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Postmarketing Clinical Experience in Patients with Skin and Skin-Structure Infections Treated with Daptomycin
The American Journal of Medicine (2007) Vol 120 (10A), S6 –S12
Postmarketing Clinical Experience in Patients with Skin and Skin-Structure Infections Treated with Daptomycin Robert C. Owens, Jr., PharmD,a,b Kenneth C. Lamp, PharmD,c Lawrence V. Friedrich, PharmD,c and Rene Russo, PharmDc a
Maine Medical Center, Portland, Maine, USA; bDepartment of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA; and cCubist Pharmaceuticals, Inc., Lexington, Massachusetts, USA ABSTRACT A registry describing daptomycin’s clinical use was analyzed to describe treatment of skin and skinstructure infections (SSSIs). The Cubicin Outcomes Registry and Experience (CORE) 2004 retrospectively collected demographic, microbiologic, and clinical outcome information of patients treated with daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA). The database was accessed to identify patients with a diagnosis of an SSSI with an outcome determined. Of 577 patients identified with a SSSI, 522 (90%) were evaluable. Diabetes mellitus and peripheral vascular disease were present in 27% and 10% of the population, respectively. Pathogens were identified for 65% of all patients—Staphylococcus aureus (75%; 85% methicillin-resistant) and Enterococcus species (19%; 44% vancomycin-resistant) most commonly. Concomitant use of other antibiotics was common (42%). Of 522 patients studied, 334 (64%) had complicated infections (cSSSIs), and 188 (36%) had uncomplicated infections (uSSSIs). Overall cure, improved, and failure rates were 53%, 43%, and 4%, respectively, for cSSSI and 66%, 32%, and 2%, respectively, for uSSSI. The median dose administered was 4.0 mg/kg for cSSSI (mean, 4.5 ⫾ 1.0 mg/kg; range, 2.3 to 12 mg/kg) and 4.0 mg/kg for uSSSI (mean, 4.2 ⫾ 0.8 mg/kg; range, 2.1 to 9 mg/kg); the dose was significantly higher in cSSSI (P ⬍0.001, median test). Median daptomycin treatment duration was 12 days (range, 1 to 148 days) and was longer for cSSSI than for uSSSI (14 vs. 10 days, P ⫽ 0.002). The results of this study support previously published reports and suggest that daptomycin is effective for the treatment of skin infections due to gram-positive pathogens. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Daptomycin; Enterococcus; Methicillin-resistant Staphylococcus aureus; Skin and skin-structure infections; Staphylococcus aureus; Vancomycin-resistant enterococci
Skin and skin-structure infections (SSSIs) are commonly encountered in both community and hospital settings and are typically caused by gram-positive bacteria. SSSIs can be categorized as either complicated (cSSSI) or uncomplicated (uSSSI). The uSSSIs commonly seen by physicians include simple abscess, cellulitis, erysipelas, impetigo, folliculitis, This study was presented in part at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16 –19, 2005; Washington, District of Columbia. Please see the Author Disclosure section at the end of this article. Requests for reprints should be addressed to Kenneth C. Lamp, PharmD, Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, Massachusetts 02421. E-mail address: [email protected].
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2007.07.009
furunculosis, and carbunculosis. In otherwise healthy patients, these infections are usually managed empirically with antibiotics that have gram-positive coverage.1 In contrast, cSSSIs are typically defined as those that meet either or both of the following criteria: hospitalization is required, and infection is known or suspected to involve deep soft tissue, such as fascia or muscle.2 Examples of cSSSI include necrotizing skin infections, deep wounds, major abscesses, surgical site infections, and diabetic ulcers. cSSSIs also include those infections that occur in patients whose immune systems are compromised by diabetes mellitus, peripheral vascular disease, and other factors.2,3 Staphylococcus aureus is the organism most frequently isolated from both cSSSIs and uSSSIs; however, cSSSIs typically have a
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Daptomycin for Skin and Skin-Structure Infections
polymicrobial etiology.4 Immunocompromised patients, patients with previous antimicrobial exposure, and those with serious underlying comorbid conditions often have infections involving multidrug-resistant aerobic and anaerobic gram-positive and gram-negative bacteria.4 Among patients with an intact immune system, the pathogens most frequently isolated are S aureus, Streptococcus pyogenes (group A -hemolytic Streptococcus), and Streptococcus agalactiae (group B -hemolytic Streptococcus).4,5 The standard of care for SSSI is a combination of appropriate surgical intervention—such as debridement, incision, and drainage—and antimicrobial therapy.2,3 Antimicrobial resistance among gram-positive bacteria is a serious problem that continues to worsen. In particular, the emergence of methicillin-resistant S aureus (MRSA) in both hospital and community settings has become a clinical challenge for clinicians and patients and carries a significant economic burden.6 –9 Reports of vancomycin-intermediate S aureus and vancomycin-resistant S aureus have surfaced, and although these problems are not currently widespread, they have heightened the awareness of the emergence of multidrugresistant S aureus as well as treatment challenges.10 –12 Moreover, the recent recognition of community-associated MRSA as a major pathogen with potentially serious clinical consequences has further increased awareness of the importance of drug-resistant organisms. Furthermore, reports of resistance and clinical failures with newer antimicrobial agents, such as linezolid and quinupristin-dalfopristin, also are emerging.13–16 The trends suggest that more effective therapies as well as targeted anti– gram-positive treatment regimens are needed to combat pathogens causing SSSIs, including antimicrobial-resistant organisms.13–16 This clinical reality continues to drive the need for better infection control compliance, a search for effective vaccines, good antimicrobial stewardship (correct drug selection, dose, and duration), and the pursuit of new and effective treatment alternatives for the treatment of infections, including SSSIs. Daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) displays in vitro activity against most of the clinically relevant gram-positive bacteria implicated in SSSIs. Methicillin resistance in staphylococci and vancomycin resistance in enterococci do not appear to affect daptomycin’s in vitro activity.17–21 Daptomycin is further characterized as having a very low frequency of spontaneous development of resistance,22 and there has been no evidence of conjugation-mediated resistance. There have been isolated reports of reduced daptomycin susceptibility.23,24 However, in some cases, they involved extremely ill and complicated patients who may have benefited from adjunctive therapies including surgery. Daptomycin was approved by the US Food and Drug Administration (FDA) for management of cSSSI in 2003.23 Results of 2 randomized, investigator-blinded, multicenter, phase 3 clinical studies have shown that the efficacy of daptomycin (4 mg/kg every 24 hours) was similar to that of
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standard therapy (penicillinase-resistant penicillins or vancomycin) in the treatment of nearly 1,100 hospitalized patients with cSSSI.25 Combined data from the studies indicate that clinical success rates were similar between the 2 treatment groups for cases judged clinically evaluable (83.4% and 84.2%, respectively, for daptomycin and comparators). These findings extended to patients with infections due to MRSA (75.0% vs. 69.4%, respectively). Because little is known about the clinical experience with daptomycin since its FDA approval, the current study was undertaken to confirm the efficacy of daptomycin in practical clinical settings. The Cubicin Outcomes Registry and Experience (CORE) 2004 database was a multicenter, retrospective, chart review conducted to assess patient-specific characteristics and clinical outcome among patients receiving daptomycin. The CORE 2004 database was used in this analysis to describe clinical outcomes among patients with SSSIs treated with daptomycin in a real-world setting.
PATIENTS AND METHODS The methods for conducting the registry are described separately by Rolston and colleagues elsewhere in this supplement.26
Record Selection and Eligibility Criteria Daptomycin-treated patients with a diagnosis of SSSI and a reported clinical outcome (cure, improved, failure) were included in this analysis. Patients with osteomyelitis, orthopedic device infections, or other serious infections were excluded from the analysis. However, those patients with a concurrent diagnosis of non– catheter-related bacteremia were included. For the purposes of this study, the following infections were considered to be uSSSIs: uncomplicated cellulitis, simple abscess, erysipelas, furuncles, acne, and impetigo. For cSSSIs, the following were included: wound infection (traumatic, animal/human bite, septic phlebitis associated with catheter sites), major abscess, surgical site infections (sternotomy, dehiscence, surgical graft site), diabetic ulcer (excluding diabetic foot), diabetic foot, and ulcer. Patients with both an uSSSI and cSSSI infection were classified as cSSSI for analysis. Those patients with ⬎1 cSSSI were reclassified as mixed cSSSI because there was no indication as to which infection might be the most severe.
Statistical Analysis Statistical summaries were provided for demographic and baseline characteristics. Categorical baseline demographic and medical variables were analyzed by 2 test using the Bonferroni correction for multiple comparisons where necessary. For continuous variables, the Student t test or analysis of variance with the Tukey-Kramer HSD post hoc test was used to compare infection types (uSSSI versus cSSSI). The Fisher exact test (2-sided, ␣ ⫽ 0.05) or 2 tests were used to detect differences in clinical success rates stratified
S8 by infection type and primary pathogen as well as for other subgroup analyses (e.g., daptomycin dose, duration of daptomycin therapy, concomitant antibiotic therapy versus type of infection). Significant differences were defined as P ⬍0.05. All statistical analyses were performed with the statistical software JMP version 5.1 (SAS Institute, Cary, NC).
RESULTS A total of 1,160 records in the CORE registry were screened to identify eligible patients. Of these, 577 patients had a diagnosis of SSSI. In all, 522 (90%) of these were evaluable for clinical efficacy assessment and compose the final study population described in this report.
Patient Population: Demographic and Baseline Medical Characteristics The patient demographics are described in Table 1. The cSSSI group was older (P ⬍0.001) and had greater rates of comorbidities—in particular, diabetes (P ⬍0.001), peripheral vascular disease (P ⫽ 0.002), and renal dysfunction (P ⫽ 0.022) at the start of daptomycin treatment. A total of 36% (188 of 522) of all infections were categorized as uSSSIs, and 64% (334 of 522) were categorized as cSSSIs. Among the most common cSSSI diagnoses were surgical site infections (43%) and wound and major abscesses, which together accounted for 38% of all cSSSIs (Table 2). Most patients had only a single SSSI (either uSSSI or cSSSI). However, there were 15 patients with both cSSSI and uSSSI, and 9 (3%) cSSSI patients had mixed cSSSI. Additionally, bacteremia was reported in 14 (3%) of all patients, occurring mostly in the cSSSI group (Table 2).
Baseline Microbiologic and Susceptibility Findings Gram-positive pathogens were isolated and identified in 65% of all patients. Patients without pathogens reported were more common in the uSSSI patient group (n ⫽ 104), representing 55% of all the patients in that group. Overall, S aureus (75%) and Enterococcus species (19%) were the most common organisms isolated. Some 85% of S aureus isolates were methicillin resistant, and 44% of Enterococcus species were reported as vancomycin resistant (VRE). The breakdown of isolated pathogens for all patients, as well as by cSSSI and uSSSI, is displayed in Table 3. The subset of patients with bacteremia (n ⫽ 14) had the following pathogens: MRSA (n ⫽ 4; 1 coinfected with group F streptococci); VRE (n ⫽ 2); S pyogenes (n ⫽ 2); and 1 each of methicillin-susceptible S aureus, coagulasenegative staphylococci, S pneumoniae, and gram-positive cocci. Two patients did not have a pathogen reported at the initiation of therapy.
The American Journal of Medicine, Vol 120 (10A), October 2007 Table 1
Patient demographics and characteristics*
Characteristic Sex Female Male Weight, mean ⫾ SD (kg) Age group (yr) ⱕ30 31–50 51–65 ⱖ66 Underlying disease (⬎5%)‡ Diabetes mellitus Hypertension Peripheral vascular disease Other cardiovascular disease Fracture, orthopedic disorder Chronic renal failure Cancer (solid organ) Renal function Creatinine clearance ⬍30 mL/min Dialysis
cSSSI (n ⫽ 334)
uSSSI (n ⫽ 188)
All SSSI (N ⫽ 522)
156 (47) 105 (56) 261 (50) 178 (53) 83 (44) 261 (50) 87.6 ⫾ 29.7 93.4 ⫾ 29.9 89.7 ⫾ 29.9 21 98 119 96
(6)† (29)† (36)† (29)†
30 81 47 30
(16) (43) (25) (16)
51 179 166 126
(10) (34) (32) (24)
117 (35)† 66 (20) 45 (13)†
26 (14) 29 (15) 9 (5)
143 (27) 95 (18) 54 (10)
31 (9)
16 (9)
47 (9)
24 (7)
6 (3)
30 (6)
25 (7)† 21 (6)
3 (2) 6 (3)
28 (5) 27 (5)
97 (29)†
38 (20)
135 (26)
25 (7)†
3 (2)
28 (5)
cSSSI ⫽ complicated skin and skin-structure infection; SSSI ⫽ skin and skin-structure infection; uSSSI ⫽ uncomplicated skin and skinstructure infection. *Values are given as number (percentage) unless otherwise indicated. † P ⬍0.001, overall for age comparison (2 test); P ⬍0.05, cSSSI vs. uSSSI (Fisher exact test). ‡ Patients may have ⬎1 underlying disease.
mg/kg) and 4 mg/kg for uSSSI (mean, 4.2 ⫾ 0.8 mg/kg; range, 2.1 to 9 mg/kg); the dose was significantly higher in cSSSI (P ⬍0.001, median test). Of all patients, 7.5% of patients received ⬍4 mg/kg, and 1.3% received ⬎6 mg/kg. The median daptomycin dose was 4 mg/kg for patients with and without bacteremia (P ⫽ 0.20). Comparing initial median prescribed dose by cSSSI infection type showed no differences. Most of the patients (312 of 320, 98%) with creatinine clearance (CrCl) ⱖ30 mL/min received their daptomycin dose every 24 hours. Of the 135 patients with CrCl ⬍30 mL/min, 40 (30%) received daptomycin every 48 hours, or 3 times per week. A small percentage of patients with doses other than 4 mg/kg received a dose of 500 ⫾ 5 mg, corresponding to the vial size available for daptomycin (cSSSI, 3.3%; uSSSI, 1.6%; P ⫽ 0.40). The median daptomycin treatment duration was 12 days (range, 1 to 148 days) and was longer for cSSSI than uSSSI (14 vs. 10 days, P ⫽ 0.002).
