|Year : 2017 | Volume
| Issue : 4 | Page : 555-562
Fecal carriage of carbapenem-resistant Enterobacteriaceae and risk factor analysis in hospitalised patients: A single centre study from India
Balvinder Mohan1, Amber Prasad2, Harsimran Kaur1, Vinaykumar Hallur3, Neha Gautam4, Neelam Taneja1
1 Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Microbiology, RIMS, Ranchi, Jharkhand, India
3 Department of Microbiology, AIIMS, Bhubhneshwar, Odisha, India
4 Department of Microbiology, Dr. YS Parmar Government Medical College, Nahan, Himachal Pradesh, India
|Date of Web Publication||1-Feb-2018|
Dr. Neelam Taneja
Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
Purpose: Carbapenem-resistant Enterobacteriaceae (CRE) have emerged and disseminated widely causing a variety of infections. In India, the carriage of CRE in hospitalised patients has not been well-studied. Therefore, we conducted the present study to observe gut carriage rate of CRE in patients admitted to our tertiary care hospital. Methods: A total of 232 faecal swabs collected from consecutive stool samples from admitted patients were inoculated on ChromID extended spectrum β-lactamase plates and members of Enterobacteriaceae family were subjected to antibiotic susceptibility as per the Clinical Laboratory Standards Institute guidelines. Polymerase chain reaction for blaVIM, blaKPC, blaIMPand blaNDM-1 genes was performed. CRE was identified if the isolates showed resistance to either imipenem or meropenem or showed the presence of resistant genes. Risk factors of patients with or without CRE colonisation were also analysed. Results: A total of 232 faecal swabs yielded 252 Enterobacteriaceae isolates, of which 49 isolates from 42 patients showed the presence of CRE (occurrence 42/232; 18.1%); 27 isolates from 22 patients carried blaNDM-1, whereas 20 isolates from 17 patients possessed blaVIMgene. No isolate was positive for blaKPCand blaIMPgenes. The CRE was common in both intensive care units (38.4%) and wards (46%) which may reflect the excessive use of broad-spectrum antibiotics in both these settings. The CRE was also found to have a significantly higher antimicrobial resistance as compared to non-CRE isolates. The logistic regression analysis of significance showed the presence of any indwelling device (P = 0.049) and nasogastric tube (P = 0.043) as independent risk factors for acquiring gut colonisation. Conclusions: The study is the first from India to show high CRE carriage in patients admitted to a tertiary care centre and emphasises the need of strict antimicrobial stewardship implementation in hospitals to prevent dissemination of multidrug-resistant CRE.
Keywords: Carbapenem-resistant Enterobacteriaceae, faecal carriage, India
|How to cite this article:|
Mohan B, Prasad A, Kaur H, Hallur V, Gautam N, Taneja N. Fecal carriage of carbapenem-resistant Enterobacteriaceae and risk factor analysis in hospitalised patients: A single centre study from India. Indian J Med Microbiol 2017;35:555-62
|How to cite this URL:|
Mohan B, Prasad A, Kaur H, Hallur V, Gautam N, Taneja N. Fecal carriage of carbapenem-resistant Enterobacteriaceae and risk factor analysis in hospitalised patients: A single centre study from India. Indian J Med Microbiol [serial online] 2017 [cited 2019 Nov 12];35:555-62. Available from: http://www.ijmm.org/text.asp?2017/35/4/555/224421
| ~ Introduction|| |
The emergence of carbapenem-resistant Enterobacteriaceae (CRE) is associated with limited therapeutic options and increased mortality in patients infected by these strains.,, These organisms also have the propensity to undergo widespread dissemination through mobile genetic elements.,,,, Enteric strains possessing these carbapenemases have shown remarkable success in the form of large-scale geographical dissemination. Such strains consist primarily of Klebsiella pneumoniae and other members of Enterobacteriaceae such as Escherichia More Details coli, Salmonella More Details spp., Shigella spp., Citrobacter spp., Proteus spp., Enterobacter spp., Providencia spp., Morganella spp. which produce the serine carbapenemases, K. pneumoniae carbapenemase (KPC) or the metallo-beta-lactamases VIM or NDM-1.,,
Gut colonisation by CRE may act as a reservoir of these pathogens for dissemination within an enclosed setting as in a hospital. Gastrointestinal carriage of CRE varies from 0.3% to 18.3% worldwide, based on single centre studies., The Centers for Disease Control and Prevention (CDC), Atlanta has recommended routine surveillance of CRE in hospitals. However, no such guidelines exist in an Indian setting. A single study is available from India where the faecal carriage of CRE has been observed in patients attending the outpatient clinic. Moreover, they have used only phenotypic tests to demonstrate the presence of carbapenemases. To the best of our knowledge, there are no studies of CRE faecal carriage using genotypic methods and those analysing risk factors leading to such colonisation in hospitalised patients in India. Therefore, considering the emerging threat of these multidrug-resistant pathogens, the present study was planned to observe the intestinal carriage rate of CRE in admitted patients in our tertiary care hospital using both phenotypic and genotypic methods and to identify the risk factors associated with CRE gut colonisation which may help in formulating policies to prevent transmission of these organisms in hospital environment.
