Forgotten Antibiotics: An Inventory in Europe, the United States, Canada, and Australia

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1 REVIEWS OF ANTI-INFECTIVE AGENTS Louis D. Saravolatz, Section Eitor MAJOR ARTICLE Forgotten Antibiotics: An Inventory in Europe, the Unite States, Canaa, an Australia Céline Pulcini, 1 Karen Bush, 2 William A. Craig, 3 Niels Frimot-Møller, 4 M. Linsay Grayson, 5 Johan W. Mouton, 6 John Turnige, 7 Stephan Harbarth, 8 Inge C. Gyssens, 9,10 an the ESCMID Stuy Group for Antibiotic Policies 1 Centre Hospitalier Universitaire e Nice, Service 'Infectiologie an Université e Nice Sophia-Antipolis, Faculté e Méecine, France; 2 Biology Department, Iniana University, Bloomington; 3 University of Wisconsin, School of Meicine an Public Health, Maison; 4 Department of Clinical Microbiology, Hviovre Hospital, Copenhagen, Denmark; 5 Infectious Diseases Department, Austin Health an Department of Meicine, University of Melbourne, Victoria, Australia; 6 Department of Meical Microbiology, Rabou University Nijmegen Meical Centre an Department of Meical Microbiology an Infectious Diseases, Canisius Wilhelmina Hospital, the Netherlans; 7 SA Pathology, The University of Aelaie, SA, Australia; 8 Geneva University Hospitals an Meical School, Switzerlan; 9 Department of Meicine, Rabou University Nijmegen Meical Centre an Department of Meical Microbiology an Infectious Diseases, Canisius Wilhelmina Hospital, the Netherlans; an 10 Hasselt University, Diepenbeek, Belgium In view of the alarming sprea of antimicrobial resistance in the absence of new antibiotics, this stuy aime at assessing the availability of potentially useful oler antibiotics. A survey was performe in 38 countries among experts incluing hospital pharmacists, microbiologists, an infectious isease specialists in Europe, the Unite States, Canaa, an Australia. An international expert panel selecte systemic antibacterial rugs for their potential to treat infections cause by resistant bacteria or their unique value for specific criteria. Twenty-two of the 33 selecte antibiotics were available in fewer than 20 of 38 countries. Economic motives were the major cause for iscontinuation of marketing of these antibiotics. Fourteen of 33 antibiotics are potentially active against either resistant Gram-positive or Gram-negative bacteria. Urgent measures are then neee to ensure better availability of these antibiotics on a global scale. In the European Union, at least persons are estimate to ie each year from an infection cause by multirug-resistant bacteria [1]. In the Unite States, just one organism, methicillin-resistant Staphylococcus aureus (MRSA), kills more Americans every year (approximately ) than emphysema, human immunoeficiency virus/aids, Parkinson s isease, an homicie combine [2]. There is a gap between the current worlwie sprea of multiresistant bacteria an the Receive 25 July 2011; accepte 13 October Presente in part: poster presentation at the European Congress of Clinical Microbiology an Infectious Diseases an oral presentations at the Journées Nationales 'Infectiologie (French Infectious Diseases Society meeting) an Interscience Conference on Antimicrobial Agents an Chemotherapy in Corresponence: Céline Pulcini, MD, PhD, Centre Hospitalier Universitaire e Nice, Service 'Infectiologie, Hôpital l'archet 1, 151 Route Saint Antoine e Ginestière, BP 3079, Nice Ceex 3, France (pulcini.c@chu-nice.fr). Clinical Infectious Diseases 2012;54(2): Ó The Author Publishe by Oxfor University Press on behalf of the Infectious Diseases Society of America. All rights reserve. For Permissions, please journals.permissions@oup.com. DOI: /ci/cir838 evelopment of new antimicrobial rugs [1, 3 5]. Few new antibiotics are in the rug evelopment pipeline; in particular, recent analyses have shown that few antibiotics in evelopment have ocumente in vitro activity against antibiotic-resistant Gram-negative bacteria [1, 3]. Furthermore, the arsenal of available antimicrobial rugs is becoming smaller because oler rugs are isappearing from the market or are temporarily unavailable. The ESCMID (European Society of Clinical Microbiology an Infectious Diseases) Stuy Group for Antibiotic Policies (ESGAP) performe a review in 2006 which showe that shortages of narrow-spectrum antibacterial rugs force clinicians to use broa-spectrum rugs, aversely influencing the policies of pruent use [6, 7]. The reasons for shortages an market withrawals of oler antibiotics are incompletely unerstoo. However, the lack of profit for rugs in limite market areas (small countries) an increasing regulatory requirements an bureaucracy appear to play a role. Several oler, potentially useful, sometimes forgotten antibiotics are not 268 CID 2012:54 (15 January) REVIEWS OF ANTI-INFECTIVE AGENTS

