Prospective Evaluation and Mortality Outcome of Nosocomial Infections in Medical Intensive Care Unit at Tertiary Care Teaching Centre in Mumbai

The term “Healthcare associated infection” is now widely used instead of the traditional “Nosocomial infection” and is defined by the Centre for Disease Control and Prevention (CDC) “as a localized or systemic condition resulting from an adverse reaction to the presence of an infectious agent(s) or its toxin(s). There must be no evidence that the infection was present or incubating at the time of admission to the acute care setting” [2].


Introduction
A Nosocomial infection also called "Hospital acquired infection" can be defined as: "An infection occurring in a patient, in a hospital or other health care facility in whom the infection was not present or incubating at the time of admission. This includes infections acquired in the hospital but appearing after discharge and also occupational infections among staff of the facility" [1].
The term "Healthcare associated infection" is now widely used instead of the traditional "Nosocomial infection" and is defined by the Centre for Disease Control and Prevention (CDC) "as a localized or systemic condition resulting from an adverse reaction to the presence of an infectious agent(s) or its toxin(s). There must be no evidence that the infection was present or incubating at the time of admission to the acute care setting" [2].
The most frequent nosocomial infections are blood stream infections, urinary tract infections, lower respiratory tract infections and infections of surgical wounds. The WHO studies, and others, have shown that the highest prevalence of nosocomial infections occurs in intensive care units and in acute surgical and orthopaedic wards. Infection rates are higher among patients with increased susceptibility because of old age, underlying disease, or chemotherapy. In the USA the most frequent type of infection, hospital wide is urinary tract infection (36%), followed by surgical site infection (20%), bloodstream infection (BSI), and pneumonia (both 11%) [3]. In France , the most common infection sites are urinary tract infections (30.3%), pneumonia (14.7%), infections of surgery sites (14.2%). infections of the skin and mucous membrane (10.2%), other respiratory infections (6.8%) and bacterial infections/blood stream infections (6.4%) [4].
A prevalence survey conducted under the auspices of WHO in 55 hospitals of 14 countries representing 4 WHO Regions (Europe, Eastern Mediterranean, South-East Asia and Western Pacific) showed an average of 8.7% of hospital pts had nosocomial infections. At any time, over 1.4 million people worldwide suffer from infectious complications acquired in hospital [5]. The highest frequencies of nosocomial infections were reported from hospitals in the Eastern Mediterranean and South-East Asia Regions (11.8 and 10.0% respectively), with a prevalence of 7.7 and 9.0% respectively in the European and Western Pacific Regions [6]. International comparisons of nosocomial infection rates in various countries are as follows United States (10%), France (21.6%), Italy (6.7%), United Kingdom (10%), Finland (8.5%), and India (19.7%) [3,[7][8][9][10][11].
A 6-year surveillance study from 2002-2007 involving intensive care units (ICUs) in Latin America, Asia, Africa, and Europe, using CDC's NNIS definitions (National nosocomial infection surveillance), revealed higher rates of central-line associated Blood Stream Infections (BSI), Ventilator Associated Pneumonias (VAP), and catheterassociated urinary tract infections than those of comparable United States ICUs [12]. In 2005, the National Healthcare Safety Network (NHSN) was established by CDC with the purpose of integrating and succeeding previous surveillance systems at the Centres for Disease Control and Prevention [13]. Percentage of most frequently isolated nosocomial organisms as per CDC, National Nosocomial Infection Surveillance (NNIS) system (January1990-March1996) and the top 3 pathogens in various nosocomial infections are shown in Tables 1 and  2 [13][14][15][16][17].

Material and Methods
It is a prospective observational study done in the Medical Intensive Care Unit (MICU) of a tertiary care teaching public hospital and, we aimed, to study rates of nosocomial infections (as per CDC definitions of nosocomial infections in adults) [18][19][20][21] , sites of infections and risk factors involved, empirical antibiotics used in treatment and its effectiveness by studying culture sensitivity of various body fluids/ secretions, time of initiation of antibiotics, effects of anti biogram on clinical outcome. We included all adult patients (pts), who have been admitted in critical care unit for more than 48 hours. Patients, who already have an infection and were on antibiotics within less than 48 hours, were followed for superadded infections. We excluded surgical, immunocompromised pts, and those below 12 years of age. Institute ' s Ethics committee approval was taken. After valid written informed consent, all patients were assessed, investigated, and treated as per the existing practices without disturbing their routine care appropriate for the disease condition till either the patient was discharged from MICU or expired. All hospital infection control practices were strictly adhered too. All the routine investigations done in MICU patients were taken into consideration. We noted all the haemodynamic parameters Type and class of antimicrobial drugs used, route of administration, dosage and its frequency, duration of antimicrobial drug used, reason for selection of drug, reason for change of drug were noted. Resistance and sensitivity of various organisms isolated in present study to the drugs used to treat patients in current study were those that were supplied under government schedule.

