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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 22  |  Issue : 2  |  Page : 76-81

Clinico-microbiological profile of sepsis with carbapenem-resistant Gram-negative isolates among patients presenting to a large tertiary care hospital in South Kerala


1 Pushpagiri Institute of Medical Sciences and Research Centre, Tiruvalla, Kerala, India
2 Department of Microbiology, Pushpagiri Institute of Medical Sciences and Research Centre, Tiruvalla, Kerala, India
3 Department of Critical Care Medicine, Pushpagiri Institute of Medical Sciences and Research Centre, Tiruvalla, Kerala, India
4 Department of Community Medicine, Pushpagiri Institute of Medical Sciences and Research Centre, Tiruvalla, Kerala, India
5 Department of Anaesthesiology, Sanjeevani Multispeciality Hospital, Alappuzha, Kerala, India

Date of Submission10-Jan-2021
Date of Decision12-Jan-2021
Date of Acceptance13-Jan-2021
Date of Web Publication5-Apr-2021

Correspondence Address:
Dr. Aneeta Mary Jacob
Department of Microbiology, Pushpagiri Institute of Medical Sciences and Research Centre, Tiruvalla, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jacm.jacm_30_21

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  Abstract 


BACKGROUND AND OBJECTIVES: Increasing antibiotic resistance, particularly among carbapenems, has made the management of sepsis very challenging. Early and aggressive use of appropriate antimicrobials is essential in improving the clinical outcome of these patients. The aim of this study was to find the various risk factors leading to sepsis with carbapenem-resistant organisms (CRO) and also to analyse the various clinical outcomes among sepsis due to CRO.
MATERIALS AND METHODS: Blood cultures were processed from patients who presented with signs and symptoms of sepsis. Analysis for predisposing factors and clinical outcome was done for those patients who grew CRO in both blood cultures. For calculation of significance, the same factors were also studied in an equal number of patients who presented with sepsis due to carbapenem-sensitive organisms.
RESULTS: Blood cultures were received from a total of 3885 patients in one year, of which 7.6% grew Gram-negative bacilli. Resistance to carbapenems was seen in 17.9% of isolates. The significant risk factors for sepsis with CRO in the present study were chronic liver disease, increased duration of hospital stay and exposure to antibiotics. Carbapenem-resistant sepsis was associated with increased mortality. This may be related to the delay in initiating definitive therapy after the onset of sepsis.
INTERPRETATION AND CONCLUSION: Colistin is the drug of choice for carbapenem-resistant sepsis. Being a reserve drug, we recommend Colistin to be restrictively used as an empiric therapy only in those patients who developed sepsis after hospital stay, who had prolonged antibiotic exposure as well as in patients with chronic liver disease.

Keywords: Carbapenem resistance, Colistin, sepsis


How to cite this article:
Chacko A, Jacob AM, Pulicken M, Mathew P, Paul J. Clinico-microbiological profile of sepsis with carbapenem-resistant Gram-negative isolates among patients presenting to a large tertiary care hospital in South Kerala. J Acad Clin Microbiol 2020;22:76-81

How to cite this URL:
Chacko A, Jacob AM, Pulicken M, Mathew P, Paul J. Clinico-microbiological profile of sepsis with carbapenem-resistant Gram-negative isolates among patients presenting to a large tertiary care hospital in South Kerala. J Acad Clin Microbiol [serial online] 2020 [cited 2021 Aug 3];22:76-81. Available from: https://www.jacmjournal.org/text.asp?2020/22/2/76/313073




  Introduction Top


Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection.[1] Here, endothelial damage progresses due to persistent release of inflammatory mediators. Before this stage in which the body can no longer control its own inflammatory response is reached, target antimicrobials should be initiated.[2] The empiric antibiotic for Gram-negative sepsis is either carbapenems or Piperacillin–Tazobactam.[3] However if the bacteria turn out to be resistant to these agents, it can lead to fatal outcome.[4]

With increasing antibiotic resistance, particularly the carbapenems, the management of sepsis is challenging.[5] The various resistance mechanisms include enzymatic inactivation or by decreasing the antibiotic concentration within the cell.[6] The Polymyxins along withTigecycline and Fosfomycin have become the last resort drugs in managing sepsis due to carbapenem-resistant organisms (CROs).[7] By the time carbapenem resistance is detected and Colistin is administered, it may be life-threatening.[8]

The aim of this study was to do a clinico-microbiological profiling of the Gram-negative isolates with carbapenem resistance and compare it with isolates without resistance. Here, the appropriateness of empirical antibiotic therapy in patients with Gram-negative sepsis was also analysed.


  Materials and Methods Top


This retrospective study was conducted in the Microbiology Department of a 1200-bedded tertiary care hospital in South Kerala from January 2018 to December 2018. Institutional Ethics Committee clearance (PIMSRC/E1/388A/22/2019) was obtained and data regarding the patient demographics, risk factors and clinical presentation were collected from medical records maintained at the hospital. A waiver of consent was obtained from the Institutional Ethics Committee as it was a retrospective study and no direct participant interaction was conducted.

Samples from patients who had sepsis due to CRO in at least two blood cultures obtained from two different sites were included in this study. Samples from paediatric patients were excluded due to low numbers and limitations in record keeping. The sample size of 28 in each study group was calculated based on the assumption that there will be at least 1 day mean difference between the two groups regarding start of definitive antibiotic therapy with a standard deviation of 1.8 days, an alpha error of 5% and a beta error of 20%. Blood cultures growing Gram-negative bacilli were identified and divided into two groups based on their susceptibility to carbapenems. The samples for the study were selected using random number tables generated electronically. An equal number of carbapenem-sensitive samples were also selected for the study, after matching for organism and intensive care requirement.

All the blood cultures were processed on automated BacT/ALERT (bioMerieux) microbial detection system. After obtaining a direct smear from those bottles that were flagged positive, they were subcultured on blood agar, chocolate agar and MacConkey agar and incubated over night at 37°C. In case of growth, organisms were identified by detailed biochemical characterisation of isolates.[9] Antibiotic sensitivity testing was done by modified Kirby–Bauer method. Isolates were interpreted as susceptible, intermediate or resistant to a particular drug as stated in the Clinical and Laboratory Standards Institute guidelines.[10] According to the standard operating procedure of our laboratory, Imipenem was commonly used for detecting carbapenem susceptibility among all Gram-negative isolates. In addition, Ertapenem sensitivity was checked for all organisms belonging to the family Enterobacteriaceae. For non-fermenters, sensitivity to both Meropenem and Doripenem were also done. Carbapenem-resistant isolates were further checked for Colistin susceptibity by microbroth dilution method using kits provided by Erba Lachema. EUCAST expert rules were followed for interpretation of Colistin minimum inhibitory concentration.[11]

The data collected from medical records were digitised using Microsoft Excel and analysed using SPSS, Version 20.0 (IBM Inc, USA). All the continuous variables were compiled as means (with standard deviations) and categorical variables as frequencies (with percentages). The differences in predisposing factors and outcomes between the two groups were assessed using tests of means and tests of proportions, wherever applicable. Non-parametric tests were used based on the distribution of the data. P < 0.05 was taken as statistically significant.


  Results Top


Blood cultures from 3885 adult patients were received in the microbiology department during the study period. Sepsis due to Gram-negative bacilli was seen in 7.6% (295/3885). The common Gram-negative organisms isolated from blood cultures are shown in [Figure 1]. The most common organism was Escherichia coli, followed by Klebsiella and Acinetobacter. Among these, 17.9% (53/295) were due to carbapenem-resistant isolates.
Figure 1: Top Gram-negative isolates in blood

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Various factors such as age, gender, underlying comorbidities, length of hospital stay, presence of invasive device and previous exposure to antibiotics were analysed for determining the characteristics associated with sepsis due to CRO [Table 1]. It was found that carbapenem resistance was significantly associated with length of hospital stay and previous exposure to antibiotics. Furthermore, there were a higher number of patients with chronic liver disease in the carbapenem-resistance group.
Table 1: Characteristics associated with carbapenem-resistant sepsis

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The choice of empirical antibiotic therapy is based on several criteria like the symptoms/signs on presentation, the severity of infection, admitting unit and the treatment protocols of the admitting intensive care unit (ICU). The most commonly used antibiotic for empirical therapy was one of the carbapenems (36%), followed by Piperacillin–Tazobactam (21%) and third-generation cephalosporins (13%) [Figure 2].
Figure 2: Empirical antibiotics given for sepsis (n = 56)

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The susceptibility of Gram-negative organisms to the commonly used empirical antibiotic therapies was also assessed. Of the E. coli isolates, 94.5% were susceptible to carbapenems, 91.4% to Piperacillin–Tazobactam and only 27.3% to third-generation cephalosporins. The Klebsiella isolates showed the least rate of susceptibility, among the commonly isolated organisms [Figure 3].
Figure 3: Percentage susceptibility of commonly isolated Gram-negative bacilli in blood to frequently given antibiotics for empiric therapy

