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   Abstract
  Introduction
  Subjects and Methods
  Results
  Discussion
  Conclusion
   References
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 Table of Contents    
RESEARCH ARTICLE
Year : 2023  |  Volume : 55  |  Issue : 2  |  Page : 89-96
 

A clinical study on the pattern of antimicrobial drug use and drug resistance in patients with ventilator-associated pneumonia in a tertiary care hospital


Department of Pharmacology, Kempegowda Institute of Medical Sciences, Bengaluru, Karnataka, India

Date of Submission23-Sep-2021
Date of Decision23-Sep-2021
Date of Acceptance28-Apr-2023
Date of Web Publication03-Jun-2023

Correspondence Address:
R Vijendra
Department of Pharmacology, Kempegowda Institute of Medical Sciences, Bengaluru - 560 070, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.ijp_759_21

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  Abstract 


CONTEXT: Ventilator-associated pneumonia (VAP) develops nearly in about one-third of the patients, 48 h after receiving mechanical ventilation. Common pathogens are Pseudomonas aeruginosa, Staphylococcus aureus, Acinetobacter spp., Klebsiella spp., Escherichia coli, Proteus spp., Enterobacter spp. and Enterococcus spp. including multidrug-resistant pathogens.
AIM: The study aims to assess the pattern of antimicrobial drug use in VAP and to assess the etiological organisms and their drug sensitivity and resistance pattern.
SETTINGS AND DESIGN: Study participants admitted to Kempegowda Institute of Medical Sciences Hospital and Research Centre, Bengaluru, and who developed VAP were included in this prospective observational study.
SUBJECTS AND METHODS: Bronchial secretions were subjected to microbiological analysis. The etiological organisms, their drug sensitivity and resistance pattern, and the outcome of drug therapy were recorded. The clinical course of the study participants was monitored till either the resolution of pneumonia or the demise of the participant.
STATISTICAL ANALYSIS USED: Qualitative data were analyzed using the Chi-square test or Fischer's exact test and quantitative data using the independent t-test.
RESULTS: Early VAP was seen in 91.7% and late VAP in 8.3% of the participants. The organisms isolated were S. aureus, Enterococcus spp., Acinetobacter spp., Klebsiella pneumoniae and P. aeruginosa. Majority of the study participants with early VAP (75%, n = 41) completely recovered from pneumonia and 80%, n = 4 participants with late VAP recovered completely.
CONCLUSION: The organisms had a varied sensitivity and resistance pattern. The clinical outcome was multifactorial and its association with specific antimicrobial agents cannot be drawn.


Keywords: Antimicrobial drug resistance, clinical pulmonary infection score, intensive care, ventilator-associated pneumonia


How to cite this article:
Rezia A, Vijendra R. A clinical study on the pattern of antimicrobial drug use and drug resistance in patients with ventilator-associated pneumonia in a tertiary care hospital. Indian J Pharmacol 2023;55:89-96

How to cite this URL:
Rezia A, Vijendra R. A clinical study on the pattern of antimicrobial drug use and drug resistance in patients with ventilator-associated pneumonia in a tertiary care hospital. Indian J Pharmacol [serial online] 2023 [cited 2023 Sep 22];55:89-96. Available from: https://www.ijp-online.com/text.asp?2023/55/2/89/378034





  Introduction Top


Pneumonia refers to infection of the pulmonary parenchyma[1] which accounts for 55.4% of deaths due to lower respiratory tract infections and 103 million loss of disability-adjusted life-year.[2] Tracheal intubation and mechanical ventilation used to support the critically ill patients puts them at a greater risk of developing nosocomial infections (NIs).[3] NIs are infections that patients acquire either in the hospital or such facilities such as nursing homes, outpatient clinics, or diagnostic laboratories.[4] NIs are seen in 5%–10% of hospitalized patients. More than 60% of these infections are due to pneumonia, urinary tract infection, and bloodstream infection.[5] Microorganisms are resistant to one or more antimicrobials in 70% of these infections.[6]

Nosocomial pneumonia broadly includes ventilator-associated pneumonia (VAP), hospital-acquired pneumonia, and healthcare-associated pneumonia.[7] Lung parenchymal infection which develops 48 h after mechanical ventilation (either endotracheal tube [ET] or tracheostomy) is referred as VAP.[8] VAP is seen in 28% of patients who receive mechanical ventilation with a mortality rate of 48%.[2],[8] The most common pathogens causing VAP are bacteria including multidrug-resistant pathogens.[9]

The objectives of this study were to assess the pattern of antimicrobial drug use in VAP, the etiological organisms involved, and their antimicrobial susceptibility.


