Megan K. Luther

Activity of Daptomycin or Linezolid in Combination with Rifampin or Gentamicin against Biofilm-Forming Enterococcus faecalis or E. faecium in an In Vitro Pharmacodynamic Model Using Simulated Endocardial Vegetations and an In Vivo Survival Assay Using Galleria mellonella Larvae

ABSTRACT Enterococci are the third most frequent cause of infective endocarditis. A high-inoculum stationary-phase in vitro pharmacodynamic model with simulated endocardial vegetations was used to simulate the human pharmacokinetics of daptomycin at 6 or 10 mg/kg of body weight/day or linezolid at 600 mg every 12 h (q12h), alone or in combination with gentamicin at 1.3 mg/kg q12h or rifampin at 300 mg q8h or 900 mg q24h. Biofilm-forming, vancomycin-susceptible Enterococcus faecalis and vancomycin-resistant Enterococcus faecium (vancomycin-resistant enterococcus [VRE]) strains were tested. At 24, 48, and 72 h, all daptomycin-containing regimens demonstrated significantly more activity (decline in CFU/g) than any linezolid-containing regimen against biofilm-forming E. faecalis. The addition of gentamicin to daptomycin (at 6 or 10 mg/kg) in the first 24 h significantly improved bactericidal activity. In contrast, the addition of rifampin delayed the bactericidal activity of daptomycin against E. faecalis, and the addition of rifampin antagonized the activities of all regimens against VRE at 24 h. Also, against VRE, the addition of gentamicin to linezolid at 72 h improved activity and was bactericidal. Rifampin significantly antagonized the activity of linezolid against VRE at 72 h. In in vivo Galleria mellonella survival assays, linezolid and daptomycin improved survival. Daptomycin at 10 mg/kg improved survival significantly over that with linezolid against E. faecalis. The addition of gentamicin improved the efficacy of daptomycin against E. faecalis and those of linezolid and daptomycin against VRE. We conclude that in enterococcal infection models, daptomycin has more activity than linezolid alone. Against biofilm-forming E. faecalis, the addition of gentamicin in the first 24 h causes the most rapid decline in CFU/g. Of interest, the addition of rifampin decreased the activity of daptomycin against both E. faecalis and VRE.

Comparison of ML8-X10 (a prototype oil-in-water micro-emulsion based on a novel free fatty acid), taurolidine/citrate/heparin and vancomycin/heparin antimicrobial lock solutions in the eradication of biofilm-producing staphylococci from central venous catheters

OBJECTIVES Antimicrobial lock solutions are used for prevention and management of catheter-related bloodstream infections. ML8-X10 (a prototype oil-in-water micro-emulsion based on a novel free fatty acid), vancomycin/heparin and taurolidine/citrate/heparin (Taurolock™-Hep500) lock solutions were tested against biofilm-forming Staphylococcus epidermidis and methicillin-susceptible Staphylococcus aureus. METHODS MICs were tested in neutral broth (pH ~7) and acidified broth (pH 5). In an established in vitro central venous catheter (CVC) lock model, solutions were introduced after 24 h of bacterial growth in a CVC incubated at 37°C. After an additional 8, 24 or 72 h of incubation, saline flush and cut catheter segments were processed for bacterial quantification. The cfu/mL at 0 h was subtracted from cfu/mL at the different timepoints. RESULTS The activities of ML8-X10 and taurolidine solutions were enhanced at lower pH (P < 0.05). Against S. epidermidis, ML8-X10 solution demonstrated less activity than taurolidine at 8 h (P < 0.001), but was not significantly different from vancomycin. At 24 h, ML8-X10 solution demonstrated significantly less activity than taurolidine (P < 0.001), but was significantly more active than vancomycin (P < 0.001). Against S. aureus, ML8-X10 solution was less active than taurolidine at 8 and 24 h (P < 0.001 for both), but was similar to vancomycin. At 72 h, all lock solutions reduced colony counts to levels that approached or reached the limit of detection against both strains. CONCLUSIONS In our in vitro catheter lock model, the novel free fatty acid emulsion demonstrated activity against biofilm-forming staphylococci similar to or greater than that of vancomycin lock solution. Taurolidine was the most active lock solution at 8 and 24 h, with all lock solutions tested demonstrating high activity at 72 h.

Ampicillin in Combination with Ceftaroline, Cefepime, or Ceftriaxone Demonstrates Equivalent Activities in a High-Inoculum Enterococcus faecalis Infection Model

ABSTRACT Ampicillin-ceftriaxone combination therapy has become a predominant treatment for serious Enterococcus faecalis infections, such as endocarditis. Unfortunately, ceftriaxone use is associated with future vancomycin-resistant enterococcus colonization. We evaluated E. faecalis in an in vitro pharmacodynamic model against simulated human concentration-time profiles of ampicillin plus ceftaroline, cefepime, ceftriaxone, or gentamicin. Ampicillin-cefepime and ampicillin-ceftaroline demonstrated activities similar to those of ampicillin-ceftriaxone against E. faecalis.

Vancomycin Plus Piperacillin-Tazobactam and Acute Kidney Injury in Adults: A Systematic Review and Meta-Analysis

Objectives: The objective of this systematic review and meta-analysis was to assess acute kidney injury with combination therapy of vancomycin plus piperacillin-tazobactam, in general, adult patients and in critically ill adults. Rates of acute kidney injury, time to acute kidney injury, and odds of acute kidney injury were compared with vancomycin monotherapy, vancomycin plus cefepime or carbapenem, or piperacillin-tazobactam monotherapy. Data Sources: Studies were identified by searching Pubmed, Embase, Web of Science, and Cochrane from inception to April 2017. Abstracts from selected conference proceedings were manually searched. Study Selection: Articles not in English, pediatric studies, and case reports were excluded. Data Extraction: Two authors independently extracted data on study methods, rates of acute kidney injury, and time to acute kidney injury. Effect estimates and 95% CIs were calculated using the random effects model in RevMan 5.3. Data Synthesis: Literature search identified 15 published studies and 17 conference abstracts with at least 24,799 patients. The overall occurrence rate of acute kidney injury was 16.7%, with 22.2% for vancomycin plus piperacillin-tazobactam and 12.9% for comparators. This yielded an overall number needed to harm of 11. Time to acute kidney injury was faster for vancomycin plus piperacillin-tazobactam than vancomycin plus cefepime or carbapenem, but not significantly (mean difference, –1.30; 95% CI, –3.00 to 0.41 d). The odds of acute kidney injury with vancomycin plus piperacillin-tazobactam were increased versus vancomycin monotherapy (odds ratio, 3.40; 95% CI, 2.57–4.50), versus vancomycin plus cefepime or carbapenem (odds ratio, 2.68; 95% CI, 1.83–3.91), and versus piperacillin-tazobactam monotherapy (odds ratio, 2.70; 95% CI, 1.97–3.69). In a small subanalysis of 968 critically ill patients, the odds of acute kidney injury were increased versus vancomycin monotherapy (odds ratio, 9.62; 95% CI, 4.48–20.68), but not significantly different for vancomycin plus cefepime or carbapenem (odds ratio, 1.43; 95% CI, 0.83–2.47) or piperacillin-tazobactam monotherapy (odds ratio, 1.35; 95% CI, 0.86–2.11). Conclusions: The combination of vancomycin plus piperacillin-tazobactam increased the odds of acute kidney injury over vancomycin monotherapy, vancomycin plus cefepime or carbapenem, and piperacillin-tazobactam monotherapy. Limited data in critically ill patients suggest the odds of acute kidney injury are increased versus vancomycin monotherapy, and mitigated versus the other comparators. Further research in the critically ill population is needed.

Observed Antagonistic Effect of Linezolid on Daptomycin or Vancomycin Activity against Biofilm-Forming Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Model

ABSTRACT Pharmacodynamic activity in antibiotic combinations of daptomycin, vancomycin, and linezolid was investigated in a 48-h in vitro pharmacodynamic model. Using human-simulated free drug concentrations, activity against clinical biofilm-forming methicillin-resistant Staphylococcus aureus isolates was evaluated. Linezolid antagonized vancomycin activity at 24 and 48 h. Linezolid antagonized daptomycin at 24 and 48 h depending on dose and strain. Adding daptomycin increased vancomycin activity at 48 h (P < 0.03). These results may be strain dependent and require further clinical investigation.

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, causes 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 cures 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 and 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.

Comparison of telavancin and vancomycin lock solutions in eradication of biofilm-producing staphylococci and enterococci from central venous catheters

PURPOSE Results of a study of the activity of antibiotic lock solutions of vancomycin and telavancin against biofilm-forming strains of Staphylococcus epidermidis, Enterococcus faecalis, and Staphylococcus aureus are reported. METHODS An established in vitro central venous catheter model was used to evaluate lock solutions containing vancomycin (5 mg/mL) or telavancin (5 mg/mL), with and without preservative-containing heparin sodium (with 0.45% benzyl alcohol) 2500 units/mL, heparin, and 0.9% sodium chloride solution. Lock solutions were introduced after 24-hour bacterial growth in catheters incubated at 35 °C. After 72 hours of exposure to the lock solutions, catheters were drained, flushed, and cut into segments for quantification of colony-forming units. RESULTS Against S. epidermidis, vancomycin and telavancin (with or without heparin) had similar activity. Against E. faecalis, vancomycin alone was more active than telavancin alone (p < 0.01). Against S. aureus, vancomycin plus heparin had activity similar to that of vancomycin alone; both lock agents had greater activity than telavancin (p < 0.02). The addition of heparin was associated with reduced activity of the vancomycin lock solution against S. epidermidis and E. faecalis (p < 0.01). Telavancin activity was not significantly changed with the addition of heparin. CONCLUSION In a central venous catheter model, vancomycin and telavancin activity was similar in reducing biofilm-producing S. epidermidis. However, vancomycin was more active than telavancin against E. faecalis and S. aureus. None of the tested agents eradicated biofilm-forming strains. The addition of preservative-containing heparin sodium 2500 units/mL to vancomycin was associated with reduced activity against S. epidermidis and E. faecalis.

Association of Higher Daptomycin Dose (7 mg/kg or Greater) with Improved Survival in Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia

Current guidelines recommend higher daptomycin doses than the daptomycin label dose of 6 mg/kg for methicillin‐resistant Staphylococcus aureus (MRSA) bacteremia; however, the evidence supporting this recommendation is from in vitro and case series studies. This study evaluated the comparative effectiveness of the daptomycin label dose versus higher daptomycin doses in patients with MRSA bacteremia.

Comparison of linezolid and vancomycin lock solutions with and without heparin against biofilm-producing bacteria

PURPOSE The activity of linezolid and vancomycin lock solutions against biofilm-producing strains of Staphylococcus aureus, S. epidermidis, and Enterococcus faecalis was studied. METHODS Two strains each of methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), and S. epidermidis, and 1 strain of vancomycin-susceptible E. faecalis and vancomycin-resistant E. faecalis were tested against vancomycin and linezolid to assess prevention of biofilm formation and eradication of these pathogens within a formed biofilm. Activity was also tested in a 72-hour in vitro central venous catheter (CVC) model. After 24 hours of biofilm growth in a CVC, a lock solution containing vancomycin (2 or 5 mg/mL) or linezolid (1 or 2 mg/mL) alone or in combination with heparin sodium (5,000 units/mL with benzyl alcohol 0.45%) was instilled and incubated at 35 °C for 72 hr. Heparin and 0.9% sodium chloride injection were also tested. RESULTS Linezolid and vancomycin prevented biofilm formation below the minimum inhibitory concentration for 88% and 25% of isolates tested, respectively. The addition of preservative-containing heparin decreased the activity of vancomycin and linezolid lock solutions against all strains. Vancomycin 2- and 5-mg/mL lock solutions had the most activity against MSSA and E. faecalis strains (p < 0.01). Linezolid 2 mg/mL was the most active lock solution against the MRSA strains tested (p < 0.01). There were no significant differences in vancomycin or linezolid lock solution activity against S. epidermidis. CONCLUSION Heparin reduced activity of vancomycin and linezolid lock solutions against S. aureus, S. epidermidis, and E. faecalis biofilms. While linezolid or vancomycin lock solution reduced overall biofilm burden, it did not completely eradicate the bacteria at tested concentrations.

Facilitators and Barriers to Antibiotic Stewardship: A Qualitative Study of Pharmacists’ Perspectives:

Background: The Veterans Affairs (VA) is a leader in the implementation and advancement of antibiotic stewardship programs throughout the nation. The Centers for Disease Control and Prevention (CDC) has also led national antibiotic stewardship efforts and has outlined core elements to improve antibiotic use in hospitals, long-term care, and outpatient settings. Many facilities still face challenges to the implementation and maintenance of successful programs, particularly in nonacute care settings. The objective of this study was to identify barriers and facilitators to antibiotic stewardship within the VA medical centers through qualitative interviews with pharmacists. Methods: Eight semi-structured telephone interviews were conducted with pharmacists from 6 VA medical centers within VA New England Healthcare System. Pharmacist respondents were either pharmacy champions (for medical centers with established programs) or pharmacists with responsibilities in making antibiotic recommendations (locations without established programs). All interviews were audio recorded and transcribed verbatim. NVivo 8 was used for data coding and analysis. Results: Pharmacists from all 8 medical centers were contacted for interviews and pharmacists from 6 medical centers agreed to interviews (75% VA New England medical center participation). Three main themes regarding antibiotic stewardship were identified from the interviews with pharmacists. Respondents described the importance of (1) a supportive organizational culture, (2) protected time for antibiotic stewardship, and (3) a cohesive organizational structure in the success of antibiotic stewardship programs. Conclusions: Our findings support the CDC core elements for antibiotic stewardship, in particular the importance of leadership commitment in the creation of a culture that supports antibiotic stewardship and in ensuring staff are given sufficient time for antibiotic stewardship efforts. Although a strong supportive culture has been built, strategies focused on fostering increased protected time for antibiotic stewardship and a cohesive organizational structure may be helpful in advancing and sustaining successful antibiotic stewardship programs that improve patient outcomes.