Cephalosporin Resistance in Enterobacteriaceae
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Cephalosporin Resistance in Enterobacteriaceae

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Cephalosporin Resistance in Enterobacteriaceae

Cephalosporin Resistance in Enterobacteriaceae

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Cephalosporin Resistance in Enterobacteriaceae Cephalosporin Resistance in Enterobacteriaceae Document Transcript

  • Cephalosporin Resistance in Enterobacteriaceae Dr.T.V.Rao MDWe are living in a world of change in Microbiology. The emergenceand spread of drug resistance in Enterobacteriaceae are complicatingthe treatment of serious nosocomial infections and threatening tocreate species resistant to all currently available agents. ESBLs areprimarily produced by the Enterobacteriaceae family of Gram-negative organisms, in particular Klebsiella pneumonia andEscherichia coli; they are also produced by nonfermentative Gram-negative organisms, such as Acinetobacter baumannii andPseudomonas aeruginosa. Resistance in K.pneumoniae to third-generation cephalosporins is typically caused by the acquisition ofplasmids containing genes that encode for extended-spectrum beta-lactamases (ESBLs), and these plasmids often carry other resistancegenes as well. ESBLs are Class A β-lactamases and may be defined asplasmid-mediated enzymes that hydrolyse oxyimino-cephalosporins,and monobactams but not Cephamycins or Carbapenems. In generalthey are inhibited in vitro by clavulanate.To understand the basicsthird-generation cephalosporins are broad-spectrum drugs with highintrinsic activity against gram-negative species. Enterobacteriaceaewith extended-spectrum β-lactamases (ESBLs) are now widespreadand simple phenotypic tests are required to detect them indiagnostic laboratories. ESBLs are bacterial enzymes that conferresistance to many highly effective antibiotic classes that can goundetected if conventional testing methods are used in thelaboratory, ultimately leading to treatment failure. Cephalosporinresistance among Enterobacteriaceae is changing in nature andprevalence worldwide, largely owing to the proliferation of CTX-M β-lactamases. In the UK, CTX-M extended-spectrum β-lactamases(ESBLs) were unknown before 2000, but are now the predominantmechanism among cephalosporin-resistant Escherichia coli andKlebsiella pneumoniae. Laboratories adopted a variety of methods toscreen for cephalosporin resistance; cefpodoxime (5 μg), cefotaxime
  • (30 μg) and ceftazidime (30 μg) discs were a used. HoweverCefpodoxime has been proposed as the best single screeningcephalosporin to detect those isolates warranting furtherinvestigation as plausible ESBL producers. Isolates found resistant toeither cefotaxime or ceftazidime during disc screening mostly (>89%)had confirmed cephalosporin resistance and a demonstrablemechanism. However, screening based on cefotaxime andceftazidime requires that both of these drugs are tested, so as toreliably detect both CTX-M producers and those with ceftazidime-type TEM variants, ESBLs are Class A β-lactamases and may bedefined as plasmid-mediated enzymes that hydrolyse oxyimino-cephalosporins, and monobactams but not Cephamycins orCarbapenems. They are inhibited in vitro by clavulanate. There arevarious genotypes of ESBLs. Of these, the most common are the SHV,TEM, and CTX-M types. Other clinically important types include VEB,PER, BEL-1, BES-1, SFO-1, TLA, and IBC. In 1995, Bush et al. devised aclassification of β-lactamases based upon their functionalcharacteristics and substrate profile, a classification which is widelyused. The enzymes are divided into three major groups: group 1cephalosporinases which are not inhibited by clavulanic acid, thelarger group 2, broad spectrum enzymes which are generallyinhibited by clavulanic acid (except for the 2d and 2f groups) and thegroup 3 metallo-β-lactamases. Most ESBLs are assigned to group2be, that is, hydrolyse penicillin’s, cephalosporins, andmonobactams, and inhibited by clavulanic acid (as per the Amblerclassification). It should be noted that the CTX-M genotype was notclassified in this original schemata but still fulfils the above criteriafor group 2be enzymes. Today Medicine is complex and advancing with technical support,critically ill patients are especially prone to infection, and the natureand epidemiology of causative agents can vary tremendously. Inparticular, drug-resistant pathogens are of a major concern, as theycarry a higher morbidity and mortality and are more difficult toidentify by routine laboratory assays, which can lead to a delay in
  • diagnosis and institution of appropriate antimicrobial therapy. Thedelay in laboratory diagnosis and time to appropriate antibiotictherapy has been strongly linked to an increased mortality in thesecases. It is also known that organisms producing ESBLs also have theready capacity to acquire resistance to other antimicrobial classessuch as the quinolones, tetracycline’s, Cotromoxazole, trimethoprim,and aminoglycosides, which further limits therapeutic options. Most developing countries do not have resources toestablish the genotypic detection but depend on the phenotypicmethods the screening tests are based on testing the organism forresistance to an indicator cephalosporin. There are a variety ofcommercial tools available to do this, including double disc synergy,combination disc method, and specific ESBL’sHowever, if the isolateproduces an additional AmpC or metallo-β-lactamase (which are notinhibited by clavulanic acid), these methods will lose their sensitivity.In 2010 CLSI,to overcome several inherent difficulties in reporting aneffective cephalosporin to treat the patients has lowered thesusceptibility breakpoints of some cephalosporins and aztreonam forEnterobacteriaceae and eliminated the need to perform ESBLscreening and confirmatory tests. The change was meant to simplifythe testing of ESBL and carbapenemase-producing organisms withthe intent to minimize the need for subsequent confirmatory testing.Reference laboratories can test for genes encoding ESBLs bymolecular analysis, primarily polymerase chain reaction amplificationof specific sequences. This is usually reserved for epidemiologicalpurposes, as it identifies the particular genotype of ESBL. Newertechnologies such as the molecular techniques and modifications ofmass spectrometry (matrix-assisted light desorption ionisation time-of-flight; MALDI-TOF) are being mooted as quicker alternatives toconventional laboratory diagnosis. However, these technologies arestill relatively new in development and are not for use in most clinicalinstitutions. There is no doubt that ESBL-producing infections are ofgrave concern to the medical world. They are associated with anincreased morbidity and mortality and can be difficult and time View slide
  • consuming to identify. Coupled with the fact that prevalence ratesare rising globally, including in nonhospital settings, and the dire lackof effective antimicrobial therapy, the future is tremendouslyconcerning. Urgent work is required to develop quicker, cost-effective and reliable diagnostic tools as well as new effectivetherapies.To make matters simple in your laboratory for the testingof ESBL and carbapenemase-producing organisms, make changes inWHONET as per the current CLSI 2012 guidelines with new zones ofsusceptibility and make an effective reporting. The science ofdetection of Antibiotic resistance is beyond the affordability ofmajority of laboratories, a little of quality work will still can benefitthe patients.Emaildoctortvrao@gmail.com View slide