Nordmann, Patrice

Poirel, Laurent

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AUTHORS: PATRICE NORDMANN & LAURENT POIREL (UNIVERSITY OF FRIBOURG, SWITZERLAND)Rapid diagnostic tests for detecting emerging antibiotic resistance are mostly available and shouldbe used now.Clinically-signicant multidrug-resistant bacteria are increasingly reported within enterobacterial species(e.g., Escherichia coli, Klebsiella pneumoniae, Enterobacter spp) and also within the two nosocomial Gram-negative pathogens, namely Pseudomonas aeruginosa and Acinetobacter baumannii [1].The antibiotic resistance traits that are currently widespread in these Gram-negatives are mostly extended-spectrum ß-lactamases (ESBL) and carbapanemases producers [2, 3]. The ESBLs confer resistance to all b-lactams, with the exception of cephamycins and carbapenems, while carbapenemases confer resistance tovirtually all b-lactams including carbapenems [2, 3]. In addition, ESBL and carbapenemase-producers areoften resistant to non-related broad-spectrum antibiotics such as aminoglycosides and uoroquinolones.Among the latest emerging antibiotic resistance traits, polymyxin resistance and pandrug resistance toaminoglycosides are also of concern [4, 5].Historically, diagnosis and evaluation of antimicrobial resistance has been based on the culture ofmicroorganisms. This ‘old-fashioned’ way of testing antibiotic susceptibility has proven to be quite accurate;however, it is time consuming, especially for slow-growing organisms (from 24 hour rapid-growth bacteriato several days), and it is neither adapted to adequate antibiotic stewardship nor to epidemiologicalpurposes including the identication of the resistance mechanism(s).As an example, bloodstream infections have the highest impact in term of morbidity, mortality and healthcare costs [6]. Empirical antibiotic therapy is the rule for treating severe sepsis and a timely and adequatetreatment has been demonstrated to signicantly reduce infection-related mortality [7, 8].KWWSGRFUHURFKPublished in "Infectious Diseases Hub https://www.id-hub.com/2017/02/13/11199/, 2017"which should be cited to refer to this work.Detection and resultant control of antimicrobial resistance has therefore become a major issue in clinicalmicrobiology. In the eld of infectious diseases, we are currently witnessing a revolution in the developmentof diagnostic techniques for diseases and their resistance traits. The rapid diagnostic techniques availablefor detection of antibiotic resistance are based on molecular biology, biochemistry, physics, immunologyand rapid culture techniques. We believe use of those techniques now may contribute to an optimaltherapeutic choice of antibiotics for treating infections due to ESBL, carbapenemase producers, polymyxinsand pan aminoglycoside resistant Gram-negatives as well as controlling their spread in nosocomial settings.Use of molecular biology and in particular PCR-based techniques is nowadays the key approach for rapidand accurate identication of many etiological agents, including those considered to be dicult, or evenimpossible, to cultivate [9].The main advantages of molecular techniques are sensitivity, specicity and rapidity. Among the currentlyused molecular-based techniques there are real-time PCR protocols that may target clinically-relevantantibiotic resistance genes. Such PCR-based detection methods of antimicrobial resistance are nowcommercially available and provided by many companies. Many of them are easy to implement and do notrequire outstanding expertise.However, the main caveat of these tests is that they remain relatively expensive, making them aordableonly for certain countries, but unaordable for many others where the problem of resistance is extremelyhigh.Furthermore, it is very important to highlight that these tests cannot fully substitute the antibiogram sincethey only target some given resistance determinants and do not evaluate the real susceptibility of theisolate to a large variety of drugs. Indeed, a good correlation between the gene identication on one hand,and the resistance phenotype on the other hand, is not always observed (gene expression and modulation).In addition, the same resistance phenotype may result from several mechanisms that can be combined andtherefore is dicult to predict through molecular approaches.Moreover, as soon as a novel resistance gene