35155

Proposed Rules Federal Register Vol. 78, No. 113

Wednesday, June 12, 2013

This section of the FEDERAL REGISTER develop this list of qualifying IV. Factors Considered and Methodology contains notices to the public of the proposed . Used for Establishing a List of Qualifying issuance of rules and regulations. The Pathogens purpose of these notices is to give interested DATES: Submit comments by August 12, A. The Impact on the Public Health Due to persons an opportunity to participate in the 2013. Drug-Resistant Organisms in Humans rule making prior to the adoption of the final ADDRESSES: You may submit comments, B. The Rate of Growth of Drug-Resistant rules. Organisms in Humans and the Increase identified by Docket No. FDA–2012–N– in Resistance Rates in Humans 1037 and/or Regulatory Information C. The Morbidity and Mortality in Humans DEPARTMENT OF HEALTH AND Number (RIN) 0910–AG92, by any of the V. Proposed Pathogens for Inclusion in the HUMAN SERVICES following methods: List A. Acinetobacter Species Electronic Submissions Food and Drug Administration B. Aspergillus Species Submit electronic comments in the C. Burkholderia cepacia Complex following way: D. Campylobacter SpeciesE. Candida 21 CFR Part 317 Species • Federal eRulemaking Portal: http:// [Docket No. FDA–2012–N–1037] F. Clostridium difficile www.regulations.gov. Follow the G. RIN 0910–AG92 instructions for submitting comments. H. Enterococcus Species Written Submissions I. Mycobacterium tuberculosis Complex Establishing a List of Qualifying J. gonorrhoeae Pathogens Under the Food and Drug Submit written submissions in the K. Administration Safety and Innovation following ways: L. Non-tuberculous Mycobacteria Species Act • Mail/Hand delivery/Courier (for M. Pseudomonas Species N. Staphylococcus aureus paper or CD–ROM submissions): AGENCY: Food and Drug Administration, O. Streptococcus agalactiae Division of Dockets Management (HFA– HHS. P. 305), Food and Drug Administration, Q. Streptococcus pyogenes ACTION: Proposed rule. 5630 Fishers Lane, Rm. 1061, Rockville, R. SUMMARY: The Food and Drug MD 20852. VI. Environmental Impact Administration (FDA or Agency) is Instructions: All submissions received VII. Analysis of Economic Impact A. Preliminary Regulatory Impact Analysis proposing a regulation to establish a list must include the Agency name, Docket No. FDA–2012–N–1037 and RIN 0910– B. Background of ‘‘qualifying pathogens’’ that have the C. Need for and Potential Effect of the potential to pose a serious threat to AG92 for this rulemaking. All comments Regulation public health. The proposed rule would received may be posted without change VIII. Paperwork Reduction Act implement a provision of the Generating to http://www.regulations.gov, including IX. Federalism Incentives Now (GAIN) title any personal information provided. For X. Comments of the Food and Drug Administration additional information on submitting XI. References Safety and Innovation Act (FDASIA). comments, see the ‘‘Comments’’ heading I. Executive Summary GAIN is intended to encourage of the SUPPLEMENTARY INFORMATION development of new antibacterial and section of this document. Purpose of the Regulatory Action antifungal drugs for the treatment of Docket: For access to the docket to Title VIII of FDASIA (Pub. L. 112– serious or life-threatening infections, read background documents or 144), the GAIN title, is intended to and provides incentives such as comments received, go to http:// encourage development of new eligibility for designation as a fast-track www.regulations.gov and insert the antibacterial and antifungal drugs for product and an additional 5 years of docket number(s), found in brackets in the treatment of serious or life- exclusivity to be added to certain the heading of this document, into the threatening infections. Among other exclusivity periods. FDA is proposing ‘‘Search’’ box and follow the prompts things, it requires that the Secretary of that the following pathogens comprise and/or go to the Division of Dockets the Department of Health and Human the list of ‘‘qualifying pathogens:’’ Management, 5630 Fishers Lane, Rm. Services (and thus FDA, by delegation): Acinetobacter species, Aspergillus 1061, Rockville, MD 20852. (1) Establish and maintain a list of species, Burkholderia cepacia complex, FOR FURTHER INFORMATION CONTACT: ‘‘qualifying pathogens’’ that have ‘‘the Campylobacter species, Candida Kristiana Brugger, Center for Drug potential to pose a serious threat to species, Clostridium difficile, Evaluation and Research, Food and public health’’ and (2) make public the Enterobacteriaceae (e.g., Klebsiella Drug Administration, 10903 New methodology for developing the list (see pneumoniae), Enterococcus species, Hampshire Ave. Bldg. 51, Rm. 6262, section 505E(f) of the Federal Food, Mycobacterium tuberculosis complex, Silver Spring, MD 20993–0002, 301– Drug, and Cosmetic Act (the FD&C Act), , N. meningitidis, 796–3601. as amended) (21 U.S.C. 355E(f)). In Non-tuberculous mycobacteria species, SUPPLEMENTARY INFORMATION: establishing and maintaining the list of Pseudomonas species, Staphylococcus ‘‘qualifying pathogens,’’ FDA must aureus, Streptococcus agalactiae, S. Table of Contents consider: The impact on the public pneumoniae, S. pyogenes, and Vibrio I. Executive Summary health due to drug-resistant organisms cholerae. The preamble to the proposed II. Background in humans; the rate of growth of drug- rule describes the factors we considered III. Consultation With Infectious Disease and resistant organisms in humans; the and the methodology we used to Antibiotic Resistance Experts increase in resistance rates in humans;

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and the morbidity and mortality in track product (sections 524A and Significantly, the statutory standard humans. FDA also is required to consult 506(a)(1) of the FD&C Act, respectively). for inclusion on FDA’s list of qualifying with infectious disease and antibiotic The term ‘‘qualified infectious disease pathogens is different from the statutory resistance experts, including those in product’’ or ‘‘QIDP’’ refers to an standard for QIDP designation. QIDP the medical and clinical research antibacterial or antifungal human drug designation, by definition, requires that communities, along with the Centers for that is intended to treat serious or life- the drug in question be an ‘‘antibacterial Disease Control and Prevention (CDC). threatening infections (section 505E(g) or antifungal drug for human use FDA is issuing this proposed rule to of the FD&C Act). It includes treatments intended to treat serious or life- fulfill these requirements. for diseases caused by antibacterial- or threatening infections’’ (section 505E(g) antifungal-resistant pathogens of the FD&C Act, as amended by Summary of the Major Provisions of the (including new or emerging pathogens), FDASIA). ‘‘Qualifying pathogens’’ are Regulatory Action or diseases caused by ‘‘qualifying defined according to a different After holding a public meeting and pathogens.’’ statutory standard; the term ‘‘means a consulting with CDC and the National The GAIN title of FDASIA requires identified and listed by the Institutes of Health (NIH), and that the Secretary of the Department of Secretary . . . that has the potential to considering the factors specified in Health and Human Services (and thus pose a serious threat to public health’’ section 505E(f)(2)(B)(i) of the FD&C Act, FDA, by designation) establish and (section 505E(f) of the FD&C Act, as as amended, FDA is proposing that the maintain a list of such ‘‘qualifying amended by FDASIA) (emphasis following pathogens comprise the list of pathogens,’’ and make public the added). That is, a drug intended to treat ‘‘qualifying pathogens:’’ Acinetobacter methodology for the developing the list. a serious or life-threatening bacterial or species, Aspergillus species, According to the statute, the term fungal infection caused by a pathogen Burkholderia cepacia complex, ‘qualifying pathogen’ means a pathogen that is not included on the list of Campylobacter species, Candida identified and listed by the Secretary ‘‘qualifying pathogens’’ may be eligible species, Clostridium difficile, * * * that has the potential to pose a for designation as a QIDP, while a drug Enterobacteriaceae (e.g., Klebsiella serious threat to public health, such as[:] that is intended to treat an infection pneumoniae), Enterococcus species, (A) resistant gram positive pathogens, caused by a pathogen on the list may Mycobacterium tuberculosis complex, including methicillin-resistant not always be eligible for QIDP Neisseria gonorrhoeae, N. meningitidis, Staphylococcus aureus, - designation. Non-tuberculous mycobacteria species, resistant Staphylococcus aureus, and FDA intends the list of qualifying Pseudomonas species, Staphylococcus vancomycin-resistant [E]nterococcus; pathogens to reflect the pathogens that, aureus, Streptococcus agalactiae, S. (B) multi-drug resistant gram[-]negative as determined by the Agency, after consulting with other experts and pneumoniae, S. pyogenes, and Vibrio , including Acinetobacter, considering the factors set forth in cholerae. The preamble to the proposed Klebsiella, Pseudomonas, and E. coli FDASIA (see section 505E(f)(2)(B)(i) of rule describes the factors FDA species; (C) multi-drug resistant the FD&C Act, as amended by FDASIA), considered and the methodology FDA tuberculosis; and (D) Clostridium have the ‘‘potential to pose a serious used to develop this list of qualifying difficile (section 505E(f)(1) of the FD&C threat to public health’’ (section pathogens. Act, as amended by FDASIA). FDA is 505E(f)(1) of the FD&C Act, as amended required under the law to consider four Costs and Benefits by FDASIA). FDA does not intend for factors in establishing and maintaining this list to be used for other purposes, The Agency has determined that this the list of qualifying pathogens: • such as the following: (1) Allocation of proposed rule is not a significant The impact on the public health research funding for bacterial or fungal regulatory action as defined by due to drug-resistant organisms in pathogens; (2) setting of priorities in Executive Order 12866. humans; research in a particular area pertaining • The rate of growth of drug-resistant II. Background to bacterial or fungal pathogens; or (3) organisms in humans; • direction of epidemiological resources Title VIII of FDASIA (Pub. L. 112– The increase in resistance rates in to a particular area of research on 144), entitled Generating Antibiotic humans; and bacterial or fungal pathogens. • Incentives Now, amended the FD&C Act The morbidity and mortality in Furthermore, as section 505E of the to add section 505E (21 U.S.C. 355E), humans (section 505E(f)(2)(B)(i), as FD&C Act makes clear, the list of among other things. This new section of amended by FDASIA). qualifying pathogens includes only the FD&C Act is intended to encourage Furthermore, in determining which bacteria or fungi that have the potential development of treatments for serious or pathogens should be listed, FDA is to pose a serious threat to public health. life-threatening infections caused by required to consult with infectious Viral pathogens or parasites, therefore, bacteria or fungi. For certain drugs that disease and antibiotic resistance were not considered for inclusion and are designated as ‘‘qualified infectious experts, including those in the medical are not included as part of this list. disease products’’ (QIDPs) under new and clinical research communities, section 505E(d) of the FD&C Act, new along with CDC (section 505E(f)(2)(B)(ii) III. Consultation With Infectious section 505E(a) provides an additional 5 of the FD&C Act, as amended by Disease and Antibiotic Resistance years of exclusivity to be added to the FDASIA). As discussed in the Experts exclusivity periods provided by sections paragraphs that follow, FDA has met GAIN requires FDA to consult with 505(c)(3)(E)(ii) to (c)(3)(E)(iv) (21 U.S.C. this requirement by convening a public infectious disease and antibiotic 355(c)(3)(E)(ii) to (c)(3)(E)(iv)), hearing, and opening an associated resistance experts, including those in 505(j)(5)(F)(ii) to (j)(5)(F)(iv) (21 U.S.C. public docket, to solicit input regarding the medical and clinical research 355(j)(5)(F)(ii) to (j)(5)(F)(iv)), and 527 the list of qualifying pathogens, as well communities, along with the CDC, in (21 U.S.C. 360cc) of the FD&C Act. In as by consulting with infectious disease determining which pathogens should be addition, an application for a drug and antibiotic resistance experts at CDC included on the list of ‘‘qualifying designated as a QIDP is eligible for and NIH during the development of this pathogens’’ (section 505E(f)(2)(B)(ii) of priority review and designation as a fast proposed rule. the FD&C Act, as amended by FDASIA).

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In order to fulfill this statutory should be included on the list of caused by a drug-resistant isolate of a obligation, on December 18, 2012, FDA qualifying pathogens. Therefore, if, after pathogen (compared with those whose convened a public hearing, at which the considering the four factors identified in illness is caused by more widely drug- Agency solicited input regarding the section 505E(f)(2)(B)(i) of the FD&C Act, susceptible pathogens); (2) number of following topics: (1) How FDA should FDA determines that the totality of resistant clinical isolates of a particular interpret and apply the four factors available evidence demonstrates that a pathogen (e.g., the known or FDASIA requires FDA to ‘‘consider’’ in pathogen ‘‘has the potential to pose a prevalence of infection with a particular establishing and maintaining the list of serious threat to public health,’’ the resistant pathogen); and (3) the ease and qualifying pathogens, (2) whether there Agency may designate the pathogen in frequency with which a proposed are any other factors FDA should question as a ‘‘qualifying pathogen.’’ pathogen can transfer and receive consider when establishing and More detailed explanations of each resistance-conferring elements (e.g., maintaining the list of qualifying factor identified in section encoding relevant enzymes, pathogens, and (3) which specific 505E(f)(2)(B)(i) are set forth in the etc.). Given the temporal limitations on pathogens FDA should list as qualifying paragraphs that follow. infectious disease data, FDA also will pathogens. The transcript of this consider evidence that a given pathogen A. The Impact on the Public Health Due hearing, as well as comments submitted currently has a strong potential for a to Drug-Resistant Organisms in Humans to the hearing docket, are available at meaningful increase in resistance rates. www.regulations.gov, docket number This first factor that section Evidence of the potential for increased FDA–2012–N–1037. FDA has 505E(f)(2)(B)(i) requires FDA to consider resistance may include, for example, considered carefully the input presented is also the broadest. Many factors projected (rather than observed) rates of at this hearing, as well as the comments associated with infectious diseases drug resistance for a given pathogen, submitted to the docket, in creating this affect public health directly, such as a and current and projected geographic proposed list of qualifying pathogens.1 pathogen’s ease of , the distribution of a drug-resistant In addition, FDA consulted with experts length and severity of the illness it pathogen. Furthermore, in in infectious disease and antibiotic causes, the risk of mortality associated acknowledgement of the growing resistance at CDC and NIH during the with its infection, and the number of problem of drug resistance, FDA may development of this proposed rule. approved products available to treat also assess other available evidence illnesses it causes. Additionally, demonstrating either existing or IV. Factors Considered and although the Agency did not consider potential increases in drug resistance Methodology Used for Establishing a financial costs in its analyses for this rates. List of Qualifying Pathogens proposed list of qualifying pathogens, C. The Morbidity and Mortality in As stated previously, section we note that the published literature Humans 505E(f)(2)(B)(i) of the FD&C Act (as supports the conclusion that amended by FDASIA) requires FDA to antimicrobial-resistant infections are Patients infected with drug-resistant consider the following factors in associated with higher healthcare costs pathogens are inherently more establishing and maintaining the list of (see, e.g., Refs. 1 and 2; Ref. 3 at pp. 807, challenging to treat than those infected qualifying pathogens: 810, 812). with drug-susceptible pathogens. For • The impact on the public health In considering a proposed pathogen’s example, in some cases, a patient due to drug-resistant organisms in impact on the public health due to drug- infected with a drug-resistant pathogen humans; resistant organisms in humans, FDA may have a delay in the initiation of • The rate of growth of drug-resistant will assess such evidence as: (1) The effective drug therapy that can result in organisms in humans; transmissibility of the pathogen and (2) poor outcomes for such patients. • The increase in resistance rates in the availability of effective therapies for Consequently, in determining whether a humans; and treatment of infections caused by the pathogen should be included in the list, • The morbidity and mortality in pathogen, including the feasibility of FDA will consider the rates of mortality humans. treatment administration and associated and morbidity (the latter as measured The Agency recognizes it is important adverse effects. However, FDA may also by, e.g., duration of illness, severity of to take a long-term view of the drug assess other public health-related illness, and risk and extent of sequelae resistance problem. For some pathogens, evidence, including evidence that may from infections caused by the pathogen, particularly those for which increased indicate a highly prevalent pathogen’s and risk associated with existing resistance is newly emerging, FDA ‘‘potential to pose a serious threat to treatments for such infections) recognizes that there may be gaps in the public health’’ due to the development associated with infection by that available data or evidence pertaining to of drug-resistance in that pathogen, even pathogen generally—and particularly by one or more of the four factors described if most documented infections are drug-resistant strains of that pathogen. in section 505E(f)(2)(B)(i) of the FD&C currently drug-susceptible. Setting quantitative thresholds for Act. Thus, consistent with GAIN’s inclusion on the list based on any pre- purpose of encouraging the B. The Rate of Growth of Drug-Resistant specified endpoint would be development of treatments for serious or Organisms in Humans and the Increase inconsistent with FDA’s approach of life-threatening infections caused by in Resistance Rates in Humans considering a totality of the evidence bacteria or fungi, the Agency intends to The second and third factors that FDA related to a given pathogen, as well as consider the totality of available must consider overlap substantially infeasible given the variety of pathogens evidence for a particular pathogen to with one another, and for the most part under consideration. Instead, in determine whether that pathogen are assessed using the same trends and considering whether this factor weighs information. Therefore, the Agency will in favor of including a given pathogen, 1 The public hearing and this proposed rule share analyze these factors together. the Agency will look for evidence of a docket numbers because they are part of the same In considering these factors with meaningful increase in morbidity and rulemaking process. Accordingly, the documents from the public hearing phase of Docket No. FDA– respect to a proposed pathogen, FDA mortality rates when infection with a 2012–N–1037 are included in the docket for this will assess such evidence as: (1) The drug-resistant strain of a pathogen is rulemaking. proportion of patients whose illness is compared to infection with a more drug-

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susceptible strain of that pathogen. The species, and some resistance infection to death (Ref. 10).5 In one Agency may also assess other evidence, mechanisms (e.g., genes encoding study of Pakistani newborns with such as overall morbidity and mortality resistance-mediating enzymes) can be infections caused by Acinetobacter rates for infection with either resistant readily transferred from one bacteria to species, 57 of 122 Acinetobacter- or susceptible strains of a pathogen to another on highly ambulatory genetic positive cultures (from 78 newborns) determine whether that pathogen has cassettes (Ref. 9). In addition, the pool showed infection in the bloodstream the potential to pose a serious threat to of available effective treatments for (Ref. 133). Approximately 71 percent of public health, in particular if drug- Acinetobacter infections is shrinking all Acinetobacter infections in the study resistant isolates of the pathogen were to (see, e.g., Ref. 5 at p. 7; Ref. 6). were susceptible to only one become more prevalent in the future. antibacterial drug (polymyxin), and Patients who acquire a drug-resistant were labeled as a ‘‘pan-resistant’’ (i.e., V. Proposed Pathogens for Inclusion in Acinetobacter bloodstream infection resistant to many drugs) Acinetobacter; the List appear more likely than those with 47 percent of the newborns in the study FDA is proposing to include the drug-susceptible infections to suffer with Acinetobacter infections died (Ref. following pathogens in its list of deleterious effects from the illness. For 133). qualifying pathogens based on the data example, in a study of patients with A. For the reasons described previously, described in the paragraphs that follow. baumannii in FDA believes that Acinetobacter species FDA expects that the inclusion of any European intensive care units (ICUs), 74 have the potential to pose a serious additional pathogens in the list would percent of A. baumannii bloodstream threat to the public health, particularly be supported by similar data. infections were resistant to a commonly for hospitalized patients and, FDA is proposing to include Acinetobacter A. Acinetobacter Species used antibacterial drug (Ref. 10 at p. 33, Table 3).3 Patients with resistant A. species in its list of qualifying Members of the genus bloodstream infections pathogens. are gram-negative bacteria that can became infected sooner after admission B. Aspergillus Species cause hospital-acquired infections such than patients with drug-susceptible A. Members of the Aspergillus genus are as , bacteremia (i.e., baumannii (9 days vs. 19 days) (Ref. 10 bloodstream infections), , fungi (specifically, hyaline molds) that at p. 33, Table 3). For those who genitourinary infections, or soft tissue have potential to cause serious survived, patients infected with infections (e.g., ) (Ref. 4 at pp. infections, typically in 2881–2883 (internal citation omitted)). resistant bacteria remained in the immunocompromised people. A total of 1,490 healthcare-associated hospital longer than those infected with Aspergillus can cause invasive infections with Acinetobacter species, susceptible bacteria (20 days vs. 9 days), infections of the lungs, skin, sinuses, 4 the majority of which were resistant to and, for those who died, patients bone, or brain, or be disseminated at least one class of antibacterial drugs, infected with resistant bacteria died throughout the body. It frequently were reported to CDC’s National sooner after infection than those with colonizes airway passages, creating the Healthcare Safety Network (NHSN) in susceptible bacteria (5 days vs. 16 days) potential for invasive disease among 2009–2010 (Ref. 132, Table 7). Thus, (Ref. 10 at p. 33, Table 3). In addition, patients who become Acinetobacter resistance is a well- ‘‘recent studies of patients in the [ICU] immunocompromised, such as patients recognized and growing problem (see who had [bloodstream infection] and who receive lung transplantation (Ref. generally, e.g., Ref. 5), and most burn infection due to [drug]-resistant 11). In one center, for example, hospital-acquired A. baumannii are now Acinetobacter species demonstrate an Aspergillus infection (i.e., colonization resistant to multiple classes of increased mortality (crude mortality, 26 or evidence of invasive disease) was antibacterial agents (Ref. 4 at p. 2884 to 68 percent), as well as increased reported in approximately 30 percent of (internal citation omitted)). Indeed, in morbidity and length of stay in the patients who received lung recognition of this problem, in 2008, the [ICU]’’ (Ref. 5 at p. 7). Similar trends transplantation (Ref. 11). These fungi Infectious Diseases Society of America have been seen for A. baumannii also may cause an allergic reaction, (IDSA) designated Acinetobacter species pneumonia in terms of: Prevalence of which may result in allergic to be among six highly problematic drug-resistant infection; time from bronchopulmonary aspergillosis, drug-resistant organisms identified as admission to infection; and time from particularly in those with cystic fibrosis the so-called ‘‘ESKAPE’’ pathogens, (CF) (Ref. 4 at pp. 3241, 3244–3249). which ‘‘currently cause the majority of Invasive aspergillosis often responds 3 All figures represent data for those strains of A. U.S. hospital infections and effectively baumannii whose resistance status was known, poorly to antifungal therapy, even when ‘escape’ the effects of antibacterial which was approximately 29 percent of all patients Aspergillus infections are susceptible to drugs.’’ 2 (Refs. 5 and 6). Acinetobacter with A. baumannii bloodstream infections (Ref. 10). antifungal drugs (Ref. 4 at p. 3250). species can survive for prolonged Numbers indicate median values (id.). Therefore, the existence throughout the 4 The point estimate of the case fatality rate for world of azole-resistant A. fumigatus periods in the environment and on the A. baumannii bloodstream infections among hands of healthcare workers, and as patients in which the results of in vitro antibacterial (i.e., A. fumigatus isolates resistant to such are well-recognized as susceptibility testing were not available for most the class of drugs comprising several transmissible nosocomial pathogens isolates, was very high at 48 percent (68/142). The different antifungal drugs in the family point estimate of the case fatality rate was slightly of ‘‘azole antifungal drugs’’), and reports (see, e.g., Ref. 7). Several independent lower for known resistant infections (13/30 or 43 resistance mechanisms, such as those percent), compared to known susceptible infections that azole resistant A. fumigatus may be mediated by cephalosporinases, beta- (6/11 or 55 percent) (Ref. 10 at pp. 33–34). The spreading in the environment (see Ref. lactamases, or carbapenemases, have small denominator of patients with known 12 at pp. 1635–1636) is of great susceptible A. baumannii bloodstream infections concern—as are the reports of multiple- been identified in Acinetobacter makes it difficult to draw conclusions about a difference in mortality rates based on the in vitro drug resistant A. fumigatus in Europe 2 The ‘‘ESKAPE’’ pathogens are: Enterococcus susceptibility profiles; therefore any A. baumannii faecium, S. aureus, , A. bloodstream infection, the majority of which appear 5 For A. baumannii pneumonia, results of in vitro baumanni, , and to be resistant to many antibacterial drugs, is susceptibility was known for only 34 percent of Enterobacter species (Ref. 6). associated with a high mortality rate. patients (Ref. 10).