Study Design and Setting
It is a prospective observational study; and was carried out in the MICU of a tertiary care, teaching, public hospital in India over a period of 2 years.

Statistical Analysis
Outcome of each nosocomial infection was classified as either survived (improved) or expired. Data thus obtained was statistically analysed, using Pearson Chi-square test and logistic regression analysis using SPSS software.

Results
Out of 2935 patients admitted to MICU during the study period, 205 patients developed nosocomial infections, with an incidence rate of 14.31% during study period. Results are noted in Tables 3-5.
In present study, majority of patients (85 pts) developing nosocomial infections were between age group of 21-40 years (41.5%) and 29.8% (61 pts) patients were between age group of 41-60 years which may be explained by the higher incidence of patients in age group of 21-40 years getting admitted with complications. The mean age of patients was 44.29 years in present study. Dahmash et al. included patients with age ranging from 14 to 100 years with median age being 54 years [28]. In another study done by Gagneja et al. it was found that 21.61% of patients were in age group of less than 17 years, 42.15% in 18-64 years and 36.38% were of more than 65 years of age [29]. The present study showed higher mortality rate in age group of >80 years (50%) followed by second peak in the age group between 41-60 years (36.1%) which was not statistically significant.
In present study, most common isolates from wound infection were Klebsiella pneumoniae (31.6%) followed by Pseudomonas aeruginosa (21.0%). Peromet et al. showed that most common organisms isolated from pressure ulcers were Proteus mirabilis, group D streptococci, Escherichia coli, Staphylococcus species, Pseudomonas species, and Corynebacterium organisms [42].
In present study, 93.4% of blood stream infections were associated with central lines, 68.1% of pneumonia with intubation, 91.7% of UTI's were associated with urinary catheter. Rosenthal [43].
In current study, patients with 1-2 risk factors (100%) had better survival than those with 3 or more risk factors (60.1%). Majority of patients in present study (85.5%) stayed for more than 7 days in MICU, mortality rate was high in patients with prolonged ICU stay (60.0%) followed by second peak in patients with ICU stay of less than 7 days (47.2%), most of these patients were referred from other hospitals in moribund condition. Wong et al. showed that the mortality for longstay patients approached 50% which is comparable with our finding [44]. Similar finding was observed in the study done by Laupland et al. [45] While Williams et al. showed that an increase in length of stay was not independently associated with an increased risk of hospital mortality with most of hospital deaths occurring within the first 10 days in ICU [46].
The patients on mechanical ventilation (56.0%) had higher mortality as compared to non-ventilated patients (11.2%), and as duration of mechanical ventilation increases, mortality also increased significantly. The risk factors such as Diabetes mellitus, hypertension, COAD and duration of mechanical ventilation were found to be associated with development of VAP, but association was not statistically significant. (Table 6) This is in contrast to the study done by Craven and Steger which showed that host factors, oropharyngeal and gastric colonization, cross-infection, and complications from the use of antibiotics and nasogastric and endotracheal tubes increased the risk of bacterial VAP [47].
In current study, increasing age was associated with higher risk, whereas Diabetes Mellitus, female sex, foley's catheter were not statistically associated with risk of developing ICU-acquired UTI in logistic regression analysis (Table 7). In a study done by Bagshaw and Laupland it was found that indwelling urinary catheters, increased duration of urinary catheterization, female sex, length of stay in a ICU, and preceding systemic antimicrobial therapy were associated with risk of developing ICU-acquired UTI [33]. No differences in vital signs on admission, routine blood tests, APACHE II and TISS scores (therapeutic intervention scoring system), or overall hospital mortality rate were observed among patients who developed an ICU-acquired UTI as compared with those who did not.
In present study, it was found that 88.21% isolates of Enterobacteriaceae, 93.75% isolates of Acinetobacter baumannii, 89.4% isolates of Klebsiella pneumoniae, and 81.5% cases of E. coli were resistant to ceftriaxone. But this finding is in contrast to studies done by Moreno et   In present study, sensitivity of E. coli isolates to Carbapenems and Polymixin was 100%. While Klebsiella pneumoniae and Acinetobacter baumannii showed a maximum sensitivity to carbepenem, polymyxin followed by piperacillin-tazobactum. Pseudomonas aeruginosa showed a maximum sensitivity to piperacillin-tazobactum followed by Imipenem. In current study 100% isolates of ESBL organisms were resistant to amoxicillin-clavunate and ceftriaxone. 60.0% isolates of ESBL Acinetobacter baumannii, 74.5% isolates of ESBL Klebsiella pneumoniae and 94.1% isolates of ESBL E. coli were sensitive to piperacillin-tazobactum. While 75.0% isolates of ESBL Acinetobacter baumannii, 88.6% isolates of ESBL Klebsiella pneumoniae and 100.0% isolates of ESBL E. coli were sensitive to meropenem. 100% isolates of ESBL organisms were sensitive to Carbapenems. While79.2% isolates of ESBL Acinetobacter baumannii, 95.6% isolates of ESBL Klebsiella pneumoniae and 100.0% isolates of ESBL E. coli were sensitive to Imipenem. Günseren et al. showed that amikacin, ciprofloxacin and imipenem were effective against, respectively, 41.3%, 48.2% and 92.0% of the ESBL producers, however, only 12.5% of these were susceptible to piperacillin-tazobactum and Cefepime was found to be active against 35.5% of these problem pathogens [49]. Thus our observations found that there is changing trend of organisms causing nosocomial infection and also change in the sensitivity patterns of these organisms to various antibiotics.
