scholarly journals Cefepime/sulbactam as an enhanced antimicrobial combination therapy for the treatment of MDR Gram-negative infections

2019 ◽  
Author(s):  
David W Wareham ◽  
M H F Abdul Momin ◽  
Lynette M Phee ◽  
Michael Hornsey ◽  
Joseph F Standing
Keyword(s):  
Fixed Ratio ◽  
Vitro Activity ◽  
Definitive Treatment ◽  
High Dose ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Pharmacodynamic Modelling ◽  
Carbapenem Resistant ◽  
Combination Regimens

Abstract Background β-Lactam (BL)/β-lactamase inhibitor (BLI) combinations are widely used for the treatment of Gram-negative infections. Cefepime has not been widely studied in combination with BLIs. Sulbactam, with dual BL/BLI activity, has been partnered with very few BLs. We investigated the potential of cefepime/sulbactam as an unorthodox BL/BLI combination against MDR Gram-negative bacteria. Methods In vitro activity of cefepime/sulbactam (1:1, 1:2 and 2:1) was assessed against 157 strains. Monte Carlo simulation was used to predict the PTA with a number of simulated cefepime combination regimens, modelled across putative cefepime/sulbactam breakpoints (≤16/≤0.25 mg/L). Results Cefepime/sulbactam was more active (MIC50/MIC90 8/8–64/128 mg/L) compared with either drug alone (MIC50/MIC90 128 to >256 mg/L). Activity was enhanced when sulbactam was added at 1:1 or 1:2 (P < 0.05). Reduction in MIC was most notable against Acinetobacter baumannii and Enterobacterales (MIC 8/8–32/64 mg/L). Pharmacokinetic/pharmacodynamic modelling highlighted that up to 48% of all isolates and 73% of carbapenem-resistant A. baumannii with a cefepime/sulbactam MIC of ≤16/≤8 mg/L may be treatable with a high-dose, fixed-ratio (1:1 or 1:2) combination of cefepime/sulbactam. Conclusions Cefepime/sulbactam (1:1 or 1:2) displays enhanced in vitro activity versus MDR Gram-negative pathogens. It could be a potential alternative to existing BL/BLI combinations for isolates with a cefepime/sulbactam MIC of 16/8 mg/L either as a definitive treatment or as a carbapenem-sparing option.

scholarly journals In Vitro Activity of Cefotetan against ESBL-Producing Escherichia coli and Klebsiella pneumoniae Bloodstream Isolates from the MERINO Trial

2021 ◽  
Author(s):  
Adam G. Stewart ◽  
Kyra Cottrell ◽  
Andrew Henderson ◽  
Kanthi Vemuri ◽  
Michelle J. Bauer ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Severe Infection ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Carbapenem Resistant

Carbapenem antibiotics remain the treatment of choice for severe infection due to ESBL- and AmpC-producing Enterobacterales . The use of carbapenems is a major driver of the emergence of carbapenem-resistant Gram-negative bacilli, which are often resistant to most available antimicrobials.

Evaluation of the in vitro activity of new polymyxin B analogue SPR206 against clinical MDR, colistin-resistant and tigecycline-resistant Gram-negative bacilli

2020 ◽  
Vol 75 (9) ◽  
pp. 2609-2615 ◽  
Author(s):  
Yawei Zhang ◽  
Chunjiang Zhao ◽  
Qi Wang ◽  
Xiaojuan Wang ◽  
Hongbin Chen ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Enterobacter Cloacae ◽  
Polymyxin B ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Resistant Strains

