scholarly journals In Vitro Synergistic Antimicrobial Activity of Combinations of Meropenem, Colistin, Tigecycline, Rifampin, and Ceftolozane/Tazobactam Against Carbapenem-Resistant Acinetobacter Baumannii

2021 ◽  
Author(s):  
Yong Guk Ju ◽  
Hak Joon Lee ◽  
Hong Soon Yim ◽  
Chang Kyu Lee ◽  
Mingoo Lee ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Effect ◽  
Drug Combinations ◽  
Synergistic Activity ◽  
Antibiotic Concentration ◽  
Carbapenem Resistant ◽  
Potential Alternative ◽  
Time Kill ◽  
Antimicrobial Combinations

Abstract The aim of this study was to investigate the in vitro activity of various antimicrobial combinations against carbapenem-resistant Acinetobacter baumannii (CRAB) isolates producing OXA-23 carbapenemases.In vitro activity of six two-drug combinations against CRAB isolates collected from patients with CRAB bacteremia was evaluated using the checkerboard method and time-kill assay [0.5 ×, 1 ×, 2 × minimum inhibitory concentrations (MIC)], to identify potential synergistic and bactericidal two-drug combinations against CRAB isolates, using meropenem, colistin, tigecycline, rifampin, and ceftolozane/tazobactam. All 10 CRAB isolates in our study carried the OXA-58-type and OXA-23-type carbapenem-hydrolyzing oxacillinase. The colistin-ceftolozane/tazobactam combination demonstrated a synergistic effect in both the time-kill assay (using an antibiotic concentration of 1 × MIC) and the checkerboard method, while simultaneously showing a bactericidal effect in the time-kill assay. For all 10 CRAB isolates, time-kill curves showed a significant synergistic bactericidal activity of the colistin-ceftolozane/tazobactam combination at 0.5 × MIC. Overall, there is substantial discordance of synergistic activity between the checkerboard microdilution and time-kill assay (with a concordance of 35%). Our study demonstrated that the two-drug combinations of colistin and ceftolozane/tazobactam can be a potential alternative for treating CRAB infections. The effect of these antibiotic combinations should be evaluated through clinical trials.

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.

scholarly journals In-Vitro Evaluation of Different Antimicrobial Combinations with and without Colistin Against Carbapenem-Resistant Acinetobacter Baumannii

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 886 ◽  
Author(s):  
Alessandra Oliva ◽  
Stefania Garzoli ◽  
Massimiliano De Angelis ◽  
Carolina Marzuillo ◽  
Vincenzo Vullo ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
High Morbidity ◽  
Synergistic Activity ◽  
Carbapenem Resistant ◽  
Resistant Strains ◽  
High Level ◽  
University Of Rome ◽  
Antimicrobial Combinations

Carbapenem-resistant Acinetobacter baumannii (CR-Ab) infections are associated with high morbidity and mortality. The aim of the study was to evaluate the in-vitro activity of different antimicrobial combinations (with and without colistin, COL) against clinical isolates of CR-Ab collected from patients with CR-Ab infection, including unconventional combinations such as COL + VANcomycin (VAN) and COL + rifampin (RIF). CR-Ab strains were collected from hospitalized patients at Sapienza University of Rome. Antimicrobial susceptibility patterns were determined throughout MIC50/90s whereas the synergistic activity was evaluated by qualitative (i.e., checkerboard) and quantitative (i.e., killing studies) methods. All the strains were found oxacillinase (OXA) producers and tigecycline (TIG) sensitive whereas 2 strains were resistant to COL. Application of the checkerboard method indicated complete synergism in COL combinations at different extension: 21.4%, 57.1%, 42.8%, 35.7% for COL + meropenem (MEM), COL + RIF, COL + VAN and COL + TIG, respectively, with the non-conventional combinations COL + VAN and COL + RIF exhibiting the highest rate of synergism. Regarding COL-free combination, complete synergism was observed in 35.7% of the strains for MEM + TIG. Killing studies showed that the combinations COL + MEM, COL + TIG and MEM + TIG were bactericidal and synergistic against both colistin-sensitive and low colistin-resistant strains whereas only the combinations COL + VAN and COL + RIF showed an early and durable bactericidal activity against all the tested strains, with absence of growth at 24 h. This study demonstrated that COL-based combinations lead to a high level of synergic and bactericidal activity, especially COL + VAN and COL + RIF, even in the presence of high level of COL resistance.

scholarly journals In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 14 (8) ◽  
pp. 823
Author(s):  
Tsung-Ying Yang ◽  
Sung-Pin Tseng ◽  
Heather Nokulunga Dlamini ◽  
Po-Liang Lu ◽  
Lin Lin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antibacterial Activities ◽  
Treated Group ◽  
Infection Model ◽  
High Dose ◽  
Mouse Infection Model ◽  
Carbapenem Resistant ◽  
Time Kill

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies.

scholarly journals Bactericidal Efficacy of Meropenem in Combination with Cefmetazole against IMP-producing Carbapenem-Resistant Enterobacteriaceae

