DSpace Repository :: Browsing by Author "Tran, Truc"

Browsing by Author "Tran, Truc"

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A liaF codon deletion abolishes daptomycin bactericidal activity against vancomycin-resistant enterococcus faecali
(American Society for Microbiology, 2013) Munita, José; Tran, Truc; Diaz, Lorena; Panesso, Diana; Reyes, Jinnethe; Murray, Barbara; Arias, Cesar
The genetic bases for antibiotic tolerance are obscure. Daptomycin (DAP) is a lipopeptide antibiotic with bactericidal activity against enterococci. Using time-kill assays, we provide evidence for the first time that a deletion of isoleucine in position 177 of LiaF, a member of the three-component regulatory system LiaFSR involved in the cell envelope response to antimicrobials, is directly responsible for a DAP-tolerant phenotype and is likely to negatively affect response to DAP therapy.
Clinical characteristics, microbiology and outcomes of a cohort of patients treated with ceftolozane/tazobactam in acute care inpatient facilities, Houston, Texas, USA
(2023) Tran, Truc; Cabrera, Nicolo; Gonzales, Anne; Carlson, Travis; Alnezary, Faris; Miller, William; Sakurai, Aki; Dinh, An; Rydell, Kirsten; Rios, Rafael; Diaz, Lorena; Hanson, Blake; Munita, Jose M.; Pedroza, Claudia; Shelburne, Samuel; Aitken, Samuel; Garey, Kevin; Dillon, Ryan; Puzniak, Laura; Arias, Cesar
Background: Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination with activity against a variety of Gram-negative bacteria, including MDR Pseudomonas aeruginosa. This agent is approved for hospital-acquired and ventilator-associated bacterial pneumonia. However, most real-world outcome data come from small observational cohorts. Thus, we sought to evaluate the utilization of ceftolozane/tazobactam at multiple tertiary hospitals in Houston, TX, USA. Methods: We conducted a multicentre retrospective study of patients receiving at least 48 h of ceftolozane/tazobactam therapy from January 2016 through to September 2019 at two hospital systems in Houston. Demographic, clinical and microbiological data were collected, including the infecting bacterial isolate, when available. The primary outcome was composite clinical success at hospital discharge. Secondary outcomes included in-hospital mortality and clinical disposition at 14 and 30 days post ceftolozane/tazobactam initiation. Multivariable logistic regression analysis was used to identify predictors of the primary outcome and mortality. Recovered isolates were tested for susceptibility to ceftolozane/tazobactam and underwent WGS. Results: A total of 263 patients were enrolled, and composite clinical success was achieved in 185 patients (70.3%). Severity of illness was the most consistent predictor of clinical success. Combination therapy with ceftolozane/tazobactam and another Gram-negative-active agent was associated with reduced odds of clinical success (OR 0.32, 95% CI 0.16-0.63). Resistance to ceftolozane/tazobactam was noted in 15.4% of isolates available for WGS; mutations in ampC and ftsI were common but did not cluster with a particular ST. Conclusions: Clinical success rate among this patient cohort treated with ceftolozane/tazobactam was similar compared with previous experiences. Ceftolozane/tazobactam remains an alternative agent for treatment of susceptible isolates of P. aeruginosa.
Contemporary Clinical and Molecular Epidemiology of Vancomycin-Resistant Enterococcal Bacteremia: A Prospective Multicenter Cohort Study (VENOUS I)
(2021) Contreras, Germán; Munita, José; Simar, Shelby; Luterbach, Courtney; Dinh, An Q.; Rydell, Kirsten; Sahasrabhojane, Pranoti; Rios, Rafael; Díaz, Lorena; Reyes, Katherine; Zervos, Marcus; Misikir, Helina; Sánchez, Gabriela; Liu, Catherine; Doi, Yohei; Abbo, Lilian; Shimose, Luis; Seifert, Harald; Gudiol, Carlota; Barberis, Fernanda; Pedroza, Claudia; Aitken, Samuel; Shelburne, Samuel; Duin, David; Tran, Truc; Hanson, Blake; Arias, Cesar
Background: Vancomycin-resistant enterococci (VRE) are major therapeutic challenges. Prospective contemporary data characterizing the clinical and molecular epidemiology of VRE bloodstream infections (BSIs) are lacking. Methods: The Vancomycin-Resistant Enterococcal BSI Outcomes Study (VENOUS I) is a prospective observational cohort of adult patients with enterococcal BSI in 11 US hospitals. We included patients with Enterococcus faecalis or Enterococcus faecium BSI with ≥1 follow-up blood culture(s) within 7 days and availability of isolate(s) for further characterization. The primary study outcome was in-hospital mortality. Secondary outcomes were mortality at days 4, 7, 10, 12, and 15 after index blood culture. A desirability of outcome ranking was constructed to assess the association of vancomycin resistance with outcomes. All index isolates were subjected to whole genome sequencing. Results: Forty-two of 232 (18%) patients died in hospital and 39 (17%) exhibited microbiological failure (lack of clearance in the first 4 days). Neutropenia (hazard ratio [HR], 3.13), microbiological failure (HR, 2.4), VRE BSI (HR, 2.13), use of urinary catheter (HR, 1.85), and Pitt BSI score ≥2 (HR, 1.83) were significant predictors of in-hospital mortality. Microbiological failure was the strongest predictor of in-hospital mortality in patients with E faecium bacteremia (HR, 5.03). The impact of vancomycin resistance on mortality in our cohort changed throughout the course of hospitalization. Enterococcus faecalis sequence type 6 was a predominant multidrug-resistant lineage, whereas a heterogeneous genomic population of E faecium was identified. Conclusions: Failure of early eradication of VRE from the bloodstream is a major factor associated with poor outcomes.
Correlation between mutations in liaFSR of enterococcus faecium and MIC of daptomycin: revisiting daptomycin breakpoints
(American Society for Microbiology, 2012) Munita, José; Panesso, Diana; Diaz, Lorena; Tran, Truc; Reyes, Jinnethe; Wanger, Audrey; Murray, Barbara; Arias, Cesar
Mutations in liaFSR, a three-component regulatory system controlling cell-envelope stress response, were recently linked with the emergence of daptomycin (DAP) resistance in enterococci. Our previous work showed that a liaF mutation increased the DAP MIC of a vancomycin-resistant Enterococcus faecalis strain from 1 to 3 μg/ml (the DAP breakpoint is 4 μg/ml), suggesting that mutations in the liaFSR system could be a pivotal initial event in the development of DAP resistance. With the hypothesis that clinical enterococcal isolates with DAP MICs between 3 and 4 μg/ml might harbor mutations in liaFSR, we studied 38 Enterococcus faecium bloodstream isolates, of which 8 had DAP MICs between 3 and 4 μg/ml by Etest in Mueller-Hinton agar. Interestingly, 6 of these 8 isolates had predicted amino acid changes in the LiaFSR system. Moreover, we previously showed that among 6 DAP-resistant E. faecium isolates (MICs of >4 μg/ml), 5 had mutations in liaFSR. In contrast, none of 16 E. faecium isolates with a DAP MIC of ≤2 μg/ml harbored mutations in this system (P < 0.0001). All but one isolate with liaFSR changes exhibited DAP MICs of ≥16 μg/ml by Etest using brain heart infusion agar (BHIA), a medium that better supports enterococcal growth. Our findings provide a strong association between DAP MICs within the upper susceptibility range and mutations in the liaFSR system. Concomitant susceptibility testing on BHIA may be useful for identifying these E. faecium first-step mutants. Our results also suggest that the current DAP breakpoint for E. faecium may need to be reevaluated.
Daptomycin non-susceptible Enterococcus faecium in leukemia patients: Role of prior daptomycin exposure
(Elsevier, 2016) DiPippo, Adam; Tverdek, Frank; Tarrand, Jeffrey; Munita, José; Tran, Truc; Arias, Cesar; Shelburne, Samuel; Aitken, Samuel L.