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The clinical outcomes of the patients who had carbapenem-resistant sepsis and carbapenem-sensitive sepsis were also compared. Almost 90% of the patients with carbapenem-sensitive sepsis had their isolates susceptible to the empiric choice of antibiotics, while only 25% of the patients from the other group had such a characteristic. Hence, the patients with carbapenem-sensitive isolates were on definitive treatment earlier than those with carbapenem resistance. Furthermore, patients with carbapenem-sensitive isolates had significantly lower mortality [Table 2].
Table 2: Comparison of various outcomes in carbapenem-resistant sepsis versus carbapenem-sensitive sepsis

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  Discussion Top


Bloodstream infections (BSI) are defined as the presence of viable bacterial or fungal microorganisms in the bloodstream (later demonstrated by the positivity of one or more blood cultures) that elicit or have elicited an inflammatory response characterised by the alteration of clinical, laboratory and haemodynamic parameters.[12] In the present study, 7.6% of the total blood samples received were positive for Gram-negative bacilli. This positivity rate is very low when compared to that in Brazil where Gram-negative sepsis rates were as high as 32.9%. However, the carbapenem-resistant Enterobacteriaceae rates were around 17.6%,[13] which is comparable to our statistics which is 17.9%. However, these rates are very low when compared to studies from North India where the carbapenem-resistant rates were as high as 45.5%.[14]

E. coli (44%) followed by Klebsiella pneumoniae (29%) were the most common organism implicated in Gram-negative sepsis in our setting. This was followed by non-fermenters such as Acinetobacter baumannii (15%) and Pseudomonas aeruginosa (7%). Among these, K. pneumoniae had the least susceptibility to carbapenems (63.9%) and Piperacillin–Tazobactam (40.7%). The susceptibility of E. coli to both these antimicrobial agent was more than 90%. Even A. baumanni had more than 80% susceptibility to carbapenems and 64.4% were susceptible to Piperacillin–Tazobactam. Although the pattern of pathogens associated with BSI is changing over the years, what is most striking in the recent decades is the increasing rates of antibiotic resistance, particularly in Gram-negative rods.[12] In a 20-year trend from the SENTRY antimicrobial surveillance programme with 45 nations, S. aureus was the most frequently isolated pathogen before 2004 and E. coli was the most common organism isolated from blood cultures after 2005. The rates of multidrug-resistant Enterobacteriaceae increased from 6.2% to 15.8% from 1997 to 2016. Colistin was the only antimicrobial with good response against A. baumanii sepsis.[15]

In a study conducted in South America, old age was associated with acquisition of sepsis by CRO.[13] However in the present study, irrespective of the resistant patterns, sepsis was seen in those above 60 years.

In a study conducted in Chandigarh, the risk of gut colonisation with a CRO increased with the presence of an indwelling device.[16] However in our study, there was no statistically significant difference between carbapenem-resistant and sensitive BSI in those with an indwelling device (central line for haemodialysis, endotracheal intubation in a ventilated patient or a Foley's catheter).

In our study, 42.9% of patients with both carbapenem-resistant and sensitive BSI had chronic kidney disease. This is in contrast to a study done in the United States where renal disease was identified as an important risk factor for BSI due to Ertapenem-resistant Gram-negative rods.[17]

In a study conducted in Vietnam, they found that increased duration of hospital stay was an independent risk factor for colonisation by CRO.[18] In a developing nation like Pakistan, ICU stay of more than three days itself was significantly associated with bloodstream infection by CRO.[19] This finding is very similar in our setting also, where we found that as the duration of hospital stay increased (>5 days), the risk of sepsis with CRO also increased from 25% to 60.5%. The odds of being colonised by CRO is 4.6 times higher as the days of hospital stay increases more than five days with a 95% confidence interval of 1.48–14.54. Hospital environment is the hub of antimicrobial-resistant genes. Moreover, these patients usually are exposed to multiple antibiotics and they may come in contact with other patients who may also be carrying multidrug-resistant organisms.[20]

Chronic liver disease was an independent risk factor for sepsis due to carbapenem-resistant E. coli.[21] In our study also, 87.5% (7/8) of those with chronic liver disease had sepsis due to CRO. We found that the odds that a person with chronic liver disease develops sepsis due to CRO are nine times more with a 95% confidence interval of 1.02–78.94. Those with liver diseases are susceptible to infections mainly due to bacterial translocation from intestine as well as abnormalities of humoral and cell-mediated immunity. The risk of these infections being caused by multidrug-resistant bacteria is higher in this group of patients due to frequent exposure to broadspectrum antibiotics, invasive procedures and prolonged hospitalisations.[22]