2019 ◽  
Author(s):  
Ryuichiro Abe ◽  
Hideharu Hagiya ◽  
Yukihiro Akeda ◽  
Norihisa Yamamoto ◽  
Yoshikazu Ishii ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Animal Studies ◽  
Bactericidal Effect ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Enterobacter Hormaechei ◽  
Time Kill ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Objective: Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to public and clinical health because of their high levels of resistance to various antibiotics. We assessed the efficacy of combination therapy with meropenem (MEM) and cefmetazole (CMZ) against Imipenemase (IMP)-producing CRE, using the checkerboard method and time-killing assay on 13 Enterobacteriaceae isolates harboring blaIMP-1 (4 Enterobacter hormaechei, 5 Escherichia coli, and 4 Klebsiella pneumoniae isolates) and 13 isolates harboring blaIMP-6 (8 E. coli and 5 K. pneumoniae isolates). Results: Minimum inhibitory concentrations (MICs) of MEM and CMZ ranged from 2 to 64 and 64 to 2048 μg/mL, respectively. Checkerboard method demonstrated the synergy of the MEM/CMZ combination in all the tested IMP-producing CRE isolates, and the time-kill assay indicated a bactericidal effect for both blaIMP-1 and blaIMP-6 positive CRE when MEM/CMZ combination was used. In vitro, the MEM/CMZ combination was potentially effective against IMP-1- or IMP-6-producing CRE. Further investigations including in vivo animal studies and clinical studies are warranted to corroborate the clinical utility of the novel combination therapy.

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.

scholarly journals In VitroResponses of Acinetobacter baumannii to Two- and Three-Drug Combinations following Exposure to Colistin and Doripenem

2013 ◽  
Vol 58 (2) ◽  
pp. 1195-1199 ◽  
Author(s):  
Louise M. Oleksiuk ◽  
M. Hong Nguyen ◽  
Ellen G. Press ◽  
Cassaundra L. Updike ◽  
Jessica A. O'Hara ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
Drug Combinations ◽  
Content Type ◽  
Before And After ◽  
Time Kill

ABSTRACTWe comparedin vitrokilling of colistin, doripenem, and sulbactam by time-kill methods againstAcinetobacter baumanniiisolates collected from patients before and after colistin-doripenem treatment (initial and recurrent isolates, respectively). Colistin-doripenem bactericidal activity against recurrent isolates was attenuated (mean log10kill, −5.74 versus −2.88;P= 0.01) but was restored by adding sulbactam. Doripenem MICs rather than colistin MICs correlated with the activity of colistin-doripenem. Among colistin-resistant isolates, colistin-doripenem-sulbactam combinations achieved greater killing than colistin-doripenem alone (−5.65 versus −2.43;P= 0.04).

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.

scholarly journals Bactericidal Efficacy of Meropenem in Combination with Cefmetazole against IMP-producing Carbapenem-Resistant Enterobacteriaceae

2019 ◽  
Author(s):  
Ryuichiro Abe ◽  
Hideharu Hagiya ◽  
Yukihiro Akeda ◽  
Norihisa Yamamoto ◽  
Yoshikazu Ishii ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Animal Studies ◽  
Bactericidal Effect ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Enterobacter Hormaechei ◽  
Time Kill ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Objective: Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to public and clinical health because of their high levels of resistance to various antibiotics. We assessed the efficacy of combination therapy with meropenem (MEM) and cefmetazole (CMZ) against IMP-producing CRE, using the checkerboard method and time-killing assay on 13 Enterobacteriaceae isolates harboring blaIMP-1 (4 Enterobacter hormaechei, 5 Escherichia coli, and 4 Klebsiella pneumoniae isolates) and 13 isolates harboring blaIMP-6 (8 E. coli and 5 K. pneumoniae isolates). Results: Minimum inhibitory concentrations (MICs) of MEM and CMZ ranged from 2 to 64 and 64 to 2048 μg/mL, respectively. Checkerboard method demonstrated the synergy of the MEM/CMZ combination in all the tested IMP-producing CRE isolates, and the time-kill assay indicated a bactericidal effect for both blaIMP-1 and blaIMP-6 positive CRE when MEM/CMZ combination was used. In vitro, the MEM/CMZ combination was potentially effective against IMP-1- or IMP-6-producing CRE. Further investigations including in vivo animal studies and clinical studies are warranted to corroborate the clinical utility of the novel combination therapy.

scholarly journals In Vitro Antibacterial Activity of Cefiderocol against Multidrug-Resistant Acinetobacter baumannii

2021 ◽  
Author(s):  
Jacinda C. Abdul-Mutakabbir ◽  
Logan Nguyen ◽  
Philip T. Maassen ◽  
Kyle C. Stamper ◽  
Razieh Kebriaei ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Susceptibility Testing ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Strong Activity ◽  
Gram Negative ◽  
In Vitro Antibacterial Activity ◽  
Time Kill

Cefiderocol (CFDC), a novel siderophore cephalosporin, demonstrates strong activity against multidrug-resistant (MDR) Acinetobacter baumannii. Limited studies have evaluated CFDC alone and in combination with other Gram-negative antibiotics against MDR A. baumannii isolates. Susceptibility testing revealed lower CFDC minimum inhibitory concentration (MIC) values than the comparator Gram-negative agents (87% of MICs ≤ 4mg/L). Six isolates, with elevated CFDC MICs (16-32 mg/L), were selected for further experiments. Time-kill analyses presented with synergistic activity and beta-lactamase inhibitors increased CFDC susceptibility in each of the isolates.

Sign in / Sign up

Export Citation Format

Share Document