2 available in many countries, either never having been introuce or having now been withrawn [8 10]. In view of the alarming evelopment of resistance in the absence of new antibiotics, it seeme opportune to collect reliable information on the availability of currently useful oler antibiotics. This stuy ha 3 objectives: (1) to select systemic antibiotics (Anatomical Therapeutic Chemical [ATC] coe J01) with (potential) activity on resistant microorganisms an/or having a unique value for specific criteria an that ha at any time been markete in Europe, the Unite States, Canaa, an Australia; (2) to assess the evience base of efficacy of these antibiotics in infections cause by current antibiotic-resistant bacteria, or their unique value; an (3) to make an inventory of these selecte antibiotics availability in Europe, the Unite States, Canaa, an Australia. MATERIALS AND METHODS Selection of Potentially Useful Antibiotics We reviewe the list of all systemic antibacterials (ATC coe J01, publications/guielines/)[11] that have been approve for human use by the US Foo an Drug Aministration (FDA) an/or the European Meicines Agency (EMA) an/or in the following countries: Europe (35 countries, Supplementary Table 1), Canaa, an Australia. Exclusion criteria inclue (1) antibiotics currently markete in all countries of interest; (2) antituberculous, antifungal, antiparasitic, an antiviral rugs; an (3) topical- or inhale-only antibacterials. Newly approve rugs, such as telavancin, ceftaroline, an fiaxomicin, were beyon the scope of our review. Six experts (2 from Europe, 2 from the Unite States, an 2 from Australia) with clinical/microbiological expertise in the fiel were chosen as assessors. Five of them were authors of a leaing reference textbook on antimicrobial rugs [12]. All authors selecte the antibiotics for their potential value against current resistant bacteria an/or for their unique value for specific criteria, base on the textbook (Kucers ) [12] an their own experience. Assessment of the Potential of These Antibiotics Against Currently Resistant Bacteria an of Their Unique Value PubMe was searche for literature relevant to the selecte antibiotics, publishe until October 2010 inclusive. Base on this literature review an the expert panel avice, the potential activity of the selecte antibiotics was assesse against a selection of resistant bacteria. For assessment of the value of the antibiotics, the metho escribe in the European Centre for Disease Prevention an Control/European Meicines Agency joint technical report 2009 the bacterial challenge: time to react was applie [1, 3]. The following antibiotic-resistant bacteria were selecte because they frequently cause bloostream infections an because the associate antibiotic resistance trait is, in most cases, a marker for multiple resistance to antibiotics: MRSA; vancomycinintermeiate S. aureus (VISA) an vancomycin-resistant S. aureus; vancomycin-resistant enterococci (VRE; eg, Enterococcus faecium); penicillin-resistant Streptococcus pneumoniae; thir-generation cephalosporin resistant Enterobacteriaceae (eg, Escherichia coli, Klebsiella pneumoniae); carbapenem-resistant Enterobacteriaceae (eg, K. pneumoniae); an carbapenem-resistant nonfermentative Gram-negative bacteria (eg, Pseuomonas aeruginosa). The selecte agents were assesse for their antibacterial activity against the selecte bacteria base on actual ata available in the reference textbook [12] an/or the literature. In the absence of available in vitro ata, the expert panel also took into account reasonable assumptions of the activity of some agents base on the properties of similar agents (ie, of the same class or with a common mechanism of action) to construct a