epidemiology of nosocomial pneumonia in the intensive care unit of bach mai hospital, 2008-2009

ABBREVIATIONS A. baumannii A. baumannii AFLP Amplified Fragment Length Polymorphism CDC Centers for Disease Control and Prevention CI Confidence Interval COPD Chronic Obstructive Pulmonary Disease DNA Deoxyribo Nucleic Acid GNB Gram-Negative Bacteria HAI Healthcare - Associated Infection HAP Healthcare-Associated Pneumonia HCFs Health Care Facilities HCW Health Care Worker HIV Human Immunodeficiency Virus IC Infection Control ICU Intensive Care Unit MDRO Multidrug-Resistant Organism MRSA Methicillin-Resistant Staphylococcus aureus OR Odds Ratio PCR Polymerase Chain Reaction PFGE Pulse-Field Gel Electrophoresis P.aeruginosa Pseudomonas aeruginosa WHO World Health Organization 1 INTRODUCTION Healthcare-associated pneumonia (HAP) is defined as pneumonia that occurs in patients that reside in or have resided in a long-term care facility, acute-care facility, or other healthcare facility. HAP occurs for at least 48 hours after admission to the hospital/healthcare facility. HAP is currently the second most common nosocomial (hospital- acquired) infection and is the leading infection among those detected in ICUs. 83% of episodes of HAP were associated with mechanical ventilation. Microorganisms colonize the stomach, upper airway and bronchi, and cause infection in the pneumonia. They are often endogenous (digestive system or nose and throat), but may be exogenous, often from contaminated respiratory equipment. According to the findings of some studies conducted in the United States and in the Europe, the mortality rate in the patients with of HAP caused by common multi-antibiotic resistant bacteria such as A. baumannii and P.aeruginosa, account for more than 70%; these pathogens are uncommon in non-ICU settings. HAP is the most common HAI in Vietnamese ICUs and it can extend hospitalization by an average of 7 to 14 days per patient and increase the costs of hospitalization. Mechanical ventilation is found the important risk factor associated with HAP. A. baumannii and P.aeruginosa are the leading isolated microorganisms contributing to HAI. More than 60% A. baumannii and P.aeruginosa are resistant to commonly used antibiotics. The emergence and dissemination of resistant organisms is considered as one of the challenging problems in medical science with clinical, economical, and public health implications. There remains a paucity of information on the magnitude, risk factors, as well as antibiotic resistance and molecular characteristics of pathogens causing HAP in the Vietnamese ICUs. The lack of such information represents a challenge for HAP control and prevention. The objectives of this study were to determine: (1) The incidence of and risk factors for HAP in ICU of Bach Mai hospital; and (2) Pathogens, antibiotic resistance and molecular characteristics of common bacteria causing HAP. SUMMARY OF NEW CONTRIBUTIONS This is the first thesis in Vietnam aimed to describe comprehensively the incidence of, risk factors for HAP, as well as antibiotic resistance and molecular characteristics of pathogens causing HAP in the Intensive care 2 unit of Bach Mai Hospital which is the area with the highest incidence density of healthcare associated infections among Vietnamese HCFs. HAP was commonly observed in patients of Intensive care unit, Bach Mai hospital. The incidence of HAP accounted for 18.9%. The overall HAP density was 11.6 per 1,000 patient-days. Higher densities found in patients with tracheotomy and endotracheal intubation. The HAP rates per 1,000 tracheotomy and endotracheal intubation-days were 27.4 and 72.1, respectively. Risk factors for nosocomial found by logistic regression analysis were: (1) Chronic respiratory diseases (OR = 1.9; p < 0.001), (2) Endotracheal intubation (OR = 3.9; p < 0.05), (3) Endotracheal intubation (OR = 6.3; p < 0.01), (4) Surgical procedure (OR = 2.5; p < 0.05). The thesis not only confirmed the increased trend in HAP caused by A. baumannii but also recognized the growth of antibiotic resistances of this pathogen. Carbapenem is one of most effective antibiotics against A. baumannii. However, the percentages of A. baumannii isolates resistant to imipenem and meropenem were 84.9% and 86.8%, respectively, which were much higher than recent studies conducted in US and Europe. PFGE analysis revealed that a