scholarly journals Role of Double-Carbapenem Regimen in the Treatment of Infections due to Carbapenemase Producing Carbapenem-Resistant Enterobacteriaceae: A Single-Center, Observational Study

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
F. Cancelli ◽  
A. Oliva ◽  
M. De Angelis ◽  
M. T. Mascellino ◽  
C. M. Mastroianni ◽  
...  
Keyword(s):  
Observational Study ◽  
Therapeutic Option ◽  
Clinical Effectiveness ◽  
Synergistic Activity ◽  
Single Center ◽  
Minimal Inhibitory Concentrations ◽  
Carbapenem Resistant ◽  
Effective Therapeutic Option ◽  
Bacteremic Infection

Purpose. (i) To compare infections caused by carbapenem-susceptible (CS) and carbapenemase producing carbapenem-resistant Enterobacteriaceae (CP-CRE); (ii) to evaluate the clinical effectiveness of the double-carbapenem (DC) regimen in comparison with the best available treatment (BAT) in infections caused by CP-CRE; and (iii) to determine the exact minimal inhibitory concentrations (MICs) of meropenem/ertapenem (MEM/ETP) and the degree of in vitro ETP+MEM synergism in subjects receiving the DC. Methodology. Over a 3-year period (2014-2017), patients with infections due to Enterobacteriaceae were included in a single-center, retrospective, observational study. According to the susceptibility to carbapenems, subjects were divided into CSE and CP-CRE groups. CP-CRE group was further divided into subjects receiving the DC regimen and those treated with other regimens (BAT group). Clinical characteristics and the presence of 5th-day response and 60-day outcome were evaluated for DC and BAT groups. The determination of MEM and ETP actual MICs and the MEM+ETP synergistic activity were performed on strains obtained from subjects receiving the DC regimen. Results. A total of 128 patients were included in the study: 55/128 (43%) with infections due to CP-CRE and 73/128 (57%) with infections due to CSE. Among CP-CRE (n=55), 21 subjects (39%) were treated with the DC regimen whereas 34 (61%) received BAT. No differences in terms of severity of infection, presence/absence of concomitant bacteremia, type of infection, and resolution of infection were found; in contrast, DC group tended to have a higher rate of sepsis or septic shock at the onset of infection and a higher rate of 5th-day response. MICs 50/90 were 256/512 and 256/256 μg/mL for MEM and ETP, respectively. Overall, complete in vitro synergism was found in 6/20 strains (30%). Conclusion. The DC regimen is a valid and effective therapeutic option in patients with infections due to KPC producing CRE, including those with bacteremic infection and more severe clinical conditions. The clinical effectiveness is maintained even in the presence of extremely high MEM MICs.

scholarly journals Combination of Colistin and Azidothymidine Demonstrates Synergistic Activity against Colistin-Resistant, Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 8 (12) ◽  
pp. 1964
Author(s):  
Ya-Ting Chang ◽  
Tsung-Ying Yang ◽  
Po-Liang Lu ◽  
Shang-Yi Lin ◽  
Liang-Chun Wang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Therapeutic Option ◽  
Rapid Evolution ◽  
Toxicity Testing ◽  
World Health ◽  
Synergistic Activity ◽  
Carbapenem Resistant

Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the “last-resort” antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant K. pneumoniae (CCRKP). Eleven of the 40 isolates harbored Klebsiella pneumoniae carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; p < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT–colistin combination could be a potentially favorable therapeutic option for treating CCRKP.

scholarly journals In Vitro Activity of Eravacycline in Combination with Colistin Against Carbapenem-Resistant A. baumannii Isolates

2019 ◽  
Author(s):  
H. Selcuk Ozger ◽  
Tugba Cuhadar ◽  
Serap Suzuk Yildiz ◽  
Zehra Demirbas Gulmez ◽  
Murat Dizbay ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Vitro Activity ◽  
Synergistic Activity ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Similar Activity ◽  
Microdilution Method ◽  
Carbapenem Resistant ◽  
Broth Microdilution Method

