|ORIGINAL CONTRIBUTION - CLINICS IN CLINICAL MICROBIOLOGY
|Year : 2018 | Volume
| Issue : 4 | Page : 210-216
Antibiotic susceptibility pattern of multidrug-resistant Enterobacteriaceae in urinary isolates and detection of suspected carbapenemase production
Prasanna L Kakarla, Anil K Bilolikar, Cheruvu V Sarma
Department of Microbiology, Krishna Institute of Medical Sciences Ltd, Secunderabad, Telangana, India
|Date of Web Publication||29-Oct-2018|
Prasanna L Kakarla
Department of Microbiology, Krishna Institute of Medical Sciences Ltd, Secunderabad, Telangana
Source of Support: None, Conflict of Interest: None
Context: Urinary tract infection (UTI) is one of the most common bacterial infections. Multidrug-resistant (MDR) Enterobacteriaceae producing carbapenemases pose a challenge for treatment. The modified Hodge test (MHT) detects carbapenemase production in isolates of Enterobacteriaceae. It is simple, accessible, inexpensive, and recommended by Clinical and Laboratory Standards Institute (CLSI). Aims: (1) To study the antibiotic susceptibility pattern of MDR urinary isolates of Enterobacteriaceae. (2) To determine percentage of carbapenem resistance due to carbapenemase production by using MHT. Settings and Design: Prospective laboratory-based observational cross-sectional study in a tertiary care hospital. Patients and Methods: Urine samples (clean and catheter catch) from both inpatients and outpatients were inoculated on cystine lactose electrolyte deficient agar by semi-quantitative method. Significance of growth was established; identification and susceptibility testing was done by using VITEK 2 compact (bioMerieux). Results were interpreted according to CLSI guidelines. MDR Enterobacteriaceae isolates were identified and further tested by MHT as described by CLSI. Statistical Analysis Used: Data were analyzed using Statistical Package for the Social Sciences version 20 (IBM Inc., SPSS Inc., Chicago, IL, USA) software. Descriptive statistics and Chi-square test were used. P values < 0.05 were considered statistically significant. Results: MDR was noted in 25.79% of Enterobacteriaceae isolates. Escherichia coli and Klebsiella pneumoniae together accounted for 87.3% of MDR isolates. Susceptible antibiotics were colistin (91.02%) and amikacin (51.15%). Pandrug resistance (PDR) was noted in 20 isolates. MHT positivity was noted in 72.3% of isolates. Conclusions: Majority of isolates were MHT positive indicating high carbapenemase production. Low susceptibility profile and occurrence of PDR in this setup deter the use of common empiric treatment for all suspected UTI cases.
Keywords: Carbapenem-resistant Enterobacteriaceae, modified Hodge test, pandrug resistant, phenotypic tests
|How to cite this article:|
Kakarla PL, Bilolikar AK, Sarma CV. Antibiotic susceptibility pattern of multidrug-resistant Enterobacteriaceae in urinary isolates and detection of suspected carbapenemase production. Astrocyte 2018;4:210-6
|How to cite this URL:|
Kakarla PL, Bilolikar AK, Sarma CV. Antibiotic susceptibility pattern of multidrug-resistant Enterobacteriaceae in urinary isolates and detection of suspected carbapenemase production. Astrocyte [serial online] 2018 [cited 2019 Jun 15];4:210-6. Available from: http://www.astrocyte.in/text.asp?2018/4/4/210/244299
| Introduction|| |
Urinary tract infection (UTI) is one of the most common bacterial infections encountered as both hospital- and community-acquired infections. Globally, 150–250 million cases of UTIs occur per year. According to the available data, 40–50% women and 5% men suffer from at least one UTI in their lifetime.,,
The microbial etiology of urinary infections has been reasonably consistent in the past decades. The most common causative agent is uropathogenic Escherichia coli. Klebsiella pneumoniae, Staphylococcus saprophyticus, Enterococcus faecalis, group B Streptococci, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida species are infrequent causes.
