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ScienceDirect Update on the antibiotic resistance crisis Gian Maria Rossolini1,2,3, Fabio Arena1, Patrizia Pecile3 and Simona Pollini1 Antibiotics tend to lose their efficacy over time due to the emergence and dissemination of resistance among bacterial pathogens. Strains with resistance to multiple antibiotic classes have emerged among major Gram-positive and Gram-negative species including Staphylococcus aureus, Enterococcus spp., Pseudomonas aeruginosa, Acinetobacter spp. Enterobacteriaceae, and Neisseria gonorrhoeae. With some Gram-negatives, resistance may involve most or even all the available antimicrobial options, resulting in extremely drugresistant or totally drug-resistant phenotypes. This so-called ‘antibiotic resistance crisis’ has been compounded by the lagging in antibiotic discovery and development programs occurred in recent years, and is jeopardizing the essential role played by antibiotics in current medical practices. Addresses 1 Department of Medical Biotechnologies, University of Siena, I-53100 Siena, Italy 2 Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy 3 Clinical Microbiology and Virology Unit, Florence Careggi University Hospital, I-50134 Florence, Italy Corresponding author: Rossolini, Gian Maria ([email protected], [email protected])
Current Opinion in Pharmacology 2014, 18:56–60 This review comes from a themed issue on Anti-infectives Edited by Jean-Denis Docquier and Maria Grazia Cusi
http://dx.doi.org/10.1016/j.coph.2014.09.006 1471-4892/# 2014 Elsevier Ltd. All right reserved.
The increasing challenge of antibiotic resistance and the antibiotic resistance ‘crisis’ Antibiotics are considered among the major breakthroughs of modern medicine. They have provided an outstanding contribution to increase the life span by changing the outcome of several community-acquired and health care-associated bacterial infections, and they play a pivotal role in the success of some advanced medical practices (e.g. surgery of ‘contaminated’ districts, implantation of medical devices, stem cell and solid organ transplantation, anti-cancer chemotherapy). Moreover, in low-resource settings where sanitation is still poor, Current Opinion in Pharmacology 2014, 18:56–60
antibiotics provide a major contribution to decrease the morbidity and mortality burden by food-borne and other poverty-related infections [1]. Unfortunately, unlike most other drugs, antibiotics tend to lose their efficacy over time due to the emergence and dissemination of antibiotic resistance among bacterial pathogens. Thus far, no antibiotic class has escaped this relentless phenomenon, although the time elapsed between introduction of the antibiotic in clinical practice and the emergence of resistance has been variable, as variable can be the dynamics of resistance dissemination. The accretion of resistance traits to multiple classes of antibiotics, resulting in strains with multidrug-resistance (MDR) phenotypes, has progressively narrowed the available treatment options for some pathogens. Although resistance can be associated with decreased fitness/virulence, some MDR strains retain a remarkable ability at cross-infection and spreading in the clinical setting and can experience a rapid epidemic diffusion (the so-called highrisk MDR clones) [2,3]. With some Gram-negative pathogens resistance may involve most or even all the available antimicrobial agents, resulting in extremely drug-resistant (XDR) or totally drug-resistant (TDR) phenotypes, which recreate situations typical of the pre-antibiotic era [4]. This so-called ‘antibiotic resistance crisis’ has been compounded by the lagging in antibiotic discovery and development programs in recent years, and has recently drawn the attention of Scientific Societies, Public Health Agencies and Political Bodies [1,5,6] (TATFAR Progress Report; URL: http://www.cdc.gov/drugresistance/ tatfar/report.html). The scope of this article is to provide an update on the most recent developments in the antibiotic resistance crisis.
