|Year : 2015 | Volume
| Issue : 2 | Page : 85-91
Carbapenem Resistance Patterns in General Intensive Care Unit of a Tertiary Care Hospital in India
Deepak K Tempe1, Jyotsna Agarwal2, Kapil Chaudhary3, Parin Lalwani4, Madhu Sudan Tudu5, Upendra Hansdah6, Bibhavati Mishra7
1 Department of Anesthesiology and Intensive Care, G.B. Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
2 Department of Anesthesiology, Army College of Medical Sciences, New Delhi, India
3 Department of Anesthesiology and Intensive Care, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India
4 Department of Anesthesiology and Intensive Care, Maulana Azad Medical College and Associated G.B. Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
5 Department of Cardiac Anesthesia, Max Super Speciality Hospital, Saket, New Delhi, India
6 Department of Anesthesiology, Acharya Harihar Regional Cancer Centre, Cuttack, Odisha, India
7 Department of Microbiology, Maulana Azad Medical College and Associated G.B. Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
|Date of Web Publication||1-Jun-2015|
Department of Anesthesiology and Intensive Care, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Aim: Carbapenems are one of the last resort drugs against drug-resistant organisms and carbapenem resistance (CR) is increasingly being reported. The present study evaluated the CR pattern in general Intensive Care Unit (ICU) of a tertiary care hospital in India. Materials and Methods: This was a retrospective analysis of data collected from May 2011 to January 2012 of 40 patients admitted in the general ICU with a stay of more than a week. The clinical and demographic data, Sequential Organ Failure Assessment (SOFA) score, need for mechanical ventilation, antibiotic sensitivity reports, and outcome were assessed. The results were statistically analyzed using Student's t-test, Mann-Whitney U-test, Chi-square test, and Fisher's exact test, where appropriate. P < 0.05 was considered statistically significant. Results: Acinetobacter baumanii was the most common organism in tracheal samples, Pseudomonas aeruginosa in blood samples and Escherichia coli in urine samples. CR in fresh episodes was seen maximally with Acinetobacter baumanii (79%) and Pseudomonas aeruginosa (70%). Meropenem resistance (MR) was more common than imipenem resistance in CR organisms. High sensitivity among CR organisms was observed to tigecycline and colistin, and among carbapenem sensitive organisms to tigecycline, piperacillin-tazobactam combination, and levofloxacin. CR was prevalent with age >50 years (P = 0.002), ICU stay of >15 days (P = 0.002), mechanical ventilation (P = 0.003), and ventilation >10 days (P = 0.008). Mortality was more common among mechanically ventilated patients (P = 0.002) and those with higher SOFA scores on admission (P = 0.012). Conclusion: Carbapenem resistance is high in microbiological cultures of ICU patients with a stay for over a week. Acinetobacter baumanii and Pseudomonas aeruginosa were the most common CR organisms. MR was more common than imipenem resistance.
Keywords: Carbapenem resistance, infection control, Intensive Care Unit
|How to cite this article:|
Tempe DK, Agarwal J, Chaudhary K, Lalwani P, Tudu MS, Hansdah U, Mishra B. Carbapenem Resistance Patterns in General Intensive Care Unit of a Tertiary Care Hospital in India. MAMC J Med Sci 2015;1:85-91
|How to cite this URL:|
Tempe DK, Agarwal J, Chaudhary K, Lalwani P, Tudu MS, Hansdah U, Mishra B. Carbapenem Resistance Patterns in General Intensive Care Unit of a Tertiary Care Hospital in India. MAMC J Med Sci [serial online] 2015 [cited 2017 Aug 23];1:85-91. Available from: http://www.mamcjms.in/text.asp?2015/1/2/85/157918
| Introduction|| |
Antibiotic resistance is steadily increasing with multi-drug resistant (MDR) and pan-drug resistant organisms being reported all over the globe. Carbapenems were the only group of antibiotics active against extended spectrum beta-lactamases producing Enterobacteriacae.  However, widespread and irrational use of carbapenems has led to emergence of resistance to this group of drugs also,  and there are at present very few available antibiotics, which are active against carbapenem-resistant (CR) organisms. Infections with CR organisms are associated with high morbidity and mortality with the attributable mortality rate as high as 40-50%. 
