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J Antimicrob Chemother 2012; 67: 2062 – 2068 doi:10.1093/jac/dks213 Advance Access publication 11 June 2012 2012 and beyond: potential for the start of a second pre-antibiotic era? Peter C. Appelbaum* 1058 Hillview Lane, Hershey, PA 17033, USA *Tel: +1-717-533-8817; E-mail: [email protected] Keywords: bacterial resistance, approval problems, lack of interest, financial considerations, lack of expertise, public apathy, misinformation The problem The novels of Thomas Mann include classic descriptions of bacterial infections in the pre-antibiotic era: bacterial pneumonia and typhoid fever in ‘Buddenbrooks’, cholera in ‘Death in Venice’, tuberculosis in ‘The Magic Mountain’, and syphilis and acute bacterial meningitis in ‘Doctor Faustus’. Infected patients die, and physicians are powerless to intervene.1 Although many antibiotics are still effective and available, therapeutic options for some infections are extremely limited and at crisis point. We run the risk of entering a second pre-antibiotic era. Since the early 1980s, the large American and European pharmaceutical companies have been divesting themselves of their antibiotic portfolios, closing their antibacterial departments and shuttering their feed-in natural products discovery units. The situation is exacerbated by recent merger and acquisition activity, whereby one new pharmaceutical company can come to represent the cumulative assets of up to six formerly independent firms. These mergers tend to be accompanied by stagnation or disappearance of the merged companies’ antibiotic portfolios, reflecting the new corporate entity’s lack of interest in antibacterials. A recent report of the intended replacement of a very well-established American corporate antibacterial research unit by one to be created de novo in Shanghai seems highly dubious.2 A very recent report that at least two large companies (one, at least on paper, still in the antibacterial research market) may start to split off some of their constituent parts complicates the matter even further.3 A few years ago it was hoped that small companies and start-ups might take up the slack by doing the preliminary preclinical and early clinical testing before out-licensing a promising product to large pharmaceutical companies for further development. However, unanticipated problems with products such as ceftobiprole, razupenem, the plectasin derivative NZ 2114 and amadacycline (PTK 0796) have dampened this hope. Companies, large and small, are reluctant to pursue the costly development of compounds perceived not to make a lot of money in the short term. Antibacterials have become victims of their own success, insofar as they are amongst the few therapeutic classes with an excellent track record of curing the disease for which they are prescribed, thereby abrogating the need for chronic administration, the mainstay of drug company income. There are only two reasons why the life expectancy in North America and Western Europe is more than double what it was a century ago: general anaesthesia, with the accompanying ability for thorough surgical interventions; and knowledge of microbiology (antibacterials, public health measures, vaccination). We tamper with either of these at our peril. Bacteria have existed for some 3.4 billion years;4 their genetic material is remarkably adaptable and unmoved by financial considerations or constraints. I retired, defunded and disillusioned at the apparent demise of my profession after nearly 40 years in clinical microbiology, antibacterial research and studies of drug resistance. My research career began with the first description, from my laboratory in South Africa, of systemic infections caused by drug-resistant pneumococci in 1977. New techniques for # The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected] 2062 Downloaded from http://jac.oxfordjournals.org/ by guest on August 16, 2013 The past decade has seen an alarming confluence of circumstances antithetical to development of new antibacterials, and most of the very few new drugs under development have problems with their microbiology, toxicity, or pharmacokinetics and pharmacodynamics. Most large pharmaceutical companies have divested themselves of their antibiotic portfolios, and the promise that start-up companies would fill the niche has not been fulfilled. What is left of the field is being stifled by bureaucratic regulations, problems with approval, lack of expertise and a general lack of understanding of how serious the situation is. In paediatrics, in particular, there is no sign of any new antibacterial in the foreseeable future. Waiting for initiatives and deliberations will probably take too long, and a vigorous and deliberate effort to educate the public—who in their turn can apply the needed pressure—seems to be the only way of achieving a rapid turnaround of this most dangerous situation. JAC Leading article during drug development, not least in a therapeutic space such as antibacterials where profitability may be marginal. On the other hand, industry has not always been as forthcoming as it should have been about the side effects of drugs, particularly in direct-to-consumer advertising. Sadly, there is sufficient blame to go around and, with the possible exception of liability lawyers, the process damages everyone. New drugs: pros and cons Let me summarize the current situation with new and experimental antibacterial agents. Daptomycin, an excellent rapidly bactericidal antistaphylococcal agent introduced for use against skin and soft tissue infections, bacteraemia and right-sided endocarditis has been shown, in vitro as well as clinically, to select for daptomycin nonsusceptible strains, particularly when the pathogen being treated is methicillin-resistant S. aureus (MRSA).7 Such strains are also often vancomycin-intermediate due to cell wall permeability abnormalities. A significant number of vancomycin-intermediate S. aureus (VISA) strains are daptomycin non-susceptible according to current CLSI breakpoints. Problems in standardization of vancomycin susceptibility testing of S. aureus preclude accurate estimation of the incidence of VISA strains.8 Widespread use of extended courses of daptomycin for treatment of bacteraemia and endocarditis leads to increased incidences of S. aureus nonsusceptible to both vancomycin and daptomycin. VISA strains are not susceptible to either dalbavancin or oritavancin (Lin G, Kosowska-Shick K, Pankuch GA, Appelbaum PC, unpublished data), two extended-half-life lipoglycopeptides under development, though they are susceptible to telavancin at the suggested CLSI breakpoint.9 Ceftaroline, the first marketed cephalosporin active against MRSA, is FDA-approved for treatment of skin and soft tissue infections and community-acquired pneumonia. The compound is active against MRSA (including glycopeptide non-susceptible strains) as well as most Streptococcus pneumoniae and H. influenzae. Ceftaroline is inactivated by most b-lactamases produced by Enterobacteriaceae and Gram-negative non-fermenters. It is active against b-lactamase-producing H. influenzae, but less so towards highly b-lactam resistant vaccine-selected pneumococci and b-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae.10,11 Initial sales of ceftaroline have been disappointing, and alternative treatments for skin and soft tissue infections and community-acquired pneumonia not caused by glycopeptide non-susceptible staphylococci are available. A new Phase 3 600 mg three times a day study will begin shortly, in an attempt to raise the existing ceftaroline susceptible breakpoint from 1 mg/L to 2 mg/L or higher. Ceftobiprole, another anti-MRSA cephalosporin which started development several years before ceftaroline, remains in limbo due to lack of insight into proper indication and marketing, as well as problems of patient enrolment in clinical studies. Published data suggest that ceftaroline and ceftobiprole do not differ significantly from one another in terms of in vitro susceptibility or clinical efficacy, and it is therefore difficult to see how the market could support both compounds. Ceftobiprole’s primary patent is not expected to expire in the seven major markets (US, Japan, France, Germany, Italy, Spain and UK) until 2019, 2063 Downloaded from http://jac.oxfordjournals.org/ by guest on August 16, 2013 studying antimicrobials, such as time –kill profiling and time –kill synergy testing, multipassage resistance selection paired with PFGE and assorted molecular methods for examining in vitro drug –bacteria interactions were invented and/or expanded in my laboratories. We reported new resistance mechanisms in streptococci and Haemophilus influenzae, as well as the second occurrence of infection caused by a vancomycin-resistant Staphylococcus aureus (VRSA). In each case, initial descriptions were followed by independent confirmation, techniques were validated in other laboratories and new resistance mechanisms were verified by other scientists. My plan to disappear quietly from the scene has been interrupted by recent developments (or, rather, the lack thereof) in what is left of commercial antibiotic development and research on antibacterial resistance, and I feel compelled to put my opinions, borne from a lifetime in the field, on paper. There is a very serious dearth of structurally or mechanistically new antibacterial agents in development, and the field of in vitro testing has become dominated by a small coterie of private laboratories operating on a for-profit basis. I worry that the current paucity of funding to support such laboratories may engender a reluctance to risk curtailment of whatever money remains for such work by presentation or publication of discouraging results, in stark contrast to the academic freedom and excellence which used to be the standard by which new antibacterials were evaluated and developed. In the USA, interest in new antibacterials has been compromised by the actions of the FDA where, especially since the scandal revolving around the approval process for telithromycin, activist staffers have tightened regulation to the point of strangulation. Even worse, capricious behaviour by some members of drug evaluation committees has led to a ‘shifting goalpost phenomenon’ in which requirements and criteria are changed in the midst of clinical studies from what had been agreed at the start of a trial, such that the accumulated data are no longer considered adequate when final results are submitted for review. Elegant studies such as double-tap trials for treatment of otitis media5 are not possible any more, nor are practical clinical studies for treatment of acute exacerbation of chronic bronchitis.6 Recently, the FDA has sought solutions to these problems, but under prevailing circumstances most clinical trials of new antibacterials can only be performed outside North America, and possibly outside Western Europe as well. The stifling grip of codices, regulations, requirements for legal compliance and confidentiality requirements have hampered even in vitro studies, and endless layers of bureaucracy retard performance, impede development and delay or suppress publication of results. Clinical studies are encumbered by paperwork which, in today’s busy clinical setting, makes them nearly impossible to execute in the drug manufacturer’s own country. There is a pressing need for cooperation and rapid harmonization between the US FDA and the European Medicines Agency (EMA), and pharmaceutical companies, clinical microbiologists and infectious disease specialists need to fix not only valid, scientifically rigorous guidelines, but also practical guidelines for performing clinical studies. No active drug, antibacterial or otherwise, is without side effects, but aggressive campaigning, especially by the legal profession in the United States, to highlight (if not exaggerate) rare side effects in otherwise valuable or even lifesaving drugs further raises the hurdles encountered Leading article 2064 GSK2251052 is a boron-containing (‘oxaborole’) leucyl-tRNA synthetase inhibitor, development of which was rewarded with a US$ 94 million Biomedical Advanced Research and Development Authority (BARDA) grant in September 2011. Its wide spectrum of in vitro activity encompasses Gram-positive and Gram-negative aerobes and anaerobes, and it does not share targets with established agents and other drugs under development.29 – 31 However, clinical studies in complicated urinary tract infections were voluntarily halted in February 2012 due to recurrence of bacteria with elevated MICs soon after onset of therapy. Perusal of the little information made publicly available suggests that bacterial resistance developed, possibly linked to upregulation of an efflux pump. In this author’s experience, properly performed single- and multi-step resistance selection studies9 would have revealed evidence of resistance development in vitro, forewarning of subsequent clinical results. Delafloxacin and WCK 771 are a pair of fluoroquinolones under clinical development. Delafloxacin is active against pneumococci but its free AUC/MIC appears too low, at currently recommended doses, for clinical activity against staphylococci, especially those with high fluoroquinolone MICs.32,33 In contrast, the pharmacodynamic profiles of WCK 771 and its orally available prodrug WCK 2349 point to clinical activity against nearly all quinolone-resistant staphylococci, and such activity has been confirmed in animal experiments. Phase 2 trials with both WCK 771 and its prodrug have been completed in India.34,35 New oxazolidinones in clinical trials include radezolid and tedizolid (formerly torezolid). Both have potential for dosing schedules more convenient than that of linezolid, and tedizolid has an intravenous/oral step-down formulation as well as a 6 day oral dosing regimen. However, their pharmacodynamic profiles suggest that neither agent will be active against linezolidresistant staphylococci. Additionally, use of either agent in serious systemic infections at doses higher than those currently recommended for complicated skin and soft tissue infections runs the risk of dose-dependent mitochondrial toxicity, an inherent property of all oxazolidinones.36 – 42 Pharmacoeconomic studies will be needed to define the potential usefulness of either compound when up against the soon-to-be generic linezolid. Manipulation of the oxazolidinone molecule with a view to broadening its spectrum to include Gram-negatives such as H. influenzae, is unlikely to succeed with current dosages, probably due to efflux mechanisms. Two broad-spectrum tetracyclines are under development. Amadacycline (PTK 0796) has been acquired and rejected by three different large pharmaceutical firms, and its subsequent development path seems doubtful. By contrast, TP 434 is being developed as an intravenous agent with oral step-down. Time will tell whether either agent has an advantage in toxicity and administration over tigecycline; the in vitro spectra of activity for these three compounds are similar.43,44 Plazomicin (ACHN 490), a new neoglycoside currently undergoing Phase 2 testing, was designed to be active against acylase and phosphatase resistance mechanisms, but not against ribosomal methylase producers, which have recently appeared and are likely to spread.45 Plazomicin has lower MICs against staphylococci than do other aminoglycosides, and it acts synergistically with daptomycin in vitro, lowering the daptomycin MIC in combination to susceptible levels in VISA strains.46 Downloaded from http://jac.oxfordjournals.org/ by guest on August 16, 2013 but it will take significant resources and time to conduct further clinical trials, and without a partnering deal to take ceftobiprole forward, the future for this drug appears bleak.12 A combination of ceftaroline plus the b-lactamase inhibitor avibactam (NXL104) is under development, but would add significantly to treatment options only in cases of communityacquired pneumonia caused by b-lactamase-producing Enterobacteriaceae requiring hospitalization, an uncommon indication. Reports of enterobacterial b-lactamases conferring resistance to avibactam, but not to tazobactam, are beginning to emerge,13 although it is not yet known whether this will occur under clinical circumstances. Additionally, the pharmacokinetic and pharmacodynamic properties of both drugs in the combination require satisfactory harmonization. CAZ104, a combination of ceftazidime and avibactam currently under development, reportedly is active against organisms with extended-spectrum b-lactamases (ESBLs), KPCs and AmpC. It is also active against most ceftazidime-resistant Pseudomonas aeruginosa, but not against metallo-b-lactamase producers such as NDM-1-producing Gram-negative bacilli. Its activity towards b-lactamase-producing anaerobes is questionable; indeed, in clinical trials on patients with complicated intra-abdominal infections, CAZ104 was combined with metronidazole in order to ensure patients received adequate anti-anaerobe cover.14 – 18 CXA201, a combination of cephalosporin CXA101 (ceftolozane) and tazobactam, has enhanced activity against P. aeruginosa, including ceftazidime-resistant strains. Not unexpectedly, CXA201 is inactive against metallo-b-lactamase producers; however, it is also inactive against KPC-producing Enterobacteriaceae, and the activity of CXA201 against b-lactamase-producing anaerobes is such that, as for CAZ104, the developers elected to combine it with metronidazole in clinical trials on patients with complicated intra-abdominal infections. The synergistic activity of tazobactam with ceftolozane against b-lactamase producers seems less significant than that observed for established b-lactam/ b-lactamase-inhibitor combinations such as amoxicillin/clavulanate or piperacillin/tazobactam.19 – 21 BAL30072 is an experimental siderophore-containing monobactam being developed as a treatment for infections with multidrug-resistant Gram-negative bacilli. However, it is not active against Enterobacteriaceae producing large amounts of AmpC or certain ESBLs, though combining BAL30072 with a carbapenem may cover some of these strains which are not carbapenemase producers.22 The compound is very active against Burkholderia spp., including Burkholderia pseudomallei, and active against some (but not all) multidrug-resistant P. aeruginosa and meropenem-resistant Acinetobacter baumannii.23,24 Page and co-workers have documented resistance selection after ,10 subcultures in 8 of 9 strains tested,23 a very rapid rate of endogenous resistance development for a member of the b-lactam class. The value of the dihydroxypyridone moiety as a strategy for introducing the monobactam into the periplasm is questionable, since induction of the iron-citrate uptake system contributes to reduced susceptibility to BAL30072.25 Very recently, three novel antimicrobial scaffolds based upon 50S ribosome inhibition, with broad-spectrum activity against resistant Gram-negative bacilli, including KPC and NDM-1 producers, were introduced.26 – 28 Further data on these compounds are eagerly awaited. Leading article This compound has also been the beneficiary of a generous grant from the United States Department of Defense. Solithromycin is a new fluoroketolide active against pneumococci and group A streptococci resistant to macrolides, azalides and ketolides. However, its activity against H. influenzae is similar to that of azithromycin47 and, like azithromycin, solithromycin is unlikely to be clinically effective against this species at the recommended dosages. What is required? dalbavancin and oritavancin, VISA strains often are not susceptible due to their thickened cell envelopes.8 Telavancin and ceftaroline ought to be suitable for infections caused by VISAs, but they are not FDA-approved for treatment of bacteraemia or endocarditis. WCK 771 and its oral prodrug hold promise for these infections but have not yet entered Phase 3 trials. Since numerous agents are already available for treatment of complicated skin and soft tissue infections, broader indications covering serious systemic infections are required to ensure the viability of new agents with this indication. Termination of the commercialization and manufacturing agreement for telavancin is believed to have resulted, at least in part, from the FDA’s refusal to approve this antibiotic for hospital-acquired pneumonia— another manifestation of the vagaries of the drug-approval process as overseen by the FDA, which changed its mind about what constitutes an appropriate endpoint for hospital-acquired pneumonia while agreed-upon clinical trials were in progress.52 Multidrug-resistant A. baumannii has emerged as a major pathogen in many intensive care units (ICUs). CAZ104 shows promise for treatment of infection with these strains (unless they are metallo-b-lactamase or OXA carbapenemase producers), though b-lactamases selectively resistant to avibactam are sure to arise in the clinic. Polymyxins (polymyxin B, colistin) and possibly tigecycline remain the only treatments for infections caused by carbapenem-resistant A. baumannii, and it is clear that more agents, of different antibacterial classes, are needed to cover adequately the entire spectrum of drugresistant Gram-negative bacilli. New drugs active against other metalloenzyme-producing Enterobacteriaceae and P. aeruginosa, currently only treatable with polymyxin, are also needed. The recent introduction of fidaxomicin for treatment of Clostridium difficile-related pseudomembranous colitis augments treatments with oral vancomycin and metronidazole that are not always successful, but more drugs are necessary for this indication. Gonococci non-susceptible to cefixime, ceftriaxone and quinolones have been reported.53 There is no current therapy for these organisms, and their inevitable spread will create an enormous public health problem. This article does not attempt to address the growing problem of multidrug-resistant mycobacteria, particularly Mycobacterium tuberculosis, in prison populations and amongst intravenous drug abusers and AIDS patients, other than to note the fact that there is also a dangerous lack of new agents to treat serious infections caused by acid-fast bacilli. What, then, can be done? We are already decades behind in the discovery, characterization and development of new antibacterials. If even more time is not to be lost, industry, commercial clinical microbiology laboratories, academia and regulatory and other governmental agencies must unite to put patients’ lives first and financial, legal, compliance and bureaucratic considerations at a distant second. In 2010, the Infectious Disease Society of America (IDSA) launched their IDSA 10/20 initiative, to bring together the diverse stakeholders needed to create a sustainable antibiotic research and development infrastructure, as well as ten new, safe and effective, systemic antibiotics by 2020.54 In Europe, the Action on Antibiotic Resistance (ReAct) initiative has been initiated in order to develop an international framework to address the problem of bacterial resistance and develop new drugs,55,56 and the BSAC has also recently launched similar 2065 Downloaded from http://jac.oxfordjournals.org/ by guest on August 16, 2013 What, then, are the most pressing needs in the field of antibacterial therapy? There is an urgent need for antibiotics active against bacterial otitis media in paediatric patients, particularly children allergic to b-lactams. Pneumococcal macrolide resistance is common, and the therapeutic utility of the macrolide –azalide – ketolide group against H. influenzae is doubtful. No matter how the macrolide –azalide –ketolide structure is manipulated, it is extremely unlikely that a member of this drug class, as a single agent, will achieve therapeutically useful activity towards H. influenzae without unduly compromising its safety profile, because of efflux mechanisms.48 The same is presumably true for solithromycin. The situation is more dire for paediatric community-acquired respiratory tract infections caused by multidrug-resistant strains selected by the 7-valent pneumococcal vaccine49 (and surely to be selected by the 11-valent and future polyvalent pneumococcal vaccines). For strains which are also ceftriaxone resistant, the only active antibacterials (none of which have FDA approval for paediatric use) are levofloxacin, moxifloxacin and linezolid. Quinolone use in paediatrics, especially in day-care settings, must be restricted to prevent emergence and dissemination of quinolone-resistant clones. Presently, no antibacterials directed towards paediatric indications are being developed. Despite its pharmacological deficiencies, faropenem, an oral b-lactam of the penem class in use in Japan since 1997, could have helped bridge this gap.49 A paediatric form was being readied for market when a nonapprovable letter from the FDA led to its demise (as well as that of its North American developer). Community-acquired infections caused by MRSA are treatable in the USA by vancomycin, linezolid or daptomycin (for skin and soft tissue infection) though telavancin is approved in Europe for nosocomially acquired MRSA infections, and off-label options (trimethoprim/sulfamethoxazole, minocycline) are available. Staphylococcal linezolid resistance is uncommon, but spread of plasmids encoding the Cfr methyltransferase is inevitable.50 Systemic infections caused by linezolid-resistant strains are more common in coagulase-negative staphylococci. There is also a need for an oral agent for treatment and suppression of MRSA. A new fusidic acid formulation is being developed for use in the United States, designed with the hope of minimizing selection of resistance.51 Time will tell whether this will be successful. The incidence of glycopeptide non-susceptibility amongst staphylococci, mainly of the VISA and hetero-VISA (hVISA) varieties, is almost certainly higher than currently estimated, due to inadequate standardization of susceptibility testing procedures. Whereas hVISA strains are fully susceptible to daptomycin, JAC Leading article 2066 potential problems. Again, insight is required. We are at a crossroads in medical care, and the direction in which we proceed depends only on our will to proceed in that direction. Acknowledgements I thank Dr Stuart Shapiro (Basel, Switzerland) for fruitful discussions. Transparency declarations The author serves as a paid advisor to Galderma Laboratories. References 1 Thomas Mann website. http://www.thomasmann.de/thomasmann/ home (11 April 2012, date last accessed). 2 Antibiotics—the perfect storm (blog). Pfizer Abandons Antibiotics R&D in China! http://antibiotics-theperfectstorm.blogspot.com/2011/11/pfizerabandons-antibiotics-r-in-china.html (11 April 2012, date last accessed). 3 Bloomberg News. http://www.bloomberg.com/news/2012-03-27/pfizerrises-after-goldman-raises-possibility-of-full-breakup.html (11 April 2012, date last accessed). 4 Wacey D, Kilburn MR, Saunders M et al. Microfossils of sulphur-metabolizing cells in 3.4-billion-year-old rocks of Western Australia. Nature Geoscience 2011; 4: 698– 702. 5 Marchant C. Design of clinical trials of antibiotic therapy for acute otitis media. FDA antiinfectives advisory meeting (11 July 2002). www.fda.gov/ ohrms/dockets/ac/02/slides/3875S2_05_Marchant.ppt (22 April 2012, date last accessed). 6 Echols RM, Tillotson GS, File TM Jr. Antibiotic development—déjà vu: Are we facing the pre-antibiotic era again? Infect Dis Clin Practice 2007; 15: 75– 8. 7 Julian K, Kosowska-Shick K, Whitener C et al. Characterization of a daptomycin nonsusceptible vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis. Antimicrob Agents Chemother 2007; 51: 3445– 8. 8 Appelbaum PC. Reduced glycopeptide susceptibility in methicillinresistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents 2007; 30: 398–408. 9 Kosowska-Shick K, Clark C, Pankuch GA et al. Activity of telavancin against staphylococci and enterococci determined by MIC and resistance selection studies. Antmicrob Agents Chemother 2009; 53: 4217– 24. 10 Saravolatz L, Pawlak J, Johnson J. In vitro activity of ceftaroline against community-associated methicillin-resistant, vancomycinintermediate, vancomycin-resistant, and daptomycin-nonsusceptible Staphylococus aureus isolates. Antimicrob Agents Chemother 2010; 54: 3027– 30. 11 Jones RN, Farrell DJ, Mendes RW et al. Comparative ceftaroline activity tested against pathogens associated with community-associated pneumonia: results from an international surveillance study. J Antimicrob Chemother 2011; 66 Suppl 3: iii69– 80. 12 Datamonitor. Product Profiles: Pipeline Antibacterials. Reference Code: HC00130-003 (publication date: January 2012; title pages and index only: complete version has to be purchased). http://www.datamonitor. com/store/Product/toc.aspx?productId=HC00130-003 (11 April 2012, date last accessed). 