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Mahmud HA, Wakeman CA. Navigating collateral sensitivity: insights into the mechanisms and applications of antibiotic resistance trade-offs. Front Microbiol 2024; 15:1478789. [PMID: 39512935 PMCID: PMC11540712 DOI: 10.3389/fmicb.2024.1478789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 10/10/2024] [Indexed: 11/15/2024] Open
Abstract
The swift rise of antibiotic resistance, coupled with limited new antibiotic discovery, presents a significant hurdle to global public health, demanding innovative therapeutic solutions. Recently, collateral sensitivity (CS), the phenomenon in which resistance to one antibiotic increases vulnerability to another, has come to light as a potential path forward in this attempt. Targeting either unidirectional or reciprocal CS holds promise for constraining the emergence of drug resistance and notably enhancing treatment outcomes. Typically, the alteration of bacterial physiology, such as bacterial membrane potential, expression of efflux pumps, cell wall structures, and endogenous enzymatic actions, are involved in evolved collateral sensitivity. In this review, we present a thorough overview of CS in antibiotic therapy, including its definition, importance, and underlying mechanisms. We describe how CS can be exploited to prevent the emergence of resistance and enhance the results of treatment, but we also discuss the challenges and restrictions that come with implementing this practice. Our review underscores the importance of continued exploration of CS mechanisms in the broad spectrum and clinical validation of therapeutic approaches, offering insights into its role as a valuable tool in combating antibiotic resistance.
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Affiliation(s)
- Hafij Al Mahmud
- Department of Biological Sciences, Texas Tech University, Lubbock, TX, United States
| | - Catherine A. Wakeman
- Department of Biological Sciences, Texas Tech University, Lubbock, TX, United States
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McNeil JC, Sommer LM, Joseph M, Hulten KG, Kaplan SL. Penicillin susceptibility among Staphylococcus aureus skin and soft tissue infections at a children's hospital. Microbiol Spectr 2024; 12:e0086924. [PMID: 39248483 PMCID: PMC11448063 DOI: 10.1128/spectrum.00869-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 08/13/2024] [Indexed: 09/10/2024] Open
Abstract
Shortly after its introduction into clinical practice, Staphylococcus aureus isolates gained resistance to penicillin via the acquisition of β-lactamases. A number of centers have recently described an increase in the proportion of invasive methicillin-susceptible S. aureus (MSSA), which are also susceptible to penicillin (PSSA). Little data are available regarding the prevalence or impact of PSSA in skin and soft tissue infections (SSTI). Community-acquired MSSA SSTI isolates were obtained through a surveillance study at Texas Children's Hospital from January 2017 to December 2021. A total of 200 random isolates underwent PCR for blaZ β-lactamase; blaZ-negative isolates then underwent penicillin susceptibility testing using macrobroth dilution. Isolates which were blaZ negative and had a penicillin MIC ≤0.125 µg/mL were regarded as PSSA with the remainder regarded as penicillin-resistant MSSA (PR-MSSA). All PSSA underwent multilocus sequence typing. Medical records were reviewed. The median age of subjects was 4.2 years (IQR: 1.6-10.5). PSSA accounted for 9% of isolates during the study period. PSSA and PR-MSSA cases were similar with respect to age, demographics, and rates of prior antibiotic exposure. PSSA isolates less often had vancomycin MIC ≥1.5 µg/mL. Furthermore, 39% of PSSA were variants of sequence type 1. In multivariable analyses, penicillin susceptibility was independently associated with both hospital admission and surgical intervention. PSSA account for a small but significant proportion of MSSA SSTI in children. Clinically distinguishing patients with PSSA and PR-MSSA SSTI is challenging. However, PSSA SSTI were independently associated with higher rates of hospital admission as well as the need for surgical intervention suggesting a significant clinical impact.IMPORTANCEThe vast majority of Staphylococcus aureus in the US are penicillin resistant with most clinical labs no longer reporting penicillin susceptibility for this organism. A number of centers, however, have reported increasing penicillin susceptibility among invasive S. aureus infections. Skin and soft tissue infections (SSTI) are far more common than invasive infections, yet the frequency and impact of penicillin-susceptible S. aureus (PSSA) in this population are uncertain. Through active surveillance at a children's hospital, we found that 9% of methicillin-susceptible S. aureus SSTI isolates were PSSA. PSSA were independently associated with hospital admission for the management of SSTI as well as the need for debridement in the operating room. Given that most SSTI are managed in the outpatient setting, these findings suggest a clinical impact of this phenotype and the need for a reassessment of the value in susceptibility testing and potentially even treatment with penicillin.
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Affiliation(s)
- J. Chase McNeil
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA
| | - Lauren M. Sommer
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA
| | - Marritta Joseph
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA
| | - Kristina G. Hulten
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA
| | - Sheldon L. Kaplan
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA
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Petersiel N, Giulieri S, Daniel DS, Fan SH, Ersoy SC, Davis JS, Bayer AS, Howden BP, Tong SYC. Genomic investigation and clinical correlates of the in vitro β-lactam: NaHCO 3 responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial. Antimicrob Agents Chemother 2024; 68:e0021824. [PMID: 38837393 PMCID: PMC11232399 DOI: 10.1128/aac.00218-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 05/12/2024] [Indexed: 06/07/2024] Open
Abstract
NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to β-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with β-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal β-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered "NaHCO3-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a β-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a β-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro β-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a β-lactam.
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Affiliation(s)
- Neta Petersiel
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Stefano Giulieri
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Diane S. Daniel
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sook-Ha Fan
- The Lundquist Institute for Biomedical Innovation, Torrance, California, USA
| | - Selvi C. Ersoy
- The Lundquist Institute for Biomedical Innovation, Torrance, California, USA
| | - Joshua S. Davis
- Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Infectious Diseases, John Hunter Hospital, Newcastle, New South Wales, Australia
| | - Arnold S. Bayer
- The Lundquist Institute for Biomedical Innovation, Torrance, California, USA
- The Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Benjamin P. Howden
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Centre for Pathogen Genomics, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia
| | - Steven Y. C. Tong
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - on behalf of the CAMERA2 study groupLyeDavid C.YahavDafnaSudArchanaRobinsonJ. OwenNelsonJaneArchuletaSophiaRobertsMatthew A.CassAlanPatersonDavid L.FooHongPaulMicalGuyStephen D.TramontanaAdrian R.WallsGenevieve B.McBrideStephenBakNarinGhoshNiladriRogersBenjamin A.RalphAnna P.DaviesJaneFergusonPatricia E.DotelRavindraMcKewGenevieve L.GrayTimothy J.HolmesNatasha E.SmithSimonWarnerMorgyn S.KalimuddinShirinYoungBarnaby E.RunnegarNaomiAndresenDavid N.AnagnostouNicholas A.JohnsonSandra A.ChatfieldMark D.ChengAllen C.FowlerVance G.Jr.HowdenBenjamin P.MeagherNiamhPriceDavid J.van HalSebastiaan J.O'SullivanMatthew V. N.
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- The Lundquist Institute for Biomedical Innovation, Torrance, California, USA
- Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Infectious Diseases, John Hunter Hospital, Newcastle, New South Wales, Australia
- The Geffen School of Medicine, University of California, Los Angeles, California, USA
- Centre for Pathogen Genomics, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia
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Bavaro DF, Belati A, Bussini L, Cento V, Diella L, Gatti M, Saracino A, Pea F, Viale P, Bartoletti M. Safety and effectiveness of fifth generation cephalosporins for the treatment of methicillin-resistant staphylococcus aureus bloodstream infections: a narrative review exploring past, present, and future. Expert Opin Drug Saf 2024; 23:9-36. [PMID: 38145925 DOI: 10.1080/14740338.2023.2299377] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/21/2023] [Indexed: 12/27/2023]
Abstract
INTRODUCTION Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a major issue in healthcare, since it is often associated with endocarditis or deep site foci. Relevant morbidity and mortality associated with MRSA-BSIs forced the development of new antibiotic strategies; in particular, this review will focus the attention on fifth-generation cephalosporins (ceftaroline/ceftobiprole), that are the only ß-lactams active against MRSA. AREAS COVERED The review discusses the available randomized controlled trials and real-world observational studies conducted on safety and effectiveness of ceftaroline/ceftobiprole for the treatment of MRSA-BSIs. Finally, a proposal of MRSA-BSI treatment flowchart, based on fifth-generation cephalosporins, is described. EXPERT OPINION The use of anti-MRSA cephalosporins is an acceptable choice either in monotherapy or combination therapy for the treatment of MRSA-BSIs due to their relevant effectiveness and safety. Particularly, their use may be advisable in combination therapy in case of severe infections (including endocarditis or persistent bacteriemia) or in monotherapy in subjects at higher risk of drugs-induced toxicity with older regimens. On the contrary, caution should be taken in case of suspected/ascertained central nervous system infections due to inconsistent data regarding penetration of these drugs in cerebrospinal fluid and brain tissues.
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Affiliation(s)
- Davide Fiore Bavaro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Infectious Disease Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alessandra Belati
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro", Bari, Italy
| | - Linda Bussini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Infectious Disease Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Valeria Cento
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Microbiology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Lucia Diella
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro", Bari, Italy
| | - Milo Gatti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
- Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Annalisa Saracino
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro", Bari, Italy
| | - Federico Pea
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
- Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Pierluigi Viale
- Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Infectious Disease Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Michele Bartoletti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Infectious Disease Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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Yang Y, Liu X, Zhou D, He J, Chen Q, Xu Q, Wu S, Zhang W, Yao Y, Fu Y, Hua X, Yu Y, Wang X. Alteration of adeS Contributes to Tigecycline Resistance and Collateral Sensitivity to Sulbactam in Acinetobacter baumannii. Microbiol Spectr 2023; 11:e0459422. [PMID: 37184390 PMCID: PMC10269438 DOI: 10.1128/spectrum.04594-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 04/13/2023] [Indexed: 05/16/2023] Open
Abstract
The treatment of extensively drug-resistant (XDR) A. baumannii has emerged as a major problem. Tigecycline (TGC) and sulbactam (SUL) are both effective antibiotics against XDR A. baumannii. Here, we investigated the in-host evolution and mechanism of collateral sensitivity (CS) phenomenon in development of tigecycline resistance accompanied by a concomitant increase of sulbactam susceptibility. A total of four XDR A. baumannii strains were sequentially isolated from the same patient suffering from bacteremia. Core-genome multilocus sequence typing separated all the strains into two clusters. Comparative analysis of isolate pair 1 revealed that multiplication of blaOXA-23 within Tn2006 on the chromosome contributed to the change in the antimicrobial susceptibility phenotype of isolate pair 1. Additionally, we observed the emergence of CS to sulbactam in isolate pair 2, as demonstrated by an 8-fold increase in the TGC MIC with a simultaneous 4-fold decrease in the SUL MIC. Compared to the parental strain Ab-3557, YZM-0406 showed partial deletion in the two-component system sensor adeS. Reconstruction of the adeS mutant in Ab-3557 in situ suggested that TGC resistance and CS to SUL were mainly caused by the mutation of adeS. Overall, our study reported a novel CS combination of TGC and SUL in A. baumannii and further revealed a mechanism of CS attributed to the mutation of adeS. This study provides a valuable foundation for developing effective regimens and sequential combinations of tigecycline and sulbactam against XDR A. baumannii. IMPORTANCE Collateral sensitivity (CS) has become an increasingly common evolutionary trade-off during adaptive bacterial evolution. Here, we report a novel combination of tigecycline (TGC) resistance and CS to sulbactam (SUL) in A. baumannii. TGC and SUL are both effective antibiotics against XDR A. baumannii, and it is essential to reveal the mechanism of CS between TGC and SUL. In our study, the partial deletion of adeS, a two-component system sensor, was confirmed to be the key factor contributing to this CS phenomenon. This study provides a valuable foundation for developing effective regimens and sequential combinations of tigecycline and sulbactam against XDR A. baumannii.
