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Introduction Ventilator associated pneumonia (VAP) is one of the most frequent intensive care unit (ICU) acquired infections. In recent years there has been an increase in antibiotic resistance among causal agents of VAP. This study was carried out to assess the profile of culture isolates and their antimicrobial sensitivity from the endotracheal aspirates (ETA) of patients with clinically suspected ventilator associated pneumonia. Methods In this observational study, ETA was collected from patients who were on mechanical ventilation for >48 hours in the ICU with clinically suspected VAP. Samples were mechanically liquefied, homogenized and serially diluted for quantitative culture. Identification and antibiotic sensitivity of the isolate was performed using Vitek2 (BioMérieux, Marcy-l'Étoile, France). Results We received a total of 196 tracheal aspirates during the study period, out of which 100 samples showed growth. The most common isolate was A. baumannii (38%) followed by K. pneumoniae (33%). Among the Enterobacteriaceae group of organisms isolated (n=41), 37 isolates (90%) were extended spectrum beta lactamase (ESBL) producing organisms and 35% were metallo-β-lactamases (MBL) producers. All Staphylococcus aureus (n=3) isolates were methicillin resistant (MRSA). Conclusions Multidrug resistant organisms are now commonly reported from patients with VAP in our ICUs. A majority of the organisms were sensitive only to tigecycline and colistin. Our data suggest the need for strengthened infection control efforts in the intensive care unit, and for reevaluating compliance with the antibiotic stewardship programme.
Ventilator-associated pneumonia (VAP) is development of pneumonia more than 48 hours after placing a patient on mechanical ventilation. As high as 9-24% of patients admitted in the intensive care unit (ICU) and kept on mechanical ventilation for more than 48 hours may develop ventilator-associated pneumonia.1 It is the most common nosocomial infection among patients kept on mechanical ventilation and overall it is the second most common healthcare associated infection in the ICU after CAUTI (catheter-associated urinary tract infection).
Development of this nosocomial infection leads to prolonged hospital stay, increase in treatment cost, increase in morbidity as well as mortality. As per Hunter JD et al. as much as 50% of antibiotics used in the ICUs goes towards managing VAP cases.2 As most of the patients who are on mechanical ventilation are critically ill, it is difficult to calculate the attributable mortality rate of VAP. The attributable mortality rate has been reported to be as high as 33-50% for VAP.3
Hence, early and accurate diagnosis is the key for timely initiation of appropriate antimicrobial therapy leading to a favorable outcome. Inaccurate diagnosis may lead to inappropriate or inadequate antimicrobial therapy resulting in either treatment failure or emergence of antimicrobial drug resistance. To confirm a case of suspected VAP, microbiological quantitative bacterial culture of specimen preferably from lower respiratory tract, like endotracheal aspirate or bronchoalveolar lavage, should be done.4
Nowadays, in most of the tertiary care centers, highly drug resistant organisms are recovered from patients suffering from VAP. Any delay in initiation of appropriate antimicrobial therapy may increase mortality associated with VAP.3 We, at a tertiary care center in Maharashtra, report a very high prevalence of multidrug resistant Gram-negative bacilli among patients suffering from VAP.
Study population
This study was carried out at a multispecialty tertiary care center in Pune, Maharashtra with a 20-bedded ICU. This study included clinically suspected cases of VAP who underwent mechanical ventilation for a duration exceeding 48 hours in ICU. We received 196 non-repeat endotracheal aspirate (ETA) samples from these patients between January to December 2014 presenting with signs and symptoms clinically suggestive of VAP.
Diagnosis of VAP
All patients on mechanical ventilation (MV) were continuously monitored for the development of VAP using both clinical as well as microbiological criteria. Six different assessments were used as part of CPIS (clinical pulmonary infection score), each worth of 0-2 points. These six parameters were temperature (°C), WBC count (cells/mm3), nature/purulence of tracheal secretions, oxygenation status (defined by PaO2, FiO2), type of abnormality seen on chest radiograph (excluding coronary heart disease and acute respiratory distress syndrome), and results of bacterial culture from endotracheal aspirate specimen.5 Presence of ≥1 bacteria per field of oil immersion lens and >10 polymorphonuclear cells per low power field on Gram stain along with growth of ≥105 CFU/mL on quantitative culture was used as criteria for microbiological confirmation.6 Early onset VAP was defined in those patients developing VAP in the first 4 days of mechanical ventilation. Late onset VAP was development of VAP after 4 days of mechanical ventilation.3 Samples growing more than two types of organisms were reported as mixed growth and were not included in this study and a fresh specimen was requested if required.4 All microorganisms isolated were identified and the antimicrobial susceptibility testing performed using VITEK 2 automated identification system (bioMérieux, Marcy-l'Étoile, France).