  Subjects and Methods Top


Source of data

The study participants admitted to Kempegowda Institute of Medical Sciences Hospital and Research Centre received mechanical ventilation and developed VAP.

Methods of collection of data

Inclusion criteria

  1. Subjects of either gender, aged ≥18 years admitted as inpatients in Kempegowda Institute of Medical Sciences and Hospital, Bengaluru, who received mechanical ventilation and developed VAP
  2. Subjects willing to give a written informed consent.


Exclusion criteria

  1. Subjects in whom adequate sputum samples cannot be obtained
  2. Subjects with viral, fungal, or aspiration pneumonia
  3. Subjects with tubercular (TB) pneumonia
  4. Subjects who are seropositive for HIV infection
  5. Subjects with diagnosed malignancy
  6. Subjects with pre-existing VAP
  7. Subjects and/or legal representative(s) not willing to give written informed consent.


Sample size

The sample size was Sixty subjects.

Sample design

Purposive sampling.

Study design

The study was designed as a prospective observational study.

Study period

Eighteen months (January 2019–June 2020).

Place of study

The study was conducted in Kempegowda Institute of Medical Sciences Hospital and Research Centre, Bengaluru.

Methodology

  1. The KIMS Institutional Ethics Committee approved the study to be conducted as per the study protocol. All study participants meeting the inclusion and exclusion criteria were included in the study after the study participants signed the written informed consent. A diagnosis of pneumonia was made based on clinical examination as well as assessment by diagnostic tests. Diagnostic tests as a part of diagnosis and management included chest X-ray, computed tomography scan (if required), bronchial secretions (microscopy, culture, and drug sensitivity), and blood tests including complete blood counts, erythrocyte sedimentation rate and blood culture and sensitivity (if required)
  2. Laboratory investigations including serum urea and creatinine, serum electrolytes, arterial blood gas analysis, and serum procalcitonin (in sepsis patients) were carried out as required for the management of pneumonia
  3. The specimen (bronchial secretions) obtained from all study subjects were subjected to microbiological analysis. [Figure 1] shows the various microbiological analysis performed in the bronchial secretions obtained
  4. Drug therapy for VAP was initiated empirically and was further adjusted according to the drug sensitivity and resistance pattern
  5. The demographic details, comorbid conditions, duration of hospital stay, and the drug therapy during the hospital stay, including antimicrobial drugs used were recorded
  6. The pattern of antimicrobial use including the class of antimicrobial agent(s), formulation, dose, route, frequency, duration of administration, and any change in antimicrobial therapy (and reasons for the change) were recorded
  7. The etiological organisms, their drug sensitivity and resistance pattern, and the outcome of drug therapy were documented
  8. Improvement/worsening of the condition was clinically assessed also using repeat chest X-rays, total blood counts (TC, DC), and other laboratory parameters. The clinical course of the study subject was monitored till either the pneumonia was resolved or the patient was discharged from the hospital or for 30 days, whichever was later
  9. The data collected from all the study subjects was entered into a case record form and was subjected to statistical analysis.
Figure 1: Microbiological analysis of the bronchial secretions

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Assessment tools

The diagnosis of VAP was made using the clinical pulmonary infection score (CPIS).

Outcome measures

  1. Duration of the patient on ventilator
  2. Duration of hospital stay
  3. 30-day mortality.


Statistical analysis

  1. Microsoft Excel data sheet was used for data entry and SPSS software, version 22, was used for data analysis. Frequencies and proportions were used for representing categorical data. The test of significance for qualitative data was either Chi-square test or Fischer's exact test
  2. Mean and standard deviation was used to represent continuous data. To identify the mean difference between two quantitative variables, the test of significance was independent t-test
  3. MS Excel and MS Word were used for graphical representation of data and to obtain various types of graphs
  4. After assuming all the rules of statistical tests, P < 0.05 was considered statistically significant
  5. MS Excel and SPSS version 22 (IBM SPSS Statistics, Somers NY, USA) were the statistical software used to analyze data.



  Results Top


This prospective observational study on the pattern of antimicrobial susceptibility among organisms in VAP and the pattern of antimicrobial drug use in the participants with VAP was conducted in the intensive care unit (ICU) of Kempegowda Institute of Medical Sciences Hospital and Research Centre. All participants recruited for the study satisfied the inclusion and exclusion criteria.

[Table 1] depicts the demographic characteristics of the study participants. Among the study participants, 39 subjects were male (65%) and 21 subjects were female (35%). [Table 2] reveals the reasons for ICU admission. [Table 3] and [Table 4] denote the comorbid conditions and the risk factors for VAP respectively. [Table 5] depicts information about the mode of mechanical ventilation that was used by the subjects. [Table 6] shows the antimicrobials used at the time of ICU admission. [Table 7] reveals the concomitant drug therapy. [Table 8] shows the change in antimicrobial agents. [Table 9] depicts the CPIS in subjects with early versus late VAP. [Table 10] provides information on the organisms isolated from ET culture. [Table 11] and [Table 12] provide information on the ET culture sensitivity pattern in early and late VAP respectively. [Table 13] and [Table 14] provide information on the ET culture resistance pattern in early and late VAP respectively. [Table 15] shows the comparison of mean duration of intubation, mean period of stay in the ICU, and mean period of hospital stay after extubation in early versus late VAP. [Table 16] depicts the clinical outcome in subjects with early versus late VAP.
Table 1: Demographic characteristics

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Table 2: Reasons for intensive care unit admission

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Table 3: Co-morbid conditions*

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Table 4: Risk factors for ventilator-associated pneumonia

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Table 5: Mode of mechanical ventilation

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Table 6: Antimicrobials used at the time of intensive care unit admission

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Table 7: Concomitant drug therapy*

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Table 8: Change of antimicrobial agent*,#

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Table 9: Clinical pulmonary infection score in early versus late ventilator-associated pneumonia

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Table 10: Organisms isolated from endotracheal tube culture

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Table 11: Endotracheal tube culture sensitivity pattern-early ventilator-associated pneumonia

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Table 12: Endotracheal tube culture sensitivity pattern-late ventilator-associated pneumonia

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Table 13: Endotracheal tube culture resistance pattern-early ventilator-associated pneumonia

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Table 14: Endotracheal tube culture resistance pattern-late ventilator-associated pneumonia

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Table 15: Comparison of mean duration of intubation, mean period of stay in the intensive care unit and mean period of hospital stay after extubation in early versus late ventilator-associated pneumonia

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Table 16: Clinical outcome in early versus late ventilator-associated pneumonia*

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[Figure 2] shows the duration of intubation in subjects with early and late VAP. [Figure 3] shows the duration of stay in the ICU in subjects with early and late VAP.
Figure 2: Duration of intubation in early versus late VAP. VAP = Ventilator-associated pneumonia

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Figure 3: Duration of stay in the ICU in early versus late VAP. VAP = Ventilator-associated pneumonia, ICU = Intensive care unit

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  Discussion Top


The risk factors for VAP included age >60 years, male gender, coma, acute respiratory distress syndrome, reintubation, neurosurgery, chronic obstructive pulmonary disease (COPD), and thoracic surgery. The purpose for ICU admission and mechanical ventilation in the study participants included acute respiratory failure, road traffic accident, congestive cardiac failure, cardiac arrest, shock, fulminant hepatic failure, and bacterial meningitis. The common comorbidities seen in the study participants were type 2 diabetes mellitus, hypertension, liver dysfunction, renal dysfunction, ischemic heart disease and COPD. None of the WHO priority pathogens were encountered in this study.[11] The risk factors for VAP, the reasons for ICU admission and mechanical ventilation and the comorbidities seen in the present study participants were akin to other reports by Karakuzu et al.,[12] Chittawatanarat et al.[13] and Ali et al.[14]

The antimicrobial agents that were used empirically in the study participants upon admission to the ICU included cefotaxime, ceftriaxone, fixed drug combination (FDC) of cefoperazone and sulbactam, azithromycin, clarithromycin, meropenem, FDC of piperacillin and tazobactam, linezolid, vancomycin, metronidazole, levofloxacin, clindamycin, and amikacin. This was also in consonance with a study by Tran et al.[15]

