scholarly journals A High-Content, Phenotypic Screen Identifies Fluorouridine as an Inhibitor of Pyoverdine Biosynthesis and Pseudomonas aeruginosa Virulence

mSphere ◽  
2016 ◽  
Vol 1 (4) ◽  
Author(s):  
Daniel R. Kirienko ◽  
Alexey V. Revtovich ◽  
Natalia V. Kirienko
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Caenorhabditis Elegans ◽  
Small Molecules ◽  
High Throughput ◽  
Research Effort ◽  
Content Type ◽  
Bacterial Rna ◽  
Phenotypic Screen ◽  
Opportunistic Human Pathogen ◽  
Hospital Acquired

ABSTRACT Despite intense research effort from scientists and the advent of the molecular age of biomedical research, many of the mechanisms that underlie pathogenesis are still understood poorly, if at all. The opportunistic human pathogen Pseudomonas aeruginosa causes a variety of soft tissue infections and is responsible for over 50,000 hospital-acquired infections per year. In addition, P. aeruginosa exhibits a striking degree of innate and acquired antimicrobial resistance, complicating treatment. It is increasingly important to understand P. aeruginosa virulence. In an effort to gain this information in an unbiased fashion, we used a high-throughput phenotypic screen to identify small molecules that disrupted bacterial pathogenesis and increased host survival using the model nematode Caenorhabditis elegans. This method led to the unexpected discovery that addition of a modified nucleotide, 5-fluorouridine, disrupted bacterial RNA metabolism and inhibited synthesis of pyoverdine, a critical toxin. Our results demonstrate that this compound specifically functions as an antivirulent. Pseudomonas aeruginosa is an opportunistic pathogen that causes severe health problems. Despite intensive investigation, many aspects of microbial virulence remain poorly understood. We used a high-throughput, high-content, whole-organism, phenotypic screen to identify small molecules that inhibit P. aeruginosa virulence in Caenorhabditis elegans. Approximately half of the hits were known antimicrobials. A large number of hits were nonantimicrobial bioactive compounds, including the cancer chemotherapeutic 5-fluorouracil. We determined that 5-fluorouracil both transiently inhibits bacterial growth and reduces pyoverdine biosynthesis. Pyoverdine is a siderophore that regulates the expression of several virulence determinants and is critical for pathogenesis in mammals. We show that 5-fluorouridine, a downstream metabolite of 5-fluorouracil, is responsible for inhibiting pyoverdine biosynthesis. We also show that 5-fluorouridine, in contrast to 5-fluorouracil, is a genuine antivirulence compound, with no bacteriostatic or bactericidal activity. To our knowledge, this is the first report utilizing a whole-organism screen to identify novel compounds with antivirulent properties effective against P. aeruginosa. IMPORTANCE Despite intense research effort from scientists and the advent of the molecular age of biomedical research, many of the mechanisms that underlie pathogenesis are still understood poorly, if at all. The opportunistic human pathogen Pseudomonas aeruginosa causes a variety of soft tissue infections and is responsible for over 50,000 hospital-acquired infections per year. In addition, P. aeruginosa exhibits a striking degree of innate and acquired antimicrobial resistance, complicating treatment. It is increasingly important to understand P. aeruginosa virulence. In an effort to gain this information in an unbiased fashion, we used a high-throughput phenotypic screen to identify small molecules that disrupted bacterial pathogenesis and increased host survival using the model nematode Caenorhabditis elegans. This method led to the unexpected discovery that addition of a modified nucleotide, 5-fluorouridine, disrupted bacterial RNA metabolism and inhibited synthesis of pyoverdine, a critical toxin. Our results demonstrate that this compound specifically functions as an antivirulent.

scholarly journals Changes to Its Peptidoglycan-Remodeling Enzyme Repertoire Modulate β-Lactam Resistance in Pseudomonas aeruginosa

2013 ◽  
Vol 57 (7) ◽  
pp. 3078-3084 ◽  
Author(s):  
Joseph F. Cavallari ◽  
Ryan P. Lamers ◽  
Edie M. Scheurwater ◽  
Andrea L. Matos ◽  
Lori L. Burrows
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Penicillin Binding Protein ◽  
Wild Type ◽  
Content Type ◽  
Lytic Transglycosylases ◽  
Phenotypic Screen ◽  
Simultaneous Activation ◽  
Mutant Phenotypes ◽  
High Level ◽  
Hospital Acquired