AbstractThe synergistic activity of eravacycline in combination with colistin on carbapenem-resistant A.baumannii (CRAB) isolates was evaluated in this study. Minimum inhibitory concentrations (MICs) of eravacycline and colistin were determined by the broth microdilution method. MICs values ranged between 1 to 4 mg and 0,5 to 128 mg/L for eravacycline and colistin, respectively. In-vitro synergy between eravacycline and colistin was evaluated by using the chequerboard methodology. Synergistic activity was found in 10 % of the strains, and additive effect in 20 %. No antagonism was detected. Similar activity was also observed in colistin resistant CRAB isolates. The result of this study indicates that eravacycline and colistin combination may be a potential therapeutic option for the treatment of CRAB related infections.

scholarly journals Percutaneous Vertebroplasty Combined with Percutaneous Pediculoplasty for Lytic Vertebral Body and Pedicle Lesions of Metastatic Tumors

2015 ◽  
Vol 3;18 (3;5) ◽  
pp. E347-E353
Author(s):  
Zhong-Liang Deng
Keyword(s):  
Observational Study ◽  
Vertebral Body ◽  
Percutaneous Vertebroplasty ◽  
Management Practice ◽  
Medical Center ◽  
Therapeutic Option ◽  
Retrospective Observational Study ◽  
Symptom Duration ◽  
Single Center ◽  
Metastatic Tumors

Background: Percutaneous pediculoplasty (PP) consists of the injection of Poly(methyl methacrylate) (PMMA) into the fractured pedicle or lytic vertebral pedicle lesions, as a technique derived from vertebroplasty. Objectives: To evaluate the short-term analgesic effect of percutaneous vertebroplasty (PV) and percutaneous pediculoplasty (PP) in patients with lytic vertebral body and pedicle lesions of metastatic tumors. Study Design: Single-center retrospective observational study. Setting: An interventional pain management practice, a medical center, major metropolitan city, China. Methods: Single-center retrospective observational study of all patients managed with PV and PP for painful vertebral body and pedicle metastatic tumors between 2007 and 2013. For each patient, symptom duration and pain intensity were recorded. PP was performed under local analgesia, in the prone position, with C-arm fluoroscopy guidance. The mixture of PMMA and Doxorubicin was delivered into the vertebral body with a non-beveled needle for the initial treatment followed by the mixture delivery into the lytic pedicle during needle withdrawal. Results: Nine patients (5 women, 4 men) were enrolled in the study with a mean age of 65.9 years (range 57 – 75). Technical success was defined as the ability to access the lesion using the approach. A positive clinical response for pain relief was achieved in these patients in whom vertebroplasty and pediculoplasty had been performed. Pain level was not significantly reduced in 3 patients in whom just vertebroplasty has been performed because the medial wall of the pedicle was destroyed by the metastatic lesion. Limitations: This study is limited by its sample size. Conclusions: PV and PP via the transpedicular approach for infiltrated vertebral bodies and infiltrated pedicles of metastatic tumors may be considered a valid therapeutic option. Key words: Percutaneous pediculoplasty, percutaneous vertebroplasty, lytic pedicular lesions, bone cement

scholarly journals Semimechanistic Pharmacokinetic/Pharmacodynamic Modeling of Fosfomycin and Sulbactam Combination against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Sazlyna Mohd Sazlly Lim ◽  
Aaron J. Heffernan ◽  
Jason A. Roberts ◽  
Fekade B. Sime
Keyword(s):  
Acinetobacter Baumannii ◽  
Treatment Options ◽  
Pharmacodynamic Modeling ◽  
Synergistic Activity ◽  
Bacterial Burden ◽  
Target Attainment ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Time Kill

ABSTRACT Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates. Synergism of FOS/SUL against 50 clinical CR-AB isolates was screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill, and 2-log kill after 24 h of combination therapy. The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased 4- to 8-fold, compared to the monotherapy MIC50 and MIC90. In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro. Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam at 4 g every 8 h demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69 to 76%, compared to ∼15 to 30% with monotherapy regimens at the highest doses. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.

