is one of the most common organisms to carry plasmids encoding 
extended-spectrum [beta]-lactamases, and bacteremia with such strains 
is associated with higher rates of treatment failure and death'' (Ref. 
4 at p. 2826 (internal citation omitted)).
    Enterobacteriaceae resistance to beta-lactam drugs, including, for 
example, cephalosporins, is well-recognized (see generally, e.g., Refs. 
46 and 47), and several resistant strains exist (see, e.g., Ref. 47). 
Extended-spectrum beta-lactamase (EBSL) enzymes may be found in several 
Enterobacteriaceae members, and these enzymes ``confer resistance 
against all [beta]-lactam antibiotics except carbapenems and 
cephamycins'' (Ref. 47 at p. 682 (internal citation omitted)).
    Additionally, Enterobacteriaceae members can become--and, 
particularly in the case of K. pneumoniae and E. coli, commonly have 
become--resistant to carbapenems (carbapenem-resistant 
Enterobacteriaceae or CRE) (see, e.g., Ref. 48), which are beta-lactam 
antibiotics that ``often are the last line of defense against [g]ram-
negative infections that are resistant to other antibiotics'' (Ref. 
49). Recently, New Delhi metallo-beta-lactamase (NDM), a plasmid-
encoded enzyme that permits bacterial resistance to broad-spectrum 
beta-lactam drugs, including carbapenems, has been reported in cases of 
Enterobacteriaceae infection in the United States (Refs. 50 and 51). 
``CRE containing New Delhi metallo-beta-lactamase (NDM), first reported 
in a patient who had been hospitalized in New Delhi, India, in 2007, 
are of particular concern because these enzymes usually are encoded on 
plasmids that harbor multiple resistance determinants and are 
transmitted easily to other Enterobacteriaceae and other genera of 
bacteria'' (Ref. 50 (internal citations omitted); see also, e.g., Ref. 
4 at p. 2820). A total of 6,470 healthcare-associated infections with 
Klebsiella species were reported to CDC's NHSN in 2009-2010; on 
average, approximately 11 percent were resistant to carbapenems and 
approximately 24 percent were non-susceptible to extended-spectrum 
cephalosporins. Among 9,351 E. coli infections reported to NHSN in 
2009-2010, approximately 2 percent were resistant to carbapenems and 
approximately 12 percent were non-susceptible to extended-spectrum 
cephalosporins (Ref. 132, table 7).
    Although NDM-related resistance is only one example, drug-
resistance genes in Enterobacteriaceae ``may be present on transposons, 
allowing them to jump to other plasmids or chromosomes, or they may be 
found on integrons, which have loci downstream of strong promoters at 
which resistance genes may insert by site-specific recombination to be 
expressed at high levels'' (Ref. 4 at p. 2820; Ref. 52). It is largely 
for this reason that FDA is proposing to include the entire 
Enterobacteriaceae family in the list of qualifying pathogens: With 
each increase in resistance rates seen in one genus or species, 
increases in antimicrobial resistance may also occur in other pathogens 
in the family. It is unsurprising, then, that the proportion of drug-
resistant, versus drug-susceptible, Enterobacteriaceae infections has 
increased in the past several years (see, e.g., Refs. 53 and 54). For 
example, a March 2013 CDC Vital Signs report documented an increase in 
the percentage of Enterobacteriaceae that were non-susceptible to 
carbapenems, from one to four percent in the past decade (Ref. 136).
    Infections with drug-resistant strains of Enterobacteriaceae also 
result in increased rates of morbidity and mortality when compared with 
drug-susceptible strains of the same pathogens. In one study, the 
mortality rate for patients with carbapenem-resistant K. pneumoniae 
infections was 48 percent--nearly double the 26 percent mortality rate 
for patients with carbapenem-susceptible K. pneumoniae infections (Ref. 
55). These differential outcomes are of particular concern, because the 
proportion of patients with drug-resistant versus drug-susceptible 
Enterobacteriaceae infections has increased over the past several years 
(see, e.g., Refs. 5 and 54).
    There are a limited number of drugs with antibacterial activity for 
infections with multiple-drug-resistant Enterobacteriaceae. This means 
that clinicians may not always be successful in selecting an 
appropriate initial antibacterial drug for treatment before the 
availability of the results of in vitro antibacterial drug 
susceptibility testing (Ref. 55 at pp. 1104-1105 (``Our study suggests 
that [polymyxins, tigecycline, and aminoglycosides], alone or in 
combination, may not be reliably effective in the treatment of 
carbapenem-resistant K. pneumoniae infection and that newer 
antimicrobial agents with improved clinical activity against 
carbapenem-resistant K. pneumoniae are needed.'')). Furthermore, some 
last-line therapies come with different and potentially more severe 
adverse effects (e.g., renal toxicity) than the drugs to which many 
Enterobacteriaceae have become resistant (see, e.g., Ref. 56).
    For the reasons described previously, FDA believes that 
Enterobacteriaceae has the potential to pose a serious threat to the 
public health, and FDA is proposing to include the Enterobacteriaceae 
family in its list of qualifying pathogens.

H. Enterococcus Species

    Species in the genus Enterococcus are gram-positive bacteria that 
normally colonize the human gastrointestinal tract (Ref. 4 at p. 2643). 
Enterococci can cause serious disease, including bacteremia or 
endocarditis; E. faecalis