total of 46 (86.7%) among 53 A. baumannii isolates belong to 6 major clusters (A, B, C, D, E and F) with the high similarity index of DNA pattern ranged from 80.0% to 96.1%. Clone D was the most predominant and had been detected through the entire 8-month study period. These findings suggest a hypothesis that is consistent with studies showing the cross-transmission of A. baumannii between patients. The dissemination of this pathogen is facilitated by poor compliance with aseptic techniques and contributes to high colonization rates among hospitalized patients, healthcare workers and frequent contamination of environments. A. baumannii colonizing might easily transmitted to other patients via invasive procedures. The thesis shows scientific evidences on HAP, antibiotic resistance and molecular characteristics of pathogens causing HAP. These findings suggest areas for intervention and for developing guideline for prevention and control of HAP in HCFs. THESIS STRUCTURE The thesis consists of 129 pages. Background: 3 pages; Overview: 39 pages; Methods: 20 pages; Results: 33 pages; Discussion: 31 pages; Conclusions: 2 pages; Recommendations: 1 page; 45 tables ans 18 3 illustrations; 155 references including 37 Vietnamese and 118 English ones. Chapter 1. OVERVIEW 1.1. Epidemiology of HAP 1.1.1. HAP in the world: HAP is currently the second most common nosocomial (hospital-acquired) infection and is the leading infection among those detected in ICUs. More than 80% of episodes of HAP were associated with mechanical ventilation. Previous multicenter cohort studies that consisted of more than 5 mixed ICUs of multidisciplinary hospitals had reported nearly comparable infection rates for ventilator associated pneumonia: 14.8 cases per 1,000 ventilator-days in Canadian ICUs, 13.3 cases per 1,000 ventilator-days in German ICUs, 9.4 cases per 1,000 ventilator-days in French ICUs, and 12.6 per 1,000 ventilator-days in Japan. HAP is the most common HAI in Vietnamese ICUs and it can extend hospitalization by an average of 7 to 14 days per patient and increase the mortality rate by from 20% to 30%. The highest rate of death is found in patients with HAP which was caused by multi-antibiotic resistant bacteria such as A. baumannii and P.aeruginosa. 1.1.2. HAP in Vietnam: A one day-prevalence study at 36 hospitals across Vietnam in 2008 showed an overall HAI prevalence of 7.8%. The most common infection was pneumonia, account for > 60% of the detected HAIs. HAP rates ranged from 20% to 25% in recent years. Respiratory invasive procedures (endotracheal intubation and tracheotomy) are the most important risk factors for HAP . The increased trend in HAP caused by multi-antibiotic resistant negative bacteria is recognized. The percentages of A. baumannii and P.aeruginosa isolates resistant to imipenem in ICU, Bach Mai hospital increased from < 20% (2002) to > 40% (2006). 1.1.3. Etiology of HAP: Bacteria have been the most frequently isolated pathogens. Among microorganisms isolated from oropharyngeal aspiration and sputum, anaerobes and fungi account for 73% and 4%, respectively. HAP tends to be associated with multiple organisms and the common bacteria are gram-negative bacilli. However, MRSA and other Gram- positive cocci including Streptococcus pneumoniae has increased in frequency in the last few years. The data collected and reported by hospitals participating in the National Nosocomial Infections Surveillance (NNIS) System showed that P.aeruginosa, Enterobacter sp., Klebsiella 4 pneumoniae, Escherichia coli, Serratia marcescens and Proteus sp. accounted for 50% isolates identified from respiratory specimens of patients with HAP. 1.1.4. Source of Infectious Agents: HCWs, patiens, visitors and hospital environment. 1.1.5. Modes of transmission 1.1.5.1. Contact Transmission: The most common mode of transmission, contact transmission is divided into 2 subgroups: direct contact and indirect contact. Indirect contact is important contributor to the pathogen transmission involving the transfer of an infectious agent through a contaminated intermediate object or person such as contaminated hands of HCWs, patient-care devices, food, water or contaminated infusion. 