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

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.     

In vitro efficacy of fosfomycin-based combinations against clinical vancomycin-resistant Enterococcus isolates

Vancomycin-resistant (VR) enterococci (VRE) are increasingly important nosocomial pathogens, commonly causing catheter-related urinary tract infections or vascular catheter-related bloodstream infections. In this study, 10 Enterococcus faecium and 9 Enterococcus faecalis different pulsed-field gel electrophoresis genome-type VR clinical isolates were detected. The potential role of fosfomycin-based combination regimens for biofilm-related VRE infection is in vitro evaluated. Anti-VRE activities of fosfomycin, ampicillin, linezolid, minocycline, rifampicin, tigecycline, teicoplanin, vancomycin alone, or fosfomycin-based combinations were studied by time-kill method and a biofilm model. Of the fosfomycin-based combinations, a synergistic effect was particularly noted for teicoplanin against 89% of the VR E. faecalis isolates. In a biofilm model, only linezolid alone was able to reduce the bacterial loads, and the use of fosfomycin-based combinations, excluding rifampicin (40%), failed to enhance antibacterial activity against VR E. faecium. For E. faecalis, an inhibitory effect was evident using ampicillin alone or fosfomycin plus rifampicin (100%), tigecycline (56%), or teicoplanin (44%). However, an antagonistic effect was found for ampicillin plus fosfomycin against 2 of 3 of the VR E. faecalis isolates. The antibacterial activities of the drugs tested against VRE in vitro varied by species. Ampicillin exhibited potential activity against planktonic- and biofilm-embedded VR E. faecalis. Fosfomycin-based combinations may have enhanced antibacterial effects against VRE even in the biofilm model, and this observation warrants further clinical studies.     

Comparison of the clinical characteristics and outcomes associated with vancomycin-resistant Enterococcus faecalis and vancomycin-resistant E. faecium bacteremia

In published studies, cohorts of patients with bacteremia due to vancomycin-resistant Enterococcus (VRE) have predominantly been infected with Enterococcus faecium. Little is known about the epidemiology and outcomes associated with bacteremia due to VR Enterococcus faecalis. A retrospective study of isolates obtained from January 2008 to October 2010 was conducted at Detroit Medical Center (DMC). Unique patients with blood cultures positive for VRE were reviewed. Outcomes were analyzed using logistic regression. During the study period, 105 cases of bacteremia due to VR E. faecalis and 197 cases of bacteremia due to VR E. faecium were identified. The mean age in the study cohort was 61.5 ± 15 years; 162 subjects (53.6%) were male. After controlling for a propensity score, bacteremia due to VR E. faecalis was associated with >2-fold-lower in-hospital mortality than bacteremia due to VR E. faecium. Interestingly, bacteremia due to VR E. faecalis was associated with longer hospital stay after VRE isolation, although total length of stay was similar for groups with VR E. faecalis and VR E. faecium. Bacteremia due to VR E. faecalis was associated with a >2-fold-lower risk for mortality than bacteremia due to VR E. faecium, possibly due to the availability of β-lactam therapeutics for treatment of VR E. faecalis.     

Systematic Review and Meta-Analysis of Linezolid versus Daptomycin for Treatment of Vancomycin-Resistant Enterococcal Bacteremia

Limited therapeutic options exist for the treatment of vancomycin-resistant Enterococcus (VRE) bacteremia; the most commonly used are daptomycin and linezolid. We attempted a systematic review and meta-analysis of the comparative efficacy of those two agents. Studies comparing daptomycin to linezolid treatment for VRE bacteremia, published until August 2012, were identified from the MEDLINE, EMBASE, CENTRAL, ISI Web of Science, and SCOPUS databases. All comparative studies on patients older than 18 years of age that provided mortality data were considered eligible for this systematic review and meta-analysis. Τhe primary outcome of the meta-analysis was 30-day all-cause mortality. Ten retrospective studies including 967 patients were identified. Patients treated with daptomycin had significantly higher 30-day all-cause mortality (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.08 to 2.40) and infection-related mortality (OR, 3.61; 95% CI, 1.42 to 9.20) rates than patients treated with linezolid. When data from all 10 studies were combined, overall mortality was also significantly increased among patients treated with daptomycin (OR, 1.41; 95% CI, 1.06 to 1.89). These findings were confirmed when odds ratios adjusted for potential confounders were pooled. Relapse rates among patients treated with daptomycin were also higher (OR, 2.51; 95% CI, 0.94 to 6.72), although this difference did not reach statistical significance. Adverse event rates were not significantly different between the two groups. Notwithstanding the absence of randomized prospective data, available evidence suggests that mortality rates may be higher with daptomycin than with linezolid among patients treated for VRE bacteremia.     

Early linezolid-associated lactic acidosis in a patient with Child's class C liver cirrhosis and end stage renal disease

Linezolid, an oxazolidinone antibiotic, does not required dose adjustment in patients with Child's class A and B liver cirrhosis. The dose adjustment data for Child's class C liver cirrhosis is inadequate. We reported a case of Child's class C liver cirrhosis, in which lactic acidosis, an adverse effect related to prolonged use, occurred only after two weeks of linezolid treatment. A 63-year old male had underlying diseases, such as end-stage renal disease (ESRD) and Child's class C liver cirrhosis, and was admitted for hepatic encephalopathy management and liver transplantation evaluation. Spontaneous bacterial peritonitis and septic shock occurred during admission. Because ascites culture revealed vancomycin-resistant Enterococci (VRE), daptomycin was initially prescribed. Subsequently, VRE bacteremia occurred, and infective endocarditis was confirmed. Following treatment failure with daptomycin use, intravenous linezolid (600 mg q12h) was added for synergic effect. VRE bacteremia quickly resolved following linezolid treatment, and vasopressor use was reduced. Despite stable hemodynamics, lactic acidosis still persisted, and linezolid therapeutic drug monitoring was ordered. High linezolid trough concentration (49 mg/L) was found by therapeutic drug monitoring, and linezolid-associated lactic acidosis was highly suspected. Therefore, linezolid treatment was stopped and patient's lactic acid level returned to normal after one week. VRE bacteremia recurred after discontinuation of linezolid; therefore, linezolid was re-prescribed at the lower dose (600 mg). Linezolid trough concentration was within the therapeutic range this time (6.1 mg/L), and lactic acidosis did not occur when linezolid dose was reduced. Therefore, empirically decreased dose and therapeutic drug monitoring should be considered in patients with Child's class C liver cirrhosis and ESRD.     

Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment

Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of β-lactam plus daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant β-lactams. We identified 106 patients who received daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a β-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with β-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.     

Comparative In Vitro Activities and Postantibiotic Effects of the Oxazolidinone Compounds Eperezolid (PNU-100592) and Linezolid (PNU-100766) versus Vancomycin against Staphylococcus aureus, Coagulase-Negative Staphylococci, Enterococcus faecalis, and Enterococcus faecium

The activities of the oxazolidinone antibacterial agents eperezolid (PNU-100592) and linezolid (PNU-100766) were compared with that of vancomycin against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (n = 200), coagulase-negative staphylococci (n = 100), and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium (n = 50). Eperezolid and linezolid demonstrated good in vitro inhibitory activity, regardless of methicillin susceptibility for staphylococci (MIC at which 90% of the isolates are inhibited [MIC₉₀] range, 1 to 4 μg/ml) or vancomycin susceptibility for enterococci (MIC₉₀ range, 1 to 4 μg/ml). In time-kill studies, eperezolid and linezolid were bacteriostatic in action. A postantibiotic effect of 0.8 ± 0.5 h was demonstrated for both eperezolid and linezolid against S. aureus, S. epidermidis, E. faecalis, and E. faecium.     

In Vitro Activities of Tedizolid and Linezolid against Gram-Positive Cocci Associated with Acute Bacterial Skin and Skin Structure Infections and Pneumonia

Tedizolid is a novel, expanded-spectrum oxazolidinone with potent activity against a wide range of Gram-positive pathogens. A total of 425 isolates of Gram-positive bacteria were obtained consecutively from patients with acute bacterial skin and skin structure infections (ABSSSIs) or pneumonia. These isolates included methicillin-susceptible Staphylococcus aureus (MSSA) (n = 100), methicillin-resistant Staphylococcus aureus (MRSA) (n = 100), Streptococcus pyogenes (n = 50), Streptococcus agalactiae (n = 50), Streptococcus anginosus group (n = 75), Enterococcus faecalis (n = 50), and vancomycin-resistant enterococci (VRE) (Enterococcus faecium) (n = 50). The MICs of tedizolid and linezolid were determined by the agar dilution method. Tedizolid exhibited better in vitro activities than linezolid against MSSA (MIC₉₀s, 0.5 versus 2 μg/ml), MRSA (MIC₉₀s, 0.5 versus 2 μg/ml), S. pyogenes (MIC₉₀s, 0.5 versus 2 μg/ml), S. agalactiae (MIC₉₀s, 0.5 versus 2 μg/ml), Streptococcus anginosus group (MIC₉₀s, 0.5 versus 2 μg/ml), E. faecalis (MIC₉₀s, 0.5 versus 2 μg/ml), and VRE (MIC₉₀s, 0.5 versus 2 μg/ml). The tedizolid MICs against E. faecalis (n = 3) and VRE (n = 2) intermediate to linezolid (MICs, 4 μg/ml) were 1 μg/ml and 0.5 μg/ml, respectively. The tedizolid MIC₉₀s against S. anginosus, S. constellatus, and S. intermedius were 0.5, 1, and 0.5 μg/ml, respectively, and the rates of susceptibility based on the U.S. FDA MIC interpretive breakpoints to the isolates were 16%, 28%, and 72%, respectively. Tedizolid exhibited 2- to 4-fold better in vitro activities than linezolid against a variety of Gram-positive cocci associated with ABSSSIs and pneumonia. The lower susceptibilities of tedizolid against isolates of S. anginosus and S. constellatus than against those of S. intermedius in Taiwan were noted.     

Antimicrobial susceptibility of daptomycin and comparator agents tested against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: trend analysis of a 6-year period in US medical centers (2005-2010)

We evaluated daptomycin activity trends against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE; MIC, ≥8 μg/mL) in a 6-year period (2005–2010) following US regulatory release for clinical use. Consecutive, unique patient strains of clinical significance were collected in 32 US medical centers and susceptibility tested in a central laboratory against daptomycin and various comparator agents by reference broth microdilution methods. A total of 22 858 S. aureus (12 181 [53.3%] MRSA), 4312 Enterococcus faecalis (195 [4.5%] VRE), and 2462 Enterococcus faecium (1867 [75.8%] VRE) were evaluated. Daptomycin susceptibility rates were 99.94%, 99.98%, and 99.68% for S. aureus, E. faecalis, and E. faecium, respectively. Among MRSA (daptomycin MIC_50/90, 0.25/0.5 μg/mL), only 13 (0.11%) daptomycin-non-susceptible (MIC, ≥2 μg/mL) isolates were observed with no MIC creep over the study interval. Daptomycin was very active against vancomycin-resistant E. faecalis (MIC_50/90, 1/2 μg/mL) and E. faecium (MIC_50/90, 2/2 μg/mL). Among VRE, only 4 daptomycin-non-susceptible isolates (all E. faecium) were detected. In conclusion, daptomycin demonstrated sustained activity against an extensive collection of clinical isolates of MRSA and VRE from numerous US medical centers over the last 6 monitored years.     

Activities of Fosfomycin and Rifampin on Planktonic and Adherent Enterococcus faecalis Strains in an Experimental Foreign-Body Infection Model

Enterococcal implant-associated infections are difficult to treat because antibiotics generally lack activity against enterococcal biofilms. We investigated fosfomycin, rifampin, and their combinations against planktonic and adherent Enterococcus faecalis (ATCC 19433) in vitro and in a foreign-body infection model. The MIC/MBC_log values were 32/>512 μg/ml for fosfomycin, 4/>64 μg/ml for rifampin, 1/2 μg/ml for ampicillin, 2/>256 μg/ml for linezolid, 16/32 μg/ml for gentamicin, 1/>64 μg/ml for vancomycin, and 1/5 μg/ml for daptomycin. In time-kill studies, fosfomycin was bactericidal at 8× and 16× MIC, but regrowth of resistant strains occurred after 24 h. With the exception of gentamicin, no complete inhibition of growth-related heat production was observed with other antimicrobials on early (3 h) or mature (24 h) biofilms. In the animal model, fosfomycin alone or in combination with daptomycin reduced planktonic counts by ≈4 log₁₀ CFU/ml below the levels before treatment. Fosfomycin cleared planktonic bacteria from 74% of cage fluids (i.e., no growth in aspirated fluid) and eradicated biofilm bacteria from 43% of cages (i.e., no growth from removed cages). In combination with gentamicin, fosfomycin cleared 77% and cured 58% of cages; in combination with vancomycin, fosfomycin cleared 33% and cured 18% of cages; in combination with daptomycin, fosfomycin cleared 75% and cured 17% of cages. Rifampin showed no activity on planktonic or adherent E. faecalis, whereas in combination with daptomycin it cured 17% and with fosfomycin it cured 25% of cages. Emergence of fosfomycin resistance was not observed in vivo. In conclusion, fosfomycin showed activity against planktonic and adherent E. faecalis. Its role against enterococcal biofilms should be further investigated, especially in combination with rifampin and/or daptomycin treatment.     

Epidemiology of Vancomycin-Resistant Enterococci in Canadian Hospitals (CANWARD Study, 2007 to 2013)

Of 1,927 Enterococcus species isolates collected across Canada from 2007 to 2013, 80 (4.2%) were identified as vancomycin-resistant enterococci (VRE). VRE infections during this time tripled in Canadian hospitals, from 1.8% to 6.0% (P = 0.03). All VRE were Enterococcus faecium, with 90% possessing vanA. The prevalence of vanB decreased from 37.5% in 2007 to 0% in 2013 (P < 0.05). The VRE were multidrug resistant, but 70.6%, 86.3%, and 100% were susceptible to doxycycline, linezolid, and daptomycin, respectively.     

Fosfomycin Synergy In Vitro with Amoxicillin,Daptomycin, and Linezolid against Vancomycin-Resistant Enterococcus faecium from Renal Transplant Patients with Infected Urinary Stents

Fosfomycin is a potential option for vancomycin-resistant enterococcus (VRE) infections despite limited in vitro and clinical data. In this study, 32 VRE isolates from renal transplant patients with urinary stent infections were susceptible to fosfomycin, daptomycin, and linezolid and resistant to amoxicillin, minocycline, and nitrofurantoin based on their MIC₅₀s and MIC₉₀s. Fosfomycin was bacteriostatic at 0.5 to 16× the MIC (32 to 2,048 μg/ml); synergy occurred when fosfomycin was combined with daptomycin (2.8 to 3.9 log₁₀ CFU/ml kill; P < 0.001) or amoxicillin (2.6 to 3.4; P < 0.05). These combinations may be potent options to treat VRE urinary infections pending investigation of clinical efficacy.     

Linezolid resistance in Enterococcus faecium isolated in Ontario,Canada

Recent studies have described linezolid-resistant MRSA and vancomycin-resistant enterococci (VRE) occurring worldwide, including an outbreak of linezolid-resistant MRSA. The objective of this study was to determine if linezolid-resistant enterococci are present in clinical isolates in Ontario, Canada. From January 2010 to June 2012, all enterococcal isolates submitted to the Public Health Ontario Laboratory (PHOL) for confirmation of VRE and susceptibility testing were included in this study. Of 2829 enterococcal isolates tested, 12 Enterococcus faecium were found to be resistant to linezolid. All linezolid-resistant isolates were also resistant to ampicillin, ciprofloxacin, and vancomycin. In addition, 33% of isolates were non-susceptible to daptomycin, whereas 41% were resistant to quinupristin/dalfopristin. Molecular characterization of these isolates showed that 8/12 isolates (66.7%) contained the mutation G2576T in 23S rRNA, which has been associated with linezolid resistance. Amplification and sequencing of L3- and L4-coding genes did not reveal mutations associated with linezolid resistance. One isolate contained the cfr gene, which is associated with linezolid resistance, and has been found in staphylococcal species and E. faecalis. These data show that occurrence of linezolid resistance is still rare among enterococcal isolates referred to PHOL though detection of cfr in E. faecium is concerning as it has the potential to disseminate among other enterococci.     

In Vitro Activities of 15 Antimicrobial Agents against Clinical Isolates of South African Enterococci

The activities of a panel of currently available antibiotics and the investigational agents LY 333328, linezolid, CL 331,002, CL 329,998, moxifloxacin (BAY 12-8039), trovafloxacin, and quinupristin-dalfopristin against 274 clinical isolates of enterococci were determined. No vancomycin resistance or β-lactamase production was observed. Except for 12 isolates (all non-Enterococcus faecalis) showing reduced susceptibility to quinupristin-dalfopristin (MIC, ≥4 μg/ml), the new agents exhibited promising in vitro antienterococcal activity.     

Risk Factors for Resistance to β-Lactam/β-Lactamase Inhibitors and Ertapenem in Bacteroides Bacteremia

The objective of this study was to determine risk factors for the development of resistance to β-lactams/β-lactamase inhibitors (βL/βLIs) and ertapenem among Bacteroides species bacteremia. We conducted a retrospective case-control study of 101 adult patients with Bacteroides species bacteremia at a 1,051-bed tertiary care medical center. The duration of exposure to βL/βLIs (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.08 to 2.31) was the only independent risk factor for resistance.     

Epidemiology of Vancomycin-Resistant Enterococcus faecalis: a Case-Case-Control Study

Although much is known about vancomycin-resistant (VR) Enterococcus faecium, little is known about the epidemiology of VR Enterococcus faecalis. The predilection of VR E. faecalis to transfer the vancomycin resistance determinant to Staphylococcus aureus is much greater than that of VR E. faecium. The epidemiology of VR E. faecalis has important implications regarding the emergence of vancomycin-resistant S. aureus (VRSA); 8 of 13 reported VRSA cases have been from Michigan. A retrospective case-case-control study was conducted at the Detroit Medical Center, located in southeastern Michigan. Unique patients with VR E. faecalis infection were matched to patients with strains of vancomycin-susceptible (VS) E. faecalis and to uninfected controls at a 1:1:1 ratio. Five hundred thirty-two VR E. faecalis cases were identified and were matched to 532 VS E. faecalis cases and 532 uninfected controls. The overall mean age of the study cohort (n = 1,596) was 63.0 ± 17.4 years, and 747 (46.8%) individuals were male. Independent predictors for the isolation of VR E. faecalis (but not VS E. faecalis) compared to uninfected controls were an age of ≥65 years, nonhome residence, diabetes mellitus, peripheral vascular disease, exposure to cephalosporins and fluoroquinolones in the prior 3 months, and immunosuppressive status. Invasive procedures and/or surgery, chronic skin ulcers, and indwelling devices were risk factors for both VR E. faecalis and VS E. faecalis isolation. Cephalosporin and fluoroquinolone exposures were unique, independent predictors for isolation of VR E. faecalis. A majority of case patients had VR E. faecalis present at the time of admission. Control of VR E. faecalis, and ultimately VRSA, will likely require regional efforts focusing on infection prevention and antimicrobial stewardship.     

High-Dose Daptomycin Therapy for Left-Sided Infective Endocarditis: a Prospective Study from the International Collaboration on Endocarditis

The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus faecalis, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.     

Multicenter Study of High-Dose Daptomycin for Treatment of Enterococcal Infections

Enterococci are among the leading pathogens isolated in hospital-acquired infections. Current antimicrobial options for vancomycin-resistant enterococci (VRE) are limited. Prior data suggest that daptomycin at >6 mg/kg of body weight/day may be used to treat enterococcal infections. We retrospectively evaluated the effectiveness and safety of high-dose daptomycin (HD-daptomycin) therapy (>6 mg/kg) in a multicenter cohort of adult patients with enterococcal infections to describe the characteristics and outcomes. Two hundred forty-five patients were evaluated. Enterococcus faecium was identified in 175 (71%), followed by Enterococcus faecalis in 49 (20%) and Enterococcus spp. in 21 (9%); overall, 204 (83%) isolates were VRE. Enterococcal infections included bacteremia (173, 71%) and intra-abdominal (35, 14%) and bone and joint (25, 10%) infections. The median dosage and duration of HD-daptomycin were 8.2 mg/kg/day (interquartile range [IQR], 7.7 to 9.7) and 10 days (IQR, 6 to 15), respectively. The overall clinical success rate was 89% (193/218), and microbiological eradication was observed in 93% (177/191) of patients. The median time to clearance of blood cultures on HD-daptomycin was 3 days (IQR, 2 to 5). The 30-day all-cause mortality rate was 27%, and 5 (2%) patients developed daptomycin-nonsusceptible enterococcal strains while on HD-daptomycin. Seven patients (3%) had creatine phosphokinase (CPK) elevation, yet no HD-daptomycin regimen was discontinued due to an elevated CPK and all patients were asymptomatic. Overall, there was a high frequency of clinical success and microbiological eradication in patients treated with HD-daptomycin for enterococcal infections, even in patients with complicated and difficult-to-treat infections. No adverse event-related discontinuation of HD-daptomycin was noted. HD-daptomycin may be an option for the treatment of enterococcal infections.     

Surotomycin Demonstrates Low In Vitro Frequency of Resistance and Rapid Bactericidal Activity in Clostridium difficile,Enterococcus faecalis,and Enterococcus faecium

Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of Clostridium difficile-associated diarrhea. The aim of this study was to evaluate the emergence of resistance in C. difficile (ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS) Enterococcus faecalis (ATCC 49452), vancomycin-resistant (VR) E. faecalis (ATCC 700802), VS Enterococcus faecium (ATCC 6569), and VR E. faecium (ATCC 51559) under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection (<10⁻⁸ to <10⁻⁹) for surotomycin at 16 and 32× the MIC for all isolates tested. Under selective pressure by serial passage, C. difficile grew in a maximum of 4 μg/ml surotomycin (final MICs of 2 to 8 μg/ml [4- to 16-fold higher than those of the naive control]) at day 15, with the exception of the C. difficile BK strain, which grew in 16 to 32 μg/ml (final MICs of 8 to 32 μg/ml [16- to 64-fold higher than those of the naive control]). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 μg/ml surotomycin (final MICs of 2 to 16 μg/ml [8- to 64-fold higher than those of the naive control]). Of the isolates tested, no cross-resistance to vancomycin, rifampin, ampicillin, metronidazole, or moxifloxacin was observed. Surotomycin at 20× MIC demonstrated equally rapid bactericidal activity (≥3-log-unit reduction in CFU/ml in ≤8 h) against naive and reduced-susceptibility isolates of C. difficile, VS Enterococcus (VSE), and VR Enterococcus (VRE), except for C. difficile BK (2.6-log-unit reductions for both). These results suggest that emergence of resistance to surotomycin against C. difficile, E. faecalis, and E. faecium is likely to be rare.     

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

Enterococcus faecalis and Enterococcus faecium are frequently resistant to vancomycin and β-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate β-lactam synergy with daptomycin (DAP) against resistant enterococci. One E. faecalis strain (R6981) and two E. faecium strains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h, in vitro models were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 μg/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P < 0.001 and log₁₀ CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (P < 0.001) against both strains. CPT, ERT, and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (P < 0.001). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted.