effectiveness and duration of daptomycin therapy in resolving clinical symptoms in the treatment of...

ORIGINAL ARTICLE

Effectiveness and duration of daptomycin therapy in resolving clinical symptoms in the treatment of complicated skin and skin structure infections*Jake E. Krige a, Kimberly Lindfield b, Lawrence Friedrich b, Constance Otradovec b, William J. Martone b, david E. Katz b and Frank Tally b,†

a University of Cape Town Health Sciences Faculty, Cape Town, South Africab Cubist Pharmaceuticals, Lexington, MA, USA

Address for correspondence: Lawrence Friedrich, PharmD, Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, MA 02421, USA. Tel.: +1 843 881 0191; Fax: +1 843 971 0426; [email protected]

Key words: Antibiotic – Daptomycin – Semisynthetic penicillin – Skin infections – Vancomycin

0300-7995

doi:10.1185/030079907X219652

All rights reserved: reproduction in whole or part not permitted

CuRREnT MEdiCAL RESEARCh And OpiniOn®

VOL. 23, NO. 9, 2007, 2147–2156

© 2007 LiBRAphARM LiMiTEd

Paper 3981 2147

Objective: Compare the rapidity of the resolution of clinical signs and symptoms of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive organisms between daptomycin and comparator agents.

Patients and methods: A subset of South African patients with Gram-positive cSSSIs and no or one comorbid condition from two phase III clinical trials were included in the analysis. Patients were treated with daptomycin (n = 174) or comparator (penicillinase-resistant penicillins [n = 146] or vancomycin [n = 6]). The presence and severity of eight clinical signs and symptoms were evaluated at baseline, day 3 or 4 of treatment, end of therapy, and at test of cure (6–20 days after the last dose).

Results: Of the 326 patients included in this analysis, the clinical success rates between daptomycin and comparator treatments was comparable. Overall, the severity of symptoms in the daptomycin-treated patients

improved more quickly ( p = 0.04) than comparator treatment. At the day 3/4 evaluation, of the eight signs and symptoms, severity significantly decreased for induration ( p = 0.03) and erythema ( p = 0.05); a statistical trend was noted for necrotic tissue ( p = 0.10) and edema ( p = 0.10) in daptomycin-treated patients. Daptomycin treatment resulted in a shorter median duration of therapy than those receiving comparator treatment (7 vs. 8 days, p < 0.0001). Both treatments were well tolerated.

Conclusion: Daptomycin produced a more rapid clinical improvement than comparators, as evidenced by significant reductions in the severity of induration and erythema, with a shorter duration of antibiotic therapy. However, this population was relatively young and healthy; therefore, these results may not be generalizable to all populations.

A B S T R A C T

IntroductionComplicated skin and skin structure infections (cSSSIs) include infections involving deep soft tissue requiring major surgical intervention (e.g., infected ulcers, burns,

and major abscesses) or occurring in patients with significant underlying diseases that complicate response to antibiotic therapy1. Pathogens typically implicated in cSSSIs include strains of methicillin-resistant

* The data and results reported in this manuscript were presented as a poster at the 17th European Congress of Clinical Microbiology and Infectious Diseases held in Munich, Germany on March 31–April 3, 2007

† Deceased

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2148 Daptomycin for skin/skin structure infections © 2007 LiBRAphARM LTd – Curr Med Res Opin 2007; 23(9)

Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA)2,3. It has become increasingly more common to encounter cSSSIs caused by resistant bacteria3. In the United States, recent reports suggest that community-associated MRSA (CaMRSA) is becoming an increasingly prevalent and serious problem4, and was the most common identifiable source of skin and soft tissue infections in patients presenting to the emergency department in several metropolitan areas5. Because cSSSIs caused by resistant bacteria are difficult to treat, they are likely to incur more healthcare costs from extended hospital stays, increased laboratory testing, and increased drug costs2,6. Shorter courses of therapy and shorter hospital stays are reflected in decreased overall healthcare costs7. Newer antibiotic agents, such as daptomycin, may provide advantages because they are effective against most methicillin- and vancomycin-resistant strains and demonstrate rapid bactericidal activity, potentially resulting in faster resolution of infection and allowing for shorter courses of therapy and shorter hospital stays, which would decrease healthcare costs.

Daptomycin is a novel cyclic lipopeptide antibiotic that exhibits rapid dose-dependent bactericidal activity in vitro against most clinically relevant Gram-positive bacteria, including isolates resistant to oxacillin, vancomycin, and linezolid8–15. Daptomycin is approved as a once-daily intravenous (IV) injection (4 mg/kg; treatment duration: 7–14 days) for the treatment of cSSSIs caused by susceptible strains of Gram-positive organisms including MRSA and MSSA16. In phase III clinical trials, daptomycin was effective in the treatment of cSSSIs, with a clinical success rate of 83%17. Clinical success rates of > 90% have also been reported for patients with cSSSIs registered in the Cubicin Outcomes Registry and Experience program, a post-marketing review of daptomycin use across the United States18,19, as well as in prospective, open-label studies of patients treated for hospital-acquired MRSA and CaMRSA infections20,21. Studies have shown that daptomycin may induce more rapid resolution of signs and symptoms of infection than treatment with semisynthetic penicillins or vancomycin17,21–23.

The two pivotal phase III clinical studies of dapto-mycin for the treatment of cSSSIs were performed in multiple countries that differed significantly in standards of care and patient population characteristics. These differences may have obscured important differences in the resolution of clinical signs and symptoms between daptomycin and other antibiotics. The South African patient subset represented a substantial proportion (approximately 40% overall [daptomycin 39%, comparator 40%]) of the clinically evaluable patients enrolled in these studies. This subset provides a more homogenous population (South African patients were generally younger, and most of their infections were

associated with trauma) without inherent differences in healthcare standards, allowing for closer discrimination of differences between daptomycin and comparator antibiotic therapy. Thus, the objective of this study was to compare the rapidity of the resolution of clinical signs and symptoms between daptomycin and comparator agents for all South African patients treated in these two phase III studies.

Methods

patients

The methodology for the two registrational studies from which this subset of South African patients was derived has been described in detail elsewhere17. Briefly, one study was conducted at 64 sites in the United States and at five sites in South Africa, and the other study was conducted at 42 sites in Europe, 20 sites in South Africa, five sites in Australia, and three sites in Israel. Both studies followed the same study design. The primary inclusion criterion was a cSSSI that was due, in part, to a Gram-positive organism and required hospitalization and parenteral antibiotic therapy for at least 96 hours. Infection types included wound infections (e.g., surgical wounds, traumatic wounds, and bites), major abscesses, diabetic ulcer infections of the lower extremity, and infected ulcers from other causes. Exclusion criteria included minor or superficial infections, perirectal abscesses, gangrene, multiple infected ulcers at distant sites, or infections of third-degree burns. Patients were also excluded if they had bacteremia, had a concomitant infection at another site, or required curative surgery for their infection (e.g., amputation).

The clinically evaluable population for this analysis included all patients in the intent-to-treat population who met specific criteria such that the clinical outcomes of their infection could be inferred to reflect the effect of the study drug. These criteria included meeting the clinical criteria for the study infection, receiving the correct study drug as randomized for an appropriate duration and at the appropriate dosage, having the necessary clinical evaluations performed, and not receiving potentially effective non-study antibiotics.

Although no demographic differences were present in the original study for the overall study population, a preliminary analysis of the patient demographic data for the South African patients used for this analysis revealed that the comparator group had a greater proportion of patients with comorbid conditions (e.g., history of diabetes, peripheral vascular disease, immunodeficiency, bacteremia, and/or systemic inflammatory response syndrome [SIRS]) than the daptomycin group. Although there were no statistically significant differences between

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© 2007 LiBRAphARM LTd – Curr Med Res Opin 2007; 23(9) Daptomycin for skin/skin structure infections Krige et al. 2149

the two treatment groups in the percentage of patients with individual comorbid conditions or the percentage of patients with no/one or more comorbid condition, further examination revealed a significant difference between the treatment groups, favoring daptomycin, with respect to those with no or one comorbid condition and those with two or more comorbid conditions ( p = 0.0001; Table 1). Because differences in the clinical improvement of signs and symptoms between the daptomycin and comparator groups may be confounded by differences in comorbidities, patients with two or more comorbid conditions were removed from the analysis of the clinically evaluable population (five patients in the daptomycin group and 25 patients in the comparator group), leaving 326 (92%) of the original 356 clinically evaluable South African patients suitable for statistical analysis. Thus, the final patient population for all subsequent analyses comprised these 326 South African patients – 174 in the daptomycin group and 152 in the comparator group with no or one comorbidity (Table 1).

Treatment

Following baseline evaluation and prior to random-ization, the investigator assigned the comparator treat-ment regimen that the patient should receive if assigned to the comparator arm. Patients were then randomized (ratio 1:1) to receive either the comparator regimen (a penicillinase-resistant penicillin 4–12 g/day in equally divided doses or vancomycin 1 g every 12 hours) or IV daptomycin 4 mg/kg daily. Patients could be switched to oral antibiotic therapy if all of the following criteria were met: there was a compelling reason (e.g., inability to receive IV medication or need to leave the hospital), the patient had received ≥ 4 days of IV therapy, there was clear clinical improvement as assessed by the blinded investigator, and the infecting organism was susceptible to an available oral therapy.

Evaluation of clinical signs and symptoms

A single investigator (blinded to treatment assignment) at each site performed clinical evaluations for each

patient at baseline, on day 3 or 4 of therapy, at the end of therapy (EOT), and 6 to 20 days after administration of the last dose (test of cure [TOC]). At each study visit, the primary infection site was assessed for eight clinical signs and symptoms (edema, erythema, fluctuance, induration, necrotic tissue, purulent drainage, tenderness, and ulceration) by a blinded investigator. The severity of these signs and symptoms was subjectively evaluated as either none, mild, moderate, or severe. For the purposes of this analysis, these four severity categories were combined into two severity categories (none/mild and moderate/severe). The percentage of patients falling into these two severity categories was calculated for each of the evaluation visits (baseline, day 3 or 4, EOT, and TOC) and then compared between daptomycin and comparator agents.

Clinical outcomes (i.e., success or failure) were based on the sponsor-defined clinical improvement at the TOC visit, which was primarily the investigator’s response adjusted for factors that could influence efficacy (e.g., potentially effective non-study antibiotics or curative surgery). For each patient, clinical success was defined as the resolution of signs and symptoms of infection requiring no further antibiotic treatment at the TOC evaluation. Clinical failure was defined as an inadequate response to therapy at any point during the study evaluation.

Microbiologic assessments

Initial microbiologic assessments of cultures from samples (taken from the infected area or of the blood) were performed at a local laboratory. All Gram-positive isolates were sent to a central laboratory to determine the minimum inhibitory concentration to each of the study antibiotics using the broth microdilution method.

Safety and tolerability evaluation

Adverse events (AE) were monitored on a daily basis. The intensity (mild, moderate, or severe) and relatedness to study drug of the AE was determined by the investigator based on standardized grading scales (e.g. World Health Organization Toxicity Grading Scale).

Statistical analysis

For binomial or ordinal categorical data, the demo-graphics for the treatment groups were compared using the Fisher exact test or chi-square test. For continuous data, comparisons were performed using the t-test. The median test was used to compare the duration of therapy between the two treatment arms. The Cochran–Mantel–Haenszel chi-square test was

Table 1. Overview of clinically evaluable patients by presence of comorbid conditions*

Treatment group 0 or 1 comorbid condition

n (%)

≥ 2 comorbid conditions

n (%)

Comparators (n = 177) 152 (86) 25 (14)

Daptomycin (n = 179) 174 (97) 5 (3)

*Chi-square test for difference between treatment groups; p = 0.0001

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used to test the overall hypothesis that there is a linear association between treatment group (daptomycin vs. comparators) and severity category (none/mild vs. moderate/severe) for any of the clinical signs and symptoms at each of the visits. Chi-square tests (without adjustment for continuity) were computed for each clinical sign and symptom/visit pair (e.g., tenderness at baseline, tenderness at EOT) to determine which pair(s) may have contributed to the significant effect of the overall model. Statistically significant p-values were defined as p ≤ 0.05, and a statistical trend was defined as 0.05 < p ≤ 0.10; p-values were not adjusted for multiple comparisons.