Antibiotic resistance in Gram-positive pathogens: a crisis but still under control Among Gram-positive pathogens, Staphylococcus aureus and Enterococcus spp. are the species which currently pose the major challenges in terms of antibiotic resistance. Methicillin-resistant S. aureus (MRSA), emerged since five decades, has been the first major player in the antibiotic resistance crisis, exhibiting a global diffusion and a significant impact on clinical outcomes versus methicillin-susceptible S. aureus [1,7,8]. The MRSA www.sciencedirect.com
Antibiotic resistance crisis Rossolini et al. 57
phenotype is due to the expression of modified penicillinbinding proteins (PBPs), encoded by the horizontally acquired mec genes, that take over the functions of the resident staphylococcal PBPs and are not inhibited by conventional b-lactams. MRSA rates are quite high in several countries in Europe, the Americas and the AsiaPacific region, where MRSA remains an important cause of human infections [9,10,11]. In some countries, however, aggressive infection control campaigns have proved successful at preventing MRSA dissemination (e.g. in the Netherlands) [9] or at curbing an already established MRSA endemicity (e.g. in the United Kingdom) [9,12], demonstrating that infection control can be highly effective at limiting MRSA dissemination. On the other hand, there are still a number of drugs which retain activity against MRSA, including the glycopeptides (e.g. vancomycin and teicoplanin), linezolid, tigecycline, daptomycin and even some new b-lactams, such as ceftaroline and ceftobiprole, that are active against the modified PBPs responsible for the methicillin-resistant phenotype [13]. Although resistance to any of these drugs has been reported, the resistance rates remain overall very low [14–16], while XDR or TDR MRSA strains have not been consistently reported. MRSA, therefore, appears to be a major but still manageable problem in the ongoing antibiotic crisis. However, MRSA has shown an outstanding versatility at emerging and spreading in different epidemiological settings over time (hospital, community and, more recently, also animals), compounding the epidemiology of MRSA infections and challenging infection control systems that only target healthcare-associated infections (HAIs) [17,18]. Moreover, although resistance to the anti-MRSA agents is usually by mutation, transferable resistance to linezolid and glycopeptides has also been reported with MRSA [15,19] and is a matter of major concern. Altogether, this scenario suggests that a strong focus on MRSA should be retained by the Medical Community. Vancomycin-resistant Enterococci (VRE, mostly contributed by Enterococcus faecium and less frequently by Enterococcus faecalis) have an overall lower epidemiological impact than MRSA. VRE are mostly restricted to healthcare settings, and their prevalence remains relatively low worldwide with the exception of United States and some European countries [20]. However, VRE retain a major role in some clinical settings, such as the hematology– oncology patients [21,22] and only few antimicrobial options are available for these MDR pathogens. These include linezolid and quinupristin–dalfopristin, while the role of daptomycin and tigecycline remains uncertain. Moreover, with the exception of daptomycin, those drugs are not cidal against VRE [23,24], and transferable linezolid resistance has been reported also in enterococcal isolates from humans [23]. Therefore, VRE remains a major player in the ongoing antibiotic resistance crisis, www.sciencedirect.com
and there is a remarkable interest for upcoming drugs that exhibit bactericidal activity against VRE, such as oritavancin [24].
Antibiotic resistance in Gram-negative pathogens: a crisis going out of control With Gram-negative pathogens the antibiotic crisis is currently more serious than with the Gram-positives. In fact, the occurrence of XDR and even TDR phenotypes has been consistently reported among Gram-negative pathogens associated with HAIs, such as Pseudomonas aeruginosa, Acinetobacter spp. and Enterobacteriaceae (mostly Klebsiella pneumoniae) [4,25,26]. On the other hand, MDR Gram-negatives are increasingly prevalent also in the community, including Escherichia coli producing extended-spectrum beta-lactamases (ESBLs) [27,28], and Neisseria gonorrhoeae resistant to fluoroquinolones, tetracycline, penicillin and azithromycin or expanded-spectrum cephalosporins [29]. P. aeruginosa has likely been the first pathogen to exhibit MDR and XDR phenotypes, with the emergence of strains resistant to all classes of anti-pseudomonal agents except polymyxins (also called Colistin-Only Susceptible—COS—strains). MDR and XDR strains of P. aeruginosa are found as representatives of high-risk clones belonging in international clonal lineages, such as ST235, ST175 and ST111 [3]. These strains have acquired several resistance determinants by mutation, such as those upregulating Mex efflux systems or the resident AmpC blactamase, or affecting the quinolone resistance determining regions of topoisomerases, and/or by horizontal acquisition of resistance genes such as those encoding aminoglycoside-modifying enzymes, ESBLs or carbapenemases. Among acquired carbapenemases, the metallob-lactamases (MBLs) are those most frequently encountered in P. aeruginosa, and are of particular concern since they exhibit a very broad substrate specificity and are not inhibited either by the conventional b-lactamase inhibitors (clavulanate, sulbactam and tazobactam) or by avibactam and related compounds [30]. Resistance to polymyxins has also been reported in P. aeruginosa, by mutations causing modification of the lipid A polymyxin target [31,32] but thus far has remained rare and has only been reported on a sporadic basis. Acinetobacter spp. (mostly Acinetobacter baumannii) has become one of the major players in the ongoing antibiotic resistance crisis. The challenge in this case is due to carbapenem-resistant Acinetobacter (CRA) strains, which are usually resistant to all the available anti-Acinetobacter agents except polymyxins [33], and are currently an important cause of HAIs in several countries, especially in Europe, Latin America and the Far East [34]. Resistance to polymyxins has also been reported in Acinetobacter, by mutations that either cause a modification of the lipid A polymyxin target by addition of phosphoethanolamine Current Opinion in Pharmacology 2014, 18:56–60
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to Lipid A or impair the synthesis of the bacterial lipopolysaccharide (LPS) [35]. However, these mutations are associated with a fitness cost and impaired virulence [36], which would explain the reason why resistance to polymyxins among CRA has remained overall uncommon [35]. Apart from polymyxins, only tigecycline retains a notable in vitro activity against CRA, although its role for treatment of severe Acinetobacter infections remains uncertain [37] Therefore, new agents with anti-CRA activity are urgently needed.