| ~ Methods|| |
The study was carried out at the Enteric Laboratory of Department of Medical Microbiology at the Postgraduate Institute of Medical Education and Research, Chandigarh. The study was approved by the Institute Ethics Committee vide number MS/1887/Res/8108. The samples were collected prospectively and a retrospective clinical chart review was done to analyse risk factors.
Sample size calculation
The sample size was calculated by using Daniel's formula for prevalence studies. The following formula was used for sample size calculation: N = (Z2 P [1 − P])/d2 where n = sample size, Z = Z statistic for a level of confidence, P = expected prevalence or proportion (in proportion of one; if 20%, P = 0.2), and d = precision (in proportion of one; if 5%, d = 0.05). Z statistic (Z): For the level of confidence of 95%, which is conventional, Z value is 1.96. In our study, we used a prevalence of 10% (based on the prevalence of 10.9% reported by Torres-Gonzalez from Mexico), and the sample size was calculated as 139. However, we wanted to have sufficient CREs for molecular analysis so we increased to 232 samples which would have given us a minimum of 30 CREs as one stool sample was expected to have more than one CRE.
Study population and sample collection
A total of 232 faecal swabs were collected from consecutive stool samples sent routinely to our laboratory for culture and sensitivity from the same number of patients admitted in our tertiary care hospital suspected of gastrointestinal infection over a period of 10 months from August 2012 to May 2013. The clinical records of the patients were extracted to note down the demographic and risk factor details. CRE was defined as organism belonging to Enterobacteriaceae which is resistant to either imipenem (IMP) or meropenem or the isolate showed the presence of a carbapenemase by genotypic methods. Patients were divided into two groups, those with or without CRE colonisation for the evaluation of risk factors associated with CRE carriage.
Phenotypic methods of identification of carbapenem-resistant Enterobacteriaceae
Faecal swabs were inoculated on ChromID extended spectrum β-lactamase (ESBL) (bioMérieux, New Delhi, India) plates and incubated at 37°C under aerobic conditions. They were assessed after 24 and 48 h incubation for colour and intensity of the colonies as per manufacturer instructions to identify ESBL producers (E. coli, pink/burgundy; Klebsiella/Enterobacter/Serratia group, blue/green; the Proteae tribe, light to dark brown)., All the isolates on ChromID ESBL (BioMerieux) medium were identified as per standard methods, and only members of Enterobacteriaceae were included in further experiments. All E. coli isolates included in the study were negative for pathotypes of diarrhoeagenic E. coli using a multiplex polymerase chain reaction (PCR) assay established in our laboratory. For Chromagar, we used E. coli ATCC 25922 as the negative control strain and K. pneumoniae ATCC 700603 ESBL producing strain as the positive control.
Antibiotic susceptibility of these strains was performed by Kirby Bauer method as per the Clinical Laboratory Standards Institute guidelines. In case of IMP and meropenem, zone size >23 mm is considered as sensitive, 20–22 mm is intermediate and <19 mm is labelled as resistant strain. Extensive drug resistance is defined as resistance to at least one drug in all but ≤2 antimicrobial categories, i.e. isolates should be susceptible only to drugs belonging to one or two different categories.
