Burkholderia pseudomallei clinical isolates are highly susceptible in vitro to cefiderocol, a siderophore cephalosporin

Cefiderocol is a cephalosporin designed to treat multidrug resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater in vitro activity against many Gram-negative bacilli than currently used carbapenems, β-lactam/β-lactamase inhibitor combinations, and cephalosporins. Thus, we investigated the in vitro activity of cefiderocol against a total of 246 clinical isolates of Burkholderia pseudomallei from Queensland, Australia. The collection was comprised primarily of bloodstream (56.1%), skin and soft tissue (16.3%) and respiratory isolates (15.9%). Minimum inhibitory concentrations (MIC) of cefiderocol ranged from ≤0.03 to 16 mg/L, where the MIC90 was 0.125 mg/L. Based upon CLSI clinical breakpoints for cefiderocol against Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia, three isolates (1.2%) would be classified as non-susceptible (MIC >4 mg/L). Using EUCAST non-species specific (PK/PD) clinical breakpoints, or those set for Pseudomonas aeruginosa, four isolates (1.6%) would be resistant (MIC >2 mg/L). Further testing for co-resistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline was performed on the four isolates with elevated cefiderocol MICs (>2 mg/L), all isolates exhibited resistance to amoxicillin-clavulanic acid, while three isolates also displayed resistance to at least one other antimicrobial. Cefiderocol was found to be highly active in vitro against B. pseudomallei primary clinical isolates. This compound shows great potential for the treatment of melioidosis in endemic countries and should be explored further.

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Burkholderia pseudomallei clinical isolates are highly susceptible in vitro to cefiderocol, a novel siderophore cephalosporin

10.1101/2020.03.26.009134 ◽

2020 ◽

Author(s):

Delaney Burnard ◽

Gemma Robertson ◽

Andrew Henderson ◽

Caitlin Falconer ◽

Michelle Bauer-Leo ◽

...

Keyword(s):

Burkholderia Pseudomallei ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Transport Systems ◽

Gram Negative ◽

Highly Active ◽

Amoxicillin Clavulanate ◽

Clinical Breakpoints ◽

Species Specific

AbstractCefiderocol is a novel cephalosporin designed to treat multidrug resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater in vitro activity against many Gram-negative bacilli than currently used carbapenems, β-lactam/β-lactamase inhibitor combinations, and cephalosporins. Thus, we investigated the in vitro activity of cefiderocol (S-649266) against a total of 271 clinical isolates of Burkholderia pseudomallei from Australia. The collection was comprised of primary isolates (92.3%) and subsequent isolates (7.7%). Minimum inhibitory concentrations (MIC) of cefiderocol ranged from ≤0.03 to 32 mg/L, where the MIC90 was 1 mg/L and 16 mg/L for primary and subsequent isolates, respectively. Based upon non-species specific (Gram-negative bacilli) clinical breakpoints for cefiderocol (MIC ≤ 4 mg/L), twelve isolates (4.4%) would be classified as non-susceptible. Further testing for co-resistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline was performed on a subset of isolates with elevated cefiderocol MICs (≥2 mg/L, 4.8%) and 84.6% of these isolates exhibited resistance to at least one of these antimicrobials. Cefiderocol was found to be highly active in vitro against B. pseudomallei primary clinical isolates. This novel compound shows great potential for the treatment of melioidosis in endemic countries and should be explored further.

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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.

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In Vitro Activity of Cefepime-Zidebactam, Ceftazidime-Avibactam, and Other Comparators against Clinical Isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii: Results from China Antimicrobial Surveillance Network (CHINET) in 2018

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01726-20 ◽

2020 ◽

Vol 65 (1) ◽

pp. e01726-20

Author(s):

Yang Yang ◽

Yan Guo ◽

Dandan Yin ◽

Yonggui Zheng ◽

Shi Wu ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Acinetobacter Baumannii ◽

