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12. In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types

Author

Teo, Jocelyn Qi-Min, primary, Fauzi, Nazira, additional, Ho, Jayden Jun-Yuan, additional, Tan, Si Hui, additional, Lee, Shannon Jing-Yi, additional, Lim, Tze Peng, additional, Cai, Yiying, additional, Chang, Hong Yi, additional, Mohamed Yusoff, Nurhayati, additional, Sim, James Heng-Chiak, additional, Tan, Thuan Tong, additional, Ong, Rick Twee-Hee, additional, and Kwa, Andrea Lay-Hoon, additional

Published
2021
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16. Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance in Escherichia coli

Author

Boulouis, Caroline, primary, Sia, Wan Rong, additional, Gulam, Muhammad Yaaseen, additional, Teo, Jocelyn Qi Min, additional, Png, Yi Tian, additional, Phan, Thanh Kha, additional, Mak, Jeffrey Y. W., additional, Fairlie, David P., additional, Poon, Ivan K. H., additional, Koh, Tse Hsien, additional, Bergman, Peter, additional, Lim, Chwee Ming, additional, Wang, Lin-Fa, additional, Kwa, Andrea Lay Hoon, additional, Sandberg, Johan K., additional, and Leeansyah, Edwin, additional

Published
2020
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17. Determining the Development of Persisters in Extensively Drug-Resistant Acinetobacter baumannii upon Exposure to Polymyxin B-Based Antibiotic Combinations Using Flow Cytometry

Author

Wong, Fiona Hui-Sian, primary, Cai, Yiying, additional, Leck, Hui, additional, Lim, Tze-Peng, additional, Teo, Jocelyn Qi-Min, additional, Lee, Winnie, additional, Koh, Tse Hsien, additional, Tan, Thuan Tong, additional, Tan, Kar Wai, additional, and Kwa, Andrea Lay-Hoon, additional

Published
2020
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19. Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections

Author

Lim,Tze-Peng, Wang,Reyna, Poh,Gang Quan, Koh,Tse-Hsien, Tan,Thean-Yen, Lee,Winnie, Teo,Jocelyn Qi-Min, Cai,Yiying, Tan,Thuan-Tong, Ee,Pui Lai Rachel, Kwa,Andrea L, Lim,Tze-Peng, Wang,Reyna, Poh,Gang Quan, Koh,Tse-Hsien, Tan,Thean-Yen, Lee,Winnie, Teo,Jocelyn Qi-Min, Cai,Yiying, Tan,Thuan-Tong, Ee,Pui Lai Rachel, and Kwa,Andrea L

Abstract

Tze-Peng Lim,1,2 Reyna Wang,1 Gang Quan Poh,3 Tse-Hsien Koh,4 Thean-Yen Tan,5 Winnie Lee,1 Jocelyn Qi-Min Teo,1 Yiying Cai,1 Thuan-Tong Tan,6 Pui Lai Rachel Ee,3 Andrea L Kwa1,3,7 1Department of Pharmacy, Singapore General Hospital, Singapore, Singapore; 2SingHealth Duke-NUS Medicine Academic Clinical Programme, Singapore, Singapore; 3Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore; 4Department of Microbiology, Singapore General Hospital, Singapore, Singapore; 5Department of Laboratory Medicine, Changi General Hospital, Singapore, Singapore; 6Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore; 7Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore Objectives: Treatment for nosocomial bloodstream infections (BSI) caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) is challenging. Rising antimicrobial resistance, especially in extended spectrum beta-lactamase production, inadvertently increases empiric carbapenem consumption. Three antipseudomonal carbapenems (imipenem, meropenem [MER], and doripenem [DOR]) are available commercially against MDR GNB in Singapore. The study aims to determine the most optimal empiric carbapenem dosing regimens (CDR) and evaluate their cost-effectiveness for GNB-BSI in the face of increasing MDR GNB. Methods: Carbapenem minimum inhibitory concentrations (MICs) were generated for non-repeat GNB-BSI obtained in 2013–2014 from two hospitals. Monte Carlo simulations were used to assess the cumulative fraction of response (CFR) of various CDRs using the percentage of time above MIC for 40% (%T > MIC of 40%) as the pharmacokinetic (PK)–pharmacodynamic (PD) parameter for efficacy. Carbapenem costs were based on patient antibiotic costs. Antibiotic cost-effectiveness was calculated as total daily drug cost/CFR. Results: A total of 1,140 bloodstream isolates were collected. They compri

