Abstract

The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide tolerance in S. aureus has underlined the importance of the newer anti-MRSA agents, particularly in the management of complicated skin and soft tissue infections (cSSTIs). The novel cyclic lipopeptide antibiotic daptomycin shows marked in vitro cidality against MRSA compared with both vancomycin and linezolid. Although comparative studies in cSSTIs have demonstrated non-inferiority with vancomycin and semi-synthetic penicillins, data from both clinical trials and observational studies suggest in vivo cidality as evidenced by rapid resolution of clinical signs of local inflammation and reduced duration of therapy. Overall success in SSTI post-marketing studies is >90%, and >88% in MRSA-infected patients, with no difference in the outcome observed between those with complicated versus uncomplicated infections. When used at licensed doses (4–6 mg/kg), daptomycin is safe and effective in SSTIs with significant muscle toxicity occurring in only 0.4% to 2.5% of patients. Clinical failure in daptomycin-treated SSTIs is associated with severity of infection (creatinine clearance <30 mL/min, intensive care unit stay and sepsis syndrome). Higher dosing at 6 mg/kg (with increased dosing interval in renal failure) should be considered in such patients as well as those at risk of bacteraemia, osteomyelitis, diabetic foot infection and in situations where there is more rapid drug clearance, such as infections complicating intravenous drug use and thermal burns. Once-daily dosing allows ease of use in both hospital and outpatient settings and may facilitate early discharge or avoided admission in some patient groups with SSTIs. Clinical experience to date suggests potential economic advantages associated with earlier hospital discharge and shorter duration of therapy, although further detailed cost-effectiveness comparisons are required to validate these observations in different healthcare settings.

Introduction

Skin and soft tissue infections (SSTIs) comprise a diverse group of anatomically and aetiologically distinct infections ranging from minor, superficial infections (such as impetigo) through severe post-operative wound infections, cellulitis and erysipelas, to life-threatening necrotizing fasciitis. SSTIs are common, contributing to ∼3% to 4% of acute hospital admissions and comprising 16% of all intravenous (iv) antibiotic-treated patients in Scottish hospitals.1 The Department of Health for England statistics for 2005–06 reported 180 435 episodes of soft tissue disorders (M60–M79), with 39% (∼70 370) admitted as emergencies and likely to represent SSTIs.2 Patients with SSTIs present variably from the community and within hospitals, and the anatomical site, severity, associated co-morbidity and need for surgical intervention will likewise vary. Given the diversity of presentations, a number of different clinical teams, including a variety of hospital and community-based specialists, are involved in delivering care to this patient group.

Irrespective of site or severity, SSTIs are predominantly caused by aerobic Gram-positive cocci, in particular the β-haemolytic streptococci (notably Streptococcus pyogenes) and Staphylococcus aureus.3 In hospitals, S. aureus dominates as a cause of surgical site infection4,5 with almost half the countries (n = 15) included in the European Antimicrobial Resistance Surveillance System (EARSS) database reporting rates of methicillin resistance in excess of 25% [Romania having rates of methicillin-resistant S. aureus (MRSA) >50% in many of its hospitals].6 Healthcare-associated MRSA SSTIs are being increasingly recognized in hospitalized patients as well as in patients presenting from the community or from long-term care facilities. Such patients will usually have an identifiable risk history including prior hospitalization, prior MRSA carriage (or infection),7 history of antibiotic use8 or other MRSA-associated chronic medical conditions such as diabetes mellitus, renal disease, vascular disease or decubitus ulcer.9,10 In addition, community-associated MRSA (CA-MRSA), characterized by Panton–Valentine toxin production and lack of healthcare-associated risk factors, is now recognized as an important cause of a broad range of SSTIs from simple abscesses to necrotizing infections in a number of different patient populations in North America and Europe.11 These include healthy young adults, contact sports teams and men who have sex with men.12–14 Although CA-MRSA has been recognized worldwide, its role and extent in community-acquired SSTIs in Europe are not yet well defined.

Management of complicated or serious SSTIs

For the purposes of clinical trials or surveillance studies, complicated SSTIs (cSSTIs) are usually defined as those that may require surgical debridement or drainage. Generally, this group incorporates wound infections, extensive or progressive cellulitis, deep abscesses and infected ulcers (including those that are diabetes-related). In the majority, there is associated heat or erythema or induration and pain, which may be rapidly evolving or have progressed despite oral antibiotic therapy. A systemic inflammatory response characterized by at least two of fever (or hypothermia), tachycardia, tachypnoea and leucocytosis (or leucopenia)15 may reflect associated bacteraemia, but is frequently absent in uncomplicated SSTIs (uSSTIs). The vast majority of patients hospitalized with SSTIs require iv antibiotic therapy targeted against aerobic Gram-positive cocci with Gram-negative and anaerobic therapy added for human or animal bites, surgical site infections following intestinal or genital tract surgery and for necrotizing infections.16,17 Adjunctive measures that are not considered further in this review include fluid resuscitation, surgical debridement and judicious use of normal human immunoglobulin (in suspected streptococcal toxic shock syndrome).18

Antibiotic choices for cSSTIs vary between specialties and institutions, reflecting differing patient populations, anatomical sites, MRSA risks and local policies. Published guidance is deliberately non-prescriptive with respect to antibiotic choice, in part reflecting these complexities but also because SSTI clinical trials typically exclude the most severely unwell patients and are powered to only show non-inferiority between agents.16,17 Current UK MRSA management guidance does not specify a particular agent for MRSA SSTIs, but indicates that when local methicillin resistance in S. aureus exceeds 10% in hospitals, then empirical antistaphylococcal therapy should incorporate activity against MRSA.19 In contrast to North America, in suspected staphylococcal SSTIs arising from the community in the UK, the risk of CA-MRSA is at the present time low, and empirical anti-MRSA therapy is not advocated except in severe, rapidly progressive infections where CA-MRSA or hospital-associated MRSA cannot be excluded on epidemiological grounds.20

Increasing recognition of reduced susceptibility and inadequate clinical response of MRSA to glycopeptides21–23 and the emergence of glycopeptide-resistant MRSA,24 CA-MRSA and linezolid resistance in S. aureus,25 combined with awareness of linezolid mitochondrial and myelo-toxicity,24,26 have underlined the importance of developing newer anti-MRSA agents. Currently, European licensed agents with activity against MRSA include vancomycin, teicoplanin, tetracyclines, co-trimoxazole, pristinamycin, quinupristin/dalfopristin, linezolid, tigecycline and daptomycin. A number of compounds are also in the advanced stages of investigation/licensing approval for this indication, including dalbavancin, ceftobiprole, telavancin, oritavancin and iclaprim. The growing list of (nearly) available agents makes the future choice of agent for SSTI potentially complex.

Daptomycin, the first cyclic lipopeptide, received marketing approval for the treatment of cSSTIs in North America in 2003 and Europe in 2006. Since its approval, more than 400 000 patients with a variety of Gram-positive infections have received daptomycin.27 Published experience of daptomycin's utility in the management of SSTIs is reviewed here.

Pharmacology of daptomycin in relation to SSTIs

Daptomycin has a novel mode of action in Gram-positive organisms. Cell death is induced by calcium-dependent efflux of potassium following insertion of its lipophilic tail into the cell membrane.28 Pharmacological studies have indicated rapid, concentration-dependent bactericidal activity, irrespective of growth phase,29,30 against a broad range of Gram-positive organisms implicated in SSTIs, including haemolytic streptococcal and S. aureus species.31 Importantly, activity is maintained against resistant Gram-positive organisms including MRSA, glycopeptide- and linezolid-resistant S. aureus and vancomycin-resistant enterococcal species.31–33 Following a 30 min iv infusion at a dosage of 4 mg/kg, peak concentrations reach 57.8–77.5 mg/L.34,35 Protein binding is ∼90%; the volume of distribution is low (∼0.1 L/kg), suggesting mainly extracellular compartment concentration; and excretion is predominantly via the renal tract with a t1/2 of ∼8–9 h.34 A post-antibiotic effect of ∼2.5 h and a sub-MIC effect lasting from 3 to 12 h have also been observed.36 In combination with concentration-dependent killing, these are ideal characteristics for once-daily dosing.