[[Page 35162]]

and E. faecium are most commonly responsible for enterococcal 
infections and E. gallinarum also has been identified as an infective 
agent (see Ref. 4 at pp. 2643-2647). Enterococci have been designated 
by the Infectious Disease Society of America as one of six highly 
problematic drug-resistant organisms (the so-called ``ESKAPE'' 
pathogens), which ``currently cause the majority of US hospital 
infections and effectively 'escape' the effects of antibacterial 
drugs.'' (Refs. 5 and 6). Although some enterococcal isolates have 
intrinsic resistance, other isolates have acquired resistance either 
from selective antibacterial pressures or from transfer of genetic 
resistance mechanisms from one bacterium to another, including from 
non-Enterococcus species (see, e.g., Ref. 4 at pp. 2647-2651; see also 
Ref. 57).
    Enterococcus infections have been reported as the second most 
common cause of hospital-acquired infection in the United States from 
1986 to 1989 (Ref. 58). Among 5,484 E. faecium infections associated 
with healthcare reported to CDC's NHSN between 2009 and 2011, 
approximately 80 percent were resistant to vancomycin; in this same 
report among 3,314 E. faecalis healthcare-associated infections, 
approximately 9 percent were resistant to vancomycin (Ref. 132, Table 
7).
    Enterococci infections, including infections caused by enterococci 
that are drug-resistant (e.g., vancomycin-resistant enterococci or 
VRE), are often nosocomial infections. Enterococci isolates can be 
resistant to multiple antibacterial drugs; in fact, Enterococcus 
faecium resistant to linezolid and resistant to vancomycin have been 
isolated from patients (Ref. 59), and isolates resistant to multiple 
antibacterial drugs were identified in a global surveillance program 
(see, e.g., Ref. 60). Patients with bacteremia due to VRE had an 
increased mortality when compared to patients who had drug-susceptible 
enterococcal bacteremia (Refs. 61 and 62).
    In sum, for the reasons described previously--and particularly 
because of the increasing threat that drug-resistant enterococci pose 
to the public health--FDA believes that Enterococcus species have the 
potential to pose a serious threat to public health, and FDA is 
proposing to include Enterococcus species in its list of qualifying 
pathogens.

I. Mycobacterium tuberculosis Complex

    M. tuberculosis, the bacterium that causes tuberculosis (TB), is a 
major global public health burden (see generally, Ref. 64). M. 
tuberculosis usually affects the lungs (pulmonary TB), but M. 
tuberculosis can affect any part of the body such as the kidney, spine, 
or brain (extrapulmonary TB) (Ref. 65). If TB is not properly treated, 
it can be fatal (see generally, Ref. 64 and Ref. 65). M. tuberculosis 
is expelled into the air when a person with TB of the lungs or throat 
coughs, sneezes, speaks, or sings (Ref. 65). People nearby may breathe 
in the organisms and become infected. M. tuberculosis can remain in the 
air for several hours, depending on the environment (Ref. 65). Factors 
essential for the spread of the organism are proximity and duration of 
contact and infectiousness of the source patient (Ref. 4 at pp. 3132, 
3134). There are at least 7 species of the genus Mycobacterium that 
also cause disease similar to pulmonary tuberculosis, for example, M. 
bovis, M. africanum, and M. microti, among other species (Ref. 137).
    Latent M. tuberculosis is found in one-third of the world's 
population (Ref. 66). In 2011, there were an estimated 8.7 million new 
cases and 1.4 million deaths associated with TB (Ref. 64). More than 
10,000 new cases of TB were reported in 2011 in the United States (Ref. 
67). Mortality figures from CDC reveal that 529 persons died in the 
United States from tuberculosis in 2009 (Ref. 67).
    For M. tuberculosis, the primary mechanism of drug resistance is 
spontaneous chromosomal mutations, which can be amplified in the 
setting of inappropriate or interrupted therapy (monotherapy and 
combination therapy) or poor patient adherence to therapy (Ref. 68 at 
p. 1321). Subsequent transmission of drug-resistant M. tuberculosis 
will exacerbate the public health problem (Ref. 68). Mobile genetic 
elements, such as plasmids or transposons, do not appear to mediate 
drug resistance in M. tuberculosis (Ref. 68 at p. 1321). Thus, the 
increase in drug-resistant tuberculosis that is seen globally (see 
generally, Ref. 64) is a public health problem driven by inappropriate, 
interrupted, or poor adherence to therapy among persons being treated 
for TB (primary resistance), and subsequent transmission of drug-
resistant M. tuberculosis from person to person (secondary resistance) 
(Ref. 68).
    Isolates of M. tuberculosis resistant to isoniazid and rifampin, 
the two most important first-line antibacterial drugs used in the 
treatment of active TB disease, are referred to as multi-drug resistant 
(MDR) strains (Ref. 65). Extensively drug resistant (XDR) TB is 
resistant to isoniazid and rifampin, as well as two second-line drug 
classes (injectable agents and fluoroquinolones) (Ref. 65). Results 
from a multinational survey showed that 20 percent of M. tuberculosis 
isolates were MDR, and 2 percent were also XDR (Ref. 69). Resistance 
mechanisms are well-established for most drugs used to treat 
tuberculosis (Ref. 70), and drug resistant strains of tuberculosis can 
be transmitted from person to person, as evidenced in a 1991-1992 
outbreak investigation in New York City (Ref. 71).
    An epidemiological evaluation by CDC of pulmonary tuberculosis 
among patients in the United States found that mortality rates were 
higher for patients with XDR tuberculosis compared with those with MDR 
tuberculosis (35 percent vs. 24 percent, respectively), with the lowest 
mortality (10 percent) observed in patients with drug-susceptible 
tuberculosis (Ref. 72 at p. 2157). The authors of this report concluded 
that, ``[t]he emergence of XDR [tuberculosis] globally has raised 
concern about a return to the pre-antibiotic era in [tuberculosis] 
control, since XDR [tuberculosis] cases face limited therapeutic 
options and consequently have poor treatment outcomes and high 
mortality,'' (Ref. 72 at p. 2158).
    For the reasons stated previously, FDA believes that M. 
tuberculosis complex has the potential to pose a serious threat to 
public health, and FDA is proposing to include M. tuberculosis complex 
in the list of qualifying pathogens.