emerges that is not included in the screening then antibioticsusceptibility testing based only on gene identication is obviously no longer reliable. Finally, it is worthhighlighting that molecular methods are overall ecient genetic tools for the prediction of resistance, butare conversely not adapted to the prediction of susceptibility, with is a major drawback when consideringantibiotic stewardship.New tests based on biochemistry, immunology and rapid cultures have now been developed. This is thecase with biochemical detection of carbapenemase activity (Rapid Carba NP test; bioMérieux, La Balme-Les-Grottes, France) and the detection of the ESBL activity (Rapid ESBL NP test) [10–12]. The main advantages ofthese tests are their speed (30 minutes) and low cost, in contrast to most other known techniques.In addition, a signicant advantage is that they can be used not only for bacterial cultures but also directlyfor blood and urine [13–15]. Consequently, they can now be used to optimize the stewardship ofcarbapenems considering that those molecules hydrolyzed by carbapenemases are spared by ESBLs. As anexample, in a context of increased prevalence of ESBL producers, rapidly conrming the lack of suchdeterminant in a given isolate means that broad-spectrum cephalosporins can be safely used, and that thelast-resort carbapenems can be spared.MALDI-TOF – a technology based on mass spectrometry coupled with a light analyzer – is now widely usedfor identication of microorganisms at the species level. Recent studies have shown that MALDI-TOF canalso be used for the purpose of detecting resistance to antibiotics based on the detection of enzymaticactivity, such as that of carbapenemases usually correlating with resistance to carbapenems [16]. This is aninteresting use of this technique; however, it still needs to be precisely tuned in a lab and currently requires30 minutes to 3 hours to get the results.Immunological lateral ow techniques have recently been successfully implemented to detectcarbapenemase producers (those producing enzymes such as KPC and OXA-48) from bacterial cultureswithin 15 minutes [17].KWWSGRFUHURFKRapid culture techniques have been recently developed for detection of polymyin and pan-aminoglycosideresistance in Enterobacteriaceae. The Rapid Polymyxin NP test (Rapid Polymyxin NP; ELITech Microbiology,Puteaux, France) may detect any polymyxin-resistant isolate, the corresponding resistance mechanismsbeing either chromosome- or plasmid-encoded (mcr-1, mcr-2) [18]. The Rapid Aminoglycoside NP testdetects pandrug resistance to aminoglycosides resulting from the expression of 16S rRNA methylases [19].Results of both rapid tests are obtained within 1–2 hours, either using bacterial cultures or blood culturesas samples [20].Advances in high-throughput sequencing technologies, often named next-generation sequencing, recentlyopened signicant research pathways, particularly in the eld of molecular diagnostics of antimicrobialresistance [9]. The latest development of next-generation sequencing will be (or is) high-resolutionepidemiology that will replace conventional epidemiological tools such as pulsed-eld gel electrophoresisand multi-locus sequence typing.Since very few novel antibiotic molecules will be marketed in the near future, control of antimicrobialresistance spread is primarily based on their rapid diagnosis. Actually, an early detection of the majorresistance traits as described above is absolutely crucial for controlling spread. In addition, we believe thatmany of the rapid diagnostic techniques that are available may be used as companion diagnostics (precisemedicine) to optimize the use of novel molecules such as the combinations of ß-lactams and ß-lactamaseinhibitors. Use of those novel and rapid diagnostic techniques may contribute to preventing antibioticoveruse or misuse.The revolution we are currently facing in rapid diagnostic techniques may allow us to optimize themanagement of treatments for infections caused by multidrug resistant bacteria and also contribute tocontrolling their spread. Rapid diagnostics contribute to the overall reduction of broad-spectrum antibioticuse and consequently could slow down the rise of resistant bacteria. This means we could expect to dealwith such diagnostics either in primary care and hospital setting situations.References1. Boucher HW, Talbot GH, Bradley JS et al. Bad bugs, no drugs: no ESKAPE! An update from theInfectious Diseases Society of America. Infect. Dis. 48, 1–12 (2009).2. Coque TM, Baquero F, Canton R, Increasing prevalence of ESBL-producing Enterobacteriaceae inEurope. Surveill. 