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

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.

Download Full-text

Novel Engineered Peptides of a Phage Lysin as Effective Antimicrobials against Multidrug-Resistant Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02972-15 ◽

2016 ◽

Vol 60 (5) ◽

pp. 2671-2679 ◽

Cited By ~ 52

Author(s):

Mya Thandar ◽

Rolf Lood ◽

Benjamin Y. Winer ◽

Douglas R. Deutsch ◽

Chad W. Euler ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Bacterial Pathogen ◽

Antibacterial Activities ◽

Polymyxin B ◽

Multidrug Resistant ◽

Gram Negative ◽

Content Type ◽

Human Red Blood Cells ◽

Phage Lysin

ABSTRACTAcinetobacter baumanniiis a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistantA. baumanniiclones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to killA. baumannii(>3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307SQ-8C(>5-log kill). Both P307 and P307SQ-8Cshowed highin vitroactivity againstA. baumanniiin biofilms. Moreover, P307SQ-8Cexhibited MICs comparable to those of levofloxacin and ceftazidime and acted synergistically with polymyxin B. Although the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model ofA. baumanniiskin infection, P307SQ-8Creduced the bacterial burden by ∼2 logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.

Download Full-text

In VitroPotential of Lycosin-I as an Alternative Antimicrobial Drug for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03279-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6999-7002 ◽

Cited By ~ 14

Author(s):

Ling Wang ◽

Yong-Jun Wang ◽

Yin-Yin Liu ◽

Hui Li ◽

Ling-Xia Guo ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Antibacterial Activities ◽

Multidrug Resistant ◽

Antimicrobial Drug ◽

High Salt ◽

Content Type ◽

Bactericidal Effects

ABSTRACTThe resistance of multidrug-resistantAcinetobacter baumannii(MDRAB) isolates to most traditional antibiotics results in huge challenges for infection therapy. We investigated thein vitroactivities of bothl- andd-lycosin-I against MDRAB. These two compounds displayed high antibacterial activities and rapid bactericidal effects against MDRAB. Moreover, the compounds retained their activity even at high salt (Mg2+or Ca2+) concentrations. These results demonstrate the potential of lycosin-I to be developed as a new antibiotic.

Download Full-text

In VitroActivities of Combinations of Rifampin with Other Antimicrobials against Multidrug-Resistant Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04089-14 ◽

2014 ◽

Vol 59 (3) ◽

pp. 1466-1471 ◽

Cited By ~ 12

Author(s):

Yan Bai ◽

Bin Liu ◽

Tianlin Wang ◽

Yun Cai ◽

Beibei Liang ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Inhibitory Concentration ◽

Multidrug Resistant ◽

Antimicrobial Treatment ◽

Clinical Isolates ◽

Content Type ◽

Synergistic Interactions ◽

Therapeutic Alternatives ◽

Concentration Indices

ABSTRACTThe antimicrobial treatment of multidrug-resistant (MDR)Acinetobacter baumanniiinfections has become a great challenge for medical staff all over the world. Increasing numbers of MDRA. baumanniiinfections have been identified and reported, but effective clinical treatments for them are decreasing. The objective of this study was to investigate thein vitroactivities of combinations of rifampin (an established antimicrobial) and other antimicrobials, including biapenem, colistin, and tigecycline, against 73 clinical isolates of MDRA. baumannii. In total, 73 clinical isolates of MDRA. baumanniiwere collected from two A-level general hospitals in Beijing, and the MICs of rifampin, biapenem, colistin, and tigecycline were determined. The checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs), that is, whether the combinations acted synergistically against these isolates. The MIC50, MIC90, and MICrangeof rifampin combined with biapenem, colistin, and tigecycline against the isolates were clearly lower than those for four antimicrobials (rifampin, biapenem, colistin, and tigecycline) that were used alone. Combinations of rifampin with biapenem, colistin, and tigecycline individually demonstrated the following interactions: synergistic interactions (FICI ≤ 0.5) for 31.51%, 34.25%, and 31.51% of the isolates, partially synergistic interactions (0.5 < FICI < 1) for 49.31%, 43.83%, and 47.94% of the isolates, and additive interactions (FICI = 1) for 19.18%, 21.92%, and 20.55% of the isolates, respectively. There were no indifferent (1 < FICI < 4) or antagonistic (FICI ≥ 4) interactions. Therefore, combinations of rifampin with biapenem, colistin, or tigecycline may be future therapeutic alternatives for the treatment of MDRA. baumanniiinfections.

