|Year : 2018 | Volume
| Issue : 1 | Page : 4-11
Prevalence of Multidrug-Resistant Pathogens and Their Antibiotic Susceptibility Pattern from Late-Onset Ventilator-Associated Pneumonia Patients from a Tertiary-Care Hospital in North India
Varsha Gupta1, Nidhi Singla1, Satinder Gombar2, Sanjeev Palta2, Jagdish Chander1
1 Department of Microbiology, Government Medical College and Hospital, Chandigarh, Punjab, India
2 Anaesthesia and Intensive Care Unit, Government Medical College and Hospital, Chandigarh, Punjab, India
|Date of Web Publication||3-Jan-2018|
Department of Microbiology, Government Medical College and Hospital, Chandigarh, Punjab
Source of Support: None, Conflict of Interest: None
Background: Ventilator-associated pneumonia (VAP) is seen as being most common in critically ill patients in intensive care units. Diagnostic protocol is challenging and the treatment is often difficult. Incorrectly selected antibiotic therapy further leads to the emergence of multidrug-resistant (MDR) organisms. Materials and Methods: The present prospective study was conducted to study patients of VAP with the aim of determining the aerobic bacterial etiological agents, antimicrobial susceptibility patterns, and molecular detection of MBL (metallo beta lactamase) genes. The antimicrobial susceptibility of the isolates by the disc diffusion method and the detection of various drug-resistance mechanisms was done. The minimum inhibitory concentration (MIC) based on E-test was determined along with the molecular analysis by polymerase chain reaction for detection of MBL genes (IMP and VIM). Results: Out of a total of 372 patients admitted in intensive care unit during the time period (March 2010 to February 2013), 40 patients were finally diagnosed as having late-onset VAP. Among the study isolates (69, due to polymicrobial infection), the maximum isolates were Acinetobacter spp. (32) followed by Pseudomonas aeruginosa (18), Klebsiella pneumoniae (8), and others. MDR was high with 34% of Acinetobacter and 50% of Pseudomonas strains being MBL producers. Among Staphylococcus aureus, 50% strains were methicillin resistant. On molecular analysis, eight of the Acinetobacter and six of the Pseudomonas isolates came out to be positive for VIM 2 gene, whereas IMP was not detected in any of the isolates. Conclusion: The present study emphasizes the threat of MDR in VAP patients from ICU as the treatment options are limited. The knowledge of prevailing organisms, resistance mechanisms, and their antibiotic profile can go a long way in deciding appropriate empirical therapy.
Keywords: Antibiotic resistance, etiology, North india, ventilator-associated pneumonia
|How to cite this article:|
Gupta V, Singla N, Gombar S, Palta S, Chander J. Prevalence of Multidrug-Resistant Pathogens and Their Antibiotic Susceptibility Pattern from Late-Onset Ventilator-Associated Pneumonia Patients from a Tertiary-Care Hospital in North India. J Assoc Chest Physicians 2018;6:4-11
|How to cite this URL:|
Gupta V, Singla N, Gombar S, Palta S, Chander J. Prevalence of Multidrug-Resistant Pathogens and Their Antibiotic Susceptibility Pattern from Late-Onset Ventilator-Associated Pneumonia Patients from a Tertiary-Care Hospital in North India. J Assoc Chest Physicians [serial online] 2018 [cited 2018 Aug 20];6:4-11. Available from: http://www.jacpjournal.org/text.asp?2018/6/1/4/217315
| Introduction|| |
Ventilator-associated pneumonia (VAP) is a form of nosocomial pneumonia in ICU patients occurring 48 to 72 h after the onset of mechanical ventilation (MV). Patients in such conditions are usually immunocompromised, and the diagnosis of the infection is difficult due to absence of typical sign and symptoms. Colonization of the upper respiratory tracts of most of the ventilated patients further complicates the problem. It has been postulated by numerous investigators that “invasive” diagnostic methods require technical expertise and adds to the cost of care. They may show both false-positive and false-negative results. In an attempt to overcome these limitations, nonbronchoscopic distal airway sampling methods have emerged, which are less demanding, simple, and inexpensive and thus, can be helpful in simplifying the diagnosis of VAP.