Published
2018

20. Evaluating Polymyxin B-Based Combinations against Carbapenem-Resistant Escherichia coli in Time-Kill Studies and in a Hollow-Fiber Infection Model

Author

Cai, Yiying, primary, Lim, Tze-Peng, additional, Teo, Jocelyn Qi-Min, additional, Sasikala, Suranthran, additional, Chan, Eric Chun Yong, additional, Hong, Yan Jun, additional, Lee, Winnie, additional, Tan, Thean Yen, additional, Tan, Thuan Tong, additional, Koh, Tse Hsien, additional, Hsu, Li Yang, additional, and Kwa, Andrea L., additional

Published
2017
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22. From Bench-Top to Bedside: A Prospective In Vitro Antibiotic Combination Testing (iACT) Service to Guide the Selection of Rationally Optimized Antimicrobial Combinations against Extensively Drug Resistant (XDR) Gram Negative Bacteria (GNB)

Author

Cai, Yiying, primary, Chua, Nathalie Grace, additional, Lim, Tze-Peng, additional, Teo, Jocelyn Qi-Min, additional, Lee, Winnie, additional, Kurup, Asok, additional, Koh, Tse-Hsien, additional, Tan, Thuan-Tong, additional, and Kwa, Andrea L., additional

Published
2016
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24. Clinical Efficacy of Polymyxin Monotherapy versus Nonvalidated Polymyxin Combination Therapy versus Validated Polymyxin Combination Therapy in Extensively Drug-Resistant Gram-Negative Bacillus Infections

Author

Cai, Bingxuan, primary, Cai, Yiying, additional, Liew, Yi Xin, additional, Chua, Nathalie Grace, additional, Teo, Jocelyn Qi-Min, additional, Lim, Tze-Peng, additional, Kurup, Asok, additional, Ee, Pui Lai Rachel, additional, Tan, Thuan Tong, additional, Lee, Winnie, additional, and Kwa, Andrea Lay-Hoon, additional

Published
2016
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27. In Vitro Pharmacodynamics of Various Antibiotics in Combination against Extensively Drug-Resistant Klebsiella pneumoniae

Author

Lim, Tze-Peng, primary, Cai, Yiying, additional, Hong, Yanjun, additional, Chan, Eric Chun Yong, additional, Suranthran, Sasikala, additional, Teo, Jocelyn Qi-Min, additional, Lee, Winnie Huiling, additional, Tan, Thean-Yen, additional, Hsu, Li-Yang, additional, Koh, Tse-Hsien, additional, Tan, Thuan-Tong, additional, and Kwa, Andrea Lay-Hoon, additional

Published
2015
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28. In VitroPharmacodynamics of Various Antibiotics in Combination against Extensively Drug-Resistant Klebsiella pneumoniae

Author

Lim, Tze-Peng, Cai, Yiying, Hong, Yanjun, Chan, Eric Chun Yong, Suranthran, Sasikala, Teo, Jocelyn Qi-Min, Lee, Winnie Huiling, Tan, Thean-Yen, Hsu, Li-Yang, Koh, Tse-Hsien, Tan, Thuan-Tong, and Kwa, Andrea Lay-Hoon

