It is a frightening fact in the history of antimicrobial therapy that the phenomenon of antibiotic resistance was described well before the introduction of penicillin into clinical trials. As such, this chance observation, initially made in Bacillus (Escherichia) coli by Edward P Abraham and Ernst B Chain in 1939, was at first regarded as being ‘irrelevant’, since penicillin was only targeted for staphylococcal or streptococcal infections, not Gram-negative infections. Thereafter, antibiotic resistance mediated by enzymatic inactivation (e.g., by β-lactamases and aminoglycoside-modifying enzymes), modification or protection of the target (e.g., through topoisomerase target modification by mutation or ribosomal target modification by Erm methylases), bypass of the antibiotic target (e.g., PBP2a in methicillin-resistant staphylococci), and reduced target attainment due to permeability barriers or efflux systems (e.g., Mef- or Mex-type efflux pumps) has threatened the efficacy of each novel antibiotic introduced into the clinical arena. It is unfortunate that no antibiotic has escaped resistance, even last-line agents, such as colistin and daptomycin that act on the cell’s exterior membrane. The diversity and power of different resistance mechanisms reflects the extraordinary evolutionary potential of bacteria and the broad repertoire of mechanisms that can be combined and exploited to antagonize the toxic effects of antibiotics.
Why is it important for us to continue to study antibiotic resistance? Despite our increasing sophistication in halting the spread of disease by infection-control measures, immense knowledge of pathogenesis, insights into immunology and successes of vaccinology, we are still challenged with many patients who absolutely require antimicrobial therapy. As clinicians, we are encountering increasing numbers of surgical, immunocompromised and elderly patients who rely heavily upon antibiotics as life-saving therapies. In low-resources countries, where infection control and hygienic measures are suboptimal, the role of antibiotics as life-saving agents is even broader. Therefore, knowledge of resistance mechanisms is essential for understanding how best to treat these patients, how to minimize the emergence of resistance and how to devise effective resistance-control strategies.
The rapid evolution of antibiotic resistance has been a major driving force for discovery of new antibiotics since the beginning of the antibiotic era. We are now in the position where the future of antimicrobial therapy depends upon our collective ability to comprehend the trajectories of resistance evolution and dissemination. So far, our success here has been limited. Do we have the will to proceed?
In this issue of Expert Review of Anti-Infective Therapy, we present a series of key papers by recognized international experts that summarize the contemporary thinking regarding antimicrobial resistance issues facing the clinical microbiologist and physician.
This dedicated issue begins with an editorial by Tillotson addressing the role of antibiotic development (R&D) in the pharmaceutical pipeline. This is followed by a perspective by Falagas et al. addressing the potential of old antibiotics to address the current need for new therapies. These two introductory pieces are followed by ten scholarly reviews addressing ‘hot’ themes in antimicrobial resistance.
Addressing the dilemma of resistant Gram-positive bacteria, the challenges of methicillin-resistant Staphylococcus aureus (MRSA) are discussed by Ratnaraja and Hawkey; the troublesome trends that are rapidly developing in the management of antibiotic-resistant Streptococcus pneumoniae are reviewed by Jacobs; while Arias and Murray review the emergence and management of enterococcal infections, with special emphasis on drug resistance. It will be very important for us to evaluate the emergence of even more drug-resistant Gram-positive bacteria as antibiotics, such as daptomyicn, linezolid, tigecycline and quinupristin/dalfoprisitn are used more frequently and drugs such as ceftobiprole, televancin, oritavancin and dalbavancin are introduced into practice. Will these agents be an important addition to our Gram-positive armamentarium or will they be subject to novel mechanisms of resistance? We fear that ‘new tricks’ will appear that will require us to extend our research capacity even further than it has already been established.
Three analyses that capture the existing predicament in Gram-negative bacteria are then presented. Each of these reviews summarizes the continuing crisis we are facing. Despite 25 years of recognition, extended-spectrum β-lactamases (ESBLs) still challenge us, and Rodriguez-Bano et al. summarize the major issues facing physicians regarding the impact of ESBLs in the hospital and community setting. It is now known that we have more than 700 unique β-lactamases. Can this resistance determinant ever be conquered? In his review, Pitout discusses how important the serious problem of multiresistant Enterobacteriaceae truly is. Martinez-Martinez et al. place in context the rapidly evolving field of plasmid-mediated quinolone resistance. Although wide ranging, this section of this edition reveals the ‘tip of the iceberg’. The impact of multidrug-resistant Gram-negative bacteria will largely evolve as an equally serious problem as MRSA or vancomycin-resistant enterococci; there are very limited antibiotics in development that truly promise a major advance in this area.
Unlike in other collections, we have also assembled four unique papers on additional perspectives on antibiotic resistance. The review by Banerjee et al. addresses the impact and mechanism of antibiotic resistance in mycobacteria, distinct to the other mechanism presented here. Pallecchi et al. discuss how antibiotic resistance emerges in the absence of antibiotic use, while Aarestrup et al. examine the emergence and propagation of antibiotic resistance in the food chain. These latter documents are complimented by a perceptive analysis of the economic and clinical burden of antibacterial resistance by Maragakis et al. Taken together, we feel that these papers may offer a broad vision of this problem.
As we read and reflect upon this scholarship, we must take stock of our situation and look towards the future. It is very likely we will always be faced with emerging antibiotic resistance despite our best efforts. Moreover, it is not possible to anticipate how new mechanisms will arise and what impact they will have. It is possible that we will be able to continue to develop novel approaches that will be ready for each threat as it emerges. The academic laboratories dedicated to the study of antibiotic resistance will need to harness even more tools from molecular biology and biochemistry to meet these challenges. We hope that, as antibiotic resistance inflicts significant burdens on our healthcare systems (as have cancer and metabolic diseases, among others), governments and regulatory agencies will learn the ‘relevance’ of antibiotic resistance and invest in science that will have a lasting impact. It is still sobering to reflect upon the impact of that initial observation made by Abraham and Chain nearly 70 years ago.
Financial & competing interests disclosure
The Veterans Affairs Merit Review Program and the National Institutes of Health (RO1 AI063517-01 and 1RO1 AI072219) supported Robert A Bonomo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.