A. Hamouda

Edwards

J. Findlay

Kahan

S. G. B. Amyes

Hamouda, A

Findlay, J

Amyes, S G B

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Carbapenems do they have a future?

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Journal of Medical Microbiology

Carbapenems: do they have a future?

Hamouda, A.

Findlay, J.

Amyes, S. G. B.

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      Carbapenems: do they have a future?Citation for published version:Hamouda, A, Findlay, J & Amyes, SGB 2011, 'Carbapenems: do they have a future?' Journal of MedicalMicrobiology, vol 60, no. 9, pp. 1229-1230. DOI: 10.1099/jmm.0.031013-0Digital Object Identifier (DOI):10.1099/jmm.0.031013-0Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:Journal of Medical MicrobiologyGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 28. Apr. 2017JMME d i t o r i a lCarbapenems: do they have a future?The pivotal role of glycopeptides in thecontrol of meticillin-resistant Staphyl-ococcus aureus is well known and thenotoriety of this organism has ensuredthat new antibacterial treatments havebeen developed. Far less publicized is thecrisis in the treatment of Gram-negativeinfections, especially those that are hos-pital-acquired. In many cases, particularlybecause of the emergence and spread ofextended-spectrum b-lactamases (ESBLs)in the Enterobacteriaceae and the increasedisolation of non-fermenting bacteria, suchas Pseudomonas aeruginosa and Acineto-bacter baumannii, the remaining standardtreatment option has been a group ofpenem antibiotics with a carbon atom inthe side ring rather than the traditionalsulphur. These are the carbapenems.In the UK, there are three main carbape-nems, imipenem, meropenem and ertape-nem, and a new addition, doripenem.Imipenem is a broad-spectrum antibiotic,derived from a compound isolated fromthe soil bacterium Streptomyces cattleya(Kahan et al., 1983), which has to be co-administered with cilastatin to prevent itsdegradation by the kidney. Mero-penem is also a broad-spectrum b-lactam,and has a therapeutic advantage overimipenem because it can be used to treatcentral nervous system infections. Theaddition of a methyl group in the 1-positionof the carbapenem moiety in meropenemmakes it structurally different from imipe-nem (Wiseman et al., 1995) and thismodification enhances the in vivo stabilityof meropenem, compared to imipenem, andit does not need to be co-administered withcilastin (Edwards, 1995). Both compoundsare used as empiric therapy for a widerange of severe Gram-negative infections.Ertapenem has a more limited spectrum andhas largely been recommended for thetreatment of community-acquired infections,especially those caused by bacteria carryingan ESBL. It can partially inhibit non-fermenting bacteria and thus would selectthose strains that have a pre-disposition tocarbapenem resistance (Amyes et al., 2007).This reason questions its use in the treatmentof hospital-acquired infections as it maypreferentially select non-fermenting bacteria.Doripenem has a profile similar to thatof imipenem and meropenem and doesnot overcome the majority of currentlyprevalent mechanisms of resistance to thecarbapenems.Mechanism of resistanceUnfortunately, resistance has emerged inmany bacteria treated with carbapenems.The most common mechanisms of resist-ance are the acquisition of carbapenem-hydrolysing b-lactamases of Ambler classD enzymes (oxacillinases) (CDO) (Poirel& Nordmann, 2002), b-lactamases belong-ing to class B (metallo-enzymes) (MBLs)(Walsh et al., 2005) and a few class Ab-lactamases such as the KPC enzymes inKlebsiella species. Often these b-lactamasesdo not act alone and are often accompan-ied by mutations in genes encodingpenicillin-binding proteins and alterationin outer-membrane permeability; forexample, the loss of porins CarO andOmp33–36 in A. baumannii (Gehrleinet al., 1991).In A. baumannii, the spread of carbapenemresistance largely results from the clonaldissemination of a resistant strain where acrucial combination of a mobile carbape-nem resistance gene (often encoding theclass D b-lactamases OXA-23 or OXA-58)has entered a congenial host (Brown &Amyes, 2006). The spread of these resistantbacteria is due as much to cross-infection asto antibiotic usage. These genes havemigrated to the congenial host because theyare closely linked to insertion sequences,which have promoted their mobility(Turton et al., 2006; Poirel & Nordmann,2006). A further complication is that allA. baumannii possess an inherent class Db-lactamase, collectively known as OXA-51-like, which can provide weak hydrolyticactivity on the carbapenems, thoughcurrently only rarely produces clinicalresistance.There are five groups of acquired MBLs(IMP-like, VIM-like, SIM-1, SPM-1 andGIM-1 enzymes). These have largely beenfound in non-fermenting bacteria; forinstance the first three have been identifiedin A. baumannii (Peleg et al., 2008). Theyare less common in other Gram-negativebacteria. Recent concern has focussed onthe emergence of resistance in theEnterobacteriaceae, particularly with theemergence of the NDM-1 b-lactamase inKlebsiella species. Coupled with the emer-gence of the KPC class A serineb-lactamases, this augurs badly for thecarbapenems (Kumarasamy et al., 2010).Unlike A. baumannii, the development andspread of resistance in Klebsiella species isless well defined and currently much rarer;the emergence of the mobile b-lactamasegenes is still in its infancy and the crucialcombination of this gene in a suitable hostdoes not yet appear to have occurred. Thusthe mobile genes are still migrating andthis would be aided by imprudent therapy.The importation of carbapenem-hydrolysingb-lactamases is not the only threat inKlebsiella species. ESBL-producing Kleb-siella pneumoniae strains are now verycommon and the carbapenems are oftenthe preferred course for treatment; inparticular, ertapenem, a once daily par-enteral 1-b-methyl carbapenem antibiotic,licensed in 2002 for the treatment of intra-abdominal and gynaecological infec-tions and community-acquired pneumonia(Livermore et al., 2003). It is considereda first-line antibiotic for complicatedcommunity-acquired infections and, as such,is often prescribed for the treatment ofESBL-producing coliform infections(Livermore et al., 2003). It has beenshown that the use of ertapenem inK. pneumoniae can select for the loss of themajor outer-membrane protein OmpK36,resulting in reduced accumulation of erta-penem in the bacterial cell and subsequentlyreduced susceptibility (Girlich et al., 2009).Studies in K. pneumoniae have shown thatthe loss of OmpK36 and the presence ofnon-carbapenemase b-lactamases, such asDOI 10.1099/jmm.0.031013-0 G 2011 SGM Printed in Great Britain 1229the ESBL CTX-M-15, are sufficient to exertresistance to ertapenem whilst causing aconcomitant reduction in susceptibility tomeropenem and imipenem (Doumith et al.,2009; Jacoby et al., 2004). The potential forcross-resistance is particularly worryingbecause if ertapenem is administered to apatient prior to other carbapenem treatmentfor a recurring infection, porin-deficientmutants may be inadvertently selected for,resulting in reduced susceptibility to theother carbapenems, which potentially canresult in therapy failure.Carbapenems, especially the broad-spec-trum variants, are an extremely importantpart of our ability to control severe Gram-negative infections, particularly thosecaused by multidrug-resistant bacteria.However, resistance is emerging in the formof new b-lactamases able to migrate toclinically important strains and confer highlevels of clinical resistance, a situationsimilar to that seen with the ESBLs twodecades ago. The situation is morecomplicated; some species of bacteria(A. baumannii, K. pneumoniae, etc.) alreadypossess b-lactamases that can, under certainconditions particularly with the assistanceof reduced permeability, reduce the sus-ceptibility of the bacterium to all carbape-nems. The alternative to carbapenemtherapy is the re-emergence of the poly-myxins, such as colistin methanesulphate,which are considered a last resort salvagetherapy (Li et al., 2006). The ESBLs causedthe decline of the cephalosporins; there arenow sufficient b-lactamases to do the sameto the carbapenems. Prudent therapy withcarbapenems should prolong their efficacyand this should not be compromised byempiric therapy with less-active drugs. Thealternative would be an increased relianceon colistin and that would appear a poorsubstitute if we allow the carbapenems tojoin the large group of excellent antibioticsthat we once had to treat severe Gram-negative infections.A. Hamouda, J. Findlayand S. G. B. AmyesCentre for Infectious Diseases, Universityof Edinburgh, Chancellor’s Building, 49Little France Crescent, Edinburgh EH164SB, UKCorrespondence: S. G. B. Amyes(s.g.b.amyes@ed.ac.uk)Amyes, S. G. B., Walsh, F. M. & Bradley, J. S.(2007). Best in class: a good principle forantibiotic usage to limit resistance development?J Antimicrob Chemother 59, 825–826.Brown, S. & Amyes, S. G. B. (2006).OXA (b)-lactamases in Acinetobacter:the story so far. J Antimicrob Chemother57, 1–3.Doumith, M., Ellington, M. J., Livermore, D. M. &Woodford, N. (2009). Molecular mechanismsdisrupting porin expression in ertapenem-resistant Klebsiella and Enterobacter spp. clinicalisolates from the UK. J Antimicrob Chemother63, 659–667.Edwards, J. R. (1995). Meropenem: amicrobiological overview. J AntimicrobChemother 36 (Suppl. A), 1–17.Gehrlein, M., Leying, H., Cullmann, W., Wendt, S.& Opferkuch, W. (1991). Imipenem resistance inAcinetobacter baumanii is due to alteredpenicillin-binding proteins. Chemotherapy 37,405–412.Girlich, D., Poirel, L. & Nordmann, P. (2009).CTX-M expression and selection ofertapenem resistance in Klebsiellapneumoniae and Escherichia coli. AntimicrobAgents Chemother 53, 832–834.Jacoby, G. A., Mills, D. M. & Chow, N. (2004).Role of b-lactamases and porins in resistance toertapenem and other b-lactams in Klebsiellapneumoniae. Antimicrob Agents Chemother 48,3203–3206.Kahan, F. M., Kropp, H., Sundelof, J. G. &Birnbaum, J. (1983). Thienamycin: developmentof imipenen-cilastatin. J Antimicrob Chemother12 (Suppl. D), 1–35.Kumarasamy, K. K., Toleman, M. A., Walsh,T. R., Bagaria, J., Butt, F., Balakrishnan, R.,Chaudhary, U., Doumith, M., Giske, C. G. &other authors (2010). Emergence of a newantibiotic resistance mechanism in India,Pakistan, and the UK: a molecular, biological,and epidemiological study. Lancet Infect Dis 10,597–602.Li, J., Nation, R. L., Turnidge, J. D., Milne, R. W.,Coulthard, K., Rayner, C. R. & Paterson, D. L.(2006). Colistin: the re-emerging antibiotic formultidrug-resistant Gram-negative bacterialinfections. Lancet Infect Dis 6, 589–601.Livermore, D. M., Sefton, A. M. & Scott, G. M.(2003). Properties and potential of ertapenem.J Antimicrob Chemother 52, 331–344.Peleg, A. Y., Seifert, H. & Paterson, D. L. (2008).Acinetobacter baumannii: emergence of asuccessful pathogen. Clin Microbiol Rev 21,538–582.Poirel, L. & Nordmann, P. (2002). Acquiredcarbapenem-hydrolyzing b-lactamases and theirgenetic support. Curr Pharm Biotechnol 3,117–127.Poirel, L. & Nordmann, P. (2006). Geneticstructures at the origin of acquisition andexpression of the carbapenem-hydrolyzingoxacillinase gene blaOXA-58 in Acinetobacterbaumannii. Antimicrob Agents Chemother 50,1442–1448.Turton, J. F., Ward, M. E., Woodford, N.,Kaufmann, M. E., Pike, R., Livermore, D. M. &Pitt, T. L. (2006). The role of ISAba1 inexpression of OXA carbapenemase genes inAcinetobacter baumannii. FEMS Microbiol Lett258, 72–77.Walsh, T. R., Toleman, M. A., Poirel, L. &Nordmann, P. (2005). Metallo-b-lactamases: thequiet before the storm? Clin Microbiol Rev 18,306–325.Wiseman, L. R., Wagstaff, A. J., Brogden, R. N. &Bryson, H. M. (1995).Meropenem. A review of itsantibacterial activity, pharmacokinetic propertiesand clinical efficacy. Drugs 50, 73–101.Editorial1230 Journal of Medical Microbiology 60

Carbapenems: do they have a future?

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