Evaluation of Standard- and High-Dose Daptomycin versus Linezolid against Vancomycin-Resistant Enterococcus Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations

Daptomycin MICs for enterococci are typically 1- to 2-fold higher than those for Staphylococcus aureus, and there is an imminent need to establish the optimal dose for appropriate treatment of enterococcal infections. We investigated the bactericidal activity of daptomycin at various dose exposures compared to that of linezolid against vancomycin-resistant enterococcus (VRE) in an in vitro pharmacokinetic/pharmacodynamic model utilizing simulated endocardial vegetations over 96 h. Daptomycin at doses of 6, 8, 10, and 12 mg/kg of body weight/day and linezolid at a dose of 600 mg every 12 h were evaluated against two clinical vancomycin-resistant Enterococcus faecium strains (EFm11499 and 09-184D1051), one of which was linezolid resistant (09-184D1051), and one clinical vancomycin-resistant Enterococcus faecalis strain (EFs11496). Daptomycin MICs were 4, 2, and 0.5 μg/ml for EFm11499, 09-184D1051, and EFs11496, respectively. Bactericidal activity, defined as a ≥3 log10 CFU/g reduction from the initial colony count, was demonstrated against all three isolates with all doses of daptomycin; however, bactericidal activity was not sustained with the daptomycin 6- and 8-mg/kg/day regimens. Linezolid was bacteriostatic against EFm11499 and displayed no appreciable activity against 09-184D1051 or EFs11496. Concentration-dependent killing was displayed with more sustained reduction in colony count (3.58 to 6.46 and 5.89 to 6.56 log10 CFU/g) at 96 h for the simulated regimen of daptomycin at doses of 10 and 12 mg/kg/day, respectively (P ≤ 0.012). No E. faecium mutants with reduced susceptibility were recovered at any dosage regimen; however, the E. faecalis strain developed reduced daptomycin susceptibility with daptomycin at 6, 8, and 10 but not at 12 mg/kg/day. Daptomycin displayed a dose-dependent response against three VRE isolates, with high-dose daptomycin producing sustained bactericidal activity. Further research is warranted.This investigator-initiated study was funded by a research grant from Cubist Pharmaceuticals. We are grateful to Audrey Wanger for providing isolate 09-184D1051 and to Marcus Zervos for providing isolates SF11496 and SF11499. M.J.R. has received grant support, has served as a consultant, or has participated as a speaker for Astellas, Cubist, Forest Laboratories, Pfizer, Rib-X, and Novartis and is supported in part by grant R21AI092055 from the NIAID. C.A.A. has received lecture fees, research support, and consulting fees from Pfizer, Inc., and Cubist and has served as a speaker for Novartis. C.A.A. is supported in part by NIH grants R00 AI72961 and R01 AI093749 from the NIAID. B.E.M. has received grant support from Johnson & Johnson, Astellas, Palumed, Intercell, and Cubist, has served as a consultant for Astellas, Cubist, The Medicines Company, Pfizer, Rib-X, AstraZeneca, and Duranta Therapeutics, and was supported in part by NIH grant R01 AI72961

Analysis of clonality and antibiotic resistance among early clinical isolates of Enterococcus faecium in the United States.

BACKGROUND: The Enterococcus faecium genogroup, referred to as clonal complex 17 (CC17), seems to possess multiple determinants that increase its ability to survive and cause disease in nosocomial environments. METHODS: Using 53 clinical and geographically diverse US E. faecium isolates dating from 1971 to 1994, we determined the multilocus sequence type; the presence of 16 putative virulence genes (hyl(Efm), esp(Efm), and fms genes); resistance to ampicillin (AMP) and vancomycin (VAN); and high-level resistance to gentamicin and streptomycin. RESULTS: Overall, 16 different sequence types (STs), mostly CC17 isolates, were identified in 9 different regions of the United States. The earliest CC17 isolates were part of an outbreak that occurred in 1982 in Richmond, Virginia. The characteristics of CC17 isolates included increases in resistance to AMP, the presence of hyl(Efm) and esp(Efm), emergence of resistance to VAN, and the presence of at least 13 of 14 fms genes. Eight of 41 of the early isolates with resistance to AMP, however, were not in CC17. CONCLUSIONS: Although not all early US AMP isolates were clonally related, E. faecium CC17 isolates have been circulating in the United States since at least 1982 and appear to have progressively acquired additional virulence and antibiotic resistance determinants, perhaps explaining the recent success of this species in the hospital environment

Phylogenomic classification and the evolution of Clonal complex 5 methicillin-resistant Staphylococcus aureus in the Western Hemisphere

Clonal complex 5 methicillin-resistant Staphylococcus aureus (CC5-MRSA) includes multiple prevalent clones that cause hospital-associated infections in the Western Hemisphere. Here, we present a phylogenomic study of these MRSA to reveal their phylogeny, spatial and temporal population structure, and the evolution of selected traits. We studied 598 genome sequences, including 409 newly generated sequences, from 11 countries in Central, North, and South America, and references from Asia and Europe. An early-branching CC5-Basal clade is well-dispersed geographically, is methicillin-susceptible and MRSA predominantly of ST5-IV such as the USA800 clone, and includes separate subclades for avian and porcine strains. In the early 1970s and early 1960s, respectively, two clades appeared that subsequently underwent major expansions in the Western Hemisphere: a CC5-I clade in South America and a CC5-II clade largely in Central and North America. The CC5-I clade includes the ST5-I Chilean/Cordobes clone, and the ST228-I South German clone as an early offshoot, but is distinct from other ST5-I clones from Europe that nest within CC5-Basal. The CC5-II clade includes divergent strains of the ST5-II USA100 clone, various other clones, and most known vancomycin-resistant strains of S. aureus, but is distinct from ST5-II strain N315 from Japan that nests within CC5-Basal. The recombination rate of CC5 was much lower than has been reported for other S. aureus genetic backgrounds, which indicates that recurrence of vancomycin resistance in CC5 is not likely due to an enhanced promiscuity. An increased number of antibiotic resistances and decreased number of toxins with distance from the CC5 tree root were observed. Of note, the expansions of the CC5-I and CC5-II clades in the Western Hemisphere were preceded by convergent gains of resistance to fluoroquinolone, macrolide, and lincosamide antibiotics, and convergent losses of the staphylococcal enterotoxin p (sep) gene from the immune evasion gene cluster of phage ΦSa3. Unique losses of surface proteins were also noted for these two clades. In summary, our study has determined the relationships of different clades and clones of CC5 and has revealed genomic changes for increased antibiotic resistance and decreased virulence associated with the expansions of these MRSA in the Western Hemisphere.Fil: Challagundla, Lavanya. University of Mississippi; Estados UnidosFil: Reyes, Jinnethe. Universidad El Bosque; ColombiaFil: Rafiqullah, Iftekhar. University of Mississippi; Estados UnidosFil: Sordelli, Daniel Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Echaniz-Aviles, Gabriela. Instituto Nacional de Salud Pùblica; MéxicoFil: Velazquez-Meza, Maria E.. Instituto Nacional de Salud Pública; MéxicoFil: Castillo-Ramírez, Santiago. Universidad Nacional Autónoma de México; MéxicoFil: Fittipaldi, Nahuel. University of Toronto; Canadá. Public Health Ontario Laboratory; CanadáFil: Feldgarden, Michael. National Institutes of Health; Estados UnidosFil: Chapman, Sinéad B.. Broad Institute of MIT and Harvard; Estados UnidosFil: Calderwood, Michael S.. Dartmouth–Hitchcock Medical Center; Estados UnidosFil: Carvajal, Lina P.. Universidad El Bosque; ColombiaFil: Rincon, Sandra. Universidad El Bosque; ColombiaFil: Blake, Hanson. University of Texas; Estados UnidosFil: Planet, Paul J.. University of Pennsylvania; Estados UnidosFil: Arias, Cesar A.. Universidad El Bosque; Colombia. University of Texas; Estados UnidosFil: Diaz, Lorena. Universidad El Bosque; ColombiaFil: Robinson, D. Ashley. University of Mississippi; Estados Unido

A Case of Successful Treatment of Recurrent Urinary Tract infection By Extended-Spectrum Β-Lactamase Producing

Recurrent urinary tract infections (UTIs) are a challenging clinical entity that can be frustrating for patient and physician alike. Repeated rounds of antibiotics can select for multidrug-resistant organisms, further complicating care. We describe the successful use of fecal microbiota transplantation (FMT) for the treatment of recurrent extended-spectrum β-lactamase (ESBL)-producin

Teaching and Safety-Net Hospital Penalization in the Hospital-Acquired Condition Reduction Program

IMPORTANCE: The Hospital-Acquired Condition Reduction Program (HACRP) evaluates acute care hospitals on the occurrence of patient safety events and health care-associated infections. Since its implementation, several studies have raised concerns about the overpenalization of teaching and safety-net hospitals, and although several changes in the program\u27s methodology have been applied in the last few years, whether these changes reversed the overpenalization of teaching and safety-net hospitals is unknown. OBJECTIVE: to determine hospital characteristics associated with HACRP penalization and penalization reversal. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study assessed data from 3117 acute care hospitals participating in the HACRP. The HACRP penalization and hospital characteristics were obtained from Hospital Compare (2020 and 2021), the Inpatient Prospective Payment System impact file (2020), and the American Hospital Association annual survey (2018). EXPOSURES: Hospital characteristics, including safety-net status and teaching intensity (no teaching and very minor, minor, major, and very major teaching levels). MAIN OUTCOMES AND MEASURES: The primary outcome was HACRP penalization (ie, hospitals that fell within the worst quartile of the program\u27s performance). Multivariable models initially included all covariates, and then backward stepwise variable selection was used. RESULTS: Of 3117 hospitals that participated in HACRP in 2020, 779 (25.0%) were safety-net hospitals and 1090 (35.0%) were teaching institutions. In total, 771 hospitals (24.7%) were penalized. The HACRP penalization was associated with safety-net status (odds ratio [OR], 1.41 [95% CI, 1.16-1.71]) and very major teaching intensity (OR, 1.94 [95% CI, 1.15-3.28]). In addition, non-federal government hospitals were more likely to be penalized than for-profit hospitals (OR, 1.62 [95% CI, 1.23-2.14]), as were level I trauma centers (OR, 2.05 [95% CI, 1.43-2.96]) and hospitals located in the New England region (OR, 1.65 [95% CI, 1.12-2.43]). Safety-net hospitals with major teaching levels were twice as likely to be penalized as non-safety-net nonteaching hospitals (OR, 2.15 [95% CI, 1.14-4.03]). Furthermore, safety-net hospitals penalized in 2020 were less likely (OR, 0.64 [95% CI, 0.43-0.96]) to revert their HACRP penalization status in 2021. CONCLUSIONS AND RELEVANCE: Findings from this cross-sectional study indicated that teaching and safety-net hospital status continued to be associated with overpenalization in the HACRP despite recent changes in its methodology. Most of these hospitals were also less likely to revert their penalization status. A reevaluation of the program methodology is needed to avoid depleting resources of hospitals caring for underserved populations

A Review of Combination Antimicrobial Therapy for Enterococcus Faecalis Bloodstream Infections and Infective Endocarditis

Enterococci, one of the most common causes of hospital-associated infections, are responsible for substantial morbidity and mortality. Enterococcus faecalis, the more common and virulent species, cause serious high-inoculum infections, namely infective endocarditis, that are associated with cardiac surgery and mortality rates that remained unchanged for the last 30 years. The best cure for these infections are observed with combination antibiotic therapy; however, optimal treatment has not been fully elucidated. It is the purpose of this review to highlight treatment options, their limitations, and provide direction for future investigative efforts to aid in the treatment of these severe infections. While ampicillin plus ceftriaxone has emerged as a preferred treatment option, mortality rates continue to be high, and from a safety standpoint, ceftriaxone, unlike other cephalosporins, promotes colonization with vancomycin resistant-enterococci due to high biliary concentrations. More research is needed to improve patient outcomes from this high mortality disease

Teaching and Safety-Net Hospital Penalization in the Hospital-Acquired Condition Reduction Program

IMPORTANCE: The Hospital-Acquired Condition Reduction Program (HACRP) evaluates acute care hospitals on the occurrence of patient safety events and health care-associated infections. Since its implementation, several studies have raised concerns about the overpenalization of teaching and safety-net hospitals, and although several changes in the program\u27s methodology have been applied in the last few years, whether these changes reversed the overpenalization of teaching and safety-net hospitals is unknown. OBJECTIVE: to determine hospital characteristics associated with HACRP penalization and penalization reversal. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study assessed data from 3117 acute care hospitals participating in the HACRP. The HACRP penalization and hospital characteristics were obtained from Hospital Compare (2020 and 2021), the Inpatient Prospective Payment System impact file (2020), and the American Hospital Association annual survey (2018). EXPOSURES: Hospital characteristics, including safety-net status and teaching intensity (no teaching and very minor, minor, major, and very major teaching levels). MAIN OUTCOMES AND MEASURES: The primary outcome was HACRP penalization (ie, hospitals that fell within the worst quartile of the program\u27s performance). Multivariable models initially included all covariates, and then backward stepwise variable selection was used. RESULTS: Of 3117 hospitals that participated in HACRP in 2020, 779 (25.0%) were safety-net hospitals and 1090 (35.0%) were teaching institutions. In total, 771 hospitals (24.7%) were penalized. The HACRP penalization was associated with safety-net status (odds ratio [OR], 1.41 [95% CI, 1.16-1.71]) and very major teaching intensity (OR, 1.94 [95% CI, 1.15-3.28]). In addition, non-federal government hospitals were more likely to be penalized than for-profit hospitals (OR, 1.62 [95% CI, 1.23-2.14]), as were level I trauma centers (OR, 2.05 [95% CI, 1.43-2.96]) and hospitals located in the New England region (OR, 1.65 [95% CI, 1.12-2.43]). Safety-net hospitals with major teaching levels were twice as likely to be penalized as non-safety-net nonteaching hospitals (OR, 2.15 [95% CI, 1.14-4.03]). Furthermore, safety-net hospitals penalized in 2020 were less likely (OR, 0.64 [95% CI, 0.43-0.96]) to revert their HACRP penalization status in 2021. CONCLUSIONS AND RELEVANCE: Findings from this cross-sectional study indicated that teaching and safety-net hospital status continued to be associated with overpenalization in the HACRP despite recent changes in its methodology. Most of these hospitals were also less likely to revert their penalization status. A reevaluation of the program methodology is needed to avoid depleting resources of hospitals caring for underserved populations

Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.

Linezolid, which targets the ribosome, is a new synthetic antibiotic that is used for treatment of infections caused by Gram-positive pathogens. Clinical resistance to linezolid, so far, has been developing only slowly and has involved exclusively target site mutations. We have discovered that linezolid resistance in a methicillin-resistant Staphylococcus aureus hospital strain from Colombia is determined by the presence of the cfr gene whose product, Cfr methyltransferase, modifies adenosine at position 2503 in 23S rRNA in the large ribosomal subunit. The molecular model of the linezolid-ribosome complex reveals localization of A2503 within the drug binding site. The natural function of cfr likely involves protection against natural antibiotics whose site of action overlaps that of linezolid. In the chromosome of the clinical strain, cfr is linked to ermB, a gene responsible for dimethylation of A2058 in 23S rRNA. Coexpression of these two genes confers resistance to all the clinically relevant antibiotics that target the large ribosomal subunit. The association of the ermB/cfr operon with transposon and plasmid genetic elements indicates its possible mobile nature. This is the first example of clinical resistance to the synthetic drug linezolid which involves a natural resistance gene with the capability of disseminating among Gram-positive pathogenic strains

An Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated State

The cyclic antimicrobial lipopeptide daptomycin (DAP) triggers the LiaFSR membrane stress response pathway in enterococci and many other Gram-positive organisms. LiaR is the response regulator that, upon phosphorylation, binds in a sequence-specific manner to DNA to regulate transcription in response to membrane stress. In clinical settings, non-susceptibility to DAP by Enterococcus faecium is correlated frequently with a mutation in LiaR of Trp73 to Cys (LiaRW73C). We have determined the structure of the activated E. faecium LiaR protein at 3.2 Å resolution and, in combination with solution studies, show that the activation of LiaR induces the formation of a LiaR dimer that increases LiaR affinity at least 40-fold for the extended regulatory regions upstream of the liaFSR and liaXYZ operons. In vitro, LiaRW73C induces phosphorylation-independent dimerization of LiaR and provides a biochemical basis for non-susceptibility to DAP by the upregulation of the LiaFSR regulon. A comparison of the E. faecalis LiaR, E. faecium LiaR, and the LiaR homolog from Staphylococcus aureus (VraR) and the mutations associated with DAP resistance suggests that physicochemical properties such as oligomerization state and DNA specificity, although tuned to the biology of each organism, share some features that could be targeted for new antimicrobials