13 (47) pii 19044 (2008).3. Nordmann P, Naas T, Poirel L, Global spread of carbapenemase-producing Enterobacteriaceae. Infect.Dis. 17, 1791–1798 (2011).4. Poirel L, Jayol A, Nordmann P. Polymyxins; antibacterial activity,susceptibility testing ,and plasmid-and chromosomally-encoded mechanisms of resistance. Microb. Rev. (2017) (In Press).5. Doi Y, Arakawa Y, Aminoglycoside resistance : the emergence of acquired 16S ribosomal RNAmethyltransferases: emerging resistance mechanism against aminoglycosides. Dis. Clin. NorthAm.30, 523–537 (2016).6. Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD, Inapropriate empirical antibiotictreatment in patients with bloodstream infection. Intern. Med. 244, 379–386 (1998).7. Kumar A, Ellis P, Arabi Y et al. Initiation of inappropriate antimicrobial therapy results in a vefoldreduction of survival in human septic shock. 136, 1237–1248 (2009).8. Vincent JL, Sakr Y, Sprung CL et al. Sepsis in European intensive care units: results of the SOAP study.Care Med. 34, 344–353 (2006).9. Fournier PE, Dubourg G, Raoult D, Clinical detection and characterization of bacterial pathogens inthe genomics area. Genome Med. 6:114 doi: 10.1186/s13073–014–0114–2 (2014).10. Nordmann P, Poirel L, Dortet L, Rapid detection of carbapenemase-producing Enterobacteriaceae.Infect. Dis. 18, 1503–1507 (2012).11. Poirel L, Nordmann P, Rapidec Carba NP test for rapid detection of carbapenemase producers. Clin.Microbiol. 53, 3003–3008 (2015).12. Nordmann P, Dortet L., Poirel L, Rapid detection of extended-spectrum b-lactamase-producingEnterobacteriaceae. Clin. Microbiol. 50, 3016–3022 (2012).13. Dortet L, Poirel L, Nordmann P, Rapid detection of extended-spectrum -lactamase-producingEnterobacteriaceae from urine using the ESBL NP test. Clin. Microbiol. 52, 3701–3706 (2014).14. Dortet L, Poirel L, Nordmann P, Rapid detection of ESBL-producing Enterobacteriaceae in bloodKWWSGRFUHURFKcultures. Infect. Dis. 21, 504–507 (2015).15. Dortet L, Boulanger A, Poirel L, Nordmann P. Bloodstream infections caused by Pseudomonas sp.;how to detect carbapenemase producers directly from blood ? Clin. Microbiol. 52, 1269–1273 (2014).16. Oviano M, Sparbier K, Barba MJ, Kostrzewas M., Bou G, Universal protocol of the rapid automateddetection of carbapenem-resistant Gram-negative bacilli directly from blood cultures by matrix-assisted laser desorption/ionization time-of-ight mass spectrometry (MALDI-TOF/MS). J. Antimicrob.Chemother. 48, 655–660 (2016).17. Glupczynksi Y, Evrard S, Ote I et al. Evaluation of two new commercial immunochromatographicassays for the rapid detection of OXA-48 and KPC carbapenemases from cultures bacteria. J.Antimicrob. Chemother. 71, 1217–1222 (2016).18. Nordmann P, Jayol A, Poirel L, Rapid detection of polymyxin resistance in Enterobacteriaceae. Infect.Dis. 22, 1031–1036 (2016).19. Jayol A, Dubois V, Poirel L, Nordmann P, Rapid detection of polymyxin-resistant Enterobacteriaceaefrom blood cultures. J. Clin. Microbiol. 54, 2273–2277 (2016).20. Nordmann P, Jayol A, Dobias J, Poirel L, Rapid Aminoglycoside NP test for rapid detection of multipleaminoglycoside resistance in Enterobacteriaceae. Clin. Microbiol. (2017) (In Press).Author aliationsPatrice Normann 1,2,3,4 and Laurent Poirel 1,2,31 Emerging Antibiotic Resistance Unit, Medical and Molecular Microbiology, Department of Medicine,University of Fribourg, Fribourg, Switzerland, 2 INSERM European Unit (IAME, France) University of Fribourg,Fribourg, Switzerland,3 Swiss National Reference Center for Emerging Antibiotic Resistance (NARA),University of Fribourg, Fribourg, Switzerland, and 4 Institute for Microbiology, University of Lausanne andUniversity hospital Center, Lausanne, SwitzerlandCorrespondence to: P Nordmann, patrice.nordmann@unifr.chantibiotics antimicrobial resistance resistance screeningKWWSGRFUHURFK

Rapid diagnostic tests for detecting emerging antibiotic resistance are mostly available and should be used now

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Rapid diagnostic tests for detecting emerging antibiotic resistance are mostly available and should be used now

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