Results

patient demographics

For the current analysis, the population of interest consisted of South African patients in the clinically

evaluable population (n = 326). There were no statistically significant differences between the two groups with respect to demographic characteristics, comorbid conditions, or primary diagnosis, with the exception of patient weight (Table 2). Slightly more than one half of the patients in both groups were men, and nearly two thirds of the patients in both groups were black. The mean age was 40 ± 13 years in each group. The major comorbid conditions were SIRS (31% of daptomycin patients and 30% of comparator patients) and diabetes (9% of daptomycin patients and 7% of comparator patients). No patients in the study had bacteremia. The most common primary diagnoses were wound infection (49% and 51% in daptomycin and comparator groups, respectively) and major abscess (21% and 20%, respectively). Other infections (22% of both groups) were primarily complicated cellulitis and infections related to traumatic injury. Adjunctive procedures were performed in 24% and 23% of daptomycin- and comparator-treated patients, respectively ( p = 0.90). Furthermore, for those

Table 2. Patient demographics for the analysis population

Demographic Daptomycin Comparators p-value

Patients, n 174 152

Sex, n (%) 0.79

Women 77 (44) 65 (43)

Men 97 (56) 87 (57)

Mean age, years (SD) 40 (13) 40 (13) 0.73

Mean weight, kg (SD) 70 (21) 65 (13) 0.005

Race, n (%) 0.31

Black 115 (66) 94 (62)

White 15 (9) 9 (6)

Other 44 (25) 49 (32)

Comorbid conditions, n (%)

SIRS 54 (31) 46 (30) 0.91

History of diabetes 15 (9) 10 (7) 0.54

PVD 3 (2) 5 (3) 0.48

Immunocompromised 1 (< 1) 0 (0) 1.00

Primary diagnosis, n (%)* 0.99

Wound infection 86 (49) 77 (51)

Major abscess 36 (21) 30 (20)

Infected ulcer (non-diabetic) 8 (5) 7 (5)

Diabetic ulcer infection 6 (3) 4 (3)

Other† 38 (22) 34 (22)

*Total exceeds 100% due to rounding†Other infections were primarily complicated cellulitis and infections related to traumatic injury for both groups PVD = peripheral vascular disease; SD = standard deviation; SIRS = systemic inflammatory response syndrome (defined as ≥ 2 of the following findings: temperature > 38ºC or < 36ºC; heart rate > 90 beats/minute; respiration rate > 20 breaths/minute; or WBC count ≥ 12 × 103 cells/µL or < 4 × 103 cells/µL or > 10% bands)

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patients who underwent incision and drainage or wound debridement, no differences were detected in the frequency of these procedures between the two groups (incision and drainage: 14% daptomycin vs. 11% comparator, p = 0.148; wound debridement: 13% daptomycin vs. 11% comparator, p = 0.275). Seventeen percent (56/326) of patients had a negative baseline culture (19% [33/174] daptomycin, 15% [23/152] comparator). A total of 348 pathogens were identified at baseline in the remaining 270 patients who constituted the microbiologically evaluable population. The most commonly cultured Gram-positive pathogens at baseline were MSSA and Streptococcus pyogenes (Table 3); therefore, most patients in the comparator group (146/152; 96%) received semisynthetic penicillinase-resistant penicillins, and only six patients (4%) received vancomycin.

Clinical outcome

There was no difference in overall clinical success rates between the two treatment groups. The clinical success rates at TOC were 93% for the daptomycin group (95% confidence interval [CI], 88–97%) and 95% for the comparator group (95% CI, 90–99%; 2% difference [95% CI, –7% to 3%]; p = 0.38).

Evaluation of clinical signs and symptoms

The evaluation of the overall relationship between treatment group and symptom severity showed a statistically significant difference ( p = 0.04) between daptomycin and comparators, indicating that the two groups differed in the severity of symptoms across visits for one or more symptoms. The two groups did not differ in the severity of any clinical signs and symptoms at baseline. Overall, the daptomycin-treated patients responded earlier than those receiving comparator agents. The difference between treatment groups in improvement was apparent by the day 3/4 evaluation. Analysis of the individual clinical signs and symptoms showed statistically significant differences between the treatment groups for induration (day 3/4 [ p = 0.03], EOT [ p = 0.04], and TOC [ p = 0.03] evaluations) and erythema (day 3/4 evaluation [ p = 0.05]) (Figure 1A and 1B). A statistical trend toward faster resolution was observed in patients treated with daptomycin versus comparator treatment, for tenderness at the EOT evaluation ( p = 0.06), edema at the day 3/4 evaluation ( p = 0.10), and necrotic tissue at the day 3/4 evaluation ( p = 0.10) (Figure 1C, 1D, and 1E). In each instance, more patients in the daptomycin group showed milder symptom severity following treatment than in the

Table 3. Cultured Gram-positive organisms at baseline*

Organism, n (%) Daptomycin (n = 178)

Comparator (n = 170)

Staphylococci 93 (52) 83 (49)

Methicillin-susceptible Staphylococcus aureus 81 (46) 76 (45)

Methicillin-resistant S. aureus 1 (< 1) 1 (< 1)

S. aureus (methicillin susceptibility not reported) 11 (6) 6 (4)†

Streptococci 78 (44) 74 (44)

Streptococcus pyogenes 59 (33) 63 (37)

Streptococcus agalactiae 5 (3) 2 (1)

Streptococcus dysgalactiae, equisimilis 3 (2) 2 (1)

Streptococcus anginosus 1 (< 1) 3 (2)

Other‡ 10 (6) 4 (2)

Enterococci 7 (4) 10 (6)

Enterococcus faecalis 5 (3) 9 (5)

E. avium 1 (< 1) 1 (< 1)

Vancomycin-intermediate E. faecalis 1 (< 1) 0

Miscellaneous§ 0 3 (2)

*Identified at a central laboratory†Four isolates were identified as methicillin-susceptible at a local laboratory. The remaining two isolates were not tested‡Includes Streptococcus constellatus (n = 2), Streptococcus intermedius (n = 1), Streptococcus milleri (n = 2), Streptococcus mitis (n = 2), Streptococcus oralis (n = 3), Streptococcus pneumoniae (n = 1), Streptococcus sanguis (n = 1), and other streptococci (n = 2)§Includes Clostridium perfringens (n = 2), Peptococcus spp. (n = 1)

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comparator group. No differences were statistically significant in resolution of ulceration, fluctuance, or purulent drainage (Figure 1F, 1G, and 1H).

duration of therapy

Patients receiving daptomycin required a shorter length of therapy than those receiving comparator agents. This was true whether all patients in the clinically evaluable population (those defined as clinical success and clinical failure) were compared (Table 4) or if only those classified as a clinical success were compared (daptomycin median 7.0 days [range, 4–15 days] vs. comparator 8.0 days [range 4–17 days]; p < 0.0001). Thus, the faster resolution of signs and symptoms for the daptomycin group occurred with shorter treatment duration. Moreover, no patients in the daptomycin group required additional oral antibiotic therapy, compared with two patients in the comparator group.

Safety and tolerability

Both daptomycin and comparator agents were well tolerated, and there were no significant differences in adverse events reported between daptomycin and com-parator groups. Adverse events related to daptomycin and comparator were reported in 10% and 11% of patients, respectively. No serious adverse events related to either daptomycin or comparator were reported. Overall, only one patient discontinued therapy owing to an adverse event. This occurred in a daptomycin-treated patient who received 6 days of daptomycin therapy and experienced a febrile reaction. The patient did not require additional treatment and was considered a cure. The most common adverse events in both groups were headache (6.4%), injection site thrombosis (5.5%), constipation (3.1%), and increased blood creatine phosphokinase (2.5%).

Discussion

In this subset analysis of South African patients from two registrational phase III studies, the rapidity of clinical improvement with daptomycin was compared with other agents for the treatment of cSSSIs caused by Gram-positive organisms. Clinical success rates and tolerability were similar between groups; however, daptomycin was more rapidly effective, with a shorter length of therapy compared with penicillinase-resistant penicillins or vancomycin. The more rapid clinical improvement induced by daptomycin is noteworthy in that both daptomycin and the penicillinase-resistant penicillins (used to treat most patients in the comparator group) are considered bactericidal agents.

Clinical success rates for daptomycin treatment and standard therapy were greater than 90% at the TOC evaluation, which is slightly higher than that observed in the overall pivotal study population (83.4% for daptomycin vs. 84.2% for comparators)17. This is not surprising because the South African population eligible for the current analysis was younger (mean age about 40 years compared with about 52 years in the overall pivotal study population) and healthier (e.g., lower incidence of diabetes mellitus; 8% in current analysis vs. > 30% of patients in the original study) than the overall population used in the original study17. The high clinical success rates are consistent with those reported by other investigators18–20,22.

Similar to previous reports17,20,22,23, daptomycin demonstrated a rapid clinical improvement relative to comparators, as shown by the decrease in the severity of some clinical symptoms (induration and erythema) by day 3 or 4. Moreover, the length of antibiotic therapy was significantly shorter relative to comparators. This may be due in part to the rapid bactericidal activity of daptomycin against Gram-positive pathogens compared with other drugs typically used for these

Treatment Number of patients Number of days p-value (median test)Mean (SD) Median (range)

Intravenous

Daptomycin 174 7.0 (1.5) 7.0 (3–15) < 0.0001

Comparators 152 7.8 (1.9) 8.0 (3–17)

Oral

Daptomycin 0 NA NA NA

Comparators 2 5.0 (1.4) 5.0 (4–6)

Total

Daptomycin 174 7.0 (1.5) 7.0 (3–15) < 0.0001

Comparators 152 7.9 (2.0) 8.0 (3–17)

NA = not applicable; SD = standard deviation

Table 4. Duration of antibiotic therapy in the clinically evaluable population (all patients)Cur

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infections. Daptomycin has a distinct mechanism of action24,25 resulting in depolarization of the membrane and inhibition of protein, DNA, and RNA synthesis, leading to bacterial cell death with minimal bacterial lysis26–28. Daptomycin is bactericidal against both growing and stationary phase bacteria29,30. In vitro studies demonstrated that daptomycin exhibits greater and more rapid bactericidal activity than vancomycin, linezolid, and quinupristin-dalfopristin against a variety of Gram-positive bacteria, including staphylococcal strains (MRSA, vancomycin-intermediate S. aureus), methicillin-resistant Staphylococcus epidermidis, and vancomycin-resistant enterococci12–14. In an in vitro pharmacodynamic model with simulated endocardial vegetations, daptomycin was more rapidly bactericidal than nafcillin, vancomycin, and linezolid at moderate and high inocula31.

In this analysis, there were no statistically significant differences in demographics (other than weight) or the severity of clinical signs and symptoms at baseline, indicating that both treatment groups were similar and were at comparable stages of infection at study entry. At the day 3/4 evaluation, differences in symptom severity began to emerge between the two groups, suggesting that daptomycin induced more rapid resolution of infection symptoms than comparators. Statistically significant improvements were seen in induration and erythema, and a statistical trend toward improvements was seen in tenderness, edema, and necrotic tissue. Of interest, moderate to severe induration, erythema, tenderness, and edema were present in > 75% of patients at baseline. In addition, these symptoms are commonly considered early signs of inflammation caused by local cellular infiltration induced by the innate immune response32,33.

