Ricardo L. Chaves

A potential role for daptomycin in enterococcal infections: what is the evidence?

Nosocomial infections caused by enterococci present a challenge for clinicians because treatment options are often limited due to the widespread occurrence of strains resistant to multiple antibiotics, including vancomycin. Daptomycin is a first-in-class cyclic lipopeptide that has proven efficacy for the treatment of Gram-positive infections. Although methicillin-resistant Staphylococcus aureus has been the most prominent target in the clinical development of daptomycin, this agent has demonstrated potent bactericidal activity in enterococcal infection models and has been used for the treatment of enterococcal infections in humans. In recent years, large-scale susceptibility studies have shown that daptomycin is active against >98% of enterococci tested, irrespective of their susceptibility to other antibacterial agents. This lack of cross-resistance reflects the fact that daptomycin has a mode of action distinct from those of other antibiotics, including glycopeptides. While there are limited data available from randomized controlled trials, extensive clinical experience with daptomycin in enterococcal infections (including bacteraemia, endocarditis, skin and soft tissue infections, bone and joint infections and urinary tract infections) has been reported. This growing body of evidence provides useful insights regarding the efficacy of daptomycin against enterococci in clinical settings.

Clinical experience with daptomycin in Europe: the first 2.5 years

Objectives To describe the patient populations and infections being treated with daptomycin, as well as the efficacy and safety outcomes. Patients and methods Data from the European Cubicin Outcomes Registry and Experience (EU-CORESM), retrospectively collected at 118 institutions between January 2006 and August 2008, were analysed. Results Daptomycin treatment was documented in 1127 patients with diverse infections, including complicated skin and soft tissue infections (33%), bacteraemia (22%), endocarditis (12%) and osteomyelitis (6%). It was used empirically, before microbiological results became available, in 53% of patients. Staphylococcus aureus was the most common pathogen (34%), with 52% of isolates resistant to methicillin; coagulase-negative staphylococci and enterococci were also frequent, with 22% of Enterococcus faecium isolates resistant to vancomycin. Daptomycin was used as first-line therapy in 302 (27%) patients. When used second line, the most common reasons for discontinuation of previous antibiotic were treatment failure and toxicity or intolerance. The use of concomitant antibiotics was reported in 65% of patients. Most frequent doses were 6 mg/kg (47%) and 4 mg/kg (32%). The median duration of daptomycin therapy was 10 days (range 1–246 days) in the inpatient setting and 13 days (range 2–189 days) in the outpatient setting. The overall clinical success rate was 79%, with a clinical failure rate of <10% for all infection types. Low failure rates were observed in first- and second-line therapy (6% and 8%, respectively). Daptomycin demonstrated a favourable safety and tolerability profile regardless of treatment duration. Conclusions Daptomycin has a relevant role in the treatment of Gram-positive infections.

Comparison of the pharmacokinetics, safety and tolerability of daptomycin in healthy adult volunteers following intravenous administration by 30 min infusion or 2 min injection

Objectives Two randomized Phase I studies in separate populations of healthy adult volunteers investigated the pharmacokinetics, safety and tolerability of daptomycin (Cubicin®; Novartis Pharma AG, Basel, Switzerland) administered as a 2 min intravenous (iv) injection, relative to the currently licensed 30 min iv infusion. Methods Study 1 was an open-label, single-dose, two-period, crossover study in which each subject received 6 mg/kg daptomycin administered as a 30 min iv infusion (n = 15) and as a 2 min iv injection (n = 16). In Study 2, a single-blind, multiple-dose, parallel-group study, subjects received a once-daily 2 min iv injection of 6 mg/kg daptomycin (n = 12), 4 mg/kg daptomycin (n = 8) or placebo (n = 4) for 7 days. Single-dose pharmacokinetics were assessed at various timepoints up to 36 and 24 h post-dose in Study 1 and Study 2, respectively, and multiple-dose pharmacokinetics were assessed in Study 2 at day 7 for 48 h post-dose. Results In Study 1, pharmacokinetic comparability between the two administration regimens was demonstrated by meeting the bioequivalence criteria for the exposure parameters, AUC0–t, AUC0–∞ and Cmax. In Study 2, time-invariant pharmacokinetic properties as well as dose-proportional pharmacokinetics were demonstrated for the daptomycin 2 min iv injection regimen. In both studies, daptomycin was well tolerated and the majority of treatment-emergent adverse events were of mild intensity and considered to be unrelated to daptomycin. Conclusions The similar pharmacokinetic and safety profiles of the two administration regimens suggest that the 2 min iv injection may be a convenient treatment option for both patients and healthcare professionals.