The agents causing VAP may be a part of the host’s endogenous flora or may be acquired exogenously from other patients, healthcare workers, devices, or the hospital environment. VAP is of two types: early-onset and late-onset. Early-onset VAP is often caused by Staphylococcus aureus, Streptococcus pneumoniae, or Haemophilus influenzae, whereas late-onset VAP is more frequently caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter spp., or methicillin-resistant S. aureus (MRSA). Antimicrobial susceptibility testing of the isolates is another determining factor. Taking all these facts into account, the present prospective study was conducted to study patients of late-onset VAP in a tertiary healthcare center of North India with the aim of determining the aerobic bacterial etiological agents involved with the help of tracheal aspirate (TA) and bronchoalveolar lavage (BAL), their antimicrobial susceptibility pattern, presence of drug-resistance mechanisms, such as β-lactamase production in relevant isolates [extended spectrum beta-lactamase (ESBL) in Enterobacteriaceae and metallo beta lactamase (MBL) in nonfermenters)], MRSA, vancomycin intermediate S. aureus, and vancomycin-resistant Enterococci. The minimum inhibitory concentration (MIC) based on Etest for ESBL and MBL was also determined for relevant isolates. The molecular analysis by PCR for detection of MBL genes (IMP and VIM 2) was done to find out the relevant subtype.
| Materials and methods|| |
The study was conducted on critically ill patients admitted in the 14-bedded ICU of a tertiary-care hospital of North India. The ICU is run by a full-fledged Department of Anaesthesia and Intensive Care with round-the-clock available faculty, residents, and paramedical staff. There is an institutional antibiotic policy in place and strict infection control practices are regularly followed. Standard infection control protocols like hand hygiene, use of personal protective equipment, transmission-based precautions of contact, droplet, and airborne disease prevention are used regularly with environment surveillance protocol.
All adult (more than 18 years) constitutive patients, irrespective of sex, who were on MV for more than 48 h, having a new and persistent (>24 h) infiltrate on chest X-ray, having macroscopically purulent TAs, and having a clinical status permitting flexible fibreoptic bronchoscopy during the 3-year period (consisting of 372 patients) were included in this study. All those patients with other causes of radiological infiltrates like pulmonary embolism, pulmonary hemorrhage, atelectasis, congestive heart failure, and adult respiratory distress syndrome were excluded. The work done was explained to all the patients in detail and due consent was taken.
The clinical diagnosis of pneumonia was established on the basis of the appearance of new or persistent radiological infiltrates along with two of the following criteria: temperature of 38°C or more, leucocytosis ≥12,000/mm3, and purulent aspirate. Endotracheal aspirate of each patient was collected and transported to laboratory within 15 to 20 min. Bronchoscopy was done and BAL was taken, whenever possible, in patients suspected of VAP and in whom endotracheal aspirate was purulent and showed significant growth. After collection of specimens, Gram stain procedure was performed on all the samples. Qualitative and quantitative analysis of growth was done using standard loop technology. The samples were inoculated onto 5% blood agar and chocolate agar using 0.01 and 0.001 mL calibrated loop and incubated for 24 h at 37°C aerobically. The cutoff criteria was taken as 105 CFU/mL for endotracheal aspirate and 104 CFU/mL for BAL to differentiate between pathogens and contaminants. Isolates in pure growth or mixture of two organisms at quantitative threshold were considered significant and identified by standard conventional methods.