Penetration into inflamed dermis has been investigated in healthy volunteers.35 Administered as a single dose of 4 mg/kg over 30 min, daptomycin yielded concentrations in blister fluid of 9.4 and 14.5 mg/L at 1 and 2 h, respectively, peaking at 3–4 h following iv administration. Peak blister fluid concentrations of 27.6 ± 9.5 mg/L compared with 77.5 ± 8.3 mg/L in serum, with overall penetration into blister fluid of 68.4% as measured by the ratio under the concentration–time curve over 24 h. The t1/2 in blister fluid was ∼17 h.35 Biofilm activity is of potential importance in medical device-related infections, particularly catheter-related infections, which may be complicated by soft tissue involvement. In vitro studies have demonstrated daptomycin to be significantly more effective than both linezolid and vancomycin in inhibiting and eradicating MRSA in biofilm.37

Pharmacological parameters are not significantly altered in the elderly and, therefore, no dose adjustment is required. When creatinine clearance is <30 mL/min, however, dosing interval—but not the administered dose—should be adjusted to 48 h.38 Similarly, in those receiving renal replacement therapy, dosing should follow dialysis as renal elimination is substantially reduced.39 Morbidly obese patients are particularly at risk of recurrent and severe SSTIs. In such patients, dosing should be based on actual total body weight rather than ideal weight, as the volume of distribution in such patients is increased.40 Intravenous drug users are also at risk of recurrent SSTIs. In early studies in drug users with bacteraemia and endocarditis, lower daptomycin Cmax and a larger volume of distribution were observed compared with healthy volunteers and as is seen with other antibiotics. These factors may be related to more rapid renal clearance in drug users, but the clinical significance is speculative.33 Currently, there are no recommendations for higher dosing in this group. However, as rates of bacteraemia are higher in intravenous drug users with SSTIs, it would be prudent to consider bacteraemia dosing at 6 mg/kg, especially when used empirically and in patients with associated sepsis syndrome. In patients with thermal burns of >18%, daptomycin pharmacokinetics are markedly altered with a 47% reduction in the AUC and an increase in the volume of distribution.41 Hence, it is predicted that higher dosing of daptomycin would be required in such patients with secondary skin infections.

Evaluation of daptomycin in comparative clinical studies

Daptomycin (at a dose of 4 mg/kg iv for 7–14 days) has been investigated in two international Phase III randomized, investigator-blinded, controlled clinical trials in comparison with vancomycin (1 g iv 12 hourly) or penicillinase-resistant penicillins (4–12 g/day iv).42 The pooled study populations comprised 1092 adult patients with cSSTIs enrolled from 139 study sites in the USA, Europe, Australia, South Africa and Israel between 1999 and 2001. Wound infection was the most common cSSTI, occurring in 44% of patients, while 24% had a major soft tissue abscess and 25% had infected ulcers. A systemic inflammatory response was present in 37%, and 32% were diabetic. More than 80% of those enrolled had a pathogenic microbial isolate, including methicillin-susceptible S. aureus (MSSA) in 52%, MRSA in 10% and S. pyogenes in 22%. Clinical success was determined at a test-of-cure visit and defined as the resolution of signs and symptoms such that no further antibiotics were required. Success in intention-to-treat, clinically evaluable and microbiologically evaluable populations were comparable (Table 1). No organism-specific difference was observed in response to treatment; however, lower success rates were seen in patients who had received vancomycin rather than penicillinase-resistant penicillins. In a subsequently published subset analysis of 133 patients with infected diabetic foot ulcers, there were no statistical differences in outcome in clinically evaluable patients who received daptomycin or comparator (66% versus 70%),43 although success rates were lower than in the overall study population (Table 1).42 Similar results were noted for microbiologically evaluable patients.

Table 1

Summary of outcomes, by study population, in patients with cSSTIs treated with either daptomycin or standard therapy (vancomycin or penicillinase-resistant penicillins)42

 Daptomycin
 
Comparator
 
Population no. of patients success rate (%) no. of patients success rate (%) 
Intent to treat 534 71.5 558 71.1 
Clinically evaluable 446 83.4 456 84.2 
Microbiologically evaluable 365 84.7 396 85.9 
Wound infection 169 84 180 87 
Major abscess 102 92 92 88 
Diabetic foot ulcer 47 66 56 70 
Non-diabetic ulcer 47 79 58 83 
 Daptomycin
 