Daptomycin use in patients with osteomyelitis: a preliminary report from the EU-CORESM database

Background Osteomyelitis is a complex and heterogeneous group of infections that require surgical and antimicrobial interventions. Because treatment failure or intolerance is common, new treatment options are needed. Daptomycin has broad Gram-positive activity, penetrates bone effectively and has bactericidal activity within biofilms. This is the first report on clinical outcomes in patients with osteomyelitis from the multicentre, retrospective, non-interventional European Cubicin® Outcomes Registry and Experience (EU-CORESM), a large database on real-world daptomycin use. Patients and methods In total, 220 patients were treated for osteomyelitis; the population was predominantly elderly, with predisposing baseline conditions such as diabetes and chronic renal/cardiac diseases. Results Most patients (76%) received prior antibiotic treatment, and first-line treatment failure was the most frequent reason to start daptomycin. Common sites of infection were the knee (22%) or hip (21%), and the most frequently isolated pathogens were Staphylococcus aureus (33%) and coagulase-negative staphylococci (32%). Overall, 52% of patients had surgery, 55% received concomitant antibiotics and 29% received a proportion of daptomycin therapy as outpatients. Clinical success was achieved in 75% of patients. Among patients with prosthetic device-related osteomyelitis, there was a trend towards higher success rates if the device was removed. Daptomycin was generally well tolerated. Conclusions This analysis suggests that daptomycin is an effective and well-tolerated treatment option for osteomyelitis and highlights the importance of optimal surgical intervention and appropriate microbiological diagnosis for clinical outcomes.

Daptomycin for the treatment of infective endocarditis: results from a European registry

OBJECTIVES Infective endocarditis (IE) is a complex infection associated with high mortality. Daptomycin, a cyclic lipopeptide antibiotic highly active against Gram-positive bacteria, has recently been incorporated into IE treatment guidelines. This retrospective analysis provides insights into the use of daptomycin in IE in the European Cubicin(®) Outcomes Registry Experience (EU-CORE(SM)) between 2006 and 2010. PATIENTS AND METHODS Three hundred and seventy-eight (10%) of 3621 enrolled patients received daptomycin for treatment of IE. Two hundred and fifty-nine (69%) had left-sided IE (LIE) and 182 patients (48%) underwent concomitant surgery. RESULTS Staphylococcus aureus was the most frequently identified pathogen (n=92; methicillin susceptible, n=50) and daptomycin was used empirically in 134 patients. Among cases of second-line therapy (n=312), the most common reason for switching to daptomycin was failure of the previous regimen (including glycopeptides and penicillins). Daptomycin was administered at 6 mg/kg in 224 patients and at ≥ 8 mg/kg in 72 patients. Clinical success rates were 80% overall, 91% for right-sided IE (RIE) and 76% for LIE, with similar rates seen for infections caused by methicillin-susceptible S. aureus (84%) and methicillin-resistant S. aureus (81%). The clinical success rate in patients treated with ≥ 8 mg/kg daptomycin was 90% [n=72 (RIE, 91%; LIE, 89%)]. No new safety signals were observed. CONCLUSIONS In patients with IE registered in EU-CORE, daptomycin was most frequently used as second-line treatment after treatment failure. The majority of patients had LIE and most commonly received daptomycin for the treatment of staphylococcal infections. Clinical success was high in this difficult-to-treat population. The role of doses ≥ 8 mg/kg per day in the empirical treatment of IE deserves further investigation.

Comparative randomised clinical trial against glycopeptides supports the use of daptomycin as first-line treatment of complicated skin and soft-tissue infections.

