Comparative in vitro activities of beta-lactam-tobramycin combinations against Pseudomonas aeruginosa and multidrug-resistant gram-negative enteric bacilli.

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 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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In Vitro Activity of Ceftazidime-Avibactam against Isolates from Patients in a Phase 3 Clinical Trial for Treatment of Complicated Intra-abdominal Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02584-17 ◽

2018 ◽

Vol 62 (7) ◽

pp. e02584-17 ◽

Cited By ~ 4

Author(s):

Gregory G. Stone ◽

Paul Newell ◽

Patricia A. Bradford

Keyword(s):

Clinical Trial ◽

Pseudomonas Aeruginosa ◽

Treatment Options ◽

Multidrug Resistant ◽

Phase 3 ◽

Gram Positive ◽

Gram Negative ◽

Content Type ◽

Abdominal Infections

ABSTRACT The increasing prevalence of multidrug-resistant Gram-negative pathogens has generated a requirement for new treatment options. Avibactam, a novel non-β-lactam–β-lactamase inhibitor, restores the activity of ceftazidime against Ambler class A, C, and some class D β-lactamase-producing strains of Enterobacteriaceae and Pseudomonas aeruginosa. The in vitro activities of ceftazidime-avibactam versus comparators were evaluated against 1,440 clinical isolates obtained in a phase 3 clinical trial in patients with complicated intra-abdominal infections (cIAI; ClinicalTrials.gov identifier NCT01499290). Overall, in vitro activities were determined for 803 Enterobacteriaceae, 70 P. aeruginosa, 304 Gram-positive aerobic, and 255 anaerobic isolates obtained from 1,066 randomized patients at baseline. Susceptibility was determined by broth microdilution. The most commonly isolated Gram-negative, Gram-positive, and anaerobic pathogens were Escherichia coli (n = 549), Streptococcus anginosus (n = 130), and Bacteroides fragilis (n = 96), respectively. Ceftazidime-avibactam was highly active against isolates of Enterobacteriaceae, with an overall MIC90 of 0.25 mg/liter. In contrast, the MIC90 for ceftazidime alone was 32 mg/liter. The MIC90 value for ceftazidime-avibactam (4 mg/liter) was one dilution lower than that of ceftazidime alone (8 mg/liter) against isolates of Pseudomonas aeruginosa. The ceftazidime-avibactam MIC90 for 109 ceftazidime-nonsusceptible Enterobacteriaceae isolates was 2 mg/liter, and the MIC range for 6 ceftazidime-nonsusceptible P. aeruginosa isolates was 8 to 32 mg/liter. The MIC90 values were within the range of susceptibility for the study drugs permitted per the protocol in the phase 3 study to provide coverage for aerobic Gram-positive and anaerobic pathogens. These findings demonstrate the in vitro activity of ceftazidime-avibactam against bacterial pathogens commonly observed in cIAI patients, including ceftazidime-nonsusceptible Enterobacteriaceae. (This study has been registered at ClinicalTrials.gov under identifier NCT01499290.)

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Characteristics and Outcomes of Complicated Intra-abdominal Infections Involving Pseudomonas aeruginosa from a Randomized, Double-Blind, Phase 3 Ceftolozane-Tazobactam Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03074-15 ◽

2016 ◽

Vol 60 (7) ◽

pp. 4387-4390 ◽

Cited By ~ 16

Author(s):

Benjamin Miller ◽

Myra W. Popejoy ◽

Ellie Hershberger ◽

Judith N. Steenbergen ◽

John Alverdy

Keyword(s):

Pseudomonas Aeruginosa ◽

Clinical Cure ◽

Multidrug Resistant ◽

Phase 3 ◽

Double Blind ◽

Gram Negative ◽

Content Type ◽

Evaluable Population ◽

Abdominal Infections

ABSTRACTCeftolozane-tazobactam is active against Gram-negative pathogens, including multidrug-resistantPseudomonas aeruginosa. In a subgroup analysis of patients with complicated intra-abdominal infections (cIAIs) involvingP. aeruginosafrom a phase 3 program, ceftolozane-tazobactam demonstrated potentin vitroactivity againstP. aeruginosa. Clinical cure in the microbiologically evaluable population was 100% (26/26) for ceftolozane-tazobactam plus metronidazole and 93.1% (27/29) for meropenem. These findings support the use of ceftolozane-tazobactam in the management of cIAI whenP. aeruginosais suspected or confirmed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01445665 and NCT01445678.)

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In Vitro Activity of Colistin (Polymyxin E) against 3,480 Isolates of Gram-Negative Bacilli Obtained from Patients in Canadian Hospitals in the CANWARD Study, 2007-2008

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00786-09 ◽

2009 ◽

Vol 53 (11) ◽

pp. 4924-4926 ◽

Cited By ~ 42

Author(s):

A. Walkty ◽

M. DeCorby ◽

K. Nichol ◽

J. A. Karlowsky ◽

D. J. Hoban ◽

...

Keyword(s):

Escherichia Coli ◽

Pseudomonas Aeruginosa ◽

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Vitro Activity ◽

In Vitro Activity ◽

Broth Microdilution ◽

Gram Negative ◽

Polymyxin E

ABSTRACT The in vitro activity of colistin was evaluated versus 3,480 isolates of gram-negative bacilli using CLSI broth microdilution methods. The MIC90 of colistin was ≤2 μg/ml against a variety of clinically important gram-negative bacilli, including Escherichia coli, Klebsiella spp., Enterobacter spp., Acinetobacter baumannii, and Pseudomonas aeruginosa. All multidrug-resistant (n = 76) P. aeruginosa isolates were susceptible to colistin (MIC, ≤2 μg/ml). These data support a role for colistin in the treatment of infections caused by multidrug-resistant P. aeruginosa.

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Global Assessment of the Activity of Tigecycline against Multidrug-Resistant Gram-Negative Pathogens between 2004 and 2014 as Part of the Tigecycline Evaluation and Surveillance Trial

mSphere ◽

10.1128/msphere.00310-16 ◽

2017 ◽

Vol 2 (1) ◽

Cited By ~ 38

Author(s):

Anna Giammanco ◽

Cinzia Calà ◽

Teresa Fasciana ◽

Michael J. Dowzicky

Keyword(s):