Targeting PI3K and CDKs as effective therapeutic option for PPGLs in vitro and in vivo

2021 ◽  
Author(s):  
Sebastian Gulde ◽  
Daniela De Martino ◽  
Hermine Mohr ◽  
Swapna Satam ◽  
Alessia Foscarini ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Effective Therapeutic Option

scholarly journals 2214. Comparison of Cefepime–Zidebactam (WCK 5222), Ceftazidime–Avibactam, and Ceftolozane–Tazobactam Tested Against Gram-Negative Organisms Causing Pneumonia in United States Hospitals in 2018

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S755-S755 ◽  
Author(s):  
Helio S Sader ◽  
Cecilia G Carvalhaes ◽  
Rodrigo E Mendes ◽  
Mariana Castanheira ◽  
Robert K Flamm
Keyword(s):  
Therapeutic Option ◽  
High Dose ◽  
Gram Negative ◽  
E Coli ◽  
Highly Active ◽  
Medical Centers ◽  
Carbapenem Resistant ◽  
Gram Negative Organisms ◽  
Dual Mechanism

Abstract Background Zidebactam (ZID) is a bicyclo-acyl hydrazide antibiotic with a dual mechanism of action: selective Gram-negative PBP2 binding and β-lactamase inhibition. We evaluated the frequency and antimicrobial susceptibility (S) of Gram-negative bacilli (GNB) isolated from patients with pneumonia in US hospitals. Methods All 3,086 clinical isolates were consecutively collected from patients hospitalized with pneumonia (1/patient) in 29 US medical centers in 2018, and the GNB (n = 2,171) were S tested against cefepime (FEP)-ZID (1:1 ratio) and comparators by reference broth microdilution methods. The FEP S breakpoint of ≤8 mg/L (CLSI, high dose) was applied to FEP-ZID for comparison purposes. An FEP-ZID S breakpoint of ≤64 mg/L has been proposed for non-fermentative GNB based on pharmacokinetic/pharmacodynamic target attainment and was applied. Enterobacterales (ENT) isolateswere screened for β-lactamase genes by whole-genome sequencing. Results GNB represented 70.3% of the collection, and the most common GNB were P. aeruginosa (PSA; 34.9% of GNB), K. pneumoniae (10.9%), E. coli (9.7%), S. marcescens (7.7%), and S. maltophilia (XM; 6.4%). FEP-ZID was highly active against PSA (MIC50/90, 2/8 mg/L; 98.8% and 99.9% inhibited at ≤8 and ≤16 mg/L, respectively; highest MIC, 32 mg/L), including resistant subsets (table). Among comparators, colistin (99.6%S), ceftazidime–avibactam (CAZ-AVI; 95.2%S), and ceftolozane–tazobactam (C-T; 94.5%S) were the most active compounds against PSA. FEP-ZID inhibited all ENT at ≤4 mg/L, including ESBL-producers (MIC90, 0.25 mg/L) and carbapenem-resistant ENT (MIC90, 4 mg/L). The most active comparators against ENT were CAZ-AVI (99.9%S), amikacin (98.5%S), and meropenem (MEM; 98.3%S). FEP-ZID inhibited 75.0% and 97.9% of XM isolates at ≤8 and ≤16 mg/L, respectively (highest MIC, 64 mg/L). The only other compounds active against XM were co-trimoxazole (MIC50/90, ≤0.12/2 mg/L; 95.7%S) and levofloxacin (MIC50/90, 1/2 mg/L; 70.7%S). FEP-ZID inhibited 71.0% and 98.9% of A. baumannii isolates at ≤8 and ≤64 mg/L,, respectively. Conclusion FEP-ZID showed potent in vitro activity against GNB causing pneumonia in US hospitals and may represent a valuable therapeutic option for these difficult-to-treat infections Disclosures All authors: No reported disclosures.

scholarly journals In Vitro Activities and Inoculum Effects of Ceftazidime-Avibactam and Aztreonam-Avibactam against Carbapenem-Resistant Enterobacterales Isolates from South Korea

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 912
Author(s):  
Taeeun Kim ◽  
Seung Cheol Lee ◽  
Moonsuk Bae ◽  
Heungsup Sung ◽  
Mi-Na Kim ◽  
...  
Keyword(s):  
Resistance Mechanism ◽  
Fold Increase ◽  
Multidrug Resistant ◽  
Minimal Inhibitory Concentrations ◽  
E Coli ◽  
Carbapenem Resistant ◽  
High Inoculum ◽  
Inoculum Effect

Ceftazidime-avibactam (CAZ-AVI) and aztreonam-avibactam (AZT-AVI) are novel antibiotic combinations active against multidrug-resistant Gram-negative pathogens. This study aimed to evaluate their in vitro activities and inoculum effects in carbapenem-resistant Enterobacterales (CRE), including carbapenemase-producing (CP)-CRE and non-CP-CRE. A total of 81 independent clinical isolates of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae were collected. CAZ-AVI and AZT-AVI minimal inhibitory concentrations (MICs) were evaluated by broth microdilution using standard and high inocula. The inoculum effect was defined as an ≥8-fold increase in MIC with high inoculum. Phenotypic determination of β-lactam resistance mechanism and PCR for carbapenemase genes were performed. Of the 81 CRE isolates, 35 (43%) were CP-CRE. Overall, 73% of the isolates were susceptible to CAZ-AVI, and 95% had low AZT-AVI MICs (≤8 µg/mL). The MIC50/MIC90s of CAZ-AVI and AZT-AVI were 4/≥512 µg/mL and 0.5/4 µg/mL, respectively. CAZ-AVI was more active against non-CP-CRE than against CP-CRE (susceptibility 80% vs. 63%, p = 0.08; MIC50/MIC90, 2/16 μg/mL vs. 4/≥512 μg/mL), whereas AZT-AVI was more active against CP-CRE (MIC50/MIC90, 0.25/1 μg/mL vs. 0.5/8 μg/mL). All four isolates with high AZT-AVI MIC (≥16 μg/mL) were resistant to CAZ-AVI, but only 18% (4/22) of CAZ-AVI-resistant isolates had high AZT-AVI MIC. The rates of the inoculum effect for CAZ-AVI and AZT-AVI were 18% and 47%, respectively (p < 0.001). Interestingly, the frequency of the AZT-AVI inoculum effect was higher in K. pneumoniae than E. coli (64% vs. 8%, p < 0.001). AZT-AVI is more active against CRE than CAZ-AVI, even in CP-CRE and CAZ-AVI-resistant isolates. The presence of a substantial inoculum effect may contribute to clinical failure in high-inoculum infections treated with AZT-AVI.

In vitro and in vivo synergistic effects of tigecycline combined with aminoglycosides on carbapenem-resistant Klebsiella pneumoniae

2021 ◽  
Author(s):  
Wentao Ni ◽  
Deqing Yang ◽  
Jie Guan ◽  
Wen Xi ◽  
Dexun Zhou ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Synergistic Effects ◽  
Molecular Characteristics ◽  
Synergistic Activity ◽  
Significant Activity ◽  
Clinical Pharmacokinetics ◽  
Carbapenem Resistant ◽  
Time Kill

Abstract Objectives Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections represent severe threats to public health worldwide. The aim of this study was to assess potential synergistic interaction between tigecycline and aminoglycosides via in vitro and in vivo studies. Methods Antibiotic resistance profiles and molecular characteristics of 168 CR-KP clinical isolates were investigated by susceptibility testing, PCR and MLST. Chequerboard tests and time–kill assays were performed for 20 CR-KP isolates to evaluate in vitro synergistic effects of tigecycline combined with aminoglycosides. A tissue-cage infection model of rats was established to evaluate in vivo synergistic effects. Different doses of tigecycline and aminoglycosides alone or in combination were administered for 7 days via tail vein injection. Antibiotic efficacy was evaluated in tissue-cage fluid and emergence of resistance was screened. Results The chequerboard tests showed that this combination displayed synergistic or partial synergistic activity against CR-KP. The time–kill assays further demonstrated that strong synergistic effects of such a combination existed against isolates that were susceptible to both drugs but for resistant isolates no synergy was observed if clinical pharmacokinetics were taken into consideration. The in vivo study showed that the therapeutic effectiveness of combination therapies was better than that of monotherapy for susceptible isolates, suggesting in vivo synergistic effects. Furthermore, combinations of tigecycline with an aminoglycoside showed significant activity in reducing the occurrence of tigecycline-resistant mutants. Conclusions Compared with single drugs, tigecycline combined with aminoglycosides could exert synergistic effects and reduce the emergence of tigecycline resistance. Such a combination might be an effective alternative when treating CR-KP infections in clinical practice.