Molecular identification of carbapenem resistant Enterobacteriaceae
PCR was performed for blaIMP (detects all IMPs except IMP-9, IMP-16, IMP-18, IMP-22 and IMP-25), blaVIM,blaKPC and blaNDM-1 for all the isolates to identify the presence of the resistance genes, using the primers described previously., Crude bacterial lysate obtained by boiling two to three colonies in 400 μl of TE buffer pH 8.0 at ~100°C for 10 min followed by centrifugation at 13,000 rpm for 5 min was used as DNA template. Total DNA (2 μl) was subjected to PCR in a 25 μl reaction mixture containing ×1 PCR buffer, 0.4 mM dNTP (Bengaluru Genei, India), 0.6 μM each of forward and reverse primer (Sigma Aldrich, India), and 1 U of Taq polymerase (Bengaluru Genei, India). Amplification was carried out as follows: initial denaturation at 94°C for 10 min; 30 cycles of 94°C for 40 s, 55°C for 40 s and 72°C for 1 min; and a final elongation step at 72°C for 7 min. The annealing temperature was 55°C for blaIMP and blaVIM and 58°C for blaNDM-1 genes. A 100 bp DNA ladder was used as a size marker. Amplicons were visualized after running at 90V for 1 h on a 2% agarose gel containing ethidium bromide in a gel documentation system (Omega LUM G, Aplegen Inc., USA). In-house blaNDM-1,blaVIM,blaKPC and blaIMP positive control strains were used for PCR assays.
Data were analysed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA). The distribution of continuous variables is presented as mean ± standard deviation. Chi-square and Fischer's exact test were used to analyse categorical variables while continuous variables were analysed using the Student's t-test. Normality of quantitative data was checked by measures of Kolmogorov–Smirnov tests of Normality. Mann–Whitney U-test was used where the data were found to be skewed (standard deviation was 50% or more of the mean value). The significant risk factors for CRE were identified on univariate analysis. To see independent predictors of CRE, binary logistic regression analysis was performed. In addition, multinomial logistic regression analysis was applied after controlling the factors which were non-significant in bivariate logistic regression analysis. All statistical tests were two-sided and performed at a significance level of α = 0.05. The analysis was conducted using IBM SPSS STATISTICS (version 22.0, New York, USA). The performance of the model (goodness of fit) was assessed using the Hosmer–Lemeshow test for its calibration.
| ~ Results|| |
A total of 271 isolates were obtained on ESBL CHROM agar from 232 faecal samples. These included a total of 252 Enterobacteriaceae isolates (205 were E. coli, 32 were K. pneumoniae, 8 were Citrobacter spp., 5 were Proteus spp. and 1 each of E. aerogenes and M. Morganii). Nineteen isolates belonged to non-Enterobacteriaceae family including Enterococci, Pseudomonas spp. and Acinetobacter spp. which were excluded from analysis. A total of 49 isolates of CRE from 42 patients were obtained (One patient had 3 carbapenem-resistant isolates, one each of E. coli, Klebsiella and Citrobacter. Five patients had carbapenem-resistant E. coli and Klebsiella) [Table 1]. The blaNDM-1 gene was present in 27 isolates and twenty isolates had blaVIM gene. Nine isolates showed the presence of both these genes [Table 1]. None of the 252 ESBL producing Enterobacteriaceae had the blaKPC or blaIMP gene. Antibiotic resistance pattern of 49 CRE is given in [Figure 1]. Of the 49 CRE isolates, 32 (65%) and 8 (16.3%) were found to be resistant and intermediately susceptible to IMP, respectively, whereas 39 (79.5%) and 4 (8.1%) isolates were resistant and intermediately susceptible to meropenem, respectively. The CRE isolates showed the significantly higher level of resistance to various antibiotics as compared to non-CRE isolates [Figure 1]. Sixteen of the strains containing blaNDM-1 were extensively drug-resistant, i.e. were resistant to at least one agent in all but two or fewer antimicrobial categories. Eleven out of 20 (55%) and 13 out of 20 (65%) of VIM producers were resistant to IMP and meropenem, respectively [Figure 2].
