Summary MULTIDRUG RESISTANT GRAM NEGATIVE ORGANISMS EPIDEMIOLOGY AND OUTCOMES IN THE ICU

DECLARATION I hereby declare that the thesis is my original work and it has been written by me entirely. I have duly acknowledged all sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. Anupama Vasudevan Date: 12-04-2015 i ACKNOWLEDGEMENTS Amidst heavy pressure of multifarious commitments, Prof. Paul Anantharajah Tambyah, MD not only suggested this topic to probe in detail but also evinced personal interest in editing, scrutinizing and correcting my thesis and this herculean task cannot be simply acknowledged by mere words. I profusely in debt my gratitude for this guidance and great help ever. I would like to thank him for providing me many opportunities to hone my epidemiological and statistical skills. I would like to acknowledge and thank Prof. Li Jialiang, PhD for rendering his expert advice with the statistical methods and analysis employed in this work. I would like to thank Prof. Lim Tow Keang and Prof. Adeline Seow, thesis advisory committee members for their continuous support in my journey with this project by offering valuable suggestions and advice. The help offered by the data entry personnel, Ms.Jaminah Ali, Ms.Anisa Shah, Mr.Satish and Mr.Jegan are immensely thanked wholeheartedly. I would also like to thank the timely help offered by Mr.Teo Ken Wah in proof reading my final thesis. The strength and moral support provided by Dr.Revathi Sridhar , Dr.Indumathi Venkatachalam and Dr. Charumathi Sabanayagam are greatly acknowledged. I would like to thank Eryanna Binte Yunus for all the administrative help rendered during this period. ii The amount of perseverance, forbearance and moral support rendered by my husband, Mr.Prakash Narasimhan cannot be thanked in mere words of praise and acknowledgements. Last but not the least, I wish to put my sincere thanks to my children, Akkshan & Akshara for their patience rendered in all occasions of family outings, gatherings and functions. I like to thank my parents, my pillars of confidence and my mother in law for providing a calm and peaceful atmosphere while working on my project. I profusely place my sincere acknowledgements to all those who directly or indirectly helped me in completing the project successfully. iii TABLE OF CONTENTS Acknowledgements Table of Contents Summary List of Tables List of Figures List of Abbreviations List of Publications, Awards & Conference presentations Publications ii iv viii xi xiv xvi xvii xx CHAPTERS Introduction and Objectives of the Study Introduction Rationale Objectives 1 2. Literature Review a. Prevalence Nosocomial Infections Drug Resistant Nosocomial Infections Drug Resistant Gram Negative Bacilli Infections Acinetobacter baumannii Pseudomonas aeruginosa Escherichia coli& Klebsiella pneumoniae 6 13 14 14 17 19 b. Risk Factors Nosocomial Infections Multidrug-Resistant Gram Negative Bacilli Intrinsic factors Extrinsic factors 22 22 23 23 24 c. Clinical Impact c1a.Multidrug-Resistant Gram-negative Bacilli Multidrug-resistant Gram-negative bacilli infection Multidrug-resistant Gram-negative bacilli bacteremia Multidrug-resistant Gram-negative bacilli site-specific Infections c1b.Impact of delayed appropriate antibiotic therapy Multidrug-resistant Gram-negative bacilli infection Multidrug-resistant Gram-negative 47 47 iv 48 50 53 54 54 bacilli bacteremia Multidrug-resistant Gram-negative bacilli site-specific Infections c2. Impact of initial choice of antibiotics on survival d. Economic Impact Nosocomial Infections Multidrug-resistant Gram-negative bacilli infection Multidrug-resistant Gram-negative bacilli bacteremia e. Prevention and Control of spread/incidence of