Prospective,Non-Comparative Study of Daptomycin for the Treatment of Superficial and Deep Incisional Surgical Site Infections

Abstract

Background:

Skin infections, including surgical site infections (SSIs), usually involve gram-positive pathogens and continue to be a leading cause of morbidity and death among hospital patients. The increasing prevalence of methicillin-resistant Staphylococcus aureus and other resistant strains accentuates the need for effective and safe therapies for such infections. This exploratory study evaluated the efficacy and safety of daptomycin in patients with gram-positive SSI according to wound classification.

Methods:

Eligible patients had an SSI with onset < 30 days after surgery, positive gram stain or culture at least three days before daptomycin therapy began, and three or more clinical signs and symptoms of infection. The incisional SSI was classified as superficial or deep according to the U.S. Centers for Disease Control and Prevention criteria. Patients with organ-space infections were excluded, as were those with major concomitant infections, foreign material in the incision that could not be removed, previous systemic antimicrobial therapy, or creatinine clearance < 30 mL/min. Daptomycin 4 mg/kg was administered intravenously once daily for 7–14 days. The primary efficacy endpoint was clinical response at the end of daptomycin therapy, and the safety assessment was based on adverse events (AEs).

Results:

Sixty-nine patients were enrolled, 60 of whom were evaluable for efficacy. Extremity wounds predominated among superficial incisional SSIs (n = 30), whereas abdominal wounds predominated among deep SSIs (n = 30). Patients with deep incisional SSI were more likely to be young, male, white, and febrile and to weigh more than patients with superficial SSIs. The overall clinical success rate was 92% (95% confidence interval [CI] 82-97%); the success rate was 100% in superficial incisional SSI and 83% in deep SSI (17% difference; 95% CI 0-33%). Staphylococcus aureus (28/36 methicillin-resistant) was the pathogen isolated most frequently. In 10 patients who were febrile at baseline, the median time to defervescence was five days, and the mean duration of treatment in the series was 11.2 days. Daptomycin was well tolerated. In most patients, AEs were mild or moderate in intensity; in two patients (one superficial, one deep), daptomycin was discontinued because of AEs.

Conclusions:

The results of this exploratory study of SSI are consistent with those of previous studies of daptomycin in the treatment of diverse complicated skin and skin-structure infections, and suggest that wound classification should be treated as an important covariate in future studies of daptomycin and other antibiotics.

Surgical site infection (SSI) continues to be a leading cause of morbidity and death in hospitals [1 –3]. For some types of surgical intervention (e.g., hepatobiliopancreatic or small bowel surgery), SSI rates can approach 25% [4]. Treatment of SSI and local (e.g., cellulitis, incisional hernia) or systemic (e.g., sepsis) complications represents a substantial burden on health care resources [5 –8]. As with other complicated skin and skin-structure infections, SSI typically involves gram-positive pathogens, notably Staphylococcus aureus [9 –11]. In recent years, the emergence of multi-drug-resistant Staphylococcus aureus—primarily methicillin-resistant S. aureus (MRSA)—as a causative pathogen has been of particular concern. In an analysis of more than 1,000 SSIs from eight hospitals between 2000 and 2005, 17% of infections were caused by MRSA, and the prevalence of MRSA infections nearly doubled during the six years of the study [12]. The issues associated with the increase in MRSA infections—including longer hospitalization times, higher mortality rates, and increased costs—have added to the sense of urgency in the development of new agents with antistaphylococcal activity [13].

Daptomycin, a first-in-class cyclic lipopeptide antibiotic, was originally approved for the treatment of complicated skin and skin-structure infections caused by susceptible strains of clinically relevant gram-positive microorganisms (including MRSA) and subsequently was approved for the treatment of bacteremia and right-sided infective endocarditis caused by S. aureus [14]. The mechanism of action of daptomycin involves depolarization of the bacterial cell membrane, thereby causing cell death in a concentration-dependent fashion [15].