Abstract Background SPR206 is a novel polymyxin analogue. Activity against clinical isolates is little documented. Methods A collection of 200 MDR, carbapenem-resistant, tigecycline-resistant, colistin-resistant and non-MDR clinical isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Stenotrophomonas maltophilia was obtained from 50 centres across China (2016–17). All isolates were derived from respiratory tract, urine and blood samples. Strains were purposely selected on the basis of phenotypes, genotypes and specimen origins. MICs of SPR206 and other antimicrobials were determined. Results SPR206 was active against all bacteria tested except colistin-resistant isolates. The MIC50/90 values of SPR206 for colistin-resistant strains were comparable to known polymyxins (16/128 versus 8/128 mg/L). SPR206 exhibited potent activity against colistin-susceptible OXA-producing A. baumannii (MIC50/90 = 0.064/0.125 mg/L), NDM-producing Enterobacteriaceae (MIC50/90 = 0.125/0.25 mg/L) and KPC-2-producing Enterobacteriaceae (MIC50/90 = 0.125/0.5 mg/L). In fact, SPR206 was the most potent agent tested, with 2- to 4-fold lower MICs than colistin and polymyxin B for A. baumannii, P. aeruginosa and Enterobacteriaceae. Additionally, MIC values of SPR206 (MIC50/90 = 0.064/0.125 mg/L) were 16- to 32-fold lower than those of tigecycline (MIC50/90 = 2/2 mg/L) for tigecycline-susceptible carbapenem-resistant A. baumannii. Conclusions SPR206 showed good in vitro activity against MDR, tigecycline-resistant and non-MDR clinical isolates of Gram-negative pathogens. SPR206 also exhibited superior potency to colistin and polymyxin B, with 2- to 4-fold lower MIC50/90 values.

scholarly journals Tigecycline: Role in the Management of cIAI and cSSTI in the Indian Context

2021 ◽  
pp. 263394472110675
Author(s):  
Subramanian Swaminathan ◽  
Prithwijit Kundu
Keyword(s):  
Health Care ◽  
Mortality Rate ◽  
Combination Therapy ◽  
Broad Spectrum ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Indian Health ◽  
Carbapenem Resistant

The current millennium has witnessed an increased antimicrobial resistance which poses a mammoth challenge for public health management. This has resulted in an increase in morbidity and mortality, resulting in an increase in financial burden to the patients. A recent analysis from 10 hospitals in India reported that mortality rate increases by 1.57 times in patients suffering from multidrug resistance (MDR) bacterial infections as compared to patients infected with similar but susceptible infections. Due to the emergence of MDR and extensively drug-resistant (XDR) bacteria, most of the broad-spectrum antibiotics have been rendered ineffective. The mortality rate with Gram-negative strains is higher than with Gram-positive strains. Tigecycline is the first in class glycylcycline antibiotic with an expanded broad-spectrum activity. Tigecycline enters bacterial cells through energy-dependent pathways or via passive diffusion, to reversibly bind to the 30S ribosomal subunit. It has potent in vitro activity against Gram-negative carbapenemase producers, except Pseudomonas aeruginosa and Proteus spp. It also has good in vitro activity against Carbapenem-resistant Klebsiella pneumoniae strains. Hence, it is considered as a therapeutic option in XDR isolates. Recent meta-analyses have shown tigecycline to be as effective as its comparators with reducing mortality rates. Due to increased resistance reported in carbapenem-resistant isolates in Indian health-care settings, a colistin/polymyxin B-based combination therapy as a treatment option is being sought. A lower mortality rate has been reported with colistin-based combination therapy in Carbapenem-resistant Enterobacteriaceae-associated infections. Combinations with tigecycline, Fosfomycin, and chloramphenicol have shown to improve treatment outcomes. Tigecycline can be a good alternative in MDR and XDR complicated intra-abdominal and complicated skin and soft tissue infections. Appropriately designed clinical trials in Indian health-care setups will reinforce clinician’s confidence in using tigecycline in complex clinical situations.

scholarly journals In vitro Activity of Cefiderocol Against Gram-Negative Clinical Isolates Collected from Urinary Track Source: SIDERO-WT-2014/SIDERO-WT-2015

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S375-S376 ◽  
Author(s):  
Masakatsu Tsuji ◽  
Meredith Hackel ◽  
Roger Echols ◽  
Yoshinori Yamano ◽  
Dan Sahm
Keyword(s):  
Vitro Activity ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Mueller Hinton ◽  
The Usa ◽  
Fermenting Bacteria