Previous and Concomitant Antibiotic Therapy Daptomycin Therapy The median initial daptomycin dose administered was 4 mg/kg for cSSSI (mean, 4.5 ⫾ 1.0 mg/kg; range, 2.3 to 12
Of all SSSI patients, 349 (67%) had received antibiotic therapy before the initiation of daptomycin therapy (71% of patients with cSSSI, 59% of patients with uSSSI).
Owens, Jr. et al Table 2
Daptomycin for Skin and Skin-Structure Infections
S9
Clinical outcomes and type of skin and skin-structure infection (SSSI)*†
Infection Uncomplicated skin Wound Major abscess Surgical site infection Diabetic ulcer Diabetic foot Ulcer SSSI ⫹ bacteremia, non–catheter-related Necrotizing infection Mixed cSSSI Outcome Success Cure Improved Failure
cSSSI (n ⫽ 334)
uSSSI (n ⫽ 188)
All SSSI (N ⫽ 522)
Success
15 64 62 142 5 39 25 10 10 9
188 — — — — — — 4 — —
203 64 62 142 5 39 25 14 10 9
200 62 59 139 5 35 22 13 9 9
319 176 143 15
(96%) (53%) (43%) (4%)
185 125 60 3
(98%) (66%) (32%) (2%)
504 301 203 18
(99%) (97%) (95%) (98%) (100%) (90%) (88%) (93%) (90%) (100%)
(97%) (58%) (39%) (3%)
cSSSI ⫽ complicated SSSI; uSSSI ⫽ uncomplicated SSSI. *Values do not add up to 522 because some patients had ⬎1 infection. † Success rate is the sum of cure or improved rates.
Table 3 Prevalence of gram-positive pathogens isolated in culturepositive patients* n (%)
Organism Isolated
cSSSI (n ⫽ 253)
uSSSI (n ⫽ 84)
All (n ⫽ 337)
MRSA MSSA† CoNS Vancomycin-resistant Enterococcus Enterococcus Enterococcus faecalis Group A streptococci Group B streptococci Streptococcus‡ Viridans group streptococci Enterococcus faecium Other§
144 30 34 28 19 14 4 4 3 1 1 8
69 9 5 0 1 0 2 1 1 1 0 1
213 39 39 28 20 14 6 5 4 2 1 9
(57) (12) (13) (11) (8) (6) (2) (2) (1) (⬍1) (⬍1) (3)
(82) (11) (6) (1) (2) (1) (1) (1) (1)
(63) (12) (12) (8) (6) (4) (2) (1) (1) (⬍1) (⬍1) (3)
CoNS ⫽ coagulase-negative staphylococci; cSSSI ⫽ complicated skin and skinstructure infection; MRSA ⫽ methicillin-resistant Staphylococcus aureus; MSSA ⫽ methicillin-susceptible S aureus; SSSI ⫽ skin and skin-structure infection; uSSSI ⫽ uncomplicated skin and skin-structure infection. *Patients may have had ⬎1 reported pathogen; 185 (35%) patients did not have a gram-positive pathogen reported or were culture negative. † Includes S aureus with unknown methicillin susceptibility. ‡ Includes S pneumoniae, group F streptococci, group G streptococci, and unspeciated streptococci. § Includes Corynebacterium sp, Staphylococcus sp, gram-positive cocci, and grampositive bacilli.
Specifics about the type and duration of previous antibiotic therapy were not recorded. Daptomycin was administered with ⱖ1 dose of concomitant antibiotic therapy in 42% of all patients, most commonly with a fluoroquinolone (20%) or a cephalosporin (18%). The percentage of patients receiving concomitant antibiotic therapy was
higher in the cSSSI than in the uSSSI group (45% vs 36%, P ⫽ 0.03). In the cSSSI group, the most frequent concomitant antibiotics prescribed were fluoroquinolones and cephalosporins (23% each). In contrast, the most frequent concomitant antibiotics for patients with uSSSI were vancomycin (34%) and clindamycin (33%).
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The American Journal of Medicine, Vol 120 (10A), October 2007
Table 4 Clinical outcomes for patients with complicated and uncomplicated skin and skin-structure infections (cSSSI and uSSSI) by cultured primary pathogen as designated by investigator* cSSSI, n (%)
uSSSI, n (%)
Pathogen
Success
Failure
Success
Failure
MRSA CoNS MSSA VRE Enterococcus (vancomycin susceptible) Streptococcus†‡ Staphylococcus Gram-positive cocci Corynebacterium Other
136 28 23 26 17
(97) (100) (96) (93) (94)
4 0 1 2 2
(3) (0) (4) (7) (10)
69 4 7 — 1
(100)
1 (1) 0 (0) 0 (0) — 0 (0)
7 2 2 1 12
(88) (67) (100) (100) (86)
1 1 0 0 2
(13) (33) (0) (0) (14)
2 (100) — — — —
0 (0) — — — —
(99) (100) (100)
CoNS ⫽ coagulase-negative staphylococci; MRSA ⫽ methicillinresistant Staphylococcus aureus; MSSA ⫽ methicillin-susceptible S aureus; VRE ⫽ vancomycin-resistant enterococcus. *Numbers of pathogens will be different from that presented in Table 3 because a single primary pathogen was chosen by the investigator. † cSSSI Streptococcus sp infections include 3 group A streptococci, 2 group B streptococci, 1 group G streptococci, 1 viridans group streptococci, and 1 S pneumoniae. ‡ uSSSI Streptococcus sp infections include 1 group A streptococci and 1 viridans group streptococci.
Clinical Outcomes and Successive Therapy Overall, use of daptomycin led to clinical success in 97% of evaluable cases of SSSI (Table 2). Clinical success was similar for patients with cSSSI (96%) and for those with uSSSI (98%). When stratified by the primary pathogen, there were no differences in outcomes between patients with a cSSSI and those with a uSSSI (Table 4). The clinical success rate ranged from 88% to 100% among the different types of infection. Additionally, outcomes were not different when analyzed by patient weight, renal function, or use of concomitant antibiotic therapy (data not shown). In all, 13 of the 14 patients with bacteremia were classified as a clinical success (either cure or improved). The 1 failure patient had underlying pulmonary disease and was reported to have a complicated ulcer, as well as bacteremia, but not pneumonia, due to S pneumoniae. This patient received 17 days of daptomycin 4 mg/kg in combination with a cephalosporin. In cases judged to be clinical successes (i.e., cure or improved outcome), the median time to clinical response as evidenced by signs and symptoms was 4 days (range, 1 to 32 days) for cSSSI and 5 days (range, 1 to 21 days) for uSSSI (P ⫽ 0.017).
DISCUSSION The CORE 2004 database quantified the characteristics of and clinical outcomes among 522 patients who received
daptomycin for treatment of a SSSI. Overall, patients had multiple comorbid conditions, with ⬎33% of the patients having underlying illnesses that left them immunocompromised (e.g., diabetes, cancer, renal insufficiency). Nearly 66% of all infections were considered complicated. Among patients with cSSSI, surgical site infections were most common, followed by wound, abscess, and diabetic foot infections. Two thirds of all patients with an SSSI had a documented baseline isolate that was consistent with anticipated gram-positive skin pathogens, namely, S aureus.4 Importantly, 85% of S aureus isolates were MRSA, and 44% of the enterococci were VRE, emphasizing the increasing role of these multidrug-resistant organisms in common infections such as SSSI. Daptomycin was associated with a high rate of clinical efficacy (97%) for the treatment of both cSSSI and uSSSI. Clinical success was not influenced by the type of grampositive pathogen or the subtype of infection (e.g., wound versus abscess versus diabetic foot ulcer). In particular, daptomycin appeared effective for the large proportion of infections due to MRSA and VRE. Daptomycin exhibits good in vitro activity against enterococci, and vancomycin susceptibility has not been demonstrated to affect its in vitro activity. However, despite the number of VRE infections, data describing daptomycin’s clinical effectiveness against this problematic pathogen are limited. One retrospective study reported daptomycin was successful for 5 of 9 (56%) infections with VRE bacteremia.27 Similar to those results, our data (26 of 28 patients with infection due to VRE achieved an outcome of cure or improvement) suggest that daptomycin is being used to treat SSSIs due to VRE and that it may be an effective therapeutic alternative. Additional rigorous clinical studies that include follow-up cultures are warranted to investigate daptomycin and its role for the treatment of VRE. Daptomycin was successful in 9 of 10 patients reported to have necrotizing infections. The spread of communityassociated MRSA has been associated with an increase in necrotizing fasciitis and necrotizing myositis.28 Additional investigations are needed to assess daptomycin for these types of infections including impact of the depth of necrosis and surgical interventions. The time to clinical response occurred at a median of 4 to 5 days after the start of daptomycin treatment regardless of whether the infection was complicated or uncomplicated. However, for patients with cSSSI, the average length of daptomycin therapy was significantly longer than for patients with uSSSI. This may be in part the result of a higher percentage of patients who received daptomycin as secondline therapy for treatment of refractory infections. In contrast to the data reported by Arbeit and associates25 in which 63% of cSSSI patients successfully treated required ⱕ7 days of therapy, in this study only 25% of successfully treated patients received ⱕ7 days of daptomycin therapy. This may reflect the different nature of the 2 studies and different patient populations, as well as a different mix of
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cSSSI and organisms treated. It also may reflect real-world antimicrobial prescribing, where therapy sometimes is extended unnecessarily “just in case.” Whether patients with cSSSI truly require a longer duration of therapy than patients with uSSSI is unclear, although there is a tendency to treat patients with more serious and deep-seated infections for longer periods to ensure a positive outcome. In this study, both the median dose and duration of daptomycin therapy were consistent with the currently approved dosing recommendations. Daptomycin penetrates well into blister fluid (68% of plasma concentrations), and the approved dose should produce concentrations well above the minimum inhibitory concentrations for gram-positive pathogens.29 For unknown reasons, a small percentage of patients received doses higher than studied for cSSSI and other infections. Conversely, there were patients who received lower than recommended doses, which might increase the propensity for the development of resistance.
SUMMARY The retrospective nature of this study poses limitations in terms of evaluating the efficacy of daptomycin for SSSI, including the role of concomitant antibiotic therapy and surgical interventions in patient outcomes. Fluoroquinolones and cephalosporins were often coadministered to patients with cSSSI in addition to daptomycin. These agents possess gram-positive activity in addition to their gramnegative activity. Furthermore, vancomycin or clindamycin were commonly administered concomitantly with daptomycin to patients with uSSSI; thus, the clinical response reported herein may have been affected by these agents. Information regarding surgical intervention (e.g., debridement) was not collected in the study. Therefore, what impact surgical therapy, or the lack thereof, may have had on these results cannot be ascertained. Furthermore, clinical response was determined at the end of therapy. Because there was no follow-up assessment, relapses and/or failures occurring after the end of therapy were not captured. Despite these limitations, the findings in this study are consistent with those of phase 3 studies showing daptomycin to be effective for the treatment of patients with cSSSI, including diabetic foot ulcers due to gram-positive bacteria.25,30 Arbeit and associates25 reported clinical success rates of approximately 80% for daptomycin therapy in the phase 3 studies. These rates were determined at the test of cure, defined in their study as 6 to 20 days after the end of therapy; this is in contrast to the present study in which clinical success was determined at the end of daptomycin therapy. This most likely accounts for a portion of the differences reported in these 2 studies. The number of patients with bacteremia in both of these studies was similar (3% for each), although the clinical outcomes data for such patients were not reported by Arbeit and associates.25 In an analysis of daptomycin treatment of diabetic foot ulcers, Lipsky and Stoutenburgh30 reported a clinical success of 66%. Again, this is somewhat lower
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than reported in the present analysis and most likely reflects differences in study design, patient demographics, and organisms treated. The data presented here suggest that daptomycin offers clinicians an effective treatment for SSSI caused by gram-positive organisms including MRSA and VRE.
Acknowledgments The authors acknowledge the contributions of the investigators and of participating institutions in the CORE 2004 registry.
AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: Lawrence V. Friedrich, PharmD, is an employee and a stockholder of Cubist Pharmaceuticals, Inc. Kenneth C. Lamp, PharmD, is an employee and a stockholder of Cubist Pharmaceuticals, Inc. Robert C. Owens, Jr., PharmD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement. Rene Russo, PharmD, is an employee and a stockholder of Cubist Pharmaceuticals, Inc.
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29.
30.
(Europe) during 2000-2001. J Antimicrob Chemother. 2003;51:639 – 649. Silverman JA, Oliver N, Andrew T, Li T. Resistance studies with daptomycin. Antimicrob Agents Chemother. 2001;45:1799 –1802. Cubicin (daptomycin for injection) [prescribing information]. Lexington, MA: Cubist Pharmaceuticals, Inc., 2006. Lewis JS II, Owens A, Cadena J, Sabol K, Patterson JE, Jorgensen JH. Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother. 2005;49: 1664 –1665. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI and the Daptomycin 98 – 01 and 99 – 01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004;38:1673–1681. Rolston KVI, Segreti JA, Lamp KC, Friedrich LV. Cubicin Outcomes Registry and Experience (CORE) methodology. Am J Med. 2007;120 (suppl 10A):S4 –S5. Segreti JA, Crank CW, Finney MS. Daptomycin for the treatment of gram-positive bacteremia and infective endocarditis: a retrospective case series of 31 patients. Pharmacotherapy. 2006;26:347–352. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352:1445– 1453. Eisenstein BI. Lipopeptides, focusing on daptomycin, for the treatment of Gram-positive infections. Expert Opin Investig Drugs. 2004;13: 1159 –1169. Lipsky BA, Stoutenburgh U. Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. J Antimicrob Chemother. 2005;55:240 –245.
Postmarketing Clinical Experience in Patients with Skin and Skin-Structure Infections Treated with Daptomycin Robert C. Owens, Jr., PharmD,a,b Kenneth C. Lamp, PharmD,c Lawrence V. Friedrich, PharmD,c and Rene Russo, PharmDc a
Maine Medical Center, Portland, Maine, USA; bDepartment of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA; and cCubist Pharmaceuticals, Inc., Lexington, Massachusetts, USA ABSTRACT A registry describing daptomycin’s clinical use was analyzed to describe treatment of skin and skinstructure infections (SSSIs). The Cubicin Outcomes Registry and Experience (CORE) 2004 retrospectively collected demographic, microbiologic, and clinical outcome information of patients treated with daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA). The database was accessed to identify patients with a diagnosis of an SSSI with an outcome determined. Of 577 patients identified with a SSSI, 522 (90%) were evaluable. Diabetes mellitus and peripheral vascular disease were present in 27% and 10% of the population, respectively. Pathogens were identified for 65% of all patients—Staphylococcus aureus (75%; 85% methicillin-resistant) and Enterococcus species (19%; 44% vancomycin-resistant) most commonly. Concomitant use of other antibiotics was common (42%). Of 522 patients studied, 334 (64%) had complicated infections (cSSSIs), and 188 (36%) had uncomplicated infections (uSSSIs). Overall cure, improved, and failure rates were 53%, 43%, and 4%, respectively, for cSSSI and 66%, 32%, and 2%, respectively, for uSSSI. The median dose administered was 4.0 mg/kg for cSSSI (mean, 4.5 ⫾ 1.0 mg/kg; range, 2.3 to 12 mg/kg) and 4.0 mg/kg for uSSSI (mean, 4.2 ⫾ 0.8 mg/kg; range, 2.1 to 9 mg/kg); the dose was significantly higher in cSSSI (P ⬍0.001, median test). Median daptomycin treatment duration was 12 days (range, 1 to 148 days) and was longer for cSSSI than for uSSSI (14 vs. 10 days, P ⫽ 0.002). The results of this study support previously published reports and suggest that daptomycin is effective for the treatment of skin infections due to gram-positive pathogens. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Daptomycin; Enterococcus; Methicillin-resistant Staphylococcus aureus; Skin and skin-structure infections; Staphylococcus aureus; Vancomycin-resistant enterococci
Skin and skin-structure infections (SSSIs) are commonly encountered in both community and hospital settings and are typically caused by gram-positive bacteria. SSSIs can be categorized as either complicated (cSSSI) or uncomplicated (uSSSI). The uSSSIs commonly seen by physicians include simple abscess, cellulitis, erysipelas, impetigo, folliculitis, This study was presented in part at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16 –19, 2005; Washington, District of Columbia. Please see the Author Disclosure section at the end of this article. Requests for reprints should be addressed to Kenneth C. Lamp, PharmD, Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, Massachusetts 02421. E-mail address: [email protected].
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2007.07.009
furunculosis, and carbunculosis. In otherwise healthy patients, these infections are usually managed empirically with antibiotics that have gram-positive coverage.1 In contrast, cSSSIs are typically defined as those that meet either or both of the following criteria: hospitalization is required, and infection is known or suspected to involve deep soft tissue, such as fascia or muscle.2 Examples of cSSSI include necrotizing skin infections, deep wounds, major abscesses, surgical site infections, and diabetic ulcers. cSSSIs also include those infections that occur in patients whose immune systems are compromised by diabetes mellitus, peripheral vascular disease, and other factors.2,3 Staphylococcus aureus is the organism most frequently isolated from both cSSSIs and uSSSIs; however, cSSSIs typically have a
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polymicrobial etiology.4 Immunocompromised patients, patients with previous antimicrobial exposure, and those with serious underlying comorbid conditions often have infections involving multidrug-resistant aerobic and anaerobic gram-positive and gram-negative bacteria.4 Among patients with an intact immune system, the pathogens most frequently isolated are S aureus, Streptococcus pyogenes (group A -hemolytic Streptococcus), and Streptococcus agalactiae (group B -hemolytic Streptococcus).4,5 The standard of care for SSSI is a combination of appropriate surgical intervention—such as debridement, incision, and drainage—and antimicrobial therapy.2,3 Antimicrobial resistance among gram-positive bacteria is a serious problem that continues to worsen. In particular, the emergence of methicillin-resistant S aureus (MRSA) in both hospital and community settings has become a clinical challenge for clinicians and patients and carries a significant economic burden.6 –9 Reports of vancomycin-intermediate S aureus and vancomycin-resistant S aureus have surfaced, and although these problems are not currently widespread, they have heightened the awareness of the emergence of multidrugresistant S aureus as well as treatment challenges.10 –12 Moreover, the recent recognition of community-associated MRSA as a major pathogen with potentially serious clinical consequences has further increased awareness of the importance of drug-resistant organisms. Furthermore, reports of resistance and clinical failures with newer antimicrobial agents, such as linezolid and quinupristin-dalfopristin, also are emerging.13–16 The trends suggest that more effective therapies as well as targeted anti– gram-positive treatment regimens are needed to combat pathogens causing SSSIs, including antimicrobial-resistant organisms.13–16 This clinical reality continues to drive the need for better infection control compliance, a search for effective vaccines, good antimicrobial stewardship (correct drug selection, dose, and duration), and the pursuit of new and effective treatment alternatives for the treatment of infections, including SSSIs. Daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) displays in vitro activity against most of the clinically relevant gram-positive bacteria implicated in SSSIs. Methicillin resistance in staphylococci and vancomycin resistance in enterococci do not appear to affect daptomycin’s in vitro activity.17–21 Daptomycin is further characterized as having a very low frequency of spontaneous development of resistance,22 and there has been no evidence of conjugation-mediated resistance. There have been isolated reports of reduced daptomycin susceptibility.23,24 However, in some cases, they involved extremely ill and complicated patients who may have benefited from adjunctive therapies including surgery. Daptomycin was approved by the US Food and Drug Administration (FDA) for management of cSSSI in 2003.23 Results of 2 randomized, investigator-blinded, multicenter, phase 3 clinical studies have shown that the efficacy of daptomycin (4 mg/kg every 24 hours) was similar to that of
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standard therapy (penicillinase-resistant penicillins or vancomycin) in the treatment of nearly 1,100 hospitalized patients with cSSSI.25 Combined data from the studies indicate that clinical success rates were similar between the 2 treatment groups for cases judged clinically evaluable (83.4% and 84.2%, respectively, for daptomycin and comparators). These findings extended to patients with infections due to MRSA (75.0% vs. 69.4%, respectively). Because little is known about the clinical experience with daptomycin since its FDA approval, the current study was undertaken to confirm the efficacy of daptomycin in practical clinical settings. The Cubicin Outcomes Registry and Experience (CORE) 2004 database was a multicenter, retrospective, chart review conducted to assess patient-specific characteristics and clinical outcome among patients receiving daptomycin. The CORE 2004 database was used in this analysis to describe clinical outcomes among patients with SSSIs treated with daptomycin in a real-world setting.