RNAi-mediated silencing of CD40 prevents leukocyte adhesion on CD154-activated endothelial cells

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3642-3646 ◽  
Author(s):  
Raquel Pluvinet ◽  
Jordi Pétriz ◽  
Joan Torras ◽  
Inmaculada Herrero-Fresneda ◽  
Josep M. Cruzado ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Leukocyte Adhesion ◽  
Therapeutic Option ◽  
Surface Expression ◽  
Costimulatory Receptor ◽  
Inflammatory Conditions ◽  
Effective Therapeutic Option ◽  
Inflammatory Processes ◽  
Interfering Rna

The CD40-CD154 dyad has a central role in the development of immune-inflammatory processes. Therefore, disruption of CD40 signaling has the potential to be therapeutically useful in a number of disease indications, including autoimmune syndromes, atherosclerosis, and allograft rejection. Blocking antibodies to CD154 have been successfully employed in experimental animal models, and recently in clinical trials, to prevent or treat these immunologically induced diseases. However, the thrombotic events observed in some of these studies raise important issues regarding future use of anti-CD154 antibodies in humans. In this study, we demonstrate that a small interfering RNA (siRNA) can effectively reduce the surface expression of the human CD40 costimulatory receptor. Moreover, by rendering endothelial cells unresponsive to CD154+ Jurkat cell–mediated activation through RNA interference, induction of endothelial cell-adhesion molecule expression and leukocyte adhesion is prevented in vitro. Thus, anti-CD40 siRNA may become a safe and effective therapeutic option for interfering with CD40-CD154–mediated acute or chronic immune-inflammatory conditions.

scholarly journals Synergistic activity of fosfomycin–meropenem and fosfomycin–colistin against carbapenem resistant Klebsiella pneumoniae: an in vitro evidence

2020 ◽  
pp. FSO461 ◽  
Author(s):  
Yamuna Devi Bakthavatchalam ◽  
Abirami Shankar ◽  
Dhiviya Prabaa Muthuirulandi Sethuvel ◽  
Kalaiarasi Asokan ◽  
Kalaiarasi Kanthan ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Klebsiella Pneumoniae ◽  
Blood Cultures ◽  
Synergistic Activity ◽  
Carbapenem Resistant ◽  
Resistant Genes ◽  
Time Kill ◽  
Synergistic Antibacterial Activity

Aim: To evaluate the antibacterial activity of fosfomycin–meropenem and fosfomycin–colistin combinations against carbapenem-resistant Klebsiella pneumoniae (CR-Kp). Methods: A total of 50 CR-Kp isolates recovered from blood cultures were included in this study. All the CR-Kp isolates were screened for the presence of carbapenem resistant genes blaIMP. blaVIM. blaNDM. blaOXA-48 like, blaKPC. blaGES.#x00A0;and blaSPM. Combination testing of fosfomycin–meropenem and fosfomycin–colistin were performed using time-kill assay. Results: Fosfomycin–meropenem combination showed synergy in 20% of the tested CR-Kp isolates. While, fosfomycin–colistin exhibited synergy against 16% of the isolates. A total of 68% (n = 34) of CR-Kp isolates were characterised as OXA-48-like producers and 22% (n = 11) as NDM producers. Synergistic activity of these combinations was observed against OXA-48, NDM and NDM + OXA-48 co-producers. Conclusion: Considerable synergistic antibacterial activity of fosfomycin–meropenem and fosfomycin–colistin was not observed against CR-Kp isolates. Therefore, these combinations may not be promising for infections associated with CR-Kp.

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