|Year : 2017 | Volume
| Issue : 4 | Page : 504-510
Incidence of ventilator-associated pneumonia and impact of multidrug-resistant infections on patient's outcome: Experience at an Apex Trauma Centre in North India
Surbhi Khurana1, Purva Mathur1, Subodh Kumar2, Kapil Dev Soni3, Richa Aggrawal3, Priyam Batra1, Nidhi Bhardwaj1
1 Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India
2 Department of Surgery, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India
3 Department of Critical & Intensive Care, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||1-Feb-2018|
Dr. Purva Mathur
Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Introduction: Ventilator-associated pneumonia (VAP) remains one of the most common nosocomial infections in the Intensive Care Unit. In the face of extremely high rates of antimicrobial resistance, it is essential to gauge the clinical significance of isolation of multidrug-resistant (MDR) pathogens from clinical samples. This study details the trend of VAP and the clinical significance of isolation of MDR pathogens from respiratory samples at an Indian tertiary care hospital. Methods: The study was conducted over a 5-year period. VAP was diagnosed on the basis of centres for disease control and prevention criteria. The trend in the rates was compared with preventive measures. Phenotypic and genotypic resistance to beta-lactamases was determined using standard methods. The correlation of isolation of a multi-resistant pathogen with the clinical outcome, length of stay and cost of antimicrobial was ascertained. A clone of Acinetobacter baumannii identified through multilocus sequence typing was used to answer the question of whether resistant bugs always have a fatal outcome. Results: The total ventilator days (VDs) for these patients amounted to 36,278. A total of 433 episodes of VAP occurred during the study, amounting to an overall VAP rate of 11.9/1000 VDs. There was a decline in the rates of VAP over the 5-year period, due to intensive surveillance and preventive activities. A. baumannii (54%) was the most common pathogen, followed by Pseudomonas aeruginosa (21%). A high rate of MDR was seen, with the presence of extended-spectrum beta-lactamases, AmpC and carbapenemase genes. The presence of MDR was not always associated with a fatal outcome. Conclusions: Isolation of MDR pathogens from bronchoalveolar lavage does not always adversely affect the outcome of patients. It requires an interdisciplinary team of clinical microbiologists, physicians and hospital infection control nurses, to collectively manage these patients.
Keywords: Infection, multidrug resistance, outcome, ventilator-associated pneumonia
|How to cite this article:|
Khurana S, Mathur P, Kumar S, Soni KD, Aggrawal R, Batra P, Bhardwaj N. Incidence of ventilator-associated pneumonia and impact of multidrug-resistant infections on patient's outcome: Experience at an Apex Trauma Centre in North India. Indian J Med Microbiol 2017;35:504-10
|How to cite this URL:|
Khurana S, Mathur P, Kumar S, Soni KD, Aggrawal R, Batra P, Bhardwaj N. Incidence of ventilator-associated pneumonia and impact of multidrug-resistant infections on patient's outcome: Experience at an Apex Trauma Centre in North India. Indian J Med Microbiol [serial online] 2017 [cited 2019 Jun 25];35:504-10. Available from: http://www.ijmm.org/text.asp?2017/35/4/504/224414
| ~ Introduction|| |
There is a lot of discussion about the world heading toward the 'post-antibiotic apocalypse'. While this is indeed theoretically true, with the extremely high rates of multidrug-resistant (MDR) bacteria and the recent reports of colistin-resistant Klebsiella,, one needs to look into the important question of the significance of such bugs in the context of their clinical outcomes., This would enable rationalising antimicrobial use for true 'infections', prevent knee-jerk reactions to culture-positive reports and limit the quantum of unnecessary antimicrobials being used for patients.
