What does multiresistance actually mean? Yohei Doi, MD, PhD University of Pittsburgh

What does multiresistance actually mean? Yohei Doi, MD, PhD University of Pittsburgh

Disclosures Merck Research grant

Clinical context of multiresistance Resistance to more classes of agents Less options to choose from Suboptimal clinical outcome Clinical relevance depends on: Options of active agents still available Options available locally

Historic perspective Multiple drug resistance in Enterobacteriaceae (1961) Resistance to streptomycin, chloramphenicol, tetracycline and sulfonamide Multiple resistance in Aerobacter (Enterobacter) and Klebsiella (1969) Resistance to ampicillin, streptomycin, tetracycline, (chloramphenicol, kanamycin, neomycin) Resistance to 3 agents The definition of MDR is dynamic Watanabe T and Fukasawa T. J Bacteriol 1961;82:202-9 Hinshaw V, et al. Appl Microbiol 1969;17:214-8

MDR Commonly included classes to define MDR: Aminoglycosides antipseudomonal penicillins Carbapenems Cephalosporins Colistin ampicillin/sulbactam (Acinetobacter spp.) Tetracyclines (except Pseudomonas spp.) Resistance to 2 or 3 classes would constitute MDR

PDR Pandrug resistance (PDR) Mostly used to describe Pseudomonas spp. and Acinetobacter spp. First appeared in 2002 to describe A. baumannii resistant to ampicillin-sulbactam, cephalosporins, aztreonam, carbapenems, aminoglycosides, and ciprofloxacin all of the antibiotics tested Colistin/polymyxin B and piperacillin-tazobactam not tested; tigecycline not available at the time Hsueh PR, et al. Emerg Infect Dis 2002;8:827-32

History of the terminology Pandrug resistance (PDR) Appeared in a 2005 case series to describe P. aeruginosa and K. pneumoniae resistant to antipseudomonal penicillins, cephalosporins, carbapenems, monobactams, quinolones, aminoglycosides, and polymyxins (but not tigecycline for K. pneumoniae) Colistin-only-sensitive (COS) defined as PDR except susceptibility to polymyxins. Falagas ME, et al. BMC Infect Dis 2005;5:24

PDR Pandrug resistance (PDR) Resistance to all routinely tested agents vs all available agents Polymyxins Tigecycline (special testing) Carbapenems Cephalosporins etc (routine testing) PDR vs Polymyxins Tigecycline (special testing) PDR Carbapenems Cephalosporins etc (routine testing)

PDR Consensus definition of PDR The most absolute type of antimicrobial resistance possible, implying that there are no approved antimicrobial agents that have activity against these strains. Polymyxins Tigecycline (special testing) PDR Carbapenems Cephalosporins etc (routine testing) Magiorakos AP, et al. Clin Microbiol Infect 2012;18:268-81

PDR Caveats of the consensus PDR definition Non-susceptibility to polymyxins and tigecycline are the obvious elements. To be adherent, more than polymyxins and tigecycline need to be tested. Ceftaroline and chloramphenicol for Enterobacteriaceae Fosfomycin for P. aeruginosa It is a microbiological definition, not clinical: P. aeruginosa causing ventilator-associated pneumonia and only susceptible to fosfomycin would not be PDR microbiologically, but would be PDR clinically

PDR Caveats of the consensus PDR definition Conversely, PDR K. pneumoniae bacteremia may be susceptible to and treated with gentamicin despite resistance to amikacin and tobramycin. A once PDR strain may no longer be PDR as new agents are introduced. Plazomicin-only-susceptible A. baumannii Ceftazidime-avibactam-only-susceptible K. pneumoniae Clinical relevance of a uniform definition depends on the local availability of specific agents. Polymyxins not available in Japan, China

PDR Rigorously defined PDR strains remain extremely rare. They are indeed rare The entire panel of agents are rarely tested The consensus definition will facilitate prudent use of the term.

XDR XDR (extensively drug-resistant, extremely drugresistant) Originally defined in Mycobacterium tuberculosis First defined in 2006 as non-susceptibility to cefepime, ceftazidime, imipenem, meropenem, piperacillintazobactam, ticarcillin-clavulanate, ampicillin-sulbactam, ciprofloxacin, levofloxacin, all aminoglycosides, tigecycline, polymyxins Analogous to the PDR definition today Paterson DL and Doi Y. Clin Infect Dis 2007;45:1179-81

XDR Alternative definition of XDR Resistance to all but 1 or 2 classes of antimicrobial agents available in most parts of the world and that are regarded as potentially effective against the respective pathogen Original definition (additional) Alternative definition (subtractive) MDR XDR XDR PDR Falagas ME and Karageorgopoulos DE. Clin Infect Dis 2008;46:1121-2

XDR Consensus definition of XDR Non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) Magiorakos AP, et al. Clin Microbiol Infect 2012;18:268-81

XDR Advantage of the consensus XDR definition The definition is generalizable across species (i.e., nonsusceptibility to all minus one or two relevant classes) Caveats of the consensus XDR definition The need to test rarely tested classes Ceftaroline, chloramphenicol, fosfomycin in the case of Enterobacteriaceae Impossible to define without access to the strains Polymyxin-resistant (or tigecycline-resistant) strain may not necessarily qualify as XDR An XDR strain may no longer be such when a new agent is approved

XDR The definition is starting to be adopted: Kiddee A, Henghiranyawong K, Yimsabai J, Tiloklurs M, Niumsup PR. Nosocomial spread of class 1 integron-carrying extensively drug-resistant Pseudomonas aeruginosa isolates in a Thai hospital. Int J Antimicrob Agents 2013 Mezzatesta ML, Gona F, Caio C, Adembri C, Dell'utri P, Santagati M, Stefani S. Emergence of an extensively drug-resistant ArmA- and KPC-2-producing ST101 Klebsiella pneumoniae clone in Italy. J Antimicrob Chemother 2013 Shields RK, Clancy CJ, Gillis LM, Kwak EJ, Silveira FP, Massih RC, Eschenauer GA, Potoski BA, Nguyen MH. Epidemiology, clinical characteristics and outcomes of extensively drugresistant Acinetobacter baumannii infections among solid organ transplant recipients. PLoS One 2012;7:e52349 Cabot G, Ocampo-Sosa AA, Domínguez MA, Gago JF, Juan C, Tubau F, Rodríguez C, Moyà B, Peña C, Martínez-Martínez L, Oliver A; Spanish Network for Research in Infectious Diseases (REIPI). Genetic markers of widespread extensively drug-resistant Pseudomonas aeruginosa high-risk clones. Antimicrob Agents Chemother 2012;56:6349-57

XDR But not in a fully adherent manner Most studies use non-susceptibility to all agents tested (not recommended) except for a polymyxin and tigecycline, which may overcall XDR Susceptibility to the untested agents is a possibility but unlikely/less relevant Probably a reasonable and practical approach for the time being Some studies continue to use resistance to all agents routinely tested without testing a polymyxin and tigecycline

Summary The definition of multiresistance (MDR) is now mostly consistent Resistance to 3 classes of agents which should otherwise be active to the species of interest The hierarchy has also been established MDR < XDR < PDR The definitions of XDR and PDR are well thought out in principle, but often require tweaks in real-life application, especially for epidemiological studies