Comparator
 
Population no. of patients success rate (%) no. of patients success rate (%) 
Intent to treat 534 71.5 558 71.1 
Clinically evaluable 446 83.4 456 84.2 
Microbiologically evaluable 365 84.7 396 85.9 
Wound infection 169 84 180 87 
Major abscess 102 92 92 88 
Diabetic foot ulcer 47 66 56 70 
Non-diabetic ulcer 47 79 58 83 

In the Arbeit study, the majority of the total study population (90%) received iv only therapy. In this group, 63% of the daptomycin-treated patients required only 4–7 days of therapy compared with 33% in the comparator group (P < 0.0001).42 Speed of resolution of clinical signs was further investigated in a homogenous subset of patients recruited from South African sites, which comprised 40% of the total study population.44 In this subset, there was earlier response in those patients treated with daptomycin compared with comparator agents with respect to skin induration and erythema at evaluation on day 3–4. In addition, daptomycin-treated patients required a shorter median duration of therapy than those treated with comparator agents (7 versus 8 days, P < 0.0001) even when including those patients who experienced treatment failure.44

In a subsequent open-label study of daptomycin in patients with prospectively evaluated cSSTIs at risk of MRSA, speed of resolution and clinical and economic outcomes were retrospectively compared with matched prospectively evaluated controls treated with vancomycin.45 Fifty-six daptomycin-treated patients were matched by age, APACHE II, Charlson score and infection type to 212 vancomycin-treated patients. In all patients, there was complete resolution of cSSSI; however, median day of clinical cure and duration of therapy were significantly reduced in the daptomycin-treated, compared with vancomycin-treated, patients. In addition, a higher proportion of patients had complete resolution of their infection when treated with daptomycin (77%), compared with vancomycin (42%); in these patients, duration of iv therapy was significantly reduced (4 versus 7 days) and resolution of signs was quicker.45 Results were similar for the subset of patients with CA-MRSA. An economic evaluation was performed, and although iv antistaphylococcal therapy was more expensive in daptomycin-treated patients, other hospital costs were reduced, including the cost of additional antimicrobials and oral step-down agents and antibiotic-related duration of stay (4 versus 8 days). Overall hospitalization costs in this study were significantly reduced in those treated with daptomycin (median $5027 versus $7816).45

Evaluation of daptomycin in non-comparative, post-marketing studies

The Cubicin Outcomes Registry and Experience (CORE) programme is a multicentre retrospective observational programme designed to collect data on patients receiving daptomycin in institutions from around the United States. Patients in clinical trials are excluded, so the data represent a sample of daptomycin use in real-life clinical practice in North America. The data should be interpreted carefully as patient outcome is assessed locally by the treating physicians at the end of treatment. This retrospective study, however, is strengthened by a standardized protocol and case report form that have been used to collect data since the daptomycin launch in November 2003.46

Data from CORE 2004 has been published in full for SSTIs47 and in part for CORE 2005.4850 Summary patient characteristics for both SSTI cohorts are shown in Table 2. In CORE 2004, 1160 patients received daptomycin including 577 (50%) treated for SSTIs, of whom 522 were evaluable.47 In CORE 2005, 486 patients with SSTIs were observed.48 The two cohorts were similar except that a smaller proportion in CORE 2005 were observed with creatinine clearance <30 mL/min (Table 2). In the CORE 2004 cohort, 41% had a healthcare setting onset of infection, with 27% overall having surgical site infection. More than 50% of patients with a positive isolate in both cohorts were treated for MRSA infection and a high proportion had received prior antibiotic therapy (Table 2). Prior antibiotic therapy has been further categorized in the CORE 2005 cohort. Thirty-six percent received prior vancomycin, of whom 32% had documented vancomycin-treatment failure.50 Overall, patients received a median dose of 4 mg/kg daptomycin, but higher mean dose and increased duration of therapy were observed in patients with cSSTIs compared with those with uSSTIs (Table 3). A high proportion of patients received concomitant antibiotic therapy (Table 3). In CORE 2004, this was most frequently with a fluoroquinolone (20%) or cephalosporin (18%).47 Overall clinical success was judged by local investigators and defined as ‘cured’ where no further antibiotic therapy was required or ‘improved’ where there was clinical improvement but further therapy was required following daptomycin.46 Overall success was >90% and in the subgroups of microbiologically evaluable patients with S. aureus infection (including a high proportion of MRSA infection in both cohorts) success rates were similarly high,49 comparing favourably with other published studies (Table 4).42,45 A small number (n = 10) in CORE 2004 were treated for necrotizing soft tissue infections, but successful treatment outcome was noted in nine (90%) patients.47

