Clinical Medicine Insights: Therapeutics
E x p e r t Re v ie w
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Safety and Efficacy of Daptomycin in the Treatment of Gram-Positive Pathogens Theodoros Kelesidis Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. Corresponding author email:
[email protected]
Abstract: Daptomycin is an antibacterial agent with activity against Gram-positive organisms and is a reliable option for the treatment of invasive Gram-positive infections. Daptomycin has been approved for the treatment of complicated skin and skin-structure infections and bacteremia including right-sided endocarditis. In methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis, it has been shown to be noninferior to conventional treatment with vancomycin with or without an aminoglycoside. It has also been used successfully in the treatment of soft-tissue infections. Little experience is available on the treatment of bone and joint infections, although initial data are encouraging. Daptomycin has rapid bactericidal activity that is associated with its unique mechanism of action on the cell membrane. It has favorable pharmacokinetic properties allowing once-daily dosing. Toxicity is rare with currently recommended dosing. With the rising antimicrobial resistance in Gram-positive infections, the use of daptomycin is expected to increase in the following years. However, as a consequence of its increased use, daptomycin resistance may emerge as a significant problem. The current data suggest that daptomycin has a relevant role in the therapeutic armamentarium of physicians for the treatment of Grampositive infections. Keywords: daptomycin, treatment, safety, efficacy, gram-positive
Clinical Medicine Insights: Therapeutics 2011:3 403–414 doi: 10.4137/CMT.S6122 This article is available from http://www.la-press.com. © the author(s), publisher and licensee Libertas Academica Ltd. This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited. The authors grant exclusive rights to all commercial reproduction and distribution to Libertas Academica. Commercial reproduction and distribution rights are reserved by Libertas Academica. No unauthorised commercial use permitted without express consent of Libertas Academica. Contact
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Introduction
Vancomycin is considered the agent of choice for the treatment of resistant Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA) infections.1 However, its excessive use has contributed to the emergence of vancomycin-resistant enterococci (VRE), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) and vancomycin has also been shown to be ineffective in eradicating Gram-positive organisms embedded in the biofilm of infected central venous catheters (CVCs) in vitro.2,3 Considering these limitations, there is a need for alternative agents. Daptomycin is the first-in-class cyclic lipopeptide antibiotic that is active against various Gram-positive bacteria and was approved for the treatment of complicated skin and soft tissue infections (cSSTIs) and for the treatment of right-sided infective endocarditis (RIE) due to Staphylococcus aureus and S. aureus bacteremia (SAB) when associated with RIE or with cSSTI.4 By mid-2010, daptomycin had been used to treat an estimated 1000000 patients with serious Gram-positive infections worldwide.5 In this review I summarize the evidence regarding safety and efficacy of daptomycin in the treatment of grampositive pathogens.
Mechanism of Action of Daptomycin
Although the mechanism of action of daptomycin is not well understood, it seems to act through insertion into the cytoplasmic membrane of Gram-positive cells.6,7 Daptomycin interacts with the membrane leading to disruption of the functional structure with membrane leakage, release of ions, and cell death.7,8 Gram-negative organisms are not affected because of a lack of permeability of the external membrane.8 The emergence of daptomycin resistance in gram positive organisms such as S. aureus and Enterococcus spp during therapy, leading to therapeutic failure, has been the subject of several recent reports.8,9 The significance of this association is not clear since most patients receive vancomycin as initial, empiric therapy of Gram-positive infections.8
Antimicrobial Activity of Daptomycin
Daptomycin is active against Gram-positive bacteria. Its spectrum includes staphylococci, streptococci including S. pneumoniae, enterococci (including 404
vancomycin-resistant strains), vancomycin-resistant strains Lactobacillus, Pediococcus and Leuconostoc, Bacillus species and corynebacteria, some anaerobic organisms, eg, peptostreptococci and clostridia, including C. difficile.10–14 Listeria may have elevated MIC values whereas it is not reliable against Actinomyces.13 Daptomycin has also potent bactericidal activity against antibiotic-resistant Gram-positive pathogens, such as vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus, vancomycinresistant S. aureus and penicillin-resistant Streptococcus pneumoniae, for which there are few therapeutic alternatives.6,7,15,16 Daptomycin showed better antibiofilm activity than vancomycin, linezolid, tigecycline or rifampin against staphylococcal biofilm formed by strains isolated from catheter-related infections.7 Daptomycin has no activity against Gram-negative bacteria.