13 Livermore DM, Mushtaq S, Barker K et al. Characterization of b-lactamase and porin mutants of Enterobacteriaceae selected with Downloaded from http://jac.oxfordjournals.org/ by guest on August 16, 2013 initiatives (The Urgent Need, Antibiotic Action).57 – 61 Most recently, Innovative Medicines Initiative (IMI) has reported the start of their NewDrugs4BadBugs private –public collaboration launched together with five pharmaceutical companies to tackle the problem of antibiotic research. The goals of this initiative are: (i) progressing of development of pipeline antibiotics; (ii) information sharing; and (iii) continuing new research and antibacterial discovery.62 While it is very much hoped that these worthy initiatives and deliberations bear fruit, we face the possibility that they may not, or may not do so quickly enough. The beginning of the AIDS pandemic teaches us that proper resonance occurred only when famous personalities started to become infected. Unfortunately, infants and those hospitalized in the ICU cannot vote, nor do they possess a government lobby. In the current politicoeconomic climate, I propose that the only way to achieve quick action is a determined and continuous flood of lay newspapers, magazines and prime-time television programmes with realistic descriptions of our current and future situation. Antibiotic Action has made a start in this regard in the UK. Only when the general public fully understands can suitable strong pressure be brought to bear on elected representatives (including officials such as the US Health and Human Services Secretary to whom alone the FDA is beholden) via the voting public, and pharmaceutical companies via their shareholders, for the type of rapid and concerted action that is required. Committee and other meetings, worthy as they are, take time, which we do not have. A start must also be made in educating the next generation in research on antibacterial susceptibility and resistance mechanisms. We cannot continue utilization of the older generation, nor of for-profit laboratories, indefinitely. Financial support for up-and-coming researchers is usually not forthcoming from the government, and pharmaceutical companies must be encouraged and deregulated to the extent that significant financial support for the type of research that is needed, to allow a new generation to enter the field, is forthcoming. The status quo, whereby pharmaceutical company sponsorship is subjected to microscopic examination at every level (largely because of the telithromycin debacle mentioned above) is unacceptable: in the real world, lack of financial support means that meeting participation as well as knowledge decreases, and that funding is limited to the ‘usual’ investigators (many of whom have been active for decades), who have no need of financial incentives nor of further knowledge. At present there is no incentive for anyone to enter the field of bacterial resistance and antibacterials: in fact the opposite is true. Pharmaceutical companies must also actively recruit scientific and marketing staff with the requisite knowledge. Even the best drug will not progress without insight into how development, approval and subsequent marketing should occur, and antibacterial development requires a set of skills different from those necessary for development of other agents. A younger generation of the latter groups must also be trained. There is no substitute for many years of trial, error and experience. Bodies such as BSAC and the European Society for Clinical Microbiology and Infectious Diseases can only do so much, and the US federal government [National Institutes of Health, Department of Defense (DoD)] does not come into the picture for such research. The DoD must also be more careful before they distribute money to pharmaceutical companies for drugs with Leading article JAC ceftaroline+avibactam (NXL104). J Antimicrob Chemother 2012; 67: 1354– 8. 093. http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2011.03557. x/pdf (02 May 2012, date last accessed). 14 Livermore D, Mushtaq S, Warner M et al. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase producing Enterobacteriaceae. Antimicrob Agents Chemother 2011; 55: 390–4. 27 DeVito J, Remy J, Bhatacharjee A et al. Antimicrobial activity of a novel programme of protein synthesis inhibitors against clinical isolates containing KPC and NDM-1 carbapenemases. In: Proceedings of the Twenty-First European Congress of Clinical Microbiology and Infectious Diseases, Milan, Italy 2011. Abstract P 1162. http://onlinelibrary.wiley. com/doi/10.1111/j.1469-0691.2011.03558.x/pdf (02 May 2012, date last accessed). 15 Levasseur P, Girard AM, Claudon M et al. In vitro antibacterial activity of the ceftazidime-avibactam (NXL 104) combination against Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother 2012; 56: 1606– 8. 16 Bell JM, Farrell DJ, Jones RN et al. Antimicrobial activity of ceftazidime/ NXL 104 avibactam (CAZ104) tested against Gram-negative organisms causing infections in medical centers from Europe (EU), Latin America (LA) and the Asia-Pacific region (APAC). In: Abstracts of the Fifty-First Interscience Conference on antimicrobial Agents and Chemotherapy, Chicago, IL, 2011. 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