Microbiology of Ventilator-associated Pneumonia in a Tertiary Care Cancer Hospital

Gender and Age Distribution

There were 710 (66.10%) males and 364 (33.90%) females in the ratio of 2:1 in our study. The VAP incidence was higher in males than in females. Sharpe et al.²⁷ studied 854 patients over 8 years in the ICU of Memphis, United States (US), observed a significantly higher incidence of VAP of 3.8% among males compared to 2.6% in females. In the present study, there was an increase in VAP with an increase in the age of the patient, but the correlation was not statistically significant (p value = 0.673).

A study conducted by Dey et al.¹⁵ showed that a significantly higher VAP was acquired in 46-to 60-year age-group. Old age, underlying chronic lung disease, and previous antibiotic exposures were associated with a higher risk for developing VAP reported in studies.^28,29

Service-wise Distribution of VAP Cases

In the cases analyzed, the highest number of patients belonged to hematolymphoid, thoracic, and head and neck services.

Groeger et al.⁶ also found that VAP was highest in hematolymphoid malignancy than solid tumor group, while study by Park³⁰ showed that the highest VAP was associated with solid tumor group, i.e., lung cancer cases, as lung cancer is among the most commonly diagnosed malignancies in the world and cigarette smoking has been shown to be a strong risk factor for the subsequent development of lung cancer. The cancer patients in our ICUs are on aggressive chemotherapy regimens, have low neutrophil count, and may develop drug toxicity. They are intubated for respiratory distress and stay in the ICU for a long duration on mechanical ventilation. These factors render them prone to developing VAP. However, surgical postoperative cases require shorter periods of ventilation, making them less prone to the development of VAP.

Microbiology

There were 827 bacterial isolates seen in this study. These included 780 (94.32%) gram-negative organisms and 47 (5.68%) gram-positive microorganisms.

In a meta-analysis of VAP in adults from developing countries, Arabi et al.⁴ reported that 41 to 92% of VAP episodes were caused by gram-negative bacilli, while 6 to 58% by gram-positive cocci. A study by Chandrakanth et al.³¹ in 2009 reported that-gram-negative organisms account for 89% of VAP. Chawla et al.,³² in their study also found that 87% of patients with VAP had gram-negative organisms. Quartin et al.³³ from New York published the results of a multicenter trial from October 2004 through January 2010. In this, 63.4% of identified organisms were gram-positives with 42.7% being MRSA. The gram-negatives constituted 36.6%. Worldwide data indicate that in Western countries gram-positive organisms predominate. Potential reasons include the use of indwelling catheters, local environmental conditions, and the administration of specific antibiotic agents, especially as prophylaxis. As per Indian studies, gram-negative organisms are the major cause of VAP. This can be linked with colonization of the gut and exposure to antimicrobials. The critically ill patients get colonized exogenously or endogenously with hospital flora within 24–48 hours of hospitalization and the oral flora shifts to a predominance of hospital microbial flora, i.e., aerobic gram-negative pathogens. Pulmonary aspiration of these oropharyngeal contents increases the risk for infection. Also, critically ill patients are on broad-spectrum empirical antibiotics, which cause selection pressures on these colonizers for the emergence of resistant strains of gram-negative pathogens.^34,35 The presence of an endotracheal tube in ventilated patients impairs mucociliary clearance and disrupts the cough reflex, thus promoting the accumulation of tracheobronchial secretions and increasing the risk of pneumonia.³⁶ In addition, insertion of an endotracheal tube could produce injury and inoculate these endogenous oropharyngeal bacteria, such as A. baumannii and P. aeruginosa in the lower airway tract and pulmonary aspiration of these oropharyngeal contents increases the risk of airway colonization and infection.³⁵ The formation of a biofilm on the surface of the endotracheal tube is related to the pathogenesis of VAP.^36-39

The common organisms isolated from cases with VAP in our study were A. baumannii followed by P. aeruginosa and K. pneumoniae. Al-Dorzi et al.¹³ from Saudi Arabia during 2003 to 2008 reported that A. baumannii was the most commonly cultured microorganism (19%), causing VAP. In a prospective study conducted by Joseph et al.,¹⁴ in 2006–2007, A. baumannii (21.3%) and P. aeruginosa (21.3%) were the most common gram-negative bacteria associated with VAP and S. aureus (14.9%) was the most common gram-positive organism. Similar findings were reported by Dey et al.,¹⁵ Rajasekhar et al.,⁴⁰ and Goel et al.,⁴¹ where A. baumannii was the commonest organism causing VAP followed by P. aeruginosa.