Ventilator-associated pneumonia (VAP) is one of the major causes of mortality and antimicrobial consumption in hospitals worldwide. This study was conducted to ascertain the rates and trend of VAP over 5 years at a Level-1 Trauma Centre of India. This study also tries to ascertain the clinical significance and outcomes of infections caused by multi-resistant pathogens. 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 VAP. Being otherwise healthy, almost all infections developed by them are hospital acquired. We included a specific subgroup of patients in the study who were infected with the phenotypically similar clones of Acinetobacter baumannii to ascertain if patient's outcome is governed solely by the MDR pathogen recovered from clinical samples. The basic premise of our study was that if patients are infected with the same clone of pathogen, their clinical outcome would be the same if MDR alone governed the outcome.
| ~ Methods|| |
This study was conducted over 5 years at a 165-bedded Level-1 Trauma Centre of the 2400 bedded-hospital, New Delhi. The hospital has a robust surveillance system for HAIs, especially device-associated infections (DAIs) such as VAP, central line-associated bloodstream infections and catheter-associated urinary tract infections. There is a multi-disciplinary infection control team, consisting of clinicians, microbiologists and ten infection control nurses., The diagnosis of HAIs is done based on the centers for disease control and prevention (CDC's) National Healthcare Safety Network definitions. Intensive surveillance, feedbacks and control measures have significantly reduced the rates of all DAIs; however, the rates of MDR in Gram-negative bacteria (GNB) is very high.,
This study is divided into two parts: Part one details the trend of VAP in the Intensive Care Units (ICUs) (polytrauma and neurosurgery) of the Trauma Centre over 5 years. Previously published methodology of surveillance was used to ascertain the rates of VAP.
For the second part of the study, we included patients, whose bronchoalveolar lavage (BAL) samples were sent for bacterial culture, due to a clinical suspicion of VAP. A total of 74 patients who had monomicrobial culture isolation from BAL samples and who did not have any other concurrent infection during that time were included and followed up, for the sake of excluding confounding influence of other infections/polymicrobial infections on the outcome. VAP was defined as per the CDC's definitions. All the patients were prospectively followed throughout the ICU stay till their final outcome, as per our published surveillance methodology. The intensivists made the final diagnosis, based on defined criteria. Antimicrobials were used for treatment based on culture reports and as per the intensivist's decision.
The microbial identification of isolates was done by Vitek 2. The antimicrobial susceptibility testing of all isolates was done by the disc diffusion method on Mueller-Hinton agar according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Escherichia More Details coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27,853 were taken as control strains. The following antimicrobials were tested: ampicillin (10 μg), ampicillin/sulbactam (10/10 μg), amoxicillin (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 spp. and Pseudomonas spp.), amikacin (30 μg), gentamicin (10 μg), netilmicin (30 μg), ciprofloxacin (5 μg), levofloxacin (5 μg), tigecycline (15 μg, except for Pseudomonas spp.), polymyxin B (300U), colistin (10 μg) and chloramphenicol (30 μg). The interpretative zone diameters were used as per the CLSI recommendations.
Testing for extended-spectrum beta-lactamases production
Any isolate showing a reduced zone diameter of ceftazidime/cefotaxime/ceftriaxone/cefpodoxime/aztreonam was included for confirmatory testing for extended-spectrum beta-lactamases (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 genera suspected to be ESBL producers. However, since the CLSI does not recommend this to be confirmatory in genera other than E. coli, Klebsiella pneumoniae, Klebsiella oxytoca and Proteus. Mirabilis, the test was not used for interpretation of ESBL status in other genera. E. coli ATCC 25,922 (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 polymerase chain reaction (PCR), using the published primers.,
Testing for AmpC production
The CLSI ESBL screen was used to screen for plasmid-mediated AmpC β-lactamases. For phenotypic confirmation, the three-dimensional extract test and AmpC disc tests were performed as per standard methods. Plasmid-mediated AmpC-producing strains of K. pneumoniae HVAMC 39 (high-level ACT-1) and K. pneumoniae UMJMH14 (low-level DHA-1) and phenotypically β-lactamase-negative E. coli ATCC 25922 (actually possesses AmpC gene but only produces an insignificant amount of AmpC β-lactamase) were used as a control. Multiplex PCR for plasmid-mediated AmpC genes was performed as per published protocol.,
Laboratory detection of carbapenemases
The following parameters were used to suspect carbapenemase production: for E. coli or Klebsiella spp., an imipenem minimum inhibitory concentration (MIC) of ≥2 μg/ml; for Enterobacter spp., Serratia spp. and Citrobacter spp., an imipenem MIC of ≥4 μg/ml; for Acinetobacter spp., an imipenem MIC of ≥8 and for P. aeruginosa, an imipenem MIC of ≥16 μg. The CLSI recommended disc diffusion method was used and the Modified Hodge test was used for confirmation of carbapenemase production. The presence of blaIMP, blaVIM, blaOXA, blaKPC and blaNDM was detected by PCR.,
Multilocus sequence typing of Acinetobacter baumannii
For 16 isolates of Acinetobacter spp., multilocus sequence typing (MLST) was performed to determine clonality of the isolates by the following method: PCR amplification was performed at an annealing temperature of 50°C for seven genes. The A. baumannii complex MLST Oxford scheme was used, which is based on fragments of the following seven housekeeping genes (7 Loci): Citrate synthase (gltA), DNA gyrase subunit B (gyrB), Glucose dehydrogenase B (gdhB), Homologous recombination factor (recA), 60-kDa chaperonin (cpn60), Glucose-6-phosphate isomerase (gpi) and RNA polymerase sigma factor (rpoD).