Pharmacokinetics of Daptomycin can Determine Its Efficacy
Studies performed with a dosage of 6 mg/kg showed that daptomycin has linear pharmacokinetics, becoming nonlinear at higher dosages.15 The efficacy of daptomycin is best correlated with the Cmax or AUC24: MIC of the bacterial strain.6,7 Daptomycin is excreted in the urine (53%–59% at 24 h) with minimal hepatic metabolization,6 and metabolites seem to be inactive and nontoxic.15 Because of its renal excretion, dosage must be adjusted in patients with renal malfunction,6,15 but not in hepatic failure.6 The half-life is 8–9 h, which allows daily administration,15 and the volume of distribution is around 0.1 l/kg, which corresponds with a predominantly extracellular distribution and high protein binding (90%–94%).6,7,15 Protein binding diminishes the activity of the drug in vitro.7 Daptomycin also has a high postantibiotic effect, which ranges between 1.7 and 6 h.6,15 Daptomycin is bactericidal for S. aureus in a concentration-dependent manner, so the use of higher dosages has been claimed as useful for biofilm-related infection, whereas lower dosages can result in therapeutic failure.17
Efficacy of Daptomycin against Gram Positive Organisms
The efficacy of daptomycin to treat infections caused by gram positive pathogens was recently studied Clinical Medicine Insights: Therapeutics 2011:3
Daptomycin in the treatment of gram-positive pathogens
in a large cohort in which daptomycin was used in Europe and Argentina to treat a variety of Grampositive infections in a severely ill patient population with multiple co-morbidities, who were commonly infected with drug-resistant pathogens [MRSA, coagulase-negative staphylococci (CoNS) and vancomycin-resistant enterococci (VRE)], and almost half of whom were aged $65 years.18 Daptomycin demonstrated a favorable safety and tolerability profile18 and low overall rates of clinical failure similar to the early results from the CORE database in the USA,19–22 despite its use in this severely ill population, frequently as second-line or salvage therapy. Unlike glycopeptides, daptomycin has proven similar efficacy against both MRSA and Methicillin-sensitive S. aureus (MSSA), making it an attractive option for empirical therapy of suspected S. aureus infections regardless of methicillin resistance risk.23 Unlike linezolid, daptomycin is bactericidal, which is expected to confer advantages in terms of efficacy, especially in serious infections.24–26 Experience in EU-CORE appears to support this concept, with 53% of patients receiving daptomycin as empirical therapy.18 There is emerging evidence that daptomycin is being used to treat infections caused by other Grampositive species that are of increasing importance in hospital and outpatient practice,27–30 particularly in orthopaedic-related and endovascular infections where other long-term treatment options may be limited. This is also reflected in published treatment guidelines where daptomycin is recommended as first alternative to vancomycin when the vancomycin MIC is no longer associated with a significant chance of clinical success.1 The efficacy of daptomycin as treatment option for specific infections such as complicated skin and soft tissue infections, bacteremia, endocarditis and orthopedic infections is reviewed separately.
Complicated skin and soft tissue infections (cSSTIs)
Skin and soft-tissue infections caused by Grampositive cocci range from a simple cellulitis to life-threatening necrotizing fasciitis. Intravenous daptomycin was approved by the Food and Drug Administration (FDA) in 2003 for the treatment of patients with complicated skin and skin-structure infections (cSSIs), including those infected with MRSA.31 Clinical Medicine Insights: Therapeutics 2011:3
Two randomized trials compared daptomycin at a dose of 4 mg/kg daily to penicillinase-resistant penicillins or vancomycin for the treatment of cSSIs.31 Among 902 evaluated patients, the clinical efficacy of daptomycin was 83.4%, compared with 84.2% for the comparator group and daptomycin required a shorter duration of administration.31 In a retrospective analysis of the Cubicin Outcomes Registry and Experience (CORE) 2004 database, 522 patients with skin and skin-structure infections (SSIs) were evaluated.19 Of these, 64% had cSSIs.19 Surgical site infections were most common, followed by wound, abscess and diabetic foot infections. Among the subset of patients with cSSIs, the reported clinical outcome was cure in 53%, improvement in 43% and failure in 4%.19 Daptomycin was also successful in 9 of 10 patients with necrotizing infections.19 The median dose of daptomycin was 4 mg/kg daily and median treatment duration was 12 days.19 Daptomycin at a dose of 4 mg/kg was compared with vancomycin and was found to have similar success rate for the treatment of cellulitis and erysipelas,32 although short-duration, high-dose (10 mg/kg for 4 days) daptomycin for cSSIs was inferior to vancomycin in another study.33 Another study examined daptomycin efficacy in 53 adult patients with cSSTIs at risk for MRSA infection compared with a matched retrospective cohort of 212 patients treated with vancomycin. The proportions of patients with clinical improvement or resolution of their infections on days three and five were 90% vs. 70% and 98% vs. 81% in the daptomycin and vancomycin groups, respectively.34 In a separate analysis of a subset of 133 patients with diabetic foot infections, clinical success rates were comparable (66% for the daptomycin arm vs. 70% in the comparator arm).35 Even with a standard 4 mg/kg regimen, daptomycin allowed for earlier patient discharge than vancomycin in one study of SSTIs, reducing infection costs from $7552 per patient to $5027.34 According to a recent metaanalysis additional research seems warranted for use of daptomycin in MRSA-confirmed cSSTIs, as adequate sample sizes were not available to draw meaningful conclusions.36 Another multi-center study demonstrated that intravenous daptomycin is safe, well tolerated, and effective in treating superficial and deep incisional SSI caused by gram-positive microorganisms, 405
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including MRSA.37 Daptomycin therapy provided overall clinical success in more than 90% of patients, including 100% of patients with superficial SSI. The microbiologic response rate was high.37 Baseline infection pathogens were eradicated in 84% of patients with superficial incisional SSI and in approximately 50% of those with deep SSI.37 Importantly, all isolates tested—including MRSA—were susceptible to daptomycin, and isolates persisting after one course of daptomycin treatment remained susceptible to the drug.37 Daptomycin was effective in eradicating 100% of superficial SSI and 67% of deep SSI caused by MRSA.37 The overall clinical success rate of 92% for daptomycin in treating SSI37 was similar to the clinical success rate of 84% for patients with infected wounds seen in previous studies.19,31 In addition, the results of this multi-center study were similar to those recently reported in a post marketing analysis of the use of daptomycin in the treatment of SSI, in which the overall clinical success rate at the end of therapy in 231 patients was 94%; 98% of patients with a superficial SSI and 89% of patients with a deep SSI achieved clinical success.38 The differential outcomes in superficial and deep SSI suggest that wound classification should be considered a stratification variable in future studies of antibacterial treatment of SSI.37
Bacteremia and endocarditis
S. aureus bacteremia and endocarditis Daptomycin was noninferior to standard treatment in a randomized trial that compared daptomycin at a dose of 6 mg/kg daily to either vancomycin or an antistaphylococcal penicillin, both with initial low-dose gentamicin for the treatment of S. aureus bacteremia with or without endocarditis.23 Success rates were comparable in subsets of patients with complicated bacteremia, right-sided endocarditis, and MRSA.23 In this study, although not statistically significant, a higher rate of microbiological failure (15.8% vs. 9.6%) was seen in the daptomycin arm.23 In cancer patients with catheter-related bloodstream infection (CRBSI), daptomycin was significantly associated with earlier clinical and microbiological response and a significantly better overall response compared with vancomycin.39 In a cost-effectiveness analysis, the overall cost of daptomycin treatment was similar to the cost of vancomycin plus gentamicin for patients with MRSA bacteremia and/or endocarditis.40 406