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(Refs. 12 and 13). The predominant reported (see, e.g., Ref. 16). ‘‘Increased apparent, with clinical disease that can resistance mechanism in A. fumigatus is mortality has been observed in CF be caused by just 500 Campylobacter thought to be a chromosomally encoded patients after colonization with Bcc,’’ organisms (Ref. 4 at p. 2795), so, for mutation in the target enzyme, although (Ref. 4 at p. 2865 (internal citations example, ‘‘[e]ven one drop of juice from alternative resistance mechanisms have omitted); Ref. 17) and, in one study, raw chicken meat can infect a person’’ been observed (see, e.g., Ref. 13). In survival rates for patients with CF who (Ref. 21). some cases antifungal drugs are were infected with B. cenocepacia (a The following indicates the potential recommended as chemical prophylaxis Bcc species) were markedly worse than for Campylobacter infections to result in to prevent invasive infections in high- rates for patients with CF who were enhanced morbidity and mortality, risk patients (Ref. 4 at p. 3253), infected with P. aeruginosa (not a Bcc regardless of whether the bacterium is including some asthmatics (see Ref. 13). species) (Ref. 150; see also Ref. 4 at p. fully susceptible or is resistant to However, the use of prophylactic 2862, Fig. 220–1 (internal citation antibacterial drugs: C. jejuni infections antifungal drugs creates selective omitted)). Because patients with CF have been linked to in pressure on these organisms, thus often require repeated or chronic a certain subset of patients (Ref. 4 at p. increasing the risk of drug-resistant administration of antibacterial drugs, 2797), C. jejuni infections are a major Aspergillus colonization and infection. antibacterial drug resistance among Bcc cause of Guillain-Barre´ syndrome (1 Moreover, European studies have found isolates can develop through these case per 2,000 C. jejuni infections, that many patients who had not selective pressures (see Ref. 18 (noting accounting for 20 to50 percent of all received antifungal therapy nevertheless that an increase in antibacterial cases of Guillain-Barre´ syndrome (id.)), were colonized with resistant strains of resistance was observed among patients and C. fetus infections ‘‘may be lethal to A. fumigatus (Ref. 13 (internal citations with CF who received a chronically patients with chronic compensated omitted)). inhaled antibacterial drug)). In fact, a diseases such as cirrhosis or diabetes Many patients with Aspergillus pan-resistant isolate of Bcc already has mellitus or may hasten the demise of infections are vulnerable already, due to been documented in patients with CF seriously compromised patients’’ (Ref. 4 concomitant conditions such as cystic (Ref. 19). Although there appear to be at p. 2799). Although many people fibrosis or some level of limited data on the exact incidence and recover from enteric Campylobacter . Should Aspergillus prevalence of Bcc infection in the CF infections without the need for drug resistance further diminish the already population, because the average life- treatment, a variety of antibacterial low efficacy of existing treatments and span for patients with CF has been drugs, including , prophylaxis, patient outcomes would, steadily increasing over the past few , or ciprofloxacin, may be similarly, be expected to worsen. For decades (Ref. 20 at p. 789, Fig. 1), it prescribed to treat severe the reasons described above, FDA stands to reason that Bcc colonization Campylobacter infections (Ref. 21; Ref. believes that Aspergillus species have and infection in patients with CF likely 4 at p. 2799). the potential to pose a serious threat to will increase. Furthermore, although Drug resistance in Campylobacter the public health, and FDA is proposing data comparing outcomes of drug- species, particularly resistance to to include Aspergillus species in its list resistant infections with outcomes of fluoroquinolones, has been increasing of qualifying pathogens. drug-susceptible infections also are rapidly (Ref. 4 at p. 2799 (internal limited, it stands to reason that C. Burkholderia cepacia Complex citation omitted); see Ref. 22; see also decreasing susceptibility and resistance Ref. 134). Indeed, in human The Burkholderia cepacia complex patterns in Bcc likely will be observed Campylobacter infections, resistance (Bcc) comprises about 10 species of during the life span of a patient with CF has been observed to many different gram-negative bacteria (Ref. 4 at p. based on selective pressures caused by 2861). The Burkholderia genus was appropriate use of antibacterial drugs. classes of antibacterial drugs (see, e.g., established relatively recently, however, For the reasons described previously, Ref. 22 (internal citations omitted); Ref. and species are being identified and FDA believes that these pathogens have 23), and resistance mechanisms can be added to the Bcc on an ongoing basis the potential to pose a serious threat to readily transferred from bacteria to (Ref. 4 at p. 2861). Bcc can cause the public health—particularly for bacteria (Ref. 22). ‘‘Infection with C. pneumonia, particularly in patients patients with CF—and FDA is proposing jejuni strains resistant to erythromycin with CF and patients with chronic to include Bcc species in its list of or fluoroquinolones is more likely to granulomatous disease (Ref. 4 at pp. qualifying pathogens. result in prolonged or invasive illness or 2862, 2865 (internal citation omitted)). death’’ (Ref. 4 at p. 2799), and it stands Bcc can also cause life-threatening D. Campylobacter Species to reason that drug-resistant strains of bacteremia among hospitalized patients The Campylobacter genus comprises other pathogenic Campylobacter species who are immunocompromised, several species of gram-negative are likely to be similarly problematic. resulting in a mortality rate of 33 bacteria, some of which are causative One survey of Campylobacter isolates percent of hematology patients with Bcc agents of diarrheal and systemic indicated increasing and high levels of bacteremia in one academic medical diseases in humans (Ref. 4 at pp. 2793– resistance to antibacterial drugs in center (Ref. 14). Other outbreaks of 2796). These are common infections: several classes, with some of the serious bacterial infections caused by Campylobacter is estimated to cause resistance encoded on transferable Bcc have been documented due to over 1.3 million cases of enteric plasmids (Ref. 24). Because nosocomial transmission, indicating the infection in the United States each year Campylobacter infections are common, potential for an ease of transmissibility (Ref. 42). It is believed that most human any increase in resistance rates may in the hospital setting in patients infections are caused by consuming translate quickly into a threat to the without CF (see, e.g., Ref. 15). contaminated food (e.g., meat) or water public health. Bcc infections cause noteworthy (Ref. 4 at p. 2794), though person to For the foregoing reasons, FDA levels of morbidity and mortality, person transmission of C. jejuni has believes that Campylobacter species particularly in patients with CF (see, been reported to occur through the have the potential to pose a serious e.g., Ref. 14), although outbreaks among fecal-oral route, and other routes (Ref. 4 threat to public health, and FDA is patients without CF also have been at p. 2795). Transmissibility is readily proposing to include bacteria from the