OBJECTIVES: We sought to determine the association between previous daptomycin exposure and daptomycin non-susceptible Enterococcus faecium (DNSEf) bloodstream infections (BSI) in adult leukemia patients. METHODS: We retrospectively identified adult (≥18 years old) leukemia patients with Enterococcus spp. bacteremia at The University of Texas MD Anderson Cancer Center (MDACC) from 6/1/2013 to 7/22/2015. Antimicrobial susceptibility and previous antibiotic exposure within the 90 days prior to bacteremia were collected. Classification and Regression Tree (CART) analysis was used to identify the most significant breakpoint between daptomycin exposure and DNSEf. RESULTS: Any amount of daptomycin received within the 90 days preceding BSI was significantly associated with isolation of DNSEf compared to daptomycin susceptible E. faecium (DSEf) (88% vs. 44%, respectively, p < 0.01). CART analysis identified receiving ≥13 days of daptomycin in the preceding 90 days as most significantly correlated with DNSEf (60% vs. 11%, relative risk [RR] 5.31, 95% Confidence interval [CI] 2.36-11.96, p < 0.01). CONCLUSIONS: Prior daptomycin exposure for ≥13 days within 90 days preceding BSI was significantly associated with isolation of DNSEf BSI in adult leukemia patients at our institution. Antimicrobial stewardship initiatives aimed at minimizing daptomycin exposure in high-risk patients may be of significant benefit in limiting the emergence of DNSEf.
Daptomycin-resistant enterococcus faecalis diverts the antibiotic molecule from the division septum and remodels cell membrane phospholipids
(American Society for Microbiology, 2013) Tran, Truc; Panesso, Diana; Mishra, Nagendra; Mileykovskaya, Eugenia; Guan, Ziqianq; Munita, José; Reyes, Jinnethe; Diaz, Lorena; Weinstock, George; Murray, Barbara; Shamoo, Yousif; Dowhan, William; Bayer, Arnold; Arias, Cesar
Treatment of multidrug-resistant enterococci has become a challenging clinical problem in hospitals around the world due to the lack of reliable therapeutic options. Daptomycin (DAP), a cell membrane-targeting cationic antimicrobial lipopeptide, is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant enterococci (VRE). However, the clinical use of DAP against VRE is threatened by emergence of resistance during therapy, but the mechanisms leading to DAP resistance are not fully understood. The mechanism of action of DAP involves interactions with the cell membrane in a calcium-dependent manner, mainly at the level of the bacterial septum. Previously, we demonstrated that development of DAP resistance in vancomycin-resistant Enterococcus faecalis is associated with mutations in genes encoding proteins with two main functions, (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase). In this work, we show that these VRE can resist DAP-elicited cell membrane damage by diverting the antibiotic away from its principal target (division septum) to other distinct cell membrane regions. DAP septal diversion by DAP-resistant E. faecalis is mediated by initial redistribution of cell membrane cardiolipin-rich microdomains associated with a single amino acid deletion within the transmembrane protein LiaF (a member of a three-component regulatory system [LiaFSR] involved in cell envelope homeostasis). Full expression of DAP resistance requires additional mutations in enzymes (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase) that alter cell membrane phospholipid content. Our findings describe a novel mechanism of bacterial resistance to cationic antimicrobial peptides. IMPORTANCE: The emergence of antibiotic resistance in bacterial pathogens is a threat to public health. Understanding the mechanisms of resistance is of crucial importance to develop new strategies to combat multidrug-resistant microorganisms. Vancomycin-resistant enterococci (VRE) are one of the most recalcitrant hospital-associated pathogens against which new therapies are urgently needed. Daptomycin (DAP) is a calcium-decorated antimicrobial lipopeptide whose target is the bacterial cell membrane. A current paradigm suggests that Gram-positive bacteria become resistant to cationic antimicrobial peptides via an electrostatic repulsion of the antibiotic molecule from a more positively charged cell surface. In this work, we provide evidence that VRE use a novel strategy to avoid DAP-elicited killing. Instead of "repelling" the antibiotic from the cell surface, VRE diverts the antibiotic molecule from the septum and "traps" it in distinct membrane regions. We provide genetic and biochemical bases responsible for the mechanism of resistance and disclose new targets for potential antimicrobial development.
Deletion of liaR reverses daptomycin resistance in enterococcus faecium independent of the genetic background
(American Society for Microbiology, 2015) Panesso, Diana; Reyes, Jinnethe; Gaston, Elizabeth; Deal, Morgan; Londoño, Alejandra; Nigo, Masayuki; Munita, José; Miller, William; Shamoo, Yousif; Tran, Truc; Arias, Cesar
We have shown previously that changes in LiaFSR, a three-component regulatory system predicted to orchestrate the cell membrane stress response, are important mediators of daptomycin (DAP) resistance in enterococci. Indeed, deletion of the gene encoding the response regulator LiaR in a clinical strain of Enterococcus faecalis reversed DAP resistance (DAP-R) and produced a strain hypersusceptible to antimicrobial peptides. Since LiaFSR is conserved in Enterococcus faecium, we investigated the role of LiaR in a variety of clinical E. faecium strains representing the most common DAP-R genetic backgrounds. Deletion of liaR in DAP-R E. faecium R446F (DAP MIC of 16 μg/ml) and R497F (MIC of 24 μg/ml; harboring changes in LiaRS) strains fully reversed resistance (DAP MICs decreasing to 0.25 and 0.094 μg/ml, respectively). Moreover, DAP at concentrations of 13 μg/ml (achieved with human doses of 12 mg/kg body weight) retained bactericidal activity against the mutants. Furthermore, the liaR deletion derivatives of these two DAP-R strains exhibited increased binding of boron-dipyrromethene difluoride (BODIPY)-daptomycin, suggesting that high-level DAP-R mediated by LiaR in E. faecium involves repulsion of the calcium-DAP complex from the cell surface. In DAP-tolerant strains HOU503F and HOU515F (DAP MICs within the susceptible range but bacteria not killed by DAP concentrations of 5× the MIC), deletion of liaR not only markedly decreased the DAP MICs (0.064 and 0.047 μg/ml, respectively) but also restored the bactericidal activity of DAP at concentrations as low as 4 μg/ml (achieved with human doses of 4 mg/kg). Our results suggest that LiaR plays a relevant role in the enterococcal cell membrane adaptive response to antimicrobial peptides independent of the genetic background and emerges as an attractive target to restore the activity of DAP against multidrug-resistant strains.
Dissecting the mechanisms of linezolid resistance in a drosophila melanogaster infection model of staphylococcus aureus
(Oxford University Press, 2013) Diaz, Lorena; Kontoyiannis, Dimitrios; Panesso, Diana; Albert, Nathaniel; Singh, Kavindra; Tran, Truc; Munita, José; Murray, Barbara; Arias, Cesar
BACKGROUND: Mini-host models are simple experimental systems to study host-pathogen interactions. We adapted a Drosophila melanogaster infection model to evaluate the in vivo effect of different mechanisms of linezolid (LNZ) resistance in Staphylococcus aureus. METHODS: Fly survival was evaluated after infection with LNZ-resistant S. aureus strains NRS119 (which has mutations in 23S ribosomal RNA [rRNA]), CM-05 and 004-737X (which carry cfr), LNZ-susceptible derivatives of CM-05 and 004-737X (which lack cfr), and ATCC 29213 (an LNZ-susceptible control). Flies were then fed food mixed with LNZ (concentration, 15-500 µg/mL). Results were compared to those in mouse peritonitis, using LNZ via oral gavage at 80 and 120 mg/kg every 12 hours. RESULTS: LNZ at 500 µg/mL in fly food protected against all strains, while concentrations of 15-250 µg/mL failed to protect against NRS119 (survival, 1.6%-20%). An in vivo effect of cfr was only detected at concentrations of 30 and 15 µg/mL. In the mouse peritonitis model, LNZ (at doses that mimic human pharmacokinetics) protected mice from challenge with the cfr+ 004-737X strain but was ineffective against the NRS119 strain, which carried 23S rRNA mutations. CONCLUSIONS: The fly model offers promising advantages to dissect the in vivo effect of LNZ resistance in S. aureus, and findings from this model appear to be concordant with those from the mouse peritonitis model.
Influence of minimum inhibitory concentration in clinical outcomes of enterococcus faecium bacteremia treated with daptomycin: is it time to change the breakpoint?
(Oxford University Press, 2016) Shukla, Bhavarth; Shelburne, Samuel; Reyes, Katherine; Kamboj, Mini; Lewis, Jessica; Rincon, Sandra; Reyes, Jinnethe; Carvajal, Lina; Panesso, Diana; Sifri, Costi; Zervos, Marcus; Pamer, Eric; Tran, Truc; Adachi, Javier; Munita, José; Hasbun, Rodrigo; Arias, Cesar
BACKGROUND: Daptomycin has become a front-line antibiotic for multidrug-resistant Enterococcus faecium bloodstream infections (BSIs). We previously showed that E. faecium strains with daptomycin minimum inhibitory concentrations (MICs) in the higher end of susceptibility frequently harbor mutations associated with daptomycin resistance. We postulate that patients with E. faecium BSIs exhibiting daptomycin MICs of 3-4 µg/mL treated with daptomycin are more likely to have worse clinical outcomes than those exhibiting daptomycin MICs ≤2 µg/mL. METHODS: We conducted a multicenter retrospective cohort study that included adult patients with E. faecium BSI for whom initial isolates, follow-up blood culture data, and daptomycin administration data were available. A central laboratory performed standardized daptomycin MIC testing for all isolates. The primary outcome was microbiologic failure, defined as clearance of bacteremia ≥4 days after the index blood culture. The secondary outcome was all-cause in-hospital mortality. RESULTS: A total of 62 patients were included. Thirty-one patients were infected with isolates that exhibited daptomycin MICs of 3-4 µg/mL. Overall, 34 patients had microbiologic failure and 25 died during hospitalization. In a multivariate logistic regression model, daptomycin MICs of 3-4 µg/mL (odds ratio [OR], 4.7 [1.37-16.12]; P = .014) and immunosuppression (OR, 5.32 [1.20-23.54]; P = .028) were significantly associated with microbiologic failure. Initial daptomycin dose of ≥8 mg/kg was not significantly associated with evaluated outcomes. CONCLUSIONS: Daptomycin MICs of 3-4 µg/mL in the initial E. faecium blood isolate predicted microbiological failure of daptomycin therapy, suggesting that modification in the daptomycin breakpoint for enterococci should be considered.
Mechanisms of drug resistance: daptomycin resistance
(New York Academy of Sciences by Wley., 2015) Tran, Truc; Munita, José; Arias, Cesar
Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction into clinical practice in 2003, DAP has become an important key frontline antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP resistance (DAP-R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp., and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP-R are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have provided novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope, such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria.
Methicillin-Susceptible, Vancomycin-Resistant Staphylococcus aureus, Brazil
(Centers for Disease Control and Prevention, 2015) Panesso, Diana; Planet, Paul; Diaz, Lorena; Hugonnet, Jean-Emmanuel; Tran, Truc; Narechania, Apurva; Munita, José; Rincon, Sandra; Carvajal, Lina; Reyes, Jinnethe; Londoño, Alejandra; Smith, Hannah; Sebra, Robert; Deikus, Gintaras; Weinstock, George; Murray, Barbara; Rossi, Flavia; Arthur, Michel; Arias, Cesar
We report characterization of a methicillin-susceptible, vancomycin-resistant bloodstream isolate of Staphylococcus aureus recovered from a patient in Brazil. Emergence of vancomycin resistance in methicillin-susceptible S. aureus would indicate that this resistance trait might be poised to disseminate more rapidly among S. aureus and represents a major public health threat.
Multicenter evaluation of ceftolozane/tazobactam for serious infections caused by carbapenem-resistant pseudomonas aeruginosa
(Oxford University Press, 2017) Munita, José; Aitken, Samuel; Miller, William; Perez, Federico; Rosa, Rossana; Shimose, Luis; Lichtenberger, Paola; Abbo, Lilian; Jain, Rupali; Nigo, Masayuki; Wanger, Audrey; Araos, Rafael; Tran, Truc; Adachi, Javier; Rakita, Robert; Shelburne, Samuel; Bonomo, Robert; Arias, Cesar
A multicenter, retrospective study of patients infected with carbapenem-resistant Pseudomonas aeruginosa who were treated with ceftolozane/tazobactam was performed. Among 35 patients, pneumonia was the most common indication and treatment was successful in 26 (74%). Treatment failure was observed in all cases where isolates demonstrated ceftolozane-tazobactam minimum inhibitory concentrations ≥8 μg/mL.
Multisite Detection of Tn 1549-Mediated vanB Vancomycin Resistance in Multidrug-Resistant Enterococcus faecalis ST6 in Texas and Florida
(2023) Simar, Shelby; Tran, Truc; Rydell, Kirsten; Panesso, Diana; Contreras, German; Munita, Jose M.; Cifuentes. Renzo; Abbo, Lilian; Sahasrabhojane, Pranoti; Dinh, An; Axell-House, Dierdre; Savidge, Tor; Shelburne, Samuel; Hanson, Blake; Arias, Cesar
In the United States, vanB-mediated resistance in enterococci is rare. We characterized three sequence type (ST) 6, vancomycin-resistant Enterococcus faecalis isolates causing bacteremia in unique patients in spatiotemporally distinct settings. Isolates were recovered between 2018 and 2020 in two cities in the United States (Houston, TX; Miami, FL). The isolates harbored the vanB operon on a chromosomally located Tn1549 transposon, and epidemiological data suggested multiple introductions of the vanB gene cluster into ST6 E. faecalis.
New Perspectives on Antimicrobial Agents: Long-Acting Lipoglycopeptides
(2022) Tran, Truc; Gomez, Sara; Aitken, Samuel; Butler, Susan; Soriano, Alex; Werth, Brian; Munita, José
The long-acting lipoglycopeptides (LGPs) dalbavancin and oritavancin are semisynthetic antimicrobials with broad and potent activity against Gram-positive bacterial pathogens. While they are approved by the Food and Drug Administration for acute bacterial skin and soft tissue infections, their pharmacological properties suggest a potential role of these agents for the treatment of deep-seated and severe infections, such as bloodstream and bone and joint infections. The use of these antimicrobials is particularly appealing when prolonged therapy, early discharge, and avoidance of long-term intravascular catheter access are desirable or when multidrug-resistant bacteria are suspected. This review describes the current evidence for the use of oritavancin and dalbavancin in the treatment of invasive infections, as well as the hurdles that are preventing their optimal use. Moreover, this review discusses the current knowledge gaps that need to be filled to understand the potential role of LGPs in highly needed clinical scenarios and the ongoing clinical studies that aim to address these voids in the upcoming years.
Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review
(2023) Doernberg, Sarah; Arias, Cesar; Altman, Deena; Babiker, Ahmed; Boucher, Helen; Creech, C Buddy; Cosgrove, Sara; Evans, Scott; Fowler, Vance; Fritz, Stephanie; Hamasaki, Toshimitsu; Kelly, Brendan; Leal, Sixto; Liu, Catherine; Lodise, Thomas; Miller, Loren; Munita, Jose M.; Murray, Barbara; Pettigrew, Melinda; Ruffin, Felicia; Scheetz, Marc; Shopsin, Bo; Tran, Truc; Turne, Nicholas; Williams, Derek; Zaharoff, Smitha; Holland, Thomas; Antibacterial Resistance Leadership Group
The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.
Transferable vancomycin resistance in a community-associated MRSA lineage
(Massachusetts Medical Society, 2014) Rossi, Flávia; Diaz, Lorena; Wollam, Aye; Panesso, Diana; Zhou, Yanjiao; Rincon, Sandra; Narechania, Apurva; Xing, Galen; Di Gioia, Thais; Doi, André; Tran, Truc; Reyes, Jinnethe; Munita, José; Carvajal, Lina; Hernandez-Roldan, Alejandra; Brandão, Denise; van der Heijden, Inneke Marie; Murray, Barbara; Planet, Paul; Weinstock, George; Arias, Cesar
We report the case of a patient from Brazil with a bloodstream infection caused by a strain of methicillin-resistant Staphylococcus aureus (MRSA) that was susceptible to vancomycin (designated BR-VSSA) but that acquired the vanA gene cluster during antibiotic therapy and became resistant to vancomycin (designated BR-VRSA). Both strains belong to the sequence type (ST) 8 community-associated genetic lineage that carries the staphylococcal chromosomal cassette mec (SCCmec) type IVa and the S. aureus protein A gene (spa) type t292 and are phylogenetically related to MRSA lineage USA300. A conjugative plasmid of 55,706 bp (pBRZ01) carrying the vanA cluster was identified and readily transferred to other staphylococci. The pBRZ01 plasmid harbors DNA sequences that are typical of the plasmid-associated replication genes rep24 or rep21 described in community-associated MRSA strains from Australia (pWBG745). The presence and dissemination of community-associated MRSA containing vanA could become a serious public health concern.
Whole-Genome Analyses of Enterococcus faecium Isolates with Diverse Daptomycin MICs
(American Society for Microbiology, 2014) Diaz, Lorena; Tran, Truc; Munita, José; Miller, William; Rincon, Sandra; Carvajal, Lina; Wollam, Aye; Reyes, Jinnethe; Panesso, Diana; Rojas, Natalia; Shamoo, Yousif; Murray, Barbara; Weinstock, George; Arias, Cesar
Daptomycin (DAP) is a lipopeptide antibiotic frequently used as a "last-resort" antibiotic against vancomycin-resistant Enterococcus faecium (VRE). However, an important limitation for DAP therapy against VRE is the emergence of resistance during therapy. Mutations in regulatory systems involved in cell envelope homeostasis are postulated to be important mediators of DAP resistance in E. faecium. Thus, in order to gain insights into the genetic bases of DAP resistance in E. faecium, we investigated the presence of changes in 43 predicted proteins previously associated with DAP resistance in enterococci and staphylococci using the genomes of 19 E. faecium with different DAP MICs (range, 3 to 48 μg/ml). Bodipy-DAP (BDP-DAP) binding to the cell membrane assays and time-kill curves (DAP alone and with ampicillin) were performed. Genetic changes involving two major pathways were identified: (i) LiaFSR, a regulatory system associated with the cell envelope stress response, and (ii) YycFGHIJ, a system involved in the regulation of cell wall homeostasis. Thr120 → Ala and Trp73 → Cys substitutions in LiaS and LiaR, respectively, were the most common changes identified. DAP bactericidal activity was abolished in the presence of liaFSR or yycFGHIJ mutations regardless of the DAP MIC and was restored in the presence of ampicillin, but only in representatives of the LiaFSR pathway. Reduced binding of BDP-DAP to the cell surface was the predominant finding correlating with resistance in isolates with DAP MICs above the susceptibility breakpoint. Our findings suggest that genotypic information may be crucial to predict response to DAP plus β-lactam combinations and continue to question the DAP breakpoint of 4 μg/ml.
Whole-genome analysis of a daptomycin-susceptible enterococcus faecium strain and its daptomycin-resistant variant arising during therapy
(American Society for Microbiology, 2013) Tran, Truc; Panesso, Diana; Gao, Hongyu; Roh, Jung; Munita, José; Reyes, Jinnethe; Diaz, Lorena; Lobos, Elizabeth; Shamoo, Yousif; Mishra, Nagendra; Bayer, Arnold; Murray, Barbara; Weinstock, George; Arias, Cesar
Development of daptomycin (DAP) resistance in Enterococcus faecalis has recently been associated with mutations in genes encoding proteins with two main functions: (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase [cls]). However, the genetic bases for DAP resistance in Enterococcus faecium are unclear. We performed whole-genome comparative analysis of a clinical strain pair, DAP-susceptible E. faecium S447 and its DAP-resistant derivative R446, which was recovered from a single patient during DAP therapy. By comparative whole-genome sequencing, DAP resistance in R446 was associated with changes in 8 genes. Two of these genes encoded proteins involved in phospholipid metabolism: (i) an R218Q substitution in Cls and (ii) an A292G reversion in a putative cyclopropane fatty acid synthase enzyme. The DAP-resistant derivative R446 also exhibited an S333L substitution in the putative histidine kinase YycG, a member of the YycFG system, which, similar to LiaFSR, has been involved in cell envelope homeostasis and DAP resistance in other Gram-positive cocci. Additional changes identified in E. faecium R446 (DAP resistant) included two putative proteins involved in transport (one for carbohydrate and one for sulfate) and three enzymes predicted to play a role in general metabolism. Exchange of the "susceptible" cls allele from S447 for the "resistant" one belonging to R446 did not affect DAP susceptibility. Our results suggest that, apart from the LiaFSR system, the essential YycFG system is likely to be an important mediator of DAP resistance in some E. faecium strains.

Browsing by Author "Tran, Truc"

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