|Figure 1: Antimicrobial susceptibility pattern of carbapenem resistant Enterobacteriaceae (n = 49) and non-carbapenem resistant Enterobacteriaceae (n = 203) isolates|
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|Table 1: Break up of stool samples and carbapenem resistant Enterobacteriaceae isolates|
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The patient wise occurrence of CRE was 18.1% (42/232) and blaNDM-1 and blaVIM genes were found in 9.5% (22/232) and 7.3% (17/232) of cases, respectively. [Table 2] shows the ward and intensive care unit (ICU) wise distribution of CRE carriage. However, looking individually in each area, it was observed that CRE isolation was maximum in newborn ICU (4/7, 57%) and in the female medical ward (9/20, 45%). We also determined the risk factors associated with CRE colonisation and compared them with the patients without CRE colonisation [Table 3]. The median age of the patients with and without CRE colonisation was 33.50 years (interquartile range [IQR] = 15.75–45.25 years) and 37 years (16.75–50 years), respectively. Overall, male gender (65.5%) was predominant. The median duration of hospitalisation in these patients and those without CRE colonisation was 9.5 days (IQR = 7–15 days) and 9 days (IQR = 5–13 days), respectively (P = 0.034). The potential risk factors for CRE colonisation included duration of hospitalisation (P = 0.035), presence of any indwelling invasive device (P = 0.000), nasogastric tube (P = 0.000), urinary catheter (P = 0.015), ventilator (P = 0.000) administration of any one of the antibiotics (P = 0.000), cephalosporins use (P = 0.014), IMP use (P = 0.034), meropenem use (P = 0.019) and vancomycin use (P = 0.016). The use of a ventilator, although highly significant was excluded from the logistic regression analysis as all the patients with CRE colonisation were on a ventilator. The use of any invasive device and nasogastric tube were found to be independent risk factors on logistic regression analysis [Table 4] and [Table 5]. The model fitted the observed data according to the Hosmer–Lemeshow goodness-of-fit test (P = 0.022; χ2 = 14.906).
|Table 2: Unit-wise distribution of cases and their carbapenem resistant Enterobacteriaceae and blaNDM and blaVIM status|
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|Table 3: Clinical characteristics of patients included in the study and comparison of these characteristics in patients with and without carbapenem resistant Enterobacteriaceae colonization|
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|Table 4: Binary logistic regression of significant variables* by standard method|
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|Table 5: Multinomial logistic regression of significant variables* after controlling the **factors which were non-significant in bivariate logistic regression analysis|
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Symptoms of underlying illness improved in 218 (93.9%) of the patients improved and were discharged from the hospital. There were six deaths and eight patients left against medical advice. CRE was isolated from only one case out of 14 who did not improve. There was no significant difference in the outcome of patients with or without CRE colonisation (P = 0.245).
| ~ Discussion|| |
The alarming increase of CRE prevalence worldwide is worrisome. In many endemic settings of UAE and Iran, prevalence as high as 24.7%–29.8% have been noted. The faecal carriage of CRE acts as a reservoir for dissemination of these multidrug-resistant pathogens through cross-transmission. These highly drug-resistant organisms may stay for prolonged periods in the intestinal tract without causing any infections or may serve as a source of endogenous urinary tract infections, intra-abdominal infections or even translocate through the gut epithelium to cause sepsis.
Currently, there are no recommendations for routine surveillance of faecal carriage in India. A single study by Rai et al. reported faecal carriage of 9.9% in outpatients attending their hospital by performing phenotypic tests. To the best of our knowledge, this is the first study from India reporting CRE faecal carriage in hospitalised patients using both phenotypic and genotypic methods. In addition, we have also carried out risk factor analysis between CRE colonisers and non-colonisers.
