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Fulltext Novel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-Resistant Klebsiella pneumoniae

Lin YW, Abdul Rahim N, Zhao J, Han ML, Yu HH, Wickremasinghe H, et al.

Antimicrob Agents Chemother, 2019 04;63(4).
PMID: 30670431 DOI: 10.1128/AAC.02176-18

Polymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-β-lactamase (NDM)-producing Klebsiella pneumoniae However, polymyxin resistance can emerge with monotherapy; therefore, novel strategies are urgently needed to minimize the resistance and maintain their clinical utility. This study aimed to investigate the pharmacodynamics of polymyxin B in combination with the antiretroviral drug zidovudine against K. pneumoniae Three isolates were evaluated in static time-kill studies (0 to 64 mg/liter) over 48 h. An in vitro one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model (IVM) was used to simulate humanized dosage regimens of polymyxin B (4 mg/liter as continuous infusion) and zidovudine (as bolus dose thrice daily to achieve maximum concentration of drug in broth [Cmax] of 6 mg/liter) against K. pneumoniae BM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model against K. pneumoniae 02. In the static time-kill studies, polymyxin B monotherapy produced rapid and extensive killing against all three isolates followed by extensive regrowth, whereas zidovudine produced modest killing followed by significant regrowth at 24 h. Polymyxin B in combination with zidovudine significantly enhanced the antimicrobial activity (≥4 log10 CFU/ml) and minimized bacterial regrowth. In the IVM, the combination was synergistic and the total bacterial loads were below the limit of detection for up to 72 h. In the murine thigh infection model, the bacterial burden at 24 h in the combination group was ≥3 log10 CFU/thigh lower than each monotherapy against K. pneumoniae 02. Overall, the polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.
Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia

Ng SC, Zeng Z, Niewiadomski O, Tang W, Bell S, Kamm MA, et al.

Gastroenterology, 2016 Jan;150(1):86-95.e3; quiz e13-4.
PMID: 26385074 DOI: 10.1053/j.gastro.2015.09.005

BACKGROUND & AIMS: The incidence of inflammatory bowel disease (IBD) is increasing in Asia, but little is known about disease progression in this region. The Asia-Pacific Crohn's and Colitis Epidemiology Study was initiated in 2011, enrolling subjects from 8 countries in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand) and Australia. We present data from this ongoing study.
METHODS: We collected data on 413 patients diagnosed with IBD (222 with ulcerative colitis [UC], 181 with Crohn's disease [CD], 10 with IBD unclassified; median age, 37 y) from 2011 through 2013. We analyzed the disease course and severity and mortality. Risks for medical and surgical therapies were assessed using Kaplan-Meier analysis.
RESULTS: The cumulative probability that CD would change from inflammatory to stricturing or penetrating disease was 19.6%. The cumulative probabilities for use of immunosuppressants or anti-tumor necrosis factor agents were 58.9% and 12.0% for patients with CD, and 12.7% and 0.9% for patients with UC, respectively. Perianal CD was associated with an increased risk of anti-tumor necrosis factor therapy within 1 year of its diagnosis (hazard ratio, 2.97; 95% confidence interval, 1.09-8.09). The cumulative probabilities for surgery 1 year after diagnosis were 9.1% for patients with CD and 0.9% for patients with UC. Patients with CD and penetrating disease had a 7-fold increase for risk of surgery, compared with patients with inflammatory disease (hazard ratio, 7.67; 95% confidence interval, 3.93-14.96). The overall mortality for patients with IBD was 0.7%.
CONCLUSIONS: In a prospective population-based study, we found that the early course of disease in patients with IBD in Asia was comparable with that of the West. Patients with CD frequently progress to complicated disease and have accelerated use of immunosuppressants. Few patients with early stage UC undergo surgery in Asia. Increasing our understanding of IBD progression in different populations can help optimize therapy and improve outcomes.
KEYWORDS: ACCESS; Natural History; Risk Factor; Treatment
Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific

Ng SC, Tang W, Leong RW, Chen M, Ko Y, Studd C, et al.

Gut, 2015 Jul;64(7):1063-71.
PMID: 25217388 DOI: 10.1136/gutjnl-2014-307410

The rising incidence of inflammatory bowel disease in Asia supports the importance of environmental risk factors in disease aetiology. This prospective population-based case-control study in Asia-Pacific examined risk factors prior to patients developing IBD.
Fulltext Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

Luk ADW, Lee PP, Mao H, Chan KW, Chen XY, Chen TX, et al.