Colonization of the respiratory tract with Acinetobacter spp., Pseudomonas spp., and MRSA may have originated from endogenous sources, such as the oropharynx or the stomach, or from exogenous sources, such as contaminated respiratory instruments, infective aerosols from the ICU environment, and contaminated hands and apparel of the healthcare workers. These act as vehicles of transmission. Handwashing is the single most effective measure of preventing transmission. Also, many of our VAP patients had risk factors for acquiring multidrug-resistant organisms (MDROs), such as advanced age, underlying immunosuppression— chronic renal failure, diabetes mellitus, acquired immunodeficiency syndrome, and on immunosuppressants—exposure to broad-spectrum antibiotics in preceding 3 months, increased severity of illness, previous multiple hospitalizations, and prolonged duration of invasive mechanical ventilation.^2,3,42

A. baumannii is omnipresent in the environment and can survive on nonliving inert environmental surfaces. It is frequently isolated from hospital water systems along with other water organisms like P. aeruginosa, Stenotrophomonas maltophilia, and Legionella pneumophila. The emergence of A. baumannii as an important cause of nosocomial infections is favored by three major factors, like resistance to drying, disinfectants, and antimicrobial agents.⁴¹ Its prolonged survival on inanimate objects in the hospital environment and hospital water can be a constant source of this organism. It may be carried on the hands of healthcare workers and patients, and spreads readily from healthcare workers to patients or from patients to patients. This can result in outbreaks in the unit which are difficult to control.^43,44 It is reported that Acinetobacter spp. has the ability to acquire resistance determinants more effectively than other bacteria. Innate colistin resistance is common in certain Acinetobacter species, such as Acinetobacter junii.⁴⁵ The majority of the A. baumannii isolates were observed during July through September. This may be attributed to the high environmental temperature and high level of humidity during the monsoon with resultant prolonged survival of organisms in the environment. Siau et al.,⁴⁶ in Hong Kong observed a seasonal variation in the isolation of Acinetobacter spp., corresponding to a peak period from July through October (the hot, humid season), during which increased numbers of Acinetobacter spp. were isolated.

Antimicrobial Susceptibility Patterns

It was observed in our study that antibiotic resistance in gram-negative organisms was on the rise in general. Resistance to aminoglycosides was high at 94% to amikacin and 90% to gentamicin. More than 90% of the strains were resistant to the tested β-lactam-β-lactamase inhibitor (BLBLI) combinations namely cefoperazone–sulbactam and piperacillin–tazobactam. However, all A. baumannii isolates were susceptible to colistin.

Sievert et al.⁴⁷ reported data from US hospitals in 2009 and 2010 and found that 63.4% of Acinetobacter isolates were resistant to aminoglycosides and piperacillin–tazobactam and 61.2% to the carbapenems. Balkhy et al.⁴⁸ studied 248 isolates of A. baumannii and found that 83 to 88% isolates were resistant to aminoglycoside group of antimicrobials, 60–71% to carbapenems like imipenem and meropenem, 86–89% to third-generation cephalosporins, and 86% to the fluoroquinolones. In a multicenter study from Turkey hospitals,⁴⁹ 90.03% of Acinetobacter were resistant to piperacillin, 87.54% to ciprofloxacin, and 78.29% to meropenem. Moreira et al. from Brazil⁵⁰ found that 80.9% of isolates of A. baumannii were resistant to carbapenems. Among the studies reported from India, Goel et al.⁴¹ found that 92.59% of Acinetobacter isolates were resistant to amikacin, 88.89% to meropenem, 85.18% to ceftazidime, and 37.04% to piperacillin–tazobactam. Gupta et al.¹⁰ conducted a prospective study in the general ICU in 2011 and reported that 50% of A. baumannii were carbapenem resistant. This shows that the resistance pattern shown by Acinetobacter isolates in our study was high compared to Western studies and was comparable with Indian studies. In the present study, resistance to the tested BLBLI combinations namely cefoperazone–sulbactam and piperacillin–tazobactam was higher than in other Indian studies. This could be because of the empirical usage of higher antibiotics in cancer patients.