The organisms isolated from ET culture in the study participants with early and late VAP included Acinetobacter spp., Enterococcus spp., Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus Scientific Name Search  including coagulase-negative S. aureus (CoNS). The organisms isolated were akin to other observations by Restrepo et al.,[16] Saravanan and Raveendaran[17] and Charles et al.[18] The other Gram-positive organisms isolated in these studies were methicillin resistant S. aureus and Streptococcus pneumoniae, but in the present study, the gram-positive isolates were S. aureus including CoNS and Enterococcus spp. The Gram-negative isolates in these studies were Citrobacter spp., Proteus spp., Enterobacter spp., and Haemophilus influenzae which were not encountered in the present study.

The Gram-positive isolates S. aureus including CoNS and Enterococcus spp. were susceptible to clindamycin, erythromycin, and vancomycin and showed resistance to penicillin, amoxyclav and cefoxitin in studies reported by Ali et al.[14] and Golia et al.[19] In the present study, the organisms were sensitive to cefepime, cefixime, levofloxacin, meropenem and vancomycin. Resistance was seen to amoxyclav, ampicillin, cefoperazone, cefoxitin, ceftriaxone, erythromycin, and clindamycin.

In the present study, Acinetobacter spp. was sensitive to FDC of piperacillin and tazobactam, cefepime, cefixime, levofloxacin, azithromycin, clarithromycin, gentamicin, netilmicin, meropenem, polymyxin B, colistin and linezolid. They were resistant to FDC of amoxicillin and clavulanic acid, ampicillin, amikacin, tobramycin, ciprofloxacin, cotrimoxazole, and tetracycline. In a study done by Patil and Patil,[20] Acinetobacter spp. was sensitive to amikacin, colistin, meropenem, and tigecycline. A study done by Joseph et al.[21] showed resistance of Acinetobacter spp. to ticarcillin, amikacin and ciprofloxacin.

P. aeruginosa was sensitive to FDC of piperacillin and tazobactam, cefepime, cefexime, levofloxacin, gentamicin, netilmicin, meropenem, vancomycin and linezolid. They were resistant to FDC of amoxicillin and clavulanic acid, ampicillin, cefoperazone, cefoxitin, ceftriaxone, ciprofloxacin, and amikacin. A similar resistance pattern was seen in the study by Joseph et al.[21] According to a study done by Patil and Patil,[20] these isolates showed sensitivity to amikacin, colistin, meropenem, and tigecycline.

In the present study, K. pneumoniae was sensitive to FDC of piperacillin and tazobactam, cefepime, cefixime, levofloxacin, gentamicin, netilmicin, azithromycin, clarithromycin, polymyxin B, colistin, meropenem, vancomycin, and linezolid. Resistance was seen with FDC of amoxicillin and clavulanic acid, ampicillin, cefoperazone, cefoxitin, ceftriaxone, ciprofloxacin, and amikacin. In a study by Ali et al.[14] K. pneumoniae was sensitive to FDC of amoxicillin and clavulanic acid, FDC of piperacillin and tazobactam, cefuroxime, ceftriaxone, cefepime, vancomycin, gentamicin, and meropenem. Resistance was seen to gentamicin, ciprofloxacin, and ceftriaxone in a study reported by Joseph et al.[21]

This study was done in a tertiary care teaching hospital with infection control measures and a hospital antimicrobial use policy, which can be considered one of the major strengths of the study. This study describes the various organisms isolated from the ET culture and their antimicrobial susceptibility along with the resistance pattern. This research had a small sample size and was carried out in a short duration, but the results can be used to frame/modify antimicrobial use policy and tighten infection control measures. Future studies done over a longer period involving a bigger sample size might show reveal new findings in terms of the pattern of antimicrobial susceptibility and resistance and organisms frequently involved in VAP. Assessment of the minimum inhibitory concentration of the antimicrobial agents to establish the degree of resistance or susceptibility of the organisms against the commonly used antimicrobial agents was not performed. Another limitation of this study was speciation of Acinetobacter spp. and Enterococcus spp. was not performed to isolate the strains involved.


  Conclusion Top


The antimicrobial agents given empirically were β-lactam antimicrobial agents, cephalosporins, macrolides, meropenem, metronidazole, amikacin, and linezolid. A change of antimicrobial agent was needed in 19 study participants based on the culture and sensitivity pattern of the organisms isolated. The organisms resistant to the empirical antimicrobial agents were commonly sensitive to linezolid, meropenem, vancomycin, polymyxin B, colistin, and levofloxacin. The common organisms isolated from the ET culture included Acinetobacter spp, K. pneumoniae, S. aureus including CoNS, Enterococcus spp. and P. aeruginosa. FDC of piperacillin and tazobactam, cefepime, cefixime, levofloxacin, azithromycin, clarithromycin, gentamicin, netilmicin, polymyxin B, colistin, meropenem, vancomycin, and linezolid have retained effectiveness in majority of the organisms isolated from ET culture. Resistance to FDC of amoxicillin and clavulanic acid, ampicillin, cefoperazone, cefoxitin, ceftriaxone, ciprofloxacin, erythromycin, amikacin, cotrimoxazole, and tetracycline was seen among the organisms isolated from ET culture.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Troeger C, Forouzanfar M, Rao PC, Khalil I, Brown A, Swartz S, et al. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: A systematic analysis for the global burden of disease study 2015. Lancet Inf Dis 2017;17:1133-61.  Back to cited text no. 8
    
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Mandell LA, Wunderink RG. Pneumonia. In: Harrison's Principles of Internal Medicine. 20th ed., Ch. 121. New Delhi: McGraw Hill Education; 2018. p. 910.  Back to cited text no. 9
    
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Sharma R. Revised Kuppuswamy's socioeconomic status scale: Explained and updated. Indian Pediatr 2017;54:867-70.  Back to cited text no. 10
    
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WHO Publishes List of Bacteria for Which New Antibiotics are Urgently Needed. WHO; 2017. Available from: https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed. [Last accessed on 2020 Sep 10].  Back to cited text no. 11
    
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Karakuzu Z, Iscimen R, Akalin H, Kelebek Girgin N, Kahveci F, Sinirtas M. Prognostic risk factors in ventilator-associated pneumonia. Med Sci Monit 2018;24:1321-8.  Back to cited text no. 12
    
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Chittawatanarat K, Jaipakdee W, Chotirosniramit N, Chandacham K, Jirapongcharoenlap T. Microbiology, resistance patterns, and risk factors of mortality in ventilator-associated bacterial pneumonia in a Northern Thai tertiary-care university based general surgical intensive care unit. Infect Drug Resist 2014;7:203-10.  Back to cited text no. 13
    
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Ali HS, Khan FY, George S, Shaikh N, Al-Ajmi J. Epidemiology and outcome of ventilator-associated pneumonia in a heterogeneous ICU population in Qatar. Biomed Res Int 2016;2016:8231787.  Back to cited text no. 14
    
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Tran GM, Ho-Le TP, Ha DT, Tran-Nguyen CH, Nguyen TS, Pham TT, et al. Patterns of antimicrobial resistance in intensive care unit patients: A study in Vietnam. BMC Infect Dis 2017;17:429.  Back to cited text no. 15
    
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Restrepo MI, Peterson J, Fernandez JF, Qin Z, Fisher AC, Nicholson SC. Comparison of the bacterial etiology of early-onset and late-onset ventilator-associated pneumonia in subjects enrolled in 2 large clinical studies. Respir Care 2013;58:1220-5.  Back to cited text no. 16
    
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Charles MP, Easow JM, Joseph NM, Ravishankar M, Kumar S, Sivaraman U. Aetiological agents of ventilator-associated pneumonia and its resistance pattern – A threat for treatment. Australas Med J 2013;6:430-4.  Back to cited text no. 18
    
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Golia S, Sangeetha KT, Vasudha CL. Microbial profile of early and late onset ventilator associated pneumonia in the intensive care unit of a tertiary care hospital in Bangalore, India. J Clin Diagn Res 2013;7:2462-6.  Back to cited text no. 19
    
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Patil HV, Patil VC. Incidence, bacteriology, and clinical outcome of ventilator-associated pneumonia at tertiary care hospital. J Nat Sci Biol Med 2017;8:46-55.  Back to cited text no. 20
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15], [Table 16]



 

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