The antimicrobial susceptibility testing was performed by standard disk diffusion method as recommended by Clinical Laboratory Standard Institute. Gram-negative bacilli were tested for the following antimicrobials (μg): amoxicillin/clavulanic acid (30), cefotaxime (30), ceftriaxone (30), ceftazidime (30), cefepime (30), cefoperazone/sulbactam (75/30), imipenem (10), amikacin (30), gentamicin (10), ciprofloxacin (5), and piperacillin-tazobactam (100/10). Gram-positive cocci were tested for penicillin (10 U), amoxicillin/ampicillin (30), cephalexin (30), erythromycin (15), clindamycin (2), cotrimoxazole (25), cefoxitin (30), linezolid (30), vancomycin (30), and tetracycline (30). All carbapenem-resistant gram-negative organisms were also checked for colistin (1) and polymyxin (1) susceptibility.
The detection of methicillin resistance and vancomycin resistance in Staphylococci and vancomycin resistance in Enterococci were done via agar screen and dilution method. MIC values were also calculated via E-test strips (AB Bio disk, Solna, Sweden) for the following drugs: cefoxitin/methicillin, vancomycin, teicoplanin, linezolid, and pristinamycin.
ESBL detection in Enterobacteriaceae organisms was done based on CLSI recommendations. The detection of MBL was done in Pseudomonas and Acinetobacter species isolates from VAP patients by modified-ethylene diamine tetra acetic acid disc synergy test and the double disc synergy test., Further, we have also used E-test strips (AB Bio disk) for ESBL and MBL detection.
Escherichia More Details coli strain ATCC 25922, S. aureus ATCC 25923, P. aeruginosa ATCC 27853, Klebsiella pneumoniae subspecies pneumoniae ATCC 700603, and Enterococcus faecalis ATCC 51299 were used as control strains.
Methodology for PCR
Extraction: Fresh culture of the test organism and the control strains were suspended in 500 μL of saline and vortexed to get a uniform suspension. The cells were lysed by heating them at 100°C for 10 min, and cellular debris were removed by centrifugation at 8000 rpm for 5 min. The supernatant was used as a source of template. An amount of 20 μL of master mix in the individual amplification tubes was dispensed with 5 μL of the extracted deoxyribose nucleic acid added in the corresponding tubes, the total volume being 25 μL.
Primers used were as follows: VIM-Forward (5′-GTT TGG TCG CAT ATC GCA AC-3′), VIM-Reverse (5′-AAT GCG CAG CAC CAG GAT AG-3′), which amplified a 382-bp amplicon and IMP-Forward (5′-GAA GGY GTT TAT GTT CAT AC-3′), IMP-Reverse (5′-GTA MGT TTC AAG AGT GAT GC-3′), which amplified a 587-bp amplicon.
Amplification was done in thermal cycler as Initial denaturation step was at 94°C for 2 min followed by 30 cycles of DNA denaturation at 94°C for 1 min, primer annealing at 54°C for 1 min, and primer extension at 72°C for 15 min with a holding temperature of 72°C for 5 min. After the last cycle, PCR products were stored at 4°C. PCR products were analyzed by electrophoresis with 1.5% Agarose gels in TBE buffer (supplied by SRL Sisco Research Laboratories Private Laboratories, Mumbai, India).
| Results|| |
A total of 372 patients, who were admitted in ICU during the time period from March 2010 to February 2013, were studied. Out of these, 40 patients were finally diagnosed as having late-onset (after 96 h of incubation) VAP. Among these, 37 patients had positive BAL findings, which correlated well with their TA culture results. However, three patients had sterile BAL but significant (>105) CFU/mL TA results and so were diagnosed as having VAP. Overall, the VAP rate was 26.4 cases per 1000 ventilator days. All these patients had clinical pulmonary infection score >6.