Two randomized, investigator-blinded, multicenter, Phase III trials showed that intravenous daptomycin 4 mg/kg once daily was not inferior to standard therapy (penicillinase-resistant penicillins or vancomycin) against complicated skin and skin-structure infections, with similar clinical success rates for daptomycin- and comparator-treated groups (83.4% and 84.2%, respectively) [16]. Although incisional infections were the most common diagnosis in both studies (approximately 40%), only 10% of patients with incisional infections had specific diagnoses of SSI (Cubist Pharmaceuticals, Inc., unpublished data). Moreover, only minimal information was collected about the location, extent, and depth of the infected surgical site. The present study was conducted to assess further the overall efficacy and safety of daptomycin in the treatment of well-categorized incisional SSI caused by gram-positive pathogens, either superficial or deep.

Patients And Methods

Eligibility criteria and study interventions

This Phase IV, multicenter, single-arm, open-label, noncomparative study evaluated daptomycin in patients 18 years of age or older who had been found in the previous 30 days to have SSI caused by a gram-positive pathogen. All isolates were susceptible to daptomycin according to the inclusion criteria. All patients were required to have a positive gram stain or incision culture within three days before treatment and a minimum of three clinical signs of infection (e.g., elevated [> 37.5°C] or reduced [< 35.6°C] temperature, elevated white blood cell count, pain, erythema, or pus formation). Patients were excluded if they had received systemic antimicrobial therapy for more than 24 h in the previous three days, if they had uncomplicated SSI (i.e., cellulitis only), or if foreign material was present in the incision. Patients also were excluded if they had concomitant osteomyelitis, pneumonia, bacteremia, endocarditis, urinary tract infection, gangrene (synergistic, necrotizing fasciitis, or Fournier), any organ space infection, history of neurologic disease, or creatinine clearance < 30 mL/min. Before the start of the study, voluntary written informed consent was obtained in accordance with the International Conference of Harmonization guidelines and informed consent requirements (Code of Federal Regulations Title 21, Parts 50.20 and 50.25).

Enrolled patients were to receive daptomycin 4 mg/kg as a 30-min intravenous infusion (50 mL) once daily for 7–14 days, in accordance with the product's prescribing information for complicated skin and skin-structure infections [14]. Treatment durations shorter or longer than this range were permitted according to the investigator's clinical judgment. Adjunctive antibacterial agents having gram-negative (aztreonam) or anaerobic coverage (metronidazole) were permitted if indicated clinically, as were oral antibacterial agents at the end of intravenous therapy.

Patients received protocol-specified assessments at baseline, daily during the course of daptomycin therapy, at the end of therapy (EOT), and at follow-up 1–4 weeks after EOT. Enrolled patients underwent baseline evaluations (days −3 to 1) consisting of medical history, physical examination, recording of signs and symptoms of SSI, and classification of incision depth (deep or superficial) in accordance with the U.S. Centers for Disease Control and Prevention (CDC) definitions of nosocomial SSI [17]. At baseline, specimens for gram stain, culture, and susceptibility testing were obtained from the infected area, and clinical laboratory tests, including serum creatine phosphokinase (CPK) assay, were performed.

During the open-label treatment period, patients' temperatures were recorded daily along with concurrent systemic antibiotic medications, treatment-emergent adverse events (AEs), and any surgical procedures (e.g., incision and drainage). Removal of sutures or staples was performed according to each investigator's usual practice and was not standardized across the study. At EOT (last dose), these evaluations were performed in addition to assessment of SSI signs and symptoms and clinical response to daptomycin, physical examination, culture of specimens (if clinically important lesion or drainage persisted), and laboratory tests. Follow-up (1–4 weeks after EOT) contact was required for patients with an investigator's response of “improved” at EOT.

Patient populations

Three patient populations were defined. The clinically evaluable (CE) population was defined prospectively as the subset of patients receiving three or more doses of daptomycin who had a clinical outcome of success or failure at EOT. The microbiologically evaluable (ME) population was the subset of patients receiving three or more doses of daptomycin with a confirmed study pathogen isolated at baseline. Three days of therapy was judged to be the minimum necessary to attribute the patient's outcome to the drug. The safety population included all enrolled patients who received at least one dose of daptomycin.