MDR Enterobacteriaceae pose great challenge for treatment and the problem is exemplified several times when they develop resistance to carbapenems, the drug of choice for MDR strains. Carbapenem-resistant Enterobacteriaceae (CRE) is broadly categorized into two groups. CP-CRE is carbapenemase producing CRE, whereas non-CP-CRE refers to carbapenem resistance due to mechanisms other than carbapenemase enzyme production. CP-CRE has the greatest potential to contribute to the overall problem of antibiotic resistance as they possess a stable and transferable form of resistance (through either clonal expansion or transfer of carbapenemase genes).
Carbapenemases, being β-lactamases, can be grouped according to Ambler classification as detailed in [Table 1]. Reliable and rapid detection of CP-CRE is important. Phenotypic tests to identify CP-CRE include the modified Hodge test (MHT), the Carba NP test and its variants, and the carbapenem inactivation method. All these tests target carbapenemase but the specific carbapenemase type produced cannot be identified.
|Table 1: Classification of Carbapenemases - Adapted From Ambler Classification|
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The MHT detects carbapenemase production in isolates of Enterobacteriaceae. It is simple, highly accessible in clinical microbiology routine settings, inexpensive, and recommended by Clinical and Laboratory Standards Institute (CLSI). It is moderately accurate with the results available the next day. MHT demonstrates good sensitivity for Klebsiella pneumoniae carbapenemase (KPC), Verona Integron-mediated Metallo-β-lactamase (VIM), Imipenemase-type Metallo-β-lactamase (IMP), and Oxacillinase type metallo-β-lactamase (OXA-48)-like enzyme producers detection. Limitations of the test include poor sensitivity for New Delhi Metallo-β-lactamase (NDM) producers and poor specificity when AmpC is present. Despite these limitations, MHT has been accepted by major regulatory bodies for detecting carbapenemases.
Frequent finding in studies done on carbapenem resistance is that carbapenem resistance is common in urinary isolates when compared to other samples. There is a paucity of data on MDR UTIs with carbapenem co-resistance in this part of the country.
Periodic, local re-evaluation of frequency of pathogen occurrence and their susceptibility profiles help in selecting appropriate antibiotics while initiating therapy. The present work aimed to study the antibiotic susceptibility pattern of MDR urinary isolates of Enterobacteriaceae, in our hospital setting. This study also tried to determine the percentage of Enterobacteriaceae in urine that is carbapenem resistant due to carbapenemase enzyme production by using MHT.
| Patients and Methods|| |
Study design: Prospective laboratory-based observational cross-sectional study.
Study setting: Department of Microbiology, tertiary care hospital, India.
Study duration: 1 November 2015 to 23 June 2016.
The study was started after getting clearance from institutional ethics committee. The study subjects were explained the purpose of the study and assured confidentiality. Written informed consent was taken before sample collection.
Study population: All patients admitted or visiting outpatient departments.
Inclusion criteria: All patients aged from 18 to 80 years presenting with symptoms suggestive of UTI to outpatient clinic or admitted in the hospital in any department with a positive urine culture (clean catch/catheter catch) showing pure growth of MDR Enterobacteriaceae family member were eligible for inclusion in the study.
Exclusion criteria: Subjects who were having urinary stents in situ/urinary tract malignancies and pregnant females were excluded from the study. Supra-pubic cystostomy samples were not included. Organisms with percentage identification <89% in VITEK 2 compact (bioMerieux, Durham, NC, USA) were excluded.
Sampling: All consecutive, nonduplicate samples were included till the sample size was met.
The following definitions were used in the study:
- Multidrug resistance – Resistance to one or more antibiotics of ≥3 classes of antibiotics [as defined by a group of International experts through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC)], one of them being carbapenems.
- Surveillance definition for CRE – Resistance to one or more carbapenems (ertapenem/meropenem/imipenem/doripenem) or documentation that the isolate possesses carbapenemase. For bacteria that have intrinsic imipenem nonsusceptibility, resistance to carbapenems other than imipenem is required. This is a phenotypic definition given by the CDC, Atlanta in January 2015.
