Clinical Relevance of the ESKAPE Pathogens

Expert Commentary & Five-year View

In the short-term, with therapeutic options dwindling, it is essential that the last remaining antimicrobials be safeguarded through rational selection and improved infection control. The establishment, maintenance and enforcement of local and international interventions to limit infection, and slow the emergence and spread of resistance are important initial steps in what will be a long-term reformation of antimicrobial practice.

The call for antibiotic stewardship has been proposed for many years by health authorities to temper the development of resistance mechanisms against the last remaining antibiotics.^[3,4,7] Adaptable selection guidelines are readily available and stringent prescribing protocols have been successfully implemented nationwide in the UK across local NHS hospital trusts. However this is not commonplace globally; it is estimated that only 48% of US hospitals operate an 'antimicrobial stewardship program'.^[206] Prescribing the most appropriate antibiotic at the correct dose and time, and for a suitable duration, has been consistently proven to improve patient outcomes and reduce the emergence of antibiotic resistance.^[72,73] Given the indisputable global nature of resistance, this fundamental malpractice is a key target for reform, and should be expected to improve in developed countries over the coming years.

Infection control protocols are another essential component for reducing the transmission of resistance and HAIs.^[207] The Cleanyourhands campaign in the UK demonstrates how national interventions for infection control in tandem with a high profile political drive can reduce selected HAIs.^[74] In the same vein, public awareness campaigns, such as the European Antibiotics Awareness Day – marked annually on 18th November^[208] – can help to highlight the mounting consequences of continued antibiotic misuse in both medicine and in agriculture, given the appropriate political and financial backing. As the crisis develops and public awareness heightens, the prevalence, frequency and recognition of such campaigns is likely to increase.

National and multinational surveillance systems have been in operation in the EU,^[209] USA^[210] and UK^[211] for over a decade, yet still increased synergy between these established networks is needed to face a threat that recognizes no borders.^[3] There are plans in the UK by the Department of Health to introduce a web-based reporting system for healthcare-associated infections.^[212] Up-to-date, open-access data sources such as this are integral to the cooperative global control of resistant infections. The short-term institution of a global surveillance network is prohibited by the axiomatic technical and logistical complexities however, but should not be ruled out in the coming decades.

Looking to the future, the EU's Innovative Medicines Initiative and an assembly of pharmaceutical giants have launched a new public–private scheme – entitled NewDrugs4BadBugs – to focus on fostering an unprecedented collaborative effort between all major stakeholders including industry, public authorities, academia, clinicians and patient representative groups. The venture is supported by an initial budget of €223.7 million – jointly sponsored by the Innovative Medicines Iniative and the associated pharmaceutical industry – and is set to accelerate the development of new antimicrobial therapies, improve clinical-trial design and promote synergy between pre-existing consortia integral to a united effort against resistant pathogens. In addition to providing financing, scientific expertise and clinical-trial managers, the pharmaceutical industry is also contributing novel antimicrobial compounds. GlaxoSmithKline have contributed a new hydrazinopyrimidine agent, GSK1322322; indicated for MDR skin and respiratory infections^[213] whereas AstraZeneca have provided two novel adjuvant treatments: MEDI4893; an antivirulence monoclonal antibody against S. aureus and AZD9773; an adjunctive treatment for septicemia.^[75,214] Adjunctive treatments that reduce the virulence and severity of infections are a fresh and attractive approach to antimicrobial chemotherapy. Such agents not only extend the therapeutic options for clinicians and help to address broad stewardship goals of health authorities, but through their non-destructive nature, they alleviate the selective pressure previously applied by antibiotics.^[75,76] One promising adjunctive strategy is that of efflux pump inhibition, offering the potential to increase intracellular concentrations of efflux-prone antimicrobials, restore the susceptibility of intractable strains and reduce the emergence of additional acquired resistance. Although there is currently limited information regarding other adjunctive agents in active clinical development, hints of their emergence may appear before the end of this decade.

In the USA, following the instigative measures that brought about NewDrugs4BadBugs, the IDSA have proposed a similar collaboration dubbed the 10 × '20 initiative, calling for ten new antibiotics by 2020 through the development of a 'sustainable global antibacterial drug R&D enterprise'.^[77] Despite alarming appeals for new antimicrobials in recent years, as of 2011, 20 new antibiotics had actually been launched since 2000 and 40 were recorded as being in active clinical development. Of the 20 reaching the market, three belonged to novel classes: linezolid, a synthetic oxazolidinone that uniquely inhibits Gram-positive protein synthesis;^[78] daptomycin, a natural lipopeptide that depolarizes Gram-positive cell membranes;^[79] and tigecycline, a semi-synthetic glycylcycline that inhibits protein synthesis in both Gram-positive and -negative bacteria, besides Pseudomonas and Proteus spp.^[80] The remainders were synthetic derivatives of pre-existing scaffolds.^[81] Although it is encouraging to see the antimicrobial 'pipeline' trickle forth again after long years of stagnation, reports of resistance to these latest antimicrobials have quickly emerged among select ESKAPE pathogens.^[82–86] Potentially, ten more novel classes are in early stage clinical development; however, the sensitivity breakpoints of these upcoming agents against increasingly common MDR isolates remain to be studied. The utility of next-generation antimicrobials released onto the market will ultimately be dictated by their spectrum of activity, tractability to synthetic derivitization and the rate of emerging resistance. Of the approaching antimicrobial vanguard, the most successful agents will be of clinical use against the most resistant pathogens, yet be afforded protection through stringent stewardship and infection control policies. Table 1 displays a selection of new antimicrobials from novel classes in various stages of development, with their sources – natural or synthetic – and application potential to the ESKAPE pathogens indicated.

