Carbapenem resistant Enterobacterales in the United Arab Emirates: a retrospective analysis from 2010 to 2021

BackgroundCarbapenem-resistant Enterobacterales (CRE) are spreading in the United Arab Emirates (UAE) where their dissemination is facilitated by international travel, trade, and tourism. The objective of this study is to describe the longitudinal changes of CRE as reported by the national AMR surveillance system of the UAE.MethodsIn this study, we retrospectively describe CRE isolated from 317 surveillance sites, including 87 hospitals and 230 centers/clinics from 2010 to 2021. The associated clinical, demographic, and microbiological characteristics are presented by relying on the UAE national AMR surveillance program. Data was analyzed using WHONET microbiology laboratory database software (http://www.whonet.org).ResultsA total of 14,593 carbapenem resistant Enterobacterales were analyzed, of which 48.1% were carbapenem resistant Klebsiella pneumoniae (CRKp), 25.1% carbapenem resistant Escherichia coli (CREc), and 26.8% represented 72 other carbapenem resistant species. Carbapenem resistant strains were mostly associated with adults and isolated from urine samples (36.9% of CRKp and 66.6% of CREc) followed by respiratory samples (26.95% for CRKp) and soft tissue samples (19.5% for CRKp). Over the studied period carbapenem resistance rates remained high, especially in K. pneumoniae, and in 2021 were equivalent to 67.6% for imipenem, 76.2% for meropenem, and 91.6% for ertapenem. Nevertheless, there was a statistically significant decreasing trend for imipenem and meropenem resistance in Klebsiella species (p < 0.01) while the decrease in ertapenem resistance was non-significant. Concerning E. coli, there was a statistically significant decreasing trend for meropenem and imipenem resistance over the 12 years, while ertapenem resistance increased significantly with 83.8% of E. coli exhibiting ertapenem resistance in 2021. Resistance rates to ceftazidime and cefotaxime remained higher than 90% (in 2021) for CRKp and cefotaxime rates increased to 90.5% in 2021 for CREc. Starting 2014, resistance to colistin and tigecycline was observed in carbapenem resistant Enterobacterales. CRE were associated with a higher mortality (RR: 6.3), admission to ICU (RR 3.9), and increased length of stay (LOS; 10 excess inpatient days per CRE case).ConclusionThis study supports the need to monitor CRE in the UAE and draws attention to the significant increase of ertapenem resistance in E. coli. Future surveillance analysis should include a genetic description of carbapenem resistance to provide new strategies

Increased pathogenicity of pneumococcal serotype 1 is driven by rapid autolysis and release of pneumolysin

Streptococcus pneumoniae serotype 1 is the predominant cause of invasive pneumococcal disease in sub-Saharan Africa, but the mechanism behind its increased invasiveness is not well understood. Here, we use mouse models of lung infection to identify virulence factors associated with severe bacteraemic pneumonia during serotype-1 (ST217) infection. We use BALB/c mice, which are highly resistant to pneumococcal pneumonia when infected with other serotypes. However, we observe 100% mortality and high levels of bacteraemia within 24 hours when BALB/c mice are intranasally infected with ST217. Serotype 1 produces large quantities of pneumolysin, which is rapidly released due to high levels of bacterial autolysis. This leads to substantial levels of cellular cytotoxicity and breakdown of tight junctions between cells, allowing a route for rapid bacterial dissemination from the respiratory tract into the blood. Thus, our results offer an explanation for the increased invasiveness of serotype 1

Pneumococcal pneumonia and carriage in Africa before and after introduction of pneumococcal conjugate vaccines, 2000-2019:protocol for systematic review