including the KPC and OXA-48 serine carbapenemases (of molecular class A and D, respectively) and the MBLs of the VIM and NDM types [40], which are structurally and mechanistically different among each other. This diversity affects the possibility of finding b-lactamase inhibitors that are active against all types of CRE. In fact, the new b-lactamase inhibitors that are currently in clinical development (e.g. avibactam, MK-7655 and RPX7009) are active only against some of the carbapenemases produced by CRE [46].
Carbapenem-resistant Enterobacteriaceae (CRE, mostly contributed by K. pneumoniae) represent the most recent and worrisome evolution of the antibiotic resistance crisis. The enterics have evolved at least two mechanisms of carbapenem resistance: reduced outer membrane permeability by porin alterations in combination with the production of an ESBL or AmpC-type b-lactamase; and production of a b-lactamase with carbapenemase activity [25]. The former mechanism is associated with a low-level carbapenem resistance and is not transferable: strains with this resistance mechanisms are detected sporadically or associated with small hospital outbreaks [38,39] On the other hand, carbapenemase production can be associated with higher-level carbapenem resistance, and is a transferable mechanism. The latter feature has allowed the dissemination of transferable carbapenemases among different clonal lineages of K. pneumoniae and E. coli, which eventually resulted in the generation of some carbapenemase-producing high-risk clones (such as K. pneumoniae of ST258 producing KPC-type carbapenemases) that are highly efficient at cross-transmission and spreading and have experienced a rapid epidemic diffusion in various epidemiological settings, resulting in conditions of high-level endemicity [40,41].
The most recent evolution of the antibiotic resistance crisis is represented by the emergence of polymyxin resistance among CRE, especially among K. pneumoniae. The first report on colistin-resistant KPC-producing K. pneumoniae of ST258 from the USA, in 2010, underscored two remarkable features: the possibility of cross-transmission of colistin-resistant strains even in the absence of colistin treatment, and the lack of a substantial impact of colistin resistance on the bacterial fitness [47], unlike what happens with Acinetobacter spp. (see above). Thereafter, colistin resistance has been repeatedly reported among KPC-producing K. pneumoniae and other CRE, with rates that in some settings have attained 20% of the isolates [48,49]. The emergence of colistin resistance in K. pneumoniae can be associated with multiple mutational mechanisms that lead to the decoration of the Lipid A colistin target with 4amino-4-deoxy-L-arabinose, which reduce its negative charge and the affinity to polymyxins [50–52] The risk of resistance selection, therefore, appears to be high, and this is the reason why the use of colistin alone is discouraged for treatment of CRE infections [42,43]. Whether colistin resistance is associated with a worse outcome of CRE infections remains to be assessed, and is the subject of ongoing studies in settings where colistin resistance is now prevalent.
