Summary
Background
Carbapenemase-producing organisms (CPO) have been largely responsible for the extensive spread of carbapenem resistance, and their prevalence is increasing in many parts of the world.
Aim
To evaluate clinical and molecular epidemiology and mortality associated with CPO among patients.
Methods
All CPO from clinical and long-term healthcare surveillance cultures across Scotland in 2003–2017 were reviewed retrospectively. Polymerase chain reaction was used to detect genes coding for carbapenemases. A generalized linear mixed model was used to identify risk factors for mortality.
Findings
In total, 290 individuals with CPO were identified. The overall incidence increased over time (P<0.001) from 0.02 to 1.38 per 100,000 population between 2003 and 2017. A total of 243 distinct CPO isolates were obtained from 269 isolations in 214 individuals with available metadata. The majority of the isolates were Enterobacterales (206/243, 84.8%), and Klebsiella pneumoniae (65/206, 31.6%) and Enterobacter cloacae (52/206, 25.2%) were the most common species. VIM (75/243, 30.9%) and NDM (56/243, 23.0%) were the most common carbapenemases. The crude 30-day mortality rate was 11.8% (25/211), while the case fatality rate was 5.7% (12/211). Age >60 years [adjusted odds ratio (aOR) 3.36, 95% confidence interval (CI) 1.06–10.63; P=0.033], presence of non-fermenters (aOR 4.88, 95% CI 1.64–14.47; P=0.005), and systemic infection or organ failure (aOR 4.21, 95% CI 1.38–12.81; P=0.032) were independently associated with 30-day mortality.
Conclusion
The incidence of CPO in Scotland is low but increasing. Awareness is required that inpatients aged >60 years, patients with systemic infection or organ failure, and patients presenting with non-fermenters are at higher risk of death from CPO.
Keywords: Carbapenemase, Epidemiology, Mortality, Risk factors
Introduction
Over the past two decades, the emergence of carbapenem-resistant organisms (CRO) has become a global public health crisis, leaving few effective therapeutic options available to treat multi-drug-resistant infections [1,2]. Resistance to carbapenems arises from two general mechanisms: carbapenemase production and non-enzymatic. CRO strains that do not produce carbapenemases (non-enzymatic) are usually less resistant to other antibiotics [3], and their carbapenem resistance trait is not transferable. Carbapenemases, in contrast, are encoded by genes frequently carried on mobile genetic elements such as plasmids and transposons, which could be transferred between different species and individuals. Therefore, carbapenemase-producing organisms (CPO) have largely been responsible for the rapid and extensive worldwide spread of CRO, and are considered to be of more clinical concern than non-enzymatic CRO.
With regard to the epidemiological stage of CPO, the UK is reported to be in a ‘regional spread’ situation, while many European countries are in an ‘inter-regional spread or endemic’ situation, such as Italy, Greece, France, Poland and Denmark [4]. In the UK, the prevalence and incidence of clinically significant CPO is currently low, but these multi-drug-resistant bacteria affect most UK regions [5]. In Scotland, the first CPO was reported in an Enterobacter cloacae complex blood culture isolate in 2003, carrying Klebsiella pneumoniae carbapenemase-4 [6]. The prevalence of CPO in Scotland (0.1 per 100,000 patient-days) was lower than that in England and Northern Ireland (0.85 per 100,000 patient-days) in healthcare settings [7]. However, there has been a 39% year-on-year increase in the prevalence of reported CPO isolates since 2013 in Scotland, from 0.4 per 100,000 population in 2013 to 2.0 per 100,000 population in 2017 [8]. The epidemiology of Scottish CPO isolates, however, remains unclear. As such, this study aimed to conduct a detailed analysis of epidemiological characteristics of CPO in Scotland. Insights based on these findings will further the development of effective and appropriate prevention and infection control strategies, thus contributing to curb future emergence and spread of CPO in Scotland.
Methods
Ethics
All data for analyses in this study were anonymized. The study was reviewed and approved by the Public Benefit and Privacy Panel for Health and Social Care, and covered by National Safe Haven generic ethics approval (Ref. No. 1617–0328). The study was conducted in accordance with the Declaration of Helsinki, and national and institutional standards.
Study design
A national retrospective observational study was conducted among patients in Scotland between January 2003 and December 2017. Specimens with suspected CPO from clinical indications or a surveillance programme were submitted to a Scottish diagnostic laboratory. Identification of isolates and antimicrobial susceptibility tests were performed using VITEK®2 (bioMérieux, Marcy-l’Étoile, France) [5]. If the isolate was non-susceptible to at least one carbapenem, the diagnostic laboratory referred the isolate to the Antimicrobial Resistance and Healthcare-Associated Infections (AMRHAI) Reference Unit at Public Health England (PHE) for confirmation of carbapenemase production by in-house polymerase chain reaction [5].