Measures of outcomes

Primary efficacy endpoint

The primary efficacy endpoint was clinical response in the CE population at EOT according to the investigator's clinical assessment of signs and symptoms. Clinical response was judged as “cured” (resolution of clinically significant baseline SSI signs and symptoms), “improved” (partial resolution of signs and symptoms), “failed,” and “unable to be evaluated.” Clinical success was defined as “cured” or “improved.” All clinical responses were compared between wound-depth categories.

Secondary efficacy endpoints

Secondary efficacy endpoints included duration of treatment, time to defervescence, and microbiologic outcomes. The duration of treatment was the number of days of daptomycin treatment for patients with clinical responses of “cured” or “improved” at EOT. The time to defervescence was the number of days from the first day of the study to the first day of defervescence, defined as two consecutive days of temperatures ≤ 37.2°C. Microbiologic response was assessed in the ME population and was assigned to one of four categories: “nothing to culture,” “no growth,” “growth,” and “not performed.” All secondary endpoints were compared between wound-depth categories.

Evaluation of safety was based on the incidence of treatment-emergent AEs in the safety population, the incidence of AE-related premature discontinuations of daptomycin, and the incidence of elevated CPK. The AEs were categorized by causal relation to the study drug and severity.

Statistical methods

This exploratory study was not powered to detect differences between subpopulations. Therefore, only descriptive statistics are presented. Confidence intervals (CIs) for absolute response rates were calculated using the Clopper-Pearson exact method for binomial measures. The CIs for differences in response rates were calculated using the normal approximation to the binomial with continuity correction.

Results

Patient disposition and demographics

Sixty-nine patients were enrolled and received at least one dose of daptomycin. Of these, 60 patients composed the CE population, and 44 patients composed the ME population. Forty-one patients were evaluable clinically and microbiologically. Of those in the CE population, most were female (60%), white (66.7%), and younger than 65 years (73.3%). Although minimal information was collected about the original operations leading to the infections, SSIs among the study participants arose from a range of common surgical procedures. The emergency or non-emergency nature of the original operations was not recorded, but some clearly were elective (e.g., breast reduction), some were likely to have been emergency (e.g., appendectomy), and some could have been either elective or emergency (e.g. coronary artery bypass graft, cesarean section).

Clinically evaluable patients with deep SSI had different demographic and baseline characteristics than those with superficial SSI (Table 1). Patients with deep incisional SSI were more likely to be young, male, white, and febrile and to have elevated white blood cell counts; to weigh more; and to have a longer interval between diagnosis and treatment than patients with superficial SSI (7.8 vs. 6.4 days, respectively). Abdominal wounds constituted approximately half the deep SSI category, whereas limb, foot, and toe wounds constituted approximately half the superficial category. Debridement was performed more frequently on patients with superficial SSI than with deep SSI (27% and 13%, respectively). Pathogens were isolated at baseline from most patients, with S. aureus (28/36 MRSA) the most frequent causative organism (Table 2). All organisms tested were susceptible to daptomycin by the Clinical and Laboratory Standards Institute (CLSI) criteria; four isolates (three MRSA, one Enterococcus faecalis) were not tested. All enterococci isolated were susceptible to vancomycin.

Table 1.

Demographics, Baseline Characteristics, and Treatment Details of Clinically Evaluable Population