The PCR primers used for sequencing, are shown in [Table 1], as given at http://pubmlst.org/abaumannii/info/primers_Oxford.shtml. The DNA extraction and PCR were done as per standard methods. The PCR program consisted of an initial denaturation step at 94°C for 3 min, followed by 35 cycles of DNA denaturation at 94°C for 30 s, primer annealing at 50°C for 30 s and primer extension at 72°C for 1 min. After the last cycle, a final extension step at 72°C for 7 min was added.
In a 96 Millipore plate, in each well, 46 μl of purified PCR product and 54 μl of sterilised and DNA-free water were added. This was followed by filtration over 10 min. About 50 μl of sterilised and DNA-free water was put in each well of the plate. The mixture was mixed on a vortex over 10 min. The purified PCR product was transferred in a plate.
Preparation for one reaction mix was done (one strain, one gene and one primer); water: 5 μl, ×5 Buffer: 1 μl, primer (4 μM): 1 μl, BigDye V1.1: 1 μl and 2 μl of purified PCR product were added in 8 μl of mix. The cycle sequencing program was standardised in our laboratory and consisted of an initial denaturation step at 94°C for 8 min, followed by 10 cycles of DNA denaturation at 94°C for 30 s, primer annealing at 41°C for 30 s and primer extension at 72°C for 1 min 15 s. After the last cycle, 20 cycles with 10 s increment on each cycle of 94°C for 30s and 41°C for 30 s. This was followed by a cycle at 72°C for 1 min 15 s and final extension step at 72°C for 10 min was added. About 10 μl of the PCR product was mixed with 6X gel loading buffer and loaded along with 100 bp plus DNA ladder in 1.5% (w/v) agarose gel prepared in 0.5 × TAE (Tris-acetate-ethylenediaminetetraacetic acid [EDTA]) buffer. The gel was examined by ultraviolet light in GEL-DOC system.
To each well of the plate, 1 μl of sodium acetate 3M, 1 μl of EDTA 125 mm and 50 μl of 95% ethanol were added. The plate was turned down 10 times followed by centrifugation for 30 min at 3300 RPM. The supernatant was discarded. The plate was returned on a paper and centrifuged for 1 min at 1000 RPM. Then, 50 μl of 70% ethanol was added and centrifuged for 15 min at 3300 RPM. The supernatant was discarded. The plate was returned on a paper and centrifuged for 1 min at 1000 RPM. The plate was dried on the laboratory table for over 15 min and conserved at-20°C.
Sequence analysis and determination of Sequence Type
The MLST genes sequences were analysed against the Sequence query – A. baumannii MLST (Oxford) to determine the alleles of each loci (http://pubmlst.org/perl/bigsdb/bigsdb.pl?db=pubmlst_abaumannii_oxford_seqdefandpage=sequenceQueryandset_id=1) followed by determination of the sequence type using search A. baumannii MLST (Oxford) database by combinations of loci (http://pubmlst.org/abaumannii/)
For each case, a specific pro forma was filled, detailing the clinical and microbiological findings. The following questions were filled by the intensivists:
- Was the pathogen causing true infection?