MBL, ESBL, MRSA detection
Detection of metallo-β-lactamase (MBL) and extended spectrum beta lactamase (ESBL) was done among all the Gram negative bacilli and MRSA detection was done among all the staphylococci grown. Combination disk method was used for detection of ESBL.7 In this method, disks of ceftazidime (30 µg) and ceftazidime (30 µg) plus clavulanic acid (10 µg) were used on a lawn culture of test organism on Mueller Hinton agar plate. If the zone of inhibition around the combined disk was greater than 5 mm than the ceftazidime disk, then the isolate was considered as ESBL positive. Imipenem-EDTA combined disk test (DDST) was used to screen for the production of MBLs.8 In this method, the Imipenem disk was combined with EDTA (ethylenediaminetetraacetic acid) and the zone of inhibition around this combined disk was compared with that of the imipenem disk alone. An increase in the zone of inhibition of 7 mm or more was considered as MBL positive. Cefoxitin disk diffusion test was used for the detection of MRSA.9
A total of 446 patients were mechanically ventilated in the 20 bedded ICU during the study period. The underlying causes for mechanical ventilation of all the patients of this study are given in Table 1. Out of these, 196 patients were clinically suspected of having VAP depending on the criteria mentioned above and their ETA samples were sent for quantitative culture. A total of 100 samples had significant growth out of these 196 samples to label them as positive. So, the prevalence of VAP in this study was 22.46% (100/446 total ventilated patients). However, the VAP prevalence among the clinically suspected cases was 51% (100/196 suspected patients).
Table 1. Underlying illnesses for mechanical ventilation in 446 patients in ICUs during the study
Most of these confirmed VAP cases were late onset cases (78/100). Only 22 patients developed early onset VAP. Klebsiella pneumoniae was the most common organism responsible for the early onset VAP followed by Acinetobacter baumannii, whereas Acinetobacter baumannii was the most common organism followed by Klebsiella pneumoniaein late onset VAP.
Overall, in our hospital, most common isolate was Acinetobacter baumannii (38%) followed by Klebsiella pneumoniae (33%). Pseudomonas aeruginosa, Proteus spp., Staphylococcus aureus and E. coli were identified in 22 (21%), 4 (3.7%), 3 (2.8%) and 2 (1.8%) patients, respectively. (Figure 1).
A. baumannii was found to be highly resistant showing >70% resistance to gentamicin (75%) and amikacin (72.5%). Piperacillin-tazobactam and imipenem were also not showing much effectiveness, with a resistance of 87.5% and 67.5% respectively. The drugs to which the least percentage of resistance was reported on antimicrobial susceptibility testing were colistin and tigecycline (Table 2). Klebsiella pneumoniae was also showing very high resistance to all the third generation cephalosporins and >70% resistance to piperacillin-tazobactam and co-trimoxazole.
ESBL was present in a very large number of isolates (67 out of 103 GNBs), whereas MBL was found in 48 isolates. All of the Staphylococcus aureus (n=3) grown in this study were found to be methicillin resistant (MRSA) – Table 3.
VAP is one of the most common HAIs among ICU patients on mechanical ventilation. It is a leading cause of increased morbidity and mortality among patients admitted to intensive care units. In many settings, it is contributing to as high as one third of all the HAIs.10 Out of all the patients who require mechanical ventilation, around 10-20% develop VAP.11,12 The mortality rate among these patients varies from 15 to 50%. Moreover, patients developing VAP stay for a longer duration in ICUs and in hospital wards. On average, there is an increase of 6 days hospital stay once VAP develops and also increase in the treatment cost.
Development of VAP was reported to be an independent risk factor for the mortality of the patient over and above the primary disease for which the patient is admitted to the hospital.12 There are many studies in literature suggestive of increased mortality among the patients suffering from VAP. However, the attributable mortality reported for VAP is debatable and studies supporting this fact as well as contrasting this fact are available in the literature. Many large studies have found no significant association between VAP and mortality.10 This difference in results among various studies may be because of the different patient profile in different studies, different microorganisms responsible for the VAP, the severity of illness, other present co-morbidities, empirical and definite antimicrobial therapy prescribed and other host factors.