Resistance of Gram-negative organisms isolated from patients with lower respiratory tract infections to various antibiotics in current study is ceftriaxone 86.0%, ceftazidime 85.7%, piperacillintazobactum 18.4%, gentamicin 73.3%, amikacin 57.8%, netlimycin 53.6%, ciprofloxacin 71.4%, meropenam 31.9% and imipenam 34.8%. Gagneja et al. showed increasing trend of resistance of Gram-negative organisms to third generation cephalosporins, amoxicillin/clavulanic acid and piperacillin-tazobactum and declining trend of resistance to aminoglycosides, they also showed increasing trend of resistance to carbapenems [29]. Thus, judicious use of older/newer antimicrobial agents is essential to prevent the emergence of multidrug-resistant bacteria in the ICU.
In our study, 3 out of 10 patients with swine flu were females while 7 were males and most common nosocomial infection was lower respiratory tract infection (70%) with HAP contributing to 50% of cases. The most common organism isolated was Klebsiella pneumoniae (80%) with ESBL strains contributing to 50% cases followed by Acinetobacter baumannii (20%). Out of 10 patients, 4 required mechanical ventilation. 3 patients had 1-2 risk factors while remaining 6 had 3 or >3 risk factors. Piperacillin-tazobactum was used in 70% cases; mostly in combination with levofloxacin (50%). The mortality in patients on mechanical ventilation was 50% and those without ventilation, was 16.7%. 70% patients of swine flu with nosocomial infection survived while 30% died.
In current study, antibiotics were started empirically in 19% cases, while in 79.5% patients antibiotics were started empirically and modified according to culture sensitivity report. Antibiotics started after culture sensitivity report in only 1.5% cases. In present study, ceftriaxone, Piperacillin-tazobactum, Meropenem was started empirically in 51.3%, 35.9%, 5.1% cases and after culture sensitivity reports in 38%, 67.5%, 17.8% cases respectively. The mortality was significantly higher (56.4%) in patients in whom antibiotics started empirically as culture sensitivity report were not made available before the patient had died, as compared to those in whom antibiotics were started empirically and modified according to culture sensitivity report or antibiotics started after culture sensitivity report (32.6%). No significant difference in mortality was found between, in those with antibiotics started empirically and modified according to culture sensitivity report and antibiotics started only after culture sensitivity report.
In our study, we found the statistically significant association between types of nosocomial infections and final outcome. In study done by Esperatti et al. it was found that the type of isolates and outcomes are similar regardless of whether pneumonia is acquired or not during ventilation, indicating they may depend on patients' underlying severity rather than previous intubation [39]. It was seen that patients with Glasgow coma score ≤10 at the time of admission had significantly high mortality as compared to patients with >10. Knaus et al. showed that the mortality was 40.0% in patients with single organ failure as against 98% in three or more organ failure which was consistent with our findings [50]. The commonest procedure performed was insertion of central venous lines in almost 96.58% of patients. It was done especially in cases of circulatory shock, acute renal failure and pulmonary edema for fluid management purpose. Intubations were performed 106 patients (51.7%) mostly for ventilatory support but also for prophylactic purposes to secure the airway. Tracheostomies were performed in 11.2% of the total patients who required prolonged ventilatory support. Amongst the 21 patients who received dialysis, 12 survived, while 9 died. Described by Knaus et al. the mean APACHE II score at time of admission in our study was 16.85; we found that as APACHE II score increases, mortality also increased significantly [50].
In present study, need of mechanical ventilation and elevated APACHE II score at the time of admission were associated with higher mortality while length of MICU stay between 16-30 days were associated with less mortality in a logistic regression analysis. No statistical significance between factors such as number of risk factors, age, gender and final outcome was found in our study by logistic regression analysis (Table 8). Yologlu et al. showed that extrinsic risk factors such as urinary catheter, mechanical ventilation, total parenteral nutrition, intubations, antimicrobial treatment prior to nosocomial infections, nasogastric catheter and central catheter were associated with nosocomial infections [51].

Conclusion
Thus our observations found that there is changing trend of organisms causing nosocomial infection as compared to the western world, compared to our study where it is multidrug resistant Gramnegative organisms and also change in the sensitivity patterns of these organisms to various antibiotics possibly due to there indiscriminate use.