scholarly journals 1580. Colistin Potentiates the In Vitro Activity of Meropenem–Vaborbactam (M/V) Against Some, but not All KPC-producing Klebsiella pneumoniae (KPC-Kp)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S577-S577
Author(s):  
Chelsea E Jones ◽  
Ellen G Kline ◽  
Minh-Hong Nguyen ◽  
Cornelius J Clancy ◽  
Ryan K Shields
Keyword(s):  
Potential Role ◽  
Stop Codon ◽  
Single Agent ◽  
Premature Stop Codon ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Wild Type ◽  
Outer Membrane Permeability ◽  
Time Kill

Abstract Background M/V demonstrates potent in vitro activity against KPC-producing organisms. It is unclear whether the combination interacts synergistically with other active agents. Methods We tested isolates for responses to M/V alone (1 and 4x MIC; V fixed at 8 µg/mL), and in combination with colistin (COL; 2 µg/mL), fosfomycin (FOS; 100 µg/mL + 25 µg/mL G6P), gentamicin (GEN; 2 µg/mL), and tigecycline (TGC; 2 µg/mL) by time-kill using a starting inoculum of 1 × 108 cFu/mL. 24h was the primary endpoint. Results 16 KPC-Kp isolates were studied (7 KPC-2 and 9 KPC-3); all were M/V-susceptible (MIC range: 0.015 – 4 µg/mL). 44% harbored ompK36 mutations (4 IS5 promoter insertion, 2 134–135 DG duplication, and 1 premature stop codon). Median M/V MICs were higher against isolates with mutant ompK36 (0.25 vs. 0.03; P = 0.002). Mean log-kills by M/V at 1x and 4x were -0.50 and -2.41, respectively; M/V was bactericidal (≥3-log kill) against 6% and 56%, respectively (Figure 1). Mean log-kills at 4× were greater against KPC-2 (-3.79) than KPC-3 (−1.33) isolates (P = 0.09), and among isolates with (−3.31) vs. without (−1.71) ompK36 mutations (P = 0.11). GEN was the most active single agent (bactericidal against 56%, mean log-kill = −3.04). In combo with M/V, rates of synergy (>2-log kill in combo) with COL, FOS, GEN, and TGC were 44%, 19%, 12.5%, and 12.5%, respectively (Figure 2). Corresponding rates of bactericidal activity were 44%, 25%, 69%, and 31%, respectively. Antagonism (> 1-log kill by most active single agent) was identified for each combo against 2 isolates. Mean log-kills by M/V + GEN were greater against isolates with GEN MICs ≤1 (−7.16) vs. ≥2 (−1.66; P = 0.001), reflecting the activity of GEN alone. Mean log-kills by M/V + COL were greater against isolates with IS5 insertions (-6.32) compared with wild type (−2.38) or other mutations (−1.77) in ompK36. Responses to M/V + FOS were not dependent upon FOS MIC, but log-kills were greater against mutant (-2.13) vs. wild-type (0.01) ompK36 (P = 0.03). Conclusion M/V + GEN is rapidly cidal if GEN MICs are ≤1, while M/V + COL resulted in highest rates of synergy against diverse KPC-Kp. Mean log-kills were highest among isolates with IS5 promoter insertions suggesting a potential role for COL combination therapy against KPC-Kp isolates with decreased outer membrane permeability. Disclosures All authors: No reported disclosures.

scholarly journals 1378. Evaluation of the In vitro Activity of Meropenem-Vaborbactam Against Carbapenem-Resistant Enterobacteriaceae, Including Isolates Resistant to Ceftazidime–Avibactam

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S422-S422
Author(s):  
William R Wilson ◽  
Ellen Kline ◽  
Chelsea Jones ◽  
Kristin Morder ◽  
Cornelius J Clancy ◽  
...  
Keyword(s):  
Premature Stop Codon ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Wild Type ◽  
In Vitro Susceptibility ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Carbapenem Resistant Enterobacteriaceae ◽  
Research Grant

