Role of mechanical ventilation & development of multidrug resistant organisms in hospital acquired pneumonia

Transcription

1 Indian J Med Res 118, December 2003, pp Role of mechanical ventilation & development of multidrug resistant organisms in hospital acquired pneumonia Chiranjoy Mukhopadhyay, Anudita Bhargava & Archana Ayyagari Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India Received December 30, 2002 Background & objectives: Among hospital-acquired infections, pneumonia is considered to be the leading cause of death mainly in patients with mechanical ventilation in intensive care units (ICUs). The present study was undertaken to estimate the occurrence of hospital-acquired pneumonia (HAP) as well as ventilator-associated pneumonia (VAP) along with the effect of different variables and to detect the presence of multi drug resistant (MDR) organisms in the intensive care unit (ICU). Methods: Of the 328 patients admitted in the ICU during 2001, 241 stayed for >72 h and 148 were ventilated. The respiratory specimens collected from the cases and controls were sent for cytology, bacterial culture and antimicrobial sensitivity. Results: The overall rate of HAP was 53.9 per cent, mortality rate was 47.3 per cent and attributable risk of mortality with ventilator was 72.3 per cent. Occurrence of VAP was 81.7 per cent. The rate of acquisition of HAP increased along with the duration of stay in the ICU. Of the total bacterial isolates, 96.2 per cent were obtained from patients on ventilator, an overall preponderance of Gram-negative bacteria, commonest being Pseudomonas spp along with 16.3 per cent polymicrobial infection was found in ICU. A significant number of ICU isolates were MDR in comparison to those from the non- ICU settings. Interpretation & conclusion: Mechanical ventilation and duration of ICU stay emerged as important risk factors for the development of HAP and VAP. MDR Gram-negative bacilli were the commonest respiratory pathogens responsible for increased mortality in patients with VAP. Key words Antibiotic resistance - hospital acquired pneumonia - hospital stay - intensive care unit - nosocomial infection - ventilator associated pneumonia Nosocomial infections represent a major health problem not only in terms of excess morbidity, mortality and personal distress, but also contribute to significant economic loss 1,2. Among hospital-acquired infections, pneumonia is considered to be the leading cause of death 3. The occurrence of pneumonia is high in the intensive care units (ICUs) mainly because of high utilization of invasive procedures like mechanical ventilation 4-6. The development and spread of antibiotic resistant bacteria are common in ICUs mainly because of heavy use of antibiotic 7,8. Antibiotic resistance increases the 229 morbidity and mortality associated with infections and contributes substantially to rising costs of care resulting from prolonged hospital stay and the need for more expensive drugs 7-9. Multiple antibiotic resistance to useful antibiotics, including the penicillins, cephalosporins, aminoglycosides, and fluoroquinolones, has gradually increased among a number of Gram negative pathogens, especially Klebsiella pneumoniae, 8,10 Enterobacter spp, 11,12 Pseudomonas aeruginosa, 13 and Acinetobacter baumannii 14,15. Epidemic and endemic infections caused by these multi-resistant strains followed intense antibiotic use in many hospitals, particularly in

2 230 INDIAN J MED RES, DECEMBER 2003 ICUs 8,11,13,15,16. In many cases, epidemic strains of these Gram negative bacilli showed resistance to nearly all available antibacterial drugs and caused serious nosocomial infections such as pneumonia and bacteraemia, which were associated with increased mortality 11-14,17. It was found in a study conducted in the United States that the percentage of resistance decreased in stepwise fashion for organisms isolated from ICU patients, non-icu inpatients, and outpatients 18. Surveillance of hospital acquired infections (HAI) was considered as one of the most effective tools of nosocomial infection control programme 19. The present study was therefore conducted to estimate the occurrence of HAI particularly hospital acquired (HAP) and ventilator associated pneumonia (VAP), and to determine the effect of different variables on HAP in a surgery ICU of a tertiary care hospital in north India. The development of MDR organisms in the ICU in comparison to non-icu settings (wards and outpatients) was also studied. Material & Methods The study was conducted at the Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow during January to December A total of 328 patients were admitted in the ICU during this period. Of these, 241 stayed for more than 72 h and 148 were ventilated. Of these 148, 121 developed HAP. Of the 93 patients who were not ventilated, 9 developed HAP. Of the 130 patients (52 from surgical gastroenterology, 36 from urology, 20 from nephrology, 13 from gastroenterology and 9 from neuromedicine) who developed HAP, 72 were non-operative cases for ventilatory support which were mainly chronic airway obstruction, massive pleural effusion in chronic renal failure, other pulmonary diseases, terminal stage illnesses in haematological, gastrointestinal and other malignancies, drug overdose, road traffic accidents with chest injuries and/or cerebral concussion and neurological emergencies and 58 were post-operative cases with respiratory failure. Cases (n=130): The patients admitted for more than 72 h in the ICU who developed a new and persistent lung infiltrate, fever, high blood counts, with purulent tracheal aspirates were considered at risk for nosocomial pneumonia. These patients were evaluated with fiberoptic bronchoscopy using a protected specimen brush and bronchoalveolar lavage (BAL). The presence of >5 per cent cells with intracellular bacteria on cytocentrifuge of BAL and presence of at least one bacterial species cultured in significant concentration (greater than 10 3 cfu/ml) from protected brush catheter specimen 20,21 were diagnosed as having pneumonia. Other respiratory specimens like endotracheal (ET) and transtracheal (TT) aspirates were also collected. Control (n=111): A control was defined as a patient similar to a case but without bacteriologic evidence of pneumonia. All these controls had undergone bronchoscopy, intracellular microorganisms were not observed in the lavage cells. Of the 937 specimens (BAL 779, ET aspirate 89 and TT aspirates 69) collected from the 241 patients in ICU, 426 were positive for microorganisms. Approximately 3-4 specimens per patient were collected. Those with isolation of the same isolate with same antibiogram collected within one week were taken as a single episode of pneumonia. The resistance pattern of organisms isolated from the ICU (n=420) and from wards (n=433) and out patient departments (OPD, n=204) during the same period (January to December, 2001) was studied and the percentage of resistance against first and second line drugs in ICU and non-icu (wards and OPDs) settings was compared. Among all respiratory isolates, there were 876 Gram negative bacilli (wards 359, OPDs 138, ICU 379) and 181 gram positive cocci (wards 74, OPDs 66, ICU 41). The organisms were identified to the species level biochemically by the standard laboratory techniques 22. The in vitro antibiotic sensitivity was checked against a panel of antibiotics using modified Stokes method 23. Statistical analysis: The statistical analysis of data was done by applying Chi square test and Z test of proportion depending upon the situation. Attributable risk is estimated by 2x2 contingency table and univariate analysis was done. Results Of the 241 patients included in the study, 130 (53.9%) developed one or more episodes of HAP. The average stay of these patients in the ICU was 17.3 days (range 3-90 days). It was observed that as the duration of stay increased,

3 MUKHOPADHYAY et al : ROLE OF MECHANICAL VENTILATION IN HOSPITAL ACQUIRED PNEUMONIA 231 Table I. Occurrence of nosocomial pneumonia in relation to duration of ICU stay Duration of Total patients Patients with HAP Control (n=111) stay (days) (n=241) HAP (n=130) (Week-wise %) ICU, Intensive care unit; HAP, hospital acquired pneumonia Table II. Univariate analysis of certain variables that influenced the development of hospital acquired pneumonia Total Control (n=111) HAP (n=130) (n=241) No. (%) No. (%) Age (yr) > Sex Male Female Ventilator No Yes * Days on ventilator Deaths On ventilator Off ventilator χ 2 = 41.31; P<0.001 *P<0.001 compared to no ventilator P<0.001 compared to patients with HAP not on ventilator HAP, hospital acquired pneumonia the per cent occurrence of HAP per patient increased significantly (P<0.001) minimum being in the first week (44.7%). There was significant association between the duration of stay and acquisition of HAP (Table I). Majority of patients and controls belonged to age group of yr where the HAP rate was 52.3 per cent (Table II). Only 9 (6.9%) of 93 patients with no mechanical ventilator support developed HAP compared to 121 (93.1%) of the 148 on ventilator and this difference was statistically significant (P<0.001). The occurrence of VAP (ventilator-associated pneumonia) was significantly (P<0.001) high (93.1%) (Table II). Though the number of patients was gradually decreasing as the

4 232 INDIAN J MED RES, DECEMBER 2003 Table III. Microorganisms isolated from patients in intensive care unit On ventilator (n=121) Off ventilator (n=9) Fig. Association of mortality with duration of stay in ICU. days on ventilator increased due to either discharge or death of the patients, the high rate of HAP was maintained all through. The mortality rate in patients with HAP on ventilator (94%, 93/99) was significantly higher (P<0.001) in comparison to the patients with HAP but not on ventilators (6%, 6/99). The occurrence of HAP in our study was 53.9/100 ventilated patients (130/241) and that of VAP was 81.7/100 patients (121/148). The attributable risk for mortality and the use of ventilator was 72.3 per cent. Patients in ICU had an overall mortality rate of 47.3 per cent (114/241) and majority of deaths occurred within two weeks of admission, in the first week 62 out of 136 (45.5%) and in the second week 27 out of 67 (40.2%) Microorganisms n (%) n (%) Gram-negative bacteria 377 (93.3) 2 (13.3) Pseudomonas aeruginosa 141 (34.9) 1 (6.6) Escherichia coli 72 (17.8) 1 (6.6) Klebsiella pneumoniae 69 (16.8) - Acinetobacter spp 58 (17) - Citrobacter spp 27 (6.6) - Enterobacter spp 5 (1.2) - Proteus vulgaris 5 (1.2) - Gram-positive cocci 27 (6.6) 13 (86.6) MRSA 14 (3.4) 8 (53.3) MSSA 10 (2.4) 5 (33.3) Enterococcus spp 3 (0.7) - Polymicrobial 68 (16.3) 2 (13.3) Total isolates (426)* 404 (94.8) 15 (3.52) *Nocardia spp and 5 Corynebacteria spp. isolated (They make total isolates on ventilator = 410 and off ventilator = 16) MRSA, Methicillin-resistant Staphylococcus aureus MSSA, Methicillin-sensitive Staphylococcus aureus died (Fig.). The mortality rate increased with increasing duration of stay in the ICU, the maximum mortality (80%) seen in days. Table IV. Resistance pattern of gram-negative bacteria (GNB) against first line antibiotics Pathogens Number Ampicillin Ampicillin Sulbactum Gentamicin Amikacin Cephalexin Cefotaxime Ceftriaxone Cotrimoxazole Ciprofloxacin Ceftazidime Piperacillin Tobramycin Carbenicillin Per cent resistance GNB Ward (n=604) OPD ** 35** 28** 20** 67 34** NT 71 21** ICU NT Ward Pseudomonas OPD 32 19** 34** 23** 30** 28** 12* (n=272) ICU OPD, out patient department; ICU, intensive care unit; NT, not tested P*<0.05, **<0.001 compared to ICU P <0.05, <0.001 compared to ICU

5 MUKHOPADHYAY et al : ROLE OF MECHANICAL VENTILATION IN HOSPITAL ACQUIRED PNEUMONIA 233 Table V. Resistance pattern of Gram-negative bacteria (GNB) against newer antibiotics as second line Pathogens Number Piperacillin Tazobactum Cefoperazonesulbactum Ticarcillin- Clavulinic acid Cefpirome Gatifloxacin Netilmycin Meropenem Per cent resistance GNB Ward (n=184) OPD 21 NT NT NT NT NT NT 0 ICU Ward Pseudomonas OPD 3 NT NT NT NT NT NT 0** (n=29) ICU OPD, Out patient department; ICU, Intensive care unit; NT, not tested P<0.05 compared to ICU, **P<0.001 compared to ICU Table VI. Resistance pattern of Gram-positive cocci (GPC) against antibiotics Pathogens Number Ampicillin Ampicillinsulbactum Amikacin Gentamicin Cotrimoxazole Erythromycin Ciprofloxacin Cephalexin Cefazoline Cefotaxime Vancomycin Per cent resistance GPC Ward (n=181) OPD 66 41** 14** 7** 11** 77 50* 8** ICU NT OPD, out patient department; ICU, intensive care unit; NT, not tested P*<0.05; **<0.001 compared to ICU P <0.05; <0.001 compared to ICU The distribution of the bacterial isolates from 426 positive specimens of the patients with HAP showed that 96.2 per cent (410/426) isolates were obtained from specimens of patients on ventilator and 3.8 per cent (16/426) from those not on ventilator. Gramnegative organisms were isolated more frequently than Gram-positive cocci in patients with HAP on ventilator; Pseudomonas aeruginosa was the most frequent isolate followed by Escherichia coli, Klebsiella pneumoniae etc. (Table III). The rate of polymicrobial infection was found to be 16.3 per cent for patients on ventilator and 13.3 per cent for patients off ventilator. However, from patients with HAP not using ventilator, Gram-positive bacteria were isolated more frequently than Gram-negative (86.6% vs 13.3%). The resistance pattern showed that the majority of the isolates from the ICU had significantly increased in vitro resistance against most of the antibiotics tested as compared to OPD and ward isolates (Tables IV-VI). The findings also showed that a significant number of the ICU isolates responsible for HAP were multi-drug resistant. Anti-pseudomonal resistance against ceftazidime, piperacillin and to the newly introdced meropenem (21%) was significantly higher in ICU isolates. No vancomycin resistant enterococci or staphylococci was detected so far. Discussion The present study revealed a high occurrence of HAP (53.9%) in ICU which was higher than most of the earlier