Table 2

Characteristics of patients with SSTIs in CORE 200447 and 200548,50

Characteristic CORE 2004 (n = 522) % CORE 2005 (n = 486) % 
Age >66 years 24 21 
Diabetes 27 30 
Malignancy 10 
Creatinine clearance <30 mL/min 26 12 
Prior antibiotic therapy 67 74 
Prior vancomycin not reported 49 
cSSTIs 64 70 
Surgical site infection 27 39 
Bacteraemia 
Healthcare setting onset of infection 41 42 
MRSA infectiona 63 52 
Characteristic CORE 2004 (n = 522) % CORE 2005 (n = 486) % 
Age >66 years 24 21 
Diabetes 27 30 
Malignancy 10 
Creatinine clearance <30 mL/min 26 12 
Prior antibiotic therapy 67 74 
Prior vancomycin not reported 49 
cSSTIs 64 70 
Surgical site infection 27 39 
Bacteraemia 
Healthcare setting onset of infection 41 42 
MRSA infectiona 63 52 

aMRSA infection; expressed as a percentage of all positive isolates.

Table 3

Treatment characteristics and outcomes of patients treated with daptomycin for SSTIs in CORE 200447 and 200548

 CORE 2004
 
CORE 2005
 
Treatment cSSTIs (n = 334) uSSTIs (n = 188) cSSTIs (n = 333) uSSTIs (n = 145) 
Mean dose, mg/kg (range) 4.5 (2.3–12) 4.2 (2.1–9) 4.7 (2–10) 4.4 (2.4–8.7) 
Median duration of therapy (days) 14 10 13 10 
Concomitant therapy (%) 45 36 36a  
Clinical success (%) 96 98 93 97 
 CORE 2004
 
CORE 2005
 
Treatment cSSTIs (n = 334) uSSTIs (n = 188) cSSTIs (n = 333) uSSTIs (n = 145) 
Mean dose, mg/kg (range) 4.5 (2.3–12) 4.2 (2.1–9) 4.7 (2–10) 4.4 (2.4–8.7) 
Median duration of therapy (days) 14 10 13 10 
Concomitant therapy (%) 45 36 36a  
Clinical success (%) 96 98 93 97 

aConcomitant therapy in total (cSSTIs and uSSTIs) population.

Table 4

Published outcomes in daptomycin-treated patients with SSTIs caused by S. aureus

Study Type of study Prior antibiotic therapy MSSA success MRSA success 
Arbeit et al.42 randomized controlled NA 170 (85.9%) 21 (75%) 
CORE 200447 retrospective 67% 30 (96.8%) 205 (97.6%) 
CORE 200549 retrospective 72% 36 (83.7%) 109 (88.9%) 
Davis et al.45 retrospective 25% 22 (100%) 22 (100%) 
Study Type of study Prior antibiotic therapy MSSA success MRSA success 
Arbeit et al.42 randomized controlled NA 170 (85.9%) 21 (75%) 
CORE 200447 retrospective 67% 30 (96.8%) 205 (97.6%) 
CORE 200549 retrospective 72% 36 (83.7%) 109 (88.9%) 
Davis et al.45 retrospective 25% 22 (100%) 22 (100%) 

Within the CORE 2005 cohort, a number of clinical variables were investigated to determine predictors of clinical failure.50 A multivariate analysis revealed sepsis, intensive care unit (ICU) stay and creatinine clearance <30 mL/min to be significantly associated with clinical failure (Table 5).50 Such markers are consistent with severe infection and therefore more likely to predict treatment failure in this patient group irrespective of the agent used. Notably, patients with diabetes were not at greater risk of treatment failure in this analysis. Uncertainty of dosing regimens, or under-dosing in particular, may partly explain the 5-fold increased risk of treatment failure with renal failure, and it is noteworthy that a smaller proportion of patients in CORE 2005 compared with CORE 2004 received daptomycin in these circumstances. Reports of reduced daptomycin susceptibility in isolates exposed to vancomycin51 have led to debate over the utility of daptomycin in glycopeptide treatment failure.52 Prior vancomycin usage was included within the CORE 2005 multivariate analysis and was not found to be associated with daptomycin clinical failure.50

