scholarly journals Minocycline alone and in combination with polymyxin B, meropenem, and sulbactam against carbapenem- susceptible and resistant Acinetobacter baumannii in in vitro pharmacodynamic model

2020 ◽  
pp. AAC.01680-20
Author(s):  
Maya Beganovic ◽  
Kathryn E. Daffinee ◽  
Megan K. Luther ◽  
Kerry L. LaPlante
Keyword(s):  
Continuous Infusion ◽  
Acinetobacter Baumannii ◽  
Triple Therapy ◽  
Bactericidal Activity ◽  
Polymyxin B ◽  
Pharmacodynamic Model ◽  
High Dose ◽  
Resistance Development ◽  
Carbapenem Resistant

Acinetobacter baumannii is recognized as an urgent public health threat by the Centers for Disease Control and Prevention (CDC). Current treatment options are scarce, particularly against carbapenem-resistant Acinetobacter baumannii (CRAB). We simulated the impact of minocycline standard (200mg load+100mg Q12h) and high-dose (700mg load+ 350mg Q12h), polymyxin B (2.5mg/kg Q12h), sulbactam (1g Q6h and 9g/24h as continuous infusion) and meropenem (intermittent 1 or 2g Q8h and 6g/24h as continuous infusion) alone or in combination against CRAB and non-CRAB isolates by simulating human therapeutic dosing regimens in a 72-hour, in vitro pharmacodynamic model (IVPD). There were no monotherapy regimens that demonstrated bactericidal activity against the tested non-CRAB and CRAB. Resistance development was common in monotherapy regimens. Against the CRAB isolate, the triple combination of high-dose minocycline (fAUC/MIC 21.21), polymyxin B (fAUC/MIC 15.63), and continuous infusion sulbactam (67% T>MIC) was the most consistently active regimen. Against non-CRAB, the triple therapy regimen of high-dose minocycline (fAUC/MIC 84.84) with continuous infusion meropenem (100%T>MIC) and continuous infusion sulbactam (83%T>MIC), as well as the double therapy of high-dose minocycline (AUC/MIC 84.84) with continuous infusion meropenem (100%T>MIC) resulted persistently bactericidal activity. In conclusion, triple therapy with high dose minocycline, continuous infusion sulbactam, and polymyxin B produced the most significant kill against the carbapenem-resistant Acinetobacter baumannii, with no regrowth and minimal resistance development.

scholarly journals Activity of Colistin against Heteroresistant Acinetobacter baumannii and Emergence of Resistance in an In Vitro Pharmacokinetic/Pharmacodynamic Model

2007 ◽  
Vol 51 (9) ◽  
pp. 3413-3415 ◽  
Author(s):  
Chun-Hong Tan ◽  
Jian Li ◽  
Roger L. Nation
Keyword(s):  
Continuous Infusion ◽  
Acinetobacter Baumannii ◽  
Population Analysis ◽  
Growth Control ◽  
Pharmacodynamic Model ◽  
Bacterial Density ◽  
Control Population ◽  
Emergence Of Resistance

ABSTRACT Three clinically relevant intermittent regimens, and a continuous infusion, of colistin were simulated in an in vitro pharmacokinetic/pharmacodynamic model against two colistin-heteroresistant strains of Acinetobacter baumannii. Extensive initial killing was followed by regrowth as early as 6 h later; bacterial density in the 24- to 72-h period was within 1 log10 CFU/ml of growth control. Population analysis profiles revealed extensive emergence of resistant subpopulations regardless of the colistin regimen.

scholarly journals Evaluation of Standard- and High-Dose Daptomycin versus Linezolid against Vancomycin-Resistant Enterococcus Isolates in anIn VitroPharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations

2012 ◽  
Vol 56 (6) ◽  
pp. 3174-3180 ◽  
Author(s):  
Ashley D. Hall ◽  
Molly E. Steed ◽  
Cesar A. Arias ◽  
Barbara E. Murray ◽  
Michael J. Rybak
Keyword(s):  
Bactericidal Activity ◽  
Optimal Dose ◽  
Pharmacodynamic Model ◽  
Colony Count ◽  
High Dose ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Sustained Reduction ◽  
Vancomycin Resistant