multidrug-resistant Gram-negative bacilli 3. Study Overview and Methodology General methodology Detailed methodology (chapter oriented) Chapter Chapter Chapter 7a Chapter 7b Chapter 7c Chapter 4. Characteristics of Patients and Prevalence of Nosocomial Multidrug-resistant Gram-negative Infection Gram-negative clinical isolates Nosocomial Gram-negative infection Nosocomial susceptible Gram-negative bacilli infection Nosocomial multidrug-resistant Gram negative bacilli infection 55 56 69 74 74 76 78 82 92 92 98 98 100 101 103 103 105 110 112 114 114 115 5. Risk Factors for Nosocomial ICU acquired Multidrug-resistant Gram-negative Infection 120 Introduction 120 Results 120 Analysis 5a: SIRS patients with no GNB 121 infection/ colonization compared with ICU acquired MDR-GNB infection Analysis 5b: SIRS patients with Nosocomial ICU acquired 125 MDR-GNB and SGNB infection v Discussion 127 6. Prediction Tool for Nosocomial ICU acquired Multidrug-resistant Gram-negative Infection Introduction Results Score Formulation Segregation into Risk categories Prospective Validation External Validation Discussion 7. Clinical Impact 7a, 7b: Impact of Nosocomial MDR-GNB infection & effect of inappropriate antibiotic therapy among patients with GNB infection. Introduction Results Analysis 7a-1: MDR-GNB infection when compared with patients with no GNB Infection Analysis 7a-2: MDR-GNB infection when compared with patients with SGNB Infection Analysis 7b: Impact of early inappropriate antibiotics on mortality among patients with GNB and MDR-GNB alone Discussion 133 133 134 134 136 137 139 142 148 148 148 148 148 156 160 163 7c: Impact of initial choice of antibiotics on survival among SIRS patients Introduction Results Analysis 7c-1: Independent Risk factors for mortality Analysis 7c-2: Effect of different groups of initial antibiotics Analysis 7c-3: Effect of Carbapenem on acquisition of MDR-GNB Discussion 168 8. Economic Impact Introduction Results Analysis 8a: Cases compared with propensity matched 181 181 182 vi 168 168 168 172 176 177 controls A (uninfected controls) Analysis 8b: Cases compared with propensity matched controls B (SGNB infected controls) Length of stay analysis Discussion 188 190 193 194 9. Summary of Key findings Summary of key findings Significance and Limitations of the study Recommendations and Future directions 198 198 200 202 Bibliography 204 Annex Annex 1: Case report forms 277 vii SUMMARY Antimicrobial resistance with the potential for global spread is a major public health threat. Paralleling the increase of resistance amongst Gram-positive bacteria, resistant Gram-negative bacteria have increased and are of grave concern with a dwindling pipeline of new antibiotics. Intensive care units (ICU) are the epicenter of nosocomial infections and drug resistant organisms cause many of these. Drug resistant nosocomial infections due to Gram-negative bacteria(GNB) result in increased morbidity and possibly increased mortality in critically ill patients. Furthermore, patients with Gram-negative nosocomial infections are often treated empirically with broad spectrum antibiotics that result in “collateral damage” by increasing the risk of resistance. We conducted a prospective observational study(August’07- December’11) and all patients who had stayed for more than 24 hours at medical and surgical ICUs of National University Hospital were included. Multidrugresistant Gram-negative bacilli(MDR-GNB) was defined in accordance with the European CDC recommendations. During the study period, a total of 2949 patients were enrolled in the study. 2364(80.2%) had systemic inflammatory response syndrome(SIRS) on ICU admission. Amongst the patients with SIRS, 183(7.7%) patients acquired nosocomial multidrug-resistant Gram-negative bacilli infection in the hospital and of these, 76(41.5%) were acquired in the ICU. viii The independent risk factors for nosocomial ICU acquired MDR-GNB infection by logistic regression were identified to be presence of any Gramnegative bacilli, administration of carbapenems in the past months, surgery, dialysis therapy with end stage renal disease and a stay of >5 days in the ICU. The accuracy of the prediction tool (GSDCS) constructed using these risk factors was measured by the area under the curve. It was 0.77(95%CI 0.68-0.89) and 0.78(95%CI 0.69-0.89) for nosocomial multidrug-resistant Gram-negative bacilli infection and bacteremia respectively by receiver operating curve analysis when prospectively validated with a different cohort of critically ill patients(JanSep 2012). When externally validated among 47 patients with Gram-negative bacilli infection from two different hospitals, the AUC was 0.7(95%CI: 0.53-0.88) for predicting nosocomial multidrug-resistant Gram-negative bacilli infection. By Cox proportional hazards survival analysis, multidrug-resistant Gramnegative bacilli infection as a time-varying covariate increased the risk of 28-day mortality while only severity of illness increased risk of in-ICU mortality. The use of initial broad spectrum antibiotics showed no survival benefit among SIRS patients but increased the risk of “collateral damage” by increasing incidence of multidrug-resistant Gram-negative bacilli during the patient’s hospital stay. Those patients with MDR-GNB infection who were continued on an inappropriate antibiotic even after 72 hours of culture had a higher risk of mortality. A nested propensity matched case control study of costs associated with multidrug-resistant Gram-negative bacilli infection showed that total costs ix associated with the hospital stay, laboratory and antibiotics increased amongst multidrug-resistant Gram-negative bacilli infected patients when compared with both uninfected controls and SGNB infected control patients. With the help of the prediction tool, the clinicians have the option to prescribe more targeted appropriate antibiotics at the bedside for critically ill patients. With a 72 hour window, clinicians now have the opportunity to modify the antibiotics after the culture results are known in order to reduce bacterial selection of future resistance. These strategies need to be validated in large cohorts in other settings to help combat the emerging global threat of antibiotic resistance. x LIST OF TABLES Chapter 2b: 2b (1): Risk factors for multidrug-resistant Gram-negative bacilli 2b (2): Risk Factors for multidrug-resistant Acinetobacter baumannii 2b (3): Risk factors for multidrug-resistant Pseudomonas aeruginosa 2b (4): Risk factors for multidrug-resistant E.coli & Klebsiella pneumoniae Chapter 2c: 2c1 (1): Mortality and multidrug-resistant Gram-negative organisms 2c1 (2): Mortality and multidrug-resistant Acinetobacter baumannii 2c1 (3): Mortality and multidrug-resistant Pseudomonas aeruginosa 2c1 (4): Mortality and Resistant Escherichia coli & Klebsiella pneumoniae 37 38 40 43 61 62 64 65 Chapter 2d: 2d (1): Costs and Resistant Gram Negative Bacteria 81 Chapter 2e: 2e (1): Prediction Tool for Resistance in Gram Negative Bacilli 91 Chapter 4: 4(1): Patient Characteristics 4(2):Gram-negative positive isolates 4(3):Prevalence of multidrug-resistant Gram-negative bacilli 4(4): Nosocomial MDR-GNB and SGNB infection (whole cohort and SIRS patients) 111 114 116 119 Chapter 5: 5a (1): Nosocomial ICU acquired MDR-GNB Infection and SIRS patients with no GNB: Patient characteristics and univariate analysis 123 5a (2): Nosocomial ICU acquired MDR-GNB Infection: Independent risk factors- logistic regression (Comparison with SIRS patients with no GNB Infection/Colonization) 124 5b (1): Nosocomial ICU acquired MDR-GNB and SGNB Infection: Patient characteristics and univariate analysis 126 xi 5b (2): Nosocomial ICU acquired MDR-GNB Infection: Independent risk factors- logistic regression (Comparison nosocomial ICU acquired SGNB Infection) Chapter 6: 6(1): Independent risk factors of ICU acquired MDR-GNB Infection 6(2): Sensitivity and Specificity values Chapter 7: 7a-1 (1): Patient Characteristics: SIRS patients with MDR-GNB infection and no GNB Infection/Colonization 7a-1 (2): Multivariable Analysis: Independent Risk factors for Mortality: MDR-GNB and no GNB patients 127 134 136 150 152 Infection/Colonization 7a-1 (3): Univariate Analysis - Effect of nosocomial MDR-GNB: MDR-GNB and no GNB patients 7a-1 (4): Multivariable Analysis - Effect of Nosocomial ICU acquired MDR-GNB Bacteremia on in-ICU mortality: MDR-GNB and no GNB patients 7a-1 (5): Multivariable Analysis - Effect of Nosocomial MDR-GNB Infection & Bacteremia on 28-day mortality: MDR-GNB and noGNB patients 7a-2(1): Patient Characteristics: MDR-GNB and SGNB Infected Patients 7a-2(2): Multivariable Analysis: Independent Risk factors for Mortality: MDR-GNB and SGNB Infected Patients 7a-2(3): Univariate Analysis - Effect of nosocomial MDR-GNB: MDR-GNB and SGNB Infected Patients 7b (1): Univariate Analysis- Effect of Inappropriate antibiotics on in-ICU mortality 7b (2): Univariate Analysis- Effect of Inappropriate antibiotics on 28-day mortality 7b (3): Multivariable analysis: Effect of inappropriate antibiotics Nosocomial MDR-GNB Infections 7b (4): Multivariable analysis: Effect of inappropriate antibiotics- Nosocomial MDR-GNB Infections 7c-1 (1): Patient Characteristics and Univariate analysis 7c-1 (2): Independent risk factors for Mortality: Cox proportional survival hazards analysis xii 154 155 155 157 158 159 161 161 162 162 170 172 7c-2(1): Univariate Analysis- Effect of different groups of antibiotics 7c-2(2): Multivariable analysis: Effect of Carbapenems within 24 H: 7-day Mortality 7c-2(3): Multivariable analysis: Effect of Carbapenems and Cefazolin @ 24 & 48 H- In-ICU Mortality 7c-2(4): Multivariable analysis: Effect of Carbapenems and Cefazolin @ 24 & 48 H- 28-day Mortality 7c-3(1): Risk of MDR-GNB with initial Carbapenem use Chapter 8: 8(1) : Balance check after Propensity Matched scoring 8a (1): Patient Characteristics: Cases and Propensity matched Uninfected Controls (Controls A) 8b (1): Patient Characteristics: Cases and Propensity matched Controls infected with SGNB(Controls B) 8a (2): Comparison of costs between the propensity matched cases and controls A 8a(3): Survivors: Comparison of costs between the propensity matched cases and controls A 8b (2): Comparison of costs between the propensity matched cases and controls B 8b (3): Survivors:Comparison of costs between the propensity matched cases and controls B 8a (3): Comparison of length of stay between the propensity matched cases and controls A 8b (3): Comparison of costs between the propensity matched cases and controls B xiii 173 174 175 176 176 183 185 187 189 190 192 192 193 193 LIST OF FIGURES Chapter 4: 4(1): Epi Curve: MDR-GNB & GNB positive clinical isolates 4(2): Nosocomial SGNB infection in ICU & Hospital: Sites 4(3): Nosocomial SGNB Infection in ICU & Hospital: Organisms 4(4-1): Nosocomial MDR-GNB infection by years 4(4-2): Prevalence of nosocomial MDR-GNB infection 4(5): Nosocomial MDR-GNB Infection in ICU & Hospital: Sites 4(7): Nosocomial MDR-GNB Infection in ICU & Hospital: Organisms Chapter 5: 5(1): Patient Flowchart 113 114 115 117 117 118 118 121 Chapter 6: 6(1): Prevalence of Nosocomial ICU acquired MDR-GNB Infection & Bacteremia - Risk categories 137 6(2): Area Under the curve- Nosocomial ICU acquired MDR-GNB Infection: Prospective Validation 138 6(3): Prevalence of Nosocomial ICU acquired MDR-GNB Infection Prospective Validation- Risk categories 138 6(4): Area Under the curve-Nosocomial ICU acquired MDR-GNB Bacteremia: Prospective Validation 139 6(5): Prevalence of Nosocomial ICU acquired MDR-GNB Bacteremia Prospective ValidationRisk categories 139 6(6): Area Under the curve- Nosocomial ICU acquired MDR-GNB Infection: External Validation 141 6(7): Prevalence of Nosocomial ICU acquired MDR-GNB Infection External Validation- Risk categories 141 6(8): Area Under the curve- Nosocomial ICU acquired MDR-GNB Infection(ICU patients): External Validation 142 6(7): Prevalence of Nosocomial ICU acquired MDR-GNB Infection(ICU patients: External ValidationRisk categories 142 Chapter 7: 7a-1(1): Kaplan-Meier survival curves: SIRS patients with MDR-GNB infection and no GNB patients 7a-2(1): Kaplan-Meier survival curves: MDR-GNB and SNB patients 7c1: Patient Inclusion flowchart xiv 153 159 169 Chapter 8: (1): Selection of cases and controls : Patient Flowchart 8a (1): Propensity score: Cases and Controls A 8b (1): Propensity score: Cases and Controls B 8a (2): Distribution of costs per day: Propensity matched Cases and Controls without GNB infection (Controls A) 8b(2): Distribution of costs per day: Propensity matched Cases and Controls with SGNB infection (Controls B) xv 184 186 188 188 191 LIST OF ABBREVIATIONS  ICU: Intensive Care Unit  MICU : Medical Intensive Care Unit  SICU : Surgical Intensive Care Unit  SIRS: Systemic Inflammatory Response Syndrome  APACHE : Acute Physiology and Chronic Health Evaluation  CPIS : Clinical pulmonary infection score  MDR: Multi Drug Resistant  GNB : Gram Negative Bacilli  MDR-GNB: Multidrug-Resistant Gram Negative Bacilli  SGNB: Susceptible Gram Negative Bacilli  MRSA : Methicillin-resistant Staphylococcus aureus  AB: Acinetobacter baumannii  PSAE: Pseudomonas aeruginosa  KPN: Klebsiella pneumoniae  VRE: Vancomycin Resistant Enterococci  ESBL: Extended Spectrum Beta-Lactamase  OR: Odds Ratio  CI: Confidence Interval  ROC: Receiver Operating Curve  AUC: Area Under the Curve  HL: Hosmer-Lemeshow xvi List of Publications, Awards & Conference presentations: Publications:  Vasudevan A, Memon BI, Mukhopadhyay A, Li J, Tambyah PA, Costs of Nosocomial Resistant Gram Negative Intensive Care Unit Infections- A propensity matched case control study, Antibiotics resistance and Infection Control, Antimicrobial Resistance and Infection Control, 2015  Vasudevan A, Mukhopadhyay A, Li J, Goh EY, Tambyah PA, A Prediction Tool for Nosocomial Multi-Drug Resistant Gram-Negative Bacilli Infections in Critically Ill Patients - Prospective Observational Study, BMC Infectious Diseases, 2014  Vasudevan A, Chuang L, Li J ,Mukhopadhyay A, Goh EY, Tambyah PA. Inappropriate empirical antimicrobial therapy for multidrug-resistant organisms in critically ill patients with pneumonia is not an independent risk factor for mortality: Results of a prospective observational study of 758 patients, Journal of Global Antimicrobial Resistance, 2013  Vasudevan A, Mukhopadhyay A, Goh EY, Li J, Tambyah PA. Risk factors for infection/colonization caused by resistant Gram negative bacilli in critically ill patients( An observational study of 1622 critically ill patients), Preventive Medicine, 2013  Tambyah PA, Vasudevan A, Epidemiology and Impact of Multi-Drug Resistant Gram Negative Infections in Critically Ill Patients in Asia, Asia Pacific Biotech News 2012 xvii Awards:  April 2013- Third prize in