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Indian Journal of Medical Microbiology, Vol. 28, No. 3, July-September, 2010, pp. 217-220 Original Article Prevalence and risk factors for colonisation with extended spectrum β-lactamase producing enterobacteriacae vis-à-vis usage of antimicrobials JB Sarma1, GU Ahmed2 1 Consultant Microbiologist and Infection Control Doctor, Northumbria Healthcare NHS Foundation Trust, Rake Lane, NE288NH, England, United Kingdom Keywords: Antibiotic consumption, ESBL producing enterobacteriacae, infection control Introduction The introduction of ceftazidime and aztreonam shortly after cefotaxime has accelerated the evolution of (ESBLs) in hospitals worldwide roughly at the same time and is now a major problem. [1] Acquired resistance to β-lactams is mainly mediated by ESBLs that confer resistance to all β-lactams except carbapenems and cephamycins, and are usually plasmid encoded which frequently carry genes encoding resistance to other drug classes. The total number of ESBLs characterised now exceeds 200 ( www.lahey.org/Studies ). There has been a recent dramatic increase of CTX-M enzymes over TEM and SHV variants. [2] CTX-M-type ESBLs exhibit powerful activity against cefotaxime and ceftriaxone but generally not against ceftazidime, however, several CTX-M variants with enhanced ceftazidimase activity have been detected. CTX-M-15, a variant of the CTX-M-3, resistant to both cefotaxime and ceftazidime, was detected in isolates from patients hospitalized in a New Delhi hospital in 2000. [3] Although ESBLs still constitute the first cause of resistance to β-lactams, alarmingly metallo-β-lactamases and Klebsiella pneumoniae Carbapenemases (KPC), and CMY enzymes conferring resistance to carbapenems and cephamycins, respectively have more recently emerged and are often associated with ESBLs. [4] This study describes the colonisation rate of ESBL producing enterobacteriacae and their antibiogram vis-à-vis usage of antimicrobials in a hospital with no or little infection control interventions which was typical of most Indian hospitals at the time of the study. Materials and Methods A point prevalence study was conducted at a teaching hospital in Assam. Three surgical, one orthopaedic and four medical units involving 182 male patients were included in a single day point prevalence study in August 2001. Baseline demographic data, diagnoses, procedures performed and antimicrobials prescribed with their duration were recorded from the patient′s medical record. Dry swabs from nose and throat, and any open wounds (not under dressing) were collected and plated on to MacConkey agar and incubated overnight. The suspect typical colonies of enterobacteriacae on the MacConkey plate were slopped in nutrient agar and shipped in triple containment packaging with labelling and marking meeting United Nation′s requirements for transportation of "Biological Substance, Category B" to the microbiology laboratory at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. No other regulatory permission was sought as the only pertinent regulation, Government of India′s Guidelines for Exchange of Human Biological Material of 19th November, 1997 for Biomedical Research Purposes which defines human material with potential for use in biomedical research, does not include infectious agents. Presumptive isolates of enterobacteriacae were identified using the LOGIC identification system (a set of conventional biochemical tests); [5],[6] a few isolates that did not give acceptable LOGIC profile were identified by API 20E® systems (Biomιrieux, Marcy l′Etoile, France). Isolates were tested against a range of antimicrobials using British Society of Antimicrobial Chemotherapy (BSAC) Standardized Disc Sensitivity Method [7] using Oxoid® (Oxoid Ltd, England) discs to generate a profile for interpretive reading. [8] Detection of extended spectrum ί-lactamases (ESBL) in E. coli and Klebsiella were carried out using (I) Double-Disc Synergy Test (DDST), (II) Etest ESBL strips (AB Biodisk, Solna, Sweden; Cambridge Diagnostic Services, Cambridge, UK) and (III) Combined disc method; results were concordant by all the three methods. [9] tection of ESBL in Enterobacter cloacae and Enterobacter aerogenes was carried out using modified DDST. [10] Inducible chromosomal Amp C ί-lactamase was detected using cefotaxime 30 μg and cefoxitin 30 μg discs applied 25 mm apart - production was inferred by the blunting of the cefotaxime zone adjacent to the cefoxitin disc. Oxoid® (Oxoid Ltd, Cambridge, CB5 8BZ, UK) discs were used for DDST and combined disc methods. Consumption of antimicrobials was calculated in Defined Daily Doses (DDD)/100 bed-days [11] using ABC Calc [12] as defined by the WHO Centre for Drug Statistics Methodology. A case was defined as a patient colonised with ESBL producing enterobacteriaceae. Equal numbers of controls (patients not colonised) matched for the duration of hospital stay were selected randomly using SPSS (version 10) from the cohort. The case-control study studied the following risk factors for acquisition of ESBL producing enterobacteriaceae (1) exposure to third generation cephalosporins, aminoglycosides and fluoroquinolones, (2) undergoing surgery and (3) the duration of hospitals stay. Age was not considered as the cohort was relatively young (mean age 34 in orthopaedic/surgery and 38 years in medicine) with no serious co-morbidities. Results Consumption of antimicrobials The overall consumption antimicrobials for systemic use were 92.6, 59.9 and 53.3 DDD/100 bed days in the surgical, orthopaedic and medical units, respectively. Consumption of cephalosporins and aminoglycosides were similar across the specialities (22-29 and 8-12 DDD/100 bed-days across the specialties) but fluoroquinolone consumption was disproportionately higher in surgery, 41 as opposed to only 7-8 DDD/100 bed-days in orthopaedic and medicine. The third generation cephalosporins, fluoroquinolone and aminoglycosides constituted the bulk of the total consumption. Colonisation of ESBL producing enterobacteriacae 65 isolates belonging E. coli (n=17), K. pneumoniae (n=30), K. oxytoca (n=2), K. ornithinolytica (n=1), C. freundii (n=1), E. aerugenes (n=1), E. cloacae (n=4), M. morganii (n=1), P. mirabilis (n=5) and P. vulgaris (n=3) were identified as ESBL producers from 40 patients. Patients colonised with ESBL producing enterobacteriacae ranged from 14% (n=10) in medicine to 41% (n=12) in orthopaedics with an intermediate 23% (n=18) in surgery. Profile of ESBL producing enterobacteriacae All these isolates were resistant to ciprofloxacin, gentamicin, tobramycin and netilmicin (P < 0.001) in addition to amoxicillin, cefuroxime, cefotaxime, ceftazidime and aztreonam. Resistance to piperacillin was 92%. A proportion (52%) of these isolates appeared sensitive amoxicillin + clavulanic acid and piperacillin + tazobactam. Resistance to others was as follows: amikacin (18%), co-trimoxazole (~50%) and chloramphenicol (~50%). All isolates were sensitive to meropenem. Profile of non-ESBL producing enterobacteriacae Non-ESBL isolates from patients with ≤ 48h and ≥ 48h of hospital-stay were analysed separately to make a distinction between community and nosocomial isolates. No resistance was detected to second and third generation cephalosporins in any non-ESBL isolates. In isolates (n=19) from patients with ≥ 48h of hospital stay, resistance was detected to multiple classes: amoxicillin (73%), co-amoxiclav (42%), cefalexin (32%), chloramphenicol (32%), co-trimoxazole (11%), trimethoprim (21%), ciprofloxacin (5%), gentamicin (5%), netilmicin (53%) and tobramycin (11%). Isolates (n=13) from patients with ≤ 48h of hospital-stay also demonstrated equally high resistance to amoxicillin (77%) but at lower level to co-amoxiclav (15%), cefalexin (17%), chloramphenicol (25%) and netilmicin (17%). No resistance was detected to trimethoprim, co-trimoxazole, ciprofloxacin, gentamicin, amikacin, and tobramycin in these community isolates. Risk factors Mantel-Haenszel odd ratio was calculated with 95% confidence interval with an associated P value for risk factors studied. Neither the duration of hospital stay (P 0.336) nor the exposure to fluoroquinolones (P 0.606) was a risk factor. However, aminoglycosides was very strongly associated with acquiring ESBL producing enterobacteriacae (P 0.007) followed by cephalosporins (P 0.025). Having a surgery during the stay was another significant risk factor (P 0.022). Discussion Although K. pneumoniae and E. coli dominated, ESBL was detected in virtually every species of Enterobacteriaceae in this study. Patients at high risk for developing colonisation or infection with ESBL-producing organisms are often seriously ill patients with prolonged hospital stays and in whom invasive medical devices are present for a prolonged duration. [13] Our study has demonstrated that young patients with no serious co-morbidities in general wads are also at risk of colonization if exposed to ′high risk′ antimicrobials. Several studies have found a relationship between third-generation cephalosporin use and acquisition of an ESBL-producing strain. [14],[15],[16],[17] Use of a variety of other antibiotic classes has been found to be associated with subsequent infections due to ESBL-producing enterobacteriaceae including fluoroquinolone [18],[19] and aminoglycosides. [14],[18] This study confirms exposure to third generation cephalosporins and aminoglycosides as strong risk factors. In contrast, the duration of hospital stay (P 0.336) was very weakly associated as risk factors in our current study. The study demonstrated that even in an environment where multi-resistant bacterial pathogens were endemic and there was no or little infection control interventions, a significant proportion of patients not exposed to high risk antimicrobials remained free from colonisation demonstrating the importance of commensals in protecting against nosocomial pathogens. Moreover, the exposure to fluoroquinolone (P 0.606) was not found to be a risk factor, which was surprising given that ESBL producing isolates was consistently resistant to ciprofloxacin. Tobramycin and netilmicin were not in use in the hospital despite observed consistent resistance suggesting the role of R-plasmids and associated linkage selection. Surgery as a risk factor is probably a marker of exposure to the ′high risk′ antimicrobial as surgical patients received prolonged course of antibiotics both as prophylaxis and therapy. In contrast, non-ESBL producing isolates, particularly, the community ones are sensitive to most including ′older′ and inexpensive antimicrobials. Four ESBL producers and one Amp C derepressed mutant (inferred using interpretive reading of resistance phenotype[20] ) were isolated from patients with ≤ 48h of hospital-stay. However, two of these ESBL producing isolates were from two patients who had been exposed to gentamicin and cefotaxime, respectively since admission, therefore, probably, hospital acquired reflecting early colonisation. The remaining two ESBL producers and one Amp C derepressed mutant could be community acquired but in absence of data about recent hospitalisation and antimicrobial exposure one could not be certain. Although isolates from nose and throat were clearly colonising flora, the same could not be said for isolates recovered from the wounds, a proportion of which probably was responsible for wound infections. However, none of the antimicrobials found in use was effective against ESBL producing enterobacteriacae; so contribution of the antibiotic therapy was in fact nil even in patients who recovered from nosocomial infection potentially caused by ESBL producing bacteria. Routine use of broad-spectrum and ′high risk′ antimicrobials such as third generation cephalosporins, fluoroquinolones and aminoglycosides in surgical patients should be avoided where ESBL is endemic. S. aureus is the main pathogen of surgical sites infections which should be treated with specific anti-staphylococcal antibiotics. This study underlines the role for of local periodic studies in defined patient cohorts for a finite period to determine the local epidemiology of resistance, associated risk factors and most cost effective antimicrobial regimen for specific infections in a setting where routine diagnostic microbiology is either not available or not cost effective. [21] References
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