Observational study to determine the optimal dose of daptomycin based on pharmacokinetic/pharmacodynamic analysis

High doses of daptomycin (DAP) (>6 mg/kg/day) have been preliminarily recommended in recent practical guidelines for methicillin-resistant Staphylococcus aureus infection, to achieve better clinical effects. While such doses can elevate the plasma trough concentration (Cmin) of DAP, there is an associated risk of creatine phosphokinase (CPK) elevation warranting further investigation. In the current study relationships between DAP Cmin and CPK elevation were investigated, and optimal DAP doses were determined. Plasma DAP concentrations were measured in 20 patients. Logistic regression analysis was performed to assess relationships between DAP Cmin and CPK elevation, then a population pharmacokinetic model of DAP was developed. To determine an optimal DAP dose a Monte Carlo simulation (MCS) was performed to minimize the risk of CPK elevation and maximize the probability of successful treatment. In logistic regression analysis DAP Cmin was significantly associated with CPK elevation (odds ratio 1.21, p = 0.048). With respect to dose-dependent increases in the probability of CPK elevation and exposure to DAP, MCS estimated an optimal DAP dose of 4–6 mg/kg/day, corresponding to a minimum inhibitory concentration (MIC) of ≤0.5 μg/mL. For an MIC of 1 μg/mL, MCS estimated an optimal DAP dose of 10 mg/kg/day. However, the probability of CPK elevation associated with high doses of DAP was higher than that associated with the approved doses. In cases where high doses of DAP are administered, close CPK monitoring is required and therapeutic drug monitoring of DAP may be desirable.     

Evaluation of daptomycin pharmacodynamics and resistance at various dosage regimens against Staphylococcus aureus isolates with reduced susceptibilities to daptomycin in an in vitro pharmacodynamic model with simulated endocardial vegetations

The need to investigate novel dosing regimens and combinations is essential in combating poor treatment outcomes for Staphylococcus aureus bacteremia and endocarditis. We evaluated the impact of simulated standard- and high-dose daptomycin in combination with gentamicin or rifampin against daptomycin-susceptible and nonsusceptible matched strains of S. aureus. These strains were collected from the daptomycin bacteremia and endocarditis clinical trial and consisted of three susceptible strains (MIC, 0.25 mg/liter) and four nonsusceptible isolates (MICs, 2 to 4 mg/liter). Daptomycin regimens of 6 and 10 mg/kg of body weight daily alone and in combination with gentamicin at 5 mg/kg daily or rifampin at 300 mg every 8 h were evaluated using an in vitro model with simulated endocardial vegetations over 96 h. Rapid bactericidal activity, identified by time to 99.9% kill, was displayed in all regimens with the daptomycin-susceptible strains. Concentration-dependent activity was noted by more-rapid killing with the 10-mg/kg/day dose. The addition of gentamicin improved activity in the majority of susceptible isolates. Daptomycin 6-mg/kg/day monotherapy displayed bactericidal activity for only one of the nonsusceptible isolates and for only two isolates with increased doses of 10 mg/kg/day. Combination regimens demonstrated improvement with some but not all nonsusceptible isolates. Three isolates developed a reduction in daptomycin susceptibility with 6-mg/kg/day monotherapy, but this was suppressed with both combination therapy and high-dose daptomycin. These results suggest that high-dose daptomycin therapy and combination therapy may be reasonable treatment options for susceptible isolates; however, more investigations are needed to confirm the variability of these regimens with nonsusceptible isolates.     

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.     

Characterization of High-Level Daptomycin Resistance in Viridans Group Streptococci Developed upon In Vitro Exposure to Daptomycin