ABSTRACTDaptomycin MICs for enterococci are typically 1- to 2-fold higher than those forStaphylococcus aureus, and there is an imminent need to establish the optimal dose for appropriate treatment of enterococcal infections. We investigated the bactericidal activity of daptomycin at various dose exposures compared to that of linezolid against vancomycin-resistant enterococcus (VRE) in anin vitropharmacokinetic/pharmacodynamic model utilizing simulated endocardial vegetations over 96 h. Daptomycin at doses of 6, 8, 10, and 12 mg/kg of body weight/day and linezolid at a dose of 600 mg every 12 h were evaluated against two clinical vancomycin-resistantEnterococcus faeciumstrains (EFm11499 and 09-184D1051), one of which was linezolid resistant (09-184D1051), and one clinical vancomycin-resistantEnterococcus faecalisstrain (EFs11496). Daptomycin MICs were 4, 2, and 0.5 μg/ml for EFm11499, 09-184D1051, and EFs11496, respectively. Bactericidal activity, defined as a ≥3 log10CFU/g reduction from the initial colony count, was demonstrated against all three isolates with all doses of daptomycin; however, bactericidal activity was not sustained with the daptomycin 6- and 8-mg/kg/day regimens. Linezolid was bacteriostatic against EFm11499 and displayed no appreciable activity against 09-184D1051 or EFs11496. Concentration-dependent killing was displayed with more sustained reduction in colony count (3.58 to 6.46 and 5.89 to 6.56 log10CFU/g) at 96 h for the simulated regimen of daptomycin at doses of 10 and 12 mg/kg/day, respectively (P≤ 0.012). NoE. faeciummutants with reduced susceptibility were recovered at any dosage regimen; however, theE. faecalisstrain developed reduced daptomycin susceptibility with daptomycin at 6, 8, and 10 but not at 12 mg/kg/day. Daptomycin displayed a dose-dependent response against three VRE isolates, with high-dose daptomycin producing sustained bactericidal activity. Further research is warranted.

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 Short-Course Gentamicin in Combination with Daptomycin or Vancomycin against Staphylococcus aureus in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

2005 ◽  
Vol 49 (7) ◽  
pp. 2735-2745 ◽  
Author(s):  
Brian T. Tsuji ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Pharmacodynamic Model ◽  
High Dose ◽  
Single High Dose ◽  
Short Course ◽  
Dosing Regimens ◽  
Combination Regimens ◽  
The Impact

ABSTRACT The ability to maximize bactericidal activity while minimizing toxicity is a therapeutic goal in the treatment of infective endocarditis. We evaluated the impact of administering short-course regimens of gentamicin in combination with daptomycin or vancomycin against one methicillin-susceptible (MSSA 1199) and one methicillin-resistant (MRSA 494) Staphylococcus aureus isolate using an in vitro pharmacodynamic model with simulated endocardial vegetations over 96 h. Human therapeutic dosing regimens for daptomycin (6 and 8 mg/kg of body weight), vancomycin, and gentamicin were simulated. Short-course combination regimens involving gentamicin were administered either as a single 5-mg/kg dose or three 1-mg/kg doses for only the first 24 h and compared to the regimens administered for the full 96-h duration. For all experiments, physiologic conditions of albumin, calcium, and pH were simulated. Both regimens of daptomycin achieved 99.9% kill by 32 h and maintained bactericidal activity against both isolates, which was significantly different from vancomycin, which displayed bacteriostatic activity (P < 0.05). The effects of all short-course regimens of gentamicin were equal to those of the full-duration regimens in combination with daptomycin. Adding three doses of gentamicin (1 mg/kg) to daptomycin resulted in enhancement and bactericidal activity at 24 h against both MRSA and MSSA. The addition of a single dose of gentamicin (5 mg/kg) enhanced or improved the activity of daptomycin and resulted in early bactericidal activity at 4 h against both isolates. The addition of three doses of gentamicin (1 mg/kg) did not improve the activity of vancomycin. However, the addition of a single 5-mg/kg dose of gentamicin to vancomycin resulted in early enhancement at 4 h and 99.9% kill at 32 h for MRSA. These results suggest that a single high dose of gentamicin in combination with daptomycin or vancomycin may be of utility to maximize synergistic and bactericidal activity and minimize toxicity. Further investigation is warranted.

scholarly journals In vitro and in vivo Activity of Combinations of Polymyxin B with Other Antimicrobials Against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol Volume 14 ◽  
pp. 4657-4666
Author(s):  
Hui Zhang ◽  
Yunzhu Zhu ◽  
Ning Yang ◽  
Qinxiang Kong ◽  
Yahong Zheng ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Polymyxin B ◽  
Carbapenem Resistant

scholarly journals In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types

2021 ◽  
Vol 12 ◽  
Author(s):  
Jocelyn Qi-Min Teo ◽  
Nazira Fauzi ◽  
Jayden Jun-Yuan Ho ◽  
Si Hui Tan ◽  
Shannon Jing-Yi Lee ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Carbapenem Resistance ◽  
Polymyxin B ◽  
Apparent Difference ◽  
Initial Inoculum ◽  
Carbapenem Resistant ◽  
Limited Effectiveness ◽  
Sequence Types

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is becoming increasingly problematic due to the limited effectiveness of new antimicrobials or other factors such as treatment cost. Thus, combination therapy remains a suitable treatment option. We aimed to evaluate the in vitro bactericidal activity of various antibiotic combinations against CRKP with different carbapenemase genotypes and sequence types (STs). Thirty-seven CRKP with various STs and carbapenemases were exposed to 11 antibiotic combinations (polymyxin B or tigecycline in combination with β-lactams including aztreonam, cefepime, piperacillin/tazobactam, doripenem, meropenem, and polymyxin B with tigecycline) in static time-kill studies (TKS) using clinically achievable concentrations. Out of the 407 isolate-combination pairs, only 146 (35.8%) were bactericidal (≥3 log10CFU/mL decrease from initial inoculum). Polymyxin B in combination with doripenem, meropenem, or cefepime was the most active, each demonstrating bactericidal activity in 27, 24, and 24 out of 37 isolates, respectively. Tigecycline in combination with β-lactams was rarely bactericidal. Aside from the lower frequency of bactericidal activity in the dual-carbapenemase producers, there was no apparent difference in combination activity among the strains with other carbapenemase types. In addition, bactericidal combinations were varied even in strains with similar STs, carbapenemases, and other genomic characteristics. Our findings demonstrate that the bactericidal activity of antibiotic combinations is highly strain-specific likely owing to the complex interplay of carbapenem-resistance mechanisms, i.e., carbapenemase genotype alone cannot predict in vitro bactericidal activity. The availability of WGS information can help rationalize the activity of certain combinations. Further studies should explore the use of genomic markers with phenotypic information to predict combination activity.

scholarly journals In vitro and in vivo Activity of Combinations of Polymyxin B with Other Antimicrobials Against Carbapenem-Resistant Acinetobacter baumannii [Corrigendum]

2021 ◽  
Vol Volume 14 ◽  
pp. 5679-5680
Author(s):  
Hui Zhang ◽  
Yunzhu Zhu ◽  
Ning Yang ◽  
Qinxiang Kong ◽  
Yahong Zheng ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Polymyxin B ◽  
Carbapenem Resistant

scholarly journals In-Vitro Activity of Polymyxin B, Rifampicin, Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii in Singapore

PLoS ONE ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. e18485 ◽  
Author(s):  
Tze-Peng Lim ◽  
Thean-Yen Tan ◽  
Winnie Lee ◽  
S. Sasikala ◽  
Thuan-Tong Tan ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Polymyxin B ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Carbapenem Resistant
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