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genus Campylobacter in the list of make it more likely that these patients recent antibacterial drug use (Ref. 37). qualifying pathogens. will be colonized by, or develop Incidence of C. difficile-associated infections with, drug-resistant fungi. illness has increased significantly over E. Candida Species Indeed, it has been noted that Candida the past several years. For example, Candida species are fungi species with antifungal resistance ‘‘[t]here was an 117% increase in the (specifically, yeast) that are part of the patterns are emerging as a common listing of [C. difficile-associated disease] normal human flora, and thus Candida fungal infection in this population (Refs. on hospital discharges in the Healthcare species can easily be transmitted and 28 and 30). Costs and Utilization Project Net Web can cause invasive disease, particularly Resistance genes in Candida species site from 2000 to 2005’’ (Ref. 4 at p. among immunocompromised patients tend to proliferate in localized 3106 (internal citation omitted)), and (see, e.g., Ref. 4 at pp. 3225–3226; Ref. populations, though they occasionally currently, ‘‘C. difficile infections are at 25). Candida can infect almost any part may be transferred through mating (Ref. an all-time high’’ (Ref. 37). Mortality has of the body to which they are 31). Some reports have documented been increasing along with infection introduced (so-called invasive continued selective pressures of oral incidence. One study showed that from ), including the central antifungal drugs administered as 1999 to 2004 in the United States (Ref. nervous system, respiratory tract, prophylaxis in certain populations, 63) there was a 35 percent increase in urinary tract, gastro-intestinal tract, or resulting in an increasing rate of mortality for which C. difficile infection heart (see Ref. 4 at pp. 3227–3235). infection caused by Candida species was listed as a contributing factor. CDC Those who are already fragile are at resistant to ‘‘azole antifungal drugs’’ has estimated a 400 percent increase in higher risk of invasive disease (e.g., (e.g., Candida glabrata and Candida deaths between 2000 and 2007 in which between 5 percent and 20 percent of krusei) (see, e.g., Refs. 32 and 33). C. difficile was a contributing factor neonates weighing less than 2.2 pounds Selective pressures from the use of oral (Ref. 37). Currently, based on a review will develop some form of invasive azole antifungal drugs can shift of death certificates, about 14,000 candidiasis (Ref. 26)), and the risk is infections from C. albicans to certain American deaths each year list C. particularly high in those who are other Candida species, such as Candida difficile infection as a contributing immunocompromised. For example, glabrata and Candida krusei, which factor; the majority of deaths occur in before the availability of highly-active both have intrinsic resistance to azole patients over 65 years of age (Ref. 135). antiretroviral therapy for the treatment antifungal drugs and eliminates any The use of antibacterial drugs in of human immunodeficiency virus/ possibility of treatment with an oral hospitals has been identified as an acquired immunodeficiency syndrome azole antifungal drug. Thus, some important risk factor for C. difficile (HIV/AIDS), invasive candidiasis (such patients with invasive candidiasis infections because C. difficile is as esophageal candidiasis) was a already have treatment options limited naturally resistant to many commonly common infection in this patient to only intravenously-administered used antibacterial drugs. However, the population, with a well-documented antifungal drugs (Ref. 34). prevalence of C. difficile infections is increase in the rates of antifungal For the foregoing reasons, FDA increasing and that has been associated resistance (Ref. 27). Many patients with believes that Candida species have the with an increased prevalence of strains HIV/AIDS did not respond to standard potential to pose a serious threat to the with new resistance to fluoroquinolones antifungal therapy and required public health, and FDA proposes that (see, e.g., Ref. 38). North American administration of parenteral antifungal Candida species be included in the list epidemiological data have shown the drugs, which limited therapeutic of qualifying pathogens. emergence of high levels of resistance to options and was directly associated F. Clostridium difficile fluoroquinolone antibacterial drugs— with the development of resistance (Ref. and this resistance emerged quickly 27). Today, infections caused by C. difficile is a toxin-producing gram- (see, e.g., Ref. 39). As noted by CDC, Candida species rank as the fourth most positive bacterium (Ref. 35) that can ‘‘even a modest decrease in [drug] common bloodstream infection in the cause serious, sometimes fatal, susceptibility might be clinically United States (Ref. 25). Candida gastrointestinal disease (e.g., toxic relevant’’ to the epidemiology of C. bloodstream infections are associated megacolon) (see, e.g., Ref. 4 at p. 3104 difficile infections (Ref. 38 at p. 446). with high mortality rates, with (internal citation omitted)). The spores Newly acquired resistance by C. difficile approximately 35 to 40 percent of of the C. difficile bacteria (see Ref. 36) to commonly used antibacterials, as in infected patients dying of Candida are difficult to eliminate from the the case of the fluoroquinolones, infections in a study involving patients environment, even after disinfection by facilitates the emergence of hyper- in one tertiary-care center (Ref. 28). hand-washing or cleansing, and virulent strains that increase the burden Although the problem of invasive individuals can acquire the pathogen of infections and deaths caused by C. candidiasis has diminished in the via contact with either contaminated difficile (Refs. 39 and 156). population of patients with HIV/AIDS surfaces or other individuals (see, e.g., C. difficile causes serious infections due to advances in antiretroviral Ref. 4 at p. 3104 (internal citation but there are a limited number of therapy, the number of patients omitted)). CDC estimates that the vast effective antibacterial drugs used to treat receiving solid organ transplants, and majority of patients with C. difficile C. difficile infection, and treatment therefore on immunosuppressive infection have had recent contact with often lasts for an extended period of therapy, is increasing (Ref. 29). Experts healthcare providers, either in an time (Ref. 38). Furthermore, relapse or are now concerned about antifungal- inpatient or outpatient setting (Ref. 37). recurrence of C. difficile is common, resistant invasive candidiasis in this Because spores of the bacteria are and often necessitates re-treatment with patient population, echoing the difficult to eliminate from the antibacterial drugs (Ref. 38). In light of concerns previously borne out in the environment, it is not surprising that these considerations, the increased population of patients with HIV/AIDS transmission of C. difficile infection in prevalence of C. difficile infections (see, e.g., Refs. 27 and 30). Transplant the hospital environment has been constitutes a serious threat to the public patients often take prophylactic noted (Ref. 37). health (Ref. 39). antifungal drugs, which exert selective Risk of infection with C. difficile Thus, FDA believes that C. difficile pressure on the Candida organisms and increases with both a patient’s age and has the potential to pose a serious threat

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to public health. For the reasons lactamase (EBSL) enzymes may be unsurprising, then, that the proportion described previously—particularly the found in several Enterobacteriaceae of drug-resistant, versus drug- high prevalence of C. difficile infections, members, and these enzymes ‘‘confer susceptible, Enterobacteriaceae the fact that acquired resistance leads to resistance against all [beta]-lactam infections has increased in the past increased infections and deaths via the except carbapenems and several years (see, e.g., Refs. 53 and 54). emergence of hypervirulent strains, and cephamycins’’ (Ref. 47 at p. 682 For example, a March 2013 CDC Vital the very limited treatment options— (internal citation omitted)). Signs report documented an increase in FDA is proposing to include C. difficile Additionally, Enterobacteriaceae the percentage of Enterobacteriaceae in its list of qualifying pathogens. members can become—and, particularly that were non-susceptible to in the case of K. pneumoniae and E. carbapenems, from one to four percent G. Enterobacteriaceae coli, commonly have become—resistant in the past decade (Ref. 136). The Enterobacteriaceae are a family of to carbapenems (carbapenem-resistant Infections with drug-resistant strains gram-negative bacteria and include Enterobacteriaceae or CRE) (see, e.g., of Enterobacteriaceae also result in species in the genera Escherichia (e.g., Ref. 48), which are beta-lactam increased rates of morbidity and E. coli), Klebsiella, Enterobacter, antibiotics that ‘‘often are the last line mortality when compared with drug- , and Salmonella (see Ref. 4 at of defense against [g]ram-negative susceptible strains of the same pp. 2815–2816). Most infections that are resistant to other pathogens. In one study, the mortality Enterobacteriaceae are toxin-secreting, antibiotics’’ (Ref. 49). Recently, New rate for patients with carbapenem- and they can cause a variety of serious Delhi metallo-beta-lactamase (NDM), a resistant K. pneumoniae infections was and life-threatening bacterial diseases -encoded enzyme that permits 48 percent—nearly double the 26 (see Ref. 4 at pp. 2819–2829). For bacterial resistance to broad-spectrum percent mortality rate for patients with example, bloodstream infections, beta-lactam drugs, including carbapenem-susceptible K. pneumoniae urinary tract infections, pneumonia, and carbapenems, has been reported in cases infections (Ref. 55). These differential complicated intra-abdominal infections of Enterobacteriaceae infection in the outcomes are of particular concern, are commonly caused by United States (Refs. 50 and 51). ‘‘CRE because the proportion of patients with Enterobacteriaceae, and increasingly containing New Delhi metallo-beta- drug-resistant versus drug-susceptible these infections are resistant to lactamase (NDM), first reported in a Enterobacteriaceae infections has antibacterial drugs (see, e.g., Refs. 40 patient who had been hospitalized in increased over the past several years and 41). In the United States, there were New Delhi, India, in 2007, are of (see, e.g., Refs. 5 and 54). 1.2 million cases of Salmonella particular concern because these There are a limited number of drugs infection each year (Ref. 42). In enzymes usually are encoded on with antibacterial activity for infections addition, the rate of hospitalization due plasmids that harbor multiple resistance with multiple-drug-resistant to bloodstream infections—many of determinants and are transmitted easily Enterobacteriaceae. This means that which are caused by to other Enterobacteriaceae and other clinicians may not always be successful Enterobacteriaceae—doubled from the genera of bacteria’’ (Ref. 50 (internal in selecting an appropriate initial years 2000 to 2008 (Ref. 43). citations omitted); see also, e.g., Ref. 4 antibacterial drug for treatment before is already a at p. 2820). A total of 6,470 healthcare- the availability of the results of in vitro problem for many genera in this family. associated infections with Klebsiella antibacterial drug susceptibility testing For example, enteropathic E. coli strains species were reported to CDC’s NHSN in (Ref. 55 at pp. 1104–1105 (‘‘Our study ‘‘are often resistant to multiple 2009–2010; on average, approximately suggests that [polymyxins, , antibiotics’’ (Ref. 4 at p. 2824 (internal 11 percent were resistant to and aminoglycosides], alone or in citation omitted)) and ‘‘resistant carbapenems and approximately 24 combination, may not be reliably mutants are already present in most percent were non-susceptible to effective in the treatment of patients with Enterobacter infections extended-spectrum . carbapenem-resistant K. pneumoniae before initiation of therapy’’ (Ref. 4 at p. Among 9,351 E. coli infections reported infection and that newer antimicrobial 2827). Increased resistance in Shigella to NHSN in 2009–2010, approximately agents with improved clinical activity strains has been documented in the 2 percent were resistant to carbapenems against carbapenem-resistant K. United States (Refs. 45 and 154) and and approximately 12 percent were non- pneumoniae are needed.’’)). abroad (Ref. 44), as has increased susceptible to extended-spectrum Furthermore, some last-line therapies resistance in Salmonella (Refs. 42 and cephalosporins (Ref. 132, table 7). come with different and potentially 155). ‘‘In addition, nosocomial isolates Although NDM-related resistance is more severe adverse effects (e.g., renal [of Klebsiella pneumoniae] are only one example, drug-resistance genes toxicity) than the drugs to which many frequently resistant to numerous in Enterobacteriaceae ‘‘may be present Enterobacteriaceae have become ‘antibacterial drugs’ as a result of the on transposons, allowing them to jump resistant (see, e.g., Ref. 56). acquisition of multidrug-resistant to other plasmids or chromosomes, or For the reasons described previously, plasmids. For example, K. pneumoniae they may be found on integrons, which FDA believes that Enterobacteriaceae is one of the most common organisms to have loci downstream of strong has the potential to pose a serious threat carry plasmids encoding extended- promoters at which resistance genes to the public health, and FDA is spectrum [beta]-lactamases, and may insert by site-specific proposing to include the bacteremia with such strains is recombination to be expressed at high Enterobacteriaceae family in its list of associated with higher rates of treatment levels’’ (Ref. 4 at p. 2820; Ref. 52). It is qualifying pathogens. failure and death’’ (Ref. 4 at p. 2826 largely for this reason that FDA is (internal citation omitted)). proposing to include the entire H. Enterococcus Species Enterobacteriaceae resistance to beta- Enterobacteriaceae family in the list of Species in the genus Enterococcus are lactam drugs, including, for example, qualifying pathogens: With each gram-positive bacteria that normally cephalosporins, is well-recognized (see increase in resistance rates seen in one colonize the human gastrointestinal generally, e.g., Refs. 46 and 47), and genus or species, increases in tract (Ref. 4 at p. 2643). Enterococci can several resistant strains exist (see, e.g., antimicrobial resistance may also occur cause serious disease, including Ref. 47). Extended-spectrum beta- in other pathogens in the family. It is bacteremia or ; E. faecalis