In comparison with other anti-meticillin-resistant Staphylococus aureus (MRSA) agents, e.g. linezolid, tigecycline, vancomycin, eicoplanin and quinupristin/dalfopristin, daptomycin has the ost potent in vitro bactericidal activity against Gram-positive athogens [1,2]. As therapy for complicated skin and soft-tissue nfections (cSSTIs) is generally initiated before susceptibility data re available, empirical antibiotic coverage with an antibiotic with qual activity against meticillin-susceptible S. aureus (MSSA) and RSA, such as daptomycin, is advantageous. The potency of daptomycin against pathogens causing cSSTIs epresents a strong rationale for its use in empirical treatment. A phase IIIb, multicentre, comparative, randomised, assessorlinded study was conducted at 29 centres across France, Germany, oland, Spain and the UK in accordance with Good Clinical Pracice (GCP) guidelines/local regulations. The primary objective was o compare the clinical efficacy of daptomycin versus vancomycin r teicoplanin for the treatment of cSSTIs by the proportion f patients achieving clinical success at the test-of-cure (TOC) isit (Days +7/+14) in the clinically evaluable (CE) population. econdary objectives were to compare microbiological efficacy eradication of baseline pathogens at TOC) and safety results. Adults equiring intravenous (i.v.) antimicrobial treatment for cSSTIs diabetic foot ulcers, major abscess, extensive cellulitis and surgial/traumatic wound infection) were included. Those treated with ancomycin/teicoplanin within the past 48 h were excluded. Randomisation used a computerised algorithm balancing for age 65 years, and systemic inflammatory response syndrome (SIRS). tudy drugs were used according to the approved labels: daptoycin 4 mg/kg i.v. once daily; vancomycin 1 g i.v. twice daily; and eicoplanin 400 mg i.v. once daily following a 400 mg loading dose dministered every 12 h on Day 1. Statistical analysis of the study esults is only descriptive (premature study stop due to logistical easons does not allow for confirmatory tests). A total of 194 patients were randomised; 189 received treatment daptomycin, n = 97; comparators, n = 92, comprising vancomycin n = 46) or teicoplanin (n = 46)] and 134 completed treatment as cheduled. Discontinuation due to adverse events (AEs) or death ccurred more frequently in the comparator group (9.8% vs. 3.1% or daptomycin). Cellulitis was the most common diagnosis (66% f the population). SIRS was present in 58% of patients. Moreover, 4 patients had relevant pathogens for cSSTI at baseline, 65.5% of hom had S. aureus infections. Baseline conditions were similar in oth treatment arms.

Daptomycin for outpatient parenteral antibiotic therapy: a European registry experience

A retrospective analysis of data from patients receiving daptomycin as outpatient parenteral antimicrobial therapy (OPAT) within the European Cubicin Outcomes Registry and Experience (EU-CORE(SM)) was performed. Of 4592 enrolled patients in 15 countries, 550 (12%) received daptomycin OPAT. Of these, 149 (27%) received daptomycin without hospital admission, 84% had significant underlying diseases and 44% were ≥65 years of age. Most frequently treated infections were complicated skin and soft-tissue infections (28%), osteomyelitis (17%), foreign body/prosthetic infections (15%) and endocarditis (14%). In patients with culture results available, Staphylococcus aureus and coagulase-negative staphylococci were the most commonly isolated primary pathogens [n = 218 (46%) and n = 102 (21%), respectively]. Daptomycin was typically used at doses of 6 mg/kg (n = 210; 38%) and 4 mg/kg (n = 160; 29%), with concomitant antibiotics used in 41%. The median treatment duration was 22 days (range 1-300 days), with a median of 13 OPAT days (range 1-290 days). Overall clinical success was observed in 89%, with high success rates across the wide range of infections, including those caused by meticillin-resistant and meticillin-susceptible S. aureus (88% and 90%, respectively). Daptomycin exhibited a favourable safety profile; 3.1% of patients discontinued treatment owing to an adverse event. These data demonstrate that daptomycin is effective and well tolerated in the treatment of a wide range of Gram-positive infections in the outpatient setting. Ease of administration of daptomycin, via a daily 2-min injection, and its efficacy and safety combine to make it an attractive treatment option for OPAT.

Effectiveness and safety of daptomycin in complicated skin and soft-tissue infections and bacteraemia in clinical practice: Results of a large non-interventional study

This retrospective analysis of patients from eight countries included in the European Cubicin(®) Outcomes Registry and Experience (EU-CORE(SM)) captures the first post-approval years of clinical experience with daptomycin in its licensed indications. Of the total 1127 patients enrolled in EU-CORE between 2006 and 2008, 373 had a primary complicated skin and soft-tissue infection (cSSTI), most commonly surgical-site infection (48%), and 244 had bacteraemia, 55% of which were catheter-related. The most common pathogens were Staphylococcus aureus in cSSTIs (43%) and coagulase-negative staphylococci in bacteraemia (36%). The most frequently prescribed daptomycin doses were 4 mg/kg and 6 mg/kg for cSSTIs, and 6 mg/kg for bacteraemia. The median duration of inpatient and outpatient treatment, respectively, was 13 days and 8 days for cSSTIs and 8 days and 10 days for bacteraemia. Clinical success was reported for 81% of patients with cSSTIs and 77% with bacteraemia, with 82% success overall for infections caused by S. aureus. A trend towards higher clinical success was noted with higher daptomycin doses in bacteraemia (78% for 6 mg/kg vs. 90% for doses >6 mg/kg). Daptomycin demonstrated a favourable safety profile. Adverse events regardless of relationship to study drug were reported for 11% of patients with cSSTIs and 24% with bacteraemia, most commonly septic shock [7 patients (2%) with cSSTIs and 5 patients (2%) with bacteraemia]. These results demonstrate that daptomycin is effective and well tolerated in the treatment of cSSTIs and bacteraemia caused by Gram-positive bacteria in clinical practice.

