Cephalosporin Resistance

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Cephalosporin Resistance in Enterobacteriaceae

Dr.T.V.Rao MD

We are living in a world of change in

Microbiology. The emergence and spread of drug resistance in

Enterobacteriaceae are complicating the treatment of serious

nosocomial infections and threatening to create species resistant to

all currently available agents. ESBLs are primarily produced by the

Enterobacteriaceae family of Gram-negative organisms, in particular

Klebsiella pneumonia and Escherichia coli; they are also produced by

nonfermentative Gram-negative organisms, such as Acinetobacterbaumannii and Pseudomonas aeruginosa. Resistance in

K.pneumoniae to third-generation cephalosporins is typically caused

by the acquisition of plasmids containing genes that encode for

extended-spectrum beta-lactamases (ESBLs), and these plasmids

often carry other resistance genes as well. ESBLs are Class A -

lactamases and may be defined as plasmid-mediated enzymes that

hydrolyse oxyimino-cephalosporins, and monobactams but not

Cephamycins or Carbapenems. In general they are inhibited in vitroby clavulanate. To understand the basics third-generation

cephalosporins are broad-spectrum drugs with high intrinsic activity

against gram-negative species. Enterobacteriaceae with extended-

spectrum -lactamases (ESBLs) are now widespread and simple

phenotypic tests are required to detect them in diagnostic

laboratories. ESBLs are bacterial enzymes that confer resistance to

many highly effective antibiotic classes that can go undetected if

conventional testing methods are used in the laboratory, ultimately

leading to treatment failure. Cephalosporin resistance among

Enterobacteriaceae is changing in nature and prevalence worldwide,

largely owing to the proliferation of CTX-M -lactamases. In the UK,

CTX-M extended-spectrum -lactamases (ESBLs) were unknown

before 2000, but are now the predominant mechanism among

cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae.

Laboratories adopted a variety of methods to screen for


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cephalosporin resistance; cefpodoxime (5 g), cefotaxime (30 g)

and ceftazidime (30 g) discs were a used. However Cefpodoxime

has been proposed as the best single screening cephalosporin to

detect those isolates warranting further investigation as plausible

ESBL producers. Isolates found resistant to either cefotaxime or

ceftazidime during disc screening mostly (>89%) had confirmed

cephalosporin resistance and a demonstrable mechanism. However,

screening based on cefotaxime and ceftazidime requires that both of

these drugs are tested, so as to reliably detect both CTX-M producers

and those with ceftazidime-type TEM variants, ESBLs are Class A -

lactamases and may be defined as plasmid-mediated enzymes that

hydrolyse oxyimino-cephalosporins, and monobactams but notCephamycins or Carbapenems. They are inhibited in vitro by

clavulanate. There are various 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 a classification of -lactamases based

upon their functional characteristics and substrate profile, a

classification which is widely used. The enzymes are divided into

three major groups: group 1 cephalosporinases which are not

inhibited by clavulanic acid, the larger group 2, broad spectrum

enzymes which are generally inhibited by clavulanic acid (except for

the 2d and 2f groups) and the group 3 metallo--lactamases. Most

ESBLs are assigned to group 2be, that is, hydrolyse penicillins,

cephalosporins, and monobactams, and inhibited by clavulanic acid

(as per the Ambler classification). It should be noted that the CTX-M

genotype was not classified in this original schemata but still fulfilsthe above criteria for group 2be enzymes.

Today Medicine is complex and advancing with

technical support, critically ill patients are especially prone to

infection, and the nature and epidemiology of causative agents can

vary tremendously. In particular, drug-resistant pathogens are of a

major concern, as they carry a higher morbidity and mortality and

are more difficult to identify by routine laboratory assays, which can


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lead to a delay in diagnosis and institution of appropriate

antimicrobial therapy. The delay in laboratory diagnosis and time to

appropriate antibiotic therapy has been strongly linked to an

increased mortality in these cases. It is also known that organisms

producing ESBLs also have the ready capacity to acquire resistance to

other antimicrobial classes such as the quinolones, tetracyclines,

Cotromoxazole, trimethoprim, and aminoglycosides, which further

limits therapeutic options.

Most developing countries do not have resources to

establish the genotypic detection but depend on the phenotypic

methods the screening tests are based on testing the organism forresistance to an indicator cephalosporin. There are a variety of

commercial tools available to do this, including double disc synergy,

combination disc method, and specific ESBLs However, if the isolate

produces an additional AmpC or metallo--lactamase (which are not

inhibited by clavulanic acid), these methods will lose their sensitivity.

In 2010 CLSI, to overcome several inherent difficulties in reporting an

effective cephalosporin to treat the patients has lowered the

susceptibility breakpoints of some cephalosporins and aztreonam for

Enterobacteriaceae and eliminated the need to perform ESBL

screening and confirmatory tests. The change was meant to simplify

the testing of ESBL and carbapenemase-producing organisms with

the intent to minimize the need for subsequent confirmatory testing.

Reference laboratories can test for genes encoding ESBLs by

molecular analysis, primarily polymerase chain reaction amplification

of specific sequences. This is usually reserved for epidemiologicalpurposes, as it identifies the particular genotype of ESBL. Newer

technologies such as the molecular techniques and modifications of

mass spectrometry (matrix-assisted light desorption ionisation time-

of-flight; MALDI-TOF) are being mooted as quicker alternatives to

conventional laboratory diagnosis. However, these technologies are

still relatively new in development and are not for use in most clinical

institutions. There is no doubt that ESBL-producing infections are of

grave concern to the medical world. They are associated with an


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increased morbidity and mortality and can be difficult and time

consuming to identify. Coupled with the fact that prevalence rates

are rising globally, including in nonhospital settings, and the dire lack

of effective antimicrobial therapy, the future is tremendously

concerning. Urgent work is required to develop quicker, cost-

effective and reliable diagnostic tools as well as new effective

therapies. To make matters simple in your laboratory for the testing

of ESBL and carbapenemase-producing organisms, make changes in

WHONET as per the current CLSI 2012 guidelines with new zones of

susceptibility and make an effective reporting. The science of

detection of Antibiotic resistance is beyond the affordability of

majority of laboratories, a little of quality work will still can benefitthe patients.

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Cephalosporin Resistance

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