the Best poster Category at SIDS Annual Practice update, Singapore  April 2013- One of the 16 posters selected for physical poster presentation at the Regional World Health Summit, Asia, Singapore  Feb 2013- Best Oral presentation Award at the 3rd International Congress of Infection Control Association (Singapore), Singapore  Jan 2013- Best poster presentation award at the YLLSOM 3rd Annual Graduate Scientific Congress (AGSC), Singapore Conference Presentations:  4th Annual Graduate Scientific Congress (AGSC) , Singapore , March 2014, Vasudevan A, Mukhopadhyay A, Tan A, Li JL, Tambyah PA.Initial Carbapenem Therapy Does Not Reduce Mortality in Critically Ill Patients  ID Week 2013, San Franscisco, CA, October 2013. Foo R, Vasudevan A, Lui T, Tan A, Mukhopadhyay A, Tambyah PA. Inappropriate Antibiotics Beyond 24 hours but not Initial Inappropriate Antibiotics associated with Increased Mortality in Critically Ill Patients  6th International Congress Of the Asia Pacific Society of Infection Control ,Shanghai, April 2013 & SIDS Annual Practice Update, Singapore, March 2014 (Third prize in the Best poster category). Vasudevan A, Leyland C , Li JL, A Mukhopadhyay, Goh EY, Tambyah PA. Inappropriate empiric xviii antimicrobial therapy for multidrug resistant organisms in critically ill patients with pneumonia is not an independent risk factor for mortality: results of a prospective observational study of 758 patients  9th International Symposium on Antimicrobial Agents And Resistance, Malaysia, March 2013. Vasudevan A, Mukhopadhyay A, Tan A, Li JL, Tambyah PA. Appropriate Definitive Antibiotics And Not Initial Empiric Appropriate Antibiotics affect the Mortality of Critically Ill Patients With Multi-Resistant Gram Negative Nosocomial Infections.  3rd International Congress of Infection Control Association(Singapore), Singapore, February 2013. Vasudevan A, Mukhopadhyay A, Tan A, Li JL, Tambyah PA. Resistant Gram Negative Infections Among Critically Ill Patients: A Prediction Tool. (Awarded Best Oral Presentation Award)  YLLSoM 3rd Annual Graduate Scientific Congress (AGSC) , Singapore, January 2013 (Awarded Best Poster Presentation Award) & Regional World Health Summit, Asia, Singapore, April 2013 (One of the 16 posters selected for Physical Poster presentation). Vasudevan A, Mukhopadhyay A, Tan A, Li JL, Tambyah PA. Economic Burden of Resistant Gram Negative Bacilli Infections among Critically Ill Patients  1st Asia Pacific Clinical Epidemiology and Evidence Based Medicine Conference, Malaysia, July 2012. Vasudevan A, A Mukhopadhyay, Goh EY, Tambyah PA. Risk Factors for Resistant Gram Negative Bacilli Among the Critically Ill Patients xix [...]... factors for multidrug- resistant Gram- negative bacilli 2b (2): Risk Factors for multidrug- resistant Acinetobacter baumannii 2b (3): Risk factors for multidrug- resistant Pseudomonas aeruginosa 2b (4): Risk factors for multidrug- resistant E.coli & Klebsiella pneumoniae Chapter 2c: 2c1 (1): Mortality and multidrug- resistant Gram- negative organisms 2c1 (2): Mortality and multidrug- resistant Acinetobacter... Mortality and multidrug- resistant Pseudomonas aeruginosa 2c1 (4): Mortality and Resistant Escherichia coli & Klebsiella pneumoniae 37 38 40 43 61 62 64 65 Chapter 2d: 2d (1): Costs and Resistant Gram Negative Bacteria 81 Chapter 2e: 2e (1): Prediction Tool for Resistance in Gram Negative Bacilli 91 Chapter 4: 4(1): Patient Characteristics 4(2) :Gram- negative positive isolates 4(3):Prevalence of multidrug- resistant. .. factors for infection/colonization caused by resistant Gram negative bacilli in critically ill patients( An observational study of 1622 critically ill patients), Preventive Medicine, 2013  Tambyah PA, Vasudevan A, Epidemiology and Impact of Multi-Drug Resistant Gram Negative Infections in Critically Ill Patients in Asia, Asia Pacific Biotech News 2012 xvii Awards:  April 2013- Third prize in the Best... matched Cases and Controls with SGNB infection (Controls B) xv 184 186 188 188 191 LIST OF ABBREVIATIONS  ICU: Intensive Care Unit  MICU : Medical Intensive Care Unit  SICU : Surgical Intensive Care Unit  SIRS: Systemic Inflammatory Response Syndrome  APACHE : Acute Physiology and Chronic Health Evaluation  CPIS : Clinical pulmonary infection score  MDR: Multi Drug Resistant  GNB : Gram Negative. .. SGNB Infection in ICU & Hospital: Organisms 4(4-1): Nosocomial MDR-GNB infection by years 4(4-2): Prevalence of nosocomial MDR-GNB infection 4(5): Nosocomial MDR-GNB Infection in ICU & Hospital: Sites 4(7): Nosocomial MDR-GNB Infection in ICU & Hospital: Organisms Chapter 5: 5(1): Patient Flowchart 113 114 115 117 117 118 118 121 Chapter 6: 6(1): Prevalence of Nosocomial ICU acquired MDR-GNB Infection... Bacilli  MDR-GNB: Multidrug- Resistant Gram Negative Bacilli  SGNB: Susceptible Gram Negative Bacilli  MRSA : Methicillin -resistant Staphylococcus aureus  AB: Acinetobacter baumannii  PSAE: Pseudomonas aeruginosa  KPN: Klebsiella pneumoniae  VRE: Vancomycin Resistant Enterococci  ESBL: Extended Spectrum Beta-Lactamase  OR: Odds Ratio  CI: Confidence Interval  ROC: Receiver Operating Curve  AUC:... 6th International Congress Of the Asia Pacific Society of Infection Control ,Shanghai, April 2013 & SIDS Annual Practice Update, Singapore, March 2014 (Third prize in the Best poster category) Vasudevan A, Leyland C , Li JL, A Mukhopadhyay, Goh EY, Tambyah PA Inappropriate empiric xviii antimicrobial therapy for multidrug resistant organisms in critically ill patients with pneumonia is not an independent... Prediction Tool for Nosocomial Multi-Drug Resistant Gram- Negative Bacilli Infections in Critically Ill Patients - Prospective Observational Study, BMC Infectious Diseases, 2014  Vasudevan A, Chuang L, Li J ,Mukhopadhyay A, Goh EY, Tambyah PA Inappropriate empirical antimicrobial therapy for multidrug- resistant organisms in critically ill patients with pneumonia is not an independent risk factor for mortality:... Infection/Colonization) 124 5b (1): Nosocomial ICU acquired MDR-GNB and SGNB Infection: Patient characteristics and univariate analysis 126 xi 5b (2): Nosocomial ICU acquired MDR-GNB Infection: Independent risk factors- logistic regression (Comparison nosocomial ICU acquired SGNB Infection) Chapter 6: 6(1): Independent risk factors of ICU acquired MDR-GNB Infection 6(2): Sensitivity and Specificity values Chapter... multidrug- resistant Gram- negative bacilli 4(4): Nosocomial MDR-GNB and SGNB infection (whole cohort and SIRS patients) 111 114 116 119 Chapter 5: 5a (1): Nosocomial ICU acquired MDR-GNB Infection and SIRS patients with no GNB: Patient characteristics and univariate analysis 123 5a (2): Nosocomial ICU acquired MDR-GNB Infection: Independent risk factors- logistic regression (Comparison with SIRS patients with no GNB Infection/Colonization) . Multidrug- Resistant Gram Negative Bacilli 23 Intrinsic factors 23 Extrinsic factors 24 c. Clinical Impact 47 c1a .Multidrug- Resistant Gram- negative Bacilli 47 Multidrug- resistant Gram- negative. appropriate antibiotic therapy 54 Multidrug- resistant Gram- negative bacilli infection 54 Multidrug- resistant Gram- negative v bacilli bacteremia 55 Multidrug- resistant Gram- negative bacilli. Patients and Prevalence of Nosocomial Multidrug- resistant Gram- negative Infection 110 Gram- negative clinical isolates 112 Nosocomial Gram- negative infection 114 Nosocomial susceptible Gram- negative