In a separate analysis of the subset of patients with MRSA bacteremia or right-sided endocarditis, daptomycin was successful in a higher proportion of patients (44.4% vs. 32.6%) compared to vancomycin/ gentamicin, but the difference did not reach statistical significance.41 In the setting of pulmonary emboli complicating S. aureus right-sided endocarditis, daptomycin may theoretically be effective, as emboli are vascular and not parenchymal events. However, this issue has not been addressed adequately and few patients with septic emboli have thus far been treated in randomized, controlled trials.9,20 Therefore, patients with septic emboli being treated solely with daptomycin should be observed carefully for evidence of failure.9 It also may be reasonable to provide additional coverage in such patients with S. aureus bacteremia complicated by septic pulmonary emboli, particularly if they are extensive.20 Daptomycin may be used in the setting of MRSA bacteremia and endocarditis when the vancomycin MIC is $2 µg/ml because of the high incidence of therapeutic failure in these cases.8,20 Daptomycin may be considered as an option for empiric therapy in S. aureus bacteremia awaiting susceptibility testing in settings where the prevalence of S. aureus isolates with a MIC of $2 µg/ml is high.8,9,20 Also, because of the high rate of cross-resistance between glycopeptides like vancomycin and daptomycin, previous exposure to vancomycin may result in increased daptomycin MIC even without exposure to the drug and a higher dose of daptomycin (10 mg/kg daily) can be used to overcome this effect.8,9,20 An ongoing clinical trial compares daptomycin at 10 mg/kg daily with vancomycin dosed to achieve levels of 15–20 µg/ml for the treatment of MRSA bacteremia (clinical trials.gov NCT00695903). Initial in vitro synergy studies were promising, but in vivo models did not confirm synergy between daptomycin and rifampin or gentamicin.42 A clinical trial is currently underway to evaluate the role of initial combination treatment with and without gentamicin in the treatment of S. aureus infective endocarditis (clinical trials.gov NCT00638157). Due to once-daily administration, daptomycin is an attractive option for the treatment of Gram-positive infections in the outpatient setting. In a survey of the agents used for the outpatient treatment of Grampositive infections in the United States, vancomycin Clinical Medicine Insights: Therapeutics 2011:3
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was the most commonly used antimicrobial (70%) followed by daptomycin (27%).43 Among 949 daptomycin-treated patients registered with the CORE database, clinical success rates were higher (94.6%) for the outpatient parenteral antimicrobial therapy (OPAT) group versus 86.3% for the inpatient group.44 In addition, in the endocarditis trial, clinical success rates were also high among patients who received daptomycin as outpatients (90% vs. 83% for standard therapy).43 Better outcomes among OPAT patients were most likely because of patient selection for OPAT and thus additional studies should focus on clinical characteristics of patients who would be ideal candidates for daptomycin OPAT. Enterococcus bacteremia The use of daptomycin in the treatment of vancomycin-resistant enterococcal (VRE) bacteremia has only been evaluated in retrospective case series. Although daptomycin has not been approved for the treatment of vancomycin-resistant enterococcal bacteremia, available data suggest that it may be as effective as linezolid.20 A Phase III study comparing daptomycin with linezolid for the treatment of VRE bacteremia was terminated because of difficulty enrolling patients.15 In a recent retrospective study of 30 patients with bacteremia due to VRE who received a median daptomycin dose of 6 mg/kg microbiological cure rate was 80%, while clinical success was observed in 17 patients (59%).45 In a retrospective study in 98 adult patients, 68 of whom received linezolid and 30 of whom received daptomycin, daptomycin and linezolid were found to be equivalent in efficacy, although there was a nonsignificant trend towards a longer duration of bacteremia (3 vs. 2 days) and a higher mortality rate (26.7% vs. 20.6%) with daptomycin.46 Success rate was observed in 87% among the subset of patients with enterococcal bacteremia from the CORE registry, excluding those with endocarditis.47 In this study, a total of 159 patients with enterococcal bacteremia, were treated with daptomycin either as first-line therapy (17%) or after prior treatment with other antibiotic agents.47 The overall clinical success rate was 87%, with similar rates between patients infected with E. faecium (87%) and those infected with E. faecalis (90%).47 In a retrospective study of nine patients with bacteremia without endocarditis Clinical Medicine Insights: Therapeutics 2011:3