Abstract Background Meropenem-vaborbactam (M-V) is a novel antibiotic for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections. Our objective was to determine the in vitro activity of meropenem-vaborbactam against genetically-diverse CRE isolates, including those that have developed resistance to Ceftazidime–Avibactam (C-A). Methods Minimum inhibitory concentrations (MICs) were determined for meropenem (MER), M-V, and C-A by reference broth microdilution (BMD) methods in triplicate. Vaborbactam and avibactam were tested at fixed concentrations of 8 and 4 µg/mL, respectively. Quality control strains were used and within expected ranges. Polymerase chain reaction (PCR) with DNA sequencing was used to detect resistance determinants, including Klebsiella pneumoniae carbapenemase (KPC) subtypes and porin mutations. Results A total of 117 CRE isolates were tested, including K. pneumoniae (Kp; n = 83), E. cloacae (n = 17), E. coli (n = 10), and E. aerogenes (n = 7). Seventy-nine percent harbored blaKPC. KPC subtypes included KPC-2 (n = 32), KPC-3 (n = 41), KPC-3 variants (n = 16), and KPC [not typed] (n = 4, all E. coli). Among 74 K. pneumoniae, 95% had a premature stop codon in ompk35 and ompK36 genotypes included wild type (n = 48), IS5 insertion (n = 13), 135–136 DG duplication (n = 9), and other mutations (n = 4). The median (range) MICs for MER, C-A, and M-V were 8 (0.06 to ≥128), 1 (0.25 to ≥512), and 0.03 (0.015––16), respectively. Corresponding rates of susceptibility were 23, 84, and 98%, respectively. Fifty-three percent and 95% of C-A-resistant isolates were susceptible to MER and M-V, respectively. Among Kp, C-A MICs did not vary by KPC subtype or porin genotype. On the other hand, median M-V MICs were higher among KPC-2 than KPC-3 Kp (0.12 vs. 0.03; P = 0.002), and among Kp with ompK36 porin mutations compared with wild type (0.25 vs. 0.03; P < 0.001). Among Kp with KPC-3 variants (n = 16), the median M-V MIC was 0.03 (0.015––2); 100% were M-V susceptible. Median M-V MICs did not vary by CRE species. Only two isolates were M-V resistant, both were E. cloacae that did not harbor blaKPC. Conclusion M-V demonstrates high rates of in vitro susceptibility against diverse CRE isolates, including those that are resistant to C-A. As this agent is introduced into the clinic, it will be important to identify K. pneumoniae isolates harboring KPC-2 with ompK36 porin mutations that demonstrate higher MICs. Disclosures M. H. Nguyen, Merck: Grant Investigator, Research grant. Astellas: Grant Investigator, Research grant.

In vitro activity of the novel antibacterial agent ibezapolstat (ACX-362E) against Clostridioides difficile

2020 ◽  
Author(s):  
Beverly Murray ◽  
Cindy Wolfe ◽  
Andrea Marra ◽  
Chris Pillar ◽  
Dean Shinabarger
Keyword(s):  
Therapeutic Potential ◽  
Oral Treatment ◽  
Clinical Development ◽  
Vitro Activity ◽  
The Novel ◽  
In Vitro Activity ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Time Kill

Abstract Background Ibezapolstat (ACX-362E) is the first DNA polymerase IIIC inhibitor undergoing clinical development for the oral treatment of Clostridioides difficile infection (CDI). Methods In this study, the in vitro activity of ibezapolstat was evaluated against a panel of 104 isolates of C. difficile, including those with characterized ribotypes (e.g. 027 and 078) and those producing toxin A or B and was shown to have similar activity to those of comparators against these strains. Results The overall MIC50/90 (mg/L) for ibezapolstat against evaluated C. difficile was 2/4, compared with 0.5/4 for metronidazole, 1/4 for vancomycin and 0.5/2 for fidaxomicin. In addition, the bactericidal activity of ibezapolstat was evaluated against actively growing C. difficile by determining the MBC against three C. difficile isolates. Time–kill kinetic assays were additionally performed against the three C. difficile isolates, with metronidazole and vancomycin as comparators. Conclusions The killing of C. difficile by ibezapolstat was observed to occur at concentrations similar to its MIC, as demonstrated by MBC:MIC ratios and reflected in time–kill kinetic assays. This activity highlights the therapeutic potential of ibezapolstat for the treatment of CDI.

scholarly journals In Vitro Activity of Pentamidine Alone and in Combination with Antibiotics against Multidrug-Resistant Clinical Pseudomonas aeruginosa Strains

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 885
Author(s):  
Soraya Herrera-Espejo ◽  
Tania Cebrero-Cangueiro ◽  
Gema Labrador-Herrera ◽  
Jerónimo Pachón ◽  
María Eugenia Pachón-Ibáñez ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Public Health Problem ◽  
Multidrug Resistant ◽  
Vitro Activity ◽  
Synergistic Activity ◽  
In Vitro Activity ◽  
Hospital Acquired Infections ◽  
Time Kill ◽  
Hospital Acquired

Multidrug-resistant (MDR) Pseudomonas aeruginosa is a public health problem causing both community and hospital-acquired infections, and thus the development of new therapies for these infections is critical. The objective of this study was to analyze in vitro the activity of pentamidine as adjuvant in combinations to antibiotics against seven clinical P. aeruginosa strains. The Minimum Inhibitory Concentration (MIC) was determined following standard protocols, and the results were interpreted according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints; however, the gentamicin activity was interpreted according to the Clinical and Laboratory Standards Institute (CLSI) recommendations. The bactericidal in vitro activity was studied at 1×MIC concentrations by time–kill curves, and also performed in three selected strains at 1/2×MIC of pentamidine. All studies were performed in triplicate. The pentamidine MIC range was 400–1600 μg/mL. Four of the strains were MDR, and the other three were resistant to two antibiotic families. The combinations of pentamidine at 1×MIC showed synergistic activity against all the tested strains, except for pentamidine plus colistin. Pentamidine plus imipenem and meropenem were the combinations that showed synergistic activity against the most strains. At 1/2×MIC, pentamidine plus antibiotics were synergistic with all three analyzed strains. In summary, pentamidine in combination with antibiotics showed in vitro synergy against multidrug-resistant P. aeruginosa clinical strains, which suggests its possible use as adjuvant to antibiotics for the therapy of infections from MDR P. aeruginosa.

scholarly journals In Vitro 24-Hour Time-Kill Studies of Vancomycin and Linezolid in Combination versus Methicillin-Resistant Staphylococcus aureus

2009 ◽  
Vol 53 (10) ◽  
pp. 4495-4497 ◽  
Author(s):  
Shveta Rani Singh ◽  
Alfred E. Bacon ◽  
David C. Young ◽  
Kimberly A. Couch
Keyword(s):  
Staphylococcus Aureus ◽  
Conventional Therapy ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Antagonistic Activity ◽  
Vitro Activity ◽  
Synergistic Activity ◽  
In Vitro Activity ◽  
Methicillin Resistant ◽  
Time Kill

ABSTRACT Many clinicians are trying unique strategies, including vancomycin and linezolid in combination, for treatment of patients who do not respond to conventional therapy against methicillin (meticillin)-resistant Staphylococcus aureus. In our study, which illustrated in vitro activity only, no synergistic activity was seen when the two agents were combined. Conversely, antagonistic activity occurred in three of five strains when linezolid was added to vancomycin. Our results indicate that vancomycin and linezolid in combination should be avoided.

scholarly journals 681. Penicillin Plus Ceftriaxone Against Enterococcus faecalis In Vitro Time-Kill Studies

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S443-S444
Author(s):  
Ruhmazia Khan ◽  
Zeel Shah ◽  
Vanthida Huang ◽  
Jaclyn Cusumano
Keyword(s):  
Enterococcus Faecalis ◽  
Single Agent ◽  
Temperature Stability ◽  
Bacterial Density ◽  
Average Increase ◽  
Wild Type ◽  
Intrinsic Resistance ◽  
Colony Forming Units ◽  
Time Kill

Abstract Background Synergistic ampicillin plus ceftriaxone (AC) for Enterococcus faecalis infective endocarditis outpatient use is precluded by ampicillin’s poor room temperature stability. Penicillin has superior stability and has been combined with ceftriaxone (PC), however there is a lack of studies to demonstrate synergy. Methods AC and PC were evaluated, in duplicate, for synergy utilizing 24-hour in vitro time-kill assays with a starting inoculum of 106 colony forming units (CFU)/mL. Six clinical E. faecalis blood isolates and one wild-type E. faecalis isolate (JH2-2) were included. All isolates were susceptible to ampicillin and penicillin, with minimum inhibitory concentrations (MICs) ranging from 0.5-1 µg/mL and 2-4 µg/mL, respectively. Ampicillin and penicillin were tested at subinhibitory concentrations (0.25x and 0.5xMIC) as monotherapy and in combination with ceftriaxone average steady state concentrations for a dose of 2g IV q12hr (CPss 17.2 µg/mL), as all ceftriaxone MICs were high due to intrinsic resistance (MICs 128-2048 µg/mL). Synergy was defined as a ≥ 2 log10 decrease in CFU/mL at 24 hours from the most active single agent. Results An average increase in bacterial density from the starting inoculum was observed for all isolates against ampicillin 0.25xMIC alone, penicillin 0.25x and 0.5xMIC alone, and ceftriaxone alone (+1.60 ± 0.62, +1.91 ± 0.37, +1.48 ± 0.42, and +1.84 ± 0.46 log10 CFU/mL, respectively) [Table 1]. Ampicillin 0.5xMIC alone average increase in bacterial density from starting inoculum for all but two isolates (e2008 and e2009) was +1.21 ± 0.59 log10 CFU/mL. Isolates e2008 and e2009 were the only isolates with a higher penicillin MIC of 4 µg/mL, and did not display synergy for all AC and all PC combinations. AC synergy was observed for all other isolates, with only one isolate (e2012) displaying synergy at 0.5xMIC. PC synergy was observed for four isolates at 0.5xMIC (-3.47 ± 0.94 log10 CFU/mL) and for only one isolate (e2014) at 0.25xMIC but the change in bacterial density was -0.38 ± 0.24 log10 CFU/mL. Conclusion PC synergy against E. faecalis was observed with higher penicillin concentrations. AC and PC did not demonstrate synergy against isolates with a higher penicillin MIC of 4 µg/mL. Further research is warranted to better understand PC synergy against E. faecalis. Disclosures All Authors: No reported disclosures