Table 5

Clinical factors associated with clinical failure in a multivariate model in CORE 200550

Variable OR (95% CI) P value 
Sepsis 4.7 (1.3–17.4) 0.02 
≥2 underlying diseases 4.4 (0.9–21.3) 0.07 
ICU stay 3.8 (1.2–10.2) 0.02 
Creatinine clearance <30 mL/min 4.9 (1.8–13.5) 0.002 
Variable OR (95% CI) P value 
Sepsis 4.7 (1.3–17.4) 0.02 
≥2 underlying diseases 4.4 (0.9–21.3) 0.07 
ICU stay 3.8 (1.2–10.2) 0.02 
Creatinine clearance <30 mL/min 4.9 (1.8–13.5) 0.002 

Infected diabetic foot ulcers are often associated with increased treatment failure compared with other patient groups. Daptomycin-treated patients with this complication have been further assessed in combined data from the CORE 2005 and 2006 cohorts.53 Within the cohort of 781 patients with SSTIs, 66 had diabetes-related cSSTIs and were evaluable, including 10 with concomitant osteomyelitis. Prior antibiotic therapy had been given to 71%, most frequently vancomycin (in 27%), and 38% switched to daptomycin due to treatment failure. Creatinine clearance was <30 mL/min in 26%, and 47% were infected with MRSA. Median dose of therapy with daptomycin was 4.7 mg/kg (without osteomyelitis) and 5.7 mg/kg (with osteomyelitis). Patients were treated for a median of 2 weeks and up to 56 days with an overall success (improvement or cure at the end of daptomycin therapy) rate of 91%. Success was independent of prior vancomycin therapy or treatment failure.53 In CORE 2004, a detailed assessment of this patient group was not presented; however, 40 (91%) patients were judged a success at the end of daptomycin therapy.47 Given that such patients are at risk of contiguous osteomyelitis, it would be sensible, until deep-seated infection has been excluded, to administer daptomycin at the higher 6 mg/kg dose.

Safety and tolerability

In the published cSSTI clinical trials, adverse events attributed to daptomycin were similar to those observed with comparator agents (18% versus 21%), the most common being constipation, nausea, injection site reaction, headache, diarrhoea, insomnia, rash and vomiting.42 Severe events were reported in 11% and 9%, respectively, with 2.8% in either study group required to discontinue therapy due to an adverse event. Skeletal muscle side effects occur less commonly and may manifest as an asymptomatic increase in creatinine phosphokinase (CPK), muscle pain, weakness, myositis or rarely rhabdomyolysis. Treatment-emergent elevation of CPK was observed in 11 (2.1%) patients receiving 4 mg/kg/day daptomycin compared with 8 (1.4%) receiving comparator agents.42 In these studies, only two (0.4%) patients receiving daptomycin had to discontinue the study drug due to significant increases in CPK, and in the one patient who was symptomatic, there was rapid resolution following discontinuation of the drug. When used at a dose of 6 mg/kg in the treatment of bacteraemia, significant increases in CPK have been observed in 6.7% of the patients with drug discontinuation necessary in only 2.5%.4,54 It is recommended that serum CPK is measured on a weekly basis irrespective of dosing regimen. Post-marketing surveillance has not revealed further unexpected adverse events. In CORE 2005, daptomycin was discontinued in 22 (5%). These included eight serious adverse events (not specified) possibly related to daptomycin in six (1.3%) patients. Adverse events resolved on average in 17 days (range 1–65 days).48 Doses of up to 12 mg/kg have been used in the treatment of cSSTIs, and to date no unexpected adverse events have been reported.47 Although not a true adverse event, it has recently been reported that daptomycin therapy may be associated with a spurious rise in the measured prothrombin time due to an interaction with test reagents.55 This is of particular relevance in patients receiving concomitant warfarin, or with sepsis-associated coagulopathy, and may lead prescribers to prematurely discontinue daptomycin or under-dose warfarin, or administer vitamin K or clotting factors unnecessarily.55,56 Under such circumstances, response to anticoagulation therapy should be interpreted carefully.