due to VRE, five achieved successful resolution of infection after treatment with daptomycin at 4–6 mg/kg while treatment was not successful in the remaining four patients who received 6 mg/kg daptomycin (three received concomitant aminoglycosides). All four of these patients died, but they all had other serious co-morbidities.48 Successful treatment of Enterococcus bacteremia with daptomycin has also been described in case reports.49,50 Effective treatment with daptomycin combination therapy in patients with bacteremia has also been reported.8,51 Several reports have focused on the use of daptomycin for the treatment of enterococcal bacteremia in neutropenic patients. In a study of 34 allogeneic haematopoietic stem cell recipients, who developed bloodstream infections, 14 (41%) were due to VRE.52 Ten of these patients received daptomycin, three of whom were reported as microbiological failures; however, the infecting strains remained susceptible to daptomycin in vitro in all three cases.52 This observation, coupled with the fact that all 10 patients treated with daptomycin had also received linezolid or other antibiotics, highlights the inherent difficulty in interpreting microbiological outcomes.52 In addition, the clinical picture was complicated by the presence of underlying conditions in these patients and the absence of a comparator group.52 In an open-label trial four out of nine (44%) febrile neutropenic patients with bacteremia due to VRE who were treated with daptomycin achieved clinical and/or microbiological cure; two patients died within 3 days of commencement of treatment, indicating the severity of their illnesses.53,54 In a retrospective study of neutropenic cancer patients, 10 of whom received linezolid and 21 of whom received daptomycin, daptomycin and linezolid were found to be equivalent in efficacy in terms of clearance of blood cultures, relapse of infection and overall mortality.28 More recently, treatment failure was observed in 13 of 31 bacteremic patients treated with daptomycin, 6 of which were due to relapses within 1 month of initiation of initial infection.55 The Infectious Diseases Society of America 2009 guidelines recommend the use of daptomycin for the treatment of catheter-related bacteremia due to VRE or ampicillin-resistant enterococci in patients with or without dialysis.1 However, no prospective trials are likely to define the role of daptomycin in this setting, because of the complicated 407
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clinical presentation and the presence of multiple co-morbidities in patients who develop enterococcal bacteremia. Staphylococcus coagulase negative (CNS) bacteremia In one study of CNS bacteremia, all strains were susceptible to daptomycin with a low level MIC and therefore the loss of vancomycin susceptibility did not influence daptomycin susceptibility.56 These results showed a high efficacy of daptomycin for CNS, and this antibiotic could be useful for the treatment of primary bacteremia or catheter associated bacteremia in severe ill patients, while in patients with high risk to develop pneumonia linezolid should be used instead.56 Enterococcus endocarditis In an analysis of the CORE database, clinical success was reported in 10 of 14 patients with Enterococcus endocarditis [9 with left-sided endocarditis (LIE) and 1 with right-sided endocarditis RIE], and 2 patients failed daptomycin therapy (1 with LIE and 1 with RIE). Outcomes were not evaluable for the remaining two patients.21 Case reports of daptomycin for endocarditis caused by Enterococcus spp. have yielded various outcomes, including death in some cases. Successful combination treatment with high-dose daptomycin (8 mg/kg every 24 h), gentamicin and ampicillin in a patient with LIE caused by a strain of E. faecium has been reported.57 In a separate case of endocarditis due to a strain of linezolid-resistant VRE the patient was successfully treated with high-dose daptomycin (started at 6 mg/kg every 24 h and subsequently increased to 8 mg/kg every 24 h) in combination with rifampicin, gentamicin and tigecycline.58 It should be noted, that all patients in these cases of Enterococcus endocarditis had significant underlying co-morbidities, with the majority failing prior antibiotic treatment. Daptomycin was usually given in combination with other antibiotics with no standardization as to concomitant treatment, and it was unclear whether cases of mortality were attributable to endocarditis or the underlying co-morbidity. Despite this evidence, more clinical data are needed to define the role of daptomycin (alone or in combination) therapy in enterococcal endocarditis. 408
Orthopedic infections
With regard to osteomyelitis and joint infections, Gram positive cocci largely predominate over other microbial pathogens and S. aureus, MSSA and MRSA, as well as coagulase-negative Staphylococci account for over 50% of recovered pathogens.9 Unfortunately, fewer data are available for the use of daptomycin in the treatment of osteomyelitis, and prospective trials are lacking. Animal studies support efficacy in orthopaedic infections; both daptomycin and vancomycin achieved 100-fold reductions in bacterial load over 21 days, in a rat osteomyelitis model. Nevertheless, neither regimen reliably eradicated infection.59 At present, there are in vitro studies showing that daptomycin has activity against slow-growing bacteria in stratified biofilms, as on a contaminated prosthetic device.60,61 However, there is a lack of published bone penetration or activity studies, more data is needed, because the compound’s activity is affected by the calcium ion concentration.62 In 67 evaluable patients with osteomyelitis from the CORE 2004 database with a median of 76 days of follow-up, clinical outcomes were reported as cure in 63%, improvement in 19% and failure in 10%.22 Success rates were high (82%) among patients with an orthopedic device and in patients with concurrent bacteremia.22 A caveat was that many patients underwent further surgery, with joint removal or debridement, which may have influenced outcome. Failures were more common if debridement was not performed.22 The median dose of daptomycin in patients with osteomyelitis was 5.6 mg/kg, and it was given for a median duration of 35 days but when a dose . 6 mg/kg was used, the success rate was significantly higher (88 vs. 63%).22 The most common organism was MRSA.22 In another report from the same database, among 22 patients with septic arthritis without osteomyelitis, 41% were cured and 50% improved.63 The median dose was 5 mg/kg and the median duration of therapy was 22 days.63 Almost two-thirds of patients received another antibiotic in addition to daptomycin, with rifampin being the most common. The effectiveness of daptomycin in the treatment of prosthetic hip or knee joint infections is the subject of an ongoing clinical trial (clinical trials.gov NCT00428844). In addition, in a case series of 31 patients with orthopedic infections,64 16 of whom had osteomyelitis, 87% were cured. In another series, all 10 patients with Clinical Medicine Insights: Therapeutics 2011:3
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o rthopedic infections were treated successfully.65 In two retrospective studies, 22 patients with osteomyelitis and three subjects with septic joint infections were treated with daptomycin.65 MRSA was the predominant pathogen in over 75% of patients. Daptomycin was used as salvage therapy, and its usual dose was 6 mg/kg/day. Clinical success rate was about 90%; follow up periods were one year or less. Daptomycin has been used for the treatment of prosthetic joint infections in many cases.65–67 These studies included patients with implant-related infection usually caused by multidrug-resistant organisms such as MRSA or VRE and showed good activity in the treatment of infection, with percentage improvements of 60%–90% at the end of therapy.65–69 However, some reports include patients treated with doses of 6 mg/kg, which are probably low for these infections. In fact, in vivo experimental studies suggest that higher dosages are needed in such cases.17 Owing to its thermostability, daptomycin can be incorporated into polymethylacrylate beads, where it shows similar release kinetics to vancomycin.70 Such beads, containing daptomycin 7.5% by weight, gave local bone concentrations of up to 178 mg/g in a rat osteomyelitis model and maintained levels above 10 mg/g for over 10 days.59 Daptomycin-containing beads have yet to be used in human orthopaedic infections, but their successful use was reported in four patients with lower-limb prosthetic vascular graft infections; vancomycin- and tobramycin-containing beads were used in other patients, but numbers were too small for meaningful comparison.71 Bone and joint infections surely warrant wider investigation, given both their numbers and associated morbidity.30
Pneumonia and lower respiratory tract infections
The currently available experimental and clinical data for mice72,73 and humans74 suggest that daptomycin has little efficacy against Gram-positive bacterial infections of the lung, possibly due to interactions of the compound with pulmonary surfactant components, and is therefore currently not recommended for use for the monotherapy of pneumonia.72
Other infections
A small number of publications documenting the use of daptomycin for the treatment of other infections Clinical Medicine Insights: Therapeutics 2011:3
have appeared recently in the literature. Lower urinary tract infections (UTIs), is a potential area of interest because ∼50% of the daptomycin dose is excreted as unchanged drug in urine over 24 h following intravenous administration.75 One open-label, single-blinded study compared daptomycin and ciprofloxacin for the treatment of adults with complicated UTIs caused by Gram-positive pathogens, the microbiological eradication rate was 81.8% for daptomycin and 78.3% for ciprofloxacin.76 In a separate report, in all five hospitalized patients with UTIs due to multidrug-resistant VRE who were treated with daptomycin for 5 days, urine cultures 2 days after completion of therapy were negative, and follow-up 10–14 days after therapy revealed no recurrence of bacteriuria.77 Daptomycin has also been used successfully in two patients receiving peritoneal dialysis for endstage renal disease who developed peritonitis due to VRE.78 A separate case report also showed that intraperitoneal daptomycin (15 mg/kg once weekly) was successful in the treatment of continuous ambulatory peritoneal dialysis-related peritonitis due to vancomycin-resistant E. faecium.79 Successful treatment of external ventricular drain-associated ventriculitis caused by E. faecalis with intraventricular daptomycin has also been reported.80
Efficacy of High Dose Daptomycin
The current literature on a high-dose daptomycin treatment strategy suggests safety and tolerability, even when given for extended durations, along with improved in vitro efficacy.81 However, evidence in support of improved in vivo efficacy from randomised, prospective clinical trials in large populations is still lacking, but necessary. With the optimum dose of daptomycin still unknown, perhaps the most appropriate situations to utilise highdose daptomycin are in difficult-to-treat infections such as endocarditis.82 A high dose regimen of daptomycin was studied in a prospective, multicentre, randomised, active-controlled study involving 100 patients.33 This study evaluated the efficacy and safety of daptomycin at 10 mg/kg/q24 h for 4 days compared with vancomycin 1 g i.v. every 12 h for up to 14 days. Despite a lack of statistical significance, lack of statistical power to detect difference between treatment groups, unblinded study investigators and imbalanced frequency of adjunctive surgical 409
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procedures this study raises efficacy concerns for a high dose daptomycin treatment regimen because of lower clinical success rates.33 The efficacy of daptomycin $ 8 mg/kg was also evaluated from data collected as part of the Cubicin® Outcomes Registry and Experience (CORE) database.83 Clinical success (clinical cure or improvement) was achieved in 66 (89%) of 74 patients. Notably, a significantly lower clinical success rate (8/12; 67%) was reported with endocarditis when judged against the other infections (P = 0.006). Comparatively, a positive clinical response occurred in 20 (91%) of 22 bacteremias and 15 (88%) of 17 SSSIs. The median duration of highdose daptomycin therapy in the patients analysed was 15 days (range 1–90 days). Limitations of this study include its retrospective, uncontrolled, nonrandomised, unblinded design. Also, there may have been a falsely elevated clinical success rate because patients’ follow-up data had not been collected; therefore the potential for relapse exists. Furthermore, microbiological cure had not been assessed as cultures were not required at the end of therapy. However, based on the study outcomes, daptomycin doses of $8 mg/kg were efficacious and welltolerated even when given over an extended period. In another retrospective study in patients with staphylococcal infections, 16 (73%) of 22 patients had documented clinical success compared with 29 (94%) of 31 patients in the high-dose (.6 mg/kg/ day) treatment group (P = 0.05).84 Microbiological success was achieved in 13 (68%) of 19 patients in the standard-dose group and in 27 (93%) of 29 patients in the high-dose treatment group (P , 0.05). Finally, although daptomycin is not approved for the treatment of enterococcal bacteremia, there is growing evidence from clinical practice that doses higher than the currently approved dose (eg, 8–12 mg/kg once a day) may be required for optimal treatment of complicated enterococcal infections.53,54,85
Safety of High Dose Daptomycin
Prior to optimization of the dosing interval to a oncedaily regimen, daptomycin had been associated with reversible CPK elevation and skeletal muscle toxicity.86 However, in clinical trials with once-daily dosing, daptomycin-associated CPK elevations were demonstrated in 7% of patients receiving the 6 mg/kg
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dose, only leading to discontinuation of daptomycin in 2.5% of patients, and did not occur in patients receiving the 4 mg/kg dose.23 In agreement with these clinical trial findings, analysis of the EU-CORE database has shown that daptomycin therapy minimally impacts upon serum CPK concentrations as reflected in the low rates of related adverse effects and discontinuations.18 A single-center, randomised, double-blinded, placebo-controlled phase 1 study involving 36 healthy volunteers, demonstrated the safety and tolerability of high-dose daptomycin in doses up to 12 mg/kg in healthy study participants over a 2-week period and provided support for further investigation of high-dose daptomycin especially in infections that are difficult to treat. The safety of a high dose regimen of daptomycin (10 mg/kg/q24 h for 4 days compared with vancomycin 1 g i.v. every 12 h for up to 14 days) was also studied in a prospective, multicentre, randomised, active-controlled study involving 100 patients.33 Importantly, none of the adverse effects that patients in the daptomycin treatment arm experienced were deemed as serious and thus this study adds to the increasing evidence of the safety and tolerability of high-dose daptomycin as no serious adverse events were observed.33 In a Phase III trial of daptomycin for the treatment of complicated skin and skin-structure infections (cSSIs), adverse effects were comparable in both groups.9 The most common side effects were gastrointestinal disturbances, headache and injection-site reactions. Daptomycin has been shown to interact with thromboplastin reagents and cause a falsely elevated International Normalized Ratio, without clinical significance.87 In a retrospective chart review of patients treated with high-dose daptomycin (.6 mg/kg/ dose) $14 days, 22 (36.1%) of 61 patients experienced mild adverse events (eg, diarrhea, nausea and arthralgia) that did not require daptomycin to be discontinued.54 In the 47 patients who had any CPK analysis, a significant CPK elevation was observed in 3 patients (6.4%). The investigators concluded that high-dose daptomycin at a mean of 8 mg/kg/dose for a median duration of 25 days was well tolerated and that the incidence of significant serum CPK elevation was similar to those previously reported when shorter courses of treatment and/or lower doses of daptomycin were utilised.54
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Daptomycin in the treatment of gram-positive pathogens
The safety of daptomycin $ 8 mg/kg was also e valuated from data collected as part of the Cubicin® Outcomes Registry and Experience (CORE) database.83 One adverse event or abnormal laboratory result was reported in 28 (30%) of 94 patients, of which 6 (6.4%) of 94 patients had adverse events assessed as possibly related to treatment with daptomycin. Amongst the six patients who had possible daptomycin-related adverse events, three experienced CPK elevations. All CPK increases were assessed and deemed as non-serious.83 In another retrospective study in patients with staphylococcal infections, comparing patients in the high-dose (.6 mg/kg/day) treatment group84 versus patients in the standard-dose group, CPK was elevated in one patient (3.2%) treated with high-dose daptomycin to .1000 U/L demonstrating the safety and possible increased efficacy with high-dose daptomycin compared with standard-dose daptomycin.84 Case reports provide further evidence in support of clinical benefit without increased toxicities when utilising a high-dose daptomycin treatment strategy.58,88–91 It is, however, important to keep in mind that the dosing interval in patients with severe renal impairment (CLCR , 30 mL/min) with or without dialysis should be adjusted to 48 h for both approved doses.18 Concomitant administration of other antibiotic agents with daptomycin such aminoglycosides is common. Although aminoglycosides are typically associated with nephrotoxicity, the rate of renal toxicity with daptomycin combination regimens was very low (1%) overall and similar to that observed for daptomycin monotherapy (0.8%).18,23 In animal models, daptomycin has been shown to attenuate the nephrotoxicity induced by the administration of gentamicin leading to postulation that daptomycin may in fact have nephron-protective properties.92 There are relatively few treatment options available for resistant Gram-positive infections that can be used for long treatment durations without an increased risk of adverse effects; eg, myelosuppression and peripheral neuropathy have been related to treatment duration with linezolid.18 Daptomycin might, therefore, represent a useful option for the treatment of chronic complicated infections where extended duration of therapy is required, such as osteoarticular or endovascular infections.
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In conclusion, toxicity is uncommon with d aptomycin use. However, the incidence of muscular toxicity may increase in patients on HMG-CoA reductase inhibitors, in patients with renal failure, and in severely ill patients. Therefore, it is reasonable to discontinue these medications while a patient is receiving daptomycin and to monitor more closely for side effects in patients with renal failure and patients in critical condition.
Conclusion
Daptomycin is an antibacterial agent with activity against Gram-positive organisms and a role in the treatment of invasive Gram-positive infections when suboptimal response to vancomycin is expected. Daptomycin has been approved for the treatment of complicated skin and skin-structure infections and bacteremia including right-sided endocarditis. Little experience is available on the treatment of bone and joint infections, although initial data are encouraging. Daptomycin has rapid bactericidal activity that is associated with its unique mechanism of action on the cell membrane. It has favorable pharmacokinetic properties allowing oncedaily dosing. Toxicity is rare with currently recommended dosing. With the rising antimicrobial resistance in Gram-positive infections, the use of daptomycin is expected to increase in the following years. However, as a consequence of its increased use, daptomycin resistance may emerge as a significant problem. The current data suggest that daptomycin has a relevant role in the therapeutic armamentarium of physicians for the treatment of Gram-positive infections.
Disclosures
Author(s) have provided signed confirmations to the publisher of their compliance with all applicable legal and ethical obligations in respect to declaration of conflicts of interest, funding, authorship and contributorship, and compliance with ethical requirements in respect to treatment of human and animal test subjects. If this article contains identifiable human subject(s) author(s) were required to supply signed patient consent prior to publication. Author(s) have confirmed that the published article is unique and not under consideration nor published by any other publication and that they have consent to reproduce any copyrighted material. The peer reviewers declared no conflicts of interest.
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References
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