Download Full-text

Novel Phage Lysin Capable of Killing the Multidrug-Resistant Gram-Negative Bacterium Acinetobacter baumannii in a Mouse Bacteremia Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04641-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 1983-1991 ◽

Cited By ~ 100

Author(s):

Rolf Lood ◽

Benjamin Y. Winer ◽

Adam J. Pelzek ◽

Roberto Diez-Martinez ◽

Mya Thandar ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Genomic Library ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Gram Negative ◽

Content Type ◽

Highly Active ◽

Genes Encoding

ABSTRACTAcinetobacter baumannii, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13A. baumanniistrains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killingA. baumannii. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all testedA. baumanniiclinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilmA. baumanniibothin vitroandin vivo. Finally, PlyF307 rescued mice from lethalA. baumanniibacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found inAcinetobacterphage.

Download Full-text

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)

Download Full-text

In VitroActivity of RX-P873 against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04840-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2280-2285 ◽

Cited By ~ 5

Author(s):

Robert K. Flamm ◽

Paul R. Rhomberg ◽

Ronald N. Jones ◽

David J. Farrell

Keyword(s):

Pseudomonas Aeruginosa ◽

Acinetobacter Baumannii ◽

Active Agent ◽

Multidrug Resistant ◽

Surveillance Program ◽

Gram Negative ◽

Content Type ◽

Highly Active ◽

Bacterial Ribosome

ABSTRACTRX-P873 is a novel antibiotic from the pyrrolocytosine series which exhibits high binding affinity for the bacterial ribosome and broad-spectrum antibiotic properties. The pyrrolocytosines have shownin vitroactivity against multidrug-resistant Gram-negative and Gram-positive strains of bacteria known to cause complicated urinary tract, skin, and lung infections, as well as sepsis.Enterobacteriaceae(657),Pseudomonas aeruginosa(200), andAcinetobacter baumannii(202) isolates from North America and Europe collected in 2012 as part of a worldwide surveillance program were testedin vitroby broth microdilution using Clinical and Laboratory Standards Institute (CLSI) methodology. RX-P873 (MIC90, 0.5 μg/ml) was >32-fold more active than ceftazidime and inhibited 97.1% and 99.5% ofEnterobacteriaceaeisolates at MIC values of ≤1 and ≤4 μg/ml, respectively. There were only three isolates with an MIC value of >4 μg/ml (all were indole-positiveProtea). RX-P873 (MIC50/90, 2/4 μg/ml) was highly active againstPseudomonas aeruginosaisolates, including isolates which were nonsusceptible to ceftazidime or meropenem. RX-P873 was 2-fold less active againstP. aeruginosathan tobramycin (MIC90, 2 μg/ml; 91.0% susceptible) and colistin (MIC90, 2 μg/ml; 99.5% susceptible) and 2-fold more potent than amikacin (MIC90, 8 μg/ml; 93.5% susceptible) and meropenem (MIC90, 8 μg/ml; 76.0% susceptible). RX-P873, the most active agent againstAcinetobacter baumannii(MIC90, 1 μg/ml), was 2-fold more active than colistin (MIC90, 2 μg/ml; 97.0% susceptible) and 4-fold more active than tigecycline (MIC90, 4 μg/ml). This novel agent merits further exploration of its potential against multidrug-resistant Gram-negative bacteria.

