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 ~ Introduction
 ~ Methods
 ~ Results
 ~ Discussion
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 34  |  Issue : 4  |  Page : 495-499
 

Does the presence of Klebsiella pneumoniae carbapenemase and New Delhi metallo-β-lactamase-1 genes in pathogens lead to fatal outcome?


1 Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, New Delhi, India
2 Department of Surgery, Jai Prakash Narayan Apex Trauma Centre, New Delhi, India
3 Department of Orthopedica, Jai Prakash Narayan Apex Trauma Centre, New Delhi, India
4 Department of Neurosurgery, Jai Prakash Narayan Apex Trauma Centre, New Delhi, India
5 Department of Forensic Medicine, Jai Prakash Narayan Apex Trauma Centre, New Delhi, India
6 Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, All Institute of Medical Sciences, New Delhi, India

Date of Submission05-Apr-2016
Date of Acceptance02-Aug-2016
Date of Web Publication8-Dec-2016

Correspondence Address:
P Mathur
Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0255-0857.195367

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 ~ Abstract 

Introduction: Infections due to multidrug-resistant (MDR) pathogens are a medical challenge. There is considerable apprehension among clinicians regarding pathogens reported as carrying New Delhi metallo-β-lactamase-1 (NDM) and Klebsiella pneumoniae carbapenemase (KPC) genes from their patients. In the face of extremely high rates of antimicrobial resistance, it is essential to gauge the clinical significance of isolation of pathogens carrying these genes from clinical samples. This study compares the outcome of patients infected with pathogens carrying NDM/KPC genes versus those without these genes. Methods: The study was conducted over a 1-year period at a Level-1 trauma centre. Hospital-acquired infections were diagnosed on the basis of CDC's criteria. The correlation of isolation of a multi-resistant pathogen carrying KPC or NDM genes with the clinical outcome was ascertained. Results: A total of 276 consecutive patients admitted to the Intensive Care Units/wards of the JPNA Trauma Centre were included in this study. Of the 371 isolates recovered from these patients, 116 were from patients who had a fatal outcome. The difference in prevalence of blaNDMand blaKPCwas not significant in any genera of Gram-negative pathogens isolated from patients who survived versus those who had a fatal outcome. Conclusion: Isolation of MDR pathogens carrying NDM/KPC genes from clinical samples is not always a harbinger of a fatal outcome. Efforts should be made to prevent cross-transmission of these pathogens.


Keywords: Fatal, Klebsiella pneumoniae carbapenemase, multidrug resistance, New Delhi metallo-β-lactamase-1, outcome


How to cite this article:
Mathur P, Sagar S, Kumar S, Sharma V, Gupta D, Lalwani S, Rani R, Muruganantham A. Does the presence of Klebsiella pneumoniae carbapenemase and New Delhi metallo-β-lactamase-1 genes in pathogens lead to fatal outcome?. Indian J Med Microbiol 2016;34:495-9

How to cite this URL:
Mathur P, Sagar S, Kumar S, Sharma V, Gupta D, Lalwani S, Rani R, Muruganantham A. Does the presence of Klebsiella pneumoniae carbapenemase and New Delhi metallo-β-lactamase-1 genes in pathogens lead to fatal outcome?. Indian J Med Microbiol [serial online] 2016 [cited 2017 Mar 26];34:495-9. Available from: http://www.ijmm.org/text.asp?2016/34/4/495/195367



 ~ Introduction Top


Infections due to multi-resistant Gram-negative pathogens are now being considered as one of the most important medical challenge facing health care sector.[1] Phrases such as the “world moving towards the pre-penicillin era”[2] are catching the imagination of medical professionals, pharmaceutical companies, civil society, media and public at large. While the momentum being generated by public forums on antimicrobial resistance will indeed be fruitful in curtailing injudicious use of antimicrobials, we need to look into the important question of the significance of presence of genes such as blaNDM and blaKPC in bugs in the context of the patient's clinical outcomes.[3],[4] This would further enable rationalising antimicrobial use for true “infections” and prevent treatment of “samples” rather than patients.

This study tries to ascertain the clinical significance and outcomes of infections caused by multidrug-resistant (MDR) pathogens. The study was conducted at a Level-1 Trauma Centre of India. The profile of trauma patients is unique in the sense that it afflicts predominantly young population, who are usually devoid of underlying risk factors for development of hospital-acquired infections. Being otherwise healthy, almost all infections developed by them are hospital-acquired. The basic hypothesis of our study was that patients infected with pathogens harboring genes causing MDR phenotypes such as New Delhi metallo-β-lactamase-1 (NDM) and Klebsiella pneumoniae carbapenemase (KPC) should have a less favourable outcome than those devoid of these genes.


 ~ Methods Top


Hospital setting

The study was conducted from January to December 2015 at the 190-bedded Level-1 JPNA Trauma Centre of the 2400 bedded - AIIMS Hospital, New Delhi. The hospital has a robust surveillance system for hospital-acquired infections (HAIs), especially device associated infections such as ventilator-associated pneumonia, central line-associated bloodstream infections and catheter-associated urinary tract infections. There is a multi-disciplinary infection control team, consisting of clinicians, microbiologists and 10 infection control nurses at the centre.[5],[6] The diagnosis of HAIs is done based on the CDC's NHSN definitions.[7] Intensive surveillance, feedbacks and control measures have significantly reduced the rates of all DAIs (Device associated Infection); however, the rates of MDR in Gram-negative bacteria are very high.[8]

All patients from whose samples clinically significant Gram-negative pathogens were isolated on culture (mono- or bi-microbial Gram-negative isolation), were included in the study. All the Gram-negative pathogens included for this study were MDR (all of them were extended-spectrum beta-lactamase [ESBL] positive, with resistance to one more other class of antibacterial). Consecutive patients admitted to the Intensive Care Units (ICUs)/wards of the JPNA Trauma Centre, fulfilling the above criteria were enrolled. All clinical samples included in this study were non-duplicate. Clinical significance of the culture report was based on definitions of HAIs, as per CDC's criteria.[7] The clinicians made the final diagnosis, based on defined criteria. All the patients were prospectively followed through their hospital stay till their outcome in the hospital, as per our published surveillance methodology.[6] Antimicrobials were used for treatment based on culture reports and as per clinical decision.

The microbial identification of all Gram-negative bacterial isolates was done by Vitek II (Biomeriux India Limited). The antimicrobial susceptibility testing of all isolates was done by the disc diffusion method on Mueller-Hinton agar according to the Clinical Laboratory Standards Institute (CLSI) guidelines.[9]Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 were taken as control strains. The following antimicrobials were tested: Ampicillin (10 µg), ampicillin/sulbactam (10/10 µg), amoxycillin (10 µg), ceftazidime (30 µg), ceftazidime/clavulanic acid (30/10 µg), cefotaxime (30 µg), ceftriaxone (30 µg), cefoperazone (30 µg), cefoxitin (30 µg), cefpodoxime (30 µg), cefepime (30 µg), aztreonam (30 µg), piperacillin (100 µg), piperacillin/tazobactam (100/10 µg), ticarcillin/clavulanic acid (75/10 µg), cefoperazone/sulbactam (75/30 µg), cefepime/tazobactam (30/10 µg), ceftriaxone/sulbactam (30/15 µg), imipenem (10 µg), meropenem (10 µg), ertapenem (10 µg; except for Acinetobacter sp. and Pseudomonas sp.), amikacin (30 µg), gentamicin (10 µg), netilmicin (30 µg), ciprofloxacin (5 µg), levofloxacin (5 µg), tigecycline (15 µg, except for Pseudomonas sp.), polymyxin B (300 U), colistin (10 µg) and chloramphenicol (30 µg). The interpretative zone diameters were used as per CLSI recommendations.[9]

Testing for ESBL production

Any isolate showing a reduced zone diameter of ceftazidime/cefotaxime/ceftriaxone/cefpodoxime/aztreonam was included for confirmatory testing for ESBL production. Phenotypic confirmatory test for ESBL production was done using the CLSI recommended cephalosporin/clavulanate combination disc method. It was performed in all Gram-negative genus suspected to be ESBL producers. Although the CLSI does not recommend this to be confirmatory in genera other than E. coli, K. pneumoniae, Klebsiella oxytoca and Proteus mirabilis, we used this test in other genera, followed by polymerase chain reaction (PCR)-based detection of ESBL genes. E. coli ATCC 25922 (non-ESBL - producer) and K. pneumoniae ATCC 700603 (ESBL producer) were taken as negative and positive controls, respectively, with each testing. Strains suspected/phenotypically confirmed to be ESBL producing were examined for the presence of the blaTEM, blaSHV, blaCTX-M, blaPER and blaVEBβ-lactamases genes by PCR, using the published primers.[10]

All the isolates confirmed to be ESBL producers were examined for the presence of blaKPC and blaNDM by PCR, using published methodology.[11],[12]

Clinical follow-up was done for each case, and the outcome was assessed as “survived”/“Fatal.”

For statistical analysis, P < 0.05 was considered as significant.


 ~ Results Top


A total of 276 consecutive patients admitted to the ICUs/wards of the JPNA Trauma Centre and fulfilling the criteria mentioned above during the study period were included in this study. A total of 359 non-duplicate samples which grew mono-/bi-microbial Gram-negative bacterial pathogens were received from these patients. Of the 276 patients, 248 (90%) were male, the age of the patients ranging from 1 to 85 years (median 25 years). Of the 359 samples, 126 (35%) were tracheal aspirates, 84 (23%) were pus, 58 (16%) were bronchoalveolar lavage (BAL), 56 (15.5%) were blood, 10 (2.7%) were urine, 9 each (2.5% each) were tissues and urine and 7 (2%) were fluids (pleural/peritoneal/drain).

A total of 68 (24.6%) of these 276 patients had a fatal outcome, of which 59 (86.7%) were male; the age of these patients ranged from 8 to 85 years (median age 45 years). A total of 112 samples growing Gram-negative pathogens were obtained from this group of 68 patients. Of these, 35 (31%) were tracheal aspirates, 24 (21.4%) were blood, 23 (20.5%) were BAL, 13 (11.6%) were pus, 6 (5.3%) were cerebrospinal fluid, 4 (3.5%) were urine, 6 (5.3%) were fluids and 1 was tissue.

A total of 371 organisms were recovered from the 359 samples included in the study. Of these, 116 organisms (from 112 samples) were recovered from the 68 patients who had a fatal outcome. The distribution of Gram-negative pathogens from 359 clinical samples of the 276 study patients and from the 112 samples of the 68 fatal patients is shown in [Table 1].
Table 1: Distribution of gram-negative pathogens from entire study population and fatal cases

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The presence of blaNDM and blaKPC genes in isolates of Gram-negative bacteria from clinical samples of patients who survived versus those who had a fatal outcome is shown in [Table 2] and [Table 3]. The difference in prevalence of blaNDM and blaKPC was not significant in any genera of Gram-negative pathogens isolated from patients who survived versus those who had a fatal outcome.
Table 2: Prevalence of blaKPC in isolates from patients who survived Vs those with fatal outcome

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Table 3: Prevalence of blaNDM in isolates from patients who survived Vs those with fatal outcome

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 ~ Discussion Top


The present study tries to answer the question of whether the mere presence of blaNDM and blaKPC genes in isolates of Gram-negative bacteria from clinical samples is the principal driver for an adverse patient outcome? We included a group of trauma patients, which in itself serves as a uniform cohort. Globally, trauma victims are predominantly middle-aged male, generally lacking underlying predisposing factors for acquiring HAIs. We excluded the patients who had mixed Gram-negative and -positive pathogens in culture to have a uniform study population infected with Gram-negative pathogens.