Abstract

ABSTRACTExtensively drug-resistant (XDR) Klebsiella pneumoniaeis an emerging pathogen in Singapore. With limited therapeutic options available, combination antibiotics may be the only viable option. In this study, we aimed to elucidate effective antibiotic combinations against XDR K. pneumoniaeisolates. Six NDM-1-producing and two OXA-181-producing K. pneumoniaestrains were exposed to 12 antibiotics alone and in combination via time-kill studies. A hollow-fiber infection model (HFIM) with pharmacokinetic validation was used to simulate clinically relevant tigecycline-plus-meropenem dosing regimens against 2 XDR K. pneumoniaeisolates over 240 h. The emergence of resistance against tigecycline was quantified using drug-free and selective (tigecycline at 3× the MIC) media. The in vitrogrowth rates were determined and serial passages on drug-free and selective media were carried out on resistant isolates obtained at 240 h. Both the polymyxin B and tigecycline MICs ranged from 1 to 4 mg/liter. In single time-kill studies, all antibiotics alone demonstrated regrowth at 24 h, except for polymyxin B against 2 isolates. Tigecycline plus meropenem was found to be bactericidal in 50% of the isolates. For the isolates that produced OXA-181-like carbapenemases, none of the 55 tested antibiotic combinations was bactericidal. Against 2 isolates in the HFIM, tigecycline plus meropenem achieved a >90% reduction in bacterial burden for 96 h before regrowth was observed until 109CFU/ml at 240 h. Phenotypically stable and resistant isolates, which were recovered from tigecycline-supplemented plates post-HFIM studies, had lower growth rates than those of their respective parent isolates, possibly implying a substantial biofitness deficit in this population. We found that tigecycline plus meropenem may be a potential antibiotic combination for XDR K. pneumoniaeinfections, but its efficacy was strain specific.

Published
2015
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30. In VitroPharmacodynamics of Fosfomycin against Carbapenem-Resistant Enterobacter cloacaeand Klebsiella aerogenes

Author

Lim, Tze-Peng, Teo, Jocelyn Qi-Min, Goh, Audrey Wei-Ling, Tan, Si-Xuan, Koh, Tse-Hsien, Lee, Winnie Hui-Ling, Cai, Yiying, Tan, Thuan-Tong, and Kwa, Andrea Lay-Hoon

Abstract

The increase of carbapenem-resistant Enterobacterales(CRE) and lack of therapeutic options due to the scarcity of new antibiotics has sparked interest toward the use of intravenous fosfomycin against systemic CRE infections. We aimed to investigate the in vitropharmacodynamics of fosfomycin against carbapenem-resistant Enterobacter cloacaeand Klebsiella aerogenes. Time-kill studies and population analysis profiles were performed with eight clinical CRE isolates, which were exposed to fosfomycin concentrations ranging from 0.

Published
2020
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31. Determining the Development of Persisters in Extensively Drug-Resistant Acinetobacter baumanniiupon Exposure to Polymyxin B-Based Antibiotic Combinations Using Flow Cytometry

Author

Wong, Fiona Hui-Sian, Cai, Yiying, Leck, Hui, Lim, Tze-Peng, Teo, Jocelyn Qi-Min, Lee, Winnie, Koh, Tse Hsien, Tan, Thuan Tong, Tan, Kar Wai, and Kwa, Andrea Lay-Hoon

Abstract

Polymyxin B-based combinations are increasingly prescribed as a last-line option against extensively drug-resistant (XDR) Acinetobacter baumannii. It is unknown if such combinations can result in the development of nondividing persister cells in XDR A. baumannii. We investigated persister development upon exposure of XDR A. baumanniito polymyxin B-based antibiotic combinations using flow cytometry.

Published
2020
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32. Evaluating Polymyxin B-Based Combinations against Carbapenem-Resistant Escherichia coliin Time-Kill Studies and in a Hollow-Fiber Infection Model

Author

Cai, Yiying, Lim, Tze-Peng, Teo, Jocelyn Qi-Min, Sasikala, Suranthran, Chan, Eric Chun Yong, Hong, Yan Jun, Lee, Winnie, Tan, Thean Yen, Tan, Thuan Tong, Koh, Tse Hsien, Hsu, Li Yang, and Kwa, Andrea L.