Viridans group streptococci (VGS) are part of the normal flora that may cause bacteremia, often leading to endocarditis. We evaluated daptomycin against four clinical strains of VGS (MICs = 1 or 2 μg/ml) using an in vitro-simulated endocardial vegetation model, a simulated bacteremia model, and kill curves. Daptomycin exposure was simulated at 6 mg/kg of body weight and 8 mg/kg every 24 h for endocardial and bacteremia models. Total drug concentrations were used for analyses containing protein (albumin and pooled human serum), and free (unbound) drug concentrations (93% protein bound) were used for analyses not containing protein. Daptomycin MICs in the presence of protein were significantly higher than those in the absence of protein. Despite MICs below or at the susceptible breakpoint, all daptomycin regimens demonstrated limited kill in both pharmacodynamic models. A reduction of approximately 1 to 2 log₁₀ CFU was seen for all isolates and dosages except daptomycin at 6 mg/kg, which achieved a reduction of 2.7 log₁₀ CFU/g against one strain (Streptococcus gordonii 1649) in the endocardial model. Activity was similar in both pharmacodynamic models in the presence or absence of protein. Similar activity was noted in the kill curves over all multiples of the MIC. Regrowth by 24 h was seen even at 8× MIC. Postexposure daptomycin MICs for both pharmacodynamic models increased to >256 μg/ml for all isolates by 24 and 72 h. Despite susceptibility to daptomycin by standard MIC methods, these VGS developed high-level daptomycin resistance (HLDR) after a short duration following drug exposure not attributed to modification or inactivation of daptomycin. Further evaluation is warranted to determine the mechanism of resistance and clinical implications.     

Randomized Controlled Trial of the Safety and Efficacy of Daptomycin versus Standard-of-Care Therapy for Management of Patients with Osteomyelitis Associated with Prosthetic Devices Undergoing Two-Stage Revision Arthroplasty

The prevalence of Staphylococcus aureus causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2- to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients.     

Evaluation of daptomycin treatment of Staphylococcus aureus bacterial endocarditis: an in vitro and in vivo simulation using historical and current dosing strategies

OBJECTIVES: A failure to daptomycin therapy and subsequent emergence of a daptomycin non-susceptible isolate occurred during the 1990 clinical investigation of daptomycin for the treatment of Staphylococcus aureus bacteraemia and endocarditis. We attempted to determine if this occurrence was reproducible in vitro and if it could be prevented by various daptomycin dosing strategies. METHODS: The daptomycin susceptible parent strain (SA-675) and the subsequent non-susceptible derivative (SA-684) were evaluated. In the rabbit endocarditis model, daptomycin 3 mg/kg every 8 h for 4 days was administered to simulate the study patient's pharmacokinetic exposure. Daptomycin doses of 1.5 and 3 mg/kg every 12 h and 6 and 10 mg/kg every 24 and 48 h were simulated in the in vitro model with simulated endocardial vegetations (SEVs). RESULTS: Daptomycin significantly reduced bacterial counts of SA-675 in rabbits, but one in 10(5)-10(6) organisms from vegetations of one animal had an 8-fold increase in MIC. Daptomycin 1.5 mg/kg every 12 h in the in vitro model demonstrated no activity against either strain; reduced susceptibility emerged in SA-675 (4-fold increase in MIC). Bactericidal activity was noted with 6 and 10 mg/kg dosing against SA-675 with no resistance detected. The activity of the 6 mg/kg regimen was reduced against SA-684 but significantly improved activity was noted with 10 mg/kg daily. CONCLUSIONS: The emergence of resistance was successfully recreated at suboptimal dosing regimens while the current recommended regimen of 6 mg/kg/day prevented the emergence of non-susceptible mutants. Daptomycin 10 mg/kg/day demonstrated even more enhanced killing. Further investigation with daptomycin 10 mg/kg is warranted.     

Daptomycin against multiple drug-resistant staphylococcus and enterococcus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations

Daptomycin is a lipopeptide antibiotic that exhibits bactericidal activity against Gram-positive bacteria. In pursuit of potential clinical dosing regimens for endocarditis, we evaluated two, once-daily daptomycin regimens against multiple, drug-resistant Gram-positive pathogens. Daptomycin susceptibility was determined in the absence and presence of physiologic concentrations of albumin. An in vitro pharmacodynamic model with simulated endocardial vegetations incorporating protein was used to simulate regimens of daptomycin at 6 and 8 mg/kg/day and vancomycin at 1 g every 12 h against methicillin-resistant S. aureus (MRSA-67 and 494) and S. epidermidis (MRSE-R227 and R617), glycopeptide-intermediate S. aureus and S. epidermidis (GISA-992 and GISE-12333), and vancomycin-resistant E. faecium (VREF-SF12047 and 12366). Bacterial quantification occurred over 72 h. Daptomycin MIC results for study isolates in the absence or presence of albumin ranged from 0.125 to 4 and 1 to 8, respectively. Both daptomycin regimens achieved greater than 99.9% kill by 8 h and demonstrated greater bacterial reduction than vancomycin against all tested isolates at 24, 48, and 72 h (p < 0.05). Undetectable limits of bacterial quantification was achieved and maintained by 8 mg/kg/day against MRSA-494 and 67, GISA-992, and VREF-590 for the study duration. Although slight regrowth was noted only for 6 mg/kg/day against MRSA-67, 99.9% kill was maintained throughout the study period without development of resistance. Pharmacodynamic profiles and drug exposure of daptomycin at 6 mg/kg/day corresponds to previously reported AUC/MIC requirements. These results suggest that 6 and 8 mg/kg/day of daptomycin represent potential regimens for further clinical evaluation in drug-resistant Gram-positive endocarditis.     

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.     

Clinical outcomes of patients receiving daptomycin for the treatment of Staphylococcus aureus infections and assessment of clinical factors for daptomycin failure: A retrospective cohort study utilizing the Cubicin® Outcomes Registry and Experience

Background: Daptomycin is most commonly used as a second-line treatment. Previous studies have not differentiated the effect of prior antibiotic therapy on daptomycin clinical outcomes.Objectives: The primary objective of this study was to compare clinical outcomes of patients treated with daptomycin as first-line therapy versus after prior antibiotic therapy (specifically, vancomycin). A secondary objective was to identify other factors associated with the clinical failure of daptomycin therapy.Methods: This was a retrospective cohort study using data from a postlabeling registry database. The effects of relevant patient characteristics on the clinical outcome of individuals treated for Staphylococcus aureus infections with daptomycin were examined in an unblinded approach using univariate and multivariate analyses. Only patients with an evaluable clinical outcome (ie, cure, improvement, failure) and culture-confirmed S aureus infection were included in the analysis cohort.Results: Of 1227 clinically evaluable patients, 250 (20%) received daptomycin as first-line therapy and 977 (80%) received daptomycin after other prior antibiotic therapy. Overall, 53% of patients were male; 64% were aged 31 to 65 years and 26% were aged ≥66 years. Race information was collected beginning in 2007; of the patients studied, 71% were white and 18% were black. The initial daptomycin dose (mean [SD]) overall was 5.1 (1.1) mg/kg and was highest for patients with endocarditis (5.9 [1.2] mg/kg) and lowest for those with uncomplicated skin and skin structure infections (4.4 [0.9] mg/kg). Clinical success, defined as an outcome of cured or improved at the end of daptomycin therapy, was reported for 1140 (93%) of the 1227 evaluable patients. The clinical success rates for first-line therapy with daptomycin and after prior antibiotics were both 93%. Using univariate analysis, 8 variables were associated with clinical failure (receipt of daptomycin in an intensive care unit setting, severe renal dysfunction [creatinine clearance <30 mL/min], dialysis, diabetes mellitus (DM), concomitant antibiotics, bacteremia, endocarditis, and failure of prior vancomycin therapy) and 3 with clinical success (outpatient daptomycin therapy and complicated and uncomplicated skin and skin structure infections). Using the stepwise multivariate regression analysis, only the presence of endocarditis (odds ratio [OR] = 2.56; 95% CI, 1.18–5.54; P = 0.017), bacteremia (OR = 1.77; 95% CI, 1.04–3.02; P = 0.037), severe renal dysfunction (OR = 1.78; 95% CI, 1.05–3.03; P = 0.034), and DM (OR = 1.79; 95% CI, 1.10–2.93; P = 0.02) were identified as factors independently associated with clinical failure of daptomycin therapy. Of the remaining patients, 9% were aged 18 to 30 years and 0.7% were aged 12 to 17 years.Conclusions: In this retrospective study, after controlling for clinical factors that are associated with suboptimal outcomes, clinical outcomes with daptomycin did not differ whether it was used as first-line therapy or after other antibiotics. Endocarditis, bacteremia, severe renal dysfunction, and DM were associated with higher rates of clinical failure of daptomycin treatment.     

Case report of a successful treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and MRSA/vancomycin-resistant Enterococcus faecium cholecystitis by daptomycin

A 72-year-old man, receiving 8 mg daptomycin/kg body weight/day for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, was diagnosed with MRSA/vancomycin-resistant Enterococcus faecium (VRE) cholecystitis (daptomycin MIC values, 1 and 2 mg/liter, respectively). After the fifth drug dose, the bile concentration of daptomycin was 66 mg/liter 5 min after drug administration, with the biliary concentration/MIC values higher than 30 for both bacterial strains. Therefore, daptomycin achieved therapeutic levels in bile, hence suggesting a role for the drug in the treatment of MRSA/VRE cholecystitis.     

Native Valve Endocarditis Caused by Corynebacterium striatum with Heterogeneous High-Level Daptomycin Resistance: Collateral Damage from Daptomycin Therapy?

We describe a patient who developed Corynebacterium striatum native valve endocarditis after receiving two 6-week courses of daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis. The organism exhibited in vitro heteroresistance to daptomycin, with two subpopulations showing daptomycin susceptibility (MIC of ≤ 0.094 μg/ml) and high-level resistance to daptomycin (MIC of ≥ 256 μg/ml). The selection of daptomycin-resistant Gram-positive skin flora with the potential of causing invasive disease may be a concern during prolonged courses of daptomycin.     

Addition of Gentamicin or Rifampin Does Not Enhance the Effectiveness of Daptomycin in Treatment of Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

This study evaluated the activity of daptomycin combined with either gentamicin or rifampin against three methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates in vitro and one isolate in vivo against a representative strain (MRSA-572). Time-kill experiments showed that daptomycin was bactericidal against these strains at concentrations over the MIC. Daptomycin at sub-MIC concentrations plus gentamicin at 1× and 2× the MIC yielded synergy, while the addition of rifampin at 2 to 4 μg/ml resulted in indifference (two strains) or antagonism (one strain). The in vivo activity of daptomycin (6 mg/kg of body weight once a day) was evaluated ± gentamicin (1 mg/kg intravenously [i.v.] every 8 h [q8h]) or rifampin (300 mg i.v. q8h) in a rabbit model of infective endocarditis by simulating human pharmacokinetics. Daptomycin plus gentamicin (median, 0 [interquartile range, 0 to 2] log₁₀ CFU/g vegetation) was as effective as daptomycin alone (0 [0 to 2] log₁₀ CFU/g vegetation) in reducing the density of bacteria in valve vegetations (P = 0.83), and both were more effective than daptomycin plus rifampin (3 [2 to 3.5] log₁₀ CFU/g vegetation; P < 0.05) for the strain studied. In addition, daptomycin sterilized a ratio of vegetations that was similar to that of daptomycin plus gentamicin (10/15 [67%] versus 9/15 [60%]; P = 0.7), and both regimens did so more than daptomycin plus rifampin (3/15 [20%]; P = 0.01 and P = 0.02, respectively). No statistical difference was noted between daptomycin plus gentamicin and daptomycin alone for MRSA treatment. In the combination arm, all isolates from vegetations remained susceptible to daptomycin, gentamicin, and rifampin. Sixty-one percent of the isolates (8/13) acquired resistance to rifampin during monotherapy. In the daptomycin arm, resistance was detected in only one case, in which the daptomycin MIC rose to 2 μg/ml among the recovered bacteria. In conclusion, the addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in the treatment of experimental endocarditis due to MRSA.Staphylococcus aureus is a common cause of infective endocarditis (IE), with methicillin-resistant S. aureus (MRSA) strains found in up to one-third of all cases (11, 28). Due to multidrug resistance among many strains, vancomycin is the standard therapy for IE caused by MRSA (1). However, vancomycin therapy has been associated with poor outcomes that may be explained by the drug''s slow bactericidal activity and insufficient diffusion into valve vegetations (5, 10, 23).Daptomycin is a cyclic lipopeptide that is rapidly bactericidal against gram-positive pathogens such as MRSA, including strains that exhibit resistance to vancomycin. It is approved for the treatment of skin and soft tissue infections, S. aureus bacteremia, and right-sided native valve endocarditis (6). However, there is limited information regarding the efficacy of daptomycin in the treatment of left-sided native valve IE caused by MRSA. In a randomized clinical trial (10), none of the patients with left-sided endocarditis treated with daptomycin at 6 mg/kg of body weight/day were cured, and postmarketing registry data (24) revealed a successful clinical outcome in only 9 out of 15 cases (60%). Therefore, given the lack of efficacy data with daptomycin monotherapy in left-sided MRSA endocarditis, the continued evaluation of methods to enhance the activity of daptomycin is warranted. It is unknown whether daptomycin''s activity against MRSA may be improved by combining it with one or more additional antibiotics to produce a potentially additive or synergistic effect. Gentamicin has been shown to augment daptomycin''s activity against strains of MRSA in vitro (4, 20, 35). The combination of daptomycin plus rifampin has demonstrated additive activity against MRSA in vitro (4) and has enhanced activity against MRSA in vivo (4, 32). The aim of this study was to evaluate the in vitro activity of daptomycin combined with gentamicin or rifampin against MRSA and compare treatment with daptomycin alone to treatment with both combinations in experimental MRSA aortic valve endocarditis using a human-adapted pharmacokinetic model.(This work was previously presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], Chicago, IL, 17 to 20 September 2007 [29a] and at the 48th Annual ICAAC-IDSA Annual Meeting, Washington, DC, 25 to 28 October 2008 [29b].)     

Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus is becoming increasingly prevalent as both a nosocomial and a community-acquired pathogen. Daptomycin, a lipopeptide antibiotic now in phase III clinical trials, is rapidly bactericidal in vitro against a range of gram-positive organisms, including methicillin-resistant S. aureus (MRSA). In this study, we compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin (MIC = 1 micro g/ml), vancomycin (MIC = 0.5 micro g/ml), and rifampin (MIC = 0.5 micro g/ml). Daptomycin was administered at 25 or 40 mg/kg q24h (q24h) by subcutaneous injection in an attempt to simulate human doses of 4 and 6 mg/kg q24h, respectively. Vancomycin was given at 150 mg/kg q24h by continuous intravenous infusion. Rifampin was given at 25 mg/kg by intramuscular injection q24h. Treatment was started 6 h postinoculation and continued for 4.5 days. Outcome was assessed by counting the residual viable bacteria in vegetations. The mean peak daptomycin levels in serum at 2 h after subcutaneous administration of 25 and 40 mg/kg were 64 and 91 micro g/ml, respectively. Daptomycin was undetectable in serum at 24 h. The total exposure was comparable to that achieved clinically in humans receiving the drug. Bacterial counts (mean log(10) number of CFU per gram +/- the standard deviation) in untreated controls reached 10.6 +/- 0.8. In treated rats, bacterial counts were as follows: vancomycin, 7.1 +/- 2.5; daptomycin at 25 mg/kg, 5.5 +/- 1.7; daptomycin at 40 mg/kg, 4.2 +/- 1.5. The difference between daptomycin at 40 mg/kg and vancomycin at 150 mg/kg was statistically significant (P = 0.004). In the study of combination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 +/- 1.6; rifampin, 3.6 +/- 1.3; vancomycin plus rifampin, 3.3 +/- 1.1; daptomycin plus rifampin, 2.9 +/- 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (P = 0.006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.     

Impact of dose de-escalation and escalation on daptomycin's pharmacodynamics against clinical methicillin-resistant Staphylococcus aureus isolates in an in vitro model

De-escalation and escalation therapeutic strategies are commonly employed by clinicians on the basis of susceptibility results and patient response. Since no in vitro or in vivo data are currently available to support one strategy over the other for daptomycin, we attempted to evaluate the effects of dose escalation and de-escalation on daptomycin activity against methicillin-resistant Staphylococcus aureus (MRSA) isolates using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations. Three clinical MRSA isolates, including one heterogeneous vancomycin-intermediate S. aureus (hVISA) isolate and one vancomycin-intermediate S. aureus (VISA) isolate, were exposed to daptomycin at 10 or 6 mg/kg of body weight/day for 8 days using a starting inoculum of ～10(9) CFU/g of vegetations, with dose escalation and de-escalation initiated on the fourth day. Daptomycin MIC values ranged from 0.5 to 1 μg/ml. In the PK/PD model, high-dose daptomycin (10 mg/kg/day) and de-escalation simulation (10 to 6 mg/kg/day) appeared to be the most efficient regimens against the three tested isolates, exhibiting the fastest bactericidal activity (4 to 8 h) compared to that of the standard regimen of 6 mg/kg/day and the escalation therapy of 6 to 10 mg/kg/day. The differences in the numbers of CFU/g observed between dose escalation and de-escalation were significant for the hVISA strain, with the de-escalation simulation exhibiting a better killing effect than the escalation simulation (P<0.024). Although our results need to be carefully considered, the use of high-dose daptomycin up front demonstrated the most efficient activity against the tested isolates. Different therapeutic scenarios including isolates with higher MICs and prolonged drug exposures are warranted to better understand the outcomes of escalation and de-escalation strategies.     

Daptomycin therapy in 6 cases of left-sided infective endocarditis and literature review北大核心CSCD

Objective To evaluate the efficacy of daptomycin in the treatment of left-sided infective endocarditis after failing to respond to vancomycin. Methods A retrospective analysis was conducted for 6 cases of infective endocarditis. Results Five of the six infective endocarditis patients were complicated with paravalvular abscess (artificial valve in 3 cases, native valve in 2 cases). Their disease deteriorated even under vancomycin treatment. Four of these patients received emergency valve replacement surgery but still febrile after operation. The antimicrobial therapy was switched to daptomycin at dose of 6 mg/kg daily for 2 to 4 weeks. The patients responded satisfactorily to daptomycin. The infection was controlled to some extent in the fifth patient after switching to daptomycin, but recurred later, and died suddenly on day 21 after reoperation. The sixth patient had infective endocarditis of native valve, and had treated with piperacillin-tazobactam for 2 weeks and vancomycin for 3 weeks, but responded poorly. The patient still had fever and enlarged vegetation. Switching to daptomycin reduced the body temperature and vegetation. Serum creatine kinase elevated moderately in one patient, and normal in the other 5 patients. No other apparent adverse reaction was reported. One patient died and the other five patient survived well for 18 months to 5 years. Conclusions Preliminary observation demonstrates the efficacy of daptomycin salvage treatment in a few cases of left-sided infective endocarditis after failing to respond to vancomycin therapy. © 2018, Editorial Department of Chinese Journal of Infection. All rights reserved.     

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.     

Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model

OBJECTIVES: To extend the mutant selection window (MSW) hypothesis to include antibiotics in addition to fluoroquinolones, the pharmacodynamics of daptomycin (DAP) and vancomycin (VAN) and their ability to prevent the selection of resistant Staphylococcus aureus were studied in an in vitro model that simulates antibiotic concentrations below the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC. METHODS: Two clinical isolates of S. aureus, S. aureus 866 (MIC(DAP) 0.35, MIC(VAN) 0.7, MPC(DAP) 1.1, MPC(VAN) 2.4 mg/L) and S. aureus 10 (MIC(DAP) 1.1, MIC(VAN) 1.3, MPC(DAP) 5.5, MPC(VAN) 11 mg/L), were exposed for five consecutive days to once-daily daptomycin (half-life 9 h) and twice-daily vancomycin (half-life 6 h) at the ratio of 24 h area under the concentration-time curve (AUC24) to MIC that varied over a 16- to 30-fold range. The cumulative antimicrobial effect was expressed by its intensity (I(E)). Changes in susceptibility and numbers of surviving organisms on agar plates containing 2x and 4x MIC of daptomycin or vancomycin were monitored daily. RESULTS: The I(E)-log AUC24/MIC plots were bacterial strain- and antibiotic-independent. This allowed combination of data obtained with both antibiotics and both organisms. Based on the sigmoid relationship between I(E) and the AUC24/MIC (r2 = 0.9), the antistaphylococcal effect of the therapeutic doses of daptomycin (4 and 6 mg/kg) against a hypothetical S. aureus with MIC equal to the MIC90 (AUC24/MIC90 380 and 570 h, respectively) was predicted to be similar to the effect of two 1 g doses of vancomycin given at a 12 h interval (AUC24/MIC90 200 h). AUC24/MIC relationships of the final-to-initial MIC ratio and logarithm of the ratio of maximal-to-initial numbers of organisms resistant to 2x and 4x MIC of daptomycin or vancomycin were bell-shaped and bacterial strain- and antibiotic-independent. Based on these relationships, an AUC24/MIC ratio that protects against the selection of resistant mutants was predicted at > or = 200 h. This protective value is less than the AUC24/MIC90s provided by the 4 mg/kg dose and considerably less than the 6 mg/kg dose of daptomycin, but it is close to the AUC24/MIC90 provided by two 1 g doses of vancomycin. CONCLUSIONS: These findings support the MSW hypothesis and suggest comparable antistaphylococcal effects of clinically achievable AUC24/MIC90s of daptomycin and vancomycin but slightly better prevention against the selection of resistant S. aureus by daptomycin.     

Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers

Daptomycin, a novel lipopeptide, is bactericidal against a broad range of gram-positive strains, including methicillin- (MRSA) and vancomycin-resistant Staphylococcus aureus. Daptomycin is approved at 4 mg/kg of body weight given intravenously once daily for the treatment of complicated skin and skin structure infections and at 6 mg/kg for the treatment of S. aureus bloodstream infections (bacteremia), including right-sided endocarditis caused by methicillin-susceptible S. aureus and MRSA. The present study was designed to evaluate the multiple-dose pharmacokinetics and safety of daptomycin at doses of 6 to 12 mg/kg in healthy volunteers. Three cohorts of 12 subjects each were given daptomycin (10 mg/kg) or placebo once daily for 14 days, daptomycin (12 mg/kg) or placebo once daily for 14 days, or daptomycin (6 or 8 mg/kg) once daily for 4 days. Daptomycin produced dose-proportional increases in the area under the plasma concentration-time curve and in trough daptomycin levels and nearly dose-proportional increases in peak daptomycin concentrations. Other pharmacokinetic parameters measured on day 1 and at steady state were independent of the dose, including the half-life (approximately 8 h), weight-normalized plasma clearance (9 to 10 ml/h/kg), and volume of distribution (approximately 100 ml/kg). Plasma protein binding was 90% to 93% and was independent of the daptomycin concentration. Daptomycin did not produce electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity. Daptomycin was well tolerated in subjects dosed with up to 12 mg/kg intravenously for 14 days. Doses of daptomycin higher than 6 mg/kg once daily may be considered in further studies to evaluate the safety and efficacy of daptomycin in difficult-to-treat infections.     

Daptomycin Pharmacokinetics and Pharmacodynamics in a Pooled Sample of Patients Receiving Thrice-Weekly Hemodialysis

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia–infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC_48–72) that were <50% of the SAB-IE AUC_48–72 values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC_48–72 values, while maintaining acceptable trough concentration (C_min) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C_min reaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of C_min being ≥24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.     

Penetration of Daptomycin into Bone and Synovial Fluid in Joint Replacement

Daptomycin exhibits clinical activity in the treatment of infections with Gram-positive organisms, including infections due to methicillin-resistant Staphylococcus aureus. However, little is known about its penetration into bone and synovial fluid. The aim of our study was to assess the penetration of daptomycin into bone and synovial fluid after a single intravenous administration. This study was conducted in 16 patients who underwent knee or hip replacement and received a single intravenous dose of 8 mg of daptomycin per kg of body weight prior to surgery. Plasma daptomycin concentrations were measured 1 h after the end of daptomycin infusion and when bone fragments were removed. Daptomycin concentrations were also measured on bone fragments and synovial fluid collected at the same time during surgery. All samples were analyzed with a diode array–high-performance liquid chromatography (HPLC) method. After a single-dose intravenous infusion, bone daptomycin concentrations were above the MIC of daptomycin for Staphylococcus aureus in all subjects, and the median bone penetration percentage was 9.0% (interquartile range [IQR], 4.4 to 11.4). These results support the use of daptomycin in the treatment of Staphylococcus aureus bone and joint infections.