INTRODUCTION:Africa harbours a high burden of pneumococcal disease, with associated high mortality rates. Despite 34 countries introducing the pneumococcal conjugate vaccine, which reduces the risk of pneumococcal carriage (a prerequisite for disease) of some of the most pathogenic pneumococcal serotypes, it remains uncertain whether they will achieve the sustained direct or indirect protection necessary to reduce pneumococcal carriage to levels sufficient to interrupt transmission and disease. We will therefore summarise the available data on the impact of the pneumococcal conjugate vaccine in reducing vaccine serotype carriage and pneumococcal pneumonia in Africa between 2000 and 2019. METHODS AND ANALYSIS:Using a predetermined search strategy, we will conduct a comprehensive search of PubMed, MEDLINE database, the Excerpta Medica Database, the ISI Web of Science (Science Citation Index), Scopus and the African Index Medicus to identify published studies reporting the prevalence of Streptococcus pneumoniae carriage (vaccine type and non-vaccine type), incidence rates of pneumococcal pneumonia and mortality among children, adults and HIV-infected (all-ages) pre-pneumococcal conjugate vaccine (PCV) and post-PCV introduction (published between 1st January 2000 and 31st December 2019) in African countries that have introduced PCVs (PCV7/PCV10/PCV13) in their routine national immunisation programme. The studies retained and data extracted will be assessed for bias using prevalidated tools and checklists. Heterogeneity across studies will be assessed using the χ2 test on Cochrane Q statistic. A random effect meta-analysis will be used to estimate the overall prevalence of pneumococcal carriage and incidence of pneumococcal pneumonia across studies with similar characteristics. Results will be reported in compliance with the Meta-Analysis Of Observational Studies in Epidemiology guidelines. The protocol has been prepared in accordance to the 2015 guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses. ETHICS AND DISSEMINATION:This systematic review will not require ethical approval as we will be using already published data. The final manuscript will be submitted for publication in a peer-reviewed journal and presented at conferences. PROSPERO REGISTRATION NUMBER:CRD42019130976

A streptococcus pneumoniae lineage usually associated with pneumococcal conjugate vaccine (PCV) serotypes is the most common cause of serotype 35B invasive disease in South Africa, following routine use of PCV

Pneumococcal serotype 35B is an important non-conjugate vaccine (non-PCV) serotype. Its continued emergence, post-PCV7 in the USA, was associated with expansion of a pre-existing 35B clone (clonal complex [CC] 558) along with post-PCV13 emergence of a non-35B clone previously associated with PCV serotypes (CC156). This study describes lineages circulating among 35B isolates in South Africa before and after PCV introduction. We also compared 35B isolates belonging to a predominant 35B lineage in South Africa (GPSC5), with isolates belonging to the same lineage in other parts of the world. Serotype 35B isolates that caused invasive pneumococcal disease in South Africa in 2005-2014 were characterized by whole-genome sequencing (WGS). Multi-locus sequence types and global pneumococcal sequence clusters (GPSCs) were derived from WGS data of 63 35B isolates obtained in 2005-2014. A total of 262 isolates that belong to GPSC5 (115 isolates from South Africa and 147 from other countries) that were sequenced as part of the global pneumococcal sequencing (GPS) project were included for comparison. Serotype 35B isolates from South Africa were differentiated into seven GPSCs and GPSC5 was most common (49 %, 31/63). While 35B was the most common serotype among GPSC5/CC172 isolates in South Africa during the PCV13 period (66 %, 29/44), 23F was the most common serotype during both the pre-PCV (80 %, 37/46) and PCV7 period (32 %, 8/25). Serotype 35B represented 15 % (40/262) of GPSC5 isolates within the global GPS database and 75 % (31/40) were from South Africa. The predominance of the GPSC5 lineage within non-vaccine serotype 35B, is possibly unique to South Africa and warrants further molecular surveillance of pneumococci

Invasive Streptococcus pneumoniae in Children, Malawi, 2004–2006

Of 176 invasive Streptococcus pneumoniae isolates from children in Malawi, common serotypes were 1 (23%), 6A/B (18%), 14 (6%), and 23F (6%). Coverage with the 7-valent pneumococcal conjugate vaccine (PCV) was 39%; PCV10 and PCV13 increased coverage to 66% and 88%, respectively. We found chloramphenicol resistance in 27% of isolates and penicillin nonsusceptibility in 10% (by using meningitis breakpoints); all were ceftriaxone susceptible

Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi (1998-2016): a surveillance study.