Carbapenem resistance is a global concern and the presence of CR genes in Indian subcontinent and its potential of international spread has been reported previously.  It is therefore, imperative to know the CR patterns in our health care settings and in the community and to take measures to prevent its spread. Since studies on CR patterns in India are limited, the present study was undertaken to find the CR patterns in the general Intensive Care Unit (ICU) of a tertiary care, public sector hospital in India. CR and antibiotic sensitivity profile of these organisms were assessed and measures to prevent emergence and spread of CR are discussed.
| Materials and Methods|| |
This is a retrospective analysis of data collected from May 2011 to January 2012 in the general ICU of G B Pant hospital, a Tertiary Care Public Hospital in New Delhi, India. The general ICU is an eight bedded open ICU and admits patients from all other departments of the hospital as well as other hospitals of New Delhi and neighboring states. The case mix includes neurosurgical, gastro surgical, cardiothoracic vascular surgical patients as well as medical patients requiring intensive care. Tracheal, blood, and urine samples were collected for culture and sensitivity on the day of admission, and every week thereafter during the ICU stay. Antibiotic sensitivity was performed for all the routine antibiotics and for imipenem and meropenem among the carbapenems. Biomerieux Vitek II automated identification and sensitivity equipment (bioMerieux, MO, Saint Louis County, USA) was used. Carbapenem sensitivity and resistance reports were given by our microbiology department based on the minimum inhibitory concentration (MIC) of the antibiotics. The MIC value for Escherichia More Details coli and Klebsiella of ≤1 μg/ml was taken as sensitive and ≥4 μg/ml was taken as resistant. The MIC values for Pseudomonas and Acinetobacter of ≤2 μg/ml was taken as sensitive and ≥8 μg/ml was taken as resistant. Antibiotics were prescribed based on the clinical condition and the antibiotic sensitivity reports as per the discretion of the treating intensivist.
Patients with a general ICU stay of more than a week were included in the study. The clinical and demographic data, Sequential Organ Failure Assessment (SOFA) score, source of admission, need for mechanical ventilation during ICU stay, culture and antibiotic sensitivity reports, and outcome were recorded for these patients. Forty patients admitted during the study period having a stay for over a week were studied. For study analysis, fresh episode was defined as either reporting of a particular organism for first time or repeat culture of an organism with negative cultures in between.
Institutional Ethics clearance waiver was obtained as the study involved only collection of data from ICU charts and microbiological reports and did not involve any intervention in patients; thus, the treatment being the standard of care. Patient consent for treatment in ICU of our hospital was taken as per the institutional protocols on admission and the study does not reveal the identity of any patient.
Data were analyzed using SPSS software (SPSS 17.0, Chicago, IL, USA). Continuous variables were analyzed using the Student's t-test or Mann-Whitney U-test and categorical variables were analyzed using the Chi-square test or Fisher's exact test, as appropriate. P < 0.05 was considered as statistically significant.
| Results|| |
The demographic and clinical profiles of the 40 patients included in the study are presented in [Table 1]. Twenty-three (58%) patients were referred from other hospitals, 11 (27%) were transferred from other wards or ICU's of our hospital (IN patients) and 6 (15%) were admitted directly without any prior hospitalization. Thirty-three (82.5%) patients required mechanical ventilation at some time during their stay in the ICU. Twenty-one (52.5%) patients expired, 18 (45%) were discharged, and one (2.5%) was still in general ICU on the last day of data collection.
Patient-wise carbapenem resistance
CR organisms were isolated from 27 (67.5%) patients in at least one sample at some point of their stay in the ICU. Of these, CR organisms were isolated in the first cultures at the time of admission in 21 (79%) patients while 6 (21%) developed CR after admission to general ICU. In patients presenting with CR on admission, 14 were admitted from other hospitals, five were IN patients and two were direct admissions without any prior hospitalization. Thirteen patients did not show CR throughout their stay in the ICU. Of these, 7 patients did not require mechanical ventilation (were on face mask). CR was observed in 76% patients who expired.
Site specific carbapenem resistance
CR organisms were most frequently isolated on microbiological cultures of tracheal samples (25 patients), followed by urine (9 patients), and blood samples (6 patients) [Figure 1]. Of 25 patients who grew CR organisms in their tracheal samples, 18 (72%) were harboring these organisms on admission, whereas CR organisms were relatively less frequently isolated from blood and urine samples on admission (2 out of 6 patients [33%] and 2 out of 9 patients [22%], respectively).
Organism wise carbapenem resistance
Total numbers of fresh episodes were 123. The overall culture positivity with CR organisms was 61% (75 episodes), with meropenem resistance (MR) (70 episodes [57%]) being slightly higher than imipenem resistance (IR) (61 episodes [49.5%]). Resistance to both carbapenems (imipenem and meropenem) was observed in 44 (36%) episodes [Table 2].