PATIENTS AND METHODS The methods for conducting the registry are described separately by Rolston and colleagues elsewhere in this supplement.26
Record Selection and Eligibility Criteria Daptomycin-treated patients with a diagnosis of SSSI and a reported clinical outcome (cure, improved, failure) were included in this analysis. Patients with osteomyelitis, orthopedic device infections, or other serious infections were excluded from the analysis. However, those patients with a concurrent diagnosis of non– catheter-related bacteremia were included. For the purposes of this study, the following infections were considered to be uSSSIs: uncomplicated cellulitis, simple abscess, erysipelas, furuncles, acne, and impetigo. For cSSSIs, the following were included: wound infection (traumatic, animal/human bite, septic phlebitis associated with catheter sites), major abscess, surgical site infections (sternotomy, dehiscence, surgical graft site), diabetic ulcer (excluding diabetic foot), diabetic foot, and ulcer. Patients with both an uSSSI and cSSSI infection were classified as cSSSI for analysis. Those patients with ⬎1 cSSSI were reclassified as mixed cSSSI because there was no indication as to which infection might be the most severe.
Statistical Analysis Statistical summaries were provided for demographic and baseline characteristics. Categorical baseline demographic and medical variables were analyzed by 2 test using the Bonferroni correction for multiple comparisons where necessary. For continuous variables, the Student t test or analysis of variance with the Tukey-Kramer HSD post hoc test was used to compare infection types (uSSSI versus cSSSI). The Fisher exact test (2-sided, ␣ ⫽ 0.05) or 2 tests were used to detect differences in clinical success rates stratified
S8 by infection type and primary pathogen as well as for other subgroup analyses (e.g., daptomycin dose, duration of daptomycin therapy, concomitant antibiotic therapy versus type of infection). Significant differences were defined as P ⬍0.05. All statistical analyses were performed with the statistical software JMP version 5.1 (SAS Institute, Cary, NC).
RESULTS A total of 1,160 records in the CORE registry were screened to identify eligible patients. Of these, 577 patients had a diagnosis of SSSI. In all, 522 (90%) of these were evaluable for clinical efficacy assessment and compose the final study population described in this report.
Patient Population: Demographic and Baseline Medical Characteristics The patient demographics are described in Table 1. The cSSSI group was older (P ⬍0.001) and had greater rates of comorbidities—in particular, diabetes (P ⬍0.001), peripheral vascular disease (P ⫽ 0.002), and renal dysfunction (P ⫽ 0.022) at the start of daptomycin treatment. A total of 36% (188 of 522) of all infections were categorized as uSSSIs, and 64% (334 of 522) were categorized as cSSSIs. Among the most common cSSSI diagnoses were surgical site infections (43%) and wound and major abscesses, which together accounted for 38% of all cSSSIs (Table 2). Most patients had only a single SSSI (either uSSSI or cSSSI). However, there were 15 patients with both cSSSI and uSSSI, and 9 (3%) cSSSI patients had mixed cSSSI. Additionally, bacteremia was reported in 14 (3%) of all patients, occurring mostly in the cSSSI group (Table 2).
Baseline Microbiologic and Susceptibility Findings Gram-positive pathogens were isolated and identified in 65% of all patients. Patients without pathogens reported were more common in the uSSSI patient group (n ⫽ 104), representing 55% of all the patients in that group. Overall, S aureus (75%) and Enterococcus species (19%) were the most common organisms isolated. Some 85% of S aureus isolates were methicillin resistant, and 44% of Enterococcus species were reported as vancomycin resistant (VRE). The breakdown of isolated pathogens for all patients, as well as by cSSSI and uSSSI, is displayed in Table 3. The subset of patients with bacteremia (n ⫽ 14) had the following pathogens: MRSA (n ⫽ 4; 1 coinfected with group F streptococci); VRE (n ⫽ 2); S pyogenes (n ⫽ 2); and 1 each of methicillin-susceptible S aureus, coagulasenegative staphylococci, S pneumoniae, and gram-positive cocci. Two patients did not have a pathogen reported at the initiation of therapy.
The American Journal of Medicine, Vol 120 (10A), October 2007 Table 1
Patient demographics and characteristics*
Characteristic Sex Female Male Weight, mean ⫾ SD (kg) Age group (yr) ⱕ30 31–50 51–65 ⱖ66 Underlying disease (⬎5%)‡ Diabetes mellitus Hypertension Peripheral vascular disease Other cardiovascular disease Fracture, orthopedic disorder Chronic renal failure Cancer (solid organ) Renal function Creatinine clearance ⬍30 mL/min Dialysis
cSSSI (n ⫽ 334)
uSSSI (n ⫽ 188)
All SSSI (N ⫽ 522)
156 (47) 105 (56) 261 (50) 178 (53) 83 (44) 261 (50) 87.6 ⫾ 29.7 93.4 ⫾ 29.9 89.7 ⫾ 29.9 21 98 119 96
(6)† (29)† (36)† (29)†
30 81 47 30
(16) (43) (25) (16)
51 179 166 126
(10) (34) (32) (24)
117 (35)† 66 (20) 45 (13)†
26 (14) 29 (15) 9 (5)
143 (27) 95 (18) 54 (10)
31 (9)
16 (9)
47 (9)
24 (7)
6 (3)
30 (6)
25 (7)† 21 (6)
3 (2) 6 (3)
28 (5) 27 (5)
97 (29)†
38 (20)
135 (26)
25 (7)†
3 (2)
28 (5)
cSSSI ⫽ complicated skin and skin-structure infection; SSSI ⫽ skin and skin-structure infection; uSSSI ⫽ uncomplicated skin and skinstructure infection. *Values are given as number (percentage) unless otherwise indicated. † P ⬍0.001, overall for age comparison (2 test); P ⬍0.05, cSSSI vs. uSSSI (Fisher exact test). ‡ Patients may have ⬎1 underlying disease.
mg/kg) and 4 mg/kg for uSSSI (mean, 4.2 ⫾ 0.8 mg/kg; range, 2.1 to 9 mg/kg); the dose was significantly higher in cSSSI (P ⬍0.001, median test). Of all patients, 7.5% of patients received ⬍4 mg/kg, and 1.3% received ⬎6 mg/kg. The median daptomycin dose was 4 mg/kg for patients with and without bacteremia (P ⫽ 0.20). Comparing initial median prescribed dose by cSSSI infection type showed no differences. Most of the patients (312 of 320, 98%) with creatinine clearance (CrCl) ⱖ30 mL/min received their daptomycin dose every 24 hours. Of the 135 patients with CrCl ⬍30 mL/min, 40 (30%) received daptomycin every 48 hours, or 3 times per week. A small percentage of patients with doses other than 4 mg/kg received a dose of 500 ⫾ 5 mg, corresponding to the vial size available for daptomycin (cSSSI, 3.3%; uSSSI, 1.6%; P ⫽ 0.40). The median daptomycin treatment duration was 12 days (range, 1 to 148 days) and was longer for cSSSI than uSSSI (14 vs. 10 days, P ⫽ 0.002).
Previous and Concomitant Antibiotic Therapy Daptomycin Therapy The median initial daptomycin dose administered was 4 mg/kg for cSSSI (mean, 4.5 ⫾ 1.0 mg/kg; range, 2.3 to 12
Of all SSSI patients, 349 (67%) had received antibiotic therapy before the initiation of daptomycin therapy (71% of patients with cSSSI, 59% of patients with uSSSI).
Owens, Jr. et al Table 2
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Clinical outcomes and type of skin and skin-structure infection (SSSI)*†
Infection Uncomplicated skin Wound Major abscess Surgical site infection Diabetic ulcer Diabetic foot Ulcer SSSI ⫹ bacteremia, non–catheter-related Necrotizing infection Mixed cSSSI Outcome Success Cure Improved Failure
cSSSI (n ⫽ 334)
uSSSI (n ⫽ 188)
All SSSI (N ⫽ 522)
Success
15 64 62 142 5 39 25 10 10 9
188 — — — — — — 4 — —
203 64 62 142 5 39 25 14 10 9
200 62 59 139 5 35 22 13 9 9
319 176 143 15
(96%) (53%) (43%) (4%)
185 125 60 3
(98%) (66%) (32%) (2%)
504 301 203 18
(99%) (97%) (95%) (98%) (100%) (90%) (88%) (93%) (90%) (100%)
(97%) (58%) (39%) (3%)
cSSSI ⫽ complicated SSSI; uSSSI ⫽ uncomplicated SSSI. *Values do not add up to 522 because some patients had ⬎1 infection. † Success rate is the sum of cure or improved rates.
Table 3 Prevalence of gram-positive pathogens isolated in culturepositive patients* n (%)
Organism Isolated
cSSSI (n ⫽ 253)
uSSSI (n ⫽ 84)
All (n ⫽ 337)
MRSA MSSA† CoNS Vancomycin-resistant Enterococcus Enterococcus Enterococcus faecalis Group A streptococci Group B streptococci Streptococcus‡ Viridans group streptococci Enterococcus faecium Other§
144 30 34 28 19 14 4 4 3 1 1 8
69 9 5 0 1 0 2 1 1 1 0 1
213 39 39 28 20 14 6 5 4 2 1 9
(57) (12) (13) (11) (8) (6) (2) (2) (1) (⬍1) (⬍1) (3)
(82) (11) (6) (1) (2) (1) (1) (1) (1)
(63) (12) (12) (8) (6) (4) (2) (1) (1) (⬍1) (⬍1) (3)
CoNS ⫽ coagulase-negative staphylococci; cSSSI ⫽ complicated skin and skinstructure infection; MRSA ⫽ methicillin-resistant Staphylococcus aureus; MSSA ⫽ methicillin-susceptible S aureus; SSSI ⫽ skin and skin-structure infection; uSSSI ⫽ uncomplicated skin and skin-structure infection. *Patients may have had ⬎1 reported pathogen; 185 (35%) patients did not have a gram-positive pathogen reported or were culture negative. † Includes S aureus with unknown methicillin susceptibility. ‡ Includes S pneumoniae, group F streptococci, group G streptococci, and unspeciated streptococci. § Includes Corynebacterium sp, Staphylococcus sp, gram-positive cocci, and grampositive bacilli.
Specifics about the type and duration of previous antibiotic therapy were not recorded. Daptomycin was administered with ⱖ1 dose of concomitant antibiotic therapy in 42% of all patients, most commonly with a fluoroquinolone (20%) or a cephalosporin (18%). The percentage of patients receiving concomitant antibiotic therapy was
higher in the cSSSI than in the uSSSI group (45% vs 36%, P ⫽ 0.03). In the cSSSI group, the most frequent concomitant antibiotics prescribed were fluoroquinolones and cephalosporins (23% each). In contrast, the most frequent concomitant antibiotics for patients with uSSSI were vancomycin (34%) and clindamycin (33%).
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The American Journal of Medicine, Vol 120 (10A), October 2007
Table 4 Clinical outcomes for patients with complicated and uncomplicated skin and skin-structure infections (cSSSI and uSSSI) by cultured primary pathogen as designated by investigator* cSSSI, n (%)
uSSSI, n (%)
Pathogen
Success
Failure
Success
Failure
MRSA CoNS MSSA VRE Enterococcus (vancomycin susceptible) Streptococcus†‡ Staphylococcus Gram-positive cocci Corynebacterium Other
136 28 23 26 17
(97) (100) (96) (93) (94)
4 0 1 2 2
(3) (0) (4) (7) (10)
69 4 7 — 1
(100)
1 (1) 0 (0) 0 (0) — 0 (0)
7 2 2 1 12
(88) (67) (100) (100) (86)
1 1 0 0 2
(13) (33) (0) (0) (14)
2 (100) — — — —
0 (0) — — — —
(99) (100) (100)
CoNS ⫽ coagulase-negative staphylococci; MRSA ⫽ methicillinresistant Staphylococcus aureus; MSSA ⫽ methicillin-susceptible S aureus; VRE ⫽ vancomycin-resistant enterococcus. *Numbers of pathogens will be different from that presented in Table 3 because a single primary pathogen was chosen by the investigator. † cSSSI Streptococcus sp infections include 3 group A streptococci, 2 group B streptococci, 1 group G streptococci, 1 viridans group streptococci, and 1 S pneumoniae. ‡ uSSSI Streptococcus sp infections include 1 group A streptococci and 1 viridans group streptococci.
Clinical Outcomes and Successive Therapy Overall, use of daptomycin led to clinical success in 97% of evaluable cases of SSSI (Table 2). Clinical success was similar for patients with cSSSI (96%) and for those with uSSSI (98%). When stratified by the primary pathogen, there were no differences in outcomes between patients with a cSSSI and those with a uSSSI (Table 4). The clinical success rate ranged from 88% to 100% among the different types of infection. Additionally, outcomes were not different when analyzed by patient weight, renal function, or use of concomitant antibiotic therapy (data not shown). In all, 13 of the 14 patients with bacteremia were classified as a clinical success (either cure or improved). The 1 failure patient had underlying pulmonary disease and was reported to have a complicated ulcer, as well as bacteremia, but not pneumonia, due to S pneumoniae. This patient received 17 days of daptomycin 4 mg/kg in combination with a cephalosporin. In cases judged to be clinical successes (i.e., cure or improved outcome), the median time to clinical response as evidenced by signs and symptoms was 4 days (range, 1 to 32 days) for cSSSI and 5 days (range, 1 to 21 days) for uSSSI (P ⫽ 0.017).
DISCUSSION The CORE 2004 database quantified the characteristics of and clinical outcomes among 522 patients who received
daptomycin for treatment of a SSSI. Overall, patients had multiple comorbid conditions, with ⬎33% of the patients having underlying illnesses that left them immunocompromised (e.g., diabetes, cancer, renal insufficiency). Nearly 66% of all infections were considered complicated. Among patients with cSSSI, surgical site infections were most common, followed by wound, abscess, and diabetic foot infections. Two thirds of all patients with an SSSI had a documented baseline isolate that was consistent with anticipated gram-positive skin pathogens, namely, S aureus.4 Importantly, 85% of S aureus isolates were MRSA, and 44% of the enterococci were VRE, emphasizing the increasing role of these multidrug-resistant organisms in common infections such as SSSI. Daptomycin was associated with a high rate of clinical efficacy (97%) for the treatment of both cSSSI and uSSSI. Clinical success was not influenced by the type of grampositive pathogen or the subtype of infection (e.g., wound versus abscess versus diabetic foot ulcer). In particular, daptomycin appeared effective for the large proportion of infections due to MRSA and VRE. Daptomycin exhibits good in vitro activity against enterococci, and vancomycin susceptibility has not been demonstrated to affect its in vitro activity. However, despite the number of VRE infections, data describing daptomycin’s clinical effectiveness against this problematic pathogen are limited. One retrospective study reported daptomycin was successful for 5 of 9 (56%) infections with VRE bacteremia.27 Similar to those results, our data (26 of 28 patients with infection due to VRE achieved an outcome of cure or improvement) suggest that daptomycin is being used to treat SSSIs due to VRE and that it may be an effective therapeutic alternative. Additional rigorous clinical studies that include follow-up cultures are warranted to investigate daptomycin and its role for the treatment of VRE. Daptomycin was successful in 9 of 10 patients reported to have necrotizing infections. The spread of communityassociated MRSA has been associated with an increase in necrotizing fasciitis and necrotizing myositis.28 Additional investigations are needed to assess daptomycin for these types of infections including impact of the depth of necrosis and surgical interventions. The time to clinical response occurred at a median of 4 to 5 days after the start of daptomycin treatment regardless of whether the infection was complicated or uncomplicated. However, for patients with cSSSI, the average length of daptomycin therapy was significantly longer than for patients with uSSSI. This may be in part the result of a higher percentage of patients who received daptomycin as secondline therapy for treatment of refractory infections. In contrast to the data reported by Arbeit and associates25 in which 63% of cSSSI patients successfully treated required ⱕ7 days of therapy, in this study only 25% of successfully treated patients received ⱕ7 days of daptomycin therapy. This may reflect the different nature of the 2 studies and different patient populations, as well as a different mix of
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cSSSI and organisms treated. It also may reflect real-world antimicrobial prescribing, where therapy sometimes is extended unnecessarily “just in case.” Whether patients with cSSSI truly require a longer duration of therapy than patients with uSSSI is unclear, although there is a tendency to treat patients with more serious and deep-seated infections for longer periods to ensure a positive outcome. In this study, both the median dose and duration of daptomycin therapy were consistent with the currently approved dosing recommendations. Daptomycin penetrates well into blister fluid (68% of plasma concentrations), and the approved dose should produce concentrations well above the minimum inhibitory concentrations for gram-positive pathogens.29 For unknown reasons, a small percentage of patients received doses higher than studied for cSSSI and other infections. Conversely, there were patients who received lower than recommended doses, which might increase the propensity for the development of resistance.
SUMMARY The retrospective nature of this study poses limitations in terms of evaluating the efficacy of daptomycin for SSSI, including the role of concomitant antibiotic therapy and surgical interventions in patient outcomes. Fluoroquinolones and cephalosporins were often coadministered to patients with cSSSI in addition to daptomycin. These agents possess gram-positive activity in addition to their gramnegative activity. Furthermore, vancomycin or clindamycin were commonly administered concomitantly with daptomycin to patients with uSSSI; thus, the clinical response reported herein may have been affected by these agents. Information regarding surgical intervention (e.g., debridement) was not collected in the study. Therefore, what impact surgical therapy, or the lack thereof, may have had on these results cannot be ascertained. Furthermore, clinical response was determined at the end of therapy. Because there was no follow-up assessment, relapses and/or failures occurring after the end of therapy were not captured. Despite these limitations, the findings in this study are consistent with those of phase 3 studies showing daptomycin to be effective for the treatment of patients with cSSSI, including diabetic foot ulcers due to gram-positive bacteria.25,30 Arbeit and associates25 reported clinical success rates of approximately 80% for daptomycin therapy in the phase 3 studies. These rates were determined at the test of cure, defined in their study as 6 to 20 days after the end of therapy; this is in contrast to the present study in which clinical success was determined at the end of daptomycin therapy. This most likely accounts for a portion of the differences reported in these 2 studies. The number of patients with bacteremia in both of these studies was similar (3% for each), although the clinical outcomes data for such patients were not reported by Arbeit and associates.25 In an analysis of daptomycin treatment of diabetic foot ulcers, Lipsky and Stoutenburgh30 reported a clinical success of 66%. Again, this is somewhat lower
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than reported in the present analysis and most likely reflects differences in study design, patient demographics, and organisms treated. The data presented here suggest that daptomycin offers clinicians an effective treatment for SSSI caused by gram-positive organisms including MRSA and VRE.
Acknowledgments The authors acknowledge the contributions of the investigators and of participating institutions in the CORE 2004 registry.
AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: Lawrence V. Friedrich, PharmD, is an employee and a stockholder of Cubist Pharmaceuticals, Inc. Kenneth C. Lamp, PharmD, is an employee and a stockholder of Cubist Pharmaceuticals, Inc. Robert C. Owens, Jr., PharmD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement. Rene Russo, PharmD, is an employee and a stockholder of Cubist Pharmaceuticals, Inc.
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