Among 18 patients who were exposed to antibiotics prior to the onset of sepsis, 77.8% grew CRO in both their blood cultures. Prolonged exposure to antibiotics exerts a selective pressure and leads to the development of antibiotic resistance. The odds in these patients with antibiotic exposure to develop sepsis due to CRO are six times higher with a 95% confidence interval of 1.65–21.84. Exposure to cephalosporins, carbapenems and antipseudomonal antibiotics are drivers of resistance among gram-negative rods.[23],[24],[25]

Bloodstream infections need to be aggressively treated. The golden period for appropriate antibiotic therapy is within the first hour of onset of symptoms.[26] The choice of empiric antibiotics used in the treatment of sepsis should be based on the local antibiogram.[27] In our study, carbapenems were the empiric choice of antibiotics in 36% of Gram-negative bloodstream infections. This was followed by Piperacillin–Tazobactam (21%) and third-generation cephalosporins (13%). Colistin was chosen as empirical therapy in 12% of Gram-negative sepsis. Cephalosporins which were one of the most effective drugs used in the empirical treatment of BSI in the last century have become almost ineffective due to the increased production of extended spectrum β-lactamases, an enzyme that inactivates ampicillin, first-, second- and third-generation cephalosporins and Aztreonam. At present, Piperacillin–Tazobactam and the carbapenems are the two high-end antibiotics that are used empirically in the treatment of Gram-negative sepsis. However in the past two decades, carbapenem resistance is also on the rise due to the production of carbapenemases.[12] In 75% of carbapenem-resistant sepsis, empirical antibiotic chosen obviously did not match with the sensitivity pattern of the organism. Colistin was started on an average of 3.2 days after the onset of sepsis. This low rate of appropriate empirical therapy is consistent with other studies as well. In a study conducted in Ethiopia, mortality was strongly associated with the growth of bacteria which was resistant to the empirical antibiotic given (odds ratio: 23.28). These patients are usually dead or dying by the time final blood culture reports with antimicrobial susceptibility pattern is dispatched.[28] The odds that a person with sepsis due to CRO dies is 3.6 times higher with a 95% confidence interval of 1.183–10.952. Around 64.3% of our patients with CRO died within 4.4 days of sepsis onset. These mortality rates were similar in the Brazil study as well (63.8%).[29] However in Bhopal, though the carbapenem-resistant rates were very high, the mortality rates were comparatively less (22.5%).[14] This is in contrast to a study done in Singapore, where they established that BSI with carbapenem-resistant Enterobacteriaceae was not a predictor for mortality.[30]

As most of the bloodstream infections acquired from the hospital are multidrug resistant, special transmission-based preventive strategies need to be implemented, particularly in patients requiring a longer duration of hospital stay. The bundle care to prevent nosocomial bloodstream infections includes maximum sterile barrier precautions for all patients on central/peripheral lines, and appropriate skin antisepsis during insertion of central lines. Medicated catheter-lock solutions and use of antiseptic/antibiotic-impregnated central venous catheter and chlorhexidine-impregnated sponge dressings are some of the other measures suggested to prevent primary BSI.[26]

This study was done in a single centre with a limited number of samples as it was meant to be a scoping study to look at characteristics of patients with carbapenem-resistant Gram-negative sepsis. Being a retrospective study, the investigators were limited by the extend of data recorded in the patient files and this could have been a source of information bias. However, the significance of this study is the information it generates regarding the characteristics of patients with carbapenem-resistant sepsis and demonstrating the need for increasing competence in all levels of healthcare delivery to handle this problem. Furthermore, there are very few studies from the state of Kerala regarding the issue of carbapenem resistance though it is generally cited as a prominent issue associated with treatment failures in intensive care settings.


  Conclusion Top


There are several factors such as prolonged hospital stay, previous antibiotic exposure and chronic liver disease which are associated with sepsis due to CRO. Selection of empirical antibiotic is a difficult decision in case of sepsis with CROs, and this may be the reason for the significantly higher mortality in these cases. Colistin is the drug of choice for carbapenem-resistant sepsis. In 75% of bloodstream infections with these organisms, Colistin has not been used in empiric treatment. Here, the definitive therapy was started only after 3.2 ± 2 days. This resulted in a high mortality rate of 64.3%. However at the same time, Colistin is a reserve drug and the use of this drug should be restricted to preserve its antimicrobial efficacy. We recommend Colistin to be restrictively used as an empiric therapy only in those patients who developed sepsis after hospital stay, had prolonged antibiotic exposure as well as in patients with chronic liver disease. Continuous surveillance for increasing trends of antibiotic resistance and judicious use of high-end antibiotics is the need of the hour to review the empirical choice of antibiotics as well as to bring in control the emerging antimicrobial resistance.

Financial support and sponsorship

Aneesh Chacko was supported by ICMR STS programme for MBBS graduates.

Conflicts of interest

There are no conflicts of interest.



 
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