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Affiliation(s)
- Yunxing Yang
- Department of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaochen Liu
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang, China
- Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Danyan Zhou
- Department of Clinical Laboratory, Xiangshan First People’s Hospital Medical and Health Group, Ningbo, Zhejiang, China
| | - Jintao He
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang, China
- Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qiong Chen
- Department of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingye Xu
- Department of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shenghai Wu
- Department of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiying Zhang
- Department of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yue Yao
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang, China
- Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ying Fu
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang, China
- Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaoting Hua
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang, China
- Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yunsong Yu
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang, China
- Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xianjun Wang
- Department of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Fan SH, Proctor RA, Ersoy SC, Manna AC, Cheung AL, Götz F, Chambers HF, Bayer AS. Role of the NaHCO 3 Transporter MpsABC in the NaHCO 3-β-Lactam-Responsive Phenotype in Methicillin-Resistant Staphylococcus aureus. Microbiol Spectr 2023; 11:e0014123. [PMID: 37102972 PMCID: PMC10269494 DOI: 10.1128/spectrum.00141-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/12/2023] [Indexed: 04/28/2023] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infections are an increasing concern due to their intrinsic resistance to most standard-of-care β-lactam antibiotics. Recent studies of clinical isolates have documented a novel phenotype, termed NaHCO3 responsiveness, in which a substantial proportion of MRSA strains exhibit enhanced susceptibility to β-lactams such as cefazolin and oxacillin in the presence of NaHCO3. A bicarbonate transporter, MpsAB (membrane potential-generating system), was recently found in S. aureus, where it plays a role in concentrating NaHCO3 for anaplerotic pathways. Here, we investigated the role of MpsAB in mediating the NaHCO3 responsiveness phenotype. Radiolabeled NaH14CO3 uptake profiling revealed significantly higher accumulation in NaHCO3-responsive vs nonresponsive MRSA strains when grown in ambient air. In contrast, under 5% CO2 conditions, NaHCO3-responsive (but not nonresponsive) strains exhibited repressed uptake. Oxacillin MICs were measured in four prototype strains and their mpsABC deletion mutants in the presence of NaHCO3 supplementation under 5% CO2 conditions. NaHCO3-mediated reductions in oxacillin MICs were observed in the responsive parental strains but not in mpsABC deletion mutants. No significant impact on oxacillin MICs was observed in the nonresponsive strains under the same conditions. Transcriptional and translational studies were carried out using both quantitative reverse transcription-PCR (qRT-PCR) and mpsA-green fluorescent protein (GFP) fusion constructs; these investigations showed that mpsA expression and translation were significantly upregulated during mid-exponential-phase growth in oxacillin-NaHCO3-supplemented medium in responsive versus nonresponsive strains. Taken together, these data show that the NaHCO3 transporter MpsABC is a key contributor to the NaHCO3-β-lactam responsiveness phenotype in MRSA. IMPORTANCE MRSA infections are increasingly difficult to treat, due in part to their resistance to most β-lactam antibiotics. A novel and relatively common phenotype, termed NaHCO3 responsiveness, has been identified in which MRSA strains show increased susceptibility in vitro and in vivo to β-lactams in the presence of NaHCO3. A recently described S. aureus NaHCO3 transporter, MpsAB, is involved in intracellular NaHCO3 concentration for anaplerotic pathways. We investigated the role of MpsAB in mediating the NaHCO3 responsiveness phenotype in four prototype MRSA strains (two responsive and two nonresponsive). We demonstrated that MpsABC is an important contributor to the NaHCO3-β-lactam responsiveness phenotype. Our study adds to the growing body of well-defined characteristics of this novel phenotype, which could potentially translate to alternative targets for MRSA treatment using β-lactams.
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Affiliation(s)
- Sook-Ha Fan
- The Lundquist Institute, Torrance, California, USA
| | - Richard A. Proctor
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
- Department of Medical Microbiology/Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | | | - Adhar C. Manna
- Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Ambrose L. Cheung
- Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Friedrich Götz
- Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine Tübingen, University of Tübingen, Germany
| | | | - Arnold S. Bayer
- The Lundquist Institute, Torrance, California, USA
- Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Antonello RM, Canetti D, Riccardi N. Daptomycin synergistic properties from in vitro and in vivo studies: a systematic review. J Antimicrob Chemother 2022; 78:52-77. [PMID: 36227704 DOI: 10.1093/jac/dkac346] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/21/2022] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Daptomycin is a bactericidal lipopeptide antibiotic approved for the treatment of systemic infections (i.e. skin and soft tissue infections, bloodstream infections, infective endocarditis) caused by Gram-positive cocci. It is often prescribed in association with a partner drug to increase its bactericidal effect and to prevent the emergence of resistant strains during treatment; however, its synergistic properties are still under evaluation. METHODS We performed a systematic review to offer clinicians an updated overview of daptomycin synergistic properties from in vitro and in vivo studies. Moreover, we reported all in vitro and in vivo data evaluating daptomycin in combination with other antibiotic agents, subdivided by antibiotic classes, and a summary graph presenting the most favourable combinations at a glance. RESULTS A total of 92 studies and 1087 isolates (723 Staphylococcus aureus, 68 Staphylococcus epidermidis, 179 Enterococcus faecium, 105 Enterococcus faecalis, 12 Enterococcus durans) were included. Synergism accounted for 30.9% of total interactions, while indifferent effect was the most frequently observed interaction (41.9%). Antagonistic effect accounted for 0.7% of total interactions. The highest synergistic rates against S. aureus were observed with daptomycin in combination with fosfomycin (55.6%). For S. epidermidis and Enterococcus spp., the most effective combinations were daptomycin plus ceftobiprole (50%) and daptomycin plus fosfomycin (63.6%) or rifampicin (62.8%), respectively. FUTURE PERSPECTIVES We believe this systematic review could be useful for the future updates of guidelines on systemic infections where daptomycin plays a key role.
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Affiliation(s)
- Roberta Maria Antonello
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50121, Italy
| | - Diana Canetti
- Department of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Niccolò Riccardi
- Department of Clinical and Experimental Medicine, Infectious Diseases Unit, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa 56124, Italy
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Does a New Antibiotic Scheme Improve the Outcome of Staphylococcus aureus-Caused Acute Prosthetic Joint Infections (PJI) Treated with Debridement, Antibiotics and Implant Retention (DAIR)? Antibiotics (Basel) 2022; 11:antibiotics11070922. [PMID: 35884176 PMCID: PMC9312051 DOI: 10.3390/antibiotics11070922] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/03/2022] [Accepted: 07/05/2022] [Indexed: 12/04/2022] Open
Abstract
One of the most commonly used treatments for acute prosthetic joint infection (PJI) is DAIR (debridement, antibiotics and implant retention), which comprises the debridement and the retention of the implant, followed by antibiotic treatment. The efficacy of DAIR remains unclear, as the literature has demonstrated variable success rates, ranging from 26% to 92%. The Staphylococcus aureus is one of the most closely related causative microorganisms, especially with acute and late-acute PJI; it has been identified as one of the most significant predictors of DAIR failure. The current guidelines consider the use of vancomycin as the therapy of choice, but it requires the close control of possible side effects. The aim of this study is to determine if a new combination of antibiotics (a highly bactericidal initial combination followed by an antibiofilm scheme) decreases the failure of DAIR-treated acute prosthetic joint infection (PJI) caused by Staphylococcus aureus. A retrospective analysis of cases of orthopedic infections during a nine-year period (2011–2019) was performed. A total of 45 acute PJI cases caused by S. aureus were diagnosed. The results of two antibiotic schemes were compared: a novel scheme comprising 5 days of daptomycin (10 mg/kg/24 h) + cloxacillin (2 g/6 h) followed by levofloxacin (500 mg/24 h) + rifampicin (600 mg/24 h), versus a traditional, less bactericidal scheme of vancomycin (1000 mg/12 h) plus rifampicin (600 mg/24 h) or levofloxacin (500 mg/24 h) plus rifampicin (600 mg/24 h). Twenty-two out of the twenty-four patients treated with the new scheme (91.6%) were free of infection after 24.8 months of mean follow-up, whereas fourteen out of twenty-one patients (66.6%) were free of infection after 46.6 months of follow-up. This difference was statistically significant (p = 0.036). Demographic comparisons demonstrated homogeneous features, except the Charlson score, which was higher in the novel scheme group (p = 0.047). The combination of high-dose daptomycin and cloxacillin, followed by levofloxacin plus rifampicin, together with surgical treatment, shows better results when compared with other antibiotic schemes for treating acute PJI caused by S. aureus in which DAIR was performed.
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Cacopardo B, Cattaneo D, Cortese F, Di Luca M, Falcone M, Marchetti G, Tascini C, Tiseo G, Venditti M. Role of dalbavancin as combination therapy: evidences from the literature and clinical scenarios. Expert Rev Anti Infect Ther 2022; 20:997-1004. [PMID: 35353020 DOI: 10.1080/14787210.2022.2060820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION The off-label use of dalbavancin in patients with infections other than acute bacterial skin and skin structure infections (ABSSSI) represents an interesting therapeutic option. Its use as monotherapy or in combination with other antibiotics should be better defined. AREAS COVERED The aim of this review is to summarize evidence about the potential role of dalbavancin in combination with other antibiotics and describe clinical scenarios in which combination regimens including dalbavancin are useful. The studies were retrieved from PubMed using different combinations of keywords ("dalbavancin", "combination", "synergy"). EXPERT OPINION Limited data about the use of dalbavancin in monotherapy or combined with other antibiotics are available. In vitro assays showed a synergistic effect of dalbavancin when combined with beta-lactam antibiotics. The use of dalbavancin as combination therapy in patients with ABSSSI did not demonstrate a superiority compared to monotherapy. Conversely, combination regimens including dalbavancin may be useful in specific infection types, such as bone and prosthetic joint infections or subacute/chronic intravascular infections with no possibility of device removal. Potential partner drugs might be rifampin, beta-lactams, fluoroquinolones, doxycycline and trimethoprim/sulfamethoxazole. The choice of the companion drug should be tailored on in vitro results of synergistic tests, patient's profile and type of infection.
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Affiliation(s)
- Bruno Cacopardo
- Department of Clinical and Molecular Biomedicine, Chair of Infectious Diseases, University of Catania, 95124 Catania, Italy
| | - Dario Cattaneo
- Unit of Clinical Pharmacology, Fatebenefratelli Sacco University Hospital, Milan, Italy
| | | | | | - Marco Falcone
- Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa
| | - Giulia Marchetti
- Clinic of Infectious Disease and Tropical Medicine, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy
| | - Carlo Tascini
- Department of Medicine, University of Udine, Udine, Italy
| | - Giusy Tiseo
- Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa
| | - Mario Venditti
- Department of Public Health and Infectious Diseases, 'Sapienza' University of Rome, Italy
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The role of mprF mutations in "see-saw effect" of Daptomycin-resistant methicillin-resistant Staphylococcus aureus isolates. Antimicrob Agents Chemother 2021; 66:e0129521. [PMID: 34662187 DOI: 10.1128/aac.01295-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The emergence of daptomycin-resistant (DAP-R) Staphylococcus aureus strains has become a global problem. Point mutations in mprF are the main cause of daptomycin (DAP) treatment failure. However, the impact of these specific point-mutations in methicillin-resistant S. aureus (MRSA) strains associated with DAP resistance and the "see-saw effect" of distinct beta-lactams remains unclear. In this study, we used three series of clinical MRSA strains with three distinct mutated mprF alleles from clone complexes (CC) 5 and 59 to explore the "see-saw effect" and the combination effect of DAP plus beta-lactams. Through construction of mprF deletion and complementation strains of SA268, we determined that mprF-S295A, mprF-S337L and one novel mutation of mprF-I348del within the bifunctional domain lead to DAP resistance. Compared with wild-type mprF cloned from a DAP-susceptible (DAP-S) strain, these three mprF mutations conferred the "see-saw effect" to distinct beta-lactams in the SA268ΔmprF strains and mutated-mprF (I348del and S337L) did not alter the cell surface positive charge (P > 0.05). The susceptibility to beta-lactams increased significantly in DAP-R CC59 strains and the "see-saw effect" was found to be associated with distinct mutated mprF alleles and the category of beta-lactams. The synergistic activity of DAP plus oxacillin was detected in all DAP-R MRSA strains. Continued progress in understanding the mechanism of restoring susceptibility to beta-lactam antibiotics mediated by the mprF mutation and its impact on beta-lactam combination therapy will provide fundamental insights into treatment of MRSA infections.
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Hines KM, Shen T, Ashford NK, Waalkes A, Penewit K, Holmes EA, McLean K, Salipante SJ, Werth BJ, Xu L. Occurrence of cross-resistance and β-lactam seesaw effect in glycopeptide-, lipopeptide- and lipoglycopeptide-resistant MRSA correlates with membrane phosphatidylglycerol levels. J Antimicrob Chemother 2021; 75:1182-1186. [PMID: 32016379 DOI: 10.1093/jac/dkz562] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 11/14/2019] [Accepted: 12/16/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Glycopeptides (GPs), lipopeptides (LPs) and lipoglycopeptides (LGPs) are related antimicrobials important for the management of invasive MRSA infections. Cross-resistance among these antibiotics in MRSA is well documented, as is the observation that susceptibility of MRSA to β-lactams increases as susceptibility to GPs and LPs decreases (i.e. the seesaw effect). Efforts to understand the relationship between GP/LP/LGP cross-resistance and the seesaw effect have focused on the PBPs, but the role of lipid metabolism has not been investigated. OBJECTIVES Since the cell membrane is structurally and metabolically integrated with the cell wall and anchors associated proteins, including PBPs, we examined the relationship between membrane lipid composition and the phenomena of cross-resistance among GPs/LPs/LGPs and the β-lactam seesaw effect. METHODS We selected for daptomycin, vancomycin and dalbavancin resistance using the USA300 strain JE2 and evaluated the resulting mutants by WGS, MS-based lipidomics and antimicrobial susceptibility testing to assess the relationship between membrane composition, cross-resistance, and the seesaw effect. RESULTS We observed cross-resistance to GPs/LPs/LGPs among the selected strains and the seesaw effect against various β-lactams, depending on the PBP targets of the particular β-lactam. We found that modification of membrane composition occurs not only in daptomycin-selected strains, but also vancomycin- and dalbavancin-selected strains. Significantly, we observed that the abundance of most phosphatidylglycerols positively correlates with MICs of GPs/LPs/LGPs and negatively correlates with the MICs of β-lactams. CONCLUSIONS These studies demonstrate a major association between membrane remodelling, cross-resistance and the seesaw effect.