CRE typically exhibit XDR phenotypes, and CRE infections are associated with high mortality rates (up to 70%) [40], making them particularly challenging from the clinical point of view. The only agents that retain activity against CRE include polymyxins, tigecycline, fosfomycin and, in some cases, gentamicin [42,43]. In retrospective surveys, combination therapy was shown to be superior to monotherapy for treatment of CRE infections [40,44], but the criteria for selection of combinations remain a matter of debate. In vitro synergy against CRE has been documented with some agents (e.g. colistin–rifampin, tigecycline–colistin, polymyxinB–doripenem, fosfomycin–meropenem) [44,45], but synergy testing is cumbersome in the diagnostic laboratory and its significance to the outcome of infections has yet to be confirmed by clinical studies. For these reasons, there is an increasing interest for synergy testing with anti-CRE agents and for assessment of their clinical correlates. Currently, there are at least four types of carbapenemases that are spreading among Enterobacteriaceae worldwide, Current Opinion in Pharmacology 2014, 18:56–60
Perspectives in managing the ongoing antibiotic resistance crisis The increasing awareness of the antibiotic resistance crisis has prompted the revamping of antibiotic discovery and development programs by the Pharma industry and the launching of initiatives by public Institutions (e.g. the ND4BB initiative, supported by the European Commission; URL: http://www.imi.europa.eu/content/nd4bb and the 10 ’20 initiative, supported by the Infectious Diseases Society of America) [53] Indeed, some new drugs with activity against MDR pathogens, including CRE, are currently found in the advanced stages (Phases 2 and 3) of the antibiotic pipeline (e.g. plazomicin, ceftazidime-avibactam and other combinations between b-lactams and new b-lactamase inhibitors, eravacycline [54]). However, the introduction of these new compounds in clinical practice is expected no sooner than 3–5 years. Waiting for these new drugs, the only options that are currently available to handle the antibiotic resistance www.sciencedirect.com
Antibiotic resistance crisis Rossolini et al. 59
crisis are represented by: strengthening behaviors aimed at reducing the dissemination of XDR pathogens (based on surveillance, infection control practices and reducing unnecessary antimicrobial pressure by antimicrobial stewardship programs); and optimization of the available antimicrobial therapy regimens by selection of the most effective dosing regimens and combinations.
Conflict of interest statement Nothing declared.
Acknowledgement The authors wish to acknowledge the financial support to the research on antibiotic resistance mechanisms in Enterobacteriaceae by a grant (EvoTAR, HEALTH-F3-2011-2011-282004) from the FP7 program of the European Commission.
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ScienceDirect Update on the antibiotic resistance crisis Gian Maria Rossolini1,2,3, Fabio Arena1, Patrizia Pecile3 and Simona Pollini1 Antibiotics tend to lose their efficacy over time due to the emergence and dissemination of resistance among bacterial pathogens. Strains with resistance to multiple antibiotic classes have emerged among major Gram-positive and Gram-negative species including Staphylococcus aureus, Enterococcus spp., Pseudomonas aeruginosa, Acinetobacter spp. Enterobacteriaceae, and Neisseria gonorrhoeae. With some Gram-negatives, resistance may involve most or even all the available antimicrobial options, resulting in extremely drugresistant or totally drug-resistant phenotypes. This so-called ‘antibiotic resistance crisis’ has been compounded by the lagging in antibiotic discovery and development programs occurred in recent years, and is jeopardizing the essential role played by antibiotics in current medical practices. Addresses 1 Department of Medical Biotechnologies, University of Siena, I-53100 Siena, Italy 2 Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy 3 Clinical Microbiology and Virology Unit, Florence Careggi University Hospital, I-50134 Florence, Italy Corresponding author: Rossolini, Gian Maria ([email protected], [email protected])
Current Opinion in Pharmacology 2014, 18:56–60 This review comes from a themed issue on Anti-infectives Edited by Jean-Denis Docquier and Maria Grazia Cusi
http://dx.doi.org/10.1016/j.coph.2014.09.006 1471-4892/# 2014 Elsevier Ltd. All right reserved.