Clinical Isolates ◽

Surveillance Network ◽

Gram Negative ◽

Content Type ◽

Highly Active ◽

Carbapenem Resistant ◽

Almost All

ABSTRACTThis study evaluated the in vitro activity of cefepime-zidebactam in comparison with that of ceftazidime-avibactam and other comparators against clinically significant Gram-negative bacillus isolates. A total of 3,400 nonduplicate Gram-negative clinical isolates were collected from 45 medical centers across China in the CHINET Program in 2018, including Enterobacterales (n = 2,228), Pseudomonas aeruginosa (n = 657), and Acinetobacter baumannii (n = 515). The activities of cefepime-zidebactam and 20 comparators were determined by broth microdilution as recommended by the Clinical and Laboratory Standards Institute. Cefepime-zidebactam demonstrated potent activity against almost all Enterobacterales (MIC50/90, 0.125/1 mg/liter) and good activity against P. aeruginosa (MIC50/90, 2/8 mg/liter). Among the 373 carbapenem-resistant Enterobacteriaceae isolates, 57.3% (213/373) and 15.3% (57/373) were positive for blaKPC-2 and blaNDM, respectively. Cefepime-zidebactam showed a MIC of ≤2 mg/liter for 92.0% (196/213) of blaKPC-2 producers and 79.7% (47/59) of blaNDM producers. Ceftazidime-avibactam showed good in vitro activity against Enterobacterales (MIC50/90, 0.25/2 mg/liter; 94.0% susceptible) and P. aeruginosa (MIC50/90, 4/16 mg/liter; 86.9% susceptible). Ceftazidime-avibactam was active against 9.1% of carbapenem-resistant Escherichia coli isolates (63.6% were blaNDM producers) and 84.6% of Klebsiella pneumoniae isolates (74.3% were blaKPC producers). Most (90.1%) blaKPC-2 producers were susceptible to ceftazidime-avibactam. Cefepime-zidebactam demonstrated limited activity (MIC50/90, 16/32 mg/liter) against the 515 A. baumannii isolates (79.2% were carbapenem resistant), and ceftazidime-avibactam was less active (MIC50/90, 64/>64 mg/liter). Cefepime-zidebactam was highly active against clinical isolates of Enterobacterales and P. aeruginosa, including blaKPC-2-positive Enterobacterales and blaNDM-positive Enterobacterales and carbapenem-resistant P. aeruginosa. And ceftazidime-avibactam was highly active against blaKPC-2-positive Enterobacterales and carbapenem-resistant P. aeruginosa.

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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.

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Detection of Extended-Spectrum β-Lactamases in Clinical Isolates of Pseudomonas aeruginosa

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01511-05 ◽

2006 ◽

Vol 50 (9) ◽

pp. 2990-2995 ◽

Cited By ~ 70

Author(s):

Xiaofei Jiang ◽

Zhe Zhang ◽

Min Li ◽

Danqiu Zhou ◽

Feiyi Ruan ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Screening Methods ◽

Extended Spectrum ◽

Pcr Product ◽

Amoxicillin Clavulanate ◽

Synergy Test ◽

Esbl Producers ◽

Disk Test

ABSTRACT With the occurrence of extended-spectrum β-lactamases (ESBLs) in Pseudomonas aeruginosa being increasingly reported worldwide, there is a need for a reliable test to detect ESBLs in clinical isolates of P. aeruginosa. In our study, a total of 75 clinical isolates of P. aeruginosa were studied. Nitrocefin tests were performed to detect the β-lactamase enzyme; isoelectric focusing electrophoresis, PCR, and PCR product sequencing were designed to further characterize the contained ESBLs. Various ESBL-screening methods were designed to compare the reliabilities of detecting ESBLs in clinical isolates of P. aeruginosa whose β-lactamases were well characterized. Thirty-four of 36 multidrug-resistant P. aeruginosa clinical isolates were positive for ESBLs. bla VEB-3 was the most prevalent ESBL gene in P. aeruginosa in our study. Among the total of 34 isolates that were considered ESBL producers, 20 strains were positive using conventional combined disk tests and 10 strains were positive using a conventional double-disk synergy test (DDST) with amoxicillin-clavulanate, expanded-spectrum cephalosporins, aztreonam, and cefepime. Modifications of the combined disk test and DDST, which consisted of shorter distances between disks (20 mm instead of 30 mm) and the use of three different plates that contained cloxacillin (200 μg/ml) alone, Phe-Arg β-naphthylamide dihydrochloride (MC-207,110; 20 μg/ml) alone, and both cloxacillin (200 μg/ml) and MC-207,110 (20 μg/ml) increased the sensitivity of the tests to 78.8%, 91.18%, 85.29%, and 97.06%.