Dosing of daptomycin in SSTIs

Current licensed dosing for SSTI is 4 mg/kg in SSTIs42 and 6 mg/kg in bacteraemia.54 The optimal dosing of daptomycin, however, is not known, and higher dosing regimens (up to 12 mg/kg) have been used successfully and safely in the context of deep-seated infections.57 For the majority of patients with uSSTI, a 4 mg/kg dosing is appropriate, but higher dosing at 6 mg/kg should be considered in certain patient groups (Table 6), particularly where there is greatest risk of treatment failure. As previously discussed, this includes more severe infections characterized by sepsis syndrome or those managed in the ICU, including patients at risk of, or proven to have, bacteraemia.50 Higher dosing should also be considered for patients with cSSTIs and creatinine clearance <30 mL/min in whom outcome is less good, but the dosing interval should be increased to alternate days or post-dialysis, and renal function must be carefully monitored.

Table 6

Circumstances where daptomycin dose should be >4 mg/kg in patients with cSSTIs

Sepsis syndrome 
Rapidly progressive SSTIs including suspected necrotizing infection 
Suspected or confirmed bacteraemia 
Suspected or confirmed osteomyelitis 
Diabetic foot infection/infected ulcer 
SSTIs in intravenous drug user 
SSTIs complicating thermal burn injury 
Glycopeptide intermediate-resistant MRSA 
Consider in MRSA infection with prior glycopeptide failure 
Consider when cSSTIs and creatinine clearance <30 mL/mina 
Sepsis syndrome 
Rapidly progressive SSTIs including suspected necrotizing infection 
Suspected or confirmed bacteraemia 
Suspected or confirmed osteomyelitis 
Diabetic foot infection/infected ulcer 
SSTIs in intravenous drug user 
SSTIs complicating thermal burn injury 
Glycopeptide intermediate-resistant MRSA 
Consider in MRSA infection with prior glycopeptide failure 
Consider when cSSTIs and creatinine clearance <30 mL/mina 

aDosing interval should be increased to 48 hourly or post-dialysis.

In the cSSTI population, particularly the diabetic population with SSTIs complicating a foot ulcer, osteoarticular infections may be difficult to exclude during the acute phase of management.57 Since penetration into osteoarticular tissue will be reduced compared with skin and soft tissue penetration, it is important to consider dosing in patients with cSSTIs at risk of osteoarticular infection. In a subset of patients with diabetic foot ulcers treated with either daptomycin 4 mg/kg or standard therapy, clinical success was lower when compared with other diagnoses (Table 1) despite osteomyelitis having been excluded within the study.42,43 Follow-up was not adequate to detect or report subsequent diagnosis of osteoarticular infections in this population. There have been no randomized control trials of daptomycin to date in patients with osteoarticular infection specifically, although a subset of such patients was identified in a randomized comparison of daptomycin 6 mg/kg versus standard of care in a complicated S. aureus bacteraemia study.54 Within this study, numbers were small and the nature of osteoarticular infection was variable, but success was observed in 14 (67%) versus 6 (55%) in the daptomycin and standard-of-care treatment groups, respectively.58 Within CORE 2004, where dosing of daptomycin was at the discretion of local clinicians, 67 patients with osteomyelitis were identified. Clinical success was significantly higher in patients treated with >4 mg/kg daptomycin compared with ≤4 mg/kg (88% versus 65%, P = 0.013).59 Considering the limitations of these data, it is not possible to give definitive recommendations over dosing in cSSTIs with (suspected) concomitant osteoarticular infection; however, dosing at ≥6 mg/kg would currently be advisable.

Certain patient groups have altered daptomycin pharmacokinetics and have been incompletely studied, particularly intravenous drug users and patients with thermal burns. Given that such patients are particularly at risk of cSSTIs and associated bacteraemia, it is important to consider higher dosing until contrary evidence is presented.

Whether higher dosing of daptomycin should be used in patients with SSTIs and vancomycin failure is currently not known, but increased dosing should be considered when there is evidence of MRSA with intermediate glycopeptide resistance.51,52 At the present time, there is little evidence to support routine use of concomitant anti-Gram-positive agents in SSTIs, although in vitro and possible in vivo synergy has been observed with a number of different agents and may be of clinical benefit in deep-seated infections. As daptomycin has no Gram-negative coverage, a concomitant agent with an appropriate spectrum of activity should be considered if Gram-negative infection is suspected.