Definitions
In this article, samples have been described as cases, isolations and isolates. A CPO case was defined as an individual from whom there has been a CPO isolation. Each CPO isolation was described on the basis of organism (e.g. K. pneumoniae), enzyme (e.g. VIM), isolation date and specimen (e.g. urine). Isolations that differ in any of these characteristics represented different isolations. For each CPO case, a CPO isolate was defined on the basis of organism and enzyme; a difference in either organism or enzyme represented different isolates. Therefore, each CPO case could contribute multiple CPO isolations with multiple CPO isolates. For one CPO case, if there were multiple isolations of the same isolate from the same specimen, only the first isolation was included in the study. This method was used in order to assess the diversity of carbapenemases and independent specimen sources for statistical analysis more uniformly. All cases were classified as healthcare-associated (HA) or community-associated (CA) [9,10] (Table S1, see online supplementary material). Specimen type of the isolations was aggregated into seven groups: urine, alimentary, wound, normally sterile site, respiratory, superficial, and site unspecified.
Data collection
The data used in this study were extracted from several national datasets. Laboratory records were extracted from the Electronic Communication of Surveillance in Scotland. Medical records at individual level were extracted from the General Acute Inpatient and Day Case – Scottish Morbidity Record. Mortality data at individual level were extracted from the National Records of Scotland Deaths. Data extraction and linkage of these datasets were performed by Public Health Scotland via the electronic Data Research and Innovation Service (eDRIS).
Outcomes and statistical analysis
The outcomes included:
-
(i)
incidence of CPO, defined as the number of new CPO cases per 100,000 population per year. Temporal trends in incidence were investigated using an exponential model; temporal trends in incidence of Enterobacterales and non-fermenters were explored using a generalized linear model, and differences in temporal trends in incidence between Enterobacterales and non-fermenters were examined by testing for an interaction between bacterial family and isolation year. Temporal trends in incidence of CPO source (HA and CA) and differences in temporal trends in incidence between HA and CA cases were examined as described above.
-
(ii)
Mortality of CPO cases. Crude 30-day mortality rate, defined as the number of deaths within 30 days of CPO isolation per 100 cases; and case fatality rate (CFR), defined as the number of CPO-attributed deaths per 100 cases.
-
(iii)
Risk factors for 30-day mortality of CPO inpatient cases. A generalized linear mixed model was used to determine the risk factors. Independent variables included demographics, microbiological characteristics, comorbidities, healthcare exposure and invasive procedures in the 90 days preceding CPO isolation. Definitions for each independent variable are listed in Table S2 (see online supplementary material).
Univariate analysis was performed first, and all variables with P<0.10 were carried forward for multi-variate analysis. Correlations between variables with P<0.10 on univariate analysis were checked by calculating correlation coefficients. Also, possible interactions between variables were checked. Model averaging was used to construct the final multi-variate model using the Akaike weights of the candidate models [11]. For statistical purposes, variables with zero values in either group were removed from multi-variate analyses. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to determine the strengths of these associations. All analyses were performed using R Version 3.3.3, and P<0.05 was considered to indicate statistical significance.
Results
Overview of the study
Up to the end of 2017, a total of 290 cases were diagnosed with CPO isolation from 13 of 14 Scottish National Health Service boards. The metadata of cases identified in 2003 (N=1) and 2017 (N=75) were not available, hence only 214 cases were included in the subsequent analyses. Clinical characteristics of CPO cases are listed in Table I. There were more female cases (N=112, 52.3%) than male cases (N=102, 47.7%). The age of CPO cases ranged from 0 to 92 years (median age 63 years, interquartile range 53–78 years). There was no difference in age between male and female cases (P=0.838). Among 214 CPO cases, 170 (79.4%) cases had a single isolation while 44 (20.6%) cases had multiple isolations, resulting in 269 unique isolations. One hundred and fifty-one (70.6%) of 214 cases were inpatients. In total, 243 CPO isolates were obtained from 214 cases. Due to incompleteness of the medical records for three CPO cases, the CPO source could be classified for only 211 cases. Among them, 149 (70.6%) were HA cases. Incidence rates of both HA and CA increased significantly over time (P<0.001), but no difference in temporal trends in incidence was found between them (P=0.310).
Table I.
