Epidemiology of carbapenemase-producing organisms (CPO) in Scotland

The emergence and spread of carbapenem-resistant organisms (CRO) is a global public health threat in healthcare settings, resulting in high mortality, prolonged healthcare and increased costs. In the last two decades, many papers aiming to identify individuals at high risk of acquiring CRO have been published. However, the results reported across these studies are inconsistent and there are no studies systematically summarising those findings. Carbapenem resistance is mediated by multiple mechanisms. Carbapenemase production is the most concerning as the encoding genes of carbapenemases are located on mobile genetic elements, facilitating horizontal genetic exchange and therefore promoting the acquisition and spread of resistance genes. Examination of the epidemiology of carbapenemase-producing organisms (CPO) will inform local infection prevention and control strategies. This thesis has two main parts. The aim of the first part is to systematically summarise risk factors for CRO infection and colonisation in healthcare facilities worldwide and identify study characteristics contributing most to the heterogeneity across studies. In the second part I focused on CPO in Scotland to investigate the incidence, microbiological characteristics and outcomes of CPO and determine risk factors associated with CPO among hospitalised patients. In the first part, I conducted a systematic review and meta-analysis to evaluate risk factors associated with infection and/or colonisation of CRO in healthcare facilities. In total, 227 papers published between 1986 and 2016 were identified. Using pooled odds ratio estimates and the likelihood of statistical significance as criteria, prior carriage of multidrug-resistant organisms, prior antibiotics usage (carbapenem or oxazolidinone), prior provision of medical devices (mechanical ventilation or nasogastric tube) and prior healthcare exposure (intensive care unit ICU stay, and longer hospital stay) were most consistently found to be leading risk factors for CRO infection and/or colonisation. Additionally, decubitus ulcer was a specific leading risk factor for CRO infection, and prior antibiotics usage (polymyxin or cefepime) and steroid treatment were specific for hospital acquired CRO infection. However, prior provision of some medical devices (parenteral nutrition or gastrostomy or urinary catheter) were only leading risk factors for CRO colonisation. Study organism, case-control selection, study population, sample size, study setting and specialty (ICU or non-ICU) were the characteristics accounting for most heterogeneity across the published studies examined. In the second part of this thesis, I focused on CPO in Scotland using data extracted from several national datasets. I performed a retrospective analysis on all CPO from clinical and screening cultures in 2003-2016 using generalised linear models and survival analyses, and then conducted a matched casecontrol study to determine risk factors for CPO infection and colonisation among hospitalised patients using conditional logistic regression models. In total, 243 CPO isolates were identified in 214 individuals from 13 of 14 NHS Boards. The overall incidence of CPO cases increased significantly (P<0.001), from 0.02 to 1.38 per 100,000 population. The case fatality rate was 5.6%. Enterobacteriaceae isolates predominated (84.8%) and increased significantly faster than non-fermenters. Community-associated CPO were more likely to be colonisations while healthcare-associated CPO were more likely to be infections. The ‘big 5’ carbapenemases (VIM, NDM, KPC, OXA-48 and IMP) predominated (96.7%). Awareness is required that older patients, with systemic infection or organ failure or presenting non-fermenters are at higher 30-day mortality risk from CPO. Patients with CPO infection had higher hospital mortality and longer hospital stay. A history of prolonged hospitalisation, prolonged ICU or high dependency unit (HDU) stay and being immunocompromised all independently increased the risk of CPO infection, while a history of HDU stay and ‘endocrine, nutritional and metabolic diseases’ were independent risk factors for CPO colonisation. In conclusion, this thesis sheds light on patients at high risk of being infected or colonised by CRO including CPO in healthcare facilities. Pre-emptive management should be prioritised for these patients. The findings also demonstrate the necessity of continuing the existing acute hospital admission screening programme for carbapenemase-producing Enterobacteriaceae in Scotland. Future efforts are required to understand underlying factors accounted for mortality, evolution and transmission of carbapenem resistance in Scotland