J. Neisseria gonorrhoeae

    N. gonorrhoeae is a nonmotile, gram-negative bacterium that can 
infect the mucous membrane of the urethra and cervix, as well as the 
rectum, oropharynx, and conjunctivae (Ref. 4 at p. 2753). The pathogen 
can be transmitted sexually (Ref. 73), as well as vertically from 
mother to newborn during delivery (Ref. 74). Gonococcal infections can 
cause complications, such as pelvic inflammatory disease, ectopic 
pregnancy, epididymitis, ophthalmitis, and endocarditis (Ref. 4 at p. 
2753). Gonorrhea is the second most commonly reported notifiable 
disease in the United States: Over 300,000 cases of gonorrhea are 
reported annually (Ref. 73). However, many infections are probably 
undetected and unreported: CDC estimates that more than 800,000 new 
gonococcal infections occur annually in the United States (Ref. 75). 
Although the gonorrhea rate is low compared with historical trends, the 
rate increased during 2009-2011 (Ref. 73).
    N. gonorrhoeae can acquire antibacterial drug resistance by

[[Page 35163]]

spontaneous chromosomal mutations arising from endogenous flora, or 
resistance can be acquired by transfer of genetic information from 
other bacteria by, for example, a plasmid-mediated resistance mechanism 
(Ref. 76). The Gonococcal Isolate Surveillance Project (GISP) monitors 
trends in antimicrobial susceptibilities of N. gonorrhoeae strains in 
the United States (Ref. 73).\6\ In 2011, 30.4 percent of isolates 
collected in the GISP were resistant to penicillin, tetracycline, 
ciprofloxacin, or a combination thereof (Ref. 73).
---------------------------------------------------------------------------

    \6\ The GISP was established by the CDC in 1986 to monitor 
trends in antimicrobial susceptibilities of strains of N. 
gonorrhoeae in the United States to establish a rational basis for 
the selection of gonococcal therapies.
---------------------------------------------------------------------------

    Since 2007, the cephalosporins have been the only antibacterial 
drug class recommended by CDC for the first line treatment of gonorrhea 
(Ref. 77). On the basis of ongoing surveillance, in 2012, CDC changed 
its treatment guidelines to recommend dual therapy with intramuscular 
ceftriaxone (instead of the previously-recommended orally-administered 
antibacterial drug), with either azithromycin or doxycycline added not 
only for treatment of coinfection with Chlamydia trachomatis, but also 
to ``potentially delay emergence and spread of resistance to 
cephalosporins'' in N. gonorrhoeae (Ref. 77). This is the only 
remaining recommended first-line treatment regimen (Ref. 77). Reduced 
susceptibility of gonococcal strains to ceftriaxone has also been 
observed (Ref. 73). Indeed, there is a growing concern that N. 
gonorrhoeae may become resistant to all available antibacterial drugs 
(Ref. 78). Significantly, ``[u]nsuccessful treatment of gonorrhea with 
oral cephalosporins, such as cefixime, has been identified in East 
Asia, beginning in the early 2000s, and in Europe within the past few 
years. Ceftriaxone-resistant isolates have been identified in Japan 
(2009), France (2010), and Spain (2011)'' (Ref. 153, internal 
references omitted). The GISP reported that cephalosporin-resistance 
may now be emerging in the United States (Ref. 153).
    For the reasons stated previously--particularly the increase in 
antibiotic resistant strains of gonorrhea together with the limited 
number of effective antibiotics for treatment of N. gonorrhoeae--FDA 
believes that N. gonorrhoeae has the potential to pose a serious threat 
to public health, and FDA is proposing to include N. gonorrhoeae on the 
list of qualifying pathogens.

K. Neisseria meningitidis

    N. meningitidis is an aerobic, gram-negative, fastidious 
diplococcus that is a leading cause of bacterial meningitis and sepsis, 
and can cause other serious infectious diseases, such as pneumonia, 
arthritis, otitis media, and epiglottitis (Ref. 79). N. meningitidis 
can be readily transmitted directly from person to person through close 
or prolonged contact via respiratory or throat droplets (e.g., kissing, 
sneezing, coughing, or living in close quarters) (Ref. 80).
    Meningococcal disease is a global public health concern that 
remains endemic in the United States, with large epidemics of invasive 
disease occurring in Africa, New Zealand, and Singapore (Ref. 4 at p. 
2740). Nasopharyngeal carriage of N. meningitidis is a precursor to 
disease (Ref. 4 at p. 2740), and while the majority of carriers do not 
develop disease, the World Health Organization estimates that, at any 
given time, 10 to 20 percent of the population carries N. meningitidis 
in their nasopharynx (Ref. 80). In the United States, the incidence 
rate is 0.15 to 0.5 per 100,000 persons (see Refs. 81 and 82). 
Mortality rates vary by the type of infectious disease caused by N. 
meningitidis, with a 40 percent mortality rate among patients with 
meningococcemia (Ref. 79), and a 13 percent mortality rate among 
children and adolescents with bacterial meningitis (Ref. 4 at p. 2741). 
Morbidity following infection with N. meningitidis can be substantial, 
including hearing loss, neurologic sequelae, and loss of limbs from 
amputation (Ref. 83 at p. 773).
    N. meningitidis is believed to acquire resistance from the wider 
gene pool of other Neisseria species (Ref. 84 at p. 890) and through 
point mutations. Antibacterial drug resistance was identified as a 
concern in N. meningitidis almost 2 decades ago, with a demonstration 
that resistance to commonly-used antibacterial drugs were increasing in 
incidence, and the identification of some isolates with beta-lactamase 
production (i.e., the production of enzymes that cause bacteria to be 
resistant to beta-lactam antibacterial drugs), with the author 
concluding that ``this finding is of great concern,'' (Ref. 85 at p. 
S98). Invasive meningococcal diseases caused by isolates with reduced 
susceptibility to penicillin were first reported in the 1980s in the 
United Kingdom, Spain, and South Africa, and are now identified 
worldwide (Ref. 139 at p. 1016). Some countries have reported a rise in 
the prevalence of meningococci with reduced susceptibility to 
penicillin (see, e.g., Refs. 85 and 141). Case reports and studies 
suggest that reduced susceptibility to common antibacterial treatments 
used for meningococcal infection results in poorer health outcomes 
(Ref. 83 at p. 776). For example, a Spanish study of isolates from 1988 
to 1992 found that patients with strains that had decreased drug 
susceptibility had higher rates of morbidity and mortality (Ref. 83 at 
p. 776; Ref. 149 at p. 28). Other sporadic cases of invasive N. 
meningitidis with reduced susceptibility to antibacterial drugs have 
been reported worldwide (see, e.g., Refs. 142 and 143). The 
identification of N. meningitidis isolates that display elevated 
mutability suggests an increased capacity to develop resistance, in 
addition to possible enhancement of transmission (see, e.g., Ref. 144).
    The detection of N. meningitidis with reduced susceptibility or 
resistance to antibacterial drugs has broad and serious implications 
for public health, not only for treatment of patients with invasive 
disease, but also when considering the use of chemoprophylaxis in order 
to prevent cases of invasive meningococcal disease among close contacts 
(see, e.g., Refs. 139,142, and 143). In sum, for the reasons described 
previously--particularly because of the potential for higher morbidity 
and mortality associated with drug-resistant meningococcal infections--
FDA believes that N. meningitidis has the potential to pose a serious 
threat to public health, and FDA is proposing to include N. 
meningitidis in the list of qualifying pathogens.