Clinical characteristics of carbapenemase-producing organism (CPO) cases
| Characteristics | N (%)a |
|---|---|
| Demographics | |
| Age (years), median (IQR, range) | 63 (53–78, 0–92) |
| Advanced age (>60 years) | 124/211 (58.8) |
| Gender, male | 102/214 (47.7) |
| Comorbidities | |
| Certain infectious and parasitic diseasesb | 70/211 (33.2) |
| Sepsis | 18/211 (8.5) |
| Copresence with other pathogens | 24/211 (11.4) |
| Neoplasms and diseases of the blood and blood-forming organs | 53/211 (25.1) |
| Malignancy | 38/211 (18.0) |
| Solid | 16/211 (7.6) |
| Haematologic | 22/211 (10.4) |
| Anaemia | 11/211 (5.2) |
| Endocrine, nutritional and metabolic diseases | 37/211 (17.5) |
| Diabetes mellitus | 21/211 (10.0) |
| With complications | 8/211 (3.8) |
| Diseases of the circulatory system | 51/211 (24.2) |
| Heart failure | 3/211 (1.4) |
| Diseases of the respiratory system | 53/211 (25.1) |
| Respiratory tract infection | 33/211 (15.6) |
| Respiratory failure | 5/211 (2.4) |
| Diseases of the digestive system | 21/211 (10.0) |
| Diseases of the genitourinary system | 58/211 (27.5) |
| Urinary tract infection | 35/211 (16.6) |
| Renal failure | 21/211 (10.0) |
| Diseases of the nervous system | 21/211 (10.0) |
| Diseases of the skin and subcutaneous tissue | 14/211 (6.6) |
| Diseases of the musculoskeletal system and connective tissue | 19/211 (9.0) |
| External causes of morbidity | 53/211 (25.1) |
| Injury, poisoning and certain other consequences of external causes | 49/211 (23.2) |
| Immunocompromised status | 44/211 (20.9) |
| Healthcare exposure | |
| HDU stay | 58/211 (27.5) |
| Duration of HDU stay (days), median (IQR, range) | 0 (0–1, 0–65) for 211 cases |
| ICU stay | 45/211 (21.3) |
| Duration of ICU stay (days), median (IQR, range) | 0 (0–0, 0–39) for 211 cases |
| Hospitalization | 87/211 (41.2) |
| Duration of hospitalization (days), median (IQR, range) | 8 (0–31.5, 0–91) for 211 cases |
| Hospital transfer | 32/211 (15.2) |
| Ward transfer | 97/211 (46.0) |
| Emergency admission | 127/150 (84.7) |
| Admission from healthcare facilities | 16/150 (10.7) |
| Surgical specialty | 69/150 (46.0) |
| TAR (days), median (IQR, range) | 6.5 (1–25, 0–91) for 150 cases |
| Discharge type, death | 32/150 (21.3) |
| Discharge to healthcare facilities | 18/150 (12.0) |
| Invasive procedures | |
| Any | 75/211 (35.5) |
| Centesis | 10/211 (4.7) |
| Ectomy | 20/211 (9.5) |
| Transplantation | 4/211 (1.9) |
| Catheterization | 19/211 (9.0) |
| Urinary catheter | 6/211 (2.8) |
| CVC | 15/211 (7.1) |
| Dialysis or drainage | 7/211 (3.3) |
| Endoscopic operation | 17/211 (8.1) |
| Invasive ventilation | 9/211 (4.3) |
| Other surgical procedures | 26/211 (12.3) |
ICU, intensive care unit; IQR, interquartile range; HDU, high dependency unit; TAR, time at risk (defined as interval between admission to hospital and CPO isolation); CVC, central venous catheter.
Number of cases with the characteristic/total number of cases investigated (percentage of cases with the characteristic), unless stated otherwise.
Certain infectious and parasitic diseases comprise sepsis (including septic shock), infections caused by CPO, and infections caused by other pathogens (Clostridium perfringens, Clostridioides difficile, Streptococcus spp., Staphylococcus spp, Salmonella spp., Aspergillus spp., Candida spp., human immunodeficiency virus, hepatitis C virus, Reoviridae).
Incidence and mortality of CPO
Figure 1 shows the number of CPO cases and temporal trends in incidence from 2003 to 2017. Overall incidence increased between 2003 and 2017 (incidence∼0.025∗1.332ˆyear; P<0.001) from 0.02 to 1.38 per 100,000 population. To evaluate the impact of active surveillance for carbapenemase-producing Enterobacterales (CPE) introduced in August 2013, an exponential model was used to fit the data before (2003–2013) its introduction. Before surveillance, the model was incidence∼0.021∗1.330ˆyear. Incidence rates of Enterobacterales and non-fermenters increased significantly over time (P<0.001), but the prevalence of Enterobacterales (annual increase of 42.5%) increased faster than that of non-fermenters (annual increase of 21.5%) (P=0.001). The crude 30-day mortality rate was 11.8% (25/211) and CFR was 5.7% (12/211).
Figure 1.
Incidence of carbapenemase-producing organisms (CPO) in Scotland 2003–2017. Black circles represent the incidence of CPO, and black lines represent the temporal trend in CPO incidence between 2003 and 2017. Green lines represent the temporal trend in CPO incidence before conduction of Scottish carbapenemase-producing Enterobacterales active surveillance (i.e. between 2003 and 2013), and green circles indicate the predicted incidence of CPO between 2014 and 2017 from the pre-surveillance model (2003–2013). The vertical distance between black circles and green circles represents the difference between actual incidence and predicted incidence from the pre-surveillance model between 2014 and 2017.
Microbiological characteristics of CPO isolates
There were 269 unique CPO isolations. Urine (N=103, 38.3%), alimentary (N=55, 20.4%) and wound (N=42, 16.0%) specimens predominated at aggregate level, with urine (N=99, 36.8%), rectal swabs (N=45, 16.7%) and wound swabs (N=32, 11.9%) being the most common specimens (Figure 2). In general, the number of CPO isolations from wound, urine and alimentary samples increased gradually. The majority of CPO isolations were from urine and alimentary samples from 2013 onwards (Figure 3). The 243 CPO isolates were represented by eight genera and 14 species; the majority were Enterobacterales (206/243, 84.8%), and K. pneumoniae (65/206, 31.6%), E. cloacae (52/206, 25.2%) and Escherichia coli (50/206, 24.3%) were the most common species. Pseudomonas aeruginosa (29/37, 78.4%) predominated among non-fermenters (Figure 4). Carbapenemases comprised VIM (75/243, 30.9%), NDM (56/243, 23.0%), KPC (43/243, 17.7%), OXA-48 (43/243, 17.7%), IMP (18/243, 7.4%), IMI (3/243, 1.2%), NDM+IMP (2/243, 0.8%), NDM+OXA-48 (2/243, 0.8%) and GES-5 (1/243, 0.4%).
