CARBAPENEM RESISTANCE From diagnosis to outbreak management TABLE OF CONTENTS INTRODUCTION CARBAPENEM RESISTANCE p. 2 Bacterial resistance to antibiotics has become a major public health 1 issue worldwide. The reality of this threat was acknowledged in the WHO 2014 report (www.who.int/drug resistance/en) on antibiotic 2 EPIDEMIOLOGY p. 6 resistance. Rising resistance is of particular concern for Gram-negative bacilli 3 CLINICAL ASPECTS p. 11 such as Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae, the latter being the most important pathogens for mankind. Carbapenems are last resort antibiotics for treating 4 TREATMENT p. 12 infections due to these Gram-negative bacilli (31). Resistance to carbapenems in these species is related either to 5 DIAGNOSIS p. 14 combined mechanisms of resistance (overexpression of broad- spectrum ß-lactamases together with efflux pumps, impermeability) SCREENING p. 20 or expression of carbapenem-hydrolyzing ß-lactamases, known as 6 carbapenemases (31). INFECTION CONTROL AND In Enterobacteriaceae, carbapenemases represent the most important 7 PREVENTION p. 23 mechanism of resistance, since the carbapenemase genes are mostly plasmid-encoded, associated with multi- or pan-drug resistance and are highly transferable, at least within the enterobacterial species, making them potentially responsible for outbreaks (31, 36, 38). CONCLUSION p. 25 LIST OF ABBREVIATIONS p. 26 This booklet covers issues related to carbapenem-resistant Gram-negative bacilli (mostly carbapenemase producers in REFERENCES p. 27 Enterobacteriaceae), as well as their clinical relevance, detection, treatment and prevention. Prof. Patrice Nordmann Dr. Laurent Poirel Emerging Antibiotic Resistance Unit, Medical and Molecular Microbiology, We wish to thank Prof. Patrice Nordmann and Dr. Laurent Poirel for INSERM European Laboratory (French National Institute for Health and Medical Research), providing the content of this booklet and sharing their valuable knowledge and National Reference Center for Emerging Antibiotic Resistance (Switzerland), on carbapenem resistance. Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland 1 CARBAPENEM RESISTANCE The carbapenemases encountered among Enterobacteriaceae differ from ESBLs in that they hydrolyze carbapenems efficiently (36). In most cases, the protein structure of the carbapenemases differs significantly from that of ESBLs with the notable exception of several GES and OXA-48-type ß-lactamases which may have point-mutant analogues with ESBL activity (31, 36, 39). CARBAPENEM RESISTANCE 1 Currently, the spread of carbapenemase producers is the most important clinical issue in antibiotic resistance in Gram negatives, particularly in Enterobacteriaceae (49). What are the mechanisms of resistance to Carbapenemases belong to one of the three groups of ß-lactamases, carbapenems in Gram-negative bacilli? namely Ambler class A, B, and D groups (36). Differences between these carbapenemase enzymes is clinically significant, since their hydrolysis profile Carbapenem resistance in Enterobacteriaceae is related: differs (Figure 1). Their species distribution and worldwide epidemiology is • either to a combination of decreased outer-membrane permeability with also different (31, 36). overexpression of ß-lactamases possessing limited carbapenemase activity (cephalosporinase [AmpC] or clavulanic-acid inhibited extended- v Ambler class A ß-lactamases: penicillinases spectrum ß-lactamase (ESBLs, mostly CTX-M) This group includes “clavulanic-acid inhibited penicillinases”. The most • or to expression of true carbapenemases. widespread representative is KPC (Klebsiella pneumoniae carbapenemase) (6, 29), but others have been identified, such as SME, NMC, IMI, GES... (36) These Non-carbapenemase related mechanisms of carbapenem resistance are enzymes have a broad-spectrum activity similar to that of ESBLs, with an (31, 36, 38) not transferable . In addition, if the resistance mechanism involves extended activity to carbapenems. Their activity is inhibited in vitro by porin deficiency, this could significantly impact bacterial fitness, contributing clinically available ß-lactamase inhibitors such as clavulanic acid, to a decreased rate of transmission. These properties may explain why tazobactam, and avibactam, in association with ceftazidime or aztreonam. carbapenem-resistant isolates that do not produce carbapenemases are considered to be less of a threat to public health than carbapenemase v Ambler class B ß-lactamases: metallo-beta lactamases (31) producers . Non-carbapenemase related mechanisms of carbapenem The second group is that of the metallo-ß-lactamases (MBLs), including IMP, resistance are prevalent in enterobacterial species that naturally produce VIM and NDM