The most common organisms isolated in fresh episodes were Acinetobacter baumanii and Pseudomonas aeruginosa (34 episodes each) followed by Klebsiella pneumoniae (31 episodes) and Escherichia coli (24 episodes). Most frequent isolates from tracheal cultures were Acinetobacter baumanii and Klebsiella pneumoniae, whereas Escherichia coli and Pseudomonas aeruginosa were the most frequent isolates from urine cultures. Blood cultures isolated Pseudomonas aeruginosa maximally, followed by Acinetobacter baumanii and Klebsiella pneumoniae. Escherichia coli was not isolated from blood samples [Figure 2].
Overall CR in fresh episodes was seen maximally with Acinetobacter baumanii (79% episodes) followed by Pseudomonas aeruginosa (70%), Klebsiella pneumoniae (45%) and Escherichia coli (41%).
The top 5 antibiotic sensitivity profile of CR and carbapenem sensitive (CS) organisms is shown in [Table 3]. Tigecycline sensitivity was found in most of the tested CR isolates of Acinetobacter baumanii (96%), Klebsiella pneumoniae (100%), and Escherichia coli (100%) while only a low sensitivity (21.4%) was observed with CR isolates of Pseudomonas aeruginosa. CR isolate of Acinetobacter baumanii and Pseudomonas aeruginosa which were tested for colistin showed high sensitivity; 100% and 91%, respectively. Colistin sensitivity was tested in only one episode of Klebsiella pneumoniae and Escherichia coli by the microbiologist and they were sensitive. Forty six percent CR Acinetobacter baumanii, 44% CR Escherichia coli, 29% CR Klebsiella pneumoniae, and 29% CR Pseudomonas aeruginosa were found sensitive to piperacillin-tazobactam combination. Sixty seven percent of CR Escherichia coli and 37% of CR Pseudomonas aeruginosa were found sensitive to amikacin whereas sensitivity was low in isolates of Acinetobacter baumanii and Klebsiella pneumoniae (8%). Netilmicin sensitivity was seen in 56% CR Escherichia coli, 27% CR Acinetobacter baumanii, and 21% CR Klebsiella. High sensitivity of CR Acinetobacter baumanii (77%) and CR Escherichia coli (60%) to Levofloxacin was observed, while sensitivity was low with Pseudomonas aeruginosa.
Among CS isolates, high sensitivity was observed with piperacillin tazobactam combination (Acinetobacter baumanii - 100%, Pseudomonas aeruginosa /i> 100%, Klebsiella pneumoniae - 87% and Escherichia coli %). One hundred percent CS Acinetobacter baumanii and 71% CS Pseudomonas aeruginosa were found to be sensitive to levofloxacin, while 80% CS K. pneumoniae were found sensitive to ofloxacin. Seventy-one percent Klebsiella pneumoniae, 71% Pseudomonas aeruginosa, and 58% Escherichia coli were found sensitive to Amikacin. All the CS Klebsiella pneumoniae, Acinetobacter baumanii and Escherichia coli were found sensitive to tigecycline. Eighty-nine percent Escherichia coli, 85% Pseudomonas aeruginosa, and 78% Klebsiella pneumoniae were also found sensitive to netilmicin. Colistin sensitivity was not done uniformly in CR sensitive isolates.
Sequential organ failure assessment score
Mean SOFA score on admission was 5.5. The mean SOFA scores at the time of admission in patients who had CR on admission (5.86 ± 1.9) and those who developed CR later on (4.67 ± 3.33) was comparable (P = 0.24). Higher mortality was observed in mechanically ventilated patients. Mean SOFA scores on admission and mean SOFA scores calculated prior to discharge/death were significantly higher in patients who expired compared to those who got discharged [Table 4]. In patients who developed CR after admission to ICU, mean SOFA score at admission (4.67 ± 3.33) and on 1 st day of CR (6.50 ± 2.81) was comparable.
Carbapenem resistance correlates
Carbapenem resistance organisms were more commonly isolated in samples of patients aged >50 years, requiring mechanical ventilation, ventilator days >10 and having ICU stay >15 days [Table 5].