The increasing challenge of antibiotic resistance and the antibiotic resistance ‘crisis’ Antibiotics are considered among the major breakthroughs of modern medicine. They have provided an outstanding contribution to increase the life span by changing the outcome of several community-acquired and health care-associated bacterial infections, and they play a pivotal role in the success of some advanced medical practices (e.g. surgery of ‘contaminated’ districts, implantation of medical devices, stem cell and solid organ transplantation, anti-cancer chemotherapy). Moreover, in low-resource settings where sanitation is still poor, Current Opinion in Pharmacology 2014, 18:56–60
antibiotics provide a major contribution to decrease the morbidity and mortality burden by food-borne and other poverty-related infections [1]. Unfortunately, unlike most other drugs, antibiotics tend to lose their efficacy over time due to the emergence and dissemination of antibiotic resistance among bacterial pathogens. Thus far, no antibiotic class has escaped this relentless phenomenon, although the time elapsed between introduction of the antibiotic in clinical practice and the emergence of resistance has been variable, as variable can be the dynamics of resistance dissemination. The accretion of resistance traits to multiple classes of antibiotics, resulting in strains with multidrug-resistance (MDR) phenotypes, has progressively narrowed the available treatment options for some pathogens. Although resistance can be associated with decreased fitness/virulence, some MDR strains retain a remarkable ability at cross-infection and spreading in the clinical setting and can experience a rapid epidemic diffusion (the so-called highrisk MDR clones) [2,3]. With some Gram-negative pathogens resistance may involve most or even all the available antimicrobial agents, resulting in extremely drug-resistant (XDR) or totally drug-resistant (TDR) phenotypes, which recreate situations typical of the pre-antibiotic era [4]. This so-called ‘antibiotic resistance crisis’ has been compounded by the lagging in antibiotic discovery and development programs in recent years, and has recently drawn the attention of Scientific Societies, Public Health Agencies and Political Bodies [1,5,6] (TATFAR Progress Report; URL: http://www.cdc.gov/drugresistance/ tatfar/report.html). The scope of this article is to provide an update on the most recent developments in the antibiotic resistance crisis.
Antibiotic resistance in Gram-positive pathogens: a crisis but still under control Among Gram-positive pathogens, Staphylococcus aureus and Enterococcus spp. are the species which currently pose the major challenges in terms of antibiotic resistance. Methicillin-resistant S. aureus (MRSA), emerged since five decades, has been the first major player in the antibiotic resistance crisis, exhibiting a global diffusion and a significant impact on clinical outcomes versus methicillin-susceptible S. aureus [1,7,8]. The MRSA www.sciencedirect.com
Antibiotic resistance crisis Rossolini et al. 57
phenotype is due to the expression of modified penicillinbinding proteins (PBPs), encoded by the horizontally acquired mec genes, that take over the functions of the resident staphylococcal PBPs and are not inhibited by conventional b-lactams. MRSA rates are quite high in several countries in Europe, the Americas and the AsiaPacific region, where MRSA remains an important cause of human infections [9,10,11]. In some countries, however, aggressive infection control campaigns have proved successful at preventing MRSA dissemination (e.g. in the Netherlands) [9] or at curbing an already established MRSA endemicity (e.g. in the United Kingdom) [9,12], demonstrating that infection control can be highly effective at limiting MRSA dissemination. On the other hand, there are still a number of drugs which retain activity against MRSA, including the glycopeptides (e.g. vancomycin and teicoplanin), linezolid, tigecycline, daptomycin and even some new b-lactams, such as ceftaroline and ceftobiprole, that are active against the modified PBPs responsible for the methicillin-resistant phenotype [13]. Although resistance to any of these drugs has been reported, the resistance rates remain overall very low [14–16], while XDR or TDR MRSA strains have not been consistently reported. MRSA, therefore, appears to be a major but still manageable problem in the ongoing antibiotic crisis. However, MRSA has shown an outstanding versatility at emerging and spreading in different epidemiological settings over time (hospital, community and, more recently, also animals), compounding the epidemiology of MRSA infections and challenging infection control systems that only target healthcare-associated infections (HAIs) [17,18]. Moreover, although resistance to the anti-MRSA agents is usually by mutation, transferable resistance to linezolid and glycopeptides has also been reported with MRSA [15,19] and is a matter of major concern. Altogether, this scenario suggests that a strong focus on MRSA should be retained by the Medical Community. Vancomycin-resistant Enterococci (VRE, mostly contributed by Enterococcus faecium and less frequently by Enterococcus faecalis) have an overall lower epidemiological impact than MRSA. VRE are mostly restricted to healthcare settings, and their prevalence remains relatively low worldwide with the exception of United States and some European countries [20]. However, VRE retain a major role in some clinical settings, such as the hematology– oncology patients [21,22] and only few antimicrobial options are available for these MDR pathogens. These include linezolid and quinupristin–dalfopristin, while the role of daptomycin and tigecycline remains uncertain. Moreover, with the exception of daptomycin, those drugs are not cidal against VRE [23,24], and transferable linezolid resistance has been reported also in enterococcal isolates from humans [23]. Therefore, VRE remains a major player in the ongoing antibiotic resistance crisis, www.sciencedirect.com
and there is a remarkable interest for upcoming drugs that exhibit bactericidal activity against VRE, such as oritavancin [24].
Antibiotic resistance in Gram-negative pathogens: a crisis going out of control With Gram-negative pathogens the antibiotic crisis is currently more serious than with the Gram-positives. In fact, the occurrence of XDR and even TDR phenotypes has been consistently reported among Gram-negative pathogens associated with HAIs, such as Pseudomonas aeruginosa, Acinetobacter spp. and Enterobacteriaceae (mostly Klebsiella pneumoniae) [4,25,26]. On the other hand, MDR Gram-negatives are increasingly prevalent also in the community, including Escherichia coli producing extended-spectrum beta-lactamases (ESBLs) [27,28], and Neisseria gonorrhoeae resistant to fluoroquinolones, tetracycline, penicillin and azithromycin or expanded-spectrum cephalosporins [29]. P. aeruginosa has likely been the first pathogen to exhibit MDR and XDR phenotypes, with the emergence of strains resistant to all classes of anti-pseudomonal agents except polymyxins (also called Colistin-Only Susceptible—COS—strains). MDR and XDR strains of P. aeruginosa are found as representatives of high-risk clones belonging in international clonal lineages, such as ST235, ST175 and ST111 [3]. These strains have acquired several resistance determinants by mutation, such as those upregulating Mex efflux systems or the resident AmpC blactamase, or affecting the quinolone resistance determining regions of topoisomerases, and/or by horizontal acquisition of resistance genes such as those encoding aminoglycoside-modifying enzymes, ESBLs or carbapenemases. Among acquired carbapenemases, the metallob-lactamases (MBLs) are those most frequently encountered in P. aeruginosa, and are of particular concern since they exhibit a very broad substrate specificity and are not inhibited either by the conventional b-lactamase inhibitors (clavulanate, sulbactam and tazobactam) or by avibactam and related compounds [30]. Resistance to polymyxins has also been reported in P. aeruginosa, by mutations causing modification of the lipid A polymyxin target [31,32] but thus far has remained rare and has only been reported on a sporadic basis. Acinetobacter spp. (mostly Acinetobacter baumannii) has become one of the major players in the ongoing antibiotic resistance crisis. The challenge in this case is due to carbapenem-resistant Acinetobacter (CRA) strains, which are usually resistant to all the available anti-Acinetobacter agents except polymyxins [33], and are currently an important cause of HAIs in several countries, especially in Europe, Latin America and the Far East [34]. Resistance to polymyxins has also been reported in Acinetobacter, by mutations that either cause a modification of the lipid A polymyxin target by addition of phosphoethanolamine Current Opinion in Pharmacology 2014, 18:56–60
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to Lipid A or impair the synthesis of the bacterial lipopolysaccharide (LPS) [35]. However, these mutations are associated with a fitness cost and impaired virulence [36], which would explain the reason why resistance to polymyxins among CRA has remained overall uncommon [35]. Apart from polymyxins, only tigecycline retains a notable in vitro activity against CRA, although its role for treatment of severe Acinetobacter infections remains uncertain [37] Therefore, new agents with anti-CRA activity are urgently needed.
including the KPC and OXA-48 serine carbapenemases (of molecular class A and D, respectively) and the MBLs of the VIM and NDM types [40], which are structurally and mechanistically different among each other. This diversity affects the possibility of finding b-lactamase inhibitors that are active against all types of CRE. In fact, the new b-lactamase inhibitors that are currently in clinical development (e.g. avibactam, MK-7655 and RPX7009) are active only against some of the carbapenemases produced by CRE [46].
