scholarly journals 1542. The Evaluation of the In Vitro Synergy of Colistin in Combination with Meropenem and Tigecycline against 50 Multi-Drug-resistant Acinetobacter baumannii strains

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S562-S563
Author(s):  
Jacinda Abdul-Mutakabbir ◽  
Juwom Yim ◽  
Logan Nguyen ◽  
Razieh Kebriaei ◽  
Kyle Stamper ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
Single Agent ◽  
Resistance Mechanisms ◽  
Drug Resistant ◽  
Initial Inoculum ◽  
Log Reduction ◽  
Carbapenem Resistant ◽  
Time Kill

Abstract Background Acinetobacter baumannii possess inherent and acquired antibiotic resistance mechanisms that have rendered most antibiotics, including carbapenems, inactive. Colistin (COL) has risen as salvage therapy against these organisms due to its retained activity against A. baumannii. However, COL monotherapy is often met with suboptimal outcomes. Recently, combination therapy with COL and meropenem (MEM) or tigecycline (TGC) has been shown to be effective in eradicating multi-drug-resistant A. baumannii infections. The objective of this study was to further evaluate the efficacy of COL in combination with MEM or TGC against 50 multi-drug-resistant A. baumannii strains. Methods Fifty carbapenem-resistant A. baumannii strains were evaluated using combination minimum inhibitory concentration (MIC) testing and time-kill analysis (TKA). Single-drug MIC testing was performed for each strain by broth microdilution. Combination MIC testing was performed for COL+MEM and COL+TGC. Each strain was evaluated via 24-hour TKA to assess the synergistic capabilities of COL+MEM, and COL+TGC. Synergy was defined as a ≥ 2-log reduction CFU/mL in either combination from the most active single agent, while bactericidal activity was defined as a ≥ 3-log reduction CFU/mL of either combination from the initial inoculum. Results All 50 strains were resistant to MEM and TGC with MICs ≥ 64 µg/mL and ≥ 4 µg/mL respectively; while 3 strains were resistant to COL, MICs ≥ 2 µg/mL. MEM and TGC MIC values were reduced as much as 128-fold (median 2-fold) and 32-fold (median 2-fold),, respectively, in the presence of subinhibitory COL. COL MIC values were reduced as much as 512-fold (median 4-fold) from baseline in the presence of subinhibitory MEM, and as high as 16-fold (median 2-fold) in the presence of TGC. In TKAs, COL+MEM was synergistic in 45/50 (90%) strains and bactericidal against 43/50 (86%) strains. COL+TGC TKAs revealed synergy in 32/50 (64%) strains, and bactericidal activity against 28/50 (56%) strains. Conclusion The combinations of COL+MEM and COL+TGC demonstrate promise in combating highly resistant A. baumannii. Further research is mandated to explore other combinations that are capable of eradicating multi-drug-resistant A. baumannii. Disclosures All authors: No reported disclosures.

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 Correlation of Checkerboard Synergy Testing with Time-Kill Analysis and Clinical Outcomes of Extensively Drug-Resistant Acinetobacter baumannii Respiratory Infections

2016 ◽  
Vol 60 (11) ◽  
pp. 6892-6895 ◽  
Author(s):  
Derek N. Bremmer ◽  
Karri A. Bauer ◽  
Stephanie M. Pouch ◽  
Keelie Thomas ◽  
Debra Smith ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Clinical Outcomes ◽  
Clinical Utility ◽  
Respiratory Infections ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Time Kill ◽  
Synergy Testing

ABSTRACTWe tested 76 extensively drug-resistant (XDR)Acinetobacter baumanniiisolates by the checkerboard method using only wells containing serum-achievable concentrations (SACs) of drugs. Checkerboard results were correlated by time-kill assay and clinical outcomes. Minocycline-colistin was the best combinationin vitro, as it inhibited growth in one or more SAC wells in all isolates. Patients who received a combination that inhibited growth in one or more SAC wells demonstrated better microbiological clearance than those who did not (88% versus 30%;P= 0.025). The checkerboard platform may have clinical utility for XDRA. baumanniiinfections.

In vitro synergy of ceftolozane/tazobactam in combination with fosfomycin or aztreonam against MDR Pseudomonas aeruginosa

2020 ◽  
Vol 75 (7) ◽  
pp. 1874-1878 ◽  
Author(s):  
Gabriel T Cuba ◽  
Gerlan Rocha-Santos ◽  
Rodrigo Cayô ◽  
Ana Paula Streling ◽  
Carolina S Nodari ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Resistance Mechanisms ◽  
Density Reduction ◽  
Carbapenem Resistant ◽  
Gradient Diffusion ◽  
Fold Reduction ◽  
The Face ◽  
Antimicrobial Synergy ◽  
Time Kill

Abstract Objectives Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-β-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA. Methods MICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n = 13), blaIMP (n = 4), blaVIM (n = 3), blaGES-1 (n = 2) and blaCTX-M-like (n = 2), and 3 isolates with no acquired β-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time–kill analysis (TKA). Results All CR-PSA isolates harbouring blaSPM-1, blaGES-1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed. Conclusions In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.

scholarly journals Activity of Tigecycline (GAR-936) against Acinetobacter baumannii Strains, Including Those Resistant to Imipenem

2004 ◽  
Vol 48 (11) ◽  
pp. 4479-4481 ◽  
Author(s):  
María Eugenia Pachón-Ibáñez ◽  
Manuel Enrique Jiménez-Mejías ◽  
Cristina Pichardo ◽  
Ana Cristina Llanos ◽  
Jerónimo Pachón
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
Bacteriostatic Activity ◽  
Time Kill

ABSTRACT We determined the in vitro activities of tigecycline and imipenem against 49 isolates of Acinetobacter baumannii, including those resistant to imipenem. The MIC at which 50% of the isolates were inhibited (MIC50) and the MIC90 for tigecycline and imipenem were 2 and 2 mg/liter and 32 and 128 mg/liter, respectively, with 92 and 20%, respectively, of the strains being susceptible. Tigecycline did not show bactericidal activity in the time-kill studies (n = 9 strains). Imipenem showed bactericidal activity against seven out of nine strains. These in vitro results show that tigecycline has good in vitro bacteriostatic activity against A. baumannii, including strains resistant to imipenem.

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 In Vitro Activities of Colistin and Sitafloxacin Combinations against Multidrug-, Carbapenem-, and Colistin-Resistant Acinetobacter baumannii Using the Broth Microdilution Checkerboard and Time-Kill Methods

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 516
Author(s):  
Vipavee Rodjun ◽  
Jantana Houngsaitong ◽  
Preecha Montakantikul ◽  
Taniya Paiboonvong ◽  
Piyatip Khuntayaporn ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Clinical Studies ◽  
Tertiary Care ◽  
Resistant Isolate ◽  
Drug Resistant ◽  
Broth Microdilution ◽  
Time Kill ◽  
Tertiary Care Hospitals

Drug-resistant Acinetobacter baumannii (A. baumannii) infections are a critical global problem, with limited treatment choices. This study aims to determine the in vitro activities of colistin–sitafloxacin combinations against multidrug-, carbapenem- and colistin-resistant A. baumannii (MDR-AB, CRAB, CoR-AB, respectively) clinical isolates from tertiary care hospitals. We used the broth microdilution checkerboard and time-kill methods in this study. Synergy was found using both methods. The colistin–sitafloxacin combination showed synergy in MDR-AB, CRAB, and CoR-AB isolates (3.4%, 3.1%, and 20.9%, respectively). No antagonism was found in any type of drug-resistant isolate. The majority of CoR-AB isolates became susceptible to colistin (95.4%). The time-kill method also showed that this combination could suppress regrowth back to the initial inocula of all representative isolates. Our results demonstrated that the colistin–sitafloxacin combination might be an interesting option for the treatment of drug-resistant A. baumannii. However, further in vivo and clinical studies are required.

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 In VitroAntibiotic Synergy in Extensively Drug-ResistantAcinetobacter baumannii: the Effect of Testing by Time-Kill, Checkerboard, and Etest Methods

2010 ◽  
Vol 55 (1) ◽  
pp. 436-438 ◽  
Author(s):  
Thean Yen Tan ◽  
Tze Peng Lim ◽  
Winnie Hui Ling Lee ◽  
Suranthran Sasikala ◽  
Li Yang Hsu ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Polymyxin B ◽  
Drug Resistant ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Time Kill

ABSTRACTThis study examined thein vitroeffects of polymyxin B, tigecycline, and rifampin combinations on 16 isolates of extensively drug-resistantAcinetobacter baumannii, including four polymyxin-resistant strains.In vitrosynergy was demonstrated in 19 (40%) of a possible 48 isolate-antibiotic combinations by time-kill methods, 8 (17%) by checkerboard methods, and only 1 (2%) by Etest methods. There was only slight agreement between Etest and checkerboard methods and no agreement between results obtained by other methods.

scholarly journals In VitroandIn VivoActivities of E-101 Solution against Acinetobacter baumannii Isolates from U.S. Military Personnel

2011 ◽  
Vol 55 (7) ◽  
pp. 3603-3608 ◽  
Author(s):  
G. A. Denys ◽  
J. C. Davis ◽  
P. D. O'Hanley ◽  
J. T. Stephens
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
Military Personnel ◽  
Multidrug Resistant ◽  
Full Thickness ◽  
Content Type ◽  
Full Thickness Excision ◽  
Time Kill

ABSTRACTWe evaluated thein vitroandin vivoactivity of a novel topical myeloperoxidase-mediated antimicrobial, E-101 solution, against 5 multidrug-resistantAcinetobacter baumanniiisolates recovered from wounded American soldiers. Time-kill studies demonstrated rapid bactericidal activity against allA. baumanniistrains tested in the presence of 3% blood. Thein vitrobactericidal activity of E-101 solution againstA. baumanniistrains was confirmed in a full-thickness excision rat model. Additionalin vivostudies appear warranted.

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.

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