Health Care ◽

Pseudomonas Aeruginosa ◽

Multidrug Resistance ◽

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Current Status ◽

Gram Negative ◽

Content Type ◽

Trial Test

ABSTRACT Multidrug resistance among bacterial pathogens is an ongoing global problem and renders antimicrobial agents ineffective at treating bacterial infections. In the health care setting, infections caused by multidrug-resistant (MDR) Gram-negative bacteria can cause increased mortality, longer hospital stays, and higher treatments costs. The aim of the Tigecycline Evaluation and Surveillance Trial (TEST) is to assess the in vitro antimicrobial activities of tigecycline and other contemporary agents against clinically relevant pathogens. This paper presents antimicrobial activity data from the TEST study between 2004 and 2014 and examines global rates of MDR Gram-negative isolates, including Acinetobacter baumannii, Pseudomonas aeruginosa, and members of the Enterobacteriaceae, during this time. Our results show that tigecycline retained in vitro activity against many MDR Gram-negative pathogens over the study period, while rates of MDR A. baumannii increased globally. Using these findings, we hope to highlight the current status of multidrug resistance in medical facilities worldwide. Multidrug-resistant (MDR) Gram-negative organisms are a burden on the global health care system. The Tigecycline Evaluation and Surveillance Trial (TEST) is an ongoing global study designed to monitor the in vitro activities of tigecycline and a panel of marketed antimicrobials against a range of clinically significant pathogens. In this study, in vitro data are presented for MDR Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, and Enterobacter cloacae isolates collected from 2004 to 2014. In total, 13% (21,967/170,759) of isolates displayed multidrug resistance globally, with the highest rates recorded among A. baumannii (overall rate, 44% [8,294/18,741], increasing from 23% [309/1,323] in 2004 to 63% [447/712] in 2014). Other multidrug resistance rates ranged from 2.5% for K. oxytoca (203/8,000) to 12% for P. aeruginosa and K. pneumoniae (3,951/32,786 and 3,895/32,888, respectively), and rates among these pathogens remained stable during the study period. Against MDR E. coli, Klebsiella spp., and E. aerogenes, the lowest rates of resistance were to tigecycline (0.2%, 6%, and 12%, respectively), and the lowest MIC90 value against A. baumannii was observed for tigecycline (2 mg/liter; MIC range, ≤0.008 to ≥32 mg/liter). The only significant change in resistance to tigecycline during the study period was for MDR E. coli (P < 0.01), among which eight resistant isolates were identified globally from 2009 to 2013. In summary, these results show that tigecycline retained in vitro activity against the majority of MDR Gram-negative organisms presented here, but the rising rates of MDR A. baumannii highlight the need for the continued monitoring of global multidrug resistance. IMPORTANCE Multidrug resistance among bacterial pathogens is an ongoing global problem and renders antimicrobial agents ineffective at treating bacterial infections. In the health care setting, infections caused by multidrug-resistant (MDR) Gram-negative bacteria can cause increased mortality, longer hospital stays, and higher treatments costs. The aim of the Tigecycline Evaluation and Surveillance Trial (TEST) is to assess the in vitro antimicrobial activities of tigecycline and other contemporary agents against clinically relevant pathogens. This paper presents antimicrobial activity data from the TEST study between 2004 and 2014 and examines global rates of MDR Gram-negative isolates, including Acinetobacter baumannii, Pseudomonas aeruginosa, and members of the Enterobacteriaceae, during this time. Our results show that tigecycline retained in vitro activity against many MDR Gram-negative pathogens over the study period, while rates of MDR A. baumannii increased globally. Using these findings, we hope to highlight the current status of multidrug resistance in medical facilities worldwide.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00685-20 ◽

2020 ◽

Author(s):

Delaney Burnard ◽

Gemma Robertson ◽

Andrew Henderson ◽

Caitlin Falconer ◽

Michelle J. Bauer ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Burkholderia Pseudomallei ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Transport Systems ◽

Gram Negative ◽

Highly Active ◽

Amoxicillin Clavulanate ◽

Clinical Breakpoints

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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In vitro synergistic activities of tobramycin and selected beta-lactams against 75 gram-negative clinical isolates.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.11.2586 ◽

1997 ◽

Vol 41 (11) ◽

pp. 2586-2588 ◽

Cited By ~ 22

Author(s):

R C Owens ◽

M A Banevicius ◽

D P Nicolau ◽

C H Nightingale ◽

R Quintiliani

Keyword(s):

Pseudomonas Aeruginosa ◽

Enterobacter Cloacae ◽

Clinical Isolates ◽

Synergistic Activity ◽

Beta Lactam ◽

Beta Lactams ◽

Acinetobacter Baumanii ◽

Gram Negative ◽

Combination Regimens

The microdilution checkerboard technique was utilized to distinguish synergistic activity between tobramycin and four beta-lactams: piperacillin-tazobactam, ticarcillin-clavulanate, ceftazidime, and ceftriaxone. Beta-lactam-aminoglycoside combinations were tested against 75 clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumanii, Citrobacterfreundii, Serratia marcescens, and Enterobacter cloacae. Despite in vitro susceptibilities, all isolates demonstrated either synergism or indifference; no antagonism was observed. Against pathogenic gram-negative nosocomial isolates, a greater percentage of synergy was consistently observed with combination regimens containing tobramycin and piperacillin-tazobactam or ticarcillin-clavulanate than with the cephalosporin-containing regimens.

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In Vitro Activity of Ceftolozane-Tazobactam against Multidrug-Resistant Nonfermenting Gram-Negative Bacilli Isolated from Patients with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02688-16 ◽

2017 ◽

Vol 61 (4) ◽

Cited By ~ 11

Author(s):

Patrick Grohs ◽

Gary Taieb ◽

Philippe Morand ◽

Iheb Kaibi ◽

Isabelle Podglajen ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Stenotrophomonas Maltophilia ◽

Active Agent ◽

Multidrug Resistant ◽

In Vitro Activity ◽

Gram Negative ◽

Content Type ◽

Time Kill

ABSTRACT Ceftolozane-tazobactam was tested against 58 multidrug-resistant nonfermenting Gram-negative bacilli (35 Pseudomonas aeruginosa, 11 Achromobacter xylosoxydans, and 12 Stenotrophomonas maltophilia isolates) isolated from cystic fibrosis patients and was compared to ceftolozane alone, ceftazidime, meropenem, and piperacillin-tazobactam. Ceftolozane-tazobactam was the most active agent against P. aeruginosa but was inactive against A. xylosoxydans and S. maltophilia. In time-kill experiments, ceftolozane-tazobactam had complete bactericidal activity against 2/6 clinical isolates (33%).

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An Evidence-Based Multidisciplinary Approach Focused on Creating Algorithms for Targeted Therapy of Infection-Related Ventilator-Associated Complications (IVACs) Caused by Pseudomonas aeruginosa and Acinetobacter baumannii in Critically Ill Adult Patients

Antibiotics ◽

10.3390/antibiotics11010033 ◽

2021 ◽

Vol 11 (1) ◽

pp. 33

Author(s):

Milo Gatti ◽

Bruno Viaggi ◽

Gian Maria Rossolini ◽

Federico Pea ◽

Pierluigi Viale

Keyword(s):

Pseudomonas Aeruginosa ◽

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Fourth Generation ◽

Evidence Based ◽

Beta Lactamase ◽

Beta Lactam ◽

Gram Negative ◽

Carbapenem Resistant ◽

Therapeutic Choice

(1) Background: To develop evidence-based algorithms for targeted antibiotic therapy of infection-related ventilator-associated complications (IVACs) caused by non-fermenting Gram-negative pathogens. (2) Methods: A multidisciplinary team of four experts had several rounds of assessments for developing algorithms devoted to targeted antimicrobial therapy of IVACs caused by two non-fermenting Gram-negative pathogens. A literature search was performed on PubMed-MEDLINE (until September 2021) to provide evidence for supporting therapeutic choices. Quality and strength of evidence was established according to a hierarchical scale of the study design. Six different algorithms with associated recommendations in terms of therapeutic choice and dosing optimization were suggested according to the susceptibility pattern of two non-fermenting Gram-negative pathogens: multi-susceptible Pseudomonas aeruginosa (PA), multidrug-resistant (MDR) metallo-beta-lactamase (MBL)-negative-PA, MBL-positive-PA, carbapenem-susceptible Acinetobacter baumannii (AB), and carbapenem-resistant AB. (3) Results: Piperacillin–tazobactam or fourth-generation cephalosporins represent the first therapeutic choice in IVACs caused by multi-susceptible PA. A carbapenem-sparing approach favouring the administration of novel beta-lactam/beta-lactamase inhibitors should be pursued in the management of MDR-MBL-negative PA infections. Cefiderocol should be used as first-line therapy for the management of IVACs caused by MBL-producing-PA or carbapenem-resistant AB. Fosfomycin-based combination therapy, as well as inhaled colistin, could be considered as a reasonable alternative for the management of IVACs due to MDR-PA and carbapenem-resistant AB. (4) Conclusions: The implementation of algorithms focused on prompt revision of antibiotic regimens guided by results of conventional and rapid diagnostic methodologies, appropriate place in therapy of novel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and pharmacokinetic/pharmacodynamic optimization of antibiotic dosing regimens is strongly suggested.

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