Figure 2.
Specimen types of 269 carbapenemase-producing organism (CPO) isolations according to aggregate specimen (inner circle) and specific specimen (outer circle).
Figure 3.
Temporal distribution of aggregate specimen types of 269 carbapenemase-producing organism (CPO) isolations.
Figure 4.
Family (inner circle), genus (middle circle) and species (outer circle) of 243 carbapenemase-producing organism isolates.
Risk factors for 30-day mortality of CPO inpatient cases
There were 151 inpatient cases; of these, 23 (15.2%) died within 30 days of CPO isolation. Univariate analysis indicated that all-cause 30-day mortality was associated with advanced age, presence of carbapenemase-producing non-fermenters, sepsis, malignancy, respiratory tract infection, and systemic infection or organ failure (Table II). Multi-variate analysis showed that age >60 years [adjusted odds ratio (aOR) 3.36, 95% CI 1.06–10.63; P=0.033], presence of carbapenemase-producing non-fermenters (aOR 4.88, 95% CI 1.64–14.47; P=0.005), and systemic infection or organ failure (aOR 4.21, 95% CI 1.38–12.81; P=0.032) were independent risk factors for 30-day mortality (Table II).
Table II.
Characteristics associated with all-cause 30-day mortality of 150 inpatient carbapenemase-producing organism (CPO) cases
| Characteristics | Survivor (%)a (N=127) | Non-survivor (%)a (N=23) | Univariate |
Multi-variate |
||
|---|---|---|---|---|---|---|
| OR (95% CI) | P-value | aOR (95% CI) | P-value | |||
| Demographics | ||||||
| Age (years), median (IQR) | 62 (49.5–74) | 71 (61–78) | 1.04 (1.00–1.07) | 0.024 | ||
| Age >60 years | 69 (54.33) | 18 (78.26) | 3.03 (1.06–8.65) | 0.039 | 3.36 (1.06–10.63) | 0.033 |
| Gender, male | 73 (57.48) | 12 (52.17) | 0.81 (0.33–1.97) | 0.637 | ||
| Microbiological characteristics | ||||||
| Organism family, non-fermenter | 21 (16.54) | 10 (43.48) | 3.88 (1.50–10.02) | 0.005 | 4.88 (1.64–14.47) | 0.005 |
| Comorbidities | ||||||
| Certain infectious and parasitic diseases | 57 (44.88) | 8 (34.78) | 0.65 (0.26–1.65) | 0.371 | ||
| Sepsis | 11 (8.66) | 6 (26.09) | 3.72 (1.22–11.38) | 0.021 | ||
| Co-presence with other pathogens | 20 (15.75) | 1 (4.35) | 0.24 (0.03–1.91) | 0.179 | ||
| Neoplasms and diseases of the blood and blood-forming organs | 37 (29.13) | 10 (43.48) | 1.87 (0.75–4.64) | 0.177 | ||
| Malignancy | 24 (18.90) | 9 (39.13) | 2.76 (1.07–7.12) | 0.036 | 1.57 (0.49–5.09) | 0.081 |
| Solid | 8 (6.30) | 3 (13.04) | 2.23 (0.55–9.13) | 0.264 | ||
| Haematologic | 16 (12.60) | 6 (26.09) | 2.45 (0.84–7.13) | 0.100 | ||
| Anaemia | 7 (5.51) | 2 (8.70) | 1.63 (0.32–8.40) | 0.558 | ||
| Endocrine, nutritional and metabolic diseases | 31 (24.41) | 5 (21.74) | 0.86 (0.29–2.51) | 0.783 | ||
| Diabetes mellitus | 20 (15.75) | 0 (0.00) | – | 0.044b | ||
| With complications | 8 (6.30) | 0 (0.00) | – | 0.609b | ||
| Diseases of the circulatory system | 38 (29.92) | 5 (21.74) | 0.65 (0.23–1.88) | 0.427 | ||
| Heart failure | 3 (2.36) | 0 (0.00) | – | 1.000b | ||
| Diseases of the respiratory system | 35 (27.56) | 11 (47.83) | 2.41 (0.97–5.96) | 0.057 | ||
| Respiratory tract infection | 21 (16.54) | 8 (34.78) | 2.69 (1.01–7.15) | 0.047 | 1.41 (0.49–4.04) | 0.185 |
| Respiratory failure | 2 (1.57) | 2 (8.70) | 5.95 (0.79–44.59) | 0.083 | 2.12 (0.21–20.96) | 0.169 |
| Diseases of the digestive system | 17 (13.39) | 3 (13.04) | 0.97 (0.26–3.62) | 0.965 | ||
| Diseases of the genitourinary system | 35 (27.56) | 8 (34.78) | 1.40 (0.55–3.60) | 0.482 | ||
| Urinary tract infection | 18 (14.17) | 4 (17.39) | 1.27 (0.39–4.18) | 0.689 | ||