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Affiliation(s)
- Kelly M Hines
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
| | - Tianwei Shen
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
| | | | - Adam Waalkes
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
| | - Kelsi Penewit
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
| | - Elizabeth A Holmes
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
| | - Kathryn McLean
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
| | - Stephen J Salipante
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
| | - Brian J Werth
- Department of Pharmacy, University of Washington, Seattle, WA, USA
| | - Libin Xu
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
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Reinert JP, Brown M, Ofori R. Dosing Considerations for Combination Antistaphylococcal β-Lactam and Glyco/lipopeptide Salvage Therapy for Resistant Gram-Positive Infections: A Systematic Review. Ann Pharmacother 2021; 56:193-204. [PMID: 34088214 DOI: 10.1177/10600280211021421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE The objective of this systematic review is to evaluate dosing regimens of combination salvage regimens used as part of infectious disease pharmacotherapy. DATA SOURCES A systematic review was conducted on PubMed, MEDLINE, Scopus, ProQuest Central, and CINAHL through March 2021 using the following terminology: "combination" OR "Seesaw" OR "see-saw" OR "salvage" AND "infection" OR "resistant infection" OR "Gram-positive" AND "beta-lactam" OR "cephalosporin" OR "carbapenem" OR "monobactam" OR "glycopeptide" OR "lipopeptide." STUDY SELECTION AND DATA EXTRACTION Following the application of inclusion and exclusion criteria, 8 pieces of literature were ultimately included in this review. DATA SYNTHESIS Vancomycin in combination with another agent was most commonly prescribed as initial or empirical therapy. The most common combination salvage therapy regimen consisted of daptomycin in doses up to 12 mg/kg IV every 24 hours with ceftaroline 200 to 600 mg IV every 8 to 12 hours. Although the duration of combination salvage therapy varied drastically, blood culture clearance was typically observed within 24 hours. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Antimicrobial-resistant Gram-positive organisms have posed an emergent threat to antimicrobial stewardship initiatives. Utilizing either a glycopeptide or lipopeptide antibiotic in combination with an antistaphylococcal β-lactam antibiotic has demonstrated efficacy in treating resistant bacteria. This work describes the heterogeneity of dosing regimens and seeks to define an optimal dose, duration, and combination of antibiotics. CONCLUSIONS Combination salvage therapy has demonstrated efficacy and safety in treatment of resistant Gram-positive infections. It appears the combination of daptomycin and ceftaroline can clear resistant infections expeditiously.
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Affiliation(s)
- Justin P Reinert
- The University of Texas at Tyler, Tyler, TX, USA.,Bon Secours Mercy Health St Vincent Medical Center, Toledo, OH, USA
| | - Matthew Brown
- Bon Secours Mercy Health St Vincent Medical Center, Toledo, OH, USA
| | - Reginald Ofori
- Bon Secours Mercy Health St Vincent Medical Center, Toledo, OH, USA
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Oh S, Chau R, Nguyen AT, Lenhard JR. Losing the Battle but Winning the War: Can Defeated Antibacterials Form Alliances to Combat Drug-Resistant Pathogens? Antibiotics (Basel) 2021; 10:antibiotics10060646. [PMID: 34071451 PMCID: PMC8227011 DOI: 10.3390/antibiotics10060646] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 11/16/2022] Open
Abstract
Despite the recent development of antibacterials that are active against multidrug-resistant pathogens, drug combinations are often necessary to optimize the killing of difficult-to-treat organisms. Antimicrobial combinations typically are composed of multiple agents that are active against the target organism; however, many studies have investigated the potential utility of combinations that consist of one or more antibacterials that individually are incapable of killing the relevant pathogen. The current review summarizes in vitro, in vivo, and clinical studies that evaluate combinations that include at least one drug that is not active individually against Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, or Staphylococcus aureus. Polymyxins were often included in combinations against all three of the Gram-negative pathogens, and carbapenems were commonly incorporated into combinations against K. pneumoniae and A. baumannii. Minocycline, sulbactam, and rifampin were also frequently investigated in combinations against A. baumannii, whereas the addition of ceftaroline or another β-lactam to vancomycin or daptomycin showed promise against S. aureus with reduced susceptibility to vancomycin or daptomycin. Although additional clinical studies are needed to define the optimal combination against specific drug-resistant pathogens, the large amount of in vitro and in vivo studies available in the literature may provide some guidance on the rational design of antibacterial combinations.
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Rose W, Fantl M, Geriak M, Nizet V, Sakoulas G. Current Paradigms of Combination therapy in Methicillin-Resistant Staphylococcus aureus (MRSA) Bacteremia: Does it Work, Which Combination and For Which Patients? Clin Infect Dis 2021; 73:2353-2360. [PMID: 33993226 DOI: 10.1093/cid/ciab452] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Indexed: 11/13/2022] Open
Abstract
The last several years have seen an emergence of literature documenting the utility of combination antimicrobial therapy, particularly in the salvage of refractory MRSA bacteremia. Recent clinical data are shaping conundrums of which regimens may be more beneficial, which can be potentially harmful, and which subset of patients stand to benefit from more aggressive treatment regimens than called for by current standards. In addition, the incorporation of combination therapy for MRSA bacteremia should be accompanied by the reminder that antimicrobial therapy does not need to be uniform for the entire duration, with an early intensive phase in high inoculum infections (e.g. with combination therapy), followed by a consolidation phase (i.e. monotherapy). This review and perspective consolidates the recent data on this subject and directs future goals in filling the knowledge gaps to methodically move forward towards improving patient outcomes.
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Affiliation(s)
- Warren Rose
- School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael Fantl
- School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA
| | - Matthew Geriak
- Pharmacy Department, Sharp Memorial Hospital, San Diego, CA, USA
| | - Victor Nizet
- Division of Host-Microbe Systems & Therapeutics, Center for Immunity, Infection & Inflammation, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - George Sakoulas
- Division of Host-Microbe Systems & Therapeutics, Center for Immunity, Infection & Inflammation, University of California-San Diego School of Medicine, La Jolla, CA, USA
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Mishra NN, Bayer AS, Baines SL, Hayes AS, Howden BP, Lapitan CK, Lew C, Rose WE. Cell Membrane Adaptations Mediate β-Lactam-Induced Resensitization of Daptomycin-Resistant (DAP-R) Staphylococcus aureus In Vitro. Microorganisms 2021; 9:1028. [PMID: 34064631 PMCID: PMC8150363 DOI: 10.3390/microorganisms9051028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 12/22/2022] Open
Abstract
The reversal of daptomycin resistance in MRSA to a daptomycin-susceptible phenotype following prolonged passage in selected β-lactams occurs coincident with the accumulation of multiple point mutations in the mprF gene. MprF regulates surface charge by modulating the content and translocation of the positively charged cell membrane phospholipid, lysyl-phosphatidylglycerol (LPG). The precise cell membrane adaptations accompanying such β-lactam-induced mprF perturbations are unknown. This study examined key cell membrane metrics relevant to antimicrobial resistance among three daptomycin-resistant MRSA clinical strains, which became daptomycin-susceptible following prolonged exposure to cloxacillin ('daptomycin-resensitized'). The causal role of such secondary mprF mutations in mediating daptomycin resensitization was confirmed through allelic exchange strategies. The daptomycin-resensitized strains derived either post-cloxacillin passage or via allelic exchange (vs. their respective daptomycin-resistant strains) showed the following cell membrane changes: (i) enhanced BODIPY-DAP binding; (ii) significant reductions in LPG content, accompanied by significant increases in phosphatidylglycerol content (p < 0.05); (iii) no significant changes in positive cell surface charge; (iv) decreased cell membrane fluidity (p < 0.05); (v) enhanced carotenoid content (p < 0.05); and (vi) lower branched chain fatty acid profiles (antiso- vs. iso-), resulting in increases in saturated fatty acid composition (p < 0.05). Overall, the cell membrane characteristics of the daptomycin-resensitized strains resembled those of parental daptomycin-susceptible strains. Daptomycin resensitization with selected β-lactams results in both definable genetic changes (i.e., mprF mutations) and a number of key cell membrane phenotype modifications, which likely facilitate daptomycin activity.
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Affiliation(s)
- Nagendra N. Mishra
- Division of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA; (A.S.B.); (C.K.L.)
- David Geffen School of Medicine, University of California (UCLA), Los Angeles, CA 90024, USA
| | - Arnold S. Bayer
- Division of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA; (A.S.B.); (C.K.L.)
- David Geffen School of Medicine, University of California (UCLA), Los Angeles, CA 90024, USA
| | - Sarah L. Baines
- Doherty Applied Microbial Genomics, Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3004, Australia; (S.L.B.); (A.S.H.); (B.P.H.)
| | - Ashleigh S. Hayes
- Doherty Applied Microbial Genomics, Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3004, Australia; (S.L.B.); (A.S.H.); (B.P.H.)
| | - Benjamin P. Howden
- Doherty Applied Microbial Genomics, Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3004, Australia; (S.L.B.); (A.S.H.); (B.P.H.)
| | - Christian K. Lapitan
- Division of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA; (A.S.B.); (C.K.L.)
| | - Cassandra Lew
- School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; (C.L.); (W.E.R.)
| | - Warren E. Rose
- School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; (C.L.); (W.E.R.)
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Impact of Bicarbonate on PBP2a Production, Maturation, and Functionality in Methicillin-Resistant Staphylococcus aureus (MRSA). Antimicrob Agents Chemother 2021; 65:AAC.02621-20. [PMID: 33649115 PMCID: PMC8092911 DOI: 10.1128/aac.02621-20] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Certain methicillin-resistant Staphylococcus aureus (MRSA) strains exhibit β-lactam-susceptibility in vitro, ex vivo and in vivo in the presence of NaHCO3 (NaHCO3-responsive MRSA). Herein, we investigate the impact of NaHCO3 on factors required for PBP2a functionality. Prototype NaHCO3-responsive and -nonresponsive MRSA strains (as defined in vitro) were assessed for the impact of NaHCO3 on: expression of genes involved in PBP2a production-maturation pathways (mecA, blaZ, pbp4, vraSR, prsA, sigB, and floA); membrane PBP2a and PrsA protein content; and membrane carotenoid content. Following NaHCO3 exposure in NaHCO3-responsive (vs - nonresponsive) MRSA, there was significantly reduced expression of: i) mecA and blaZ; ii) the vraSR-prsA gene axis; and iii) pbp4 Carotenoid production was reduced, while floA expression was increased by NaHCO3 exposure in all MRSA strains. This work underscores the distinct regulatory impact of NaHCO3 on a cadre of genes encoding factors required for maintenance of the MRSA phenotype through PBP2a functionality and maturation.
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Morrisette T, Alosaimy S, Abdul-Mutakabbir JC, Kebriaei R, Rybak MJ. The Evolving Reduction of Vancomycin and Daptomycin Susceptibility in MRSA-Salvaging the Gold Standards with Combination Therapy. Antibiotics (Basel) 2020; 9:E762. [PMID: 33143290 PMCID: PMC7692208 DOI: 10.3390/antibiotics9110762] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/21/2020] [Accepted: 10/26/2020] [Indexed: 01/27/2023] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is associated with substantial morbidity and mortality. Vancomycin (VAN) has been used as the gold standard treatment for invasive MRSA infections for decades but, unfortunately, the reliance of VAN as the primary treatment option against these infections has led to a reduction in VAN susceptibility in MRSA isolates. Although daptomycin (DAP) is another common treatment option against invasive MRSA infections, it has been shown that the development of VAN resistance can lead to DAP nonsusceptibility. VAN or DAP backbone regimens in combination with other antibiotics has been advocated as an alternative approach to improve patient outcomes in VAN/DAP-susceptible infections, enhance outcomes in infections caused by isolates with reduced VAN/DAP susceptibility, and/or prevent the emergence of VAN/DAP resistance or further resistance. A peer-reviewed literature search was conducted using Medline, Google Scholar and PubMed databases. The primary purpose of this review is to describe the mechanisms and epidemiology of MRSA isolates with a reduction in VAN and/or DAP susceptibility, evaluate in vitro and in vivo literature describing combination therapy (CT) against MRSA isolates with reduced VAN and/or DAP susceptibility and describe studies involving the clinical outcomes of patients treated with CT against invasive MRSA infections.
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Affiliation(s)
- Taylor Morrisette
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (T.M.); (S.A.); (J.C.A.-M.); (R.K.)
| | - Sara Alosaimy
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (T.M.); (S.A.); (J.C.A.-M.); (R.K.)
| | - Jacinda C. Abdul-Mutakabbir
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (T.M.); (S.A.); (J.C.A.-M.); (R.K.)
| | - Razieh Kebriaei
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (T.M.); (S.A.); (J.C.A.-M.); (R.K.)
| | - Michael J. Rybak
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (T.M.); (S.A.); (J.C.A.-M.); (R.K.)
- Division of Infectious Diseases, Department of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Pharmacy, Detroit Receiving Hospital, Detroit, MI 48201, USA
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ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in Streptococcus pyogenes. mBio 2020; 11:mBio.01804-20. [PMID: 32934083 PMCID: PMC7492735 DOI: 10.1128/mbio.01804-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Bacterial two-component systems sense and induce transcriptional changes in response to environmental stressors, including antimicrobials and human antimicrobial peptides. Since the stresses imposed by the host’s defensive responses may act as markers of specific temporal stages of disease progression or host compartments, pathogens often coordinately regulate stress response programs with virulence factor expression. The mechanism by which bacteria recognize these stresses and subsequently induce transcriptional responses remains not well understood. In this study, we showed that LiaFSR senses cell envelope stress through colocalization of LiaF and LiaS with the group A Streptococcus (GAS) ExPortal and is activated in direct response to ExPortal disruption by antimicrobials or human antimicrobial peptides. Our studies shed new light on the sensing of cell envelope stress in Gram-positive bacteria and may contribute to the development of therapies targeting these processes. LiaFSR is a gene regulatory system important for response to cell membrane stress in Gram-positive bacteria but is minimally studied in the important human pathogen group A Streptococcus (GAS). Using immunofluorescence and immunogold electron microscopy, we discovered that LiaF (a membrane-bound repressor protein) and LiaS (a sensor kinase) reside within the GAS membrane microdomain (ExPortal). Cell envelope stress induced by antimicrobials resulted in ExPortal disruption and activation of the LiaFSR system. The only human antimicrobial peptide whose presence resulted in ExPortal disruption and LiaFSR activation was the alpha-defensin human neutrophil peptide 1 (hNP-1). Elimination of membrane cardiolipin through targeted gene deletion resulted in loss of LiaS colocalization with the GAS ExPortal and activation of LiaFSR, whereas LiaF membrane localization was unaffected. Isogenic mutants lacking either LiaF or LiaS revealed a critical role of LiaF in ExPortal integrity. Thus, LiaF and LiaS colocalize with the GAS ExPortal by distinct mechanisms, further supporting codependence. These are the first data identifying a multicomponent signal system within the ExPortal, thereby providing new insight into bacterial intramembrane signaling in GAS that may serve as a paradigm for Gram-positive bacteria.
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Updates on Combination Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia. Curr Infect Dis Rep 2020. [DOI: 10.1007/s11908-020-00737-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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The Emerging Role of β-Lactams in the Treatment of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections. Antimicrob Agents Chemother 2020; 64:AAC.00468-20. [PMID: 32312776 DOI: 10.1128/aac.00468-20] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN and DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the "seesaw effect," where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.
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Morrisette T, Kebriaei R, Lev KL, Morales S, Rybak MJ. Bacteriophage Therapeutics: A Primer for Clinicians on Phage-Antibiotic Combinations. Pharmacotherapy 2020; 40:153-168. [PMID: 31872889 DOI: 10.1002/phar.2358] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Multidrug-resistant organisms have caused a marked depletion of effective antimicrobials, and the narrow pipeline of antibiotics has demanded the need to find novel therapeutic alternatives including nonantibiotic agents. Bacteriophages (phages) are viruses that use the bacterial machinery to infect, replicate, and kill bacterial cells. Although a marked decline in their use was driven by the discovery of antibiotics, the era of antibiotic resistance has led to a resurgence of phage therapy into clinical practice. The term phage-antibiotic synergy (PAS) was coined just over a decade ago and described that sublethal concentrations of antibiotics could stimulate phage production by bacterial cells. Recent literature has described PAS and other encouraging interactions with various phage and antibiotic combinations against a variety of bacterial strains. The primary objective of this review is to discuss the positive interactions between phage and antibiotic combinations, with an emphasis on PAS, reductions in bacterial growth or minimum inhibitory concentrations, enhanced biofilm eradication, and alterations in the emergence of bacterial resistance. A peer-reviewed literature search was conducted (1890-2019) using the PubMed, Medline, and Google Scholar databases. Although more investigation is certainly needed, the combination of bacteriophages with antibiotics is a promising strategy to target organisms with limited or no therapeutic options. This approach may also foster the ability to lower the antibiotic dose and may reduce the potential for antibiotic resistance emergence during therapy.
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Affiliation(s)
- Taylor Morrisette
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan
| | - Razieh Kebriaei
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan
| | - Katherine L Lev
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan
| | | | - Michael J Rybak
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.,Division of Infectious Diseases, Department of Medicine, Wayne State University, Detroit, Michigan.,Department of Pharmacy, Detroit Medical Center, Detroit, Michigan
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Daptomycin resistance in methicillin-resistant Staphylococcus aureus is conferred by IS256 insertion in the promoter of mprF along with mutations in mprF and walK. Int J Antimicrob Agents 2019; 54:673-680. [PMID: 31479743 DOI: 10.1016/j.ijantimicag.2019.08.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/26/2019] [Accepted: 08/24/2019] [Indexed: 01/20/2023]
Abstract
Mechanisms underlying the emergence of daptomycin resistance in Staphylococcus aureus remain unclear. In this study, Staphylococcus aureus strain 3d0, isolated from a patient with bloodstream infection and belonging to the predominant Chinese hospital-associated methicillin-resistant S. aureus (MRSA) clone ST239, was serially passaged on gradient broth containing daptomycin for 34 days. The whole genomes of 3d0 and its serial passage strains were sequenced and compared. Five single nucleotide polymorphisms, four IS256 insertions, and one 39-bp insert occurred in the progress of daptomycin resistance acquisition. IS256 insertion in the mprF promoter region resulted in mprF overexpression. Two novel point mutations in mprF and walK, leading to amino acid substitutions in MprF (G299V and L473I) and WalK (L7Q and Y225N), were shown by allelic replacement experiments to increase the minimum inhibitory concentration (MIC) of daptomycin by 2-4 times. Allelic replacement of both mprF and walK in strain 3d0 increased the daptomycin MIC by 4-8-fold, indicating that mprF and walK mutations synergistically contribute to daptomycin non-susceptibility. Notably, these mutants acquired resistance without losing fitness and exhibited decreased expression of cell wall degradation-related genes. In conclusion, this study revealed novel mutations of MRSA daptomycin resistance acquisition in vitro as well as several novel mutations in walK and mprF, and includes the first in-depth analysis of the mprF promoter. This study sheds light on how MRSA may acquire daptomycin resistance during daptomycin treatment.
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Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics. Antimicrob Agents Chemother 2019; 63:AAC.00496-19. [PMID: 31010857 PMCID: PMC6591647 DOI: 10.1128/aac.00496-19] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 04/07/2019] [Indexed: 12/24/2022] Open
Abstract
Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as “resistant” to β-lactams, often leading to the use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as “resistant” to β-lactams, often leading to the use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the antistaphylococcal β-lactams oxacillin and cefazolin (NaHCO3 responsive) and one resistant to such agents (NaHCO3 nonresponsive). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam. Mechanistically, NaHCO3 reduced the expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.
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Kebriaei R, Rice SA, Stamper KC, Rybak MJ. Dalbavancin Alone and in Combination with Ceftaroline against Four Different Phenotypes of Staphylococcus aureus in a Simulated Pharmacodynamic/Pharmacokinetic Model. Antimicrob Agents Chemother 2019; 63:e01743-18. [PMID: 30670436 PMCID: PMC6437528 DOI: 10.1128/aac.01743-18] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 01/15/2019] [Indexed: 12/17/2022] Open
Abstract
Glycopeptides such as vancomycin have been used as the first-line therapy against MRSA infections for over half a century. Reduced susceptibility and emergence of resistance to first-generation glycopeptides has led to development of second-generation lipoglycopeptide derivatives such as dalbavancin which hold broader ranges of activity and enhanced pharmacokinetic properties. We evaluated the MIC values for a total of 100 isolates, including 25 methicillin-resistant Staphylococcus aureus (MRSA), 25 heterogeneus vancomycin-intermediate S. aureus, 25 daptomycin nonsusceptible (DNS), and 25 vancomycin-intermediate S. aureus strains against dalbavancin, ceftaroline, and vancomycin alone and in combination. Dalbavancin was highly active against hVISA, DNS, and MRSA strains, achieving 96 to 100% susceptibility and 72% susceptibility against VISA strains. The combination of dalbavancin plus ceftaroline reduced dalbavancin MICs 62.5-fold and demonstrated enhanced killing against all four phenotypes in pharmacokinetic/pharmacodynamic models. Four strains of the aforementioned phenotypes were randomly chosen for pharmacodynamic/pharmacokinetic simulation models. Of interest, while both dalbavancin and vancomycin in combination with ceftaroline demonstrated significant improvement in glycopeptide fAUC/MIC values against these four phenotypes, the dalbavancin-ceftaroline combinations exhibited a 44- to 11,270-fold higher fAUC/MIC value in comparison to vancomycin-ceftaroline combinations. In addition, the time to detection limit was reduced for this combination (24 to 32 h) versus the vancomycin-ceftaroline combination (24 to 72h). To our knowledge, this is the first comprehensive study of dalbavancin and vancomycin combinations with ceftaroline. These data provide a novel approach for combating recalcitrant MRSA infections.
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Affiliation(s)
- Razieh Kebriaei
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
| | - Seth A Rice
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
| | - Kyle C Stamper
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
| | - Michael J Rybak
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA
- Division of Infectious Diseases, School of Medicine, Wayne State University, Detroit, Michigan, USA
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Sumon ZE, Berenson CS, Sellick JA, Bulman ZP, Tsuji BT, Mergenhagen KA. Successful cure of daptomycin-non-susceptible, vancomycin-intermediate Staphylococcus aureus prosthetic aortic valve endocarditis directed by synergistic in vitro time-kill study. Infect Dis (Lond) 2019; 51:287-292. [PMID: 30760062 DOI: 10.1080/23744235.2018.1533646] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Infectious complications following surgical valve replacements are extremely difficult to treat, often requiring prolonged antimicrobials therapy with or without surgery. Vancomycin-intermediate Staphylococcus aureus is an infrequent pathogen, with an estimated prevalence of less than 0.3%, but presents even greater challenges. We report a case of successful cure of daptomycin-non-susceptible and vancomycin-intermediate Staphylococcus aureus prosthetic valve endocarditis using an eight-week course of combination antimicrobial therapy. Using time-kill study, the combination of daptomycin plus ceftaroline and rifampin resulted in a greater than 4 log reduction of bacterial growth at 24 hours. This antimicrobial combination was used for a total of eight weeks with a successful outcome.
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Affiliation(s)
- Zarchi E Sumon
- a Department of Medicine, Infectious Diseases Division , University at Buffalo, Jacobs School of Medicine and Biomedical Sciences , Buffalo , NY , USA
| | - Charles S Berenson
- a Department of Medicine, Infectious Diseases Division , University at Buffalo, Jacobs School of Medicine and Biomedical Sciences , Buffalo , NY , USA.,b Department of Medicine, Infectious Diseases Division , Veterans Administration Western New York Healthcare System , Buffalo , NY , USA
| | - John A Sellick
- a Department of Medicine, Infectious Diseases Division , University at Buffalo, Jacobs School of Medicine and Biomedical Sciences , Buffalo , NY , USA.,b Department of Medicine, Infectious Diseases Division , Veterans Administration Western New York Healthcare System , Buffalo , NY , USA
| | - Zackery P Bulman
- c Laboratory for Antimicrobial Pharmacodynamics , University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo , NY , USA
| | - Brian T Tsuji
- c Laboratory for Antimicrobial Pharmacodynamics , University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo , NY , USA
| | - Kari A Mergenhagen
- d Department of Pharmacy , Veterans Administration Western New York Healthcare System , Buffalo , NY , USA
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Ceftobripole: Experience in staphylococcal bacteremia. REVISTA ESPANOLA DE QUIMIOTERAPIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE QUIMIOTERAPIA 2019; 32 Suppl 3:24-28. [PMID: 31364338 PMCID: PMC6755346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Ceftobiprole is a new cephalosporin with an extended spectrum activity against the majority of microorganisms isolated in bacteremia including methicillin-susceptible (MSSA) and -resistant S. aureus (MRSA). This antibiotic has demonstrated a potent activity against MRSA in animal models of endocarditis in monotherapy but particularly in combination with daptomycin, suggesting that this combination could be a future option to improve the outcome of staphylococcal endovascular infections. In addition, the extended-spectrum ceftobiprole activity, including coagulase-negative staphylococci, Enterococcus faecalis, Enterobacteriaceae and Pseudomonas aeruginosa represents an advantage for use as empirical therapy in bacteremia potentially caused by a broad spectrum of microorganisms, such as in catheter-related bacteremia.
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Zapata B, Alvarez DN, Farah S, Garcia-de-la-Maria C, Miro JM, Sakoulas G, Bayer AS, Mishra NN. Prevention of High-Level Daptomycin-Resistance Emergence In Vitro in Streptococcus mitis-oralis by Using Combination Antimicrobial Strategies. Curr Microbiol 2018; 75:1062-1067. [PMID: 29651552 DOI: 10.1007/s00284-018-1491-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 04/09/2018] [Indexed: 01/04/2023]
Abstract
Among the viridans group streptococci, S. mitis-oralis strains are frequently resistant to multiple β-lactams and tolerant to vancomycin (VAN). This scenario has led to the proposed clinical use of newer agents, like daptomycin (DAP) for such S. mitis-oralis strains. However, recent recognition of the rapid and durable emergence of high-level DAP-resistance (DAP-R; DAP MICs > 256 µg/ml) induced by DAP exposures in vitro and in vivo has dampened enthusiasm for such approaches. In this study, we evaluated a broad range of DAP combination regimens in vitro for their capacity to prevent emergence of high-level DAP-R in a prototype S. mitis-oralis strain (351) during serial passage experiments, including DAP + either gentamicin (GEN), rifampin (RIF), trimethoprim-sulfamethoxazole (TMP-SMX), imipenem (IMP), ceftaroline (CPT), tedizolid (TDZ), or linezolid (LDZ). In addition, we assessed selected DAP combination regimens for their ability to exert either an early bactericidal impact and/or synergistically kill the S. mitis-oralis study strain. During serial passage, three of the eight antibiotic combinations (DAP + GEN, CPT, or TMP- SMX) exhibited significantly reduced DAP MICs (≈ by 8-40 fold) vs serial exposure in DAP alone (DAP MICs > 256 µg/ml). In addition, combinations of DAP + GEN and DAP + CPT were both bactericidal and synergistic in early time-kill curve interactions.
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Affiliation(s)
- Brianne Zapata
- Divison of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Danya N Alvarez
- Divison of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Center for Infectious Diseases, California State Department of Public Health, Richmond, CA, USA
| | - Sabrina Farah
- Divison of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | | | - Jose M Miro
- Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
| | - George Sakoulas
- Division of Host-Microbe Systems & Therapeutics, University of California San Diego, School of Medicine, La Jolla, CA, USA
| | - Arnold S Bayer
- Divison of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- David Geffen School of Medicine at University of California, Los Angeles, CA, USA
| | - Nagendra N Mishra
- Divison of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
- David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
- Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor - UCLA Medical Center, Torrance, CA, USA.
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Chen FJ, Lauderdale TL, Lee CH, Hsu YC, Huang IW, Hsu PC, Yang CS. Effect of a Point Mutation in mprF on Susceptibility to Daptomycin, Vancomycin, and Oxacillin in an MRSA Clinical Strain. Front Microbiol 2018; 9:1086. [PMID: 29887848 PMCID: PMC5980971 DOI: 10.3389/fmicb.2018.01086] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/07/2018] [Indexed: 12/22/2022] Open
Abstract
We previously reported the sequential recovery of daptomycin-nonsusceptible MRSA clinical isolates with an L431F substitution in the MprF protein. The aim of the present study is to determine the effect of this mutation by replacing the mprF gene on the chromosome of a daptomycin-susceptible progenitor strain, CGK5, to obtain CGK5mut having the L431F MprF mutation. Compared to CGK5, the daptomycin and vancomycin MICs of CGK5mut increased from 0.5 to 3 μg/ml and from 1.5 to 3 μg/ml, respectively; however, its oxacillin MIC decreased from 128 to 1 μg/ml in medium without added 2% NaCl. The expression levels of vraSR and several other cell-wall synthesis-related genes were significantly increased in CGK5mut, and the mutant also had significantly reduced negative cell membrane charge, thicker cell wall, and longer doubling time. These features were abolished in the reverse mutant carrying F431L MprF, confirming the pleiotropic effects of the L431F MprF mutation. We believe that this is the first work that shows a single MprF missense mutation can lead to not only changes in the cell membrane but also increased expression of vraSR and subsequently increased resistance to daptomycin and vancomycin while simultaneously conferring increased susceptibility to oxacillin in an isogenic MRSA strain.
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Affiliation(s)
- Feng-Jui Chen
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan
| | - Tsai-Ling Lauderdale
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan
| | - Chen-Hsiang Lee
- Division of Infectious Diseases, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung, Taiwan
| | - Yu-Chieh Hsu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan
| | - I-Wen Huang
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan
| | - Pei-Chi Hsu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan
| | - Chung-Shi Yang
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan
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Association of Vancomycin MIC and Molecular Characteristics with Clinical Outcomes in Methicillin-Susceptible Staphylococcus aureus Acute Hematogenous Osteoarticular Infections in Children. Antimicrob Agents Chemother 2018. [PMID: 29530845 DOI: 10.1128/aac.00084-18] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Strains of methicillin-resistant Staphylococcus aureus (MRSA), particularly those belonging to the USA300 pulsotype, have been well described to cause severe osteoarticular infections (OAIs). A vancomycin MIC of ≥1.5 μg/ml has been demonstrated to contribute to disease severity in adults with MRSA and even methicillin-susceptible S. aureus (MSSA) bacteremia. Little data exist describing the outcomes of MSSA OAIs in terms of molecular characteristics and vancomycin MIC. All patients/isolates were chosen from a surveillance study at Texas Children's Hospital (TCH). S. aureus OAI isolates were identified from 2011 to 2016 and subjected to vancomycin Etests, pulsed-field gel electrophoresis (PFGE), and PCR to determine Panton-Valentine leucocidin (PVL) production and agr group. Two hundred fifty-two cases of S. aureus OAI were identified; 183 cases were MSSA (72.6%). During the study period, a decrease in the proportion of cases secondary to MRSA was observed, declining from 37.8% to 15.9% (P = 0.02). Of the MSSA isolates, 26.2% and 23.5% were USA300 and PVL positive, respectively. An increase in the proportion of MSSA isolates with a vancomycin MIC of ≥1.5 μg/ml occurred in the study period (P = 0.004). In MSSA, an elevated vancomycin MIC was associated with multiple surgical procedures and venous thromboses, even when adjusting for empirical β-lactam use. An increase in vancomycin MIC was noted among isolates belonging to agr group 4 during the study period. Methicillin resistance is declining among S. aureus OAI isolates at TCH. Simultaneously, vancomycin Etest MICs are increasing among MSSA isolates. Vancomycin MICs of ≥2 μg/ml are associated with adverse clinical outcomes in MSSA irrespective of antibiotic choice, suggesting that this may be a surrogate for organism virulence.
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Scasso F, Ferrari G, DE Vincentiis GC, Arosio A, Bottero S, Carretti M, Ciardo A, Cocuzza S, Colombo A, Conti B, Cordone A, DE Ciccio M, Delehaye E, Della Vecchia L, DE Macina I, Dentone C, DI Mauro P, Dorati R, Fazio R, Ferrari A, Ferrea G, Giannantonio S, Genta I, Giuliani M, Lucidi D, Maiolino L, Marini G, Marsella P, Meucci D, Modena T, Montemurri B, Odone A, Palma S, Panatta ML, Piemonte M, Pisani P, Pisani S, Prioglio L, Scorpecci A, Scotto DI Santillo L, Serra A, Signorelli C, Sitzia E, Tropiano ML, Trozzi M, Tucci FM, Vezzosi L, Viaggi B. Emerging and re-emerging infectious disease in otorhinolaryngology. ACTA OTORHINOLARYNGOLOGICA ITALICA : ORGANO UFFICIALE DELLA SOCIETA ITALIANA DI OTORINOLARINGOLOGIA E CHIRURGIA CERVICO-FACCIALE 2018; 38:S1-S106. [PMID: 29967548 PMCID: PMC6056203 DOI: 10.14639/0392-100x-suppl.1-38-2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
SUMMARY Emerging and re-emerging infectious disease in otorhinolaryngology (ENT) are an area of growing epidemiological and clinical interest. The aim of this section is to comprehensively report on the epidemiology of key infectious disease in otorhinolaryngology, reporting on their burden at the national and international level, expanding of the need of promoting and implementing preventive interventions, and the rationale of applying evidence-based, effective and cost- effective diagnostic, curative and preventive approaches. In particular, we focus on i) ENT viral infections (HIV, Epstein-Barr virus, Human Papilloma virus), retrieving the available evidence on their oncogenic potential; ii) typical and atypical mycobacteria infections; iii) non-specific granulomatous lymphadenopathy; iv) emerging paediatric ENT infectious diseases and the prevention of their complications; v) the growing burden of antimicrobial resistance in ENT and the strategies for its control in different clinical settings. We conclude by outlining knowledge gaps and action needed in ENT infectious diseases research and clinical practice and we make references to economic analysis in the field of ENT infectious diseases prevention and care.
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Affiliation(s)
- F Scasso
- SOC Otorinolaringoiatria, ASL 3 Genovese, Ospedale P.A. Micone, Genova, Italy
| | - G Ferrari
- SOC Otorinolaringoiatria, ASL 5 Genovese, Ospedale P.A. Levante Ligure, La Spezia, Italy
| | - G C DE Vincentiis
- UOC Otorinolaringoiatria, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - A Arosio
- Clinica Otorinolaringoiatria, Ospedale Macchi, ASST Settelaghi, Varese, Italy
| | - S Bottero
- UOC Chirurgia delle Vie Aeree, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - M Carretti
- UOC Otorinolaringoiatria, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - A Ciardo
- SOC Otorinolaringoiatria, ASL 5 Genovese, Ospedale P.A. Levante Ligure, La Spezia, Italy
| | - S Cocuzza
- Clinica di Otorinolaringoiatria, Università degli Studi di Catania, Catania, Italy
| | - A Colombo
- SOC Otorinolaringoiatria, Ospedale Cardinal Massaia, Asti, Italy
| | - B Conti
- Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Pavia, Italy
| | - A Cordone
- SOC Otorinolaringoiatria, ASL 3 Genovese, Ospedale P.A. Micone, Genova, Italy
| | - M DE Ciccio
- SOC Otorinolaringoiatria, ASL 5 Genovese, Ospedale P.A. Levante Ligure, La Spezia, Italy
| | - E Delehaye
- SOC Otorinolaringoiatria, ASL 5 Genovese, Ospedale P.A. Levante Ligure, La Spezia, Italy
| | - L Della Vecchia
- Clinica Otorinolaringoiatria, Ospedale Macchi, ASST Settelaghi, Varese, Italy
| | - I DE Macina
- SOC Malattie Infettive, ASL 1 Imperiese, Ospedale di Sanremo, Italy
| | - C Dentone
- SOC Malattie Infettive, ASL 1 Imperiese, Ospedale di Sanremo, Italy
| | - P DI Mauro
- Clinica di Otorinolaringoiatria, Università degli Studi di Catania, Catania, Italy
| | - R Dorati
- Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Pavia, Italy
| | - R Fazio
- SOC Otorinolaringoiatria, ASL 5 Genovese, Ospedale P.A. Levante Ligure, La Spezia, Italy
| | - A Ferrari
- Direzione Sanitaria, AOU Parma, Italy
| | - G Ferrea
- SOC Malattie Infettive, ASL 1 Imperiese, Ospedale di Sanremo, Italy
| | - S Giannantonio
- UOC Audiologia e Otochirurgia, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - I Genta
- Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Pavia, Italy
| | - M Giuliani
- UOC Otorinolaringoiatria, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - D Lucidi
- UOC Audiologia e Otochirurgia, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - L Maiolino
- Clinica di Otorinolaringoiatria, Università degli Studi di Catania, Catania, Italy
| | - G Marini
- UOC Otorinolaringoiatria, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - P Marsella
- UOC Audiologia e Otochirurgia, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - D Meucci
- UOC Chirurgia delle Vie Aeree, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - T Modena
- Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Pavia, Italy
| | - B Montemurri
- UOC Audiologia e Otochirurgia, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - A Odone
- Facoltà di Medicina e Chirurgia, Università Vita-Salute San Raffaele, Milano, Italy
| | - S Palma
- SOC Otorinolaringoiatria, Azienda Sanitaria Universitaria di Udine (ASUIUD), Italy
| | - M L Panatta
- UOC Otorinolaringoiatria, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - M Piemonte
- SOC Otorinolaringoiatria, Azienda Sanitaria Universitaria di Udine (ASUIUD), Italy
| | - P Pisani
- SOC Otorinolaringoiatria, Ospedale Cardinal Massaia, Asti, Italy
| | - S Pisani
- Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Pavia, Italy
| | - L Prioglio
- SOC Otorinolaringoiatria, ASL 3 Genovese, Ospedale P.A. Micone, Genova, Italy
| | - A Scorpecci
- UOC Audiologia e Otochirurgia, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | | | - A Serra
- Clinica di Otorinolaringoiatria, Università degli Studi di Catania, Catania, Italy
| | - C Signorelli
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Italy; Facoltà di Medicina e Chirurgia, Università Vita-Salute San Raffaele, Milano, Italy
| | - E Sitzia
- UOC Otorinolaringoiatria, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - M L Tropiano
- UOC Chirurgia delle Vie Aeree, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - M Trozzi
- UOC Chirurgia delle Vie Aeree, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - F M Tucci
- UOS Chirurgia Cervicale ORL, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
| | - L Vezzosi
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Italy; Dipartimento di Medicina Sperimentale, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - B Viaggi
- SOC Neuroanestesia e Rianimazione, A.O.U. Careggi, Firenze, Italy
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Madhavilatha B, Bhattacharjee D, Sabitha G, Reddy BVS, Yadav JS, Jain N, Reddy BJM. Synthesis andIn VitroAnticancer Activity of Novel 1,3,4-Oxadiazole-Linked 1,2,3-Triazole/Isoxazole Hybrids. J Heterocycl Chem 2018. [DOI: 10.1002/jhet.3110] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- B. Madhavilatha
- Natural Products Chemistry Division; CSIR Indian Institute of Chemical Technology; Hyderabad 500007 India
| | - Debanjan Bhattacharjee
- Center for Chemical Biology; CSIR Indian Institute of Chemical Technology; Hyderabad 500007 India
| | - Gowravaram Sabitha
- Natural Products Chemistry Division; CSIR Indian Institute of Chemical Technology; Hyderabad 500007 India
- Academy of Scientific and Innovative Research (AcSIR); 2 Rafi Marg New Delhi 110 001 India
| | - B. V. Subba Reddy
- Academy of Scientific and Innovative Research (AcSIR); 2 Rafi Marg New Delhi 110 001 India
- Center for Semiochemicals; CSIR Indian Institute of Chemical Technology; Hyderabad 500007 India
| | - J. S. Yadav
- Academy of Scientific and Innovative Research (AcSIR); 2 Rafi Marg New Delhi 110 001 India
- Center for Semiochemicals; CSIR Indian Institute of Chemical Technology; Hyderabad 500007 India
| | - Nishant Jain
- Center for Chemical Biology; CSIR Indian Institute of Chemical Technology; Hyderabad 500007 India
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32
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Yang SJ, Mishra NN, Kang KM, Lee GY, Park JH, Bayer AS. Impact of Multiple Single-Nucleotide Polymorphisms Within mprF on Daptomycin Resistance in Staphylococcus aureus. Microb Drug Resist 2018; 24:1075-1081. [PMID: 29381428 DOI: 10.1089/mdr.2017.0156] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
A number of single nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) have been associated with daptomycin-resistance (DAP-R) in Staphylococcus aureus. Such SNPs have been found throughout the mprF ORF, although there are clearly preferred "hot spots" within this gene frequently linked to DAP-R phenotype. These mprF SNPs are often correlated with a gain-in-function phenotype, either in terms of increased production (synthase activity) and/or enhanced translocation (translocase activity) of lysyl-phosphatidylglycerol (L-PG) within its cell membrane. However, it is unclear if multiple hot spot mprF SNPs can accumulate within mprF ORFs and cause additive elevations of DAP minimum inhibitory concentrations (MICs). In this study, we used a previously well-characterized plasmid complementation system in S. aureus Newman ΔmprF mutant to express: (1) single point-mutated forms of mprF ORFs cloned from two DAP-R S. aureus strains (mprFS295L or mprFT345A) and (2) dual point-mutated forms of mprF ORFs simultaneously harboring SNPs in the central bifunctional domain and synthase domain in MprF, respectively (mprFS295L+L826F or mprFT345A+L826F). The current study revealed that, although individual hot spot point mutations within mprF ORF can recapitulate signature DAP-R-associated phenotypes (i.e., increased DAP MICs, enhanced surface positive charge, and increased L-PG synthesis), accumulation of such hot spot point mutations paradoxically caused reduction in these latter three metrics.
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Affiliation(s)
- Soo-Jin Yang
- 1 Department of Animal Science and Technology, Chung-Ang University , Anseong-si, Republic of Korea
| | - Nagendra N Mishra
- 2 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center , Torrance, California.,3 David Geffen School of Medicine at UCLA , Los Angeles, California
| | - Kyoung-Mi Kang
- 1 Department of Animal Science and Technology, Chung-Ang University , Anseong-si, Republic of Korea
| | - Gi-Yong Lee
- 1 Department of Animal Science and Technology, Chung-Ang University , Anseong-si, Republic of Korea
| | - Jong-Hwan Park
- 4 Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University , Gwangju, Republic of Korea
| | - Arnold S Bayer
- 2 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center , Torrance, California.,3 David Geffen School of Medicine at UCLA , Los Angeles, California
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33
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Combination Antibiotic Exposure Selectively Alters the Development of Vancomycin Intermediate Resistance in Staphylococcus aureus. Antimicrob Agents Chemother 2018; 62:AAC.02100-17. [PMID: 29158272 DOI: 10.1128/aac.02100-17] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 11/10/2017] [Indexed: 01/02/2023] Open
Abstract
Invasive methicillin-resistant Staphylococcus aureus (MRSA) treated with vancomycin (VAN) is associated with reduced VAN susceptibility and treatment failure. VAN combination therapy is one strategy to improve response, but comprehensive assessments of combinations to prevent resistance are limited. This study identifies optimal combinations to prevent the emergence of VAN-intermediate Staphylococcus aureus (VISA). Two standard MRSA and two heterogeneous VISA (hVISA) strains were exposed for 28 days in vitro to VAN alone, VAN with cefazolin (CFZ), fosfomycin, gentamicin, meropenem, rifampin, piperacillin-tazobactam (TZP), or trimethoprim-sulfamethoxazole. In addition to VAN susceptibility testing, cell wall thickness (CWT), carotenoid content, and membrane fluidity were determined for Mu3. VAN plus any β-lactam limited the VAN MIC increase to 1 to 4 mg/liter throughout the 28-day exposure, with CFZ and TZP being the most effective agents (VAN MIC = 1 to 2 mg/liter). Similar MIC trends occurred with the lipo-/glycopeptide agents daptomycin and telavancin, where β-lactam combinations with VAN prevented MIC increases to these agents as well. Combinations with non-β-lactams were ineffective in preventing VAN MIC increases with VAN MICs of 4 to 16 mg/liter emerging during weeks 2 to 4 of treatment. VAN plus β-lactam decreased CWT significantly, whereas VAN plus other antibiotics significantly increased the CWT. No correlation was observed between carotenoid content or membrane fluidity and antibiotic exposure. Only the combination exposures of VAN plus β-lactam suppress the development of VISA. Rational selection of VAN plus β-lactam should be further explored as a long-term combination treatment of MRSA infections due to their ability to suppress VAN resistance.
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Müller A, Grein F, Otto A, Gries K, Orlov D, Zarubaev V, Girard M, Sher X, Shamova O, Roemer T, François P, Becher D, Schneider T, Sahl HG. Differential daptomycin resistance development in Staphylococcus aureus strains with active and mutated gra regulatory systems. Int J Med Microbiol 2017; 308:335-348. [PMID: 29429584 DOI: 10.1016/j.ijmm.2017.12.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 12/13/2017] [Accepted: 12/18/2017] [Indexed: 02/03/2023] Open
Abstract
The first-in-class lipopeptide antibiotic daptomycin (DAP) is highly active against Gram-positive pathogens including ß-lactam and glycopeptide resistant strains. Its molecular mode of action remains enigmatic, since a defined target has not been identified so far and multiple effects, primarily on the cell envelope have been observed. Reduced DAP susceptibility has been described in S. aureus and enterococci after prolonged treatment courses. In line with its pleiotropic antibiotic activities, a unique, defined molecular mechanism of resistance has not emerged, instead non-susceptibility appears often accompanied by alterations in membrane composition and changes in cell wall homeostasis. We compared S. aureus strains HG001 and SG511, which differ primarily in the functionality of the histidine kinase GraS, to evaluate the impact of the GraRS regulatory system on the development of DAP non-susceptibility. After extensive serial passing, both DAPR variants reached a minimal inhibitory concentration of 31 μg/ml and shared some phenotypic characteristics (e.g. thicker cell wall, reduced autolysis). However, based on comprehensive analysis of the underlying genetic, transcriptomic and proteomic changes, we found that both strains took different routes to achieve DAP resistance. Our study highlights the impressive genetic and physiological capacity of S. aureus to counteract pleiotropic activities of cell wall- and membrane-active compounds even when a major cell wall regulatory system is dysfunctional.
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Affiliation(s)
- Anna Müller
- Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn.
| | - Fabian Grein
- Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn
| | - Andreas Otto
- Institute for Microbiology, University of Greifswald, Greifswald, Germany
| | - Kathrin Gries
- Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Dmitriy Orlov
- Institute for Experimental Medicine, Saint Petersburg, Russia; Saint Petersburg University, Saint Petersburg, Russia
| | - Vladimir Zarubaev
- Pasteur Institute of Epidemiology and Microbiology, Saint Petersburg Russia
| | - Myriam Girard
- Genomic Research Laboratory, Department of Medical Specialties, University Hospitals of Geneva, University of Geneva, Geneva, Switzerland
| | - Xinwei Sher
- Merck & Co., Infectious Diseases, Kenilworth, NJ, USA
| | - Olga Shamova
- Institute for Experimental Medicine, Saint Petersburg, Russia; Saint Petersburg University, Saint Petersburg, Russia
| | | | - Patrice François
- Genomic Research Laboratory, Department of Medical Specialties, University Hospitals of Geneva, University of Geneva, Geneva, Switzerland
| | - Dörte Becher
- Institute for Microbiology, University of Greifswald, Greifswald, Germany
| | - Tanja Schneider
- Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn
| | - Hans-Georg Sahl
- German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn; Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, University of Bonn, Bonn, Germany
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35
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Bartash R, Nori P. Beta-lactam combination therapy for the treatment of Staphylococcus aureus and Enterococcus species bacteremia: A summary and appraisal of the evidence. Int J Infect Dis 2017; 63:7-12. [PMID: 28789974 DOI: 10.1016/j.ijid.2017.07.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/20/2017] [Accepted: 07/21/2017] [Indexed: 11/15/2022] Open
Abstract
Staphylococcal bacteremia and enterococcal bacteremia are prevalent in hospitalized or recently instrumented patients, and are associated with significant morbidity and mortality. They are often difficult to treat due to the pathogenicity of the organisms, poor response to antibiotics, and increasing development of multidrug resistance. Therefore, there has been increasing interest in combination therapy for the treatment of these infections. The aim of this review was to summarize and assess the evidence supporting combination beta-lactam therapy for both Staphylococcus aureus and Enterococcus species blood stream infections. Currently, there is promising in vitro data but little clinical evidence supporting combination beta-lactam therapy for this indication. Further clinical investigations are needed to elucidate the potential benefits of beta-lactam combination therapy over monotherapy for Gram-positive bacteremia, although combination therapy may be useful in refractory cases of bacteremia that do not respond to standard antibiotic therapy.
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Affiliation(s)
- Rachel Bartash
- Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA.
| | - Priya Nori
- Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA
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36
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Garcia-de-la-Maria C, Xiong YQ, Pericas JM, Armero Y, Moreno A, Mishra NN, Rybak MJ, Tran TT, Arias CA, Sullam PM, Bayer AS, Miro JM. Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis. Antimicrob Agents Chemother 2017; 61:e02418-16. [PMID: 28264848 PMCID: PMC5404581 DOI: 10.1128/aac.02418-16] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/16/2017] [Indexed: 11/20/2022] Open
Abstract
Among the viridans group streptococci, the Streptococcus mitis group is the most common cause of infective endocarditis. These bacteria have a propensity to be β-lactam resistant, as well as to rapidly develop high-level and durable resistance to daptomycin (DAP). We compared a parental, daptomycin-susceptible (DAPs) S. mitis/S. oralis strain and its daptomycin-resistant (DAPr) variant in a model of experimental endocarditis in terms of (i) their relative fitness in multiple target organs in this model (vegetations, kidneys, spleen) when animals were challenged individually and in a coinfection strategy and (ii) their survivability during therapy with daptomycin-gentamicin (an in vitro combination synergistic against the parental strain). The DAPr variant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAPs strain following treatment with daptomycin. The parental strain and the DAPr variant were comparably virulent when animals were individually challenged. In contrast, in the coinfection model without daptomycin therapy, at both the 106- and 107-CFU/ml challenge inocula, the parental strain outcompeted the DAPr variant in all target organs, especially the kidneys and spleen. When the animals in the coinfection model of endocarditis were treated with DAP-gentamicin, the DAPs strain was completely eliminated, while the DAPr variant persisted in all target tissues. These data underscore that the acquisition of DAPr in S. mitis/S. oralis does come at an intrinsic fitness cost, although this resistance phenotype is completely protective against therapy with a potentially synergistic DAP regimen.
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Affiliation(s)
| | - Y Q Xiong
- LA Biomedical Research Institute, Torrance, California, USA
- Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - J M Pericas
- Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Y Armero
- Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
| | - A Moreno
- Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
| | - N N Mishra
- LA Biomedical Research Institute, Torrance, California, USA
- Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - M J Rybak
- Anti-Infective Research Laboratory, Wayne State University, Detroit, Michigan, USA
| | - T T Tran
- University of Texas School of Medicine, Houston, Texas, USA
| | - C A Arias
- University of Texas School of Medicine, Houston, Texas, USA
| | - P M Sullam
- Veterans Affairs Medical Center and the University of California, San Francisco, California, USA
| | - A S Bayer
- LA Biomedical Research Institute, Torrance, California, USA
- Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - J M Miro
- Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
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37
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Shafiq I, Bulman ZP, Spitznogle SL, Osorio JE, Reilly IS, Lesse AJ, Parameswaran GI, Mergenhagen KA, Tsuji BT. A combination of ceftaroline and daptomycin has synergistic and bactericidal activity in vitro against daptomycin nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA). Infect Dis (Lond) 2017; 49:410-416. [PMID: 28116950 DOI: 10.1080/23744235.2016.1277587] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
There is an urgent need to optimize therapeutic options in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia who have failed conventional therapy. Two clinical isolates were obtained from a 68-year-old male with persistent MRSA bacteremia before and after the development of daptomycin nonsusceptibility. The pharmacodynamic activity of monotherapies and combinations of ceftaroline, daptomycin, cefoxitin, nafcillin and vancomycin were evaluated in time-kill experiments versus 108 CFU/mL of the pre- and post-daptomycin nonsusceptible MRSA isolates. Cefoxitin, nafcillin and vancomycin alone or in combination with ceftaroline failed to generate prolonged bactericidal activity against the post-daptomycin nonsusceptible isolate whereas a ceftaroline-daptomycin combination resulted in 6, 24 and 48 h log10(CFU/mL) reductions of 3.90, 4.40 and 6.32. Population analysis profiles revealed a daptomycin heteroresistant subpopulation of the pre-daptomycin nonsusceptible MRSA isolate that expanded by >10,000× on daptomycin agar containing 2-16 mg/L in the post-daptomycin nonsusceptible isolate. Daptomycin and ceftaroline combinations may be promising against persistent MRSA bacteremia.
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Affiliation(s)
- Iffat Shafiq
- a Laboratory for Antimicrobial Pharmacodynamics, Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo , NY , USA
| | - Zackery P Bulman
- a Laboratory for Antimicrobial Pharmacodynamics, Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo , NY , USA
| | - Sarah L Spitznogle
- a Laboratory for Antimicrobial Pharmacodynamics, Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo , NY , USA
| | - Justin E Osorio
- a Laboratory for Antimicrobial Pharmacodynamics, Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo , NY , USA
| | - Irene S Reilly
- a Laboratory for Antimicrobial Pharmacodynamics, Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo , NY , USA
| | - Alan J Lesse
- b Infectious Diseases Department, Veterans Affairs Western New York Healthcare System , Buffalo , NY , USA
| | - Ganapathi I Parameswaran
- b Infectious Diseases Department, Veterans Affairs Western New York Healthcare System , Buffalo , NY , USA
| | - Kari A Mergenhagen
- b Infectious Diseases Department, Veterans Affairs Western New York Healthcare System , Buffalo , NY , USA
| | - Brian T Tsuji
- a Laboratory for Antimicrobial Pharmacodynamics, Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo , NY , USA
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38
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Nigo M, Diaz L, Carvajal LP, Tran TT, Rios R, Panesso D, Garavito JD, Miller WR, Wanger A, Weinstock G, Munita JM, Arias CA, Chambers HF. Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis. Antimicrob Agents Chemother 2017; 61:e01235-16. [PMID: 28232309 PMCID: PMC5328541 DOI: 10.1128/aac.01235-16] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
We report a case of infective endocarditis (IE) caused by ceftaroline-resistant, daptomycin-tolerant, and heterogeneous vancomycin-intermediate methicillin-resistant S. aureus (MRSA). Resistance to ceftaroline emerged in the absence of drug exposure, and the E447K substitution in the active site of PBP2a previously associated with ceftaroline resistance was identified. Additionally, we present evidence of patient-to-patient transmission of the strain within the same unit. This case illustrates the difficulties in treating MRSA IE in the setting of a multidrug-resistant phenotype.
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Affiliation(s)
- Masayuki Nigo
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, Houston, Texas, USA
| | - Lorena Diaz
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogotá, Colombia
- Center for Antimicrobial Resistance and Microbial Genomics, University of Texas McGovern Medical School, Houston, Texas, USA
| | - Lina P Carvajal
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogotá, Colombia
| | - Truc T Tran
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, Houston, Texas, USA
- Center for Antimicrobial Resistance and Microbial Genomics, University of Texas McGovern Medical School, Houston, Texas, USA
| | - Rafael Rios
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogotá, Colombia
| | - Diana Panesso
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, Houston, Texas, USA
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogotá, Colombia
- Center for Antimicrobial Resistance and Microbial Genomics, University of Texas McGovern Medical School, Houston, Texas, USA
| | - Juan D Garavito
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogotá, Colombia
| | - William R Miller
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, Houston, Texas, USA
- Center for Antimicrobial Resistance and Microbial Genomics, University of Texas McGovern Medical School, Houston, Texas, USA
| | - Audrey Wanger
- Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Houston, Texas, USA
| | - George Weinstock
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
| | - Jose M Munita
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, Houston, Texas, USA
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogotá, Colombia
- Center for Antimicrobial Resistance and Microbial Genomics, University of Texas McGovern Medical School, Houston, Texas, USA
- Department of Medicine, Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile
| | - Cesar A Arias
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, Houston, Texas, USA
- Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogotá, Colombia
- Center for Antimicrobial Resistance and Microbial Genomics, University of Texas McGovern Medical School, Houston, Texas, USA
| | - Henry F Chambers
- Department of Medicine, Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA
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Fakhri A, Tahami S, Naji M. Synthesis and characterization of core-shell bimetallic nanoparticles for synergistic antimicrobial effect studies in combination with doxycycline on burn specific pathogens. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2017; 169:21-26. [PMID: 28254569 DOI: 10.1016/j.jphotobiol.2017.02.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 01/11/2017] [Accepted: 02/21/2017] [Indexed: 11/30/2022]
Abstract
Nano-medicine is a breakthrough discovery in the healthcare sector. Doxycycline is a new generation antibiotic which is proved to be a boon in the treatment of patients with complicated skin infections. We have tried to explore the benefits of synthesized bimetallic silver-gold nanoparticles in combination with new generation antibiotic for burn infections. The bimetallic nanoparticles synthesized by core-shell method were characterized using scanning electron microscopy equipped with an energy dispersive spectrometer, transmission electron microscopy, X-ray diffraction and UV-Vis spectroscopy. The calculated average particle sizes of the Ag-Au NPs were found to be 27.5nm. The Ag-Au core-shell BNPs show a characteristic Plasmon peak at 525nm which is broad and red shifted. The synergistic antimicrobial activity of doxycycline conjugated bimetallic nanoparticles was investigated against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Micrococcus luteus. This combined therapeutic agent showed greater bactericidal activity. Synergy of antibiotic with bimetallic nanoparticles is quite promising for significant application in burn healing therapy. The mechanism of the antibacterial activity was studied through the formation of reactive oxygen species (ROS) that was later suppressed with antioxidant to establish correlation with the Ag-Au NPs antimicrobial activity. Ag-Au NPs showed effective antiproliferative activity toward A549 human lung cancer (CCL-185) and MCF-7 human breast cancer (HTB-22) cell lines.
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Affiliation(s)
- Ali Fakhri
- Young Researchers and Elites Club, Science and Research Branch, Islamic Azad University, Tehran, Iran.
| | - Shiva Tahami
- Department of Biology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Mahsa Naji
- Department of Materials Engineering, Karaj Branch, Islamic Azad University, Karaj, Iran
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40
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Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus. Antimicrob Agents Chemother 2016; 61:AAC.01634-16. [PMID: 27795377 DOI: 10.1128/aac.01634-16] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 10/12/2016] [Indexed: 12/18/2022] Open
Abstract
Antimicrobial resistance is recognized as one of the principal threats to public health worldwide, yet the problem is increasing. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most difficult to treat in clinical settings due to the resistance of MRSA to nearly all available antibiotics. The cyclic anionic lipopeptide antibiotic daptomycin (DAP) is the clinical mainstay of anti-MRSA therapy. The decreased susceptibility to DAP (DAP resistance [DAPr]) reported in MRSA is frequently accompanied by a paradoxical decrease in β-lactam resistance, a process known as the "seesaw effect." Despite the observed discordance in resistance phenotypes, the combination of DAP and β-lactams has been proven to be clinically effective for the prevention and treatment of infections due to DAPr MRSA strains. However, the mechanisms underlying the interactions between DAP and β-lactams are largely unknown. In the study described here, we studied the role of mprF with DAP-induced mutations in β-lactam sensitization and its involvement in the effective killing by the DAP-oxacillin (OXA) combination. DAP-OXA-mediated effects resulted in cell wall perturbations, including changes in peptidoglycan insertion, penicillin-binding protein 2 (PBP 2) delocalization, and reduced membrane amounts of PBP 2a, despite the increased transcription of mecA through mec regulatory elements. We have found that the VraSR sensor-regulator is a key component of DAP resistance, triggering mutated mprF-mediated cell membrane (CM) modifications that result in impairment of PrsA location and chaperone functions, both of which are essential for PBP 2a maturation, the key determinant of β-lactam resistance. These observations provide for the first time evidence that synergistic effects between DAP and β-lactams involve PrsA posttranscriptional regulation of CM-associated PBP 2a.
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41
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Zilahi G, Artigas A, Martin-Loeches I. What's new in multidrug-resistant pathogens in the ICU? Ann Intensive Care 2016; 6:96. [PMID: 27714706 PMCID: PMC5053965 DOI: 10.1186/s13613-016-0199-4] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 09/29/2016] [Indexed: 12/28/2022] Open
Abstract
Over the last several decades, antibacterial drug use has become widespread with their misuse being an ever-increasing phenomenon. Consequently, antibacterial drugs have become less effective or even ineffective, resulting in a global health security emergency. The prevalence of multidrug-resistant organisms (MDROs) varies widely among regions and countries. The primary aim of antibiotic stewardship programs is to supervise the three most influential factors contributing to the development and transmission of MDROs, namely: (1) appropriate antibiotic prescribing; (2) early detection and prevention of cross-colonization of MDROs; and (3) elimination of reservoirs. In the future, it is expected that a number of countries will experience a rise in MDROs. These infections will be associated with a high consumption of healthcare resources manifested by a prolonged hospital stay and high mortality. As a counteractive strategy, minimization of broad-spectrum antibiotic use and prompt antibiotic administration will aid in reduction of antibiotic resistance. Innovative management approaches include development and implementation of rapid diagnostic tests that will help in both shortening the duration of therapy and allowing early targeted therapy. The institution of more accessible therapeutic drug monitoring will help to optimize drug administration and support a patient-specific approach. Areas where further research is required are investigation into the heterogeneity of critically ill patients and the need for new antibacterial drug development.