Demographically, the maximum numbers of VAP patients (14) were in age group 16 to 30 years [Table 1]. The maximum number of patients of VAP were admitted in ICU due to surgical intervention following roadside accidents, perforation, respiratory illness, and others [Table 2]. Out of 40 patients, the total stay in ICU during the present visit was less than 5 days for only two patients but was more than 6 days for 38 patients. The number of patients who were on MV for ≤30 days were 20, 17 patients stayed on ventilator for 31 to 90 days, and only three patients stayed on ventilator for upto 120 days [Table 3]. As far as risk factors are concerned, maximum patients of VAP had undergone surgery due to one or the other reason. In a number of patients, parenteral therapy was one of the risk factors; antibiotic therapy was also commonly related risk factor. The final outcome was not favorable for 15 patients who expired; the rest who recovered well were shifted to their respective wards before discharge.
|Table 1: Age- and sex-wise distribution of ventilator-associated pneumonia and nonventilator-associated pneumonia patients|
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|Table 3: Variables influencing the development of ventilator associated pneumonia|
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Polymicrobial infection was seen in 24 (60%) patients, whereas monomicrobial was seen in 16 (40%) patients. The total number of isolates were 69 [Table 4].
|Table 4: Organism profile from ventilator-associated pneumonia patients (total number of isolates – 69)|
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Among Acinetobacter spp. (32), a high level of resistance was seen to ciprofloxacin (81%), amikacin (71.8%), gentamicin (70.7%), cefoperazonesulbactam (59.3%), piperacillin-tazobactam (53.1%), and imipenem (40.6%), whereas less resistance was seen to cefotaxime (31.2%) and cefepime (21.05%). The resistance to meropenem was seen in 43.7% of the isolates [Table 5]. All the strains tested were sensitive to colistin and polymyxin B. These strains were further tested for MBL production by meropenem − EDTA-combined disk test and Etest. Out of these, 11 were found to be MBL producers by meropenem − EDTA-combined disk test and all of them were further confirmed by Etest too. On molecular analysis, eight of the isolates came out to be positive for VIM 2 whereas IMP gene was not detected in any of the isolates.
|Table 5: Resistance percentages of three most common isolates from ventilator-associated pneumonia patients|
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Among Pseudomonas spp. (18), the isolates were mostly susceptible to colistin and polymyxin B (100%), whereas a high level resistance was seen to antibiotics namely, cefoperazone-sulbactam (88.8%), gentamicin (88.8%), ciprofloxacin (77.7%), amikacin (72.2%), piperacillin-tazobactam (55.5%), and meropenem (50%) (9/18) [Table 5]. These strains were further tested for MBL production by meropenem − EDTA combined disk test and Etest. Out of these, all nine were found to be MBL producers by meropenem − EDTA combined disk test and all of them were further confirmed by Etest too. On molecular analysis, six of the isolates came out to be positive for VIM 2, whereas IMP gene was not detected in any of the isolates [Table 6].
|Table 6: Determination of drug resistance-mechanisms (phenotypic and molecular) in multidrug-resistant pathogens|
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Among Enterobacteriaceae, maximum isolates were K. pneumoniae (8), followed by E. coli (4) and Proteus mirabilis (2) [Table 5]. All ceftriaxone-resistant strains of Klebsiella and E. coli were also found to be ESBL producers.
Among Gram-positive cocci (5), three were E. faecalis, whereas two were MRSA and MSSA (Methicillin sensitive S. aureus), respectively. All were sensitive to vancomycin and linezolid.
| Discussion|| |
VAP contributes to approximately half of all cases of hospital-acquired pneumonia. VAP is estimated to occur in 9 to 27% of all mechanically ventilated patients, with the highest risk being early in the course of hospitalization. Epidemiologic investigations have shown that rates vary according to clinical population and type of critical care but are in the order of 7.5 to 34 per 1000 ventilator days. According to data from the National Nosocomial Infection Surveillance System, VAP occurs at a rate of 7.5 per 1000 ventilator days in medical ICUs and 13.6 per 1000 ventilator days in surgical ICUs. Crude mortality rates of 10 to 40% are being reported by different studies with attributable mortality rates between 5 and 27%. However, it could be higher for organisms such as Pseudomonas or Acinetobacter. Certainly the length of hospital stay and cost are both increased in patients who develop VAP. In our study, out of 372 patients, 40 developed VAP, that is, 10.7%, and the incidence density was 26.4 per 1000 ventilator days.