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and E. faecium are most commonly usually affects the lungs (pulmonary (injectable agents and fluoroquinolones) responsible for enterococcal infections TB), but M. tuberculosis can affect any (Ref. 65). Results from a multinational and E. gallinarum also has been part of the body such as the kidney, survey showed that 20 percent of M. identified as an infective agent (see Ref. spine, or brain (extrapulmonary TB) tuberculosis isolates were MDR, and 2 4 at pp. 2643–2647). Enterococci have (Ref. 65). If TB is not properly treated, percent were also XDR (Ref. 69). been designated by the Infectious it can be fatal (see generally, Ref. 64 and Resistance mechanisms are well- Disease Society of America as one of six Ref. 65). M. tuberculosis is expelled into established for most drugs used to treat highly problematic drug-resistant the air when a person with TB of the tuberculosis (Ref. 70), and drug resistant organisms (the so-called ‘‘ESKAPE’’ lungs or throat coughs, sneezes, speaks, strains of tuberculosis can be pathogens), which ‘‘currently cause the or sings (Ref. 65). People nearby may transmitted from person to person, as majority of US hospital infections and breathe in the organisms and become evidenced in a 1991–1992 outbreak effectively ’escape’ the effects of infected. M. tuberculosis can remain in investigation in New York City (Ref. 71). antibacterial drugs.’’ (Refs. 5 and 6). the air for several hours, depending on An epidemiological evaluation by Although some enterococcal isolates the environment (Ref. 65). Factors CDC of pulmonary tuberculosis among have intrinsic resistance, other isolates essential for the spread of the organism patients in the United States found that have acquired resistance either from are proximity and duration of contact mortality rates were higher for patients selective antibacterial pressures or from and infectiousness of the source patient with XDR tuberculosis compared with transfer of genetic resistance (Ref. 4 at pp. 3132, 3134). There are at those with MDR tuberculosis (35 mechanisms from one bacterium to least 7 species of the genus percent vs. 24 percent, respectively), another, including from non- Mycobacterium that also cause disease with the lowest mortality (10 percent) Enterococcus species (see, e.g., Ref. 4 at similar to pulmonary tuberculosis, for observed in patients with drug- pp. 2647–2651; see also Ref. 57). example, M. bovis, M. africanum, and susceptible tuberculosis (Ref. 72 at p. Enterococcus infections have been M. microti, among other species (Ref. 2157). The authors of this report reported as the second most common 137). concluded that, ‘‘[t]he emergence of cause of hospital-acquired infection in Latent M. tuberculosis is found in XDR [tuberculosis] globally has raised the United States from 1986 to 1989 one-third of the world’s population (Ref. concern about a return to the pre- (Ref. 58). Among 5,484 E. faecium 66). In 2011, there were an estimated 8.7 antibiotic era in [tuberculosis] control, infections associated with healthcare million new cases and 1.4 million since XDR [tuberculosis] cases face reported to CDC’s NHSN between 2009 deaths associated with TB (Ref. 64). limited therapeutic options and and 2011, approximately 80 percent More than 10,000 new cases of TB were consequently have poor treatment were resistant to vancomycin; in this reported in 2011 in the United States outcomes and high mortality,’’ (Ref. 72 same report among 3,314 E. faecalis (Ref. 67). Mortality figures from CDC at p. 2158). healthcare-associated infections, reveal that 529 persons died in the For the reasons stated previously, approximately 9 percent were resistant United States from tuberculosis in 2009 FDA believes that M. tuberculosis to vancomycin (Ref. 132, Table 7). (Ref. 67). complex has the potential to pose a Enterococci infections, including For M. tuberculosis, the primary serious threat to public health, and FDA infections caused by enterococci that are mechanism of drug resistance is is proposing to include M. tuberculosis drug-resistant (e.g., vancomycin- spontaneous chromosomal mutations, complex in the list of qualifying resistant enterococci or VRE), are often which can be amplified in the setting of pathogens. nosocomial infections. Enterococci inappropriate or interrupted therapy J. Neisseria gonorrhoeae isolates can be resistant to multiple (monotherapy and combination therapy) antibacterial drugs; in fact, Enterococcus or poor patient adherence to therapy N. gonorrhoeae is a nonmotile, gram- faecium resistant to linezolid and (Ref. 68 at p. 1321). Subsequent negative bacterium that can infect the resistant to vancomycin have been transmission of drug-resistant M. mucous membrane of the and isolated from patients (Ref. 59), and tuberculosis will exacerbate the public , as well as the rectum, isolates resistant to multiple health problem (Ref. 68). Mobile genetic oropharynx, and conjunctivae (Ref. 4 at antibacterial drugs were identified in a elements, such as plasmids or p. 2753). The pathogen can be global surveillance program (see, e.g., transposons, do not appear to mediate transmitted sexually (Ref. 73), as well as Ref. 60). Patients with bacteremia due to drug resistance in M. tuberculosis (Ref. vertically from mother to newborn VRE had an increased mortality when 68 at p. 1321). Thus, the increase in during delivery (Ref. 74). Gonococcal compared to patients who had drug- drug-resistant tuberculosis that is seen infections can cause complications, susceptible enterococcal bacteremia globally (see generally, Ref. 64) is a such as pelvic inflammatory disease, (Refs. 61 and 62). public health problem driven by ectopic pregnancy, , In sum, for the reasons described inappropriate, interrupted, or poor ophthalmitis, and endocarditis (Ref. 4 at previously—and particularly because of adherence to therapy among persons p. 2753). is the second most the increasing threat that drug-resistant being treated for TB (primary commonly reported notifiable disease in enterococci pose to the public health— resistance), and subsequent the United States: Over 300,000 cases of FDA believes that Enterococcus species transmission of drug-resistant M. gonorrhea are reported annually (Ref. have the potential to pose a serious tuberculosis from person to person 73). However, many infections are threat to public health, and FDA is (secondary resistance) (Ref. 68). probably undetected and unreported: proposing to include Enterococcus Isolates of M. tuberculosis resistant to CDC estimates that more than 800,000 species in its list of qualifying isoniazid and rifampin, the two most new gonococcal infections occur pathogens. important first-line antibacterial drugs annually in the United States (Ref. 75). used in the treatment of active TB Although the gonorrhea rate is low I. Mycobacterium tuberculosis Complex disease, are referred to as multi-drug compared with historical trends, the M. tuberculosis, the bacterium that resistant (MDR) strains (Ref. 65). rate increased during 2009–2011 (Ref. causes tuberculosis (TB), is a major Extensively drug resistant (XDR) TB is 73). global public health burden (see resistant to isoniazid and rifampin, as N. gonorrhoeae can acquire generally, Ref. 64). M. tuberculosis well as two second-line drug classes antibacterial drug resistance by

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spontaneous chromosomal mutations K. Neisseria meningitidis and studies suggest that reduced arising from endogenous flora, or N. meningitidis is an aerobic, gram- susceptibility to common antibacterial resistance can be acquired by transfer of negative, fastidious that is treatments used for meningococcal genetic information from other bacteria a leading cause of bacterial meningitis infection results in poorer health by, for example, a plasmid-mediated and , and can cause other serious outcomes (Ref. 83 at p. 776). For resistance mechanism (Ref. 76). The infectious diseases, such as pneumonia, example, a Spanish study of isolates Gonococcal Isolate Surveillance Project arthritis, otitis media, and epiglottitis from 1988 to 1992 found that patients (GISP) monitors trends in antimicrobial (Ref. 79). N. meningitidis can be readily with strains that had decreased drug susceptibilities of N. gonorrhoeae transmitted directly from person to susceptibility had higher rates of strains in the United States (Ref. 73).6 In person through close or prolonged morbidity and mortality (Ref. 83 at p. 2011, 30.4 percent of isolates collected contact via respiratory or throat droplets 776; Ref. 149 at p. 28). Other sporadic in the GISP were resistant to , (e.g., kissing, sneezing, coughing, or cases of invasive N. meningitidis with , ciprofloxacin, or a living in close quarters) (Ref. 80). reduced susceptibility to antibacterial combination thereof (Ref. 73). is a global drugs have been reported worldwide public health concern that remains (see, e.g., Refs. 142 and 143). The Since 2007, the cephalosporins have identification of N. meningitidis isolates been the only antibacterial drug class endemic in the United States, with large of invasive disease occurring that display elevated mutability suggests recommended by CDC for the first line in Africa, New Zealand, and Singapore an increased capacity to develop treatment of gonorrhea (Ref. 77). On the (Ref. 4 at p. 2740). Nasopharyngeal resistance, in addition to possible basis of ongoing surveillance, in 2012, carriage of N. meningitidis is a precursor enhancement of transmission (see, e.g., CDC changed its treatment guidelines to to disease (Ref. 4 at p. 2740), and while Ref. 144). recommend dual therapy with the majority of carriers do not develop The detection of N. meningitidis with intramuscular (instead of the disease, the World Health Organization reduced susceptibility or resistance to previously-recommended orally- estimates that, at any given time, 10 to antibacterial drugs has broad and administered antibacterial drug), with 20 percent of the population carries N. serious implications for public health, either azithromycin or doxycycline meningitidis in their nasopharynx (Ref. not only for treatment of patients with added not only for treatment of 80). In the United States, the incidence invasive disease, but also when coinfection with rate is 0.15 to 0.5 per 100,000 persons considering the use of trachomatis, but also to ‘‘potentially (see Refs. 81 and 82). Mortality rates chemoprophylaxis in order to prevent delay emergence and spread of vary by the type of infectious disease cases of invasive meningococcal disease resistance to cephalosporins’’ in N. caused by N. meningitidis, with a 40 among close contacts (see, e.g., Refs. gonorrhoeae (Ref. 77). This is the only percent mortality rate among patients 139,142, and 143). In sum, for the remaining recommended first-line with meningococcemia (Ref. 79), and a reasons described previously— treatment regimen (Ref. 77). Reduced 13 percent mortality rate among particularly because of the potential for susceptibility of gonococcal strains to children and adolescents with bacterial higher morbidity and mortality ceftriaxone has also been observed (Ref. meningitis (Ref. 4 at p. 2741). Morbidity associated with drug-resistant 73). Indeed, there is a growing concern following infection with N. meningitidis meningococcal infections—FDA that N. gonorrhoeae may become can be substantial, including hearing believes that N. meningitidis has the resistant to all available antibacterial loss, neurologic sequelae, and loss of potential to pose a serious threat to drugs (Ref. 78). Significantly, limbs from amputation (Ref. 83 at p. public health, and FDA is proposing to ‘‘[u]nsuccessful treatment of gonorrhea 773). include N. meningitidis in the list of with oral cephalosporins, such as N. meningitidis is believed to acquire qualifying pathogens. cefixime, has been identified in East resistance from the wider gene pool of L. Non-Tuberculous Mycobacteria Asia, beginning in the early 2000s, and other Neisseria species (Ref. 84 at p. Species in Europe within the past few years. 890) and through point mutations. Ceftriaxone-resistant isolates have been Antibacterial drug resistance was Non-tuberculous mycobacterium identified in Japan (2009), France identified as a concern in N. (NTM) comprises several species of (2010), and Spain (2011)’’ (Ref. 153, meningitidis almost 2 decades ago, with bacterium, including Mycobacterium internal references omitted). The GISP a demonstration that resistance to avium complex, M. kansasii, and M. reported that -resistance commonly-used antibacterial drugs abscessus (Ref. 4 at p. 3191; Ref. 86). may now be emerging in the United were increasing in incidence, and the Other species known to cause disease States (Ref. 153). identification of some isolates with beta- include M. fortuitum, M. chelonae, M. lactamase production (i.e., the marinum, and M. ulcerans (Ref. 4 at p. For the reasons stated previously— production of enzymes that cause 3191). NTM are widely distributed in particularly the increase in antibiotic bacteria to be resistant to beta-lactam the environment and can be found in resistant strains of gonorrhea together antibacterial drugs), with the author soil, water, plants, and animals (Ref. 4 with the limited number of effective concluding that ‘‘this finding is of great at p. 3191). Transmission is not antibiotics for treatment of N. concern,’’ (Ref. 85 at p. S98). Invasive communicable, and it appears to occur gonorrhoeae—FDA believes that N. meningococcal diseases caused by from environmental exposure to or gonorrhoeae has the potential to pose a isolates with reduced susceptibility to inhalation of the pathogen (Ref. 87 at p. serious threat to public health, and FDA penicillin were first reported in the 370). NTM causes many serious and is proposing to include N. gonorrhoeae 1980s in the United Kingdom, Spain, life-threatening diseases, including on the list of qualifying pathogens. and South Africa, and are now pulmonary disease, catheter-related identified worldwide (Ref. 139 at p. infections, lymphadenitis, skin and soft 6 The GISP was established by the CDC in 1986 1016). Some countries have reported a tissue disease, joint infections, and, in to monitor trends in antimicrobial susceptibilities of strains of N. gonorrhoeae in the United States to rise in the prevalence of meningococci immunocompromised individuals, establish a rational basis for the selection of with reduced susceptibility to penicillin disseminated infection (Ref. 4 at p. gonococcal therapies. (see, e.g., Refs. 85 and 141). Case reports 3192).