- Was antimicrobial changed after culture reports?
- Did the patient improve?
- In their opinion, did the patient have an increased length of stay?
- Was there an increase in the antimicrobial cost?
- Was there an increase in antimicrobial duration?
- Was this infection a trigger for patient's death?
- What was the duration of treatment?
- Was monotherapy/combination therapy used for treatment?
For statistical analysis, a P < 0.05 was considered as statistically significant.
The study was funded by a grant from the Indian Council of Medical Research and was ethically approved by the institute's ethical committee.
| ~ Results|| |
This study was conducted from January 2010 to July 2015. A pilot study was conducted from January to April, 2010 to ascertain the baseline rate of DAIs. Subsequently, an automated, systematic surveillance was conducted using an indigenously developed software, which has become a routine practice at our centre. For the purpose of assessing the impact of the surveillance and infection prevention activities on the rates of VAP, the data were stratified into yearly time periods.
During the study period, a total of 5459 patients were admitted to the ICUs of the trauma centre for >48 h, amounting to a total of 52,360 patient days. The details of these patients are given in [Table 2].
|Table 2: Trend of ventilator-associated pneumonia and effect of preventive measures over the study period|
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The total ventilator days (VDs) for these patients amounted to 36,278. A total of 433 episodes of VAP occurred during the study, amounting to an overall VAP rate of 11.9/1000 VDs. The declining rates of VAP over the study years are shown in [Table 2]. A. baumannii (54%) was the most common pathogen, followed by P. aeruginosa (21%), K. pneumoniae (13%), E. coli (3%), S. aureus (3%), Stenotrophomonas maltophilia (2%), Burkholderia cepacia (1%), Providencia spp. (0.7%) and Candida spp. (0.7%). The percentage susceptibility of pathogens is shown in [Table 3]. The details of ESBL, AmpC and carbapenemase production is shown in [Table 4].
|Table 3: Percentage antimicrobial susceptibility of bacterial pathogens isolated from cases of ventilator-associated pneumonia|
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|Table 4: Prevalence of extended-spectrum beta-lactamase, AmpC and carbapenemases in multidrug-resistant pathogens from ventilator-associated pneumonia and non-ventilator-associated pneumonia cases (n=74)|
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Correlation between ventilator days and development of ventilator-associated pneumonia
[Table 5] shows the correlation between VDs and predisposition for development of VAP. There was a highly significant correlation between VDs and development of VAP. Thus, the 1008 patients having VDs of >10 had a significantly higher rate of VAP (P < 0.0001), as compared to 4137 patients having VDs <10.
|Table 5: Correlation between ventilator days and development of ventilator-associated pneumonia|
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To ascertain the significance of MDR bugs on the outcome of VAP, a total 74 patients were included in the second part of the study, with 61 (82%) were male and 13 (17.5%) were female. The age group of the patients ranged from 5 to 78 years.
Of these, 34 (46%) patients had VAP as per the CDC's definition. The remaining 40 (54%) did not fit into the definition of VAP; for the purpose of this study, they were coined as colonisers/culture-positive MDR isolates since the organisms were isolated in pure culture in counts ≥105/ml of BAL, but the patients did not fit into the CDC's diagnostic criteria for VAP. The most common GNB causing both infections and colonisation was Acinetobacter spp.; 12 (35%) and 17 (42.5%), respectively. Representative strains of Acinetobacter spp. were subjected to MLST to ascertain clonality.
Among the patients diagnosed with VAP, 21 (61%) were discharged with complete recovery. Septic shock, head injury and cardiac arrest were the most common causes of death in the 13 patients who had a fatal outcome. Among the patients who only had a culture-positive BAL, 5 (12.5%) had a fatal outcome. The profile of patients, their clinical outcome and details of antimicrobial treatment are provided in [Table 6].
|Table 6: Comparison of patient profile and outcome in ventilator-associated pneumonia cases and culture positive, non-ventilator-associated pneumonia cases|
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Clonal strains of Acinetobacter spp. and their clinical outcomes
The MLST analysis revealed that the representative strains of Acinetobacter spp. were closely related. [Table 7] shows the relatedness of the strains. Strains in each group were closely related strains. S1 and S3 in group I and S4, S5 and S12 in Group V were found to be 100% clonal. S8 and S21 belonged to already existing sequence types; rest of the strains did not belong to any existing sequence type.
As shown in [Table 8], it was found that only one (S14) of the three very closely strains in Group I caused VAP while the other two (S1 and S3) were found to be colonisers. Two closely related strains (S8 and S9) in Group II caused VAP, but only one of these patient's final outcome was fatal. Similar outcomes were observed in patients from whom strains belonging to Group III (S15 and S20) were isolated. Despite being infected with genetically similar strains, only 50% (1) of the strains in each group caused infections and the patient outcomes were also not identical, only 50% (1) of the patients affected by these strains belonging to each group survived. However, the patients from whom strains belonging to Group V were isolated, were all discharged.
|Table 8: Correlation of relatedness and pathogenicity of the strains with patient outcomes|
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| ~ Discussion|| |
We are witnessing unprecedented antimicrobial resistance (AMR), with a very few new agents in sight. It is important to save last resort antimicrobial agents for only those in dire need. Our study highlights that not all 'MDR isolations' need treatment. Moreover, the final objective outcome of fatality was not always governed by the presence of a highly resistant bug isolated from the patients.
We can significantly reduce the bulk of antimicrobial consumption if due consideration is given to clinical definition of infections and risk-modification. More time and money need to be invested in developing antimicrobial stewardship programs and bundle-based preventive approaches to DAIs. We have found that intensive surveillance, feedbacks, training and preventive interventions can significantly reduce the burden of fatal infections like VAP, which are the most common causes of antimicrobial administration in the ICUs. Developing a taskforce trained in preventive efforts and quality-assured laboratory detection of MDR will reap much more dividends for developing nations. AMR control through infection prevention has been a major theme of the Global Health Security Agenda (GHSA), for which India is a signatory. Our institute will be leading one such agenda on AMR control as a core action package of GHSA.
A. baumannii is known to be a significant opportunistic pathogen causing nosocomial infections. Despite carbapenems being the drug of choice to treat infections caused by multidrug-resistant A. baumannii, our strains had high resistance to carbapenems (93%) along with up to 50% carbapenem genes positivity. Thus, we specifically included a group of patients who were infected with the same clone of A. baumannii. A variable outcome in these 16 patients signifies that patient-factors (type and severity of trauma in our case), nutrition, general constitution, age and probably immune response may be equally responsible for governing outcome of patients.
A close liaising between microbiology, infection control specialists and clinical services would help to curb the excessive use of antimicrobials.
Infections, even with multi- and pan-drug-resistant GNB are not always fatal and need to be rationally treated.
| ~ Conclusions|| |
Even with a considerable attributable mortality, VAP remains a single a component of a larger assemblage of unfavorable events, such as acute respiratory distress syndrome and multiorgan dysfunction syndrome, which potentially increase the morbidity, mortality, hospital length of stay and cost of care in mechanically ventilated patients. Mere isolation of MDR pathogen does not always adversely affect the outcome of patients. Adherence to the best practices standards of hospital infection control, decreasing antibiotic exposure during hospitalisation would, in turn, reduce the acquisition and even the spread of MDR pathogens. In addition, this leads to reduction of the duration of ventilator dependence and the subsequent incidence of all classifications of ventilator-associated events. With such practices, reduced incidence and mortality among hospitalised patients suffering from VAP has been observed in other developed countries as well., It requires an interdisciplinary team of clinical microbiologists, physicians and hospital infection control nurses, to collectively manage these patients.
We acknowledge the support of Trauma Centre for providing the facilities for the performance of this study.
Financial support and sponsorship
This study was funded by a grant from the Indian Council of Medical Research.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]