| Discussion|| |
The present study found that among the patients presenting with CR on admission to the general ICU, the majority were admitted from other hospitals and IN patients. Acinetobacter baumanii was the most common organism in tracheal samples, Pseudomonas aeruginosa in blood samples, and Escherichia coli in urine samples. CR in fresh episodes was seen maximally with Acinetobacter baumanii (79% episodes) followed by Pseudomonas aeruginosa (70%), Klebsiella pneumoniae (45%), and Escherichia coli (41%). CR organisms were isolated on admission to general ICU from tracheal samples of 72% patients, blood samples of 33% patients, and urine samples of 22% patients. Resistance to meropenem was more common as compared with imipenem in CR organisms. High sensitivity among CR organisms was observed to Tigecycline and Colistin, and among CS organisms to Tigecycline, Piperacillin-Tazobactam combination, and Levofloxacin. Increased resistance to Piperacillin-Tazobactam combination and Levofloxacin was observed in CR organisms in comparison to CS organisms. CR organisms at any time during general ICU stay were more commonly isolated in patients aged >50 years, having ICU stay of >15 days, on mechanical ventilation and ventilation >10 days (P = 0.002, 0.002, 0.003, and 0.008, respectively). Mortality was more common among mechanically ventilated patients and those with higher SOFA scores on admission (P = 0.002 and 0.012, respectively).
CR has been reported globally. ,,,, The prevalence varies from 4% to 74%, ,, similar to the present study (67.5%). Although there are reports of CR from North India, , the exact prevalence in India is not known.  Majority of the currently published data relate to microbiological survey focusing on the magnitude of CR in various organisms isolated from their health care units. The present study evaluated not only the microbiological aspect, but also patient wise and site specific analysis of CR and its correlation with clinical profile and SOFA score of the patient. Furthermore, the assessment of antibiotic sensitivity in CS isolates is the strength of the present study.
CR organisms were isolated from 67.5% patients in the present study. A large number of these patients had CR on admission. Most of these patients had a previous ICU stay, were mechanically ventilated, were on invasive monitoring or were exposed to various groups of antibiotics before admission to our ICU, all of which are risk factors for infection with MDR organisms. ,,,, In two patients without any history of prior hospitalization, CR organisms were isolated. This is a matter of serious concern as the development of CR in community without the above-stated risk factors is a serious threat to public health as CR Enterobacteriacae can widely spread via feco-oral route. 
The common organisms isolated in the present study were Acinetobacter baumanii and Pseudomonas aeruginosa followed by Klebsiella pneumoniae and Escherichia coli. These belong to the "ESKAPE" pathogens group described by Infectious Diseases Society of America which is known to escape the effects of almost all available antibiotics. Previous studies have also found these four organisms to be the common isolates in ICU settings. 
The MR (73%) and IR (79%) in Acinetobacter baumanii isolates in the present study is comparable to that found in ICU isolates in a recent study (MR = 73.4%; IR = 71.6%).  The overall MR (57%) was higher than IR (49.5%) in the present study in accordance with previous studies; , however the overall resistance to these antibiotics is much higher than what was reported in a previous study performed about 7 years ago (MR: 22.16% and IR: 17.32%).  This indicates increasing resistance to these antibiotics over the years.
The present study also showed that the CR organisms are sensitive to tigecycline and colistin suggesting that these two antibiotics should be exclusively reserved for the CR organisms that do not have sensitivity to any other antibiotics. In the present study, it was found that the CR organisms were also sensitive to piperacillin-tazobactam and Levofloxacin. Hence, these antibiotics should be preferred over tigecycline and colistin wherever possible. Other studies have found different antibiotics such as cefepime, cefoperazone, aztreonam, cefoxitin, chloramphenicol-thiamphenicol, ertapenem, fosfomycin, temocillin, methanamide, micillinam + pivmecillinam, nitrofurantoin, tobramycin, colistin, and trimethoprim that are effective against the CR organisms.  This indicates that each ICU has a different profile and should, therefore, formulate its own policy of using antibiotics other than tigecycline and colistin wherever possible. Similar concerns should be extended in patients with CS organisms. Here too, antibiotics other than tigecycline, colistin, and carbapenems should be used as far as possible. According to the results of the present study, it seems that the choice of antibiotics should be piperacillin tazobactam combination (nearly 100% sensitivity in Acinetobacter baumanii and Pseudomonas aeruginosa), fluoroquinolones or amikacin in CS organisms. Interesting new finding was the high sensitivity of netilmicin in CS Acinetobacter baumanii (60%), Pseudomonas aeruginosa (85%), Klebsiella pneumoniae (78%) and Escherichia coli (89%) compared to CR Acinetobacter baumanii (27%), Pseudomonas aeruginosa (5%), Klebsiella pneumoniae (21%), and Escherichia coli (56%).
The present study found the mean SOFA scores on admission and mean SOFA scores calculated prior to discharge/death to be significantly higher in patients who expired compared to those who got discharged. However, the mean SOFA scores on admission were comparable among patients with CR on admission and those developing CR later on, as well as among patients with CR and without CR throughout the stay in the ICU. Also in patients who developed CR after admission to ICU, mean SOFA score at admission, and on 1 st day of CR was comparable. Thus, SOFA scores correlated poorly with CR but were indicative of mortality.