Abstract

ABSTRACTPolymyxin B-based combinations have emerged as a mainstay treatment against carbapenem-resistant Escherichia coli(CREC). We investigated the activity of polymyxin B-based two-antibiotic combinations against CREC using time-kill studies (TKS) and validated the findings in a hollow-fiber infection model (HFIM). TKS were conducted using 5 clinical CREC strains at 5 log10CFU/ml against 10 polymyxin B-based two-antibiotic combinations at maximum clinically achievable concentrations. HFIMs simulating dosing regimens with polymyxin B (30,000U/kg/day) and tigecycline (100 mg every 12 h) alone and in combination were conducted against two CREC strains at 5 log10CFU/ml over 120 h. Emergence of resistance was quantified using antibiotic-containing media. Phenotypic characterization (growth rate and stability of resistant phenotypes) of the resistant isolates was performed. All five CREC strains harbored carbapenemases. Polymyxin B and tigecycline MICs ranged from 0.5 mg/liter to 2 mg/liter and from 0.25 mg/liter to 8 mg/liter, respectively. All antibiotics alone did not have bactericidal activity at 24 h in the TKS, except for polymyxin B against two strains. In combination TKS, only polymyxin B plus tigecycline demonstrated both bactericidal activity and synergy in two out of five strains. In the HFIM, polymyxin B alone was bactericidal against both CREC strains before regrowth was observed at 8 h. Phenotypically stable polymyxin B-resistant mutants were observed for both strains, with a reduced growth rate observed in one strain. Tigecycline alone resulted in a slow reduction in bacterial counts. Polymyxin B plus tigecycline resulted in rapid and sustained bactericidal killing up to 120 h. Polymyxin B plus tigecycline is a promising combination against CREC. The clinical relevance of our results warrants further investigations.

Published
2016
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33. Whole genome sequencing of multidrug resistant Enterobacterales identified in children and their household members within Siem Reap, Cambodia.

Author

Singh SR, Tang CY, Mao B, Soeng S, Ling CL, Teo JQ, Vonthanak S, Turner P, Hsu LY, and Ong RT

Abstract

Objectives: To explore the association of recent hospitalization and asymptomatic carriage of multidrug-resistant Enterobacterales (MDRE) and determine the prevailing strains and antibiotic resistance genes in Siem Reap, Cambodia using WGS., Methods: In this cross-sectional study, faecal samples were collected from two arms: a hospital-associated arm consisted of recently hospitalized children (2-14 years), with their family members; and a community-associated arm comprising children in the matching age group and their family members with no recent hospitalization. Forty-two families in each study arm were recruited, with 376 enrolled participants (169 adults and 207 children) and 290 stool specimens collected from participants. The DNA of ESBL- and carbapenemase-producing Enterobacterales cultured from the faecal samples was subject to WGS on the Illumina NovaSeq platform., Results: Of the 290 stool specimens, 277 Escherichia coli isolates and 130 Klebsiella spp. were identified on CHROMagar ESBL and KPC plates. The DNA of 276 E. coli (one isolate failed quality control test), 89 Klebsiella pneumoniae , 40 Klebsiella quasipneumoniae and 1 Klebsiella variicola was sequenced. CTX-M-15 was the most common ESBL gene found in E. coli ( n  = 104, 38%), K. pneumoniae ( n  = 50, 56%) and K. quasipneumoniae ( n  = 16, 40%). The prevalence of bacterial lineages and ESBL genes was not associated with any specific arm., Conclusions: Our results demonstrate that MDRE is likely to be endemic within the Siem Reap community. ESBL genes, specifically bla CTX-M , can be found in almost all E. coli commensals, indicating that these genes are continuously propagated in the community through various unknown channels at present., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Published
2023
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34. Evaluating Polymyxin B-Based Combinations against Carbapenem-Resistant Escherichia coli in Time-Kill Studies and in a Hollow-Fiber Infection Model.