BACKGROUND Bacterial bloodstream infection is a common cause of morbidity and mortality in sub-Saharan Africa, yet few facilities are able to maintain long-term surveillance. The Malawi-Liverpool-Wellcome Trust Clinical Research Programme has done sentinel surveillance of bacteraemia since 1998. We report long-term trends in bloodstream infection and antimicrobial resistance from this surveillance. METHODS In this surveillance study, we analysed blood cultures that were routinely taken from adult and paediatric patients with fever or suspicion of sepsis admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi from 1998 to 2016. The hospital served an urban population of 920 000 in 2016, with 1000 beds, although occupancy often exceeds capacity. The hospital admits about 10 000 adults and 30 000 children each year. Antimicrobial susceptibility tests were done by the disc diffusion method according to British Society of Antimicrobial Chemotherapy guidelines. We used the Cochran-Armitage test for trend to examine trends in rates of antimicrobial resistance, and negative binomial regression to examine trends in icidence of bloodstream infection over time. FINDINGS Between Jan 1, 1998, and Dec 31, 2016, we isolated 29 183 pathogens from 194 539 blood cultures. Pathogen detection decreased significantly from 327·1/100 000 in 1998 to 120·2/100 000 in 2016 (p<0·0001). 13 366 (51·1%) of 26 174 bacterial isolates were resistant to the Malawian first-line antibiotics amoxicillin or penicillin, chloramphenicol, and co-trimoxazole; 68·3% of Gram-negative and 6·6% of Gram-positive pathogens. The proportions of non-Salmonella Enterobacteriaceae with extended spectrum beta-lactamase (ESBL) or fluoroquinolone resistance rose significantly after 2003 to 61·9% in 2016 (p<0·0001). Between 2003 and 2016, ESBL resistance rose from 0·7% to 30·3% in Escherichia coli, from 11·8% to 90·5% in Klebsiella spp and from 30·4% to 71·9% in other Enterobacteriaceae. Similarly, resistance to ciprofloxacin rose from 2·5% to 31·1% in E coli, from 1·7% to 70·2% in Klebsiella spp and from 5·9% to 68·8% in other Enterobacteriaceae. By contrast, more than 92·0% of common Gram-positive pathogens remain susceptible to either penicillin or chloramphenicol. Meticillin-resistant Staphylococcus aureus (MRSA) was first reported in 1998 at 7·7% and represented 18·4% of S aureus isolates in 2016. INTERPRETATION The rapid expansion of ESBL and fluoroquinolone resistance among common Gram-negative pathogens, and the emergence of MRSA, highlight the growing challenge of bloodstream infections that are effectively impossible to treat in this resource-limited setting. FUNDING Wellcome Trust, H3ABionet, Southern Africa Consortium for Research Excellence (SACORE)

Lower density and shorter duration of nasopharyngeal carriage by pneumococcal serotype 1 (St217) may explain its increased invasiveness over other serotypes

ABSTRACT Streptococcus pneumoniae is a frequent colonizer of the human nasopharynx and a major cause of life-threating invasive infections such as pneumonia, meningitis and sepsis. Over 1 million people die every year due to invasive pneumococcal disease (IPD), mainly in developing countries. Serotype 1 is a common cause of IPD; however, unlike other serotypes, it is rarely found in the carrier state in the nasopharynx, which is often considered a prerequisite for disease. The aim of this study was to understand this dichotomy. We used murine models of carriage and IPD to characterize the pathogenesis of African serotype 1 (sequence type 217) pneumococcal strains obtained from the Queen Elizabeth Central Hospital in Blantyre, Malawi. We found that ST217 pneumococcal strains were highly virulent in a mouse model of invasive pneumonia, but in contrast to the generally accepted assumption, can also successfully establish nasopharyngeal carriage. Interestingly, we found that cocolonizing serotypes may proliferate in the presence of serotype 1, suggesting that acquisition of serotype 1 carriage could increase the risk of developing IPD by other serotypes. RNA sequencing analysis confirmed that key virulence genes associated with inflammation and tissue invasiveness were upregulated in serotype 1. These data reveal important new insights into serotype 1 pathogenesis, with implications for carriage potential and risk of invasive disease through interactions with other cocolonizing serotypes, an often-overlooked factor in transmission and disease progression. IMPORTANCE The pneumococcus causes serious diseases such as pneumonia, sepsis, and meningitis and is a major cause of morbidity and mortality worldwide. Serotype 1 accounts for the majority of invasive pneumococcal disease cases in sub-Saharan Africa but is rarely found during nasopharyngeal carriage. Understanding the mechanisms leading to nasopharyngeal carriage and invasive disease by this serotype can help reduce its burden on health care systems worldwide. In this study, we also uncovered the potential impact of serotype 1 on disease progression of other coinfecting serotypes, which can have important implications for vaccine efficacy. Understanding the interactions between different serotypes during nasopharyngeal carriage may lead to improved intervention methods and therapies to reduce pneumococcal invasive disease levels