The primary end point of fatality is an easy objective measure to assess. It is important to ascertain the actual burden of mortality being caused due to infections with MDR pathogens. In our study, we did not find any significant difference in the mortality rate of patients infected with pathogens carrying blaNDM and blaKPC genes as compared to those without these genes. This may mean that other host- or pathogen-related factors might be more important drivers of a fatal outcome. While conveying reports of presence of genes, an informed reporting should be done to the clinicians regarding the relevance of presence of these genes. Most clinicians are apprehensive of infections caused by pathogens carrying blaNDM and blaKPC genes, a common misconception being that such infections are invariably fatal.

Our study has a number of lacunae

We did not ascertain other parameters such as length of stay and cost of treatment with reference to presence of blaNDM and blaKPC genes. The impact of other resistance genes can also not be negated based on this study.

A study encompassing genotyping of all prevalent resistant mechanisms along with detailed clinical indices, and the outcome would be able to answer these questions. However, considering the paucity of new antimicrobials, infection control programs should aim to prevent the spread of these pathogens in health set-ups to reduce the quantum of MDR bugs in the hospital environment.

Acknowledgement

This study was funded by a grant from the Indian Council of Medical Research. We acknowledge the financial support of ICMR for the performance of this study.

Financial support and sponsorship

The study was funded by a grant from the Indian Council of Medical Research and was ethically approved by the Institute's Ethical Committee.

Conflicts of interest

There are no conflicts of interest.

 
 ~ References Top

1.
Appelbaum PC. 2012 and beyond: Potential for the start of a second pre-antibiotic era? J Antimicrob Chemother 2012;67:2062-8.  Back to cited text no. 1
    
2.
Tuon FF, Santos TA, Almeida R, Rocha JL, Cieslinsk J, Becker GN, et al. Colistin-resistant Enterobacteriaceae bacteraemia: Real-life challenges and options. Clin Microbiol Infect 2016;22:e9-e10.  Back to cited text no. 2
    
3.
Bogaerts P, Verroken A, Jans B, Denis O, Glupczynski Y. Global spread of New Delhi metallo-ß-lactamase 1. Lancet Infect Dis 2010;10:831-2.  Back to cited text no. 3
    
4.
Vincent JL. Does microbial resistance matter? Lancet Infect Dis 2011;11:3-4.  Back to cited text no. 4
    
5.
Mathur P, Tak V, Gunjiyal J, Nair SA, Lalwani S, Kumar S, et al. Device-associated infections at a level-1 trauma centre of a developing nation: impact of automated surveillance, training and feedbacks. Indian J Med Microbiol 2015;33:51-62.  Back to cited text no. 5
[PUBMED]  Medknow Journal  
6.
Gunjiyal J, Thomas SM, Gupta AK, Sharma BS, Mathur P, Gupta B, et al. Device-associated and multidrug-resistant infections in critically ill trauma patients: towards development of automated surveillance in developing countries. J Hosp Infect 2011;77:176-7.  Back to cited text no. 6
    
7.
Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 2008;36:309-32.  Back to cited text no. 7
    
8.
Mathur P. Antimicrobial consumption in hospitals of developing nations: When will the Gap Bridge between infection rates and prescription patterns? Indian J Med Microbiol 2016;34:3-4.  Back to cited text no. 8
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Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing, 20th Informational Supplement, January and June, 2010; M100-S21. Wayne, PA, USA: CLSI; 2010.  Back to cited text no. 9
    
10.
Moland ES, Hanson ND, Black JA, Hossain A, Song W, Thomson KS. Prevalence of newer beta-lactamases in gram-negative clinical isolates collected in the United States from 2001 to 2002. J Clin Microbiol 2006;44:3318-24.  Back to cited text no. 10
    
11.
Fontana C, Favaro M, Sarmati L, Natoli S, Altieri A, Bossa MC, et al. Emergence of KPC-producing Klebsiella pneumoniae in Italy. BMC Res Notes 2010;3:40.  Back to cited text no. 11
    
12.
Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010;10:597-602.  Back to cited text no. 12
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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