best-case scenario. In vitro activity of each agent against the selecte bacteria was assigne base on the following approaches: Actual ata on in vitro activity were reviewe whenever available. If actual ata on in vitro activity were not reporte for an agent against any of the selecte pathogens, assumptions were mae regaring likely activity base on the properties of the antibiotic class or of the mechanism of action involve. The assessment of in vitro activity isregare any known potential for cross-resistance an coresistance. Although in vitro activity alone cannot preict in vivo efficacy, it was ecie not to take into account any available pharmacokinetic ata or pharmacokinetics/ pharmacoynamics (PK/PD) analyses when scoring the antibacterial activity of agents because the amount of ata available was very variable. However, if there was alreay information available on nonclinical or clinical efficacy, these ata were factore into the assessment. The assignment of in vitro activity, which took into account available ata together with assumptions base on class properties or mechanisms of action as well as the route of aministration, took the most optimistic view of what the agent might be able to achieve an represents a best-case scenario. The unique value of each of these antibiotics, accoring to specific criteria (eg, oxacillin allows a narrow-spectrum treatment of methicillin-susceptible S. aureus [MSSA]), was also etermine, base on the comments of the expert panel. Criteria inclue (1) microbiological criteria: spectrum, mechanism of action; (2) pharmacokinetic criteria; an (3) clinical criteria: niche antibiotic (unique value for specific pathogens or inications), last available molecule of its class, an absence of alternative. Each antibiotic was ranomly assigne to 2 experts for assessment, except for those antibiotics where 1 of the experts was REVIEWS OF ANTI-INFECTIVE AGENTS CID 2012:54 (15 January) 269

3 Figure 1. Availability of the selecte 33 antibiotics in 38 countries (Europe, Unite States, Canaa, an Australia), isplaye by antibiotic. the author of the Kucers chapter, in which case the antibiotic was assigne to the author. If the 2 assessments were concorant, the evaluation was final. In case of nonagreement between the 2 experts, the antibiotic was evaluate by all 6 experts to reach a consensus. Survey on the Availability of Selecte Antibiotics in Europe, the Unite States, Canaa, an Australia Contacts (belonging to personal networks of the authors an/or being members of ESGAP an/or ESCMID PK/PD of Anti-infectives Stuy Group) in the selecte countries were approache by in the northern hemisphere in Autumn 2010 Winter 2011 to report on the availability of the selecte antibiotics in their country. The ata collecte were entere in a Microsoft Excel spreasheet. These ata were compare by the lea author (C. P.) with information on the national rug agencies Web sites (Supplementary Table 2) an the Martinale pharmacopoeia [13]. Whenever possible, a istinction was mae between antibiotics easily available through usual marketing processes an antibiotics available via a special regulatory scheme. The availability of inhalational formulations an reasons for withrawal or abbreviate (,1 year) marketing of the antibiotic were also explore. RESULTS Thirty-three valuable antibiotics were selecte (Figure 1). Many ha multiple features consiere to be of value. Assessment of the Potential of Selecte Antibiotics Against Resistant Bacteria an of Their Unique Value Thirty-one of 33 antibiotics were foun to be either active against resistant bacteria or having unique value after the literature review; cefpooxime an ceftibuten were inclue in the survey but, upon inspection of their current susceptibility profiles, i not meet any of the criteria establishe for future utility. A summary of the results is presente in Tables 1 an 2 (a more etaile assessment by antibiotic is available as Supplementary Appenix 1). Fourteen of 33 antibiotics were active against resistant Gram-positive bacteria (MRSA, VISA, penicillin-resistant pneumococci, or VRE). Fourteen of 33 antibiotics were active against resistant Gram-negative bacteria (thir-generation cephalosporin resistant Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, or non-fermentative bacteria). Twenty-two antibiotics were consiere to have a unique value, incluing 9 antibiotics having a unique value for treating specific pathogens or for specific inications 270 CID 2012:54 (15 January) REVIEWS OF ANTI-INFECTIVE AGENTS

4 Table 1. Selecte Systemic Antibacterial Agents an In Vitro/In Vivo Activity Against Selecte Resistant Bacteria Base on Actual Data Gram-positive bacteria Gram-negative bacteria 3r gen. Carb. Carb. R Agent MRSA VISA/VRSA PRSP VRE cep. R ENB R ENB NF GNB Antistaphylococcal penicillins: nafcillin an isoxazolyl penicillins: oxacillin, cloxacillin, icloxacillin, an flucloxacillin Aztreonam h a h a Cefepime n h b Cefoperazone-sulbactam n n Cefoxitin Cefpooxime an ceftibuten Chloramphenicol an thiamphenicol n n h n h h Colistin n n n Ertapenem h h Fosfomycin n n n n n h Fusiic aci n n n Mecillinam an pivmecillinam h Methenamine n n n n n n Nitrofurantoin n n n Penicillin V an penicillin G Pristinamycin n n h Quinupristin-alfopristin n n n n e Spectinomycin h Teicoplanin n n n f Temocillin n n Tobramycin h h h n n n Trimethoprim n n n Summary of the potential activity of the antibacterial agents against selecte resistant bacteria n h Total Activity: n inicates usually active an h inicates sometimes active. The activity of each rug is variable, accoring to the clinical situation (eg, bacterial species for Gram-negative bacteria, mechanism of resistance, site of infection, pharmacokinetics/pharmacoynamics inices). Data presente in the table represent the bestcase scenario, are mainly level 3 quality of evience, an are not treatment guielines. A more in-epth analysis is available in Supplementary Appenix 1. Abbreviations: Carb. R ENB, carbapenem-resistant Enterobacteriaceae; Carb. R NF GNB, carbapenem-resistant nonfermentative Gram-negative bacteria; ESBL, extene-spectrum b-lactamase; 3r gen. cep. R ENB, thir-generation cephalosporin resistant Enterobacteriaceae; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; PRSP, penicillin-resistant Streptococcus pneumoniae (MIC.2 mg/l); VISA, vancomycin-intermeiate S. aureus; VRSA, vancomycin-resistant S. aureus; VRE, vancomycin-resistant enterococci. a Active only if a metallo-b-lactamase is prouce in the absence of overexpresse AmpC or in the absence of an ESBL. b Active on AmpC chromosomally meiate b-lactamases; active on ESBLs only if MIC,4 mg/l. c Inactive on some Enterobacteriaceae such as Enterobacter species, Citrobacter species, Serratia species, an Proviencia species. Potentially active against resistant bacteria because it is converte to formalehye in aciic urine an therefore has broa-spectrum isinfectant properties (except on urease-proucing strains), but lacks evience. e Active on Enterococcus faecium. f Active except on VanA type. h c (5 antistaphylococcal penicillins for MSSA infections, penicillin G for syphilis, spectinomycin for gonorrhea, penicillin V, an temocillin). Availability of These Antibiotics in Europe, the Unite States, Canaa, an Australia The availability ata obtaine for the Unite States, Canaa, Australia, an 35 European countries are shown in Figure 1 an Supplementary Figure 1. Detaile information is available in Supplementary Appenix 2. We ha no ata for 1 European country, an ata regaring 2 other European countries were collecte using national Web sites, in the absence of national contacts. Surprisingly, the number an the moe of availability (markete or via a special system) iffere consierably from one country to another. Twenty-two of the 33 selecte antibiotics were markete in fewer than 20 countries. REVIEWS OF ANTI-INFECTIVE AGENTS CID 2012:54 (15 January) 271

5 Table 2. Unique Value of the Selecte Antibacterial Agents, Using Microbiological, Pharmacokinetic, an Clinical Criteria Criteria The 22 Antibiotics Having Unique Value for 1 or Several Criteria Microbiological criteria: spectrum, 14 antibiotics Microbiological criteria: mechanism of action, 6 antibiotics PK criteria, 5 antibiotics Clinical criteria: niche agent (unique value for specific pathogens or inications), 9 antibiotics Clinical criteria: last (only) available antibiotic of its class, 8 antibiotics Clinical criteria: absence of alternative, 2 antibiotics - Antistaphylococcal penicillins (nafcillin an isoxazolyl penicillins: oxacillin, cloxacillin, icloxacillin, an flucloxacillin): narrow-spectrum rug to treat MSSA infections - Cefoxitin: infections ue to Mycobacterium abscessus, Mycobacterium fortuitum, an Mycobacterium chelonae - Chloramphenicol an thiamphenicol: gonococci, broa-spectrum rug (eg, Rickettsia, Stenotrophomonas maltophilia) - Penicillin G: Treponema pallium - Quinupristin-alfopristin: Enterococcus faecium - Spectinomycin: Neisseria gonorrhoeae - Teicoplanin: E. faecium with vanb/c resistance an amoxicillin-resistant Enterococcus gallinarum/casseliflavus - Temocillin: Burkholeria cepacia - Tobramycin: Pseuomonas aeruginosa - Chloramphenicol an thiamphenicol - Colistin - Fosfomycin - Fusiic aci - Nitrofurantoin - Chloramphenicol an thiamphenicol: excellent iffusion into central nervous system an eye - Ertapenem: once-aily parenteral (IV/IM) aministration; convenient as OPAT - Fosfomycin oral formulations: 1 ose only for uncomplicate cystitis - IV fosfomycin: excellent iffusion into central nervous system an eye - Teicoplanin: OPAT possible - Antistaphylococcal penicillins (nafcillin an isoxazolyl penicillins: oxacillin, cloxacillin, icloxacillin, an flucloxacillin): niche agent for MSSA infections - Penicillin V: rheumatic fever an postsplenectomy prophylaxis regimens - Penicillin G: T. pallium - Long-acting forms of penicillin G: syphilis an chemoprophylaxis of rheumatic fever - Spectinomycin: niche agent for gonorrhoea - Temocillin: niche agent for B. cepacia infections (EMA/FDA: orphan status in cystic fibrosis) - Aztreonam (only monobactam): useful in case of b-lactam allergy because cross-reactivity with penicillins an cephalosporins is rare - Chloramphenicol an thiamphenicol - Colistin (only available polymyxin E) - Fosfomycin - Fusiic aci - Methenamine - Spectinomycin - Colistin: absence of alternative for some multiresistant Gram-negative strains - Quinupristin-alfopristin: amoxicillin-, aptomycin-, an vancomycin-resistant E. faecium Abbreviations: EMA, European Meicines Agency; FDA, US Foo an Drug Aministration; IV, intravenous; IM, intramuscular; MSSA, methicillin-susceptible Staphylococcus aureus; OPAT, Outpatient Parenteral Antibiotic Therapy; PK, pharmacokinetics. Economic motives are the major cause for iscontinuation of marketing of these antibiotics, for example, penicillin G an cloxacillin in Croatia (not profitable to the local inustry) or penicillin V an oxacillin in Latvia (for more information, see Supplementary Appenix 2). In Switzerlan, cefoxitin an aztreonam were withrawn ue to small volume sales. In Turkey, 272 CID 2012:54 (15 January) REVIEWS OF ANTI-INFECTIVE AGENTS

6 colistin was recently approve, prouce, an markete by a local company, in response to the urgent nee following the countrywie rise in multirug-resistant Gram-negative infections. DISCUSSION The major fining of this inventory was that many potentially useful antibiotics, usually low cost an markete as generics, an with a long history of tolerability an safety ata, are not available in many countries. This is a worrisome situation, given the current worlwie bacterial resistance crisis. Urgent measures are neee to ensure a better availability of these antibiotics on a global scale. It is also worrisome that obtaining a reliable overview on the availability of these antibiotics in the selecte Western countries was quite ifficult. We also note iscrepancies between the ata sent by the national contacts, many of whom were senior specialists in the fiel, an the ata available on the national rug agencies Web sites an/or in the Martinale rug reference, which illustrates the lack of transparency an information on rug availability. Moreover, in many ifferent countries, some antibiotics are available through special an sometimes complicate regulatory systems, usually elaying the elivery of the rug, at the price of time-consuming paperwork. Temocillin an mecillinam coul be useful for extenespectrum b-lactamase proucing organisms (but only if there is a low minimal inhibitory concentration for mecillinam an low inoculum); fosfomycin an colistin may also be use to treat infections cause by carbapenem-resistant Gram-negative bacilli (Table 1). These are agents that, in the opinion of the authors, hol the greatest promise of utility worlwie for managing infections that result from many currently resistant Gram-negative organisms. However, they were available in only 2, 2, 5, an 25 countries, respectively. In half of the cases, neither PK/PD ata nor clinical ata were available for rugs known to be active in vitro (Supplementary Appenix 1) [14]. Stuies on PK/PD coul justify greater availability of those proucts with avantageous PK/PD characteristics. In particular, more ata on animal moels an clinical stuies are neee; in vitro surveillance ata on these rugs are lacking in the available networks such as the European Antimicrobial Resistance Surveillance Network an SENTRY; clinical registers are nonexistent. We hope that our inventory can contribute to the renewe interest of the proucers to market their proucts in the respective countries. In view of our results, we woul recommen that treating physicians consier the forgotten antibiotics on our list for treatment of resistant pathogens. However, use of these rugs shoul be base on susceptibility testing provie that stanarize susceptibility testing an interpretive criteria are available (from the Clinical an Laboratory Stanars Institute or the European Committee on Antimicrobial Susceptibility Testing); not all resistant species may respon to each of the rugs as preicte in the tables. Our assessment was base on a best-case scenario an therefore oes not represent treatment guielines. Companies shoul give full transparency on the marketing, istribution, an ispensing of meicines in all countries, an these ata must be easily available. Many of the oler antibiotics are now only prouce by pharmaceutical inustries in eveloping nations, which may further impee the access to these rugs, because there may be a lack of influence of regulatory boies in Europe an elsewhere. In such cases, the EMA an similar regulators in other regions shoul establish formal contact to enhance the availability of these antibiotics. In case of withrawal of a rug in an iniviual country because of economic reasons, all possible efforts shoul be mae to guarantee the availability in case of urgent meical nee. In aition, the rug agencies shoul inform the meical community before withrawal of the rug in orer for the latter to possibly respon an perhaps prevent the withrawal. There is a role for rug agencies (such as the EMA an FDA) in aapting regulations accoringly. In our opinion, policy makers are well avise to guarantee the availability of oler an generic antibiotics an other rugs that are essential for meical care, beyon marketriven agenas. Reuction of the market registration fees for such neee antibiotics might be one metho to relieve the costs for the pharmaceutical companies. An equally challenging problem for manufacturers an potential prescribers is obtaining registration of oler antibiotics that have never been registere before in that country or region. In many cases, the ata available o not reach moern regulatory requirements an stanars. For example, the introuction of fusiic aci into the US market has require a small US-base pharmaceutical company to unertake extensive in vitro, animal, an clinical stuies to comply with the FDA requirements for new agents [15]. This process is ongoing, costly, an will take years, an it is occurring in the face of extensive clinical experience with the agent in several countries over the course of nearly 40 years. To expeite the process of newly registering oler antibiotics, it is a matter of urgency that regulatory agencies worlwie evelop new, perhaps less burensome proceures so that these agents can be use globally in a timely manner. Better international harmonization is certainly neee for the regulatory agencies to attain all of these objectives. Our stuy is strengthene by the use of an alreay publishe metho, thus allowing us to compare ata on oler antibiotics with ata on new antibiotics that are still in evelopment [3]. Due to the chosen metho, our inventory was limite to selecte countries/regions. However, it woul be interesting to exten the inventory to other regions such as Asia, South America, an Africa, epening on the complexity an iversity of their regulatory environments. REVIEWS OF ANTI-INFECTIVE AGENTS CID 2012:54 (15 January) 273

