Download 2012 and beyond: potential for the start of a second pre

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]
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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.
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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,
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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
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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
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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
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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,
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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:
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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
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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
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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.
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