Front Immunol, 2017;8:808.
PMID: 28747913 DOI: 10.3389/fimmu.2017.00808

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless treated with hematopoietic stem cell transplant. Delay in diagnosis is common without newborn screening. Family history of infant death due to infection or known SCID (FH) has been associated with earlier diagnosis.
OBJECTIVE: The aim of this study was to identify the clinical features that affect age at diagnosis (AD) and time to the diagnosis of SCID.
METHODS: From 2005 to 2016, 147 SCID patients were referred to the Asian Primary Immunodeficiency Network. Patients with genetic diagnosis, age at presentation (AP), and AD were selected for study.
RESULTS: A total of 88 different SCID gene mutations were identified in 94 patients, including 49 IL2RG mutations, 12 RAG1 mutations, 8 RAG2 mutations, 7 JAK3 mutations, 4 DCLRE1C mutations, 4 IL7R mutations, 2 RFXANK mutations, and 2 ADA mutations. A total of 29 mutations were previously unreported. Eighty-three of the 94 patients fulfilled the selection criteria. Their median AD was 4 months, and the time to diagnosis was 2 months. The commonest SCID was X-linked (n = 57). A total of 29 patients had a positive FH. Candidiasis (n = 27) and bacillus Calmette-Guérin (BCG) vaccine infection (n = 19) were the commonest infections. The median age for candidiasis and BCG infection documented were 3 months and 4 months, respectively. The median absolute lymphocyte count (ALC) was 1.05 × 10(9)/L with over 88% patients below 3 × 10(9)/L. Positive FH was associated with earlier AP by 1 month (p = 0.002) and diagnosis by 2 months (p = 0.008), but not shorter time to diagnosis (p = 0.494). Candidiasis was associated with later AD by 2 months (p = 0.008) and longer time to diagnosis by 0.55 months (p = 0.003). BCG infections were not associated with age or time to diagnosis.
CONCLUSION: FH was useful to aid earlier diagnosis but was overlooked by clinicians and not by parents. Similarly, typical clinical features of SCID were not recognized by clinicians to shorten the time to diagnosis. We suggest that lymphocyte subset should be performed for any infant with one or more of the following four clinical features: FH, candidiasis, BCG infections, and ALC below 3 × 10(9)/L.
Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study

Ng SC, Tang W, Ching JY, Wong M, Chow CM, Hui AJ, et al.

Gastroenterology, 2013 Jul;145(1):158-165.e2.
PMID: 23583432 DOI: 10.1053/j.gastro.2013.04.007

BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are becoming more common in Asia, but epidemiologic data are lacking. The Asia-Pacific Crohn's and Colitis Epidemiology Study aimed to determine the incidence and phenotype of IBD in 8 countries across Asia and in Australia.
METHODS: We performed a prospective, population-based study of IBD incidence in predefined catchment areas, collecting data for 1 year, starting on April 1, 2011. New cases were ascertained from multiple overlapping sources and entered into a Web-based database. Cases were confirmed using standard criteria. Local endoscopy, pathology, and pharmacy records were searched to ensure completeness of case capture.
RESULTS: We identified 419 new cases of IBD (232 of ulcerative colitis [UC], 166 of Crohn's disease [CD], and 21 IBD-undetermined). The crude annual overall incidence values per 100,000 individuals were 1.37 for IBD in Asia (95% confidence interval: 1.25-1.51; 0.76 for UC, 0.54 for CD, and 0.07 for IBD-undetermined) and 23.67 in Australia (95% confidence interval: 18.46-29.85; 7.33 for UC, 14.00 for CD, and 2.33 for IBD-undetermined). China had the highest incidence of IBD in Asia (3.44 per 100,000 individuals). The ratios of UC to CD were 2.0 in Asia and 0.5 in Australia. Median time from symptom onset to diagnosis was 5.5 months (interquartile range, 1.4-15 months). Complicated CD (stricturing, penetrating, or perianal disease) was more common in Asia than Australia (52% vs 24%; P = .001), and a family history of IBD was less common in Asia (3% vs 17%; P < .001).
CONCLUSIONS: We performed a large-scale population-based study and found that although the incidence of IBD varies throughout Asia, it is still lower than in the West. IBD can be as severe or more severe in Asia than in the West. The emergence of IBD in Asia will result in the need for specific health care resources, and offers a unique opportunity to study etiologic factors in developing nations.
Population Density and Risk of Inflammatory Bowel Disease: A Prospective Population-Based Study in 13 Countries or Regions in Asia-Pacific

Ng SC, Kaplan GG, Tang W, Banerjee R, Adigopula B, Underwood FE, et al.

Am J Gastroenterol, 2019 01;114(1):107-115.
PMID: 30177785 DOI: 10.1038/s41395-018-0233-2

INTRODUCTION: Living in an urban environment may increase the risk of developing inflammatory bowel disease (IBD). It is unclear if this observation is seen globally. We conducted a population-based study to assess the relationship between urbanization and incidence of IBD in the Asia-Pacific region.
METHODS: Newly diagnosed IBD cases between 2011 and 2013 from 13 countries or regions in Asia-Pacific were included. Incidence was calculated with 95% confidence interval (CI) and pooled using random-effects model. Meta-regression analysis was used to assess incidence rates and their association with population density, latitude, and longitude.
RESULTS: We identified 1175 ulcerative colitis (UC), 656 Crohn's disease (CD), and 37 IBD undetermined (IBD-U). Mean annual IBD incidence per 100 000 was 1.50 (95% CI: 1.43-1.57). India (9.31; 95% CI: 8.38-10.31) and China (3.64; 95% CI, 2.97-4.42) had the highest IBD incidence in Asia. Incidence of overall IBD (incidence rate ratio [IRR]: 2.19; 95% CI: 1.01-4.76]) and CD (IRR: 3.28; 95% CI: 1.83-9.12) was higher across 19 areas of Asia with a higher population density. In China, incidence of IBD (IRR: 2.37; 95% CI: 1.10-5.16) and UC (IRR: 2.63; 95% CI: 1.2-5.8) was positively associated with gross domestic product. A south-to-north disease gradient (IRR: 0.94; 95% CI: 0.91-0.98) was observed for IBD incidence and a west-to-east gradient (IRR: 1.14; 95% CI: 1.05-1.24) was observed for CD incidence in China. This study received IRB approval.
CONCLUSIONS: Regions in Asia with a high population density had a higher CD and UC incidence. Coastal areas within China had higher IBD incidence. With increasing urbanization and a shift from rural areas to cities, disease incidence may continue to climb in Asia.