7 In conclusion, we have ientifie 31 particularly useful antibiotics that are available in a limite number of countries surveye. These antibiotics will be forgotten by new generations of clinicians, unless they are remine of their potential utility, thus limiting the best meical practice in that country. Urgent measures are now neee to ensure a better availability of these antibiotics on a global scale an to conuct aitional research regaring the benefit of these antibiotics in current clinical infections. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online ( Supplementary materials consist of ata provie by the author that are publishe to benefit the reaer. The poste materials are not copyeite. The contents of all supplementary ata are the sole responsibility of the authors. Questions or messages regaring errors shoul be aresse to the author. Notes Authors contributions. I. C. G., N. F. M., an W. A. C. conceive the iea of the article. C. P. collecte the ata an wrote the article with contributions from all authors. All authors contribute to the ata analysis an rea an approve the final version. Acknowlegments. The following persons provie the ata on the availability of the selecte antibiotics in their countries: Albania (Ahmet Hysa an Pellumb Pipero), Australia (John Turnige), Austria (Ursula Theuretzbacher), Belgium (Inge Gyssens), Bulgaria (Toor Kantarjiev), Canaa (Donna Lowe), Croatia (Vera Vlahovic-Palcevski), Denmark (Niels Frimot-Møller), Estonia (Ott Laius an Irja Lutsar), Finlan (Miika Bergman), France (Céline Pulcini), Germany (Sibylle Matz an Antina Ziegelmann), Greece (Helen Giamarellou), Hungary (Ria Benkö an Elisabeth Nagy), Icelan (Mímir Arnórsson), Republic of Irelan (Colm Bergin an Muireann O Connor), Italy (Evelina Tacconelli), Kosovo (Lul Raka), Latvia (Uga Dumpis), Lithuania (Asta Jurkevičien_e), Luxembourg (Marcel Bruch an Elisabeth Heisbourg), Republic of Maceonia (Golubinka Bosevska), Malta (Peter Zarb), the Netherlans (Inge Gyssens), Norway (Gunnar Skov Simonsen), Polan (Waleria Hryniewicz), Portugal (Liliana Cristina Ramos Dias), Romania (Mihaela Lupse), Serbia (Biljana Carevic), Slovenia (Bojana Beović), Spain (José Ramón Paño Paro), Sween (Hakan Hanberger), Switzerlan (Stephan Harbarth), Turkey (Murat Akova), Unite Kingom (Heather Kenney an Charis Marwick), Unite States (William Craig). We also thank Pieter-Jan Cortoos (Belgium) for valiating the ata. Potential conflicts of interest. K. B. receives retirement income from Bristol-Myers Squibb, Pfizer (Wyeth/Leerle), an Johnson & Johnson an has serve as a consultant for Anacor, Basilea, Cempra, Cubist, Merck, an Shionogi. W. A. C. has serve on scientific avisory boars as a consultant an receive research grants for animal stuies from numerous pharmaceutical companies. M. L. G. is Eitor-in-Chief of Kucers The Use of Antibiotics. I. G. has serve as a consultant for Bayer Healthcare an Pfizer an has receive a research grant from Bayer Healthcare. S. H. is a member of the speakers bureau for biomérieux an Brahms, participates on the scientific avisory boars of biomérieux, Destiny Pharma, LASCCO, an DaVolterra, an has receive research funing for investigator-initiate research by Pfizer. J. W. M. has serve as a consultant for Astellas, Astra- Zeneca, Basilea, Merck an Novartis an has receive research grants from Astellas, Cubist, Jansen an Merck. C. P. has receive funing for travel/ accommoations/meeting expenses from MSD an Pfizer. J. T. has serve on avisory boars for Pfizer Australia, Novartis Australia, Janssen-Cilag Australia, an AstraZeneca Australia. N. F.-M. reports no potential conflicts of interest. All authors have submitte the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the eitors consier relevant to the content of the manuscript have been isclose. References 1. ECDC/EMEA. Joint technical report. The bacterial challenge: time to react a call to narrow the gap between multirug-resistant bacteria in the EU an the evelopment of new antibacterial agents Available at: Report/2009/11/WC pf. Accesse 18 November Spellberg B, Blaser M, Guios RJ, et al. Combating antimicrobial resistance: policy recommenations to save lives. 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