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In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02356-19 ◽

2020 ◽

Vol 64 (5) ◽

Cited By ~ 2

Author(s):

Gregory G. Stone ◽

Patricia A. Bradford ◽

Margaret Tawadrous ◽

Dianna Taylor ◽

Mary Jane Cadatal ◽

...

Keyword(s):

Nosocomial Pneumonia ◽

Bacterial Pathogen ◽

Multidrug Resistant ◽

Ventilator Associated Pneumonia ◽

Phase 3 ◽

Gram Positive ◽

Gram Negative ◽

Content Type ◽

Highly Active

ABSTRACT Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

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In Vitro Bactericidal Activity of Human β-Defensin 3 against Multidrug-Resistant Nosocomial Strains

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.2.806-809.2006 ◽

2006 ◽

Vol 50 (2) ◽

pp. 806-809 ◽

Cited By ~ 80

Author(s):

Giuseppantonio Maisetta ◽

Giovanna Batoni ◽

Semih Esin ◽

Walter Florio ◽

Daria Bottai ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Pseudomonas Aeruginosa ◽

Antimicrobial Activity ◽

Bactericidal Activity ◽

Stenotrophomonas Maltophilia ◽

Bactericidal Effect ◽

Multidrug Resistant ◽

Bacterial Strains ◽

Gram Negative

ABSTRACT The antimicrobial activity of human β-defensin 3 (hBD-3) against multidrug-resistant clinical isolates of Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter baumannii was evaluated. A fast bactericidal effect (within 20 min) against all bacterial strains tested was observed. The presence of 20% human serum abolished the bactericidal activity of hBD-3 against gram-negative strains and reduced the activity of the peptide against gram-positive strains.

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Inactivation of the Pseudomonas -Derived Cephalosporinase-3 (PDC-3) by Relebactam

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02406-17 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 12

Author(s):

Melissa D. Barnes ◽

Christopher R. Bethel ◽

Jim Alsop ◽

Scott A. Becka ◽

Joseph D. Rutter ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Gram Negative ◽

Content Type ◽

Life Threatening ◽

Lactamase Inhibitor

ABSTRACT Pseudomonas aeruginosa is a prevalent and life-threatening Gram-negative pathogen. Pseudomonas -derived cephlosporinase (PDC) is the major inducible cephalosporinase in P. aeruginosa . In this investigation, we show that relebactam, a diazabicyclooctane β-lactamase inhibitor, potently inactivates PDC-3, with a k 2 / K of 41,400 M −1 s −1 and a k off of 0.00095 s −1 . Relebactam restored susceptibility to imipenem in 62% of multidrug-resistant P. aeruginosa clinical isolates, while only 21% of isolates were susceptible to imipenem-cilastatin alone. Relebactam promises to increase the efficacy of imipenem-cilastatin against P. aeruginosa .

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Volatile Oils ofNepeta tenuifolia(Jing Jie) as an Alternative Medicine against Multidrug-Resistant Pathogenic Microbes

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2018/8347403 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Yi-Hsuan Lee ◽

Chao-Min Wang ◽

Po-Yu Liu ◽

Ching-Chang Cheng ◽

Zong-Yen Wu ◽

...

Keyword(s):

Essential Oils ◽

In Vitro Study ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Gram Negative ◽

E Coli ◽

Wide Range ◽

Main Component ◽

Reference Strains

Essential oils from the dried spikes ofNepeta tenuifolia(Benth) are obtained by steam distillation. Pulegone was identified as the main component in the spikes ofN. tenuifoliathrough analysis, with greater than 85% purity obtained in this study. The essential oils are extremely active against all Gram-positive and some Gram-negative reference bacteria, particularlySalmonella enterica,Citrobacter freundii, andEscherichia coli. The minimum inhibitory concentration was found to be between 0.08 and 0.78% (againstS. enterica), 0.39 and 0.78% (againstC. freundii), and 0.097 and 0.39% (againstE. coli), whereas the minimum bactericidal concentration varied in range from 0.097% to 1.04%. In general, the essential oils show a strong inhibitory action against all tested reference strains and clinical isolates. However, the antibacterial activity of EOs against bothPseudomonas aeruginosareference strains and clinical isolates was relatively lower than other Gram-negative pathogens. The essential oils ofN. tenuifoliaalso displayed bactericidal activities (MBC/MIC < 4) in this study. These findings reflect the bactericidal activity of the essential oils against a wide range of multidrug-resistant clinical pathogens in an in vitro study. In addition, we propose the fragmentation pathways of pulegone and its derivatives by LC-ESI-MS/MS in this study.

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In Vitro Activity of Ceftolozane-Tazobactam vs. Antimicrobial Non-Susceptible Pseudomonas aeruginosa Clinical Isolates Obtained from Across Canada as Part of the CANWARD Study, 2008–2016

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.913 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S372-S372

Author(s):

Andrew Walkty ◽

Heather J Adam ◽

Melanie Baxter ◽

Philippe Lagace-Wiens ◽

James Karlowsky ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Multidrug Resistant ◽

Vitro Activity ◽

Clinical Isolates ◽

In Vitro Activity ◽

Research Support ◽

Research Relationship ◽

Inhibitor Combination ◽

Patient Infection

Abstract Background Ceftolozane-tazobactam (C/T) is a novel β-lactam β-lactamase inhibitor combination with a broad spectrum of activity that includes Pseudomonas aeruginosa. The purpose of this study was to evaluate the in vitro activity of C/T and relevant comparators vs. a large collection of antimicrobial non-susceptible (NS) P. aeruginosa clinical isolates obtained from patients across Canada (CANWARD, 2008–2016). Methods From January 2008 to December 2016, inclusive, 12 to 15 sentinel hospitals across Canada submitted clinical isolates from patients attending ERs, medical and surgical wards, hospital clinics, and ICUs (CANWARD). Each center was asked to annually submit clinical isolates (consecutive, one per patient/infection site) from blood, respiratory, urine, and wound infections. Susceptibility testing was performed using broth microdilution as described by CLSI. Multidrug-resistant (MDR) P. aeruginosa were defined as isolates that tested NS to at least one antimicrobial from ≥3 classes. Extensively drug-resistant (XDR) P. aeruginosa were defined as isolates that tested NS to at least one antimicrobial from ≥5 classes. Results 3229 P. aeruginosa isolates were obtained as a part of CANWARD. The in vitro activity of C/T and relevant comparators is presented below. Conclusion C/T demonstrated excellent in vitro activity vs. antimicrobial NS P. aeruginosa clinical isolates, including MDR, XDR, and meropenem NS subsets. It may prove useful in the treatment of infections caused by these organisms. Disclosures D. Hoban, Abbott: Research relationship, Research support Achaogen: Research relationship, Research support Astellas: Research relationship, Research support Merck Canada: Research relationship, Research support Merck USA: Research relationship, Research support Paratek Pharma: Research relationship, Research support Pharmascience: Research relationship, Research support Sunovion: Research relationship, Research support Tetraphase: Research relationship, Research support The Medicines Co.: Research relationship, Research support Zoetis: Research relationship, Research support; G. Zhanel, Achaogen: Research relationship, Research support Astellas: Research relationship, Research support Merck Canada: Research relationship, Research support Merck USA: Research relationship, Research support Paratek Pharma: Research relationship, Research support Pharmascience: Research relationship, Research support Sunovion: Research relationship, Research support Tetraphase: Research relationship, Research support The Medicines Co.: Research relationship, Research support Zoetis: Research relationship, Research support

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