CR organisms were more commonly isolated in patients aged >50 years, requiring mechanical ventilation and having ICU stay >15 days. Higher mortality was observed in mechanically ventilated patients. Infections with CR organisms are difficult to treat, require more invasive and intensive care leading to high cost of treatment and are associated with high morbidity and mortality rates. The attributable mortality rate to CR infections may be as high as 40-50%. , CR organisms were isolated in about 76% patients who expired in our study indicating an increasing mortality from CR organisms over years. It is therefore, extremely important to control the emergence and spread of CR organisms.
Early detection and implementation of aggressive infection control strategies can prevent the infection spread. Centre for Disease Control has laid down guidelines for prevention of CR Enterobacteriacae infection.  It includes 8 core measures which have been included in the prevention strategies and include laboratory detection; rigorous implementation and monitoring of infection control measures such as hand hygiene, contact precautions, isolation, setting up of infection control committee, proper medical waste disposal, and maintenance of environmental hygiene; education and training of health care personnel on proper use and rationale of infection control measures along with appreciation/reward of units/staff for best infection control; minimal use of invasive devices; antibiotic stewardship; effective and rational dosing of antibiotics integrating pharmacokinetic and pharmacodynamic profiles of the antibiotic with the microbiological data (minimal inhibitory concentration); screening (rectal and perirectal sampling) of epidemiologically linked contacts of colonized or infected patients, active surveillance; and coordinated efforts among health care facilities and encouragement of antimicrobial research and development.
Hospital antibiotic policy should be formulated using the antimicrobial sensitivity data of ICU and referral intrahospital units. Empiric therapy should be based on local antibiograms and antimicrobial susceptibility patterns. Carbapenems are time-dependent bactericidal agents and optimizing carbapenem therapy includes correct dosing and extending time above MIC. , In addition, the carbapenem use should be restricted, and they should be used as "reserve drugs," to decrease the selection pressure from antibiotic exposure. , Early aggressive therapy and de-escalation, when possible has been shown to enhance patient recovery and also prevent the emergence of resistance. 
The recent Chennai declaration is a practical, implementable, and step-by-step strategy to tackle antibiotic resistance in India and other developing countries.  Among other known usual precautions, it emphasizes on hospital antibiotic policy and formulation of the infection control team. The present study highlights how the profile of organisms and their sensitivity patterns can be variable emphasizing the need for formulation of local antibiotic policies which could be labeled as rational and hence, would prevent emergence of antibiotic resistance. Need of the hour is infection control and developing an effective antibiotic stewardship program. Multidisciplinary approach and community physician awareness are key measures to prevent CR.
The present study had several limitations. It was a single center study with small sample size and the details of previous antibiotic treatment were not available in all patients. Inherent limitations of retrospective analysis were present like lack of data of sample wise culture positivity and culture negativity, isolations in fresh and repeated cultures, etc., Testing for other carbapenems like ertapenem and doripenem could not be studied as these are not routinely tested in our microbiology laboratory. Furthermore, fungal culture and sensitivity testing for all the 14 forgotten antibiotics favored by Pulcini et al.  was not performed. Colistin sensitivity was performed only in samples of Escherichia coli and Klebsiella pneumoniae and the data are insufficient to form any conclusion. MIC values were not reported in the culture sensitivity reports and were not available for analysis. Although repeat surveillance cultures have not convincingly been shown to be of value, weekly cultures after admission were sent as a protocol to identify any new colonization. However, the antibiotic treatment was modified only if there was no clinical response to the previously administered antibiotic.
| Conclusion|| |
CR organisms were isolated in high number of ICU patients with a stay for over a week. Acinetobacter baumanii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli were the most frequently isolated organisms with Acinetobacter baumanii being the most resistant. MR was more common than IR in CR organisms. Judicious use of antibiotics, infection control measures and regular antibiotic surveillance are essential to prevent the spread of infection in hospital and in community. Further multicentric studies are required.
| Acknowledgments|| |
Dr. Devesh Dutta, Department of Cardiac Anesthesia, Escorts Heart Institute, Faridabad; Dr. Kiran Kiro, Department of Anesthesiology and Intensive Care, Maulana Azad Medical College and Associated G.B. Pant Institute of Postgraduate Medical Education and Research, New Delhi, India and Dr. Mukesh Garg, Department of Cardiac Anesthesia, Metro M.A.S. Heart Care and Multispeciality Hospital, Jaipur, India for their help in data collection.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]