Pretreatment characteristics	Superficial incisional SSI (n = 30)	Deep incisional SSI (n = 30)
Mean age, years (SD; range)	56.9	52.6
	(16.3; 26–82)	(12.7; 29–79)
No. (%) < 65 years of age	18 (60.0)	26 (86.7)
No. (%) male	10 (33)	14 (47)
No. (%) white	15 (50)	25 (83)
Mean weight, kg (SD; range)	85.9 (20.2; 47.5–123.6)	95.7 (29.9; 58.5–204.0)
Site of incision, n (%)
Limb/foot/toe	16 (53.3)	8 (26.7)
Abdomen	6 (20.0)	14 (46.7)
Back/buttock	5 (16.7)	2 (6.7)
Sternum	1 (3.3)	0
Head and neck	0	2 (6.7)
Other chest	1 (3.3)	1 (3.3)
Groin	0	2 (6.7)
Axilla	1 (3.3)	0
Rectal/sacral	0	1 (3.3)
Debridement performed (%)	8 (26.6)	4 (13.3)
Temperature ≥37.8°C (%)	0	8 (26.7)
Elevated white blood cell count (%)	3 (10.0)	13 (43.3)
Mean time from surgery to diagnosis of SSI, days (SD)	9.8 (9.64)	9.6 (8.06)
Mean time from diagnosis of SSI to treatment, days (SD)	6.4 (6.49)	7.8 (10.23)
Mean duration of daptomycin treatment, days (SD)	10.9 (3.40)	11.3 (4.05)
Percent of doses administered as outpatient	83.2	56.0

Clinically evaluable patients were those who received at least three doses of daptomycin and had clinical outcomes of “success” or “failure” at the end of therapy.

SD = standard deviation; SSI = surgical site infection.

Table 2.

Baseline Microbiological Culture of Clinically Evaluable Population: Culture Results for Growth of Protocol-specified Pathogens

Pretreatment characteristics	Superficial SSI (n = 30) (%)	Deep SSI (n = 30) (%)	Total (n = 60) (%)
No growth	11 (36.7)	8 (26.7)	19 (31.7)
Growth	19 (63.3)	22 (73.3)	41 (68.3)
Staphylococcus aureus	17 (56.7)	19 (63.3)	36 (60.0)
MSSA	4 (13.3)	4 (13.3)	8 (13.3)
MRSA	13 (43.3)	15 (50.0)	28 (46.7)
Streptococcus agalactiae	0	2 (6.7)	2 (3.3)
Streptococcus pyogenes (group A)	1 (3.3)	0	1 (1.7)
Enterococcus faecalis	0	1 (3.3)	1 (1.7)
Enterococcus faecium	1 (3.3)	0	1 (1.7)
Enterococcus not otherwise specified	1 (3.3)	0	1 (1.7)

Clinically evaluable patients received at least three doses of daptomycin and had clinical outcomes of “success” or “failure” at the end of daptomycin therapy.

MRSA = methicillin-resistant S. aureus; MSSA = methicillin-susceptible S. aureus; SSI = incisional surgical site infection.

Nine patients, seven with deep incisional SSI and two with superficial infections, were not evaluable because of the lack of an EOT assessment (three patients), receipt of less than three days of daptomycin therapy (three patients), or both (three patients). Other baseline clinical and microbiological characteristics of the patients who were not evaluable were similar to those of the evaluable populations (data not shown).

Efficacy outcomes

The overall clinical success rate in the CE population at EOT was 92% (55/60; 95% CI 82%-97%; Fig. 1). The clinical success rate was 100% (30/30; 95% CI 88%-100%) in the superficial SSI group and 83% (25/30; 95% CI 65%-94%) in the deep SSI group (p = 0.052; Fisher exact test, two-tailed). Twenty-one patients had outcomes of “improved” at EOT (eight with superficial SSI, 13 with deep SSI). Of these patients, none with superficial SSI and three with deep SSI had outcomes of “failed” at the follow-up visit. Thus, among patients whose conditions were “improved” at EOT, the overall clinical success rate at follow-up was 86% (18/21; 95% CI 64%-97%); 100% (8/8; 95% CI 63%-100%) of patients with superficial SSI and 77% (10/13; 95% CI 46%-95%) of patients with deep incisional SSI achieved clinical success.

FIG. 1.

Overall success rate in clinically evaluable population.

The overall mean duration of daptomycin therapy for the 60 CE subjects was 11.0 days (range 4–19 days), with eight patients (13.3%) receiving < 7 days and three (5.0%), all with deep SSI, receiving > 14 days. The mean duration of treatment was similar for patients with outcomes of clinical success in the superficial and deep SSI groups (10.7 vs. 11.8 days, respectively; 95% CI for the difference −0.86–3.14 days). The mean duration of treatment for the five patients who failed therapy was eight days (range 4–12 days). The median time to defervescence was five days. In the safety population, only one patient with a superficial SSI was febrile at baseline; this patient experienced defervescence in two days. Nine patients with deep SSI were febrile at baseline. The maximum time to defervescence in the deep SSI group was nine days.

In patients with superficial SSI, microbiologic culture results at EOT from the ME population indicated “nothing to culture” or “no growth” in 16 of 19 patients (84%) (Table 3). In patients with deep SSI, culture results indicated “growth” in 6 of 25 patients (24%) and “nothing to culture” or “no growth” in 12 (48%). Five MRSA and one methicillin-susceptible S. aureus (MSSA) infections were present at EOT, all from patients with deep SSI. Ten patients in the ME population did not have a microbiologic assessment at EOT. Overall, treatment with daptomycin resulted in a resolution of 100% (13/13) of superficial SSI and 67% (10/15) of deep SSI caused by MRSA.

Table 3.

Culture Results at End of Therapy in Microbiologically Evaluable Population ^*

Culture results	Superficial SSI (n = 19) (%)	Deep SSI (n = 25) (%)	Overall (n = 44) (%)
Nothing to culture	11 (57.9)	6 (24.0)	17 (38.6)
No growth	5 (26.3)	6 (24.0)	11 (25.0)
Growth	0	6 (24.0)	6 (13.6)
Not performed	3 (15.8)	7 (28.0)	10 (22.7)
Staphylococcus aureus	0	6 (24.0)	6 (13.6)
MSSA	0	1 (4.0)	1 (2.3)
MRSA	0	5 (20.0)	5 (11.4)

All organisms tested were susceptible to daptomycin by CLSI criteria. One MRSA and one MSSA isolate were not tested for susceptibility to daptomycin.

Microbiologically evaluable population = enrolled patients who received at least three doses of daptomycin and had a confirmed study pathogen at baseline.

CLSI = Clinical and Laboratory Standards Institute; MRSA = methicillin-resistant S. aureus; MSSA = methicillin-susceptible S. aureus; SSI = incisional surgical site infection.

Safety outcomes

Patients (n = 69) who received at least one dose of daptomycin were included in the safety assessment. Overall, 24.6% (17/69) of patients experienced 49 treatment-emergent AEs. Most (80%) of these events were described as mild or moderate in severity, and most (80%) were judged to be unrelated to daptomycin. Nine AEs that occurred in six patients were assessed by the investigator as possibly related to daptomycin. These were injection-site irritation (two cases), hematochezia, candidiasis, vaginal mycosis, arthralgia, joint stiffness, pain in extremity, and azotemia. No patients died during the study. Eight patients experienced serious AEs, of whom two discontinued daptomycin as a result: One patient with a deep abdominal SSI caused by Streptococcus agalactiae experienced left leg venous thrombosis and discontinued treatment after 11 days, and one patient with a superficial incisional SSI of the limb attributable to E. faecalis experienced sepsis and multiple-organ dysfunction and discontinued treatment after two days. None of the serious AEs were considered related to daptomycin. One additional patient with a deep abdominal infection caused by MRSA developed bacteremia. This patient received a total of 12 days of daptomycin and was considered a clinical success. In 46 patients, serum CPK concentrations were determined at EOT. All values were within normal limits, including those from a patient who had elevated (more than twice the upper limit of normal) CPK at baseline.

Discussion

The results of this multi-center study demonstrate that intravenous daptomycin is safe, well tolerated, and effective in treating superficial and deep incisional SSI caused by gram-positive microorganisms, including MRSA. Daptomycin therapy provided overall clinical success in more than 90% of patients, including 100% of patients with superficial SSI. The microbiologic response rate was high. Baseline infection pathