scholarly journals Multicenter Evaluation of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Inhibitory Activity against Meropenem-Nonsusceptible Pseudomonas aeruginosa from Blood, Respiratory Tract, and Wounds

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Mordechai Grupper ◽  
Christina Sutherland ◽  
David P. Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Activity ◽  
Clinical Utility ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Broth Microdilution ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACT The recent escalation of occurrences of carbapenem-resistant Pseudomonas aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of the carbapenem class of compounds for this prevalent health care-associated pathogen. Here, we compared the in vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem-nonsusceptible Pseudomonas aeruginosa nonduplicate clinical isolates from 34 U.S. hospitals using reference broth microdilution methods. Ceftazidime-avibactam and ceftolozane-tazobactam were active, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam. The heightened inhibitory activity of ceftolozane-tazobactam was sustained when the site of origin (respiratory, blood, or wound) and nonsusceptibility to other β-lactam antimicrobials was considered. An extensive genotypic search for enzymatically driven β-lactam resistance mechanisms revealed the exclusive presence of the VIM metallo-β-lactamase among only 4% of the subset of isolates nonsusceptible to ceftazidime-avibactam, ceftolozane-tazobactam, or both. These findings suggest an important role for both ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem-nonsusceptible Pseudomonas aeruginosa. Further in vitro and in vivo studies are needed to better define the clinical utility of these novel therapies against the increasingly prevalent threat of multidrug-resistant Pseudomonas aeruginosa.

scholarly journals Synergistic Efficacy of Aedes aegypti Antimicrobial Peptide Cecropin A2 and Tetracycline against Pseudomonas aeruginosa

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Zhaojun Zheng ◽  
Nagendran Tharmalingam ◽  
Qingzhong Liu ◽  
Elamparithi Jayamani ◽  
Wooseong Kim ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Aedes Aegypti ◽  
Mammalian Cells ◽  
Galleria Mellonella ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Synergistic Activity ◽  
Content Type

ABSTRACT The increasing prevalence of antibiotic resistance has created an urgent need for alternative drugs with new mechanisms of action. Antimicrobial peptides (AMPs) are promising candidates that could address the spread of multidrug-resistant bacteria, either alone or in combination with conventional antibiotics. We studied the antimicrobial efficacy and bactericidal mechanism of cecropin A2, a 36-residue α-helical cationic peptide derived from Aedes aegypti cecropin A, focusing on the common pathogen Pseudomonas aeruginosa. The peptide showed little hemolytic activity and toxicity toward mammalian cells, and the MICs against most clinical P. aeruginosa isolates were 32 to 64 μg/ml, and its MICs versus other Gram-negative bacteria were 2 to 32 μg/ml. Importantly, cecropin A2 demonstrated synergistic activity against P. aeruginosa when combined with tetracycline, reducing the MICs of both agents by 8-fold. The combination was also effective in vivo in the P. aeruginosa/Galleria mellonella model (P < 0.001). We found that cecropin A2 bound to P. aeruginosa lipopolysaccharides, permeabilized the membrane, and interacted with the bacterial genomic DNA, thus facilitating the translocation of tetracycline into the cytoplasm. In summary, the combination of cecropin A2 and tetracycline demonstrated synergistic antibacterial activity against P. aeruginosa in vitro and in vivo, offering an alternative approach for the treatment of P. aeruginosa infections.

scholarly journals New β-Lactam–β-Lactamase Inhibitor Combinations

2020 ◽  
Vol 34 (1) ◽  
Author(s):  
Dafna Yahav ◽  
Christian G. Giske ◽  
Alise Grāmatniece ◽  
Henrietta Abodakpi ◽  
Vincent H. Tam ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Treatment Option ◽  
Clinical Data ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Lactamase Inhibitor

SUMMARY The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa. Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa. Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales. Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa. Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii. Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

scholarly journals Prevalence, Risk Factors, and Molecular Epidemiology of Intestinal Carbapenem-Resistant Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Yanyan Hu ◽  
Yan Qing ◽  
Jiawei Chen ◽  
Congcong Liu ◽  
Jiayue Lu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Pseudomonas Aeruginosa ◽  
Gastrointestinal Tract ◽  
Resistance Genes ◽  
Acquired Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Human Gastrointestinal Tract ◽  
Content Type ◽  
Carbapenem Resistant

Pseudomonas aeruginosa may become multidrug-resistant (MDR) due to multiple inherited and acquired resistance mechanisms. The human gastrointestinal tract is known as a reservoir of P. aeruginosa and its resistance genes.