Urine samples received in the laboratory were promptly inoculated on cystine lactose electrolyte deficient agar by semi-quantitative technique using a calibrated loop (0.01 ml). Significance of growth was established depending on sample type, colony types, number of colony forming unit/ml and clinical history according to standard guidelines.
Identification and susceptibility testing was done using VITEK 2 compact (bioMerieux, Durham, NC, USA). A total of 18 antibiotics were tested, including three carbapenems (ertapenem, imipenem, and meropenem) for all the isolates. Entire processing was done in strict adherence to the manufacturer's instructions. Minimal inhibitory concentration interpretive standards for Enterobacteriaceae as given by CLSI were followed., As CLSI guidelines are not available for colistin and tigecycline, European Committee on Antibiotic Susceptibility Testing (EUCAST) guidelines were followed. However, tigecycline was not reported for these isolates as it has poor urine drug concentrations (only 15–22% is excreted in the urine as the active drug).
MDR Enterobacteriaceae isolates were identified. Isolates that are resistant to one or more carbapenems were further tested by MHT as described by CLSI. Organisms producing a clover leaf-like indentation were considered as carbapenemase producers.
Outcome data were collected and entered manually in an Excel format from the computer attached to automated machine. VITEK 2 compact (bioMerieux, Durham, NC, USA) was used for identification and antibiotic susceptibility detection and drug resistance was defined according to CLSI guidelines prevailing at that point of time.
Sample size calculation and justification
Sample size (n) = Z2 × P × (1 − P)/C2 = 266 ⩰ 260
where n = sample size
Z = 1.96 for 95% confidence level
P = Population proportion (0.5)
C = Confidence interval expressed as decimal (0.06)
Sample size: 260 nonduplicate samples.
Data were entered and recorded in Microsoft Excel 2010. Statistical analysis was done using Statistical Package for the Social Sciences version 20 (IBM Inc., SPSS Inc., Chicago, IL, USA) software and results were presented through suitable tables and graphs. Descriptive statistics such as mean ± SD and percentages were used to describe frequency of bacterial pathogens and antibiotic susceptibility. Association between drugs and type of bacterium was measured using Chi-square test. P values < 0.05 were considered statistically significant.
| Results|| |
The study profile is detailed in [Figure 1].
|Figure 1: Study Profile of a Prospective Laboratory Based Observational Study on Antibiotic Susceptibility Pattern of MDR Urinary Isolates of Enterobacteriaceae and MHT Results.|
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Out of 4830 samples received for culture, 20.86% (n = 1008) showed significant, single-colony type growth of Enterobacteriaceae members. MDR (n = 260) was noted in 25.79% of these isolates. The mean (SD) age of patients with MDR isolates was 54.90 (16.19) years. [Figure 2] shows the age group and sex distribution of patients with MDR isolates. Male patients contributed to 58.46% (n = 152) of samples and female patients to 41.53% (n = 108). Majority of patients were in 51–80 years age group.
Clean catch constituted 70% (n = 182) of samples and catheter catch constituted 30% (n = 78). Most of the MDR isolates were from wards (n = 95, 36.53%), closely followed by Intensive Care Units (ICUs) (n = 80, 30.76%). Other areas observed were outpatients (n = 68, 26.15%) and emergency (n = 17, 6.53%).
Escherichia coli (51.15%) followed by Klebsiella pneumoniae (36.15%) were the most common organisms isolated. Other organisms and their isolation in numbers are shown in [Table 2].
|Table 2: Frequency of Isolation of MDR Organisms From Clean Catch and Catheter Catch Urine Samples|
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Antibiotic susceptibility characteristics
The antibiotic susceptibility pattern of various isolates is detailed in [Table 3]. The most susceptible antibiotic among the antibiotics tested was colistin (81.92%). Excluding the intrinsically resistant organisms (n = 26) (Providencia rettgeri, Morganella morgannii, Proteus mirabilis, Serratia fonticola, and Serratia liquefaciens), 91.02% of organisms were susceptible to colistin. A total of 51.15% (n = 133) of isolates were susceptible to amikacin. Percentage susceptibility to 15 other antibiotics tested was <50%.