L. Non-Tuberculous Mycobacteria Species

    Non-tuberculous mycobacterium (NTM) comprises several species of 
bacterium, including Mycobacterium avium complex, M. kansasii, and M. 
abscessus (Ref. 4 at p. 3191; Ref. 86). Other species known to cause 
disease include M. fortuitum, M. chelonae, M. marinum, and M. ulcerans 
(Ref. 4 at p. 3191). NTM are widely distributed in the environment and 
can be found in soil, water, plants, and animals (Ref. 4 at p. 3191). 
Transmission is not communicable, and it appears to occur from 
environmental exposure to or inhalation of the pathogen (Ref. 87 at p. 
370). NTM causes many serious and life-threatening diseases, including 
pulmonary disease, catheter-related infections, lymphadenitis, skin and 
soft tissue disease, joint infections, and, in immunocompromised 
individuals, disseminated infection (Ref. 4 at p. 3192).

[[Page 35164]]

    NTM infections appear to be increasing in the United States (see, 
e.g., Refs. 88 and 89). A recently published study of Medicare patients 
showed an increasing prevalence of pulmonary NTM across all regions in 
the United States (Ref. 89 at p. 882). The authors concluded that the 
annual prevalence significantly increased from 1997 to 2007 from 20 to 
47 cases per 100,000 persons, respectively, or an 8.2 percent per year 
increase in prevalence among the Medicare population. Similarly, a 
population-based study in Ontario, Canada suggests an increase in the 
frequency of NTM infections from 9.1 per 100,000 persons in 1997 to 
14.1 per 100,000 persons in 2003, resulting in an average annual 
increase of 8.4 percent (Ref. 90).
    Antibacterial drug resistance in these organisms is ``the result of 
a highly complex interplay between natural resistance, inducible 
resistance and mutational resistance acquired during suboptimal drug 
exposure and selection,'' (Ref. 91 at p. 150). Treatment for NTM lung 
infections requires long courses of therapy, often 18 to 24 months or 
longer (Ref. 92 at p. 123). Because NTM is resistant to many 
antibacterial drugs currently available, infections caused by NTM can 
be difficult to treat. While there are no data from NTM isolates that 
indicate increasing antibacterial drug resistance, the incidence of NTM 
infections with intrinsic antibacterial resistance is increasing (Ref. 
91). This observation raises concerns that resistant NTM may be 
responsible for a disproportionate share of clinical infection.
    For the reasons stated previously, FDA believes that non-
tuberculous mycobacteria species has the potential to pose a serious 
threat to public health and, FDA is proposing to include non-
tuberculous mycobacteria species on the list of qualifying pathogens.

M. Pseudomonas Species

    Species of the Pseudomonas genus are gram-negative bacteria that 
can cause serious infections (Ref. 4 at p. 3025). This is particularly 
true of P. aeruginosa, which ``accounted for 18.1% of hospital-acquired 
pneumonias and a significant percentage of urinary tract infections 
(16.3%), surgical site infections (9.5%), and bloodstream infections 
(3.4%)'' in the United States. ICUs in 2003 (Ref. 4 at p. 2837 (citing 
Ref. 151)). P. aeruginosa is ``among the top five causes of nosocomial 
bacteremia, and severe infection can lead to sepsis'' (Ref. 4 at p. 
2847). It can grow in many environments (e.g., soil, water, and plants) 
(Ref. 4 at p. 2835) including moist hospital environments (e.g., 
showers, ventilators, mop water), and some healthy people have P. 
aeruginosa as a colonizing bacterium in their skin, throat, nose, or 
stool (Ref. 4 at p. 2836). P. aeruginosa is among the so-called 
``ESKAPE'' pathogens, which ``currently cause the majority of US 
hospital infections and effectively 'escape' the effects of 
antibacterial drugs.'' (Refs. 5 and 6). P. aeruginosa pulmonary 
infection among patients with CF is associated with a more rapid 
decline in lung function (Ref. 18 (internal citation omitted)).
    ``P. aeruginosa now carries multiple genetically-based resistance 
determinants, which may act independently or in concert with others'' 
(Ref. 4 at p. 2856 (citing Ref. 152)). Furthermore, P. aeruginosa is 
known for its ability to ``acquire'' resistance mechanisms (see, e.g., 
Ref. 9). P. aeruginosa has been noted to develop resistance during 
antibacterial drug therapy even when the results of in vitro 
susceptibility show that the bacterium is fully susceptible when 
initially exposed to the antibacterial drug. (see, e.g., Ref. 93 
(internal citations omitted); see also, e.g., Ref. 4 at p. 2855 (noting 
that in patients with P. aeruginosa endocarditis there is a 
``likelihood of the patient's becoming resistant to therapy even if 
there is initially bloodstream sterilization'')). Resistant P. 
aeruginosa strains may be transmitted from person to person, or via 
contamination in the environment (see, e.g., Ref. 94). In a recent 
report from CDC's NHSN, approximately 8 percent of all healthcare-
associated infections were caused by P. aeruginosa; among the 6,111 P. 
aeruginosa infections that were reported, approximately 25 percent were 
resistant to carbapenems and approximately 15 percent showed resistance 
in at least 3 different classes of antibacterial drugs (i.e., ``multi-
drug resistant'') (Ref. 132 at Table 7).
    Morbidity and mortality rates for P. aeruginosa infection are 
generally recognized as being high (see, e.g., Ref. 93 (internal 
citations omitted)), and infection with drug-resistant strains may have 
a negative effect on clinical outcomes, including an association with 
higher mortality (Ref. 93). Pneumonia and bloodstream infections due to 
drug-resistant P. aeruginosa have been associated with higher mortality 
rates in comparison to the same infections due to drug-susceptible P. 
aeruginosa (Ref. 10 at pp. 32-33, Tables 2 and 3). Although Pseudomonas 
non-aeruginosa infections are rare, pathogenic members of the 
Pseudomonas genus can cause serious infections and can show resistance 
to multiple antibacterial drugs (Ref. 95).
    For the reasons described previously--including the prevalence of 
Pseudomonas infections (particularly P. aeruginosa), the associated 
high morbidity and mortality rates, the increasing antibacterial drug 
resistance, and the fact that the last-line antibacterial drug 
treatments (required to treat Pseudomonas infections because of its 
resistance to multiple classes of antibacterial drugs) often have 
different or more serious adverse effects--FDA believes that 
Pseudomonas has the potential to pose a serious threat to public 
health, and FDA is proposing to include Pseudomonas species in its list 
of qualifying pathogens.

N. Staphylococcus aureus

    Staphylococcus aureus is a gram-positive bacterium that causes a 
variety of serious infectious diseases (Ref. 4 at p. 2543). S. aureus 
infections commonly result in skin or soft tissue infections (see, 
e.g., Ref. 4 at pp. 2543, 2559), and may result in more life-
threatening infections (e.g., pneumonia, bloodstream), often due to 
infection via catheters, ventilators, or other medical devices or 
procedures (Ref. 96). S. aureus is one of the most common bacterial 
pathogens in hospital-acquired infections, and resistance rates for S. 
aureus have been increasing (see, e.g., Refs. 3 and 97). In addition, 
in the first decade of the 21st century, resistant strains of S. aureus 
(e.g., methicillin-resistant S. aureus or MRSA) that emerged in the 
community and in some hospitals are now responsible for the majority of 
S. aureus infections among outpatients (Ref. 98). In the United States 
in 2005, the rate of invasive MRSA infections was approximately 31.8 
infections per 100,000 people (Ref. 99). S. aureus is also a member of 
the so-called ``ESKAPE'' pathogens, which ``currently cause the 
majority of U.S. hospital infections and effectively `escape' the 
effects of antibacterial drugs.'' (Refs. 5 and 6). Reports of rapid 
increases in the proportion of patients hospitalized due to infections 
caused by MRSA were largely due to increases in skin and soft tissue 
infections caused by MRSA acquired in the community setting (Ref. 145). 
The national burden of disease due to MRSA on an outpatient basis is 
substantial in the United States, with an estimated 51,290 infections 
reported in 2010 (Ref. 146).
    ``S. aureus has developed resistance to virtually all antibiotic 
classes available for clinical use,'' as demonstrated by a combination 
of in vivo and in vitro data (Ref. 4 at p. 2558). In fact, numerous 
antibacterial resistance mechanisms have been documented in S. aureus, 
including the

[[Page 35165]]

transmission of resistance that can occur via plasmids shared between 
bacteria, or even transfer of resistance mechanisms from different 
genera of bacteria (see Ref. 100).
    Patients with drug-resistant S. aureus infections appear to have 
higher mortality when compared to patients with drug-susceptible S. 
aureus infection (Ref. 10, Table 3 (showing a case fatality rate for 
patients with susceptible S. aureus bloodstream infections of 74/284 
(26 percent) and a case fatality rate for patients with resistant S. 
aureus bloodstream infections of 65/171 (38 percent)). Although 
infections caused by vancomycin-resistant S. aureus (VRSA) have been 
very rare (see, e.g., Ref. 101), the fact that VRSA has been observed 
at all underscores that antibacterial drug use can exert selective 
pressures on S. aureus, effectively creating antibacterial drug 
resistance. When patients have infection with drug-resistant S. aureus, 
the limited options for therapy may result in concerns about the 
feasibility of certain therapies (e.g., some treatments involve 
intravenous administration, which might require hospital admission) or 
different adverse effect profiles that may negatively affect patients' 
lives (Ref. 102). It is clear, then, that drug-resistant S. aureus 
poses an increasingly serious threat to public health.
    Therefore, for the reasons described previously, FDA believes that 
S. aureus has the potential to pose a serious threat to public health, 
and FDA is proposing to include S. aureus in its list of qualifying 
pathogens.

O. Streptococcus agalactiae

    Infections caused by S. agalactiae (Group B streptococcus or GBS) 
are considered a major public health concern, particularly because the 
organism causes meningitis and sepsis in newborns due to transmission 
from the mother during labor and delivery (see generally, Refs. 103, 
104, and 105). Maternal intrapartum antibacterial prophylaxis is 
recommended for pregnant women colonized with GBS, and resistance to 
antibacterial drugs commonly prescribed for prophylaxis is increasing 
(Ref. 103), thus having the potential to limit options for prophylaxis 
in this population. The most common diseases caused by GBS in adults 
are bloodstream infections, pneumonia, endocarditis, skin and soft-
tissue infections, and bone and joint infections (see generally, Ref. 4 
at pp. 2655-2661; Ref. 104). GBS infections can also result in other 
public health concerns, such as miscarriages, stillbirths, and preterm 
deliveries (Ref. 105).
    Over the past two decades, the incidence rates of GBS have 
increased twofold to fourfold in nonpregnant adults, ``most of whom 
have underlying medical conditions or are 65 years of age or older,'' 
(Ref. 4 at p. 2655). The rate of invasive disease is approximately 7 
per 100,000 nonpregnant adults, with the highest rate in adults aged 65 
years and older at 20-25 per 100,000 persons (Ref. 106). Case-fatality 
rates range from 5 to 25 percent in nonpregnant adults (Ref. 4 at p. 
2659).
    Resistance to antibacterial drugs has emerged in GBS, with most 
mechanisms believed to be an inducible chromosomally-mediated 
resistance that can occur due to selective pressures of antibacterial 
drugs (Ref. 103). Recent epidemiological surveillance shows that 
resistance to beta-lactam antibacterial drugs, the mainstay of 
treatment and prevention of GBS infections, has not been identified in 
the United States (Ref. 107). However, there is the potential in GBS of 
chromosomally-mediated mechanisms conferring decreased susceptibility 
to beta-lactam antibacterial drugs (Ref. 108). In addition, the 
potential for the spread of beta-lactamases via plasmid or other 
genetic transfer mechanisms (see Ref. 109) to GBS will continue to be a 
grave concern for public health, given the pivotal role of beta-lactam 
antibacterial drugs for treatment and prevention of GBS infections.
    CDC and researchers from other countries have described patterns of 
reduced susceptibility and resistance of GBS strains to common 
antibacterial drugs, including penicillin, macrolides, and clindamycin 
(see, e.g., Refs. 110 and 111). Because GBS is a common infectious 
disease and resistance to antibacterial drugs has been observed, it 
stands to reason that resistance may increase in the future.
    For the foregoing reasons, FDA believes that S. agalactiae has the 
potential to pose a serious threat to public health, and FDA is 
proposing to include S. agalactiae in the list of qualifying pathogens.

P. Streptococcus pneumoniae

    S. pneumoniae is a gram-positive bacterium that causes bacterial 
meningitis, bacteremia, respiratory tract infections including 
pneumonia, and otitis media (see, e.g., Refs. 112 and 113). S. 
pneumoniae can colonize the nasopharynx region, and transmission from 
person to person, via close contact by respiratory droplets, is thought 
to be common (Ref. 112). Although not all persons with S. pneumoniae 
colonization go on to develop invasive disease, colonization is a risk 
factor for disease.
    Outbreaks of invasive pneumococcal disease are known to occur in 
closed populations, such as nursing homes, childcare institutions, 
prisons, or other institutions (Ref. 112). Invasive disease from S. 
pneumoniae is a major cause of illness and death in the United States, 
with an estimated 43,500 cases and 5,000 deaths in 2009 (Ref. 114). In 
the United States, among elderly adults hospitalized with invasive 
pneumonia, the mortality rate is approximately 14 percent (Ref. 115). 
Resistance to commonly used antibacterial drugs for treatment of S. 
pneumoniae has been observed: Surveillance studies conducted in the 
United States between 1994 and 2007 showed that 9 to 24 percent of 
pneumococci were resistant to at least 3 classes of antibiotics (Ref. 
113).
    High rates of antibacterial drug resistance in S. pneumoniae have 
been documented worldwide. For example, S. pneumoniae resistance to 
commonly-used antibacterial drugs has been established for several 
decades, with incidence of resistance to penicillin in the United 
States approaching 40 percent in the late 1990s (Ref. 116). In China, 
approximately 96 percent of all recent S. pneumoniae isolates were 
resistant to erythromycin, and multidrug resistance was prevalent in 
many Asian countries (Ref. 117). In certain European countries, the 
proportion of isolates with resistance to multiple antibacterial drugs 
increased from 2006 to 2009 (e.g., in Bulgaria, resistance to 
penicillin increased from approximately 7 percent of isolates in 2006 
to approximately 37 percent of isolates in 2009) (Ref. 118 at pp. 20, 
23). In the United States, some children with middle ear infection had 
strains of S. pneumoniae that were resistant to all antibacterial drugs 
that have an FDA-approved label for treatment of acute bacterial otitis 
media in children (Ref. 147). Development of resistance by S. 
pneumoniae strains to macrolide antibacterial drugs and the closely-
related azolide drugs, which has been increasing in incidence, can be 
due to efflux-mediated mechanisms or target modifications caused by a 
ribosomal methylase (Ref. 148). It is speculated that increased use of 
macrolide antibacterial drugs may have exerted pressures in which 
resistance mechanisms spontaneously occurred (Ref. 148).
    For the reasons described previously, including that current 
strains of pneumococcal disease are associated with increased 
resistance to commonly

[[Page 35166]]

used antibacterial drugs, FDA believes that S. pneumoniae has the 
potential to pose a serious threat to public health, and FDA is 
proposing to include S. pneumoniae in the list of qualifying pathogens.

Q. Streptococcus pyogenes

    S. pyogenes (group A streptococcus or GAS) is a gram-positive 
bacterium that causes acute pharyngitis, in addition to other serious 
infectious diseases, such as necrotizing fasciitis and toxic shock 
syndrome (see generally, Ref. 4 at pp. 2593-2596). GAS is likely 
transmitted from person to person via respiratory droplets. Close 
personal contact, such as in schools, appears to favor spread of the 
organism (Ref. 4 at p. 2595).
    A study published in 2003 found that approximately 1.8 million 
people in the United States are diagnosed with streptococcal 
pharyngitis annually (Refs. 119 and 120). Although streptococcal 
pharyngitis is typically a mild disease, in rare cases, it can result 
in severe post-infectious complications (see generally, Ref. 121). 
Though the annual incidence of invasive GAS disease is estimated to be 
approximately 4.3 per 100,000 persons per year, the rate of mortality 
associated with invasive GAS infections is high, with an estimate of 
0.5 per 100,000 persons per year (Ref. 122). This means that in the 
United States, each year over 13,000 people are estimated to acquire an 
invasive GAS infection annually, and over 1,500 people are estimated to 
die from an invasive GAS infection (Ref. 122).
    For over 80 years, GAS isolates have remained susceptible to 
penicillin, though reports of resistance to other antibacterial drugs 
have emerged in GAS, primarily by chromosomally mediated mechanisms 
(see generally, Refs. 123 and 124). However, recently identified genes 
in GAS encode for several penicillin-binding proteins, but a reason for 
why these genes are not expressed has yet to be determined (Ref. 123). 
In addition, there is an ongoing concern that transfer of antibacterial 
resistance to GAS by plasmid or other genetic transfer might occur at 
some point in the future (Ref. 109). Indeed, microbiology laboratories 
are encouraged to continue to perform in vitro susceptibility testing 
on all GAS isolates in order to monitor for the possibility of 
resistance (Ref. 123). Thus, given the pivotal role of the beta-lactam 
antibiotic penicillin in the treatment of GAS, any resistance that 
would occur in the future would be of great concern for public health. 
Antibacterial resistance in S. pyogenes to commonly used drugs has been 
reported in many countries, including the United States (Ref. 4 at p. 
2599). Resistance to macrolide antibiotics and the closely related 
azolide group is common and poses a threat because these drugs are 
often used in penicillin-allergic patients (see Ref. 157). Resistance 
to clindamycin, a drug used for treatment of patients with necrotizing 
fasciitis, has also emerged (see Ref. 157).
    For the reasons described previously, including the high morbidity 
and mortality associated with invasive infections, the frequency of 
less severe infections, the existing resistance to some commonly used 
agents and the possibility for an increase in resistant strains, GAS 
infections have the potential to pose a serious threat to public health 
and, FDA is proposing to include S. pyogenes in the list of qualifying 
pathogens.

R. Vibrio cholerae

    Vibrio cholerae is a gram-negative bacterium (Ref. 4 at p. 2777) 
that can cause cholera, an acute diarrheal illness that can lead to 
severe dehydration (Ref. 125). Although cholera is found mainly in 
developing countries with poor sanitation and unsafe water supplies, in 
the United States, disease may occur in travelers returning from such 
countries or, more rarely, in those who have eaten contaminated food 
(see, e.g., Refs. 125 and 126). V. cholerae has the potential to cause 
pandemics and ``the ability to remain endemic in all affected areas'' 
(Ref. 4 at p. 2778 (internal citation omitted)), possibly due to the 
fact that infected people may shed the bacteria for several months 
after infection (Ref. 4 at p. 2779).
    Antibacterial drug resistance in cholera-causing strains of V. 
cholerae has increased between 1990 and 2000 in U.S. patients with both 
domestically- and internationally-acquired infections (Ref. 126), and 
antibacterial drug resistance in V. cholerae is still increasing 
generally (Refs. 126, 127, 128, and 129). ``Antimicrobial drug 
resistance in Vibrio [species] can develop through mutation or through 
acquisition of resistance genes on mobile genetic elements, such as 
plasmids, transposons, integrons, and integrating conjugative 
elements,'' or ICEs (Ref. 127). ICEs in particular ``commonly carry 
several antimicrobial drug resistance genes and play a major role in 
the spread of antimicrobial drug resistance in V. cholerae'' (Ref. 127 
at p. 2151; Ref. 130).
    Cholera-causing strains of V. cholerae may not cause disease in all 
people (Ref. 131). However, an estimated 10 percent of those infected 
with the O1 serogroup will develop a severe enough form of the illness 
that they need treatment (Ref. 131). Rehydration therapy is the most 
critical component of cholera treatment (see, e.g., Ref. 140). 
Approximately 25 to 50 percent of untreated cholera cases may prove 
fatal (Ref. 125). Antibiotic therapy is recommended for severely ill 
patients. It stands to reason that the risk of mortality in particular 
is likely to increase for drug-resistant V. cholerae infections among 
patients with limited treatment options.
    For the reasons described previously, including the epidemic 
potential of toxigenic V. cholerae strains, as well as the ease with 
which this pathogen may be transmitted, this bacterium has the 
potential to pose a serious threat to public health, and, FDA is 
proposing to include V. cholerae in the list of qualifying pathogens.

VI. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Analysis of Economic Impact

A. Preliminary Regulatory Impact Analysis

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The Agency believes that this proposed rule is not a 
significant regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the proposed rule would not impose direct 
costs on any entity, regardless of size, but rather would clarify 
certain types of pathogens for which the development of approved 
treatments might result in the awarding of QIDP designation and 
exclusivity to sponsoring firms, FDA proposes to certify that the final 
rule would not have

[[Page 35167]]

a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $139 million, using the most current (2011) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.

B. Background

    Antibacterial research and development has reportedly declined in 
recent years. A decrease in the number of new antibacterial products 
reaching the market in recent years has led to concerns that the 
current drug pipeline for antibacterial drugs may not be adequate to 
address the growing public health needs arising from the increase in 
antibiotic resistance. A number of reasons have been cited as barriers 
to robust antibacterial drug development including smaller profits for 
short-course administration of antibacterial drugs compared with long-
term use drugs to treat chronic illnesses, challenges in conducting 
informative clinical trials demonstrating efficacy in treating 
bacterial infections, and growing pressure to develop appropriate 
limits on antibacterial drug use.
    One mechanism that has been used to encourage the development of 
new drugs is exclusivity provisions which provide for a defined period 
during which an approved drug is protected from submission or approval 
of certain potential competitor applications. By securing additional 
guaranteed periods of exclusive marketing, during which a drug sponsor 
would be expected to benefit from associated higher profits, drugs that 
might not otherwise be developed due to unfavorable economic factors 
may become commercially attractive to drug developers.
    In recognition of the need to stimulate investments in new 
antibiotic drugs, Congress enacted the GAIN title of FDASIA to create 
an incentive system. The primary framework for encouraging antibiotic 
development became effective on July 9, 2012, through a self-
implementing provision that authorizes FDA to designate human 
antibiotic or antifungal drugs that treat ``serious or life-threatening 
infections'' as QIDPs. With certain limitations set forth in the 
statute, a sponsor of an application for an antibiotic or antifungal 
drug that receives a QIDP designation gains an additional 5 years of 
exclusivity to be added to certain exclusivity periods for that 
product. Drugs that receive a QIDP designation are also eligible for 
designation as a fast-track product and an application for such a drug 
is eligible for priority review.

C. Need for and Potential Effect of the Regulation

    Between July 9, 2012, when the GAIN title of FDASIA went into 
effect, and January 31, 2013, FDA granted 11 QIDP designations. As 
explained previously, the statutory provision that authorizes FDA to 
designate certain drugs as QIDPs is self-implementing, and inclusion of 
a pathogen on the list of ``qualifying pathogens'' does not determine 
whether a drug proposed to treat an infection caused by that pathogen 
will be given QIDP designation. However, section 505E(f) of the FD&C 
Act, added by the GAIN title of FDASIA, requires that FDA establish a 
list of ``qualifying pathogens.'' This proposed rule is intended to 
satisfy that obligation, as well as the statute's directive to make 
public the methodology for developing such a list of ``qualifying 
pathogens.'' The proposed rule identifies 18 ``qualifying pathogens,'' 
including those provided as examples in the statute, which FDA has 
concluded have ``the potential to pose a serious threat to public 
health'' and proposes to include on the list of ``qualifying 
pathogens.''
    As previously stated, this proposed rule would not change the 
criteria or process for awarding QIDP designation, or for awarding 
extensions of exclusivity periods. That is, the development of a 
treatment for an infection caused by a pathogen included in the list of 
``qualifying pathogens'' is neither a necessary nor a sufficient 
condition for obtaining QIDP designation, and, as stated in section 
505E(c) of the FD&C Act, not all applications for a QIDP are eligible 
for an extension of exclusivity. Relative to the baseline in which the 
exclusivity program under GAIN is in effect, we anticipate that the 
incremental effect of this rule would be negligible.
    To the extent that this rule causes research and development to 
shift toward treatments for infections caused by pathogens on the list 
and away from treatments for infections caused by other pathogens, the 
opportunity costs of this rule would include the forgone net benefits 
of products that treat or prevent pathogens not included in the list, 
while recipients of products to treat infections caused by pathogens on 
the list would receive benefits in the form of reduced morbidity and 
premature mortality. Sponsoring firms would experience both the cost of 
product development and the economic benefit of an extension of 
exclusivity and of potentially accelerating the drug development and 
review process with fast-track status and priority review. If this rule 
induces greater interest in seeking QIDP designation than would 
otherwise occur, FDA would also incur additional costs of reviewing 
applications for newly-developed antibacterial or antifungal drug 
products under a more expedited schedule.
    Given that the methodology for including a pathogen in the list of 
``qualifying pathogens'' was developed with broad input, including 
input from industry stakeholders and the scientific and medical 
community involved in anti-infective research, we expect that the 
pathogens listed in this proposed rule reflect not only current 
thinking regarding the types of pathogens which have the potential to 
pose serious threat to the public health, but also current thinking 
regarding the types of pathogens that cause infections for which 
treatments might be eligible for QIDP designation. To the extent that 
there is overlap between drugs designated as QIDPs and drugs developed 
to treat serious or life-threatening infections caused by pathogens 
listed in this proposed rule, this proposed rule would have a minimal 
impact in terms of influencing the volume or composition of 
applications seeking QIDP designation, compared to what would otherwise 
occur in the absence of this rule.

VIII. Paperwork Reduction Act

    FDA concludes that this proposed rule does not contain a 
``collection of information'' that is subject to review by the Office 
of Management and Budget under the Paperwork Reduction Act of 1995 (the 
PRA) (44 U.S.C. 3501-3520). This proposed rule interprets some of the 
terms used in section 505E of the FD&C Act and proposes ``qualifying 
pathogen'' candidates. Inclusion of a pathogen on the list of 
``qualifying pathogens'' does not confer any information collection 
requirement upon any party, particularly because inclusion of a 
pathogen on the list of ``qualifying pathogens,'' and the QIDP 
designation process, are distinct processes with differing standards.
    The QIDP designation process will be addressed separately by the 
Agency at a later date. Accordingly, the Agency will analyze any 
collection of information or

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additional PRA-related burdens associated with the QIDP designation 
process separately.

IX. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized, would not contain policies that would 
have substantial direct effects on the States, on the relationship 
between the National Government and the States, or on the distribution 
of power and responsibilities among the various levels of government. 
Accordingly, the Agency tentatively concludes that the proposed rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

X. Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

XI. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified the Web site addresses in this reference section, but we 
are not responsible for any subsequent changes to Web sites after this 
document publishes in the Federal Register.)

1. Roberts, R. R., B. Hota, I. Ahmad, et al., ``Hospital and 
Societal Costs of Antimicrobial-Resistant Infections in a Chicago 
Teaching Hospital: Implications for Antibiotic Stewardship,'' 
Clinical Infectious Diseases, 2009;49:1175-1184 (available at http://cid.oxfordjournals.org/content/49/8/1175.full.pdf+html).
2. Howard, D. H., R. D. Scott II, R. Packard, et al., ``The Global 
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List of Subjects in 21 CFR Part 317

    Antibiotics, Communicable diseases, Drugs, Health, Health care, 
Immunization, Prescription drugs, Public health.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, 21 CFR 
part 317 is proposed to be added to read as follows:

PART 317--QUALIFYING PATHOGENS

Sec.
317.1 [Reserved]
317.2 List of qualifying pathogens that have the potential to pose a 
serious threat to public health.

    Authority:  21 U.S.C. 355E, 371.


Sec.  317.2  List of qualifying pathogens that have the potential to 
pose a serious threat to public health.

    The term ``qualifying pathogen'' in section 505E(f) of the Federal 
Food, Drug, and Cosmetic Act is defined to mean any of the following:

    (a) Acinetobacter species.
    (b) Aspergillus species.
    (c) Burkholderia cepacia complex.
    (d) Campylobacter species.
    (e) Candida species.
    (f) Clostridium difficile.
    (g) Enterobacteriaceae.
    (h) Enterococcus species.
    (i) Mycobacterium tuberculosis complex.
    (j) Neisseria gonorrhoeae.
    (k) Neisseria meningitidis.
    (l) Non-tuberculous mycobacteria species.
    (m) Pseudomonas species.
    (n) Staphylococcus aureus.
    (o) Streptococcus agalactiae.
    (p) Streptococcus pneumoniae.
    (q) Streptococcus pyogenes.
    (r) Vibrio cholerae.

    Dated: June 5, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-13865 Filed 6-11-13; 8:45 am]
BILLING CODE 4160-01-P