Incremental synthetic tailoring is an appropriate short-term strategy, but has ultimately led to the current crisis of global AMR. A more sustainable approach against resistance over the next 5 years may be the pursuit of novel antimicrobial scaffolds from natural products hidden in unexplored ecological niches. In contrast to depleted terrestrial sources, the marine environment offers abundant untapped ecological niches – among sediment,^[87] sponges^[88] and seaweeds.^[89] In tandem with modern bio-informatic approaches and contemporary systematic derivitization, the rational maximization of these potential new scaffolds may start to swell the 'pipeline' flow.

The current dearth of antimicrobial therapies for recalcitrant infections has necessitated the reinstatement of previously repudiated antimicrobial agents active against multiresistant bacteria. These 'old' antibiotics – having never undergone contemporary drug development procedures – may be redeveloped in order to overcome the limitations that led to their initial abandonment.

Polymyxins – a class of multicomponent cationic polypeptides comprising polymyxin B and E (colistin) – exemplifies the resurgence of these older compounds, finding application in multiresistant Gram-negative infections, many of which are caused by ESKAPE pathogens. First released in the 1960s, colistin – amid claims of high nephro- and neurotoxicity incidences – was replaced by the aminoglycosides only after a decade of use.^[90–92] As with newly discovered antimicrobial scaffolds, these rediscovered compounds may be subject to contemporary optimization through structure–activity relationship studies and derivative compounds may reach the market in years to come.

While the importance of antimicrobial development and usage has been duly recognized, a contemporary appreciation for microbial growth appears to be lacking from not only the literature, but the pharmaceutical and governmental strategies of recent years. An equally radical shift in antimicrobial R&D may be required in concert with the downstream clinical reform already taking place in order to fully rise to the challenge of AMR.

Within current antimicrobial fora, amid vociferous concerns for AMR, MDR, HAIs and agricultural growth promoters, a highly significant microbiological factor has failed to receive appropriate attention. Despite their recognition over 330 years ago, the fundamental principles underpinning the contemporary theory of bacterial growth have only found appreciation in the last 80 years. It is now understood that bacteria exist ubiquitously as biofilms: phenotypically heterogeneous, matrix-embedded, sessile, multispecies communities attached to surfaces and not as the phenotypically homogenous, isolated, planktonic, mono-species organisms free-floating in suspension traditionally observed in the laboratory. While it is accepted that biofilms exist ubiquitously in natural environments, despite substantial evidence the implication of biofilms in infectious disease is still debated.^[93]

Over 150 years ago, the pioneering methodologies of Louis Pasteur and Robert Koch established the field of classical microbiology and formed the foundation of antimicrobial suspension-based susceptibility tests still in use today.^[94–96] However, a growing number of microbiologists believe that obviating the more complex biofilm mode in preference for the more easily reproducible planktonic mode has misdirected generations of research.^[93,97]

Bacterial biofilms are of great clinical relevance as they provide a distinct survival advantage against antimicrobials in contrast to their planktonic counterparts, requiring up to a 1000-fold increase in concentration for some agents.^[98,99] An estimated 80% of microbial infections in humans are biofilm-mediated, and have been implicated in an assortment of conditions, from dental plaques and periodontitis^[40] to chronic CF lung disease^[100] and endocarditis.^[101] Biofilm growth is the underlying basis for refractory HAIs associated with indwelling medical devices,^[40] the majority of which are caused by ESKAPE pathogens.

A paradigm shift in antimicrobial development, diagnostics and application has been called for to reflect the increased tolerance of biofilms. In the pursuit of next-generation antibiotics, selection should be directed towards agents showing antibiofilm activity; screening must therefore be revised in consideration of biofilm growth.^[99] In vitro biofilm studies have shown – in the case of rifampicin – that existing lipophilic antibiotics of low molecular weight, with a biocidal action independent of bacterial growth stage are more likely to penetrate and kill species-specific biofilms, either alone^[102] or when used in synergistic combinations.^[103]

Paralleling the clinical disassociation between planktonic susceptibility and therapeutic success, it stands to reason that traditional activity screening has also misdirected decades of antimicrobial discovery. Biofilm susceptibility screens could be directed towards previously disregarded combinatorial compounds scoring poorly in traditional suspension tests, as well as synergistic cocktails, and previously disfavored narrow-spectrum agents, widening the cohort of potential next-generation antibiotics already residing in the libraries of pharmaceutical companies.^[99] Revolutionary measures such as this require clear goals and direction. Narrowing the field to key clinical targets such as the ESKAPE pathogens would streamline the process, focus efforts, introduce a sustainable continuity to R&D, improve efficiency and ultimately maximize return on investment. This revolution in the status quo will take at least a decade to fully affect antimicrobial R&D, as well as clinical policy- and decision-making; however, some early signs of this important consideration may be seen in the next 5 years.

Expert Rev Anti Infect Ther. 2013;11(3):297-308. © 2013  Expert Reviews Ltd.