Download Full-text

In VitroActivity of AZD5847 against Geographically Diverse Clinical Isolates of Mycobacterium tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02718-14 ◽

2014 ◽

Vol 58 (7) ◽

pp. 4222-4223 ◽

Cited By ~ 7

Author(s):

Jim Werngren ◽

Maria Wijkander ◽

Nasrin Perskvist ◽

V. Balasubramanian ◽

Vasan K. Sambandamurthy ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Lavage Fluid ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Cross Resistance ◽

Drug Candidate ◽

Content Type ◽

Geographical Regions ◽

Lung Biopsies

ABSTRACTThe MIC of the novel antituberculosis (anti-TB) drug AZD5847 was determined against 146 clinical isolates from diverse geographical regions, including eastern Europe, North America, Africa, and Asia, using the automated Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system. These isolates originated from specimen sources such as sputum, bronchial alveolar lavage fluid, pleural fluid, abscess material, lung biopsies, and feces. The overall MIC90was 1.0 mg/liter (range, 0.125 to 4 mg/liter). The MICs of AZD5847 for isolates ofMycobacterium tuberculosiswere similar among drug-sensitive strains, multidrug-resistant (MDR) strains, and extensively drug resistant (XDR) strains. The goodin vitroactivity of AZD5847 againstM. tuberculosisand the lack of cross-resistance make this agent a promising anti-TB drug candidate.

Download Full-text

Draft Genome Sequences of Clinical Isolates of Multidrug-Resistant Acinetobacter baumannii

Genome Announcements ◽

10.1128/genomea.01547-16 ◽

2017 ◽

Vol 5 (5) ◽

Author(s):

Keesha E. Erickson ◽

Nancy E. Madinger ◽

Anushree Chatterjee

Keyword(s):

Acinetobacter Baumannii ◽

Resistance Genes ◽

Draft Genome ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Genome Sequences ◽

Content Type ◽

University Of Colorado ◽

The University

ABSTRACT We report here the draft genome sequences of two clinically isolated Acinetobacter baumannii strains. These samples were obtained from patients at the University of Colorado Hospital in 2007 and 2013 and encode an estimated 20 and 13 resistance genes, respectively.

Download Full-text

In vitro activity of colistin against multidrug-resistant Acinetobacter baumannii isolates harboring blaOXA-23-like and blaOXA-24-like genes: A multicenter based study

Acta Microbiologica et Immunologica Hungarica ◽

10.1556/030.2020.01031 ◽

2020 ◽

Vol 67 (3) ◽

pp. 182-186

Author(s):

Susan Khanjani ◽

Hadi Sedigh Ebrahim-Saraie ◽

Mohammad Shenagari ◽

Ali Ashraf ◽

Ali Mojtahedi ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Carbapenem Resistance ◽

Multidrug Resistant ◽

Resistance Rate ◽

Clinical Isolates ◽

Clinical Samples ◽

Cross Sectional ◽

The North ◽

North Of Iran

AbstractThis study was aimed to evaluate occurrence of antibiotic resistance and the presence of resistance determinants among clinical isolates of Acinetobacter baumannii. This cross-sectional study from January to September 2018 was performed on 59 A. baumannii strains isolated from clinical samples in the north of Iran. Isolates were identified by standard microbiologic tests and molecular method. Antimicrobial susceptibility testing was carried out by disk diffusion and broth microdilution methods. The presence of carbapenem resistance genes was detected by PCR method. All isolates were resistant to cefepime, meropenem, imipenem and ceftazidime. The lowest resistance rate was observed against doxycycline with 33.9%. Minimum inhibitory concentration (MIC) results showed that all carbapenem-resistant A. baumannii (CRAB) isolates were susceptible to colistin with MIC50 and MIC90 values of 1/2 µg/mL. Among 59 CRAB, blaOXA-23-like was the most prevalent gene (86.4%) followed by blaOXA-24-like (69.5%). Meanwhile, none of the clinical isolates harbored blaOXA-58-like gene. We found a high prevalence of CRAB strains harboring OXA-type carbapenemases in the north of Iran. Our results suggests that the presence of OXA-type genes was not directly correlated with the increase of imipenem MIC level, but can be clinically important as they contribute to the selection of CRAB strains.

Download Full-text