ABSTRACTPseudomonas aeruginosais a leading cause of hospital-acquired infections and is resistant to many antibiotics. Among its primary mechanisms of resistance is expression of a chromosomally encoded AmpC β-lactamase that inactivates β-lactams. The mechanisms leading to AmpC expression inP. aeruginosaremain incompletely understood but are intricately linked to cell wall metabolism. To better understand the roles of peptidoglycan-active enzymes in AmpC expression—and consequent β-lactam resistance—a phenotypic screen ofP. aeruginosamutants lacking such enzymes was performed. Mutants lacking one of four lytic transglycosylases (LTs) or the nonessential penicillin-binding protein PBP4 (dacB) had altered β-lactam resistance.mltFandsltmutants with reduced β-lactam resistance were designated WIMPs (wall-impaired mutant phenotypes), while highly resistantdacB,sltB1, andmltBmutants were designated HARMs (high-level AmpC resistant mutants). Double mutants lackingdacBandsltB1had extreme piperacillin resistance (>256 μg/ml) compared to either of the single knockouts (64 μg/ml for adacBmutant and 12 μg/ml for ansltB1mutant). Inactivation ofampCreverted these mutants to wild-type susceptibility, confirming that AmpC expression underlies resistance.dacBmutants had constitutively elevated AmpC expression, but the LT mutants had wild-type levels of AmpC in the absence of antibiotic exposure. These data suggest that there are at least two different pathways leading to AmpC expression inP. aeruginosaand that their simultaneous activation leads to extreme β-lactam resistance.

scholarly journals Regulation of Rab5 Function during Phagocytosis of Live Pseudomonas aeruginosa in Macrophages

2013 ◽  
Vol 81 (7) ◽  
pp. 2426-2436 ◽  
Author(s):  
Sushmita Mustafi ◽  
Nathalie Rivero ◽  
Joan C. Olson ◽  
Philip D. Stahl ◽  
M. Alejandro Barbieri
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Membrane Trafficking ◽  
Rho Gtpase ◽  
Critical Role ◽  
Rab Gtpases ◽  
Content Type ◽  
Host Cell Proteins ◽  
Opportunistic Human Pathogen ◽  
Hospital Acquired ◽  
Adp Ribosyltransferase

ABSTRACTPseudomonas aeruginosa, a Gram-negative opportunistic human pathogen, is a frequent cause of severe hospital-acquired infections. Effectors produced by the type III secretion system disrupt mammalian cell membrane trafficking and signaling and are integral to the establishment ofP. aeruginosainfection. One of these effectors, ExoS, ADP-ribosylates several host cell proteins, including Ras and Rab GTPases. In this study, we demonstrated that Rab5 plays a critical role during early stages ofP. aeruginosainvasion of J774-Eclone macrophages. We showed that live, but not heat-inactivated,P. aeruginosainhibited phagocytosis and that this occurred in conjunction with downregulation of Rab5 activity. Inactivation of Rab5 was dependent on ExoS ADP-ribosyltransferase activity, and in J744-Eclone cells, ExoS ADP-ribosyltransferase activity caused a more severe inhibition of phagocytosis than ExoS Rho GTPase activity. Furthermore, we found that expression of Rin1, a Rab5 guanine exchange factor, but not Rabex5 and Rap6, partially reversed the inactivation of Rab5 during invasion of liveP. aeruginosa. These studies provide evidence that liveP. aeruginosacells are able to influence their rate of phagocytosis in macrophages by directly regulating activation of Rab5.

scholarly journals High-Throughput Approaches for the Identification of Pseudomonas aeruginosa Antivirulents

mBio ◽  
2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Donghoon Kang ◽  
Liyang Zhang ◽  
Natalia V. Kirienko
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Throughput ◽  
Bacterial Virulence ◽  
Special Focus ◽  
Content Type ◽  
Opportunistic Human Pathogen ◽  
New Treatments ◽  
High Throughput Screens ◽  
Synthetic Small Molecule ◽  
New Strategies

ABSTRACT Antimicrobial resistance is a serious medical threat, particularly given the decreasing rate of discovery of new treatments. Although attempts to find new treatments continue, it has become clear that merely discovering new antimicrobials, even if they are new classes, will be insufficient. It is essential that new strategies be aggressively pursued. Toward that end, the search for treatments that can mitigate bacterial virulence and tilt the balance of host-pathogen interactions in favor of the host has become increasingly popular. In this review, we will discuss recent progress in this field, with a special focus on synthetic small molecule antivirulents that have been identified from high-throughput screens and on treatments that are effective against the opportunistic human pathogen Pseudomonas aeruginosa.

scholarly journals High-Quality Complete Genome Sequences of Three Pseudomonas aeruginosa Isolates Retrieved from Patients Hospitalized in Intensive Care Units

2019 ◽  
Vol 8 (9) ◽  
Author(s):  
Bárbara Magalhães ◽  
Laurence Senn ◽  
Dominique S. Blanc
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Intensive Care ◽  
Intensive Care Units ◽  
Genome Sequences ◽  
High Quality ◽  
Gram Negative ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Hospital Acquired ◽  
High Quality Genome

Pseudomonas aeruginosa is one of the major Gram-negative pathogens responsible for hospital-acquired infections. Here, we present high-quality genome sequences of isolates from three P. aeruginosa genotypes retrieved from patients hospitalized in intensive care units.

scholarly journals Host Mucin Is Exploited by Pseudomonas aeruginosa To Provide Monosaccharides Required for a Successful Infection

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Casandra L. Hoffman ◽  
Jonathan Lalsiamthara ◽  
Alejandro Aballay
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Caenorhabditis Elegans ◽  
Epithelial Cells ◽  
Human Lung ◽  
Innate Immune ◽  
Alveolar Epithelial Cells ◽  
Content Type ◽  
Alveolar Epithelial ◽  
Successful Infection ◽  
Wide Range

ABSTRACT One of the primary functions of the mucosal barrier, found lining epithelial cells, is to serve as a first-line of defense against microbial pathogens. The major structural components of mucus are heavily glycosylated proteins called mucins. Mucins are key components of the innate immune system as they aid in the clearance of pathogens and can decrease pathogen virulence. It has also been recently reported that individual mucins and derived glycans can attenuate the virulence of the human pathogen Pseudomonas aeruginosa. Here, we show data indicating that mucins not only play a role in host defense but that they can also be subverted by P. aeruginosa to cause disease. We found that the mucin MUL-1 and mucin-derived monosaccharides N-acetyl-galactosamine and N-acetylglucosamine are required for P. aeruginosa killing of Caenorhabditis elegans. We also found that the defective adhesion of P. aeruginosa to human lung alveolar epithelial cells, deficient in the mucin MUC1, can be reversed by the addition of individual monosaccharides. The monosaccharides identified in this study are found in a wide range of organisms where they act as host factors required for bacterial pathogenesis. While mucins in C. elegans lack sialic acid caps, which makes their monosaccharides readily available, they are capped in other species. Pathogens such as P. aeruginosa that lack sialidases may rely on enzymes from other bacteria to utilize mucin-derived monosaccharides. IMPORTANCE One of the first lines of defense present at mucosal epithelial tissues is mucus, which is a highly viscous material formed by mucin glycoproteins. Mucins serve various functions, but importantly they aid in the clearance of pathogens and debris from epithelial barriers and serve as innate immune factors. In this study, we describe a requirement of host monosaccharides, likely derived from host mucins, for the ability of Pseudomonas aeruginosa to colonize the intestine and ultimately cause death in Caenorhabditis elegans. We also demonstrate that monosaccharides alter the ability of bacteria to bind to both Caenorhabditis elegans intestinal cells and human lung alveolar epithelial cells, suggesting that there are conserved mechanisms underlying host-pathogen interactions in a range of organisms. By gaining a better understanding of pathogen-mucin interactions, we can develop better approaches to protect against pathogen infection.