The susceptibility of P. aeruginosa isolates was highest to colistin (99%). Resistance to amikacin and piperacillin–tazobactam was 37%. Resistance to ceftazidime and ciprofloxacin was 41% and to cefoperazone–sulbactam was 46 and 42% to carbapenems. Balkhy et al.⁴⁸ found that P. aeruginosa had 31% resistance to carbapenems, 27–28% to third-generation cephalosporins, and 13–25% to aminoglycosides. Sievert et al.⁴⁷ reported that

P. aeruginosa isolates showed 11.3% resistance to amikacin, 19.1% to piperacillin–tazobactam, 28.4% to cefepime and ceftazidime, 32.7% to ciprofloxacin/levofloxacin, and 30.2% to imipenem/meropenem. In Indian studies, Goel et al.⁴¹ found that P. aeruginosa showed 100% resistance to gentamicin, 82.35% to amikacin and ciprofloxacin, 47.06% to imipenem, 35.29% to ceftazidime, and 23.53% to piperacillin–tazobactam. The levels of resistance shown by P. aeruginosa in this study were high compared to the Western literature. In comparison to other Indian studies, higher resistance was observed to the BLBLI combination piperacillin–tazobactam.

Our study shows that there was a high level of resistance to BLBLIs and carbapenems in the case of K. pneumoniae. Haeili et al.⁵¹ in a retrospective study observed that 20.4% of K. pneumoniae were resistant to carbapenems and 50% were resistant to amikacin and gentamicin. Sievert et al.⁴⁷ reported that K. pneumoniae isolates showed 23.8% resistance to cefepime, cefotaxime, ceftazidime, and ceftriaxone, and 11.2% resistance to imipenem and meropenem.

All S. aureus isolates were susceptible to vancomycin, teicoplanin, and linezolid, and 44.45% were MRSA which showed 100% resistance to ciprofloxacin and gentamicin. Balkhy et al.⁴⁸ found that all isolates of S. aureus were susceptible to vancomycin and 42% of isolates were methicillin-resistant strains.

The findings in the current study were consistent with these studies. It was observed that multidrug resistance is increasing gradually in hospital isolates, particularly in case of Acinetobacter spp., P. aeruginosa, K. pneumoniae, and S. aureus. A number of studies in the literature also indicate a gradual increase in the emergence of antibiotic-resistant microorganisms in VAP patients.

Studies from Indian hospitals from International Nosocomial Infection Control Consortium have shown that MDR P. aeruginosa was the most common bacterial isolate in VAP patients,⁵² which inevitably resulted in the increased use of carbapenems that might have contributed to the emergence of MDR nonfermentative gram-negative bacilli, mainly A. baumannii. In this study, the increase in the incidence of VAP due to MDR A. baumannii again resulted in increased clinical use of carbapenems and polymyxins like colistin. A study conducted by Mulin et al.⁵³ showed the association of third-generation cephalosporins with colonization and infection with MDROs Acinetobacter spp. Risk factors for VAP were commonly prevalent in our patients, making them more susceptible to acquiring VAP. Multidrug resistance is defined as resistance to either three or four classes of antimicrobial agents, including penicillins, cephalosporins, carbapenems, fluoroquinolones, and aminoglycosides. MDR P. aeruginosa and gram-negative bacteria producing ESBL enzymes have created treatment challenges for critical care clinicians, leaving the carbapenem class of antimicrobial agents as the last choice to treat patients with these resistant infections. Prevention and control of MDROs in critical care units is a major task. There are very few antimicrobials in the pipeline and there is an urgent need to change the approach from “treatment” to “prevention.” Robust antimicrobial stewardship programs involving pharmacists, physicians, and other healthcare providers to optimize antibiotic selection, dose, and duration thereby increasing the efficacy in targeting causative pathogens for the best clinical outcome are the way forward.