ß-lactamases (5, 35, 54). MBLs hydrolyze all ß-lactams except (31) a cephalosporinase, such as Enterobacter sp. aztreonam. Carbapenemase related mechanisms of carbapenem resistance, on the other hand, are mostly plasmid-encoded, making them highly transferable, v Ambler class D ß-lactamases: oxacillinases at least within the enterobacterial species, and therefore potentially The third group comprises several (but not all!) oxacillinase OXA-48 responsible for outbreaks. They are also largely associated with multi- or derivatives (42, 43). They hydrolyze penicillins and 1st generation cephalosporins. pan-drug resistance (31, 36, 38). They do not significantly hydrolyze nd2 and 3rd generation cephalosporins such as cefotaxime and ceftazidime. Finally, they do hydrolyze carbapenems although at a low level. They are not inhibited by clinically-available CARBAPENEM RESISTANCE ß-lactamase inhibitors, but are inhibited by avibactam. Carbapenem Not transferable impermeability V LOW RISK of transmission between patients None of the ß-lactamase inhibitors currently available Carbapenemase Transferable through plasmid allows inhibition of the three carbapenemase V HIGH RISK of transmission between patients groups (A, B, D). 2 3 CARBAPENEM RESISTANCE CARBAPENEM RESISTANCE In Pseudomonas aeruginosa, resistance to carbapenems is mostly due to These enzymes hydrolyze carbapenems at a low level and are not inhibited by impermeability to imipenem, associated with qualitative or quantitative commercially-available ß-lactamase inhibitors (42). Most, if not all, carbapenem- changes of the porin OprD2 (28). Overexpression of the MexXY-OprM porin may resistant A. baumannii strains produce at least one carbapenemase which is lead to decreased susceptibility to meropenem. However, carbapenemases often associated with a permeability defect and/or overexpression of efflux have been also reported in P. aeruginosa. They are mostly MBLs (VIM, IMP) (5). pumps (2). In the healthcare-associated pathogen Acinetobacter baumannii, CARBAPENEM CARBAPENEMASE resistance to carbapenems is also extensively observed and is associated IMPERMEABILITY with different types of carbapenemases such as those identified in Enterobacteriaceae (NDM, IMP, VIM) (2). Several carbapenemases in Enterobacteriaceae +++ ++ the Ambler class D are specific to A. baumannii: OXA-23, OXA-40 and OXA-58 P. aeruginosa + +++ (42) derivatives (but not OXA-48 derivatives !) . A. baumannii Frequently both simultaneously Figure 1: Main resistance profiles observed in Gram-negatives n Resistance n Decreased susceptibility n Susceptible Main Antibiotic Antibiotic classes representatives Natural Penicillinase Natural Cephalosporinase Natural Penicillinase Level Low Acquired R penicillinase Inhibitor Penicillinase High Level Acquired ESBL cephalosporinase HL (AmpC) impermeability Carbapenem Enterobacteriaceae impermeability Carbapenem Pseudomonas Ambler Carbapenemases A class GES… IMI, KPC, Penicillinase: B Ambler class Carbapenemases VIM, Metallo-beta lactamases: NDM IMP, D Ambler class Carbapenemases 48 and others OXA Oxacillinase: Penicillin A Amoxicillin Aminopenicillin Ampicillin Penicillin C Carboxipenicillin Ticarcillin Penicillin U Ureidopenicillin Piperacillin B lactam + Inhibitor Amoxicillin Clav. ac Ticarcillin Clav. ac Piperacillin Tazobactam Ampicillin Sulbactam Cephalosporin I Cefazolin Cephalosporin II Cefuroxime Cephalosporin III Ceftriaxone Ceftazidime Cephalosporin III Cefixime oral Cefpodoxime Cephalosporin IV Cefepime Cefpirome Cephamycins Cefoxitin Cefotetan Carbapenems Imipenem Ertapenem Meropenem Doripenem Monobactams Aztreonam 4 5 EPIDEMIOLOGY Figure 2: Geographical distribution of KPC producers 2 EPIDEMIOLOGY What is the extent of the spread of carbapenem-resistant bacilli worldwide ? Unknown distribution of KPC producers Outbreaks due to KPC producers Sporadic spread of KPC producers Endemicity of KPC producers A Spread of carbapenem resistance by impermeability Adapted from Nordmann P, Poirel L. Clin Microbiol Infect. 2014;20(9):821-3 Carbapenem-resistant enterobacterial isolates that do not produce a carbapenemase are mostly K. pneumoniae and Enterobacter sp. They usually express decreased outer-membrane permeability associated with a In Latin America, KPC producers are endemic in some areas, such as CTX-M-type enzyme or overexpression of a cephalosporinase, respectively. Colombia and Argentina (25). In Europe, KPC producers are found almost Although epidemiological data for these carbapenem-resistant isolates is everywhere, most often linked to imports from endemic areas (29). Greece limited, the prevalence rate appears to vary quite significantly from and Italy are endemic areas in Europe. In Israel, the endemicity of KPC one country to another