|Table 3: Antibiotic Susceptibility Pattern Among Various MDR Isolates in the Study|
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Susceptibility of Klebsiella pneumoniae to colistin (88.3%) was less than Escherichia coli (92.4%). Pearson's Chi-square analysis revealed that this was not statistically significant (P = 0.345). Susceptibility of Klebsiella pneumoniae to amikacin (43.6%) was less than Escherichia coli (60.9%). Pearson's Chi-square analysis revealed that this was statistically significant (P = 0.037) as the P value is < 0.05.
A total of 20 (7.69%) pandrug resistant (PDR) isolates were identified. These were Providencia rettgeri (n = 9, 3.46%), Klebsiella pneumoniae (n = 5, 1.92%), Escherichia coli (n = 3, 1.15%), Morganella morgannii (n = 1, 0.38%), Proteus mirabilis (n = 1, 0.38%), and Serratia fonticola (n = 1, 0.38%). Nineteen (95%) of these isolates were from inpatients and one from outpatient. All the Providencia rettgeri isolates were from catheter catch urine.
Modified Hodge test
Modified Hodge test was performed on 260 isolates and it was positive in 72.30% (n = 188) isolates. Majority of the isolates (n = 179, 68.84%) were resistant to all the three carbapenems tested. 75% PDR isolates were MHT positive. Resistance patterns for different carbapenems are shown in [Table 4]. A photograph with clover leaf-shaped indentation of positive control and patient sample in MHT is shown in [Figure 3].
|Table 4: Resistance Patterns Detected for Different Carbapenems in MHT Positive and Negative Isolates|
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|Figure 3: Photograph Showing Clover Leaf Formation (positive) in Modified Hodge Test highlighted by Black Arrows.|
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MHT positive isolates were more drug resistant when compared to MHT negative isolates. There was a statistically significant difference when Chi-square test was done for carbapenems (P < 0.001) and amikacin (P = 0.009). This is depicted as a bar graph in [Figure 4].
|Figure 4: Comparison of Sensitivity Pattern of MHT Positive and Negative Isolates to Various Antibiotics Tested in the Study.|
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| Discussion|| |
The present study details susceptibility pattern of bacterial isolates from urine in a tertiary care hospital in South India. MDR UTIs were more common in elderly (51–80 years), with a male female ratio of 1.4:1. The slight male predisposition observed could be due to higher use of mechanical devices. Inpatients (wards and ICUs) had frequent isolation of MDR isolates but closely followed by the outpatients, demonstrating an overall increase of resistance to antibiotics in the community. ICUs accommodate debilitated patients who require catheterization and hence higher rates were observed in catheter catch urine from ICUs. Midstream clean catch urine was the common sample growing MDR pathogens among other patient groups (wards, emergency, and outpatient departments).
The most common organism isolated was Escherichia coli similar to other studies.,,, Escherichia coli and Klebsiella pneumoniae together constituted 87% of all MDR Enterobacteriaceae. Providencia rettgeri, a less common cause of UTI, is isolated at a frequency of 3.86% in our setting. All the isolates were from catheter catch urine, highlighting the association of this organism with indwelling urinary devices.
Percentage susceptibility of MDR organisms to various antibiotics was surprisingly low. High susceptibility among the antibiotics tested was noted for colistin; however, this was not 100% as mentioned in other studies. Susceptibility to amikacin was 51%, suggesting resistance levels higher than expected. Nitrofurantoin and gentamicin showed in vitro efficacy in approximately one-third of isolates. Percentage susceptibility to all other antibiotics tested was very less. The choices of antibiotics available were even more limited for organisms intrinsically resistant to colistin.
