scholarly journals Genetic Basis for Vancomycin-Enhanced Cephalosporin Susceptibility in Vancomycin-Resistant Enterococci Revealed Using Counterselection with Dominant-Negative Thymidylate Synthase

2013 ◽  
Vol 58 (3) ◽  
pp. 1556-1564 ◽  
Author(s):  
Christopher J. Kristich ◽  
Dušanka Djorić ◽  
Jaime L. Little
Keyword(s):  
Thymidylate Synthase ◽  
Genetic Basis ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant

ABSTRACTAntibiotic-resistant enterococci are major causes of hospital-acquired infections. All enterococci are intrinsically resistant to most cephalosporins, antibiotics in the beta-lactam family that impair peptidoglycan synthesis by inactivating the transpeptidases responsible for cross-linking. In addition, clinical isolates of enterococci often possess acquired resistance to vancomycin, a glycopeptide antibiotic that impairs peptidoglycan biosynthesis by a mechanism distinct from that of the beta-lactams, namely, by binding to thed-Ala-d-Ala termini found in peptidoglycan precursors to prevent their utilization by biosynthetic transglycosylases. Antimicrobial synergism between vancomycin and beta-lactams against vancomycin-resistant enterococci was originally described decades ago, but the genetic basis for synergy has remained unknown. Because a complete understanding of the mechanism underlying synergy between vancomycin and beta-lactams might suggest new targets or strategies for therapeutic intervention against antibiotic-resistant enterococci, we explored the genetic basis for synergy between vancomycin and cephalosporins inEnterococcus faecalis. To do so, we developed a counterselection strategy based on a dominant-negative mutant of thymidylate synthase and implemented this approach to create a panel of mutants in vancomycin-resistantE. faecalis. Our results confirm that vancomycin promotes synergy by inducing expression of thevanresistance genes, as a mutant in which thevangenes are expressed in the absence of vancomycin exhibits susceptibility to cephalosporins. Further, we show that peptidoglycan precursors substituted withd-Ala-d-Lac are not required for vancomycin-enhanced cephalosporin sensitivity. Instead, production of thed,d-carboxypeptidase VanYBis both necessary and sufficient to dramatically sensitizeE. faecalisto cephalosporins.

scholarly journals Quantifying the Exposure to Antibiotic-Resistant Pathogens Among Patients Discharged From a Single Hospital Across All California Healthcare Facilities

2015 ◽  
Vol 36 (11) ◽  
pp. 1275-1282 ◽  
Author(s):  
Rupak Datta ◽  
Shawn Brown ◽  
Vinh Q. Nguyen ◽  
Chenghua Cao ◽  
John Billimek ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Nursing Homes ◽  
Hospital Readmissions ◽  
Time Dependent ◽  
Antibiotic Resistant ◽  
Total Exposure ◽  
Healthcare Facilities ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant

OBJECTIVETo assess the time-dependent exposure of California healthcare facilities to patients harboring methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamase (ESBL)–producing Escherichia coli and Klebsiella pneumoniae, and Clostridium difficile infection (CDI) upon discharge from 1 hospital.METHODSRetrospective multiple-cohort study of adults discharged from 1 hospital in 2005–2009, counting hospitals, nursing homes, cities, and counties in which carriers were readmitted, and comparing the number and length of stay of readmissions and the number of distinct readmission facilities among carriers versus noncarriers.RESULTSWe evaluated 45,772 inpatients including those with MRSA (N=1,198), VRE (N=547), ESBL (N=121), and CDI (N=300). Within 1 year of discharge, MRSA, VRE, and ESBL carriers exposed 137, 117, and 45 hospitals and 103, 83, and 37 nursing homes, generating 58,804, 33,486, and 15,508 total exposure-days, respectively. Within 90 days of discharge, CDI patients exposed 36 hospitals and 35 nursing homes, generating 7,318 total exposure-days. Compared with noncarriers, carriers had more readmissions to hospitals (MRSA:1.8 vs 0.9/patient; VRE: 2.6 vs 0.9; ESBL: 2.3 vs 0.9; CDI: 0.8 vs 0.4; all P<.001) and nursing homes (MRSA: 0.4 vs 0.1/patient; VRE: 0.7 vs 0.1; ESBL: 0.7 vs 0.1; CDI: 0.3 vs 0.1; all P<.001) and longer hospital readmissions (MRSA: 8.9 vs 7.3 days; VRE: 8.9 vs 7.4; ESBL: 9.6 vs 7.5; CDI: 12.3 vs 8.2; all P<.01).CONCLUSIONSPatients harboring antibiotic-resistant pathogens rapidly expose numerous facilities during readmissions; regional containment strategies are needed.Infect. Control Hosp. Epidemiol. 2015;36(11):1275–1282

scholarly journals Could Dampening Expression of theNeisseria gonorrhoeaemtrCDE-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Shaochun Chen ◽  
Kristie L. Connolly ◽  
Corinne Rouquette-Loughlin ◽  
Alexander D’Andrea ◽  
Ann E. Jerse ◽  
...  
Keyword(s):  
Genital Tract ◽  
Efflux Pump ◽  
Health Concern ◽  
Third Generation ◽  
Global Public Health ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Genital Tract Infection ◽  
Infected Female ◽  
Content Type

ABSTRACTNeisseria gonorrhoeaehas developed resistance to every antibiotic introduced for treatment of gonorrhea since 1938, and concern now exists that gonorrheal infections may become refractory to all available antibiotics approved for therapy. The current recommended dual antibiotic treatment regimen of ceftriaxone (CRO) and azithromycin (AZM) is threatened with the emergence of gonococcal strains displaying resistance to one or both of these antibiotics. Non-beta-lactamase resistance to penicillin and third-generation cephalosporins, as well as low-level AZM resistance expressed by gonococci, requires overexpression of themtrCDE-encoded efflux pump, which in wild-type (WT) strains is subject to transcriptional repression by MtrR. Since earlier studies showed that loss of MtrCDE renders gonococci hypersusceptible to beta-lactams and macrolides, we hypothesized that transcriptional dampening ofmtrCDEwould render an otherwise resistant strain susceptible to these antibiotics as assessed by antibiotic susceptibility testing and during experimental infection. In order to test this hypothesis, we ectopically expressed a WT copy of themtrRgene, which encodes the repressor of themtrCDEefflux pump operon, inN. gonorrhoeaestrain H041, the first reported gonococcal strain to cause a third-generation-cephalosporin-resistant infection. We now report that MtrR production can repress the expression ofmtrCDE, increase antimicrobial susceptibilityin vitro, and enhance beta-lactam efficacy in eliminating gonococci as assessed in a female mouse model of lower genital tract infection. We propose that strategies that target the MtrCDE efflux pump should be considered to counteract the increasing problem of antibiotic-resistant gonococci.IMPORTANCEThe emergence of gonococcal strains resistant to past or currently used antibiotics is a global public health concern, given the estimated 78 million infections that occur annually. The dearth of new antibiotics to treat gonorrhea demands that alternative curative strategies be considered to counteract antibiotic resistance expressed by gonococci. Herein, we show that decreased expression of a drug efflux pump that participates in gonococcal resistance to antibiotics can increase gonococcal susceptibility to beta-lactams and macrolides under laboratory conditions, as well as improve antibiotic-mediated clearance of gonococci from the genital tract of experimentally infected female mice.

scholarly journals Activities of Oxadiazole Antibacterials against Staphylococcus aureus and Other Gram-Positive Bacteria

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Sara Ceballos ◽  
Choon Kim ◽  
Derong Ding ◽  
Shahriar Mobashery ◽  
Mayland Chang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Mrsa Strains

ABSTRACT The activities of four oxadiazoles were investigated with 210 methicillin-resistant Staphylococcus aureus (MRSA) strains. MIC50 and MIC90 values of 1 to 2 and 4 μg/ml, respectively, were observed. We also evaluated the activity of oxadiazole ND-421 against other staphylococci and enterococci and in the presence of oxacillin for selected MRSA strains. The MIC for ND-421 is lowered severalfold in combination with oxacillin, as they synergize. The MIC90 of ND-421 against vancomycin-resistant enterococci is ≤1 μg/ml.

scholarly journals In Vivo Activity of QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor, in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Klebsiella Pneumoniae ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Bacterial Killing ◽  
Clinical Issue ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT Resistance to beta-lactams has created a major clinical issue. QPX7728 is a novel ultrabroad-spectrum cyclic boronic acid beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases developed to address this resistance for use in combination with beta-lactam antibiotics. The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant Klebsiella pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤2 mg/liter in the presence of 8 mg/liter QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg of body weight of QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or allowed for bacterial growth. The combination of QPX7728 plus each of these beta-lactams produced bacterial killing at all QPX7728 doses tested. Overall, these data suggest that QPX7728 administered in combination with different partner beta-lactam antibiotics may have utility in the treatment of bacterial infections due to carbapenem-resistant K. pneumoniae.

scholarly journals Oritavancin Activity against Vancomycin-Susceptible and Vancomycin-Resistant Enterococci with Molecularly Characterized Glycopeptide Resistance Genes Recovered from Bacteremic Patients, 2009-2010

2011 ◽  
Vol 56 (3) ◽  
pp. 1639-1642 ◽  
Author(s):  
Rodrigo E. Mendes ◽  
Leah N. Woosley ◽  
David J. Farrell ◽  
Helio S. Sader ◽  
Ronald N. Jones
Keyword(s):  
Resistance Genes ◽  
Glycopeptide Resistance ◽  
Content Type ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant

ABSTRACTOritavancin exhibited potent activity against vancomycin-susceptible (MIC50and MIC90, 0.015/0.03 μg/ml) andvanB-carryingE. faecalisisolates (MIC50and MIC90, 0.015 and 0.015 μg/ml). Higher (16- to 32-fold) MIC50s and MIC90s forvanA-harboringE. faecaliswere noted (MIC50and MIC90, 0.25 and 0.5 μg/ml), although oritavancin inhibited all strains at ≤0.5 μg/ml. Vancomycin-susceptible andvanB-carryingE. faeciumstrains (MIC50and MIC90, ≤0.008 and ≤0.008 μg/ml for both) were very susceptible to oritavancin, as were VanA-producing isolates (MIC50and MIC90, 0.03 and 0.06 μg/ml). Oritavancin exhibited goodin vitropotency against this collection of organisms, including vancomycin-resistant enterococci.

scholarly journals New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides

2016 ◽  
Vol 54 (9) ◽  
pp. 2225-2232 ◽  
Author(s):  
Matthew P. Crotty ◽  
Tamara Krekel ◽  
Carey-Ann D. Burnham ◽  
David J. Ritchie
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Resistance ◽  
Next Generation ◽  
Gram Positive ◽  
Content Type ◽  
Skin Structure ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
The U.S

The growing problem of antimicrobial resistance among bacterial pathogens, including methicillin-resistantStaphylococcus aureus(MRSA) and vancomycin-resistant enterococci (VRE), has reached a critical state. Tedizolid phosphate, dalbavancin, and oritavancin have recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and represent the next generation of oxazolidinones and lipoglycopeptides. All three agents exhibitin vitroactivity and clinical efficacy against MRSA. Tedizolid phosphate and oritavancin demonstratein vitroactivity against VRE. These new Gram-positive agents are reviewed here.

scholarly journals Addition of Ceftaroline to Daptomycin after Emergence of Daptomycin-Nonsusceptible Staphylococcus aureus during Therapy Improves Antibacterial Activity