| Renal failure | 15 (11.81) | 4 (17.39) | 1.57 (0.47–5.25) | 0.462 | ||
| Diseases of the nervous system | 19 (14.96) | 0 (0.00) | – | 0.046b | ||
| Diseases of the skin and subcutaneous tissue | 11 (8.66) | 3 (13.04) | 1.58 (0.41–6.18) | 0.509 | ||
| Diseases of the musculoskeletal system and connective tissue | 17 (13.39) | 0 (0.00) | – | 0.076b | ||
| External causes of morbidity | 44 (34.65) | 4 (17.39) | 0.40 (0.13–1.24) | 0.112 | ||
| Injury, poisoning and certain other consequences of external causes | 40 (31.50) | 4 (17.39) | 0.46 (0.15–1.43) | 0.180 | ||
| Systemic infection or organ failure | 24 (18.90) | 11 (47.83) | 3.93 (1.55–9.98) | 0.004 | 4.21 (1.38–12.81) | 0.032 |
| Immunocompromised status | 29 (22.83) | 9 (39.13) | 2.17 (0.85–5.53) | 0.104 | ||
| Healthcare exposure | ||||||
| Emergency admission | 98 (77.17) | 20 (86.96) | 1.97 (0.55–7.11) | 0.299 | ||
| Admission from healthcare facilities | 13 (10.24) | 3 (13.04) | 1.32 (0.34–5.04) | 0.689 | ||
| Surgical specialty | 60 (47.24) | 9 (39.13) | 0.72 (0.29–1.78) | 0.474 | ||
| TAR (days), median (IQR) | 5 (1–25.5) | 13 (2–20.5) | 1.01 (0.98–1.03) | 0.593 | ||
| HDU stay | 47 (37.01) | 8 (34.78) | 0.91 (0.36–2.30) | 0.839 | ||
| Duration of HDU stay (days), median (IQR) | 0 (0–2.5) | 0 (0–2.5) | 1.01 (0.97–1.06) | 0.523 | ||
| ICU stay | 33 (25.98) | 9 (39.13) | 1.83 (0.72–4.63) | 0.201 | ||
| Duration of ICU stay (days), median (IQR) | 0 (0–0) | 0 (0–0.5) | 1.02 (0.94–1.11) | 0.636 | ||
| Hospitalization | 53 (41.73) | 11 (47.83) | 1.28 (0.53–3.12) | 0.587 | ||
| Duration of hospitalization (days), median (IQR) | 17 (1–39) | 18 (9–38) | 1.00 (0.98–1.02) | 0.799 | ||
| Hospital transfer | 23 (18.11) | 4 (17.39) | 0.95 (0.30–3.06) | 0.934 | ||
| Ward transfer | 65 (51.18) | 15 (65.22) | 1.79 (0.71–4.51) | 0.218 | ||
| Invasive procedures | ||||||
| Any | 52 (40.94) | 12 (52.17) | 1.57 (0.65–3.84) | 0.319 | ||
| Centesis | 7 (5.51) | 3 (13.04) | 2.57 (0.61–10.78) | 0.196 | ||
| Ectomy | 15 (11.81) | 3 (13.04) | 1.12 (0.30–4.23) | 0.867 | ||
| Transplantation | 4 (3.15) | 0 (0.00) | – | 1.000b | ||
| Catheterization | 15 (11.81) | 2 (8.70) | 0.71 (0.15–3.34) | 0.666 | ||
| Urinary catheter | 3 (2.36) | 1 (4.35) | 1.88 (0.19–18.89) | 0.592 | ||
| CVC | 12 (9.45) | 2 (8.70) | 0.91 (0.19–4.38) | 0.909 | ||
| Dialysis or drainage | 6 (4.72) | 1 (4.35) | 0.92 (0.11–7.99) | 0.937 | ||
| Endoscopic operation | 8 (6.30) | 3 (13.04) | 2.23 (0.55–9.13) | 0.264 | ||
| Invasive ventilation | 6 (4.72) | 2 (8.70) | 1.92 (0.36–10.16) | 0.443 | ||
| Other surgical procedures | 17 (13.39) | 3 (13.04) | 0.97 (0.26–3.62) | 0.965 | ||
OR, odds ratio; CI, confidence interval; aOR, adjusted odds ratio; CPO, carbapenemase-producing organisms; IQR, interquartile range; ICU, intensive care unit; HDU, high dependency unit; TAR, time at risk; CVC, central venous catheter; –, not applicable.
Number of survivors/non-survivors with the characteristic (percentage of survivors/non-survivors with the characteristic among all the survivors/non-survivors investigated), unless stated otherwise.
Fisher's exact test.
Discussion
According to guidance from the European Centre for Disease Prevention and Control, understanding and monitoring the local epidemiological situation is necessary to implement and refine CRO prevention and control strategies [12]. To date, no comprehensive epidemiological study of CPO has been conducted in Scotland at national or individual level. To the authors' knowledge, this is the first epidemiological study of CPO in Scotland since it was first reported in 2003.