The resistance pattern of carbapenemase-producing strains from the SENTRY Antimicrobial Surveillance Program, India, conducted in 2006–2007 is well in correlation with our findings. They were highly resistant to β-lactams, including cefepime, ceftazidime, aztreonam, and piperacillin-tazobactam. Polymyxin B susceptibility was 92.3% and tigecycline susceptibility was 100%. Susceptibility to colistin, belonging to polymyxin group was comparable. Tigecycline was not included as urine was our sample of study.
There are many studies that suggest the utility of nitrofurantoin and amikacin in this scenario of antibiotic resistance.,, Our study did not find these antibiotics to be much useful for MDR organisms with carbapenem co-resistance.
Klebsiella pneumoniae was more resistant to amikacin than Escherichia coli and this was statistically significant (P = 0.037). No statistical significance could be established comparing sensitivity of these organisms to colistin. Higher susceptibility of Klebsiella pneumoniae to few antibiotics such as nalidixic acid, ciprofloxacin, and cotrimoxazole is probably due to their lesser usage in respiratory infections, where it is a common pathogen.
One of the significant findings of this study is the isolation of PDR organisms in higher proportion (7.69%) when compared to other studies, which implies increasing resistance., Urine was the most common sample from which PDR isolates were obtained in other studies also., Twenty isolates were PDR; nine of them being Providencia rettgeri from catheter catch urine. Majority of PDR isolates were from inpatients; however, one isolate was from outpatient, indicating existence of such organisms in the community also.
MHT detected an alarming percentage of MDR isolates to be carbapenemase producers. This supports the statement that “majority of carbapenem resistance is due to carbapenemase production.” Resistance mechanism for the other 27.7% of isolates could be noncarbapenemase-based or nondetectable by MHT. The genes for carbapenemase are frequently carried on plasmids along with other resistance genes creating MDR CRE. Because of this, the sensitivity pattern of MHT negative isolates to majority of antibiotics was better statistically when compared to MHT positive isolates.
Studies from various parts of the world have varying percentage positivity with MHT.,,,,, Deshpande et al. from Mumbai could detect all NDM PCR positive isolates by MHT. They also detected two non-NDM CREs by MHT. A study to evaluate methods for identifying KPC in Enterobacteriaceae from CDC, Atlanta found out MHT to be 100% sensitive and 100% specific. This study has a limitation of testing less number of samples.
In SENTRY Antimicrobial Surveillance Program, India, two-thirds of isolates with reduced carbapenem susceptibility were MHT positive. They were also positive by PCR done with custom primers targeting multiple genes. But, negative or weakly positive MHT results were observed for 11 out of 15 NDM-1 producing strains. In their opinion, MHT can be problematic as NDM-1 producers are disseminating worldwide. Based on the above studies, MHT can reliably detect majority of NDM and KPC types of carbapenemases. Taking into account the cost, the turnaround time, the accuracy, the ease of incorporation into laboratory, and the information provided, we chose MHT for phenotypic carbapenemase detection.
Limitations of the study
Limitations of the study include limited generalizability of these findings to settings with different patient populations and mechanisms of resistance. Risk factors for MDR infections and clinical outcome of the patients with MDR UTI receiving antibiotic therapy were not in the scope of this study. The study neither confirmed nor classified the types of carbapenemase of MHT positive isolates by molecular methods, as they are not available in the institute. The study might have missed few carbapenemase producers because of the documented false negativity with MHT.
| Conclusions|| |
One out of four isolates of Enterobacteriaceae was MDR, which is a matter of concern. This increased occurrence of MDR could be a reflection of the resistance levels in the community. Nearly two-thirds of isolates demonstrated nil susceptibility to all the three carbapenems tested. A disturbingly high percentage of isolates were resistant to all the antibiotics tested, classifying them as PDR. Providencia rettgeri was the most encountered organism among PDR and its high isolation warrants judicious use of urinary catheters. A large majority of isolates were MHT positive, indicating high carbapenemase production. Low susceptibility profile and occurrence of PDR in this setup deter the use of common empiric treatment for all suspected UTI cases. High-risk patients for developing MDR UTI need to be identified, urine cultures to be sent at the earliest, and treatment optimized for them. Further studies are recommended to identify such risk factors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]