Author

Cai Y, Lim TP, Teo JQ, Sasikala S, Chan EC, Hong YJ, Lee W, Tan TY, Tan TT, Koh TH, Hsu LY, and Kwa AL

Subjects
Drug Resistance, Bacterial genetics, Escherichia coli enzymology, Microbial Sensitivity Tests, Minocycline analogs & derivatives, Minocycline pharmacology, Tigecycline, Anti-Bacterial Agents pharmacology, Carbapenems pharmacology, Escherichia coli drug effects, Polymyxin B pharmacology
Abstract

Polymyxin B-based combinations have emerged as a mainstay treatment against carbapenem-resistant Escherichia coli (CREC). We investigated the activity of polymyxin B-based two-antibiotic combinations against CREC using time-kill studies (TKS) and validated the findings in a hollow-fiber infection model (HFIM). TKS were conducted using 5 clinical CREC strains at 5 log 10 CFU/ml against 10 polymyxin B-based two-antibiotic combinations at maximum clinically achievable concentrations. HFIMs simulating dosing regimens with polymyxin B (30,000U/kg/day) and tigecycline (100 mg every 12 h) alone and in combination were conducted against two CREC strains at 5 log 10 CFU/ml over 120 h. Emergence of resistance was quantified using antibiotic-containing media. Phenotypic characterization (growth rate and stability of resistant phenotypes) of the resistant isolates was performed. All five CREC strains harbored carbapenemases. Polymyxin B and tigecycline MICs ranged from 0.5 mg/liter to 2 mg/liter and from 0.25 mg/liter to 8 mg/liter, respectively. All antibiotics alone did not have bactericidal activity at 24 h in the TKS, except for polymyxin B against two strains. In combination TKS, only polymyxin B plus tigecycline demonstrated both bactericidal activity and synergy in two out of five strains. In the HFIM, polymyxin B alone was bactericidal against both CREC strains before regrowth was observed at 8 h. Phenotypically stable polymyxin B-resistant mutants were observed for both strains, with a reduced growth rate observed in one strain. Tigecycline alone resulted in a slow reduction in bacterial counts. Polymyxin B plus tigecycline resulted in rapid and sustained bactericidal killing up to 120 h. Polymyxin B plus tigecycline is a promising combination against CREC. The clinical relevance of our results warrants further investigations., (Copyright © 2016 American Society for Microbiology.)

Published
2016
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35. mcr-1 in Multidrug-Resistant blaKPC-2-Producing Clinical Enterobacteriaceae Isolates in Singapore.

Author

Teo JQ, Ong RT, Xia E, Koh TH, Khor CC, Lee SJ, Lim TP, and Kwa AL

Subjects
Bacterial Proteins genetics, Drug Resistance, Bacterial, Enterobacteriaceae drug effects, Enterobacteriaceae genetics, Enterobacteriaceae isolation & purification, Humans, Plasmids genetics, Sequence Analysis, DNA, Singapore, Anti-Bacterial Agents pharmacology, Enterobacteriaceae enzymology, Enterobacteriaceae Infections microbiology, Genome, Bacterial genetics, Polymyxins pharmacology, beta-Lactamases genetics
Published
2016
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36. Carbapenem Resistance in Gram-Negative Bacteria: The Not-So-Little Problem in the Little Red Dot.

Author

Teo JQ, Cai Y, Lim TP, Tan TT, and Kwa AL

Abstract

Singapore is an international travel and medical hub and faces a genuine threat for import and dissemination of bacteria with broad-spectrum resistance. In this review, we described the current landscape and management of carbapenem resistance in Gram-negative bacteria (GNB) in Singapore. Notably, the number of carbapenem-resistant Enterobacteriaceae has exponentially increased in the past two years. Resistance is largely mediated by a variety of mechanisms. Polymyxin resistance has also emerged. Interestingly, two Escherichia coli isolates with plasmid-mediated mcr-1 genes have been detected. Evidently, surveillance and infection control becomes critical in the local setting where resistance is commonly related to plasmid-mediated mechanisms, such as carbapenemases. Combination antibiotic therapy has been proposed as a last-resort strategy in the treatment of extensively drug-resistant (XDR) GNB infections, and is widely adopted in Singapore. The diversity of carbapenemases encountered, however, presents complexities in both carbapenemase detection and the selection of optimal antibiotic combinations. One unique strategy introduced in Singapore is a prospective in vitro combination testing service, which aids physicians in the selection of individualized combinations. The outcome of this treatment strategy has been promising. Unlike countries with a predominant carbapenemase type, Singapore has to adopt management strategies which accounts for diversity in resistance mechanisms., Competing Interests: The authors declare no conflict of interest.

Published
2016
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