Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii

ABSTRACTCarbapenem-resistantAcinetobacter baumanniiis increasing in prevalence. Polymyxin B and tigecycline are among the most active antibiotics used against this pathogenin vitro. Pastin vitrostudies, however, neglected the importance of simulating exposures observed in humans to determine their antibacterial effects. In this study, four carbapenem-resistantA. baumanniiisolates were evaluated using anin vitropharmacodynamic model. Free-drug exposures using 1 mg/kg of body weight of polymyxin B every 12 h (q12h), 100 and 200 mg tigecycline q12h, and the combination of these regimens were simulated. The microbiological responses to these treatments were measured by the change in log10CFU/ml over 24 h and the area under the bacterial killing and regrowth curve (AUBC). Resistance was assessed by a population analysis profile (PAP) conducted after 24 h of treatment. Polymyxin B achieved a reduction on the order of −2.05 ± 0.68 log10CFU/ml against theseA. baumanniiisolates, while all isolates grew to control levels with tigecycline monotherapy. Combination therapy with polymyxin B plus 200 mg tigecycline q12h achieved a greater reduction in bacterial density than did therapy with polymyxin B alone (−3.31 ± 0.71 versus −2.05 ± 0.68 log10CFU/ml,P< 0.001) but not significantly different than combination therapy with 100 mg tigecycline q12h (−2.45 ± 1.00 log10CFU/ml,P= 0.370). Likewise, combination therapy with polymyxin B plus 200 mg tigecycline q12h significantly reduced the AUBC compared to that with polymyxin B alone (62.8 ± 8.9 versus 79.4 ± 10.5 log10CFU/ml,P< 0.05). No changes in the PAP from baseline were observed for either antibiotic alone. In this study, combination therapy with simulated exposures of polymyxin B and tigecycline at an aggressive dose of 200 mg q12h produced synergistic or additive effects on humans against these multidrug-resistantA. baumanniistrains.

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Effectiveness of carbapenems in combination therapy with fosfomycin on multidrug-resistant Acinetobacter baumannii

10.26226/morressier.56d6be74d462b80296c97560 ◽

2016 ◽

Author(s):

Mullika Chomnawang

Keyword(s):

Combination Therapy ◽

Acinetobacter Baumannii ◽

Multidrug Resistant

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1293. Sulbactam-durlobactam is active against recent, multi-drug resistant Acinetobacter baumannii clinical isolates from the Middle East

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1476 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S662-S662

Author(s):

Alita Miller ◽

Sarah McLeod ◽

Samir Moussa ◽

Meredith Hackel

Keyword(s):

Antibacterial Activity ◽

Middle East ◽

Acinetobacter Baumannii ◽

United Arab Emirates ◽

Blood Stream ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Surveillance Systems ◽

Spectrum Activity

Abstract Background The incidence of infections caused by multidrug-resistant (MDR) Acinetobacter baumannii (Ab) is increasing at an alarming rate in certain regions of the world, including the Middle East. Sulbactam (SUL) has intrinsic antibacterial activity against Ab; however, the prevalence of β-lactamases in Ab has limited its therapeutic utility. Durlobactam (DUR, formerly ETX2514) is a diazabicyclooctenone β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases that restores SUL activity in vitro against MDR Ab. SUL-DUR is an antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug-resistant strains, that is currently in Phase 3 clinical development. In global surveillance studies of >3600 isolates from 2012-2017, the MIC90 of SUL-DUR was 2 mg/L. Although surveillance systems to monitor MDR infections in the Middle East are currently being established, quantitative, prevalence-based data are not yet available. Therefore, the potency of SUL-DUR was determined against 190 recent, diverse Ab clinical isolates from this region. Methods 190 Ab isolates were collected between 2016 - 2018 from medical centers located in Israel (N = 47), Jordan (N = 36), Qatar (N = 13), Kuwait (N = 42), Lebanon (N = 8), Saudi Arabia (N = 24) and United Arab Emirates (N = 20). Seventy-five percent and 20.5% of these isolates were from respiratory and blood stream infections, respectively. Susceptibility to SUL-DUR and comparator agents was performed according to CLSI guidelines, and data analysis was performed using CLSI and EUCAST breakpoint criteria where available. Results This collection of isolates was 86% carbapenem-resistant and 90% sulbactam-resistant (based on a breakpoint of 4 mg/L). The addition of SUL-DUR (fixed at 4 mg/L) decreased the sulbactam MIC90 from 64 mg/L to 4 mg/L. Only 3 isolates (1.6%) had SUL-DUR MIC values of > 4 mg/L. This potency was consistent across countries, sources of infection and subsets of resistance phenotypes. Conclusion SUL-DUR demonstrated potent antibacterial activity against recent clinical isolates of Ab from the Middle East, including MDR isolates. These data support the global development of SUL-DUR for the treatment of MDR Ab infections. Disclosures Alita Miller, PhD, Entasis Therapeutics (Employee) Sarah McLeod, PhD, Entasis Therapeutics (Employee) Samir Moussa, PhD, Entasis Therapeutics (Employee)

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Analysis of Antimicrobial and Antibiofilm Activity of Human Milk Lactoferrin Compared to Bovine Lactoferrin against Multidrug Resistant and Susceptible Acinetobacter baumannii Clinical Isolates

ACS Infectious Diseases ◽

10.1021/acsinfecdis.1c00087 ◽

2021 ◽

Author(s):

Tyra M. Avery ◽

RaNashia L. Boone ◽

Jacky Lu ◽

Sabrina K. Spicer ◽

Miriam A. Guevara ◽

...

Keyword(s):

Human Milk ◽

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Antibiofilm Activity ◽

Bovine Lactoferrin

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Comparative metabolomics reveals key pathways associated with the synergistic activity of polymyxin B and rifampicin combination against multidrug-resistant Acinetobacter baumannii

Biochemical Pharmacology ◽

10.1016/j.bcp.2020.114400 ◽

2021 ◽

Vol 184 ◽

pp. 114400

Author(s):

Jinxin Zhao ◽

Mei-Ling Han ◽

Yan Zhu ◽

Yu-Wei Lin ◽

Yi-Wen Wang ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Polymyxin B ◽

Multidrug Resistant ◽

Synergistic Activity ◽

Comparative Metabolomics ◽

Key Pathways

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Genetic Basis of Multidrug-resistant Acinetobacter baumannii Clinical Isolates from Three University Hospitals in Chungcheong Province, Korea

Annals of Laboratory Medicine ◽

10.3343/kjlm.2010.30.5.498 ◽

2010 ◽

Vol 30 (5) ◽

pp. 498-506 ◽

Cited By ~ 16

Author(s):

Sun Hoe Koo ◽

Kye Chul Kwon ◽

Hye Hyun Cho ◽

Ji Youn Sung

Keyword(s):

Acinetobacter Baumannii ◽

Genetic Basis ◽

Multidrug Resistant ◽

Clinical Isolates ◽

University Hospitals

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Antibacterial activity of exogenous glutathione and its synergism on antibiotics sensitize carbapenem-associated multidrug resistant clinical isolates of Acinetobacter baumannii

International Journal of Medical Microbiology ◽

10.1016/j.ijmm.2017.07.009 ◽

2017 ◽

Vol 307 (7) ◽

pp. 409-414 ◽

Cited By ~ 2

Author(s):

Roaa Alharbe ◽

Ayidh Almansour ◽

Dong H. Kwon

Keyword(s):

Antibacterial Activity ◽

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Clinical Isolates

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In Vitro Activity of Sulbactam-Durlobactam against Acinetobacter baumannii-calcoaceticus Complex Isolates Collected Globally in 2016 and 2017

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02534-19 ◽

2020 ◽

Vol 64 (4) ◽

Cited By ~ 4

Author(s):

Sarah M. McLeod ◽

Samir H. Moussa ◽

Meredith A. Hackel ◽

Alita A. Miller

Keyword(s):

Acinetobacter Baumannii ◽

Antibacterial Activities ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Single Amino Acid ◽

Content Type ◽

Level Of Activity ◽

Severe Infections ◽

Sources Of Infection

ABSTRACT Acinetobacter baumannii-calcoaceticus complex (ABC) organisms cause severe infections that are difficult to treat due to preexisting antibiotic resistance. Sulbactam-durlobactam (formerly sulbactam-ETX2514) (SUL-DUR) is a β-lactam–β-lactamase inhibitor combination antibiotic designed to treat serious infections caused by ABC organisms, including multidrug-resistant (MDR) strains. The in vitro antibacterial activities of SUL-DUR and comparator agents were determined by broth microdilution against 1,722 clinical isolates of ABC organisms collected in 2016 and 2017 from 31 countries across Asia/South Pacific, Europe, Latin America, the Middle East, and North America. Over 50% of these isolates were resistant to carbapenems. Against this collection of global isolates, SUL-DUR had a MIC50/MIC90 of 1/2 μg/ml compared to a MIC50/MIC90 of 8/64 μg/ml for sulbactam alone. This level of activity was found to be consistent across organisms, regions, sources of infection, and subsets of resistance phenotypes, including MDR and extensively drug-resistant isolates. The SUL-DUR activity was superior to those of the tested comparators, with only colistin having similar potency. Whole-genome sequencing of the 39 isolates (2.3%) with a SUL-DUR MIC of >4 μg/ml revealed that these strains encoded either the metallo-β-lactamase NDM-1, which durlobactam does not inhibit, or single amino acid substitutions near the active site of penicillin binding protein 3 (PBP3), the primary target of sulbactam. In summary, SUL-DUR demonstrated potent antibacterial activity against recent, geographically diverse clinical isolates of ABC organisms, including MDR isolates.

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