6 234 INDIAN J MED RES, DECEMBER 2003 studies 5,24. The occurrence of VAP found in the present study was alarmingly high (81.7%) from the very first week since in other studies the incidence of VAP ranged from 6-30 cases per 100 patients and the rate of VAP increased with the length of stay It is reported that the devices like ventilator or endotracheal tubes that circumvent host defenses or facilitate the entry of bacteria into the lung were of great concern In our ICU the endotracheal tube was changed once in a fortnight. Isolation of the same organisms with similar antibiograms from the patient s respiratory specimens (data not shown) from ICU during routine hospital infection control programme showed improper aseptic precautions that might have led to colonization of organisms within the ventilators and subsequently high incidence of VAP. Higher occurrence (52.3%) of HAP among the young adults and middle age group (26-50 yr) was found in accordance with an earlier study 32. The mortality rate and the attributable risk to the use of ventilator were remarkably higher than that reported in western countries 32,33. The rate of mortality in patients admitted in ICU increased with the duration of stay, the number being notably higher in the first two weeks in the present study. Sudden exposure to the ICU environment and use of numerous devices including ventilator could be the reason. The gradual increase in the mortality showed that the length of stay in ICU might have a serious effect on the survival of the patients which corroborated with previous studies 33,34. An overt predominance of multi drug resistant Pseudomonas aeruginosa and members of family enterobacteriacea in ICU leading to high mortality were similar to the earlier findings 4,24,25,33. The development of higher resistance to the antibiotics in the ICU as compared to non-icu settings (wards and OPDs), especially to the newer antibiotics was of great concern and because of improper antibiotics utilization. Alterations and rotation in antibiotic prescribing patterns might decline the antibiotic resistance 35,36. In conclusion, the present findings showed a gradual increase in HAP, mainly VAP along with the duration of stay in ICU, with its occurrence being most in the age group yr. VAP was constantly and significantly high throughout the duration on ventilator and mortality increased with the duration of stay in the ICU, mainly due to development of multi drug resistance in the organisms. References 1. Dixon RE. Costs of nosocomial infections and benefits of infection control programs. In: Wenzel RP, editor. Prevention and control of nosocomial infections, 1st ed. Baltimore: Williams & Wilkins; 1987 p Haley RW, Culver DH, White JW, Morgan WM, Emori TG. The nationwide nosocomial infection rate: A new need for vital statistics. Am J Epidemiol 1985; 121 : Pennington JE. Hospital-acquired pneumonia. In: Wenzel RP, editor. Prevention and control of nosocomial infections, 1st ed. Baltimore: Williams & Wilkins; 1987 p Craven DE, Kunches LM, Lichtenberg DA, Kollisch NR, Barry MA, Heeren TC, et al. Nosocomial infection and fatality in medical and surgical intensive care unit patients. Arch Intern Med 1988; 148 : Hemming VG, Overall JC Jr, Britt MR. Nosocomial infections in a newborn intensive-care unit. Results of forty one months of surveillance. N Engl J Med 1976; 294 : Craven DE, Kunches LM, Kilinsky V, Lichtenberg DA, Make BJ, McCabe WR. Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation. Am Rev Respir Dis 1986; 133 : Flaherty JP, Weinstein RA. Nosocomial infection caused by antibiotic-resistant organisms in the intensive-care unit. Infect Control Hosp Epidemiol 1996; 17 : Gold HS, Moellering RC Jr. Antimicrobial-drug resistance. N Engl J Med 1996; 335 : Cohen ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. Science 1992; 257 : Livermore DM, Yuan M. Antibiotic resistance and production of extended-spectrum beta-lactamases amongst Klebsiella spp from intensive care units in Europe. J Antimicrob Chemother 1996; 38 : Chow JW, Fine MJ, Shlaes DM, Quinn JP, Hooper DC, Johnson MP, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med 1991; 115 : De Gheldre Y, Maes N, Rost F, De Ryck R, Clevenbergh P, Vincent JL, et al. Molecular epidemiology of an outbreak of multidrug-resistant Enterobacter aerogenes infections and in vivo emergence of imipenem resistance. J Clin Microbiol 1997; 35 : Richard P, Le Floch R, Chamoux C, Pannier M, Espaze E, Richet H. Pseudomonas aeruginosa outbreak in a burn unit: role of antimicrobials in the emergence of multiple resistant strains. J Infect Dis 1994; 170 : Towner KJ. Clinical importance and antibiotic resistance of Acinetobacter spp. Proceedings of a symposium held on 4-5 November 1996 at Eihat, Israel. J Med Microbiol 1997; 46 :