The present study recorded a very high occurrence of 18.1% of CRE colonisation in hospitalised patients in contrast to the other reports available in the literature. In USA, nursing home residents it was found to be 1.4%. A multi-centric study from France by Pantel et al. reported a low faecal carriage of CRE (0.7%). Few other studies from France and Spain have also reported a lower prevalence of CRE varying from 0.3% to 1.1%, respectively. CRE faecal carriage has been reported to be 6.6% in China  and 10.9% in Mexico. Girlich et al. from Morocco and Day et al. from Pakistan have reported a higher prevalence of 11% and 18.3%, respectively., The high occurrence seen in our study may be attributed to the stay in hospital which predisposes the patients to higher exposure of antibiotics and colonisation by carbapenemase-producing bacteria. Another reason could be that our hospital is a tertiary care centre where the referred patients are already exposed to a variety of antimicrobials before admission. This high occurrence of CRE in patients with a complaint of diarrhoea increases the probability of spread of CRE within the hospital. The above-mentioned studies also detected oxacillinase type (OXA) carbapenemases which is the major limitation of our study. OXA carbapenemases are reported most commonly from Mediterranean and European countries and also from India. Not looking for OXA carbapenemases was one of the major limitation of our study. Their detection would have further increased the occurrence rate.
Out of various members of Enterobacteriacae, the presence of carbapenemases was observed mainly in E. coli and Klebsiella spp. which is in agreement with a previous study by Xu et al. where K. pneumoniae (39.3%) and E. coli (21.97%) were reported to have a high resistance to carbapenems. Overall, the resistance to IMP and meropenem in CRE in the present study was 81.6% (40/49) and 87.6% (43/49), respectively. The higher resistance to meropenem may be explained by the additional mechanisms of increased efflux pumps extruding the drug out of the cell which is absent in IMP. There are other mechanisms of carbapenem resistance like decreased porin expression or AmpC type of enzymes which we did not look into in the present study. The carriage rate of blaNDM and blaVIM genes in CRE was observed as 9.5% and 7.3%, whereas there was the absence of IMP and KPC producers. This is in contrast to a study conducted by Perry et al. from Pakistan according to which blaNDMa higher prevalence of 27.1% had in hospitalised patients while there was no producer of the blaVIM gene. The CRE was common in both ICUs and wards which may reflect the excessive use of broad-spectrum antibiotics in both these settings (10/26 [38.4%] of ICU patients and 95/206 [46%] of ward patients were receiving antibiotics).
We also analysed the risk factors which may play a role in CRE faecal carriage. The factors significantly present in CRE colonised patients included the duration of hospitalisation, any type of invasive device (nasogastric tube, ventilator and urinary catheter), any antibiotic administration (including IMP, meropenem, vancomycin and cephalosporins). The logistic regression analysis of risk factors showed the presence of any indwelling device (P = 0.049) and nasogastric tube (P = 0.043) as independent risk factors for acquiring gut colonisation.[Table 4] and [Table 5] The use of antimicrobials and invasive devices is a known risk factor for colonisation of various pathogens. The duration of hospital stay was an important observation which increases the risk of faecal carriage by CRE. Use of cephalosporins and fluoroquinolones as a risk factor for infections by CRE has been noticed in earlier studies.,, However, Zhao et al. did not find any such relation. However, they found vancomycin use to be a risk factor which was being administered to seriously ill cases along with other broad-spectrum antibiotics. Earlier studies have also shown its use as a potential risk factor for drug-resistant bacteria., However, the exact association still needs to be investigated. Invasive devices may act as a portal of entry for MDR pathogens which also need to be studied further. A case-control study by Marchaim et al. emphasised the significant role of antimicrobial exposure in the prediction of CRE colonisation which is known to predispose the patient to nosocomial infection. The study is not a case-control study. The variations in risk factors in different studies need to be investigated in a large scale case-control studies involving patients from outpatient department, wards and ICUs.
| ~ Conclusion|| |
The present study is the first from India to show a high occurrence of 18.1% of CRE colonisation in hospitalised patients. Widespread use of antimicrobials, use of invasive devices and prolonged hospital stay are significant factors contributing to the faecal carriage of CRE which acts as a reservoir for dissemination within a hospital. The study highlights the widespread use of broad-spectrum antibiotics and strengthens the importance of antimicrobial stewardship in hospital settings to prevent CRE colonisation. More surveillance studies in India are required for CRE as an important component of infection control programme.
Financial support and sponsorship
The work was funded by PGIMER, Chandigarh.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]