scholarly journals Contextual Flexibility in Pseudomonas aeruginosa Central Carbon Metabolism during Growth in Single Carbon Sources

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Stephen K. Dolan ◽  
Michael Kohlstedt ◽  
Stephen Trigg ◽  
Pedro Vallejo Ramirez ◽  
Clemens F. Kaminski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Metabolic Flux ◽  
Antimicrobial Agents ◽  
Carbon Sources ◽  
Aerobic Denitrification ◽  
Human Pathogen ◽  
Content Type ◽  
Opportunistic Human Pathogen

ABSTRACT Pseudomonas aeruginosa is an opportunistic human pathogen, particularly noted for causing infections in the lungs of people with cystic fibrosis (CF). Previous studies have shown that the gene expression profile of P. aeruginosa appears to converge toward a common metabolic program as the organism adapts to the CF airway environment. However, we still have only a limited understanding of how these transcriptional changes impact metabolic flux at the systems level. To address this, we analyzed the transcriptome, proteome, and fluxome of P. aeruginosa grown on glycerol or acetate. These carbon sources were chosen because they are the primary breakdown products of an airway surfactant, phosphatidylcholine, which is known to be a major carbon source for P. aeruginosa in CF airways. We show that the fluxes of carbon throughout central metabolism are radically different among carbon sources. For example, the newly recognized “EDEMP cycle” (which incorporates elements of the Entner-Doudoroff [ED] pathway, the Embden-Meyerhof-Parnas [EMP] pathway, and the pentose phosphate [PP] pathway) plays an important role in supplying NADPH during growth on glycerol. In contrast, the EDEMP cycle is attenuated during growth on acetate, and instead, NADPH is primarily supplied by the reaction catalyzed by isocitrate dehydrogenase(s). Perhaps more importantly, our proteomic and transcriptomic analyses revealed a global remodeling of gene expression during growth on the different carbon sources, with unanticipated impacts on aerobic denitrification, electron transport chain architecture, and the redox economy of the cell. Collectively, these data highlight the remarkable metabolic plasticity of P. aeruginosa; that plasticity allows the organism to seamlessly segue between different carbon sources, maximizing the energetic yield from each. IMPORTANCE Pseudomonas aeruginosa is an opportunistic human pathogen that is well known for causing infections in the airways of people with cystic fibrosis. Although it is clear that P. aeruginosa is metabolically well adapted to life in the CF lung, little is currently known about how the organism metabolizes the nutrients available in the airways. In this work, we used a combination of gene expression and isotope tracer (“fluxomic”) analyses to find out exactly where the input carbon goes during growth on two CF-relevant carbon sources, acetate and glycerol (derived from the breakdown of lung surfactant). We found that carbon is routed (“fluxed”) through very different pathways during growth on these substrates and that this is accompanied by an unexpected remodeling of the cell’s electron transfer pathways. Having access to this “blueprint” is important because the metabolism of P. aeruginosa is increasingly being recognized as a target for the development of much-needed antimicrobial agents.

scholarly journals A rhlI 5′ UTR-Derived sRNA Regulates RhlR-Dependent Quorum Sensing in Pseudomonas aeruginosa

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Maureen K. Thomason ◽  
Maya Voichek ◽  
Daniel Dar ◽  
Victoria Addis ◽  
David Fitzgerald ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Homoserine Lactone ◽  
Regulatory Elements ◽  
Content Type ◽  
Reading Frame ◽  
Bacterial Physiology ◽  
Small Regulatory Rna ◽  
Key Enzyme ◽  
Opportunistic Human Pathogen

ABSTRACT N-Acyl homoserine lactone (AHL) quorum sensing (QS) controls expression of over 200 genes in Pseudomonas aeruginosa. There are two AHL regulatory systems: the LasR-LasI circuit and the RhlR-RhlI system. We mapped transcription termination sites affected by AHL QS in P. aeruginosa, and in doing so we identified AHL-regulated small RNAs (sRNAs). Of interest, we noted that one particular sRNA was located within the rhlI locus. We found that rhlI, which encodes the enzyme that produces the AHL N-butanoyl-homoserine lactone (C4-HSL), is controlled by a 5′ untranslated region (UTR)-derived sRNA we name RhlS. We also identified an antisense RNA encoded opposite the beginning of the rhlI open reading frame, which we name asRhlS. RhlS accumulates as wild-type cells enter stationary phase and is required for the production of normal levels of C4-HSL through activation of rhlI translation. RhlS also directly posttranscriptionally regulates at least one other unlinked gene, fpvA. The asRhlS appears to be expressed at maximal levels during logarithmic growth, and we suggest RhlS may act antagonistically to the asRhlS to regulate rhlI translation. The rhlI-encoded sRNAs represent a novel aspect of RNA-mediated tuning of P. aeruginosa QS. IMPORTANCE The opportunistic human pathogen Pseudomonas aeruginosa possesses multiple quorum sensing systems that regulate and coordinate production of virulence factors and adaptation to different environments. Despite extensive research, the regulatory elements that play a role in this complex network are still not fully understood. By using several RNA sequencing techniques, we were able to identify a small regulatory RNA we named RhlS. RhlS increases translation of RhlI, a key enzyme in the quorum sensing pathway, and represses the fpvA mRNA encoding one of the siderophore pyoverdine receptors. Our results highlight a new regulatory layer of P. aeruginosa quorum sensing and contribute to the growing understanding of the role regulatory RNAs play in bacterial physiology.

scholarly journals Activation Mechanism and Cellular Localization of Membrane-Anchored Alginate Polymerase in Pseudomonas aeruginosa

2017 ◽  
Vol 83 (9) ◽  
Author(s):  
M. Fata Moradali ◽  
Shirin Ghods ◽  
Bernd H. A. Rehm
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Amino Acid ◽  
Structural Model ◽  
Second Messenger ◽  
Catalytic Site ◽  
Activation Mechanism ◽  
Amino Acid Residues ◽  
Human Pathogen ◽  
Content Type ◽  
Opportunistic Human Pathogen

ABSTRACT The exopolysaccharide alginate, produced by the opportunistic human pathogen Pseudomonas aeruginosa, confers a survival advantage to the bacterium by contributing to the formation of characteristic biofilms during infection. Membrane-anchored proteins Alg8 (catalytic subunit) and Alg44 (copolymerase) constitute the alginate polymerase that is being activated by the second messenger molecule bis-(3′, 5′)-cyclic dimeric GMP (c-di-GMP), but the mechanism of activation remains elusive. To shed light on the c-di-GMP-mediated activation of alginate polymerization in vivo, an in silico structural model of Alg8 fused to the c-di-GMP binding PilZ domain informed by the structure of cellulose synthase, BcsA, was developed. This structural model was probed by site-specific mutagenesis and different cellular levels of c-di-GMP. Results suggested that c-di-GMP-mediated activation of alginate polymerization involves amino acids residing at two loops, including H323 (loop A) and T457 and E460 (loop B), surrounding the catalytic site in the predicted model. The activities of the respective Alg8 variants suggested that c-di-GMP-mediated control of substrate access to the catalytic site of Alg8 is dissimilar to the known activation mechanism of BcsA. Alg8 variants responded differently to various c-di-GMP levels, while MucR imparted c-di-GMP for activation of alginate polymerase. Furthermore, we showed that Alg44 copolymerase constituted a stable dimer, with its periplasmic domains required for protein localization and alginate polymerization and modification. Superfolder green fluorescent protein (GFP) fusions of Alg8 and Alg44 showed a nonuniform, punctate, and patchy arrangement of both proteins surrounding the cell. Overall, this study provides insights into the c-di-GMP-mediated activation of alginate polymerization while assigning functional roles to Alg8 and Alg44, including their subcellular localization and distribution. IMPORTANCE The exopolysaccharide alginate is an important biofilm component of the opportunistic human pathogen P. aeruginosa and the principal cause of the mucoid phenotype that is the hallmark of chronic infections of cystic fibrosis patients. The production of alginate is mediated by interacting membrane proteins Alg8 and Alg44, while their activity is posttranslationally regulated by the second messenger c-di-GMP, a well-known regulator of the synthesis of a range of other exopolysaccharides in bacteria. This study provides new insights into the unknown activation mechanism of alginate polymerization by c-di-GMP. Experimental evidence that the activation of alginate polymerization requires the engagement of specific amino acid residues residing at the catalytic domain of Alg8 glycosyltransferase was obtained, and these residues are proposed to exert an allosteric effect on the PilZAlg44 domain upon c-di-GMP binding. This mechanism is dissimilar to the proposed mechanism of the autoinhibition of cellulose polymerization imposed by salt bridge formation between amino acid residues and released upon c-di-GMP binding, leading to activation of polymerization. On the other hand, conserved amino acid residues in the periplasmic domain of Alg44 were found to be involved in alginate polymerization as well as modification events, i.e., acetylation and epimerization. Due to the critical role of c-di-GMP in the regulation of many biological processes, particularly the motility-sessility switch and also the emergence of persisting mucoid phenotypes, these results aid to reach a better understanding of biofilm-associated regulatory networks and c-di-GMP signaling and might assist the development of inhibitory drugs.