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Affiliation(s)
- Gabor Zilahi
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Multidisciplinary Intensive Care Research Organization (MICRO), Wellcome Trust‐HRB Clinical Research, St James’s Hospital, St James’s University Hospital, Dublin 8, Ireland
| | - Antonio Artigas
- Critical Care Center, Parc Taulí Hospital-Sabadell, CIBERes, Parc Tauli s/n., Sabadell, Barcelona, Spain
- Centros de Investigación Biomédica en Red (CIBER), Madrid, Spain
| | - Ignacio Martin-Loeches
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Multidisciplinary Intensive Care Research Organization (MICRO), Wellcome Trust‐HRB Clinical Research, St James’s Hospital, St James’s University Hospital, Dublin 8, Ireland
- Centros de Investigación Biomédica en Red (CIBER), Madrid, Spain
- Wellcome Trust‐HRB Clinical Research, Dublin, Ireland
- Department of Clinical Medicine, Trinity Centre for Health Sciences, Dublin, Ireland
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Molina KC, Huang V. Resistance to Non-glycopeptide Agents in Serious Staphylococcus aureus Infections. Curr Infect Dis Rep 2016; 18:47. [PMID: 27873126 DOI: 10.1007/s11908-016-0553-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The role of vancomycin in the treatment of serious Staphylococcus aureus infections, both methicillin-susceptible and methicillin-resistant, is becoming increasingly ineffective due to increasing MIC and failure. The development of reduced vancomycin susceptibility by S. aureus to glycopeptides highlights the need for clinicians to reexamine the roles of non-glycopeptide therapy. As the use of these alternative non-glycopeptides antimicrobials increases, it will become pertinent to monitor the rates of resistance. Large surveillance programs have provided data for resistance against S. aureus for the non-glycopeptides (daptomycin, ceftaroline, tigecycline, linezolid, and tedizolid). The current published literatures suggest that worldwide resistance rates to these non-glycopeptides for serious MRSA infections are still low. Implementation of antimicrobial stewardship programs will be crucial in prevention of resistance of these antimicrobials against S. aureus.
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Affiliation(s)
- Kyle C Molina
- Department of Pharmacy Practice, College of Pharmacy-Glendale, Midwestern University, 19555 N. 59th Ave., Glendale, AZ, 85308, USA
| | - Vanthida Huang
- Department of Pharmacy Practice, College of Pharmacy-Glendale, Midwestern University, 19555 N. 59th Ave., Glendale, AZ, 85308, USA.
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Zhao M, Lepak AJ, Andes DR. Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents. Bioorg Med Chem 2016; 24:6390-6400. [PMID: 27887963 DOI: 10.1016/j.bmc.2016.11.008] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 11/02/2016] [Accepted: 11/03/2016] [Indexed: 12/28/2022]
Abstract
Animal infection models in the pharmacokinetic/pharmacodynamic (PK/PD) evaluation of antimicrobial therapy serve an important role in preclinical assessments of new antibiotics, dosing optimization for those that are clinically approved, and setting or confirming susceptibility breakpoints. The goal of animal model studies is to mimic the infectious diseases seen in humans to allow for robust PK/PD studies to find the optimal drug exposures that lead to therapeutic success. The PK/PD index and target drug exposures obtained in validated animal infection models are critical components in optimizing dosing regimen design in order to maximize efficacy while minimize the cost and duration of clinical trials. This review outlines the key components in animal infection models which have been used extensively in antibiotic discovery and development including PK/PD analyses.
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Affiliation(s)
- Miao Zhao
- Institute of Antibiotics Hua-shan Hospital, Fudan University & Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, China; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Alexander J Lepak
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - David R Andes
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA; William S. Middleton Memorial VA Hospital, Madison, WI, USA.
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Müller S, Wolf AJ, Iliev ID, Berg BL, Underhill DM, Liu GY. Poorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology. Cell Host Microbe 2016; 18:604-12. [PMID: 26567511 DOI: 10.1016/j.chom.2015.10.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/23/2015] [Accepted: 10/20/2015] [Indexed: 10/22/2022]
Abstract
Methicillin-resistant S. aureus (MRSA) is a leading health problem. Compared to methicillin-sensitive S. aureus, MRSA infections are associated with greater morbidity and mortality, but the mechanisms underlying MRSA pathogenicity are unclear. Here we show that the protein conferring β-lactam antibiotic resistance, penicillin-binding protein 2A (encoded by the mecA gene), directly contributes to pathogenicity during MRSA infection. MecA induction leads to a reduction in peptidoglycan cross-linking that allows for enhanced degradation and detection by phagocytes, resulting in robust IL-1β production. Peptidoglycan isolated from β-lactam-challenged MRSA strongly induces the NLRP3 inflammasome in macrophages, but these effects are lost upon peptidoglycan solubilization. Mutant MRSA bacteria with naturally occurring reduced peptidoglycan cross-links induce high IL-1β levels in vitro and cause increased pathology in vivo. β-lactam treatment of MRSA skin infection exacerbates immunopathology, which is IL-1 dependent. Thus, antibiotic-induced expression of mecA during MRSA skin infection contributes to immunopathology by altering peptidoglycan structure.
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Affiliation(s)
- Sabrina Müller
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Andrea J Wolf
- Division of Biomedical Sciences and the F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Iliyan D Iliev
- Division of Biomedical Sciences and the F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Bethany L Berg
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - David M Underhill
- Division of Biomedical Sciences and the F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
| | - George Y Liu
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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Daptomycin-β-Lactam Combinations in a Rabbit Model of Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Endocarditis. Antimicrob Agents Chemother 2016; 60:3976-9. [PMID: 27090173 DOI: 10.1128/aac.00589-16] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 04/10/2016] [Indexed: 11/20/2022] Open
Abstract
Beta-lactams enhance the in vitro activity of daptomycin against methicillin-resistant strains of Staphylococcus aureus Experiments were performed in a rabbit model of aortic valve endocarditis caused by methicillin-resistant daptomycin-nonsusceptible S. aureus strain CB5054 to determine if a cephalosporin, ceftriaxone, administered as a once-daily dose of 100 mg/kg of body weight, or a carbapenem, ertapenem, administered as a once-daily dose of 40 mg/kg, improved the efficacy of daptomycin, administered as a once-daily dose of 12 mg/kg. Daptomycin was ineffective alone in reducing organism densities compared to untreated controls in vegetations and spleen, but densities were 1.4 log10 CFU/g lower in kidney. The combination of daptomycin plus ceftriaxone or daptomycin plus ertapenem reduced bacterial densities in all tissues compared to single agents, with 0.6 to 1.0 log10 CFU/g fewer organisms in vegetations, 1.5 to 2.5 log10 CFU/g fewer organisms in spleen, and 1.8 to 2.5 log10 CFU/g fewer organisms in kidney, although differences were statistically significant only in spleen for daptomycin plus ceftriaxone and in kidney for daptomycin plus ertapenem. Drug exposures in rabbits were less than those achievable in humans, which may have limited the in vivo activity, particularly in vegetations.
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Daptomycin in Combination with Ceftolozane-Tazobactam or Cefazolin against Daptomycin-Susceptible and -Nonsusceptible Staphylococcus aureus in an In Vitro, Hollow-Fiber Model. Antimicrob Agents Chemother 2016; 60:3970-5. [PMID: 27090172 DOI: 10.1128/aac.01666-15] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 04/04/2016] [Indexed: 11/20/2022] Open
Abstract
Ceftolozane-tazobactam (TOL-TAZ) is a novel cephalosporin/beta-lactamase inhibitor with activity against several Gram-negative pathogens. Daptomycin (DAP) has demonstrated synergistic activity with beta-lactams against methicillin-resistant Staphylococcus aureus (MRSA) isolates with reduced lipopeptide and glycopeptide susceptibilities. Our objective was to determine if DAP and TOL-TAZ possess synergy in hollow-fiber pharmacokinetic/pharmacodynamic (PK/PD) models. One isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible MRSA strains was evaluated. DAP, TOL-TAZ, and cefazolin (CFZ) MIC determinations were performed. DAP MIC determinations were also performed in the presence of subinhibitory concentrations of TOL-TAZ and CFZ. Ninety-six-hour in vitro models were run, simulating DAP at 10 mg/kg of body weight/day; TOL-TAZ at 1,500 mg every 8 h; TOL at 1,000 mg every 8 h; and DAP combined with TOL-TAZ (DAP+TOL-TAZ), DAP+TOL, DAP+TAZ, and DAP+CFZ at 2,000 mg every 8 h. DAP MICs were 0.5 and 4 μg/ml for strains R8845 and R8846, respectively. In the presence of CFZ, R8845 and R8846 DAP MICs were reduced 8-fold and 16-fold, respectively. TOL and TAZ had no effect on DAP MICs. PK/PD models demonstrated bactericidal activity with DAP+CFZ against both strains. The combination of DAP+TOL-TAZ was bactericidal against R8845 but was not bactericidal against daptomycin-nonsusceptible strain R8846. DAP+TOL and DAP+TAZ were not bactericidal. No other regimens were bactericidal. DAP+TOL-TAZ did not demonstrate synergistic activity against daptomycin-nonsusceptible S. aureus but prevented daptomycin-nonsusceptible MRSA emergence. Because DAP+TOL or TAZ alone did not prevent daptomycin-nonsusceptible MRSA emergence, the combination TOL-TAZ may be necessary for synergy with DAP. DAP+CFZ demonstrated enhancement against both strains. The combination of DAP+CFZ warrants further clinical study.
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Munita JM, Bayer AS, Arias CA. Evolving resistance among Gram-positive pathogens. Clin Infect Dis 2016; 61 Suppl 2:S48-57. [PMID: 26316558 DOI: 10.1093/cid/civ523] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Antimicrobial therapy is a key component of modern medical practice and a cornerstone for the development of complex clinical interventions in critically ill patients. Unfortunately, the increasing problem of antimicrobial resistance is now recognized as a major public health threat jeopardizing the care of thousands of patients worldwide. Gram-positive pathogens exhibit an immense genetic repertoire to adapt and develop resistance to virtually all antimicrobials clinically available. As more molecules become available to treat resistant gram-positive infections, resistance emerges as an evolutionary response. Thus, antimicrobial resistance has to be envisaged as an evolving phenomenon that demands constant surveillance and continuous efforts to identify emerging mechanisms of resistance to optimize the use of antibiotics and create strategies to circumvent this problem. Here, we will provide a broad perspective on the clinical aspects of antibiotic resistance in relevant gram-positive pathogens with emphasis on the mechanistic strategies used by these organisms to avoid being killed by commonly used antimicrobial agents.
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Affiliation(s)
- Jose M Munita
- Division of Infectious Diseases, Department of Internal Medicine International Center for Microbial Genomics Clinica Alemana de Santiago, Universidad del Desarrollo, Chile
| | - Arnold S Bayer
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Cesar A Arias
- Division of Infectious Diseases, Department of Internal Medicine Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston International Center for Microbial Genomics Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, Colombia
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Rapoport B, Klastersky J, Raftopoulos H, Freifeld A, Aoun M, Zinner SH, Rolston KVI. The emerging problem of bacterial resistance in cancer patients; proceedings of a workshop held by MASCC "Neutropenia, Infection and Myelosuppression" Study Group during the MASCC annual meeting held in Berlin on 27-29 June 2013. Support Care Cancer 2016; 24:2819-26. [PMID: 27098065 DOI: 10.1007/s00520-016-3183-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 03/21/2016] [Indexed: 11/25/2022]
Affiliation(s)
| | - Jean Klastersky
- Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Brussels, Belgium
| | | | | | - Mickael Aoun
- Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Brussels, Belgium
| | - Stephen H Zinner
- Department of Medicine, Mount Auburn Hospital, Cambridge, MA, USA.,Harvard Medical School, Boston, MA, USA
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Xue S, Liu J, Wang C. DBU-Mediated [3+2] Cycloaddition Reactions of Donor-Acceptor Cyclopropanes with Nitromethane: Efficient Strategy for the Construction of Isoxazole Skeletons. European J Org Chem 2016. [DOI: 10.1002/ejoc.201600227] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Gonzalez-Ruiz A, Seaton RA, Hamed K. Daptomycin: an evidence-based review of its role in the treatment of Gram-positive infections. Infect Drug Resist 2016; 9:47-58. [PMID: 27143941 PMCID: PMC4846043 DOI: 10.2147/idr.s99046] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Infections caused by Gram-positive pathogens remain a major public health burden and are associated with high morbidity and mortality. Increasing rates of infection with Gram-positive bacteria and the emergence of resistance to commonly used antibiotics have led to the need for novel antibiotics. Daptomycin, a cyclic lipopeptide with rapid bactericidal activity against a wide range of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, has been shown to be effective and has a good safety profile for the approved indications of complicated skin and soft tissue infections (4 mg/kg/day), right-sided infective endocarditis caused by S. aureus, and bacteremia associated with complicated skin and soft tissue infections or right-sided infective endocarditis (6 mg/kg/day). Based on its pharmacokinetic profile and concentration-dependent bactericidal activity, high-dose (>6 mg/kg/day) daptomycin is considered an important treatment option in the management of various difficult-to-treat Gram-positive infections. Although daptomycin resistance has been documented, it remains uncommon despite the increasing use of daptomycin. To enhance activity and to minimize resistance, daptomycin in combination with other antibiotics has also been explored and found to be beneficial in certain severe infections. The availability of daptomycin via a 2-minute intravenous bolus facilitates its outpatient administration, providing an opportunity to reduce risk of health care-associated infections, improve patient satisfaction, and minimize health care costs. Daptomycin, not currently approved for use in the pediatric population, has been shown to be widely used for treating Gram-positive infections in children.
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Affiliation(s)
| | | | - Kamal Hamed
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
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