[Federal Register Volume 78, Number 113 (Wednesday, June 12, 2013)]
[Proposed Rules]
[Pages 35155-35173]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-13865]
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Proposed Rules
Federal Register
________________________________________________________________________
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).
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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-
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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).
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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).
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\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).
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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
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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
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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
[[Page 35168]]
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
Impact of Drug Resistance,'' Clinical Infectious Diseases,
2003;36(Suppl 1):S4-S10 (available at http://cid.oxfordjournals.org/content/36/Supplement_1/S4.full.pdf+html).
3. Niedell, M.J., B. Cohen, Y. Furuya, et al., ``Costs of
Healthcare- and Community-Associated Infections With Antimicrobial-
Resistant Versus Antimicrobial-Susceptible Organisms,'' Clinical
Infectious Diseases, 2012;55(6):807-15 (available at http://cid.oxfordjournals.org/content/55/6/807.full.pdf+html).
4. Mandell, G.L., J.E. Bennett, R. Dolin, et al., Mandell, Douglas,
and Bennett's Principles and Practice of Infectious Diseases. 7th
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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