DI-ICR-FT-MS-based high-throughput deep metabotyping: a case study of the Caenorhabditis elegans–Pseudomonas aeruginosa infection model

2014 ◽  
Vol 407 (4) ◽  
pp. 1059-1073 ◽  
Author(s):  
Michael Witting ◽  
Marianna Lucio ◽  
Dimitrios Tziotis ◽  
Brigitte Wägele ◽  
Karsten Suhre ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Caenorhabditis Elegans ◽  
High Throughput ◽  
Infection Model ◽  
Pseudomonas Aeruginosa Infection

scholarly journals In Vitro Comparison of Ceftolozane-Tazobactam to Traditional Beta-Lactams and Ceftolozane-Tazobactam as an Alternative to Combination Antimicrobial Therapy for Pseudomonas aeruginosa

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Kellie J. Goodlet ◽  
David P. Nicolau ◽  
Michael D. Nailor
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Single Agent ◽  
Cross Resistance ◽  
Combination Therapies ◽  
Beta Lactams ◽  
Content Type ◽  
Risk Patients ◽  
Hospital Acquired Pneumonia ◽  
Hospital Acquired

ABSTRACT Guidelines for the treatment of sepsis, febrile neutropenia, and hospital-acquired pneumonia caused by Pseudomonas aeruginosa include empirical regimens incorporating two antibiotics from different classes with activity against P. aeruginosa for select at-risk patients to increase the likelihood that the organism will be susceptible to at least one agent. The activity against P. aeruginosa and the rates of cross-resistance of ceftolozane-tazobactam were compared to those of the β-lactam comparators cefepime, ceftazidime, piperacillin-tazobactam, and meropenem alone and cumulatively with ciprofloxacin or tobramycin. Nonurine P. aeruginosa isolates were collected from adult inpatients at 44 geographically diverse U.S. hospitals. MICs were determined using reference broth microdilution methods. Of the 1,257 isolates collected, 29% were from patients in intensive care units and 39% were from respiratory sites. The overall rate of susceptibility to ceftolozane-tazobactam was high at 97%, whereas it was 72 to 76% for cefepime, ceftazidime, piperacillin-tazobactam, and meropenem. The rate of nonsusceptibility to all four comparator β-lactams was 11%; of the isolates nonsusceptible to the four comparator β-lactams, 80% remained susceptible to ceftolozane-tazobactam. Among the isolates nonsusceptible to the tested β-lactam comparators, less than half were susceptible to ciprofloxacin. By comparison, approximately 80% of the β-lactam-nonsusceptible isolates were susceptible to tobramycin, for overall cumulative susceptibility rates of 94 to 95%, nearly 10% higher than that of the ciprofloxacin–β-lactam combinations and approaching that of ceftolozane-tazobactam as a single agent. The rates of susceptibility to ceftolozane-tazobactam were consistently high, with little observable cross-resistance. Ceftolozane-tazobactam monotherapy performed at or above the level of commonly utilized combination therapies on the basis of in vitro susceptibilities. Ceftolozane-tazobactam should be considered for use in patients at high risk for resistant P. aeruginosa infection and as an alternative to empirical combination therapy, especially for patients unable to tolerate aminoglycosides.

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