To date, there is no acknowledged definition of an episode or de-duplication criterion for a CPO case. The longest interval between isolations with the same organism and carbapenemase from the same individual was 740 days in this study, indicating possible long-term persistence of CPO. As a result, no definition of episodes was attempted in this study, and the analysis was based on patients (i.e. CPO cases), using the first isolation for patients with multiple CPO isolations, unless stated otherwise. In 2013, Scotland launched an acute hospital admission screening programme for CPE [13]. However, carbapenemase-producing non-fermenters from CPE screening samples were also reported to Public Health Scotland and included in this study. Therefore, the subsequent increase in CPO cases reported, particularly CPE, may reflect increased awareness and testing due to the introduction of CPE screening, noting that: (i) the true incidence was higher than the extrapolations from the model in 2003–2013 (Figure 1); (ii) the incidence of Enterobacterales increased significantly faster than that of non-fermenters; and (iii) most of the isolates were from alimentary and urine samples which were usually used for screening, and the number of isolates from these specimens increased from 2013 (Figure 2, Figure 3). The prevalence of CPO may have been underestimated as only approximately three-quarters of patients audited had undergone CPE screening in line with the national policy (76.1%) [14].
Similar to English data [15], the ‘big five’ carbapenemases (VIM, NDM, KPC, OXA-48 and IMP) accounted for 96.7% of all 243 CPO isolates. In contrast to a London study that reported 34% carbapenem-resistant non-fermenters [16], only 15.2% of all the CPO isolates in Scotland were non-fermenters. This study highlights another urgent public health threat, namely the presence and transmission of CPO in the community. The overall CA rate was 29.4% (62/211) and the incidence of CA cases increased significantly over time (P<0.001). However, the CA rate could have been overestimated due to possible long-term persistence as stated above (up to 740 days) while using 1 year from last hospitalization in the definition of CA. A scoping review found that the percentage of either CA or community-onset carbapenemase-resistant Enterobacterales ranged from 0.04% to 29.5% [17], while a study reported the rate of community-onset infections caused by CPE as 22.9% [18]. Moreover, 69.4% of the 62 CA cases in the present study were NDM/OXA-48 producers. The occurrence of OXA-48 producers in the community is often a consequence of importations from endemic countries [19]. Also, it has been reported that many NDM-1-positive patients in the UK had travelled to India or Pakistan within the preceding year, or had links with these countries [20]. Unfortunately, travel information is not available in this study. Although enhanced data in the electronic reporting system submitted to the AMRHAI Reference Unit include foreign travel, such information is filled in retrospectively on a voluntary basis following confirmation of carbapenemase production, and only 26% of records included foreign travel information [15]. As travel is known to be associated with increased risk for CPO, it is essential that information on travel history, particularly foreign travel to endemic countries, should be collected routinely in the community and on admission to healthcare facilities.
Both host- and pathogen-related factors were reported to be drivers of adverse outcomes. This study found that advanced age, presence of carbapenemase-producing non-fermenters, malignancy, respiratory tract infection, and systemic infection or organ failure were associated with overall 30-day mortality. Advanced age has been reported to be a risk factor for mortality by many researchers, as this group represents a vulnerable population for drug-resistant pathogens [[21], [22], [23]]. Patients with malignancies usually have more frequent exposure to health care such as immunocompromised therapy (radiotherapy and chemotherapy), invasive procedures (biopsies, bone marrow and spinal puncture) and longer hospitalization. Respiratory infection has been described as a risk factor for 30-day mortality in other studies [24,25]. Mucosal barrier injury in the respiratory tract and altered lung tissue would decrease the capacity for bacterial clearance and increase the probability of bacterial colonization and/or infection. Multi-variate analysis revealed that both carrying non-fermenters and systemic infection or organ failure were independently associated with 30-day mortality. To the authors' knowledge, only one study has investigated the association between organisms and mortality, and this study did not find any particular organism to be linked to mortality [26]. Both virulence status and antimicrobial resistance may account for this. First, some studies have demonstrated that virulence determinants of Pseudomonas spp., such as the secretion of toxins and elastase activity, could enhance pathogenicity against host defence mechanisms, thus having an unfavourable impact on outcome. In addition, biofilm formation on the lumen of the respiratory tract could result in a higher risk of mortality by posing greater resistance to antibiotics [27,28]. Second, carbapenem resistance in non-fermenters usually stems from a combination of beta-lactamases, porin mutations and efflux pump overexpression, conferring reduced susceptibility to antibiotics and implying fewer treatment options and more treatment failure [29]. Systemic infection or organ failure is a surrogate marker of critical illness which has been widely reported as a predictor of poorer outcome [21,22,27,30]. Aggressive therapy and infection prevention and control measures should be initiated rapidly in this population.
This study had a few limitations. First, no classification of infection and colonization was made due to lack of clinical symptoms and laboratory testing data. Second, data on comprehensive antimicrobial susceptibility and antimicrobial treatment in hospital at individual level were not available. Third, no genomic data were available to identify possible clonal spread, outbreak and virulence. Further molecular study is warranted to better understand the phylogeny and pathogenicity of local CPO isolates.