7 MUKHOPADHYAY et al : ROLE OF MECHANICAL VENTILATION IN HOSPITAL ACQUIRED PNEUMONIA Struelens MJ, Carlier E, Maes N, Serruys E, Quint WG, van Belkum A. Nosocomial colonization and infection with multiresistant Acinetobacter baumannii: outbreak delineation using DNA macrorestriction analysis and PCR-fingerprinting. J Hosp Infect 1993; 25 : McGowan JE Jr. Antimicrobial resistance in hospital organisms and its relation to antibiotic use. Rev Infect Dis 1983; 5 : Lortholary O, Fagon JY, Hoi AB, Slama MA, Pierre J, Giral P, et al. Nosocomial acquisition of multiresistant Acinetobacter baumannii: risk factors and prognosis. Clin Infect Dis 1995; 20 : Archibald L, Phillips L, Monnet D, Mc Gowan JE Jr, Tenover F, Gaynes R. Antimicrobial resistance in isolates from inpatients and outpatients in the United States: increasing importance of the intensive care unit. Clin Infect Dis 1997; 24 : Haley RW, Culver DH, White JW, Morgan WM, Emori TG, Munn VP, et al. The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals. Am J Epidemiol 1985; 121 : Wimberley N, Faling LT, Bartlett JG. A fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial culture. Am Rev Respir Dis 1979; 119 : Fagon JY, Chastre J, Hance AJ, Guignet M, Trouillet JL, Domart Y, Pierre J, et al. Detection of nosocomial lung infection in ventilated patients. Use of a protected specimen brush and quantitative culture techniques in 147 patients. Am Rev Respir Dis 1988; 138 : Bergey s manual of determinative bacteriology, Holt JG, Krieg NR, Sneath PHA, Staley JT, Williams ST, editors, 9th ed. London: Williams & Wilkins; Agarwal KC. Antibiotic sensitivity test by disc diffusion method: standardization and interpretation. Indian J Pathol Bacteriol 1974; 17 : Stevens RM, Teres D, Skillman JJ, Feingold DS. Pneumonia in an intensive care unit. A 30-month experience. Arch Intern Med 1974; 134 : Fagon JY, Chastre J, Domart Y, Trouillet JL, Pierre J, Darne C, et al. Nosocomial pneumonia in patients receiving continuous mechanical ventilation. Prospective analysis of 52 episodes with use of a protected specimen brush and quantitative culture techniques. Am Rev Respir Dis 1989; 139 : Pavia M, Bianco A, Viggiani NM, Angelillo IF. Prevalence of hospital-acquired infections in Italy. J Hosp Infect 2000; 44 : George DL. Epidemiology of nosocomial ventilator-associated pneumonia. Infect Control Hosp Epidemiol 1993; 14 : Celis R, Torres A, Gatell JM, Almela M, Rodriguez-Roisin R, Agusti-Vital A. Nosocomial pneumonia. A multivariate analysis of risk and prognosis. Chest 1988; 93 : Craven DE, Barber TW, Steger KA, Montecalvo MA. Nosocomial pneumonia in the 1990 s: update of epidemiology and risk factors. Semin Respir Infect 1990; 5 : Langer M, Mosconi P, Cigada M, Mandelli M. Long-term respiratory support and risk of pneumonia in critically ill patients. Intensive Care Unit Group of Infection Control. Am Rev Respir Dis 1989; 140 : Rashkin MC, Davis T. Acute complications of endotracheal intubation. Relationship to reintubation, route, urgency and duration. Chest 1986; 89 : Craven DE, Steger KA. Epidemiology of nosocomial pneumonia. New perspectives on an old disease. Chest 1995; 108 (2 Suppl) : 1-16S. 33. Fagon JY, Chastre J, Hance AJ, Montravers P, Novara A, Gibert C. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am J Med 1993; 94 : Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicolas-Chanoin MH, et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) study. EPIC International Advisory Committee. JAMA 1995; 274 : Fridkin SK, Gaynes RP. Antimicrobial resistance in intensive care units. Clin Chest Med 1999; 20 : Niederman MS. Is 'Crop rotation' of antibiotics the solution to a 'resistant' problem in the ICU? Am J Respir Crit Care Med 1997; 156 : Reprint requests : Dr A. Ayyagari, Professor & Head, Department of Microbiology Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road Lucknow , India archana@sgpgi.ac.in; aayyagari@yahoo.com