A Reduction in Adult Blood Stream Infection and Case Fatality at a Large African Hospital following Antiretroviral Therapy Roll-Out

Introduction Blood-stream infection (BSI) is one of the principle determinants of the morbidity and mortality associated with advanced HIV infection, especially in sub-Saharan Africa. Over the last 10 years, there has been rapid roll-out of anti-retroviral therapy (ART) and cotrimoxazole prophylactic therapy (CPT) in many high HIV prevalence African countries. Methods A prospective cohort of adults with suspected BSI presenting to Queen's Hospital, Malawi was recruited between 2009 and 2010 to describe causes of and outcomes from BSI. Comparison was made with a cohort pre-dating ART roll-out to investigate whether and how ART and CPT have affected BSI. Malawian census and Ministry of Health ART data were used to estimate minimum incidence of BSI in Blantyre district. Results 2,007 patients were recruited, 90% were HIV infected. Since 1997/8, culture-confirmed BSI has fallen from 16% of suspected cases to 10% (p<0.001) and case fatality rate from confirmed BSI has fallen from 40% to 14% (p<0.001). Minimum incidence of BSI was estimated at 0.03/1000 years in HIV uninfected vs. 2.16/1000 years in HIV infected adults. Compared to HIV seronegative patients, the estimated incidence rate-ratio for BSI was 80 (95% CI:46–139) in HIV-infected/untreated adults, 568 (95% CI:302–1069) during the first 3 months of ART and 30 (95% CI:16–59) after 3 months of ART. Conclusions Following ART roll-out, the incidence of BSI has fallen and clinical outcomes have improved markedly. Nonetheless, BSI incidence remains high in the first 3 months of ART despite CPT. Further interventions to reduce BSI-associated mortality in the first 3 months of ART require urgent evaluation

Recombination in Streptococcus pneumoniae Lineages Increase with Carriage Duration and Size of the Polysaccharide Capsule

Streptococcus pneumoniae causes a high burden of invasive pneumococcal disease (IPD) globally, especially in children from resource-poor settings. Like many bacteria, the pneumococcus can import DNA from other strains or even species by transformation and homologous recombination, which has allowed the pneumococcus to evade clinical interventions such as antibiotics and pneumococcal conjugate vaccines (PCVs). Pneumococci are enclosed in a complex polysaccharide capsule that determines the serotype; the capsule varies in size and is associated with properties including carriage prevalence and virulence. We determined and quantified the association between capsule and recombination events using genomic data from a diverse collection of serotypes sampled in Malawi. We determined both the amount of variation introduced by recombination relative to mutation (the relative rate) and how many individual recombination events occur per isolate (the frequency). Using univariate analyses, we found an association between both recombination measures and multiple factors associated with the capsule, including duration and prevalence of carriage. Because many capsular factors are correlated, we used multivariate analysis to correct for collinearity. Capsule size and carriage duration remained positively associated with recombination, although with a reduced P value, and this effect may be mediated through some unassayed additional property associated with larger capsules. This work describes an important impact of serotype on recombination that has been previously overlooked. While the details of how this effect is achieved remain to be determined, it may have important consequences for the serotype-specific response to vaccines and other interventions