Original ArticleTherapeutic challenges of ESBLS and AmpC beta-lactamase producers in a tertiary care center
Introduction
The rapid emergence of antibiotic resistance among the hospital pathogens is a serious threat to the management of infectious diseases. β-lactam antibiotics are the most frequently used antimicrobials for empirical therapy. Production of β-lactamases is one of the strategies adopted by bacteria to develop resistance to β-Lactam class of antibiotics. The first plasmid mediated β-lactamase: TEM-1 (Temoniera-1) was reported in 1965 from an Escherichia coli isolated from a patient in Greece. Since then the TEM-1 β-lactamase has spread worldwide in different species of bacteria. Another plasmid mediated β-lactamase found in Klebsiella pneumoniae and E. coli is SHV-1 (sulfhydryl “variable”).1 The introduction of the third generation cephalosporins into clinical practice in the early 1980s was considered as a major breakthrough to fight against such β-lactamases producers. Soon after that, the first report of plasmid encoded β-lactamase capable of hydrolyzing the extended spectrum cephalosporins was published in 1983 from Germany.2 These new β-lactamases termed Extended spectrum beta lactamases (ESBLs), commonly involved in nosocomial infections, are derived from mutation in older beta-lactamases like (TEM-1, TEM-2 and SHV-1). ESBLs are enzymes that mediate resistance to extended spectrum cephalosporins (third generation cephalosporin, 3GCs) and monobactams (aztreonam) but do not affect cefamycins (cefoxitin, cefotetan, cefmetazole, flomoxef) or carbapenems (imipenem, meropenem, ertapenem, doripenem etc). They are inhibited by β-Lactamase inhibitor combinations (BLIs) such as clavulanic acid, sulbactam and tazobactam. Therefore, any strain resistant to 3GC but sensitive to β-Lactam/β-lactam inhibitor combination (BL/BLI) is likely to contain ESBL. ESBLs are encoded by transferable conjugative plasmids, which are responsible for the dissemination of resistance to other gram negative bacteria in a hospital and in the community.2 ESBLs are most commonly produced by Klebsiella spp. and E. coli. However, Enterobacter, Salmonella, Proteus, Citrobacter, Morganella, Serratia, Shigella, Pseudomonas and Burkholderia spp. also produce them.
AmpC beta-lactamases (AmpC βLs) first reported in 1970's3 usually confers on the bacterium, resistance to penicillins, cephalosporins, cephamycins and monobactams. The organisms develop resistance to BL/BLI combinations but are usually sensitive to the carbapenems. This lack of inhibition by cephamycins and β-lactamase inhibitors differentiates AmpC βL producers from the ESBL producers. Mechanism of drug resistance in AmpC βL can be chromosomal or plasmid mediated. Chromosomal mediated resistance is due to mutation in the nucleotide sequence at some point of the DNA of the bacteria and such genes are not easily transferable to other bacterial species. Plasmid mediated AmpC βLs have arisen by the transfer of chromosomal genes for AmpC β-lactamase onto plasmids. These genetic determinants can spread laterally and to other bacteria through lateral transfer of plasmids. Majority of AmpC βLs are chromosomally mediated (Unlike ESBLs which are Plasmid mediated) and are found in SPACE bugs (Serratia, Pseudomonas, Acinetobacter, Citrobacter and Enterobacter spp.). Plasmid mediated AmpC βLs are seen in isolates of E. coli, K. pneumoniae, Salmonella spp., Citrobacter freundii, Enterobacter aerogenes, and Proteus mirabilis.3, 4
Recently, Gram negative organisms that produce both ESBLs and AmpC βLs are being increasingly reported worldwide.5 These organisms usually exhibit multidrug resistance that is not always detected in routine antimicrobial susceptibility tests. It is necessary to know their prevalence in a hospital setting so as to enable the clinician to select appropriate antibiotic regimens at the earliest to reduce average length of stay in a hospital there by reducing health-care costs and to formulate an effective antibiotic policy. The inability to detect such complex resistance phenotypes is a serious challenge and a major determinant in the uncontrolled spread of ESBL-producing organisms and related treatment failures in a hospital setting.5
Section snippets
Materials and methods
A prospective study was conducted over a period of one year (January to December 2009) with an aim to detect the prevalence of ESBL and AmpC βL producing strains in the intensive care unit of a large tertiary care center of Armed Forces Medical Services.
Results
A total of 262 isolates of E. coli (n = 141), Klebsiella spp. (n = 114) and P. mirabilis (n = 07) were recovered from different clinical samples comprising of urine, pus, blood and body fluids. The total of potential ESBL producers showing reduced susceptibility to 3GCs was 154. Confirmatory tests for ESBL production were performed subsequently on these 154 isolates.
Out of 154 isolates, 101 isolates were found to be ESBL producers by phenotypic confirmatory tests using CLSI disc and DDST method
Discussion
This study demonstrates the prevalence of ESBL mediated drug resistance to third generation cephalosporin by Gram negative bacilli belonging to the Enterobacteriaceae family in the critically ill patients admitted in Intensive Care Unit of a tertiary hospital. ESBL and AmpC βL detection is not routinely carried out in many microbiology units of service laboratories. This could be attributed to lack of awareness or lack of resources and facilities to conduct ESBL identification.
In the present
Conclusion
In the present study, we found an alarming number of ESBL producing E. coli and K. pneumoniae strains which simultaneously produced AmpC beta lactamase. The Hospital laboratories should screen possible ESBL and AmpC producers by including 3GC, ceftazidime/clavulanic acid and cefoxitin discs along with the standard antibiotic discs as part of their protocol of testing Enterobacteriaceae. The laboratories should have the capacity to detect multiple beta lactamases that are already designated as
Intellectual contribution
Study concept: Col Naveen Grover, Brig AK Sahni
Drafting and manuscript revision: Col Naveen Grover, Brig AK Sahni
Statistical analysis: Col Naveen Grover, Brig AK Sahni
Study supervision: Col S Bhattacharya (Retd)
Conflicts of interest
All authors have none to declare.
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Available online 17 July 2012