Demographically, the maximum number of VAP patients were in age group of 16 to 30 years. The majority were males. The fact has been supported by other authors previously. The maximum number of patients were admitted in ICU due to surgical intervention followed by roadside accidents, respiratory illness, and others. Out of 40 VAP patients, the total stay in ICU during the present visit was more than 10 days for 35 patients. The number of patients who were on MV for less than 30 days were 20 (one patient was on MV for less than 4 days), 17 patients stayed on ventilator for 31 to 90 days and only three patients stayed on ventilator for upto 120 days. The most important risk factor for nosocomial pneumonia is tracheal intubation; associated with a 3 to 21-fold risk. The duration of MV increases the risk of infection. Ventilator-associated conditions (VACs) and infection-related ventilator-associated complications (iVACs) are new surveillance paradigms for patients who are mechanically ventilated in the Centers for Disease Control and Prevention’s. Little is known regarding the clinical impact and preventability of VACs and iVACs, and their relationship to VAP. VACs and iVACs are associated with significant morbidity and mortality. Although the agreement among VAC, iVAC, and VAP is poor, a higher adoption of measures to prevent VAP was associated with lower VAP and VAC rates.
As far as other risk factors are concerned, independent risk factors for development of VAP are taken to be male sex, admission for trauma, and intermediate underlying disease severity, with odds ratios of 1.58, 1.75, and 1.47 to 1.70, respectively. In our study, maximum patients of VAP had undergone surgery due to one or the other reason. In a number of patients, parenteral therapy was one of the risk factors, and antibiotic therapy was also a commonly related risk factor. The effect of prior antibiotic therapy is still controversial. Once clinically suspected, empiric coverage decreases morbidity and mortality. In a study, it has been demonstrated that patients who received empiric coverage exhibited a significantly different microbiologic profile compared to those who had an initial positive BAL culture. Initial empiric antibiotics in BAL-negative patients were not associated with an increase in MDR organisms, hospital, length of stay in intensive care units, ventilator days, and mortality or secondary infections. However, there is a risk that prior antibiotic exposure predisposes patients to subsequent colonization and infection with resistant pathogens.
The final outcome was not in favor for 15 patients who expired, whereas 25 patients who recovered well were shifted to their respective wards before discharge. Earlier studies places the attributable mortality for VAP at between 33 and 50%, but this rate is highly variable and depends on the underlying medical illness. Over the years, the attributable mortality has decreased and is presently estimated to be 9 to 13%, due to advanced prevention strategies and their effective implementation. This is true of the picture in developed countries, in India figures would still be high.
Infectious organisms which cause VAP are generally different from those that are associated with community-acquired pneumonia. Early-onset pneumonia in mechanically ventilated patients (within 4 days) may be caused by indigenous flora. Gram-negative organisms, typically P. aeruginosa, Enterobacter species, K. pneumoniae, and Acinetobacter species, are responsible for the majority of late-onset VAP and are commonly antibiotic resistant. Among the study isolates, maximum isolates were Acinetobacter spp. (32) followed by P. aeruginosa (18). Polymicrobial infection was seen in 24 patients (60%), whereas monomicrobial was seen in 16 patients. Polymicrobial infection rate is usually high in VAP patients., In our study, the incidence of nonfermenters like Acinetobacter baumannii and P. aeruginosa was quite high. These organisms are commonly associated with certain risk factors like increased use of corticosteroid therapy, malnutrition, pre-existing lung disease (bronchiectasis, cystic fibrosis), late-onset VAP, and prior antibiotic exposure. In many of our patients, history of prior antibiotic use was present, and all were late-onset VAP.