Abstract Background The global rise of carbapenem resistant Gram-negative bacteria such as carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant non-fermenting bacteria is alarming and become threats to patient as only a few drugs remain active (e.g. colistin). Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin with potent activity against a wide variety of Gram-negative pathogens including carbapenem-resistant strains. This study evaluated the in vitro activity of cefiderocol and comparator agents against clinical isolates collected from urinary track source from North America. Methods A total of 3,323 Enterobacteriaceae, 263 Acinetobacter spp, 509 Pseudomonas aeruginosa, and 38 Stenotrophomonas maltophilia collected from the USA and Canada in 2014–2016 were tested. MIC was determined for cefiderocol, cefepime (FEP), ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and meropenem (MEM) by broth microdilution and interpreted according to CLSI 2016 guidelines. All testing was done at IHMA, Inc. As recommended by CLSI, cefiderocol was tested in iron-depleted cation-adjusted Mueller Hinton broth. Based upon CLSI breakpoints, carbapenem-non-susceptible (CarbNS) strains were defined as follows: MEM: MIC ≥2 µg/mL for Enterobacteriaceae, ≥4 µg/mL for non-fermenters. Quality control testing was performed on each day of testing by using E. coli ATCC25922 and P. aeruginosa ATCC27853. Results Cefiderocol exhibited in vitro activity against 4,133 strains of Gram-negative bacteria with an overall MIC90 of 0.5 µg/mL. At 4 µg/mL cefiderocol inhibited the growth of 99.9% of the all isolates. MIC90 of cefiderocol against CarbNS Enterobacteriaceae was 4 µg/mL although MIC90 of other comparators were &gt;64 or &gt;8 (CST) µg/mL. The cefiderocol MIC90value was 1 µg/mL for CarbNS non-fermeneters. Conclusion Cefiderocol demonstrated potent in vitro activity against Enterobacteriaceae, A. baumannii, P. aeruginosa, and S. maltophilia isolates collected from a UTI source, with greater than 99.9% of isolates having MIC values ≤4 µg/mL. These findings indicate that this agent has high potential for treating cUTI infections caused by these problematic organisms, including isolates resistant to colistin. Disclosures M. Tsuji, Shionogi & Co.: Employee, Salary; M. Hackel, IHMA: Employee, Salary; R. Echols, Shionogi & CO., LTD: Consultant, Consulting fee; Y. Yamano, Shionogi & Co.: Employee, Salary

scholarly journals 1252. In Vitro Activity of Cefiderocol Against Metallo-β-Lactamase-Producing Gram-Negative Bacteria Collected in North America and Europe Between 2014 and 2017: SIDERO-WT-2014–2016 Studies

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S643-S644
Author(s):  
Miki Takemura ◽  
Krystyna Kazmierczak ◽  
Meredith Hackel ◽  
Daniel F Sahm ◽  
Roger Echols ◽  
...  
Keyword(s):  
North America ◽  
Vitro Activity ◽  
Gram Negative Bacteria ◽  
In Vitro Activity ◽  
Independent Contractor ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
The Usa ◽  
Cephalosporin Antibiotic

Abstract Background Metallo-β-lactamases (MBLs; eg, NDM, VIM, and IMP) can inactivate most commonly-used β-lactam antibiotics, including carbapenems. Infections caused by MBL producers are difficult to treat due to their resistance to many antibiotics. Cefiderocol (CFDC) is a siderophore cephalosporin antibiotic approved in the USA in 2019, with potent activity against carbapenem-resistant Gram-negative bacteria (GNB), including both serine- and metallo-carbapenemase positive strains. We evaluated the in vitro activity of CFDC and comparator agents against MBL-producing strains of GNB from North America and Europe in 3 years’ of consecutive surveillance studies (SIDERO-WT-2014–2016). Methods Susceptibility testing for CFDC, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), meropenem (MEM), cefepime (FEP), ciprofloxacin (CIP), and colistin (CST) was performed by broth microdilution according to CLSI guidance. CFDC was tested in iron-depleted medium. A total of 275 MBL-producing strains, consisting of 120 Enterobacterales (45 NDM; 75 VIM), 5 NDM-producing Acinetobacter baumannii, and 150 Pseudomonas aeruginosa (134 VIM; 16 IMP), identified among 4985 (654 Enterobacterales and 4331 non-fermenters) MEM non-susceptible (based on CLSI breakpoints) strains were used for the current analysis. Results The minimum inhibitory concentration (MIC) range and MIC90 for CFDC and comparators for each MBL-producing organism group are shown in the Table. Against NDM-producing Enterobacterales, of which 42% and 33% were isolated in Turkey and Russia, respectively, CFDC inhibited the growth of 84% of isolates tested at ≤4 µg/mL. CFDC MIC90 was 4 μg/mL for VIM-producing Enterobacterales (41% and 31% isolated in Greece and Italy, respectively), 1 μg/mL for VIM-producing P. aeruginosa (50% isolated in Russia), and 4 μg/mL for IMP-producing P. aeruginosa (88% isolated in Czech Republic). Other comparators (except for CST) were not active against these MBL producers. Table. MIC range and MIC90 (μg/mL) for CFDC and comparators of MBL-producing organisms Conclusion CFDC inhibited the growth of 100% of MBL-positive GNB at ≤8 mg/mL and showed MIC90 of 4 μg/mL against all 275 MBL producers, indicating that CFDC has high potential for treating infections caused by these difficult-to-treat strains. Disclosures Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Krystyna Kazmierczak, PhD, Shionogi & Co., Ltd. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor) Roger Echols, MD, Shionogi Inc. (Consultant) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee)

scholarly journals 1613. Global 2018 Surveillance of Eravacycline Against Gram-negative Pathogens, Including Multi-drug Resistant Isolates

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S800-S800
Author(s):  
Virgil Lijfrock ◽  
Steven Morgan ◽  
Sara Hwang ◽  
Ekaterina Efimova ◽  
Kenneth Lawrence ◽  
...  
Keyword(s):  
Research Study ◽  
Scientific Research ◽  
Vitro Activity ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Study Investigator ◽  
Abdominal Infections

Abstract Background Eravacycline (ERV) is a fully-synthetic, fluorocycline antibacterial approved by the FDA and EMA for treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age. The purpose of this study was to describe the in vitro activity of ERV against Gram-negative pathogens, including multi-drug resistant (MDR) isolates, collected in 2018. Methods Isolates were collected during 2018 from various body sites. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. Antibiotic susceptibility was determined using the most updated CLSI breakpoints, except for ERV and tigecycline (TGC) where FDA breakpoints established in 2018 and 2005 respectively, were used. MDR was defined as resistance to ≥3 antibiotics from aztreonam, a carbapenem (meropenem or ertapenem [ETP]), cefepime/cefotaxime/ceftazidime/ceftriaxone (any one), gentamicin, levofloxacin, piperacillin-tazobactam TZP, tetracycline or TGC. Results Summary MIC data for ERV and select comparators are shown in the Table. ERV MIC90 for all-Enterobacteriaceae was 0.5 μg/ml and for MDR-Enterobacteriaceae was 1μg/ml. The susceptibilities for all-Enterobacteriaceae were 93%, 95%, 93% and 82% for ERV, TGC, ETP and TZP, respectively. ERV further demonstrated higher rates of susceptibility than ETP and TZP against MDR-Enterobateriaceae, 81% vs 71% vs 38%. ERV MIC50/90 for carbapenem-resistant Acinetobacter baumannii (CRAB) were 4-fold lower than TGC. Table Conclusion ERV in vitro activity was demonstrated and comparable susceptibility rates were observed for clinically important Gram-negative pathogens, including resistant isolates. Overall, ERV MIC90 values were 2- to 8- fold lower than TGC. this study further highlights the in vitro activity of ERV against Gram-negative pathogens identified in patients with cIAI. Disclosures Virgil Lijfrock, PharMD, Tetraphase (Employee) Steven Morgan, PharMD, Tetraphase Pharmaceuticals (Employee) Sara Hwang, PharMD, Tetraphase Pharmaceuticals (Employee) Ekaterina Efimova, PharMD, Tetraphase Pharmaceuticals (Employee) Kenneth Lawrence, PharmD, Tetraphase Pharmaceuticals (Employee) Stephen Hawser, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator) Ian Morrissey, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator)

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