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NTM infections appear to be (e.g., showers, ventilators, mop water), For the reasons described increasing in the United States (see, e.g., and some healthy people have P. previously—including the prevalence of Refs. 88 and 89). A recently published aeruginosa as a colonizing bacterium in Pseudomonas infections (particularly P. study of Medicare patients showed an their skin, throat, nose, or stool (Ref. 4 aeruginosa), the associated high increasing prevalence of pulmonary at p. 2836). P. aeruginosa is among the morbidity and mortality rates, the NTM across all regions in the United so-called ‘‘ESKAPE’’ pathogens, which increasing antibacterial drug resistance, States (Ref. 89 at p. 882). The authors ‘‘currently cause the majority of US and the fact that the last-line concluded that the annual prevalence hospital infections and effectively antibacterial drug treatments (required significantly increased from 1997 to ’escape’ the effects of antibacterial to treat Pseudomonas infections because 2007 from 20 to 47 cases per 100,000 drugs.’’ (Refs. 5 and 6). P. aeruginosa of its resistance to multiple classes of persons, respectively, or an 8.2 percent pulmonary infection among patients antibacterial drugs) often have different per year increase in prevalence among with CF is associated with a more rapid or more serious adverse effects—FDA the Medicare population. Similarly, a decline in lung function (Ref. 18 believes that Pseudomonas has the population-based study in Ontario, (internal citation omitted)). potential to pose a serious threat to Canada suggests an increase in the ‘‘P. aeruginosa now carries multiple public health, and FDA is proposing to frequency of NTM infections from 9.1 genetically-based resistance include Pseudomonas species in its list per 100,000 persons in 1997 to 14.1 per determinants, which may act of qualifying pathogens. 100,000 persons in 2003, resulting in an independently or in concert with N. Staphylococcus aureus average annual increase of 8.4 percent others’’ (Ref. 4 at p. 2856 (citing Ref. (Ref. 90). 152)). Furthermore, P. aeruginosa is Staphylococcus aureus is a gram- Antibacterial drug resistance in these known for its ability to ‘‘acquire’’ positive bacterium that causes a variety organisms is ‘‘the result of a highly resistance mechanisms (see, e.g., Ref. 9). of serious infectious diseases (Ref. 4 at complex interplay between natural P. aeruginosa has been noted to develop p. 2543). S. aureus infections commonly resistance, inducible resistance and resistance during antibacterial drug result in skin or soft tissue infections mutational resistance acquired during therapy even when the results of in vitro (see, e.g., Ref. 4 at pp. 2543, 2559), and suboptimal drug exposure and susceptibility show that the bacterium is may result in more life-threatening selection,’’ (Ref. 91 at p. 150). Treatment fully susceptible when initially exposed infections (e.g., pneumonia, for NTM lung infections requires long to the antibacterial drug. (see, e.g., Ref. bloodstream), often due to infection via courses of therapy, often 18 to 24 93 (internal citations omitted); see also, catheters, ventilators, or other medical months or longer (Ref. 92 at p. 123). e.g., Ref. 4 at p. 2855 (noting that in devices or procedures (Ref. 96). S. Because NTM is resistant to many patients with P. aeruginosa endocarditis aureus is one of the most common antibacterial drugs currently available, there is a ‘‘likelihood of the patient’s bacterial pathogens in hospital-acquired infections caused by NTM can be becoming resistant to therapy even if infections, and resistance rates for S. difficult to treat. While there are no data there is initially bloodstream aureus have been increasing (see, e.g., from NTM isolates that indicate sterilization’’)). Resistant P. aeruginosa Refs. 3 and 97). In addition, in the first increasing antibacterial drug resistance, strains may be transmitted from person decade of the 21st century, resistant the incidence of NTM infections with to person, or via contamination in the strains of S. aureus (e.g., methicillin- intrinsic antibacterial resistance is environment (see, e.g., Ref. 94). In a resistant S. aureus or MRSA) that increasing (Ref. 91). This observation recent report from CDC’s NHSN, emerged in the community and in some raises concerns that resistant NTM may approximately 8 percent of all hospitals are now responsible for the be responsible for a disproportionate healthcare-associated infections were majority of S. aureus infections among share of clinical infection. caused by P. aeruginosa; among the outpatients (Ref. 98). In the United For the reasons stated previously, 6,111 P. aeruginosa infections that were States in 2005, the rate of invasive FDA believes that non-tuberculous reported, approximately 25 percent MRSA infections was approximately mycobacteria species has the potential were resistant to carbapenems and 31.8 infections per 100,000 people (Ref. to pose a serious threat to public health approximately 15 percent showed 99). S. aureus is also a member of the and, FDA is proposing to include non- resistance in at least 3 different classes so-called ‘‘ESKAPE’’ pathogens, which tuberculous mycobacteria species on the of antibacterial drugs (i.e., ‘‘multi-drug ‘‘currently cause the majority of U.S. list of qualifying pathogens. resistant’’) (Ref. 132 at Table 7). hospital infections and effectively Morbidity and mortality rates for P. ‘escape’ the effects of antibacterial M. Pseudomonas Species aeruginosa infection are generally drugs.’’ (Refs. 5 and 6). Reports of rapid Species of the Pseudomonas genus are recognized as being high (see, e.g., Ref. increases in the proportion of patients gram-negative bacteria that can cause 93 (internal citations omitted)), and hospitalized due to infections caused by serious infections (Ref. 4 at p. 3025). infection with drug-resistant strains may MRSA were largely due to increases in This is particularly true of P. have a negative effect on clinical skin and soft tissue infections caused by aeruginosa, which ‘‘accounted for outcomes, including an association with MRSA acquired in the community 18.1% of hospital-acquired higher mortality (Ref. 93). Pneumonia setting (Ref. 145). The national burden and a significant percentage of urinary and bloodstream infections due to drug- of disease due to MRSA on an tract infections (16.3%), surgical site resistant P. aeruginosa have been outpatient basis is substantial in the infections (9.5%), and bloodstream associated with higher mortality rates in United States, with an estimated 51,290 infections (3.4%)’’ in the United States. comparison to the same infections due infections reported in 2010 (Ref. 146). ICUs in 2003 (Ref. 4 at p. 2837 (citing to drug-susceptible P. aeruginosa (Ref. ‘‘S. aureus has developed resistance Ref. 151)). P. aeruginosa is ‘‘among the 10 at pp. 32–33, Tables 2 and 3). to virtually all antibiotic classes top five causes of nosocomial Although Pseudomonas non-aeruginosa available for clinical use,’’ as bacteremia, and severe infection can infections are rare, pathogenic members demonstrated by a combination of in lead to sepsis’’ (Ref. 4 at p. 2847). It can of the Pseudomonas genus can cause vivo and in vitro data (Ref. 4 at p. 2558). grow in many environments (e.g., soil, serious infections and can show In fact, numerous antibacterial water, and plants) (Ref. 4 at p. 2835) resistance to multiple antibacterial resistance mechanisms have been including moist hospital environments drugs (Ref. 95). documented in S. aureus, including the

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transmission of resistance that can occur stillbirths, and preterm deliveries (Ref. colonization go on to develop invasive via plasmids shared between bacteria, or 105). disease, colonization is a risk factor for even transfer of resistance mechanisms Over the past two decades, the disease. from different genera of bacteria (see incidence rates of GBS have increased Outbreaks of invasive pneumococcal Ref. 100). twofold to fourfold in nonpregnant disease are known to occur in closed Patients with drug-resistant S. aureus adults, ‘‘most of whom have underlying populations, such as nursing homes, infections appear to have higher medical conditions or are 65 years of childcare institutions, prisons, or other mortality when compared to patients age or older,’’ (Ref. 4 at p. 2655). The institutions (Ref. 112). Invasive disease with drug-susceptible S. aureus rate of invasive disease is approximately from S. pneumoniae is a major cause of infection (Ref. 10, Table 3 (showing a 7 per 100,000 nonpregnant adults, with illness and death in the United States, case fatality rate for patients with the highest rate in adults aged 65 years with an estimated 43,500 cases and susceptible S. aureus bloodstream and older at 20–25 per 100,000 persons 5,000 deaths in 2009 (Ref. 114). In the infections of 74/284 (26 percent) and a (Ref. 106). Case-fatality rates range from United States, among elderly adults case fatality rate for patients with 5 to 25 percent in nonpregnant adults hospitalized with invasive pneumonia, resistant S. aureus bloodstream (Ref. 4 at p. 2659). the mortality rate is approximately 14 infections of 65/171 (38 percent)). Resistance to antibacterial drugs has percent (Ref. 115). Resistance to Although infections caused by emerged in GBS, with most mechanisms commonly used antibacterial drugs for vancomycin-resistant S. aureus (VRSA) believed to be an inducible treatment of S. pneumoniae has been have been very rare (see, e.g., Ref. 101), chromosomally-mediated resistance that observed: Surveillance studies the fact that VRSA has been observed at can occur due to selective pressures of conducted in the United States between all underscores that antibacterial drug antibacterial drugs (Ref. 103). Recent 1994 and 2007 showed that 9 to 24 epidemiological surveillance shows that use can exert selective pressures on S. percent of pneumococci were resistant resistance to beta-lactam antibacterial aureus, effectively creating antibacterial to at least 3 classes of antibiotics (Ref. drugs, the mainstay of treatment and drug resistance. When patients have 113). prevention of GBS infections, has not High rates of antibacterial drug infection with drug-resistant S. aureus, been identified in the United States resistance in S. pneumoniae have been the limited options for therapy may (Ref. 107). However, there is the documented worldwide. For example, result in concerns about the feasibility potential in GBS of chromosomally- S. pneumoniae resistance to commonly- of certain therapies (e.g., some mediated mechanisms conferring used antibacterial drugs has been treatments involve intravenous decreased susceptibility to beta-lactam established for several decades, with administration, which might require antibacterial drugs (Ref. 108). In incidence of resistance to penicillin in hospital admission) or different adverse addition, the potential for the spread of the United States approaching 40 effect profiles that may negatively affect beta-lactamases via plasmid or other percent in the late 1990s (Ref. 116). In patients’ lives (Ref. 102). It is clear, genetic transfer mechanisms (see Ref. China, approximately 96 percent of all then, that drug-resistant S. aureus poses 109) to GBS will continue to be a grave recent S. pneumoniae isolates were an increasingly serious threat to public concern for public health, given the resistant to erythromycin, and health. pivotal role of beta-lactam antibacterial multidrug resistance was prevalent in Therefore, for the reasons described drugs for treatment and prevention of many Asian countries (Ref. 117). In previously, FDA believes that S. aureus GBS infections. certain European countries, the has the potential to pose a serious threat CDC and researchers from other proportion of isolates with resistance to to public health, and FDA is proposing countries have described patterns of multiple antibacterial drugs increased to include S. aureus in its list of reduced susceptibility and resistance of from 2006 to 2009 (e.g., in Bulgaria, qualifying pathogens. GBS strains to common antibacterial resistance to penicillin increased from O. Streptococcus agalactiae drugs, including penicillin, macrolides, approximately 7 percent of isolates in and clindamycin (see, e.g., Refs. 110 and 2006 to approximately 37 percent of Infections caused by S. agalactiae 111). Because GBS is a common isolates in 2009) (Ref. 118 at pp. 20, 23). (Group B streptococcus or GBS) are infectious disease and resistance to In the United States, some children with considered a major public health antibacterial drugs has been observed, it middle ear infection had strains of S. concern, particularly because the stands to reason that resistance may pneumoniae that were resistant to all organism causes meningitis and sepsis increase in the future. antibacterial drugs that have an FDA- in newborns due to transmission from For the foregoing reasons, FDA approved label for treatment of acute the mother during labor and delivery believes that S. agalactiae has the bacterial otitis media in children (Ref. (see generally, Refs. 103, 104, and 105). potential to pose a serious threat to 147). Development of resistance by S. Maternal intrapartum antibacterial public health, and FDA is proposing to pneumoniae strains to macrolide prophylaxis is recommended for include S. agalactiae in the list of antibacterial drugs and the closely- pregnant women colonized with GBS, qualifying pathogens. related azolide drugs, which has been and resistance to antibacterial drugs increasing in incidence, can be due to commonly prescribed for prophylaxis is P. Streptococcus pneumoniae efflux-mediated mechanisms or target increasing (Ref. 103), thus having the S. pneumoniae is a gram-positive modifications caused by a ribosomal potential to limit options for bacterium that causes bacterial methylase (Ref. 148). It is speculated prophylaxis in this population. The meningitis, bacteremia, respiratory tract that increased use of macrolide most common diseases caused by GBS infections including pneumonia, and antibacterial drugs may have exerted in adults are bloodstream infections, otitis media (see, e.g., Refs. 112 and pressures in which resistance pneumonia, endocarditis, skin and soft- 113). S. pneumoniae can colonize the mechanisms spontaneously occurred tissue infections, and bone and joint nasopharynx region, and transmission (Ref. 148). infections (see generally, Ref. 4 at pp. from person to person, via close contact For the reasons described previously, 2655–2661; Ref. 104). GBS infections by respiratory droplets, is thought to be including that current strains of can also result in other public health common (Ref. 112). Although not all pneumococcal disease are associated concerns, such as miscarriages, persons with S. pneumoniae with increased resistance to commonly