Both Pseudomonas and Acinetobacter are being reported increasingly from VAP cases. Also antibiotic resistance is quite prevalent. Carbapenem resistance is also increasingly being reported. In our study, among Acinetobacter spp. (32), high-level resistance was seen to ciprofloxacin (81%), amikacin (71.8%), gentamicin (70.7%), cefoperazone sulbactam (59.3%), piperacillin-tazobactam (53.1%), and Imipenem (40.6%). The resistance to meropenem was seen in 43.7% isolates. Out of 32, 11 isolates were found to be MBL producers. Among Pseudomonas spp. (18), the isolates were most susceptible to colistin (100%) and polymyxin B (100%), but high-level resistance was seen to cefoperazonesulbactam (88.8%), gentamicin (88.8%), ciprofloxacin (77.7%), amikacin (72.2%), piperacillin-tazobactam (55.5%), and meropenem (50%) (9/18). These nine strains were also MBL positive by phenotypic testing. On molecular analysis, eight of the Acinetobacter isolates and six of the Pseudomonas isolates came out to be positive for VIM 2 gene, whereas IMP was not detected in any of the isolates.
MDR is a growing problem in hospital settings. In our study, more than 70% of nonfermenters and more than 80% of K. pneumoniae strains were MDR, which is a huge burden of MDR organisms being isolated. VAP patients are also known to harbor these organisms. The incidence of MDR P. aeruginosa and Acinetobacter has been found to be 40 and 37.5%, respectively, in VAP patients by Golia et al. in Bangalore, India. In another study from Karnataka, the prevalence of MDR among the Acinetobacter group was to the tune of 84.5%, whereas from Lucknow, carbapenem-resistant Acinetobacter was reported to be 75% among VAP isolates., blaIMP- and blaVIM-mediated carbapenem resistance in Pseudomonas and Acinetobacter species has been reported from India.
Longer hospital and ICU stay, longer time on MV, exposure to antimicrobial agents, colonization pressure, invasive procedures, underlying severity of illness, and reintubation, all are recognized factors for increasing the risk of MDR A. baumannii infection.
There have been reports of prevalence of MBLs in P. aeruginosa and Acinetobacter species in intensive care areas in a tertiary-care hospital from India.
Emergence of carbapenem-resistant A. baumannii and Pseudomonas in ICUs led to modification in empirical therapy of VAP to incorporate the polymyxin and colistin. However, there is concern that like emergence of resistance to carbapenems, colistin resistance will also emerge due to clonal selection and will leave us with effectively untreatable diseases A. baumannii infections.
The present study shows the appearance of MDR organisms in the hospital settings and is called as post-antibiotic era. In such patients, treatment options are already severely limited and the disease process can be fatal.
From time to time, the guidelines for prevention of VAP are issued by CDC (Centre for Disease control and Prevention). Just like other infectious diseases, in the case of VAP too, prevention is the best cure, and the key is in hands of healthcare personnel, especially the nursing staff taking care of patients. An initiative was taken by Institute for Healthcare Improvement in 2005 and the “VAP bundle” was introduced as part of the “100,000 Lives Campaign” to take care of ventilated patients, another parameter of daily oral care with chlorhexidine was added in 2010., It has been observed that evidence-based medicine strongly favors these interventions and if implemented together can significantly improve the outcome in the ventilated patients.
We conclude that determination of the organism profile and their antibiotic sensitivity can go a long way in prescribing appropriate regimen which could be life saving. Another important aspect in VAP group of patients is that if the antibiotic therapy is delayed, there could be excessive mortality. Early report regarding antibiotic susceptibility patterns could be significant in deciding the antibiotic regimens. In this regard, we suggest the use of E-test strips which can tell not just about drug resistance patterns but also about respective MIC values which can be difficult and time consuming if determined by conventional method of broth microdilution. Molecular testing further can be rapid and can detect low quantity of target sequences of drug-resistant genes independent of the viability of target organisms. They can also be multiplexed to detect multiple resistance mechanisms simultaneously, so that the requisite and effective treatment can be initiated at the earliest in a life-threatening condition such as VAP.
Financial support and sponsorship
This work has been funded by ICMR as an extramural research project.
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]