BURDEN, ETIOLOGY, AND CONTROL OF HOSPITAL ACQUIRED INFECTION IN INTENSIVE CARE UNITS IN VIETNAM By Vu Dinh Phu A thesis submitted to the Open University U.K For the degree of Doctor of Philosophy in the field of Life Sciences Oxford University Clinical Research Unit Hanoi, Vietnam March, 2017 Abstract Hospital acquired infection (HAI) is one of the most frequent adverse event in healthcare worldwide, affecting hundreds of millions of patients annually. In both developed and developing countries, this burden falls mainly on the critically ill. In Vietnam, HAI data are limited, particularly from the intensive care units (ICUs). Robust data are needed to evaluate these problems. This thesis addresses this need. A point prevalence survey (PPS) of HAI and antibiotics use was conducted monthly at 15 ICUs of 14 tertiary and provincial hospitals across Vietnam from October 2012 to September 2013. Subsequently an observational study focused on ventilator associated pneumonia (VAP) and ventilator associated respiratory infections (VARI) at the ICUs of three referral hospitals in Hanoi and Ho Chi Minh City from November 2013 to November 2015. Analysis of 3287 patients in the PPS showed that 29.5% patients had at least one HAI on the surveyed day of which 80% was hospital acquired pneumonia. Antibiotics were being administered to 84.8% patients. A. baumannii, P. aeruginosa, and K. pneumoniae accounted for > 50% of HAI pathogens with carbapenem resistance rates of 89.2%, 55.7%, and 14.9% respectively. The presence of an invasive device was associated with significantly higher risk for HAI. The incidence of VAP and VARI in 374 patients analysed as part of the second study was 9.9% and 24.6% respectively with corresponding incidence densities of 7.6 and 21.4 episodes/1000 ventilation days respectively. Patients with VARI had an excess ICU stay of 11 days, ventilation duration 12.5 days, antibiotic consumption 11 DOT; and ICU cost 2189 US$ compared with those without VARI. Given an estimated 22,570 patients admitted to the ICUs of 14 surveyed hospitals in 2012 and VARI prevalence of 24.6%, we would expect 5552 patients developed VARI leading to an extra 69,403 ventilation days, 61,074 ICU days, 61,074 DOT antibiotic consumption, and an extra ICU cost of 12,153,810 US$. With a total ii of 40 tertiary and 304 provincial acute care hospitals across Vietnam, the extra cost for VARI nationally would be many times higher. In conclusion, this thesis provides compelling evidence that the burden of HAI in Vietnamese ICUs, particularly VAP/VARI, is substantial. There is also a high level of antibiotic consumption and widespread bacterial resistance to carbapenem antibiotics. Effective infection control measures and antibiotic stewardship programmes are urgently needed to address these problems in Vietnamese ICUs. iii Co-Authorship The majority of the work presented in this thesis was carried out by me with essential support from my supervisors and colleagues. I implemented most of the work with guidance from the study directors, Professor Heiman FL Wertheim, Professor Hakan Hanberger, and Dr. Behzad Nadjm. The point prevalence survey was done in collaboration with 14 hospitals under the management of the National Hospital for Tropical Diseases and Oxford University Clinical Unit in Hanoi. The ventilator associated pneumonia study was conducted with the support from Oxford University Clinical Unit in Hanoi and Ho Chi Minh City in cooperation with three hospitals: The National Hospital for Tropical Diseases, Bach Mai Hospital, and the Hospital for Tropical Diseases in Ho Chi Minh City. For the statistical analysis, I worked mainly myself with support from Mr. Vu Tien Viet Dung, statistician of Oxford University Clinical Unit (OUCRU) – Hanoi, Vietnam. Throughout my PhD programme, I received great training from OUCRU faculties, my supervisors, and my third-party monitor. iv Acknowledgements Firstly, I would like to express my deepest gratitude to my director of studies, Professor Heiman FL Wertheim and Dr. Behzad Nadjm, and my co-supervisors, Professor Guy Thwaites and Professor Hakan Hanberger, for their invaluable advice and instruction during my study period. I would like to give my deep gratitude to Dr. Louise Thwaites, Dr. Annette Fox, Dr. Rogier van Doorn for their great support along my PhD programme. I particularly acknowledge Professor Nguyen Van Kinh, director of the National Hospital for Tropical Diseases, for being my mentor and always supporting me in accomplishment of this thesis. A special acknowledgement is given to Professor Jeremy Farrar for his essential help in the start of my PhD programme, to Dr. Carl Suetens for his help in having permission for the use of the ECDC point prevalence survey protocol, and to Mr. Mats Fredriksson, a statistician at Linkoping University, for bring my first steps on logistic regression analysis. I would like to thanks Dr. Mattias Larsson, Dr. Lennart E Nilsson, and Dr. Ulf Rydell for their kind support in this thesis. I would like to give deepest thanks to Mr Vu Tien Viet Dung, Dr. Quynh-Dao Dinh, and all staff in Oxford University Clinical Research Unit in Hanoi for their warm support during my study period. I would like to express my respect and thanks to Dr. Mary Chambers, Ms. Le Thi Kim Yen, Ms. Leigh Jones, and all staff at Training Department, OUCRU - Vietnam, for their support throughout my PhD programme. I would like to thank all the patients, their relatives, the doctors, pharmacists, microbiologists, infection control staff, nurses and administrators from the 14 participating hospitals for their contribution to the studies in this thesis. I would also like to thank the Ministry of Health in Vietnam for their support. v I would like to give thanks to the Wellcome Trust Major Overseas Programme and the Swedish International Development Cooperation Agency for their financial support in the conduction of the studies in this thesis. Finally, I would like to dedicate this thesis to my family, particularly my wife and children who have sacrificed to support and encourage me to accomplish this thesis. vi Declaration Except for the assistance presented in the authorship and acknowledgment, I can confirm that the majority of work presented in this thesis is my own and was conducted under the supervision of Professor Heiman FL Wertheim and Dr. Behzad Nadjm at Oxford University Clinical Research Unit in Hanoi, Vietnam. The work presented in Chapter 3 and 4 has been published in the PLOS ONE journal in 2016, which has been updated with more recent literature. This thesis has not been submitted for a degree or other qualification to any other universities. vii Abbreviations & And °C The degree Celsius AB Antibiotics ACCP American College of Chest Physicians AIDS Acquired Immunodeficiency Syndrome AMR Antimicrobial Resistance APACHE II Acute Physiology and Chronic Health Evaluation Score BAL Bronchoalveolar Lavage BMH Bach Mai Hospital BSI Blood Stream Infection BYT Vietnam Ministry of Health C3-R 3rd cephalosporin generation resistant C3-S 3rd cephalosporin generation susceptible CABSI Catheter Associated Blood Stream Infection CAI Community Acquired Infection Car-R Carbapenems resistant Car-S Carbapenems susceptible CDC Centers for Disease Control and Prevention CFU Colony Forming Unit CI Confidence Interval CLSI The Clinical and Laboratory Standards Institute guidelines on Performance Standards for Antimicrobial Susceptibility Testing CNS Central Nervous System COPD Chronic Obstructive Pulmonary Disease viii CPIS Clinical Pulmonary Infection Score CRBSI Catheter Related Blood Stream Infection CRUTI Catheter Related Blood Urinary Tract Infection DDD Defined Daily Dose DOT Day of Therapy ECDC The European Centre for Disease Prevention and Control ECMO Extracorporeal Membrane Oxygenation FiO2 Fraction of Inspired Oxygen Glyco-R Glycopeptides resistant Glyco-S Glycopeptides susceptible GDP Gross Domestic Product HAI Hospital Acquired Infection HAP Hospital Acquired Pneumonia HBV Hepatitis B Virus HCAI Healthcare Associated Infection HCV Hepatitis C Virus HELICS Hospital in Europe Link for Infection Control through Surveillance HIV Human Immunodeficiency Virus HTD Ho Chi Minh City Hospital for Tropical Diseases ICU Intensive Care Unit INICC The International Nosocomial Infection Control Consortium IPC Infection Prevention and Control IQR Interquartile Ranges IVAC Infection related Ventilator Associated Complication LMIC Low and Middle Income Country LRTI Low Respiratory Tract Infection ix MIC Minimum Inhibitor Concentration MIU Million International Units mm3 Cubic Millimeter MRSA Methicillin resistant Staphylococcus aureus MSSA Methicillin susceptible Staphylococcus aureus NA Not applicable NHSN The National Healthcare Safety Network NHTD National Hospital for Tropical Diseases OR Odds Ratio Oxa-R Oxacillin Resistant Oxa-S Oxacillin Susceptible PaO2 Partial pressure of arterial dissolved oxygen PD Patient Day PEEP Positive End-Expiratory Pressure PN Pneumonia PNU1 Clinical Defined Pneumonia PPS Point Prevalence Survey SOFA The Sequential Organ Failure Assessment Score SPSS Statistical Package for the Social Sciences SSI Surgical Site Infection UK The United Kingdom of Great Britain & Northern Ireland UK NEQAS The United Kingdom National External Quality Assessment Service UNK Unknown or missing data US The United States of America USA The United States of America UTI Urinary Tract Infection x VAC Ventilator Associated Condition VAE Ventilator Associated Event VAP Ventilator Associated Pneumonia VARI Ventilator