2012 ◽  
Vol 56 (10) ◽  
pp. 5296-5302 ◽  
Author(s):  
Warren E. Rose ◽  
Lucas T. Schulz ◽  
David Andes ◽  
Rob Striker ◽  
Andrew D. Berti ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Membrane Damage ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Bacterial Killing ◽  
Content Type ◽  
Cell Membrane Damage

ABSTRACTAntistaphylococcal beta-lactams enhance daptomycin activity and have been used successfully in combination for refractory methicillin-resistantStaphylococcus aureus(MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with daptomycin in combination with ceftaroline, which resulted in clearance of a daptomycin-nonsusceptible strain. Anin vitropharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of daptomycin resistance and evaluate the microbiologic effects of daptomycin plus ceftaroline treatment. Combination therapy with daptomycin and ceftaroline restored daptomycin sensitivityin vivoand resulted in clearance of persistent blood cultures. Daptomycin susceptibilityin vitrowas increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of daptomycin resistance enhanced bacterial killing. Importantly, daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented daptomycin resistance. Bothin vivo- andin vitro-derived daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initialin vivoisolate. Daptomycin-resistant isolates required high daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with daptomycin alone. Ceftaroline combined with daptomycin was effective in eliminating daptomycin-resistant MRSA, and these results further justify the potential use of daptomycin plus beta-lactam therapy for these refractory infections.

scholarly journals ThemecAHomologmecCConfers Resistance against β-Lactams in Staphylococcus aureus Irrespective of the Genetic Strain Background

2014 ◽  
Vol 58 (7) ◽  
pp. 3791-3798 ◽  
Author(s):  
Britta Ballhausen ◽  
André Kriegeskorte ◽  
Nina Schleimer ◽  
Georg Peters ◽  
Karsten Becker
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistance ◽  
Regulatory System ◽  
Wild Type ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Content Type ◽  
Genetic Strain ◽  
Mrsa Strains ◽  
Strain Background

ABSTRACTIn staphylococci, methicillin resistance is mediated bymecA-encoded penicillin-binding protein 2a (PBP2a), which has a low affinity for beta-lactams. Recently, a novel PBP2a homolog was described as being encoded bymecC, which shares only 70% similarity tomecA. To prove thatmecCis the genetic determinant that confers methicillin resistance inStaphylococcus aureus, amecCknockout strain was generated. TheS. aureusΔmecCstrain showed considerably reduced oxacillin and cefoxitin MICs (0.25 and 4 μg/ml, respectively) compared to those of the corresponding wild-type methicillin-resistantS. aureus(MRSA) strain (8 and 16 μg/ml, respectively). Complementing the mutant intranswith wild-typemecCrestored the resistance to oxacillin and cefoxitin. By expressingmecCandmecAin differentS. aureusclonal lineages, we found thatmecCmediates resistance irrespective of the genetic strain background, yielding oxacillin and cefoxitin MIC values comparable to those withmecA. In addition, we showed thatmecCexpression is inducible by oxacillin, which supports the assumption that a functional beta-lactam-dependent regulatory system is active in MRSA strains possessing staphylococcal cassette chromosomemec(SCCmec) type XI. In summary, we showed thatmecCis inducible by oxacillin and mediates beta-lactam resistance in SCCmectype XI-carrying strains as well as in differentS. aureusgenetic backgrounds. Furthermore, our results could explain the comparatively low MICs for clinicalmecC-harboringS. aureusisolates.

scholarly journals Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an In Vitro Biofilm Model

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Seyedehameneh Jahanbakhsh ◽  
Nivedita B. Singh ◽  
Juwon Yim ◽  
Razieh Kebriaei ◽  
Jordan R. Smith ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Enterococcus Faecium ◽  
Biofilm Reactor ◽  
Content Type ◽  
Biofilm Model ◽  
Vancomycin Resistant Enterococci ◽  
Dosing Regimens ◽  
Vancomycin Resistant ◽  
Reactor Models

ABSTRACT Enterococcus faecium strains are commonly resistant to vancomycin and β-lactams. In addition, E. faecium often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.

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