VAP is frequently associated with multidrug resistant bacteria further complicating the management of VAP and its final clinical outcome. Isolation of multidrug resistant bacteria increases the chances of inadequate empirical therapy and decreases the options for antimicrobial treatment, associating prolonged ICU stay and high chances of treatment failure. This increasing frequency of isolation of multidrug resistant microorganisms from VAP patients puts pressure on clinicians for starting appropriate empirical antibiotic therapy with reserved third line antibiotics. This leads to increase in overall antibiotic consumption in intensive care units. Many authors have found no increase in mortality due to high antimicrobial resistance, although few have reported association between resistant bacteria and increase in morality among VAP patients.13-15 As per Parker CM et al. patients with VAP growing multidrug resistant organisms or Pseudomonas aeruginosa from their cultures were showing significantly high 30-day mortality.14 Sandiumenge A et al. reported that VAP caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE group of organisms) pathogens had higher mortality as compared to non-ESKAPE VAP. Moreover, if the ESKAPE organisms were MDR, then the mortality rate was double as compared to other VAP patients.13 Tseng CC et al. also reported that among the patients with VAP, presence of MDR pathogens and Acinetobacter baumannii as causative agents, act as independent risk factors to increase mortality.15
Several methods for collecting a lower respiratory tract specimen have been proposed for diagnosing a case of VAP e.g., invasive bronchoscopic methods, bronchial biopsy, and a protected specimen brush. In observational studies, it was found that as compared to endotracheal aspirates, quantitative cultures of bronchoalveolar lavage fluid leads to better decision making, less antibiotic usage and lower mortality rates.16 However, there may be a delay in treatment of VAP if the bronchoscopic technique is used, because of various reasons such as: bronchoscopy requires trained manpower, it has an invasive nature leading to higher chances of complications, as well as its availability and the cost. Studies showed that when endotracheal aspirate (ETA) was used as the specimen of choice, the results of quantitative cultures were comparable to those of cultures using specimens collected with invasive bronchoscopic methods while comparing the clinical outcomes and the use of antibiotics. We have taken ETA as the specimen of choice from the lower respiratory tract for diagnosing VAP in this study.
Acinetobacter baumannii was found to be the most common organism isolated from 38% of patients suffering from VAP. Rajasekhar T et al. (2006) and Mukhopadhyay C et al. (2010) have also reported A. baumannii as the most common organism among patients suffering from VAP.17,18 However, few studies have reported other organisms such as those from the Enterobacteriaceae group of organisms, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus as the most common organism causing VAP. A. baumannii was found to be resistant to most of the antibiotics tested in this study with resistance as high as 50% and more for all the antibiotics tested except for colistin (Table 2).
Klebsiella pneumoniae was the second most common organism causing VAP in our hospital. Many authors have reported it as the least common organism causing VAP in the literature. Organisms such as Pseudomonas aeruginosa and E coli are reported to be more common than Klebsiella pneumoniae in many other studies.3 It is a known fact that all strains of K. pneumoniae are resistant to ampicillin as a result of the presence of a chromosomal gene encoding a penicillin-specific β-lactamase. Moreover, the hospital strains are commonly found to be carrying multidrug-resistant plasmids leading to resistance to multiple drugs.
P. aeruginosa was the third most common organism isolated in this study. As per Kollef MH et al. it is the most frequent species detected globally among ICU patients suffering from VAP.19 This organism carries special tropism for the epithelium lining the trachea. It can also colonize the lungs, mainly the lower respiratory tract of patients on mechanical ventilation.
There were no significant differences among the organisms isolated and their antibiotic susceptibility between the early and late onset VAP cases. Gastmeier P et al. and some other studies have also reported no difference among the early and late onset VAP isolates.20 Moreover, there was no association found between time of onset of VAP and ICU or hospital mortality due to VAP.
The isolated organisms were seen to be highly sensitive to colistin. Rit K et al. have also reported very high colistin sensitivity among organisms causing VAP.21 Many studies have shown that prevalence of extensively drug resistant (XDR) Acinetobacter spp. and Klebsiella spp. is increasing and colistin seems to be the only treatment left for these superbugs.22 Extensive drug resistance was defined as presence of resistance to all classes of antimicrobial agents except for one or two classes. As per Yun Cai et al., many studies have reported up to 40% colistin resistance among Acinetobacter baumannii spp.23 As per Aydin et al., maximum colistin resistance was observed in Klebsiella pneumoniae.24 It was also brought out that if colistin is used inappropriately, the chances of rapid development of resistance and therapeutic failure increase substantially. In addition to inappropriate use, past history of colistin use might also be a risk factor for a higher rate of heteroresistance to colistin.23
Rapid and reliable diagnosis of VAP is essentially required for optimal antibiotic treatment especially in the era of ever-increasing antimicrobial drug resistance. The emergence and spread of multidrug resistant pathogens can be prevented by an efficient infection control policy and practicing antibiotic stewardship. Practicing good infection control protocols, keeping a high degree of suspicion for development of VAP in the early days of mechanical ventilation, and timely diagnosis of VAP may lead to better outcomes.
Among the ICU patients suffering from VAP, inadequate empirical antimicrobial therapy is an independent predictor of mortality.25 Looking at very high drug resistance reported among microorganisms from patients suffering from VAP, it is highly recommended to start the patient on adequate empirical therapy with last resort reserve antibiotics and then to deescalate once the microbiology culture and antimicrobial susceptibility test report is available.
The most common organisms causing VAP were Acinetobacter spp., and Klebsiella spp. The maximum sensitivity was seen for tigecycline and colistin. Multidrug resistant organisms are now frequently reported in our ICUs, which is a cause of concern. Strengthened infection control efforts in the ICUs can decrease patient to patient transmission of these deadly multidrug resistant organisms.
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