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used antibacterial drugs, FDA believes including the United States (Ref. 4 at p. the illness that they need treatment (Ref. that S. pneumoniae has the potential to 2599). Resistance to macrolide 131). Rehydration therapy is the most pose a serious threat to public health, antibiotics and the closely related critical component of treatment and FDA is proposing to include S. azolide group is common and poses a (see, e.g., Ref. 140). Approximately 25 to pneumoniae in the list of qualifying threat because these drugs are often 50 percent of untreated cholera cases pathogens. used in penicillin-allergic patients (see may prove fatal (Ref. 125). Antibiotic Ref. 157). Resistance to clindamycin, a Q. Streptococcus pyogenes therapy is recommended for severely ill drug used for treatment of patients with patients. It stands to reason that the risk S. pyogenes (group A streptococcus or necrotizing fasciitis, has also emerged of mortality in particular is likely to GAS) is a gram-positive bacterium that (see Ref. 157). increase for drug-resistant V. cholerae causes acute , in addition to For the reasons described previously, infections among patients with limited other serious infectious diseases, such including the high morbidity and treatment options. as necrotizing fasciitis and toxic shock mortality associated with invasive For the reasons described previously, syndrome (see generally, Ref. 4 at pp. infections, the frequency of less severe including the potential of 2593–2596). GAS is likely transmitted infections, the existing resistance to toxigenic V. cholerae strains, as well as from person to person via respiratory some commonly used agents and the the ease with which this pathogen may droplets. Close personal contact, such as possibility for an increase in resistant be transmitted, this bacterium has the in schools, appears to favor spread of strains, GAS infections have the potential to pose a serious threat to the organism (Ref. 4 at p. 2595). potential to pose a serious threat to public health, and, FDA is proposing to A study published in 2003 found that public health and, FDA is proposing to include V. cholerae in the list of approximately 1.8 million people in the include S. pyogenes in the list of qualifying pathogens. United States are diagnosed with qualifying pathogens. streptococcal pharyngitis annually VI. Environmental Impact (Refs. 119 and 120). Although R. Vibrio cholerae streptococcal pharyngitis is typically a Vibrio cholerae is a gram-negative The Agency has determined under 21 mild disease, in rare cases, it can result bacterium (Ref. 4 at p. 2777) that can CFR 25.30(h) that this action is of a type in severe post-infectious complications cause cholera, an acute diarrheal illness that does not individually or (see generally, Ref. 121). Though the that can lead to severe (Ref. cumulatively have a significant effect on annual incidence of invasive GAS 125). Although cholera is found mainly the human environment. Therefore, disease is estimated to be approximately in developing countries with poor neither an environmental assessment 4.3 per 100,000 persons per year, the sanitation and unsafe water supplies, in nor an environmental impact statement rate of mortality associated with the United States, disease may occur in is required. invasive GAS infections is high, with an travelers returning from such countries VII. Analysis of Economic Impact estimate of 0.5 per 100,000 persons per or, more rarely, in those who have eaten year (Ref. 122). This means that in the contaminated food (see, e.g., Refs. 125 A. Preliminary Regulatory Impact United States, each year over 13,000 and 126). V. cholerae has the potential Analysis people are estimated to acquire an to cause pandemics and ‘‘the ability to invasive GAS infection annually, and remain endemic in all affected areas’’ FDA has examined the impacts of the over 1,500 people are estimated to die (Ref. 4 at p. 2778 (internal citation proposed rule under Executive Order from an invasive GAS infection (Ref. omitted)), possibly due to the fact that 12866, Executive Order 13563, the 122). infected people may shed the bacteria Regulatory Flexibility Act (5 U.S.C. For over 80 years, GAS isolates have for several months after infection (Ref. 601–612), and the Unfunded Mandates remained susceptible to penicillin, 4 at p. 2779). Reform Act of 1995 (Pub. L. 104–4). though reports of resistance to other Antibacterial drug resistance in Executive Orders 12866 and 13563 antibacterial drugs have emerged in cholera-causing strains of V. cholerae direct agencies to assess all costs and GAS, primarily by chromosomally has increased between 1990 and 2000 in benefits of available regulatory mediated mechanisms (see generally, U.S. patients with both domestically- alternatives and, when regulation is Refs. 123 and 124). However, recently and internationally-acquired infections necessary, to select regulatory identified genes in GAS encode for (Ref. 126), and antibacterial drug approaches that maximize net benefits several penicillin-binding proteins, but resistance in V. cholerae is still (including potential economic, a reason for why these genes are not increasing generally (Refs. 126, 127, environmental, public health and safety, expressed has yet to be determined (Ref. 128, and 129). ‘‘Antimicrobial drug and other advantages; distributive 123). In addition, there is an ongoing resistance in Vibrio [species] can impacts; and equity). The Agency concern that transfer of antibacterial develop through mutation or through believes that this proposed rule is not a resistance to GAS by plasmid or other acquisition of resistance genes on significant regulatory action as defined genetic transfer might occur at some mobile genetic elements, such as by Executive Order 12866. point in the future (Ref. 109). Indeed, plasmids, transposons, integrons, and The Regulatory Flexibility Act microbiology laboratories are integrating conjugative elements,’’ or requires agencies to analyze regulatory encouraged to continue to perform in ICEs (Ref. 127). ICEs in particular options that would minimize any vitro susceptibility testing on all GAS ‘‘commonly carry several antimicrobial significant impact of a rule on small isolates in order to monitor for the drug resistance genes and play a major entities. Because the proposed rule possibility of resistance (Ref. 123). Thus, role in the spread of antimicrobial drug would not impose direct costs on any given the pivotal role of the beta-lactam resistance in V. cholerae’’ (Ref. 127 at p. entity, regardless of size, but rather antibiotic penicillin in the treatment of 2151; Ref. 130). would clarify certain types of pathogens GAS, any resistance that would occur in Cholera-causing strains of V. cholerae for which the development of approved the future would be of great concern for may not cause disease in all people (Ref. treatments might result in the awarding public health. Antibacterial resistance 131). However, an estimated 10 percent of QIDP designation and exclusivity to in S. pyogenes to commonly used drugs of those infected with the O1 serogroup sponsoring firms, FDA proposes to has been reported in many countries, will develop a severe enough form of certify that the final rule would not have

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a significant economic impact on a life-threatening infections’’ as QIDPs. list, while recipients of products to treat substantial number of small entities. With certain limitations set forth in the infections caused by pathogens on the Section 202(a) of the Unfunded statute, a sponsor of an application for list would receive benefits in the form Mandates Reform Act of 1995 requires an antibiotic or antifungal drug that of reduced morbidity and premature that agencies prepare a written receives a QIDP designation gains an mortality. Sponsoring firms would statement, which includes an additional 5 years of exclusivity to be experience both the cost of product assessment of anticipated costs and added to certain exclusivity periods for development and the economic benefit benefits, before proposing ‘‘any rule that that product. Drugs that receive a QIDP of an extension of exclusivity and of includes any Federal mandate that may designation are also eligible for potentially accelerating the drug result in the expenditure by State, local, designation as a fast-track product and development and review process with and tribal governments, in the aggregate, an application for such a drug is eligible fast-track status and priority review. If or by the private sector, of $100,000,000 for priority review. this rule induces greater interest in or more (adjusted annually for inflation) seeking QIDP designation than would C. Need for and Potential Effect of the in any one year.’’ The current threshold otherwise occur, FDA would also incur Regulation after adjustment for inflation is $139 additional costs of reviewing million, using the most current (2011) Between July 9, 2012, when the GAIN applications for newly-developed Implicit Price Deflator for the Gross title of FDASIA went into effect, and antibacterial or antifungal drug products Domestic Product. FDA does not expect January 31, 2013, FDA granted 11 QIDP under a more expedited schedule. this proposed rule to result in any 1- designations. As explained previously, Given that the methodology for year expenditure that would meet or the statutory provision that authorizes including a pathogen in the list of exceed this amount. FDA to designate certain drugs as QIDPs ‘‘qualifying pathogens’’ was developed is self-implementing, and inclusion of a with broad input, including input from B. Background pathogen on the list of ‘‘qualifying industry stakeholders and the scientific Antibacterial research and pathogens’’ does not determine whether and medical community involved in development has reportedly declined in a drug proposed to treat an infection anti-infective research, we expect that recent years. A decrease in the number caused by that pathogen will be given the pathogens listed in this proposed of new antibacterial products reaching QIDP designation. However, section rule reflect not only current thinking the market in recent years has led to 505E(f) of the FD&C Act, added by the regarding the types of pathogens which concerns that the current drug pipeline GAIN title of FDASIA, requires that have the potential to pose serious threat for antibacterial drugs may not be FDA establish a list of ‘‘qualifying to the public health, but also current adequate to address the growing public pathogens.’’ This proposed rule is thinking regarding the types of health needs arising from the increase in intended to satisfy that obligation, as pathogens that cause infections for antibiotic resistance. A number of well as the statute’s directive to make which treatments might be eligible for reasons have been cited as barriers to public the methodology for developing QIDP designation. To the extent that robust antibacterial drug development such a list of ‘‘qualifying pathogens.’’ there is overlap between drugs including smaller profits for short- The proposed rule identifies 18 designated as QIDPs and drugs course administration of antibacterial ‘‘qualifying pathogens,’’ including those developed to treat serious or life- drugs compared with long-term use provided as examples in the statute, threatening infections caused by drugs to treat chronic illnesses, which FDA has concluded have ‘‘the pathogens listed in this proposed rule, challenges in conducting informative potential to pose a serious threat to this proposed rule would have a clinical trials demonstrating efficacy in public health’’ and proposes to include minimal impact in terms of influencing treating bacterial infections, and on the list of ‘‘qualifying pathogens.’’ the volume or composition of growing pressure to develop appropriate As previously stated, this proposed applications seeking QIDP designation, limits on antibacterial drug use. rule would not change the criteria or compared to what would otherwise One mechanism that has been used to process for awarding QIDP designation, occur in the absence of this rule. encourage the development of new or for awarding extensions of drugs is exclusivity provisions which exclusivity periods. That is, the VIII. Paperwork Reduction Act provide for a defined period during development of a treatment for an FDA concludes that this proposed which an approved drug is protected infection caused by a pathogen included rule does not contain a ‘‘collection of from submission or approval of certain in the list of ‘‘qualifying pathogens’’ is information’’ that is subject to review by potential competitor applications. By neither a necessary nor a sufficient the Office of Management and Budget securing additional guaranteed periods condition for obtaining QIDP under the Paperwork Reduction Act of of exclusive marketing, during which a designation, and, as stated in section 1995 (the PRA) (44 U.S.C. 3501–3520). drug sponsor would be expected to 505E(c) of the FD&C Act, not all This proposed rule interprets some of benefit from associated higher profits, applications for a QIDP are eligible for the terms used in section 505E of the drugs that might not otherwise be an extension of exclusivity. Relative to FD&C Act and proposes ‘‘qualifying developed due to unfavorable economic the baseline in which the exclusivity pathogen’’ candidates. Inclusion of a factors may become commercially program under GAIN is in effect, we pathogen on the list of ‘‘qualifying attractive to drug developers. anticipate that the incremental effect of pathogens’’ does not confer any In recognition of the need to stimulate this rule would be negligible. information collection requirement investments in new antibiotic drugs, To the extent that this rule causes upon any party, particularly because Congress enacted the GAIN title of research and development to shift inclusion of a pathogen on the list of FDASIA to create an incentive system. toward treatments for infections caused ‘‘qualifying pathogens,’’ and the QIDP The primary framework for encouraging by pathogens on the list and away from designation process, are distinct antibiotic development became effective treatments for infections caused by processes with differing standards. on July 9, 2012, through a self- other pathogens, the opportunity costs The QIDP designation process will be implementing provision that authorizes of this rule would include the forgone addressed separately by the Agency at a FDA to designate human antibiotic or net benefits of products that treat or later date. Accordingly, the Agency will antifungal drugs that treat ‘‘serious or prevent pathogens not included in the analyze any collection of information or

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additional PRA-related burdens 3. Niedell, M.J., B. Cohen, Y. Furuya, et al., Focus on Aspergillus,’’ Current associated with the QIDP designation ‘‘Costs of Healthcare- and Community- Infectious Diseases Reports, published process separately. Associated Infections With online September 20, 2011 (available at Antimicrobial-Resistant Versus http://130.88.242.202/medicine/ IX. Federalism Antimicrobial-Susceptible Organisms,’’ Aspergillus/Dropbox/Aspergillus_Web Clinical Infectious Diseases, site/aspergillus-web/articlesoverflow/ FDA has analyzed this proposed rule 2012;55(6):807–15 (available at http:// 21931980.pdf). in accordance with the principles set cid.oxfordjournals.org/content/55/6/807. 14. Vardi, A., A. Sirigou, C. Lalayanni, et al., forth in Executive Order 13132. FDA full.pdf+html). ‘‘An outbreak of Burkholderia cepacia has determined that the proposed rule, 4. Mandell, G.L., J.E. Bennett, R. Dolin, et al., Bacteremia in Hospitalized Hematology if finalized, would not contain policies Mandell, Douglas, and Bennett’s Patients Selectively Affecting Those that would have substantial direct Principles and Practice of Infectious With Acute Myeloid Leukemia,’’ Diseases. 7th Ed., 2010. American Journal of Infection Control, effects on the States, on the relationship 5. Boucher, H. W., G. H. Talbot, J. S. Bradley, April 2013;41(4):312–316 (available at between the National Government and et al., ‘‘Bad Bugs, No Drugs: No ESKAPE! http://ac.els-cdn.com/S019665531 the States, or on the distribution of An Update from the Infectious Diseases 2008073/1-s2.0-S0196655312008073- power and responsibilities among the Society of America,’’ Clinical Infectious main.pdf?_tid=ee958312-5999-11e2- various levels of government. Diseases, 2009;48:1–12 (available at 819f-00000aacb360&acdnat=13576 Accordingly, the Agency tentatively http://cid.oxfordjournals.org/content/48/ 53024_abb49ea2a3c9ab83b110c616 concludes that the proposed rule does 1/1.full.pdf+html). be32adba). not contain policies that have 6. Rice, L. B., ‘‘Federal Funding for the Study 15. Liao, C., H. Chang, C. Lai, et al., ‘‘Clinical of Antimicrobial Resistance in Characteristics and Outcomes of Patients federalism implications as defined in Nosocomial Pathogens: No ESKAPE,’’ With Burkholderia cepacia Bacteremia the Executive order and, consequently, The Journal of Infectious Diseases, in an Intensive Care Unit,’’ Diagnostic a federalism summary impact statement 2008;197:1079–81 (available at http:// Microbiology and Infectious Disease, is not required. jid.oxfordjournals.org/content/197/8/ 2011;70:260–266 (available at http://ac. 1079.full.pdf+html). els-cdn.com/S0732889311000149/1-s2.0- X. Comments 7. Sunenshine, R. H., M. Wright, L. L. S0732889311000149-main.pdf?_tid= Maragakis, et al., ‘‘Multidrug-Resistant 96b0ff9e-599b-11e2-9e5a-00000 Interested persons may submit either _ electronic comments regarding this Acinetobacter Infection Mortality Rate aab0f6b&acdnat=1357653735 and Length of Hospitalization,’’ 4a18e7244f5de98f01968ed49c7e6e2d). document to http://www.regulations.gov Emerging Infectious Diseases, January 16. Siddiqui, A. H., M. E. Mulligan, E. or written comments to the Division of 2007;13(1):97–103 (available at http:// Mahenthiralingam, et al., ‘‘An Episodic Dockets Management (see ADDRESSES). It www.ncbi.nlm.nih.gov/pmc/articles/ Outbreak of Genetically Related is only necessary to send one set of PMC2725827/). Burkholderia cepacia Among Non-Cystic comments. Identify comments with the 8. Walsh, T. R., ‘‘The Emergence and Fibrosis Patients at a University docket number found in brackets in the Implications of Metallo-Beta-Lactamases Hospital,’’ Infection Control and heading of this document. Received in Gram-Negative Bacteria,’’ Clinical Hospital Epidemiology, July comments may be seen in the Division Microbiology and Infection, 2005;11 2001;22(7):419–422 (available at http:// of Dockets Management between 9 a.m. (Suppl 6):2–9 (available at http:// www.jstor.org/stable/pdfplus/10.1086/ onlinelibrary.wiley.com/doi/10.1111/ 501927.pdf?acceptTC=true). and 4 p.m., Monday through Friday, and j.1469-0691.2005.01264.x/pdf). 17. Courtney, J. M., J. Bradley, J. Mccaughan, will be posted to the docket at http:// 9. Bonomo, R. A. and D. Szabo, ‘‘Mechanisms et al., ‘‘Predictors of Mortality in Adults www.regulations.gov. of Multidrug Resistance in Acinetobacter With Cystic Fibrosis,’’ Pediatric XI. References Species and Pseudomonas aeruginosa,’’ Pulmonology, 2007;42:525–532 Clinical Infectious Diseases, (available at http:// The following references have been 2006;43:S49–56 (available at http://cid. onlinelibrary.wiley.com/doi/10.1002/ placed on display in the Division of oxfordjournals.org/content/43/ ppul.20619/pdf). Supplement_2/S49.full.pdf). 18. Flume, P. A., B. P. O’Sullivan, K. A. Dockets Management (see ADDRESSES) 10. Lambert, M. L., C. Seutens, A. Savey, et Robinson, et al., ‘‘Cystic Fibrosis and may be seen by interested persons al., ‘‘Clinical Outcomes of Health-Care Pulmonary Guidelines: Chronic between 9 a.m. and 4 p.m., Monday Associated Infections and Antimicrobial Medications for Maintenance of Lung through Friday, and are available Resistance in Patients Admitted to Health,’’ American Journal of electronically at http:// European Intensive-Care Units: A Cohort Respiratory and Critical Care Medicine, www.regulations.gov. (FDA has verified Study,’’ The Lancet, 2011;11:30–38 2007;176:957–969 (available at http:// the Web site addresses in this reference (available at http://www.sciencedirect. www.sgpp-schweiz.ch/downloads_cms/ section, but we are not responsible for com/science/article/pii/S147330991 cf_pulmonary_guidelines_ajrccm_ _ any subsequent changes to Web sites 0702589). 2007 .pdf). after this document publishes in the 11. Iverson, M., C. M. Burton, S. Vand, et al., 19. Moore, J. E., M. Crowe, A. Shaw, et al., ‘‘Aspergillus Infection in Lung ‘‘Antibiotic Resistance in Burkholderia Federal Register.) Transplant Patients: Incidence and cepacia at Two Regional Centres in 1. Roberts, R. R., B. Hota, I. Ahmad, et al., Prognosis,’’ European Journal of Clinical Northern Ireland: Is There a Need for ‘‘Hospital and Societal Costs of Microbiology & Infectious Diseases, Synergy Testing?,’’ Journal of Antimicrobial-Resistant Infections in a 2007;26:879–886 (available at http://link. 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Nightmare?’’ Clinical Infectious Diseases, Electronic Submissions 2002;34:634–640 (available at http:// § 317.2 List of qualifying pathogens that Submit electronic comments in the cid.oxfordjournals.org/content/34/5/ have the potential to pose a serious threat 634.full.pdf). to public health. following way: • Federal eRulemaking Portal: http:// 153. Centers for Disease Control and The term ‘‘qualifying pathogen’’ in Prevention, ‘‘CDC Grand Rounds: The www.regulations.gov. Follow the section 505E(f) of the Federal Food, instructions for submitting comments. Growing Threat of Multidrug-Resistant Drug, and Cosmetic Act is defined to Gonorrhea,’’ Morbidity and Mortality Written Submissions Weekly Report, February 15, mean any of the following: 2013;62(06):103–106 (available at http:// (a) Acinetobacter species. Submit written submissions in the www.cdc.gov/MMWR/preview/mmwr (b) Aspergillus species. following ways:

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