In vitro activity of ampicillin/sulbactam against enterococci determined by the time-kill method

1989 ◽  
Vol 12 (1) ◽  
pp. 9-11 ◽  
Author(s):  
Richard F. D'Amato ◽  
Anna Mathew ◽  
Lisa Hochstein ◽  
Dennis J. Cleri ◽  
Janet Johnson
Keyword(s):  
Vitro Activity ◽  
In Vitro Activity ◽  
Time Kill

scholarly journals Antistaphylococcal Activity of DX-619 Alone and in Combination with Vancomycin, Teicoplanin, and Linezolid Assessed by Time-Kill Synergy Testing

2007 ◽  
Vol 51 (4) ◽  
pp. 1508-1511
Author(s):  
Kim Credito ◽  
Genrong Lin ◽  
Peter C. Appelbaum
Keyword(s):  
Staphylococcus Aureus ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Antistaphylococcal Activity ◽  
Time Kill ◽  
Synergy Testing

ABSTRACT Time-kill synergy studies testing in vitro activity of DX-619 alone and with added vancomycin, teicoplanin, or linezolid against 101 Staphylococcus aureus strains showed synergy between DX-619 and teicoplanin at 12 to 24 h in 72 strains and between DX-619 and vancomycin in 28 strains. No synergy was found with linezolid, and no antagonism was observed with any combination.

scholarly journals Time-Kill and Synergism Studies of Ceftobiprole against Enterococcus faecalis, Including β-Lactamase-Producing and Vancomycin-Resistant Isolates

2007 ◽  
Vol 51 (6) ◽  
pp. 2043-2047 ◽  
Author(s):  
Cesar A. Arias ◽  
Kavindra V. Singh ◽  
Diana Panesso ◽  
Barbara E. Murray
Keyword(s):  
Enterococcus Faecalis ◽  
Vitro Activity ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
In Vitro Activity ◽  
Inoculum Concentration ◽  
High Inoculum ◽  
Vancomycin Resistant ◽  
Time Kill

ABSTRACT Ceftobiprole (BAL9141) is an investigational cephalosporin with broad in vitro activity against gram-positive cocci, including enterococci. Ceftobiprole MICs were determined for 93 isolates of Enterococcus faecalis (including 16 β-lactamase [Bla] producers and 17 vancomycin-resistant isolates) by an agar dilution method following the Clinical and Laboratory Standards Institute recommendations. Ceftobiprole MICs were also determined with a high inoculum concentration (107 CFU/ml) for a subset of five Bla producers belonging to different previously characterized clones by a broth dilution method. Time-kill and synergism studies (with either streptomycin or gentamicin) were performed with two β-lactamase-producing isolates (TX0630 and TX5070) and two vancomycin-resistant isolates (TX2484 [VanB] and TX2784 [VanA]). The MICs of ceftobiprole for 50 and 90% of the isolates tested were 0.25 and 1 μg/ml, respectively. All Bla producers and vancomycin-resistant isolates were inhibited by concentrations of ≤1 and ≤4 μg/ml, respectively, at the standard inoculum concentration. Ceftobiprole MICs at a high inoculum concentration for a subset of five Bla+ E. faecalis isolates were ≤1 μg/ml. Bactericidal activity was observed against four isolates tested at concentrations as low as 1 μg/ml regardless of the production of β-lactamase or vancomycin resistance. A combination of ceftobiprole (0.5 μg/ml) and streptomycin (25 μg/ml) was synergistic against Bla+ TX0630 and TX5070. Ceftobiprole (0.5 μg/ml) plus gentamicin (10 μg/ml) was synergistic against VanB isolate TX2484 and showed enhanced killing, but not synergism, against TX2784 (VanA), despite the absence of high-level resistance to gentamicin. In conclusion, ceftobiprole exhibited good in vitro activity against E. faecalis, including Bla+ and vancomycin-resistant strains, and exhibited synergism with aminoglycosides against selected isolates.

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