Clinical and pharmacokinetic considerations for the use of daptomycin in patients with Staphylococcus aureus bacteraemia and severe renal impairment

OBJECTIVES To support daptomycin dosing recommendations in patients with Staphylococcus aureus bacteraemia (SAB) and severe renal impairment using simulations from a population pharmacokinetic model for daptomycin. METHODS A population pharmacokinetic model was developed using 4875 daptomycin plasma concentrations from 442 subjects. Daptomycin 24 h AUC and Cmax were then simulated for subjects with a CL(CR) < 30 mL/min [with or without haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD)] for different dosing frequencies (every 24 h, every 48 h and three times weekly) with doses of 4 mg/kg and 6 mg/kg. These results were compared with efficacy and safety exposure references based on daily dosing to understand the implications of less frequent dosing (for example, higher exposures on day 1 versus day 2) and to evaluate the 4 mg/kg versus 6 mg/kg regimens. RESULTS Substantially more patients with SAB and severe renal impairment were underexposed (24 h AUCs compared with an efficacy reference of 6 mg/kg/day, CLCR ≥ 30 mL/min, pivotal trial population) at 4 mg/kg every 48 h compared with 6 mg/kg. Cmax results also favoured 6 mg/kg every 48 h over 4 mg/kg every 48 h. Both exposure metrics at 6 mg/kg every 48 h also stayed below the defined safety limits (based on 12 mg/kg/day, CL(CR) >80 mL/min, the highest dose in controlled clinical trials). CONCLUSIONS For patients with SAB and CLCR <30 mL/min, or receiving HD or CAPD, the dose recommendation of 6 mg/kg every 48 h provides appropriate daptomycin exposure for this indication; this will not be the case for patients receiving 4 mg/kg every 48 h.

Efficacy and safety of diclofenac in osteoarthritis: Results of a network meta-analysis of unpublished legacy studies

Abstract Background and aim Diclofenac is widely prescribed for the treatment of pain. Several network meta-analyses (NMA), largely of published trials have evaluated the efficacy, tolerability, and safety of nonsteroidal anti-inflammatory drugs (NSAIDs). The present NMA extends these analyses to unpublished older (legacy) diclofenac trials. Methods We identified randomised controlled trials (RCTs) of diclofenac with planned study duration of at least 4 weeks for the treatment of osteoarthritis (OA) from ‘legacy’ studies conducted by Novartis but not published in a peer reviewed journal or included in any previous pooled analyses. All studies reporting efficacy and/or safety of treatment with diclofenac or other active therapies or placebo were included. We used a Bayesian NMA model, and estimated relative treatment effects between pairwise treatments. Main outcomes included pain relief measured using visual analogue scale at 2, 4 and 12 weeks and patient global assessment (PGA) at 4 and 12 weeks for efficacy, all-cause withdrawals, and adverse events. Results A total of 19 RCTs (5030 patients) were included; 18 of which were double-blind and one singleblind. All studies were conducted before cyclooxygenase 2 inhibitors (COXIBs) became commercially available. Data permitted robust efficacy comparison between diclofenac and ibuprofen, but the amount of data for other comparators was limited. Diclofenac 150 mg/day was more efficacious than ibuprofen 1200 mg/day and had likely favourable outcomes for pain relief compared to ibuprofen 2400 mg/day. Diclofenac 100 mg/day had likely favourable outcomes compared to ibuprofen 1200 mg/day in alleviating pain. Based on PGA, diclofenac 150 mg/day was more efficacious and likely to be favourable than ibuprofen 1200 mg/day and 2400 mg/day, respectively. Risk of withdrawal due to all causes with diclofenac and ibuprofen were comparable. Diclofenac 150 mg/day was likely to have favourable efficacy and comparable tolerability with diclofenac 100 mg/day. Results comparing diclofenac and ibuprofen were similar to those from NMAs of published trials. Conclusions Results from these unpublished ‘legacy’ studies were similar to those from NMAs of published trials. The favourable efficacy results of diclofenac compared to ibuprofen expand the amount of available evidence comparing these two NSAIDs. The overall benefit-risk profile of diclofenac was comparable to that of ibuprofen in OA. Implications The present NMA results reassures that the older unpublished blinded trials have similar results compared to more recently published trials and also contributes to increase the transparency of clinical trials performed with diclofenac further back in the past.