The differential effects of daptomycin on clinical signs and symptoms may be the result of its unique mechanism of action in addition to its rapid bactericidal activity. Daptomycin is a bactericidal agent but does not induce significant bacterial cell lysis, in contrast to other cell wall active agents, including beta-lactams. Bacterial cell lysis releases intracellular and cell wall components that interact with host toll-like receptors to stimulate innate immune responses, including inflammation34,35. Recent in vitro studies have shown that daptomycin decreases inflammatory responses of macrophages27,36. Thus, it may be that daptomycin also reduces inflam-matory responses in vivo, leading to faster resolution of the early clinical signs of inflammation (e.g., induration and erythema). Therefore, the combination of rapid bactericidal activity with minimal bacterial lysis at the time of cellular death may contribute to the faster resolution of clinical signs and symptoms.

The shorter duration of antibiotic therapy required by patients in the daptomycin group suggests that

shorter courses of daptomycin might be sufficient to achieve clinical efficacy in medical practice. It is well established that shorter treatment courses of IV antibiotics resulting in early conversion to oral antibiotic therapy and early hospital discharge can reduce hospitalization costs and overall costs of therapy37–41. Indeed, recent data showed that daptomycin-treated patients with cSSSIs had lower hospitalization costs than historical controls treated with vancomycin20,22. In patients achieving a complete resolution of cSSSIs, the median time to achieve clinical cure was significantly shorter with daptomycin than with vancomycin (4 vs. 8 days; p < 0.001)22. This resulted in a shorter median length of antibiotic related hospital stay in the daptomycin group (5 vs. 14 days; p < 0.01) and lower corresponding hospitalization costs ($4260 vs. $11 928)22. Similar findings for both time to cure and costs were reported by Hall et al.20 in their analysis of CaMRSA cSSSI.

There were a number of limitations with this study that should be considered. First, this was a post hoc analysis of a subset of patients from two prospective studies, which is susceptible to bias in data selection and analysis. Another potential limitation is the use of data from only the South African patients for the analysis. However, this was done to minimize the inherent differences in healthcare resources, utilization, and treatment patterns among patients from the original phase III studies. To further reduce variability that might confound clinical efficacy findings, patients with two or more comorbid conditions were removed from the analysis population because they were not equally represented in the two treatment groups. Many of these comorbid conditions have been previously identified as risk factors for poorer outcomes42–46. This adjustment made the study population more homogenous and, consequently, eliminated this potential bias and reduced any covariation between or among clinical signs and symptoms.

Another limitation is the study evaluation schedule; the earliest time point in the present study was day 3 or 4. Because daptomycin is rapidly bactericidal, it is possible that greater differences in the resolution of clinical signs and symptoms might be evident at earlier time points. Furthermore, several clinical signs and symptoms (e.g., ulceration, necrotic tissue, and fluctuance) were either not present or were mild in the majority of patients, so differences in these signs and symptoms were difficult to detect. Finally, there are limitations when using a subjective assessment to classify the severity of clinical signs and symptoms. Variation can occur during the assessment and some of the early changes may not have been readily identified. However, because the investigator was blinded to the treatment, this limitation would be equally applicable to both treatment arms.

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Conclusion

In conclusion, daptomycin produced a more rapid clinical improvement than comparators (predominantly semisynthetic penicillins) as evidenced by a more rapid decrease in certain clinical signs and symptoms and shorter duration of antibiotic therapy. It should be noted that this was a young and otherwise healthy study population, with primarily wound infections and major abscesses. Therefore, these results may not be directly applicable to other patient populations or types of infections. These results may carry the potential for cost savings as a result of the shorter treatment duration with daptomycin and indicate that further pharmacoeconomic studies are warranted.

Acknowledgments

Declaration of interest: This study was sponsored by Cubist Pharmaceuticals, Inc. The authors thank Rick Davis, MS, RPh and Mary E. Dominiecki, PhD for assistance in the drafting of this manuscript. JK is a consultant for Cubist Pharmaceuticals, Inc. KL, LF, CO, WM, and DK are employees of Cubist Pharmaceuticals, Inc.

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CrossRef links are available in the online published version of this paper:http://www.cmrojournal.com

Paper CMRO-3981_3, Accepted for publication: 06 July 2007Published Online: 31 July 2007

doi:10.1185/030079907X219652

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effectiveness and duration of daptomycin therapy in resolving clinical symptoms in the treatment of...

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