In conclusion, the incidence of CPO in Scotland is relatively low but is increasing rapidly. Awareness is required that patients of advanced age, patients with systemic infection or organ failure, and patients presenting with non-fermenters are at higher risk of death from CPO. There is a need to continue the existing Scottish CPE surveillance programme, and infection prevention and control measures for both Enterobacterales and non-fermenters warrant further consideration in both health care and the community to help control the spread of CPO. The findings of this study will also inform other countries with similar epidemiological situations.
Acknowledgements
The authors wish to thank the eDRIS Team (National Services Scotland) for their involvement in obtaining approvals, provisioning and linking data, and use of the secure analytical platform within the National Safe Haven.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhin.2021.01.028.
Conflict of interest statement
None declared.
Funding sources
This study was supported by the UK Medical Research Council (Grant No. MR/R000093/1, STARCS).
Appendix A. Supplementary data
The following is the Supplementary data to this article:
References
- 1.Kim U.J., Kim H.K., An J.H., Cho S.K., Park K.H., Jang H.C. Update on the epidemiology, treatment, and outcomes of carbapenem-resistant acinetobacter infections. Chonnam Med J. 2014;50:37–44. doi: 10.4068/cmj.2014.50.2.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Kim Y.J., Kim S.I., Hong K.W., Kim Y.R., Park Y.J., Kang M.W. Risk factors for mortality in patients with carbapenem-resistant Acinetobacter baumannii bacteremia: impact of appropriate antimicrobial therapy. J Korean Med Sci. 2012;27:471–475. doi: 10.3346/jkms.2012.27.5.471. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Nordmann P., Dortet L., Poirel L. Carbapenem resistance in Enterobacteriaceae: here is the storm! Trends Mol Med. 2012;18:263–272. doi: 10.1016/j.molmed.2012.03.003. [DOI] [PubMed] [Google Scholar]
- 4.European Centre for Disease Prevention and Control . ECDC; Stockholm: 2019. Surveillance of antimicrobial resistance in Europe.https://ecdc.europa.eu/sites/portal/files/documents/EARS-Net-report-2017-update-jan-2019.pdf Available at: [last accessed August 2020] [Google Scholar]
- 5.Trepanier P., Mallard K., Meunier D., Pike R., Brown D., Ashby J.P. Carbapenemase-producing Enterobacteriaceae in the UK: a national study (EuSCAPE-UK) on prevalence, incidence, laboratory detection methods and infection control measures. J Antimicrob Chemother. 2017;72:596–603. doi: 10.1093/jac/dkw414. [DOI] [PubMed] [Google Scholar]
- 6.Palepou M.-F., Woodford N., Hope R., Colman M., Glover J., Kaufmann M.E. 15th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) April 2005. Novel class A carbapenemase, KPC-4, in an enterobacter isolate from Scotland; pp. 2–5. Copenhagen, Denmark: Abstract P427. [Google Scholar]
- 7.Grundmann H., Glasner C., Albiger B., Aanensen D.M., Tomlinson C.T., Andrasevic A.T. Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study. Lancet Infect Dis. 2017;17:153–163. doi: 10.1016/S1473-3099(16)30257-2. [DOI] [PubMed] [Google Scholar]
- 8.Health Protection Scotland . HPS; Glasgow: 2018. Scottish One Health antimicrobial use and antimicrobial resistance in 2017.https://hpspubsrepo.blob.core.windows.net/hps-website/nss/2647/documents/1_SONAAR-report-2017-revised-november-2019.pdf Available at: [last accessed August 2020] [Google Scholar]
- 9.Cardoso T., Almeida M., Friedman N.D., Aragao I., Costa-Pereira A., Sarmento A.E. Classification of healthcare-associated infection: a systematic review 10 years after the first proposal. BMC Med. 2014;12:40. doi: 10.1186/1741-7015-12-40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Garner J.S., Jarvis W.R., Emori T.G., Horan T.C., Hughes J.M. CDC definitions for nosocomial infections, 1988. Am J Infect Control. 1988;16:128–140. doi: 10.1016/0196-6553(88)90053-3. [DOI] [PubMed] [Google Scholar]
- 11.Anderson D.R., Burnham K.P., Thompson W.L. Null hypothesis testing: problems, prevalence, and an alternative. J Wildl Manag. 2000;64:912–923. [Google Scholar]
- 12.Magiorakos A.P., Burns K., Bano J.R., Borg M., Daikos G., Dumpis U. Infection prevention and control measures and tools for the prevention of entry of carbapenem-resistant Enterobacteriaceae into healthcare settings: guidance from the European Centre for Disease Prevention and Control. Antimicrob Resist Infect Control. 2017;6:113. doi: 10.1186/s13756-017-0259-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Scottish Government . Vol. 14. Scottish Government; Edinburgh: 2013. www.sehd.scot.nhs.uk/cmo/CMO(2013)14.pdf (Antimicrobial resistance. CMO/SGHD). Available at: [last accessed August 2020] [Google Scholar]
- 14.Health Protection Scotland . HPS; Glasgow: 2019. Healthcare associated infection annual report 2018.https://hpspubsrepo.blob.core.windows.net/hps-website/nss/2776/documents/1_HAI-Annual-Report-2018-final-v1%201.pdf Available at: [last accessed August 2020] [Google Scholar]
- 15.Public Health England . PHE; London: 2018. English surveillance programme for antimicrobial utilisation and resistance (ESPAUR) report 2018.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/759975/ESPAUR_2018_report.pdf Available at: [last accessed August 2020] [Google Scholar]
- 16.Freeman R., Moore L.S.P., Charlett A., Donaldson H., Holmes A.H. Exploring the epidemiology of carbapenem-resistant Gram-negative bacteria in west London and the utility of routinely collected hospital microbiology data. J Antimicrob Chemother. 2015;70:1212–1218. doi: 10.1093/jac/dku500. [DOI] [PubMed] [Google Scholar]
- 17.Kelly A.M., Mathema B., Larson E.L. Carbapenem-resistant Enterobacteriaceae in the community: a scoping review. Int J Antimicrob Agents. 2017;50:127–134. doi: 10.1016/j.ijantimicag.2017.03.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Pano-Pardo J.R., Lopez Quintana B., Lazaro Perona F., Ruiz Carrascoso G., Romero-Gomez M.P., Loeches Yague B. Community-onset bloodstream and other infections, caused by carbapenemase-producing Enterobacteriaceae: epidemiological, microbiological, and clinical features. Open Forum Infect Di. 2016;3:ofw136. doi: 10.1093/ofid/ofw136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Poirel L., Potron A., Nordmann P. OXA-48-like carbapenemases: the phantom menace. J Antimicrob Chemother. 2012;67:1597–1606. doi: 10.1093/jac/dks121. [DOI] [PubMed] [Google Scholar]
- 20.Kumarasamy K.K., Toleman M.A., Walsh T.R., Bagaria J., Butt F., Balakrishnan R. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010;10:597–602. doi: 10.1016/S1473-3099(10)70143-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Mouloudi E., Protonotariou E., Zagorianou A., Iosifidis E., Karapanagiotou A., Giasnetsova T. Bloodstream infections caused by metallo-beta-lactamase/Klebsiella pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit patients in Greece: risk factors for infection and impact of type of resistance on outcomes. Infect Control Hosp Epidemiol. 2010;31:1250–1256. doi: 10.1086/657135. [DOI] [PubMed] [Google Scholar]
- 22.Daikos G.L., Petrikkos P., Psichogiou M., Kosmidis C., Vryonis E., Skoutelis A. Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother. 2009;53:1868–1873. doi: 10.1128/AAC.00782-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Akgul F., Bozkurt I., Sunbul M., Esen S., Leblebicioglu H. Risk factors and mortality in the carbapenem-resistant Klebsiella pneumoniae infection: case control study. Pathogen Glob Health. 2016;110:321–325. doi: 10.1080/20477724.2016.1254976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Jiao Y., Qin Y.H., Liu J.J., Li Q., Dong Y.C., Shang Y. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection/colonization and predictors of mortality: a retrospective study. Pathogen Glob Health. 2015;109:68–74. doi: 10.1179/2047773215Y.0000000004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Li X., Ye H. Clinical and mortality risk factors in bloodstream infections with carbapenem-resistant Enterobacteriaceae. Can J Infect Dis Med Microbiol. 2017;2017:6212910. doi: 10.1155/2017/6212910. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kalam K., Qamar F., Kumar S., Ali S., Baqi S. Risk factors for carbapenem resistant bacteraemia and mortality due to Gram negative bacteraemia in a developing country. J Pak Med Assoc. 2014;64:530–536. [PubMed] [Google Scholar]
- 27.Jeong S.J., Yoon S.S., Bae I.K., Jeong S.H., Kim J.M., Lee K. Risk factors for mortality in patients with bloodstream infections caused by carbapenem-resistant Pseudomonas aeruginosa: clinical impact of bacterial virulence and strains on outcome. Diagn Microbiol Infect Dis. 2014;80:130–135. doi: 10.1016/j.diagmicrobio.2014.07.003. [DOI] [PubMed] [Google Scholar]
- 28.Rossi Goncalves I., Dantas R.C.C., Ferreira M.L., Batistao D., Gontijo-Filho P.P., Ribas R.M. Carbapenem-resistant Pseudomonas aeruginosa: association with virulence genes and biofilm formation. Braz J Microbiol. 2017;48:211–217. doi: 10.1016/j.bjm.2016.11.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Buehrle D.J., Shields R.K., Clarke L.G., Potoski B.A., Clancy C.J., Hong Nguyen M. Carbapenem-resistant Pseudomonas aeruginosa bacteremia: risk factors for mortality and microbiologic treatment failure. Antimicrob Agents Chemother. 2017;61 doi: 10.1128/AAC.01243-16. e01243-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Bar-Yoseph H., Cohen N., Korytny A., Andrawus E.R., Even Dar R., Geffen Y. Risk factors for mortality among carbapenem-resistant Enterobacteriaceae carriers with focus on immunosuppression. J Infect. 2019;78:101–105. doi: 10.1016/j.jinf.2018.10.003. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.