scholarly journals Inhibition of Pseudomonas aeruginosa by Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
James J. Howard ◽  
Carolyn R. Sturge ◽  
Dina A. Moustafa ◽  
Seth M. Daly ◽  
Kimberly R. Marshall-Batty ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Essential Genes ◽  
Content Type ◽  
Novel Approach ◽  
Phosphorodiamidate Morpholino Oligomers

ABSTRACT Pseudomonas aeruginosa is a highly virulent, multidrug-resistant pathogen that causes significant morbidity and mortality in hospitalized patients and is particularly devastating in patients with cystic fibrosis. Increasing antibiotic resistance coupled with decreasing numbers of antibiotics in the developmental pipeline demands novel antibacterial approaches. Here, we tested peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), which inhibit translation of complementary mRNA from specific, essential genes in P. aeruginosa. PPMOs targeted to acpP, lpxC, and rpsJ, inhibited P. aeruginosa growth in many clinical strains and activity of PPMOs could be enhanced 2- to 8-fold by the addition of polymyxin B nonapeptide at subinhibitory concentrations. The PPMO targeting acpP was also effective at preventing P. aeruginosa PAO1 biofilm formation and at reducing existing biofilms. Importantly, treatment with various combinations of a PPMO and a traditional antibiotic demonstrated synergistic growth inhibition, the most effective of which was the PPMO targeting rpsJ with tobramycin. Furthermore, treatment of P. aeruginosa PA103-infected mice with PPMOs targeting acpP, lpxC, or rpsJ significantly reduced the bacterial burden in the lungs at 24 h by almost 3 logs. Altogether, this study demonstrates that PPMOs targeting the essential genes acpP, lpxC, or rpsJ in P. aeruginosa are highly effective at inhibiting growth in vitro and in vivo. These data suggest that PPMOs alone or in combination with antibiotics represent a novel approach to addressing the problems associated with rapidly increasing antibiotic resistance in P. aeruginosa.

scholarly journals A 2.5-Year Within-Patient Evolution of Pseudomonas aeruginosa Isolates with In Vivo Acquisition of Ceftolozane-Tazobactam and Ceftazidime-Avibactam Resistance upon Treatment

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Thibaud Boulant ◽  
Agnès B. Jousset ◽  
Rémy A. Bonnin ◽  
Aurélie Barrail-Tran ◽  
Adrien Borgel ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acquired Resistance ◽  
Multidrug Resistant ◽  
Sequencing Analysis ◽  
Nucleotide Polymorphisms ◽  
Related Sequence ◽  
Content Type ◽  
Partial Restoration

ABSTRACT Ceftolozane-tazobactam is considered to be a last-resort treatment for infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. Although resistance to this antimicrobial has been described in vitro, the development of resistance in vivo has rarely been reported. Here, we describe the evolution of resistance to ceftolozane-tazobactam of P. aeruginosa isolates recovered from the same patient during recurrent infections over 2.5 years. Antimicrobial susceptibility testing results showed that 24 of the 27 P. aeruginosa isolates recovered from blood (n = 18), wound (n = 2), pulmonary (n = 1), bile (n = 2), and stool (n = 4) samples from the same patient were susceptible to ceftolozane-tazobactam and ceftazidime-avibactam but resistant to ceftazidime, piperacillin-tazobactam, imipenem, and meropenem. Three clinical isolates acquired resistance to ceftolozane-tazobactam and ceftazidime-avibactam along with a partial restoration of piperacillin-tazobactam and carbapenem susceptibilities. Whole-genome sequencing analysis reveals that all isolates were clonally related (sequence type 111 [ST-111]), with a median of 24.9 single nucleotide polymorphisms (SNPs) (range, 8 to 48 SNPs). The ceftolozane-tazobactam and ceftazidime-avibactam resistance was likely linked to the same G183D substitution in the chromosome-encoded cephalosporinase. Our results suggest that resistance to ceftolozane-tazobactam in P. aeruginosa might occur in vivo upon treatment through an amino acid substitution in the intrinsic AmpC leading to ceftolozane-tazobactam and ceftazidime-avibactam resistance, accompanied by resensitization to piperacillin-tazobactam and carbapenems.

scholarly journals Activity of Meropenem with a Novel Broader-Spectrum β-Lactamase Inhibitor, WCK 4234, against Gram-Negative Pathogens Endemic to New York City

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Alejandro Iregui ◽  
Zeb Khan ◽  
David Landman ◽  
John Quale
Keyword(s):  
New York ◽  
New York City ◽  
York City ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT WCK 4234 is a novel diazabicyclooctane with potent inhibitory activity against class A and D carbapenemases and class C enzymes. We examined the in vitro activity of meropenem plus WCK 4234 (4 or 8 μg/ml) against Gram-negative pathogens from New York City. Three groups of isolates were analyzed: a contemporary collection of isolates, a collection of known carbapenem-resistant isolates, and a collection of isolates with defined resistance mechanisms. From the contemporary collection, we found (i) that all Enterobacteriaceae were susceptible to meropenem plus WCK 4234, (ii) that susceptibility rates for Acinetobacter baumannii were 56.5% for meropenem alone, 82.6% with 4 μg/ml WCK 4234, and 95.7% with 8 μg/ml WCK 4234, and (iii) that WCK 4234 had a modest effect on susceptibility of Pseudomonas aeruginosa. Against a collection of carbapenem-resistant isolates, the addition of WCK 4234 to meropenem (i) restored meropenem susceptibility against Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae isolates, (ii) improved susceptibility against A. baumannii, and (iii) had a negligible effect against P. aeruginosa. When tested against isolates with defined mechanisms of resistance, MICs of meropenem plus WCK 4234 were higher for K. pneumoniae with blaKPC albeit well below the susceptibility breakpoint; efflux systems or porins did not correlate with susceptibility. For A. baumannii, MICs of meropenem plus WCK 4234 did not correlate with efflux systems, outer membrane protein, blaampC, or blaoxa-51; however, MICs were higher in isolates with extended-spectrum β-lactamases (ESBLs). For P. aeruginosa, isolates with relatively higher MICs of meropenem plus WCK 4234 had increased expression of ampC. WCK 4234 is a potent β-lactamase inhibitor that, when combined with meropenem, displays promising activity against multidrug-resistant pathogens.

scholarly journals In Vitro and In Vivo Activities of β-Lactams in Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Bartolome Moya ◽  
Isabel M. Barcelo ◽  
Gabriel Cabot ◽  
Gabriel Torrens ◽  
Snehal Palwe ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Molecular Targets ◽  
Multidrug Resistant ◽  
The Novel ◽  
Penicillin Binding Protein ◽  
Content Type ◽  
Time Kill

ABSTRACT Zidebactam and WCK 5153 are novel bicyclo-acyl hydrazide (BCH) agents that have previously been shown to act as β-lactam enhancer (BLE) antibiotics in Pseudomonas aeruginosa and Acinetobacter baumannii. The objectives of this work were to identify the molecular targets of these BCHs in Klebsiella pneumoniae and to investigate their potential BLE activity for cefepime and aztreonam against metallo-β-lactamase (MBL)-producing strains in vitro and in vivo. Penicillin binding protein (PBP) binding profiles were determined by Bocillin FL assay, and 50% inhibitory concentrations (IC50s) were determined using ImageQuant TL software. MICs and kill kinetics for zidebactam, WCK 5153, and cefepime or aztreonam, alone and in combination, were determined against clinical K. pneumoniae isolates producing MBLs VIM-1 or NDM-1 (plus ESBLs and class C β-lactamases) to assess the in vitro enhancer effect of BCH compounds in conjunction with β-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effects in vivo. Zidebactam and WCK 5153 showed specific, high PBP2 affinity in K. pneumoniae. The MICs of BLEs were >64 μg/ml for all MBL-producing strains. Time-kill studies showed that a combination of these BLEs with either cefepime or aztreonam provided 1 to >3 log10 kill against MBL-producing K. pneumoniae strains. Furthermore, the bactericidal synergy observed for these BLE–β-lactam combinations translated well into in vivo efficacy even in the absence of MBL inhibition by BLEs, a characteristic feature of the β-lactam enhancer mechanism of action. Zidebactam and WCK 5153 are potent PBP2 inhibitors and display in vitro and in vivo BLE effects against multidrug-resistant (MDR) K. pneumoniae clinical isolates producing MBLs.

scholarly journals Activity of Ceftolozane-Tazobactam against Carbapenem-Resistant, Non-Carbapenemase-Producing Pseudomonas aeruginosa and Associated Resistance Mechanisms

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Yu Mi Wi ◽  
Kerryl E. Greenwood-Quaintance ◽  
Audrey N. Schuetz ◽  
Kwan Soo Ko ◽  
Kyong Ran Peck ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistance Rate ◽  
Content Type ◽  
Reverse Transcription Pcr ◽  
Carbapenem Resistant ◽  
Kill Curve ◽  
Time Kill

ABSTRACT Although carbapenems are effective for treating serious multidrug-resistant Pseudomonas aeruginosa infections, carbapenem-resistant P. aeruginosa (CRPA) is now being reported worldwide. Ceftolozane-tazobactam (C/T) demonstrates activity against many multidrug-resistant isolates. We evaluated the activity of C/T and compared its activity to that of ceftazidime-avibactam (C/A) using a well-characterized collection of non-carbapenemase-producing CRPA isolates. Forty-two non-carbapenemase-producing CRPA isolates from a previous study (J. Y. Lee and K. S. Ko, Int J Antimicrob Agents 40:168–172, 2012, https://doi.org/10.1016/j.ijantimicag.2012.04.004) were included. All had been previously shown to be negative for bla IMP, bla VIM, bla SPM, bla GIM, bla SIM, and bla KPC by PCR. In the prior study, expression of oprD, ampC, and several efflux pump genes had been defined by quantitative reverse transcription-PCR. Here, antimicrobial susceptibility was determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Time-kill curve assays were performed using three C/T- and C/A-susceptible CRPA isolates. Among 42 non-carbapenemase-producing CRPA isolates, overall susceptibility to C/T was 95.2%, compared to 71.4%, 42.9%, 23.8%, 21.4%, and 2.4% for C/A, ceftazidime, piperacillin-tazobactam, cefepime, and meropenem, respectively. The C/T resistance rate was significantly lower than that of C/A among isolates showing decreased oprD and increased mexB expression (5.1% versus 25.6%, P = 0.025, and 4.3% versus 34.8%, P = 0.022, respectively). In time-kill curve studies, C/T was less bactericidal than C/A against an isolate with decreased oprD and increased ampC expression. C/T was active against 95.2% of non-carbapenemase-producing CRPA clinical isolates. No apparent correlation of C/T MIC values with specific mutation-driven resistance mechanisms was noted.

scholarly journals In VitroActivity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa Isolates Obtained from Patients in Canadian Hospitals in the CANWARD Study, 2007 to 2012

2013 ◽  
Vol 57 (11) ◽  
pp. 5707-5709 ◽  
Author(s):  
A. Walkty ◽  
J. A. Karlowsky ◽  
H. Adam ◽  
M. Baxter ◽  
P. Lagacé-Wiens ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Broth Microdilution ◽  
Content Type ◽  
Fixed Concentration

ABSTRACTThein vitroactivity of ceftolozane in combination with tazobactam (fixed concentration of 4 μg/ml) was evaluated against 2,435Pseudomonas aeruginosaclinical isolates obtained from across Canada using Clinical and Laboratory Standards Institute broth microdilution methods. The MIC50and MIC90values for ceftolozane-tazobactam were 0.5 μg/ml and 1 μg/ml, respectively (a 32-fold-lower MIC90than that for ceftazidime). Eighty-nine percent (141/158) of multidrug-resistant isolates were inhibited by ≤8 μg/ml of ceftolozane-tazobactam.

scholarly journals In Vitro Activity of Ceftazidime Combined with NXL104 versus Pseudomonas aeruginosa Isolates Obtained from Patients in Canadian Hospitals (CANWARD 2009 Study)

2011 ◽  
Vol 55 (6) ◽  
pp. 2992-2994 ◽  
Author(s):  
A. Walkty ◽  
M. DeCorby ◽  
P. R. S. Lagacé-Wiens ◽  
J. A. Karlowsky ◽  
D. J. Hoban ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Content Type ◽  
Presence And Absence

ABSTRACTThein vitroactivity of ceftazidime in combination with NXL104 versus 470Pseudomonas aeruginosaclinical isolates was evaluated using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods. Ceftazidime had MIC90s of 8 μg/ml and 32 μg/ml in the presence and absence of NXL104, respectively. Of 25 multidrug-resistantP. aeruginosaisolates, the percentages with a ceftazidime MIC of ≤8 μg/ml with and without NXL104 were 60% and 4%, respectively. These data suggest that the ceftazidime-NXL104 combination may prove useful for treating manyP. aeruginosainfections.

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