1.1.5.2. Airborne transmission: Microorganisms from infectious individual or person who is colonized with bacteria, may be inhaled by susceptible individuals through the dissemination of either airborne droplet nuclei or small particles (< 5μm)in the respirable size range containing infectious agents that remain infective over time and distance (eg, spores of Aspergillus spp and M. tuberculosis). 1.1.5.3. Droplet transmission: Respiratory droplets (> 5 μm) carrying infectious pathogens transmit infection when they travel directly from the respiratory tract of the infectious individual to susceptible mucosal surfaces of the recipient, generally over short distances. 1.1.6. Susceptible individuals: age 65 years or more, underlying conditions, especially chronic respiratory diseases, depressed level of consciousness, thoracic or chest surgery, continuous mechanical ventilation, use of paralytic agents, severe trauma, upper abdominal surgery, and recent bronchoscop. 1.1.7. Pathogenesis of HAP: (1) HAP is caused by bacteria from remote infection sites; (2) HAP is caused by bacteria from adjadcent aer subdiaphragmatic abscesseas of lungs (subdiaphragmatic abscess, mediastinal abscess, pleural infection v.v), (3) Aspiration of oropharyngeal bacteria is the most common initiating event. These bacteria come from exogenous sources (environment, medical devices, HCWs) or from endogenous flora (hollow viscera such as respiaratory tract or gastrointestinal tract). 1.1.8. Risk factors for HAP 1.1.8.1. Host related: age 65 years or more, underlying conditions, especially chronic respiratory diseases, depressed level of consciousness, 5 thoracic or chest surgery, use of paralytic agents, severe trauma, upper abdominal surgery, and recent bronchoscopy. 1.1.8.2. Device related: Tracheal intubation, continuous mechanical ventilation, orogastric or nasogastric tube placement, and frequent (e.g., every 24 hours) ventilator circuit changes. 1.1.8.3. Increased colonization: Admission to the ICU, administration of broad-spectrum antibiotics, prophylaxis for stress ulcer bleeding with antacids or H2 blocker, exposure to contaminated medical equipment, and inadequate hand hygiene 1.1.8.4. MDRO: Hospitalization for more than 7 days before the diagnosis of HAP, transferred from another care facility, ventilation for more than 3 days before the diagnosis of HAP, active malignancy, AIDS, end-stage liver or renal disease, steroids (e.g., prednisone 10 mg/day or more for more than 7 days), active chemotherapy or radiotherapy, and bronchiectasis. Prior antibiotic use for more than 3 days within the previous 14 days of the diagnosis of HAP also is considered a risk factor for resistant organisms. 1.1.8.5. Treatment related: No recommendation can be made for routinely acidifying gastric feeding. It creates favorable conditions for the growth of bacteria. 1.1.8.6. Others: Inhalation of contaminated aerosols or airborne microbes can also introduce bacteria into the lower respiratory tract. This can occur during events such as utility interruptions, remodeling, or construction where infection control recommendations have not been followed . 1.1.9. Control and prevention of HAP 1.1.9.1. Prevention of person-to-person transmission of bacteria: Respiratory equipment must be properly cleaned and sterilized. Ventilator tubing must be handled appropriately to avoid spilling condensate into the patient’s airway. Sandard and transmission based precautions must be applied in patient care. 1.1.9.2. Pneumococcal vaccination: Vaccinate patients at high risk for severe pneumococcal infections. 1.1.9.3. Precautions for prevention of aspiration: rinsing oral for patients, positioning the patient supine with the head elevated 30–45 degrees, suctioning measures including continuous suctioning of subglottic secretions, and minimizing the use of sedating or paralytic agents. 6 1.1.9.4. Precautions for MDRO: Selection of appropriate therapy is essential to avoid the detrimental effects of antibiotic overuse and the production of selective pressure for resistant organisms. 1.1.9.5. Other precautions: Educate HCWs about measures to prevent and control HAP, conduct surveillance for HAP in ICU patients and provide feedback on HAP rates and the compliance of HCWs with aseptic techniques. 1.2. Antibiotic resistance characteristics of bacteria causing HAP Growing cause of HAP including Acinetobacter baumannii, P.aeruginosa which are associated with increasing antibiotic resistance in HCFs. Exposure to any antibiotic active against GNB has been associated with the emergence of multidrug-resistant. 3 classes of antibiotics have been most frequently implicated. The use of third-generation cephalosporins has been implicated in numerous case-control studies. In addition, Landman found that aggregate use of cephalosporins plus aztreonam, but not other antibiotic classes, was associated with the presence of multidrug-resistant (including carbapenem-resistant) Acinetobacter isolates. Numerous subsequent studies have shown that the higher rate of multiantibiotic resistance in the strains can be responsible for oligoclonal outbreaks. Therefore, MDROs illustrate the potential for outbreak isolates. Four major mechanisms of antimicrobial resistance include: (1) Drug inactivation: Occurs when a bacterium produces an enzyme that can destroy or inactivate the antimicrobial; (2) Alteration in target site: Drug receptor or target sites may undergo alteration; (3) Decreased permeability or efflux: Changes in drug permeability or an efflux of drug may be observed as in the case of P. aeruginosa that has developed resistance to the carbapenem; (4) Bypass of a metabolic pathway: bacteria may develop alternative metabolic pathways to bypass the pathway that was inhibited by the antimicrobial; resistance to trimethoprim-sulfamethoxazole commonly occurs in this manner. 1.3. Molecular epidemiological profile of infection with multidrug- resistant A. baumannii and Pseudomonas species Early studies of panresistance in Pseudomonas aeruginosa showed little evidence of clonality among these strains. However, numerous subsequent studies have shown that these strains can be responsible for 7 oligoclonal outbreaks, particularly in ICU, clearly illustrating the potential for person-to-person spread. It is not clear whether transmission occurred via common environmental sources or the hands of health care workers. 1.4. Application of Molecular Techniques to the Study of HAI 1.4.1. Characteristics of typing methods 1.4.1.1. PFGE: The principle of this technique is to digest chromosomal DNA with restriction enzymes, resulting in a series of fragments of different sizes that form different patterns when analyzed by agarose gel electrophoresis. By periodically changing the direction of the electrical field in which the DNA is separated, PFGE allows the separation of DNA molecules of over 50 kbp in length. In general PFGE is one of most reproducible and highly discriminatory typing methods available, and it generally is the method of choice for many hospital epidemiologic evaluations. 1.4.1.2. Southern blot analysis: The bacterial DNA is digested using a frequent cutting restriction enzyme, the DNA fragments are separated by agarose gel electrophoresis, and then the fragments are transferred (blotted) onto a nitrocellulose or nylon membrane. Next, a labeled (colorimetric or radioactive) piece of homologous DNA is used to probe the membrane. The discriminatory power of this method is related to the copy numbers of the targeted genetic elements in the bacterial genome and their distribution among the restriction fragments following electrophoresis. 1.4.1.3. Plasmid Analysis: Typing is performed through the isolation of plasmid DNA and comparison of the numbers and sizes of the plasmids by agarose gel electrophoresis. Evaluation of plasmid content is not generally useful in delineation of strain relatedness. Plasmid analysis has been applied in clinical situations to determine the evolution and spread of antibiotic resistance among isolates with different PFGE profiles or among different species of organisms within hospitals. 1.4.1.4. Typing Methods Using PCR: This technique is a biochemical in vitro reaction that permits the synthesis of large quantities of a targeted nucleic acid sequence. The procedure requires template DNA from the organism being typed, two complementary oligonucleotide primers that are designed to flank the sequence on the template DNA to be amplified, and a heat-stable DNA polymerase. A growing number of organisms have been studied using this approach. 8 1.4.1.5. AFLP: This is a typing method that utilizes a combination of restriction enzyme digestion and PCR. The method utilizes the benefits of restriction fragment length polymorphisms analysis with the increased sensitivity of PCR to generate profiles that are reproducible and relatively easy to interpret and compare to those for other isolates from a nosocomial outbreak. 1.4.2. Cost-effective application of typing methods in HAI study Understanding pathogen distribution and relatedness is essential for determining the epidemiology of HAIs. Molecular techniques can be very effective in tracking the spread of nosocomial infections due to genetically related pathogens, which would allow infection control personnel to more rationally identify potential sources of pathogens and aid infectious disease physicians in the development of treatment regimens to manage patients affected by related organisms. In addition, the incorporation of molecular testing in the infection control program for endemic HAIs is associated with the ability to enact early interventions following the identification of pathogen clonality, which could be an early indication of an outbreak. Conversely, the determination of the unrelatedness of isolates (sporadic infections), avoids triggering unneeded and costly epidemic investigations. Cost reduction was also accomplished by earlier recognition of person-to- person spread of isolates compared to that with traditional surveillance, thus potentially preventing the spread to additional patients. Chapter 2. STUDY Population, matERIALS and METHODS 2.1. Study population: Patients admitted to the ICU of Bach Mai hospital for at least 48 hours and microbial isolates identified from clinical samples of suspected/confirmed patients with HAP. 2.2. Study design: Descriptive and molecular study. 2.2.1. Selection of study sample - Study patients: Patients admitted to the ICU for at least 48 hours were assessed during the study period from September 2008 to April 2009. - Bacteria and fungi were isolated from patients with HAP. 2.2.2. Sample size: The caculation was based on WHO formula for estimating a population proportion with specified relative precision. The details are as follows: 9 z 2 (1-α/2) .p.q n = p. ε 2 In which: n = Minimum sample size; z (1- α /2) = Confidence coefficient, with confidence level of 95% → z (1- α /2) = 1.96; ε: Relative precision = 0.16, p: Anticipated population proportion (p = 0.25) was calculated by prospective study on HAP in ICU, Bach Mai hospital - 2002, q = 1-p. In this case, a sample size of 450 patients would be needed. The real number of observed patients in this study was 477 . 2.3. Methods: Data collection techniques include clinical/paraclinical examination, microbiologic evaluation and PFGE analyses of common bacteria causing HAP. 2.3.1. Study indicators: 2.3.1.1. HAP characteristics:(1) Incidence and density of HAP; (2) Etiology of HAP: The distribution of HAP pathogens and their antibiotic resistant level, (3) Risk factors for HAP and (4) Outcomes of HAP: length of stay in ICU, patient outcomes, and hospital cost. 2.3.1.2. Molecular characteristics of common bacteria causing HAP: Number of bacteria, number of clusters, the similarity index of each cluster and between clusters. 2.3.2. Determination of study indicators 2.3.2.1. HAP surveillance: surveillance team included IC practitioners (an IC nurse and doctor) and 1 representative physician and nurse from the ICU who had been trained on the study objectives, surveillance methodology, HAP definition, clinical sample and data collection. 2.3.2.2. HAP ascertainment: HAIs were diagnosed and ascertained using surveillance criteria established by the Bach Mai hospital. This criteria was adjusted from criteria of CDC, USA (1988). HAI case definitions were based on the combination of objective clinical findings and supportive data (eg, radiographs, ultrasound scans, endoscopy findings, and pathology reports). Isolates from any patients with suspected or confirmed HAIs were identified, speciated, and tested for susceptibility to a panel of antimicrobials susceptibility commonly used at the Bach Mai hospital. 2.3.2.3. Determination of risk factors: Based on clinical findings and the review of nursing and medical charts. Data were collected by recording study variables (age, gender, primary admission diagnosis, conditions associated with increased risk of APACHE II index scores, operation, [...]... patient supine with the head elevated 30–45 degrees, suctioning measures including continuous suctioning of subglottic secretions, and minimizing the use of sedating or paralytic agents 23 HAP control program in HCFs is only effective when the multimodal and multidisciplinary approach is implemented in combination with efforts on methods that could improve the behavior of HCWs in patient care Institute... have seen a swing in the pattern of infecting organisms towards gram-negative infections such as P aeruginosa, Acinetobacter spp, E coli and K pneumoniae Fungal pathogens, especially Candida spp, are becoming increasingly common In HCFs where the use of excess antibiotic doses and poor infection prevention and control practices have been associated with the development of many strains of multiantibiotic... tubing must be handled appropriately to avoid spilling condensate into the patient’s airway Ventilator circuits should not be routinely replaced to decrease the risk of pneumonia Rather, replace circuits if malfunctioning or if visibly contaminated Specific instructions can be found in the CDC guidelines for preventing HAP, 2003 Measures that can decrease the risk of aspiration include positioning the. .. confirm other previous reports showing the higher rate of HAP in ICU patients who have a high risk of infection as a result of the predisposing factors associated with their underlying conditions, chronic admission diseases and of the risk associated with the respiratory invasive procedures that they undergo The HAP density reported in our study appears to be 2 time higher than that reported in developing... 4.1 Incidence and risk factors for HAP 4.1.1 The incidence of HAP HAP incidences have accurately described with the HAP levels Data on HAP incidences usually used to compare the difference in HAP levels between studies Our study showed the high incidence of HAP (18.9%) among 477 surveyed patients This finding is similar to that reported in some studies of similar design in the ICUs of Vietnam and other... collection methods were approved by the Ethics and Health Research Review Committee of Bach Mai hospital and Ministry of Health, Vietnam - All prospective research participants were fully informed about the study objectives, research activities The principle of voluntary participation requires that people not be coerced into participating in research In the case of the patients who were unable to discuss... imipenem Inappropriate use of antibiotics is one of main reasons causing the rapid global emergence of antibiotic resistant A baumannii strains and can lead to increased mortality in infected patients with these bacteria HAIs caused by A baumannii, which is associated with a attributable mortality rate of 25% in hospital wide and of 50% in ICUs only Although antibiotic resistance is rising, no new... against multiantibiotic resistant A baumannii expected to be in use in the next several decades It is necessary to consider the use of colistin in infected patients with these bacteria Moreover, the surveillance of HAIs caused by these multidrug resistant bacteria should seem to be the first priority in IC activities Similar surveillance systems should also consider presenting prevalence rates of multidrug... 80.0% to 96.1% Of them, 23 isolates belong to cluster D and F, accounted for 50% Cluster D was the most predominant and had been detected through the entire 8-month study period Other clusters survived less than 3 months Epidemic investigations using PFGE technique are often used to help determine the sources of organism in environments However, in some cases, increased infection rates of specific pathogens... become the routine activities in the ICU due to limited resources In this situation, colonized or infected patients with A baumannii could be the sources for the crosstransmission of A baumannii between patients Further research on the transmission of these bacteria is needed to implement effective interventions, which contribute to reduce the HAP rates caused by A baumannii in ICUs 4.3 Strategies for the . exogenous, often from contaminated respiratory equipment. According to the findings of some studies conducted in the United States and in the Europe, the mortality rate in the patients with of HAP. characteristics of pathogens causing HAP in the Intensive care 2 unit of Bach Mai Hospital which is the area with the highest incidence density of healthcare associated infections among Vietnamese. observed in patients of Intensive care unit, Bach Mai hospital. The incidence of HAP accounted for 18.9%. The overall HAP density was 11.6 per 1,000 patient-days. Higher densities found in patients