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

Cai, Bingxuan; Cai, Yiying; Liew, Yi Xin; Chua, Nathalie Grace; Teo, Jin Yao; Lim, Tze-Peng; Kurup, Asok; Ee, Pui Lai Rachel; Tan, Thuan Tong; Lee, Winnie; Kwa, Andrea Lay-Hoon

doi:10.1128/aac.03064-15

Cited by 26 publications

(22 citation statements)

References 38 publications

(46 reference statements)

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“…Antagonism was observed in all polymyxin B-based combinations except polymyxin B plus tigecycline against one or more CREC strains. This finding suggested that the empirical selection of polymyxin B-based combinations can be counterproductive and emphasized the importance of in vitro testing in guiding the selection of effective combinations (18,19).…”

Section: Discussionmentioning

confidence: 99%

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

Cai

Lim

Teo

et al. 2017

Antimicrob Agents Chemother

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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. KEYWORDS hollow-fiber infection model, antibiotic combination testing, polymyxin B, carbapenem-resistant Enterobacteriaceae O ver the past decade, the emergence of carbapenem-resistant Enterobacteriaceae (CRE) has challenged the utility of carbapenems worldwide (1, 2). Infections caused by carbapenem-resistant Escherichia coli (CREC) are particularly problematic for several reasons. First, E. coli is a major etiologic agent for a range of life-threatening infections, such as ventilator-associated pneumonia and complicated intra-abdominal infections

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Section: Discussionmentioning

confidence: 99%

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

Cai

Lim

Teo

et al. 2017

Antimicrob Agents Chemother

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“…For colistin and amikacin, total concentrations were used because either total or free concentrations have been shown to be important for pharmacokinetics/pharmacodynamics (PK/PD) by several different reports ( 10 – 13 ). One of the colistin-based combination therapies was used as a positive control because this is an important currently available option for combatting carbapenem-resistant Gram-negative pathogens, including MBL producers ( 14 , 15 ). As the isolates used in this study were resistant to multiple classes of antibiotics, colistin-amikacin combination therapy was evaluated, although these isolates were resistant to amikacin.…”

Section: Textmentioning

confidence: 99%

Activities of Cefiderocol with Simulated Human Plasma Concentrations against Carbapenem-Resistant Gram-Negative Bacilli in an In Vitro Chemostat Model

Matsumoto

Kanazawa

Sato

et al. 2020

Antimicrob Agents Chemother

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Activity of cefiderocol under simulated human plasma concentrations at the recommended dosing regimen of 2 g every 8 h with a 3-h infusion were evaluated using an in vitro chemostat model. Against a total of 6 meropenem-resistant Gram-negative strains with cefiderocol MIC of 0.5 to 4 μg/ml including metallo-β-lactamase producers and carbapenem-resistant Acinetobacter baumannii, cefiderocol treatment showed bactericidal effect within 8 h, and sustained efficacy with no marked bacterial regrowth over 24 h.

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“…The HFIM is used to simulate the pharmacokinetics and pharmacodynamics of the tested drugs singly and in combination with time-kill studies. Thirty patients with drug-resistant Gram-negative bacterial infections were managed with combination antimicrobials based on synergistic drug testing with lower mortality rate compared to controls (Cai et al, 2016a ). Further prospective studies are required to further correlate HFIM testing or other antimicrobial synergy testing methodologies with clinical outcomes.…”

Section: Laboratory Testing and Treatment In The Era Of Carbapenem Rementioning

confidence: 99%

Klebsiella pneumoniae in Singapore: Hypervirulent Infections and the Carbapenemase Threat

Chew

Lin

Teo

2017

Front. Cell. Infect. Microbiol.

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Klebsiella pneumoniae remains a major pathogen responsible for localized infections such as cystitis and pneumonia, and disseminated infections that may result in severe sepsis and death. Invasive disease such as liver abscesses and endogenous endophthalmitis are associated with capsular serotypes K1 and K2. These infections require a prolonged course of antimicrobial treatment which has evolved over the years from inpatient treatment to outpatient parenteral antibiotic therapy. The emergence of plasmid-mediated resistance began with extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases. This was followed by carbapenemase genes and now plasmid transmissible colistin resistance (mcr), thus limiting viable treatment options. Plasmid-mediated carbapenemase production in Singapore was first reported in 1996. Carbapenemase production has since become the predominant mechanism of carbapenem resistance and incidence rates continue to increase over time. Although carbapenemases can occur in all Enterobacteriaceae, K. pneumoniae are the most common carrier of carbapenemase genes. Alternative treatment options are urgently required before the simplest infections, let alone invasive infections are left potentially untreatable. Clinical management requires guidance from robust laboratory testing methods to optimize patient outcomes. We explore past and present trends in treatment of K. pneumoniae infections, and discuss future treatment options and gaps in knowledge for further study.

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

Cited by 26 publications

References 38 publications

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

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

Activities of Cefiderocol with Simulated Human Plasma Concentrations against Carbapenem-Resistant Gram-Negative Bacilli in an In Vitro Chemostat Model

Klebsiella pneumoniae in Singapore: Hypervirulent Infections and the Carbapenemase Threat

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