Carbapenem-resistant Enterobacteriaceae (CRE, mostly contributed by K. pneumoniae) represent the most recent and worrisome evolution of the antibiotic resistance crisis. The enterics have evolved at least two mechanisms of carbapenem resistance: reduced outer membrane permeability by porin alterations in combination with the production of an ESBL or AmpC-type b-lactamase; and production of a b-lactamase with carbapenemase activity [25]. The former mechanism is associated with a low-level carbapenem resistance and is not transferable: strains with this resistance mechanisms are detected sporadically or associated with small hospital outbreaks [38,39] On the other hand, carbapenemase production can be associated with higher-level carbapenem resistance, and is a transferable mechanism. The latter feature has allowed the dissemination of transferable carbapenemases among different clonal lineages of K. pneumoniae and E. coli, which eventually resulted in the generation of some carbapenemase-producing high-risk clones (such as K. pneumoniae of ST258 producing KPC-type carbapenemases) that are highly efficient at cross-transmission and spreading and have experienced a rapid epidemic diffusion in various epidemiological settings, resulting in conditions of high-level endemicity [40,41].
The most recent evolution of the antibiotic resistance crisis is represented by the emergence of polymyxin resistance among CRE, especially among K. pneumoniae. The first report on colistin-resistant KPC-producing K. pneumoniae of ST258 from the USA, in 2010, underscored two remarkable features: the possibility of cross-transmission of colistin-resistant strains even in the absence of colistin treatment, and the lack of a substantial impact of colistin resistance on the bacterial fitness [47], unlike what happens with Acinetobacter spp. (see above). Thereafter, colistin resistance has been repeatedly reported among KPC-producing K. pneumoniae and other CRE, with rates that in some settings have attained 20% of the isolates [48,49]. The emergence of colistin resistance in K. pneumoniae can be associated with multiple mutational mechanisms that lead to the decoration of the Lipid A colistin target with 4amino-4-deoxy-L-arabinose, which reduce its negative charge and the affinity to polymyxins [50–52] The risk of resistance selection, therefore, appears to be high, and this is the reason why the use of colistin alone is discouraged for treatment of CRE infections [42,43]. Whether colistin resistance is associated with a worse outcome of CRE infections remains to be assessed, and is the subject of ongoing studies in settings where colistin resistance is now prevalent.
CRE typically exhibit XDR phenotypes, and CRE infections are associated with high mortality rates (up to 70%) [40], making them particularly challenging from the clinical point of view. The only agents that retain activity against CRE include polymyxins, tigecycline, fosfomycin and, in some cases, gentamicin [42,43]. In retrospective surveys, combination therapy was shown to be superior to monotherapy for treatment of CRE infections [40,44], but the criteria for selection of combinations remain a matter of debate. In vitro synergy against CRE has been documented with some agents (e.g. colistin–rifampin, tigecycline–colistin, polymyxinB–doripenem, fosfomycin–meropenem) [44,45], but synergy testing is cumbersome in the diagnostic laboratory and its significance to the outcome of infections has yet to be confirmed by clinical studies. For these reasons, there is an increasing interest for synergy testing with anti-CRE agents and for assessment of their clinical correlates. Currently, there are at least four types of carbapenemases that are spreading among Enterobacteriaceae worldwide, Current Opinion in Pharmacology 2014, 18:56–60
Perspectives in managing the ongoing antibiotic resistance crisis The increasing awareness of the antibiotic resistance crisis has prompted the revamping of antibiotic discovery and development programs by the Pharma industry and the launching of initiatives by public Institutions (e.g. the ND4BB initiative, supported by the European Commission; URL: http://www.imi.europa.eu/content/nd4bb and the 10 ’20 initiative, supported by the Infectious Diseases Society of America) [53] Indeed, some new drugs with activity against MDR pathogens, including CRE, are currently found in the advanced stages (Phases 2 and 3) of the antibiotic pipeline (e.g. plazomicin, ceftazidime-avibactam and other combinations between b-lactams and new b-lactamase inhibitors, eravacycline [54]). However, the introduction of these new compounds in clinical practice is expected no sooner than 3–5 years. Waiting for these new drugs, the only options that are currently available to handle the antibiotic resistance www.sciencedirect.com
Antibiotic resistance crisis Rossolini et al. 59
crisis are represented by: strengthening behaviors aimed at reducing the dissemination of XDR pathogens (based on surveillance, infection control practices and reducing unnecessary antimicrobial pressure by antimicrobial stewardship programs); and optimization of the available antimicrobial therapy regimens by selection of the most effective dosing regimens and combinations.
Conflict of interest statement Nothing declared.
Acknowledgement The authors wish to acknowledge the financial support to the research on antibiotic resistance mechanisms in Enterobacteriaceae by a grant (EvoTAR, HEALTH-F3-2011-2011-282004) from the FP7 program of the European Commission.
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