Utility of daptomycin in outpatient practice

Outpatient parenteral antibiotic therapy (OPAT) for SSTIs is a cost-effective management option in both publicly and privately funded health services when the appropriate guidance and expertise are available.60–62 Hospital admission may be either avoided entirely or duration of admission reduced. Suitable patients should be clinically stable, both with respect to the SSTIs and co-morbidity, and should have reliable access to transport and communication with the specialist service.60,61 Once-daily administration, proven clinical efficacy in cSSTIs, low and predictable toxicity profile and activity versus MRSA make daptomycin ideal for outpatient administration. In addition, bolus iv administration has recently been shown in healthy volunteers to have pharmacokinetics and a safety profile comparable to a 30 min infusion, which may further enhance its utility in the outpatient setting.63 In a recent review of daptomycin use in a community hospital in Ohio, 28% of the hospital-initiated patients, predominantly with cSSTIs, completed therapy without adverse effects as outpatients. Overall, there was 96% clinical success and early discharge was associated with hospital-charge savings of $102 340.64 In a single-centre report from the UK, 29 consecutive patients were treated with daptomycin, predominantly following glycopeptide failure or allergy over 12 months. Of these, 66% were treated at least in part in the outpatient setting, 38% treated entirely as outpatients, with more than half of those treated through OPAT trained to self-administer or to receive therapy through their carer.65 In CORE 2005, of a total of 949 patients receiving daptomycin, 56.8% received at least a portion of their care in the OPAT setting. Of note in the 435 patients with SSTIs is that 63% were treated at least partially through an OPAT service.66

Conclusions

SSTIs are a diverse and challenging group of infections, of which both healthcare-associated and community-acquired MRSA infections are of increasing importance. There are good comparative and observational data now to support the use of daptomycin in such infections. In particular, daptomycin may offer advantages in cSSTIs where in vivo cidality with more rapid resolution of clinical signs may be of critical importance (e.g. rapidly progressive SSTIs where MRSA is suspected or cannot be excluded). Based on current evidence, licensed dosing regimens of 4 mg/kg are appropriate for most SSTIs. However, higher dosing regimens should be considered in patients at risk of bacteraemia or osteomyelitis and those with increased risk of treatment failure (Table 6). As glycopeptide tolerance increases in MRSA, CA-MRSA becomes more prevalent, and as OPAT models of care develop, there will be a greater role for daptomycin in first-line therapy for serious infections, for facilitating early discharge and for avoiding hospital admission (Table 7). Further pharmacoeconomic analysis is required to assess and compare daptomycin's cost-effectiveness more completely not only with the glycopeptides, but also with other recently licensed anti-Gram-positive agents and with those in advanced development.

Table 7

When should daptomycin be used in SSTIs?

Second-line therapy: 
 following glycopeptide failure, allergy or intolerance 
First-line therapy: 
 in a patient with previous glycopeptide failure or intolerance or allergy 
 glycopeptide resistance (full or intermediate) 
Consider first-line: 
 rapidly progressive SSTIs with (suspected) MRSA SSTIs 
OPAT setting: 
 suspected MRSA SSTIs or SSTIs with β-lactam allergy, requiring iv therapy and suitable for ambulatory care 
Second-line therapy: 
 following glycopeptide failure, allergy or intolerance 
First-line therapy: 
 in a patient with previous glycopeptide failure or intolerance or allergy 
 glycopeptide resistance (full or intermediate) 
Consider first-line: 
 rapidly progressive SSTIs with (suspected) MRSA SSTIs 
OPAT setting: 
 suspected MRSA SSTIs or SSTIs with β-lactam allergy, requiring iv therapy and suitable for ambulatory care 

Funding

R. A. S. received an honorarium from Novartis for the production of this article. The editorial support of MSC Ltd was funded by Novartis.

Transparency declarations

This article is part of a Supplement sponsored by Novartis.

R. A. S. has participated in and received institutional funding for clinical studies on daptomycin, has served on advisory boards for Novartis and spoken at Novartis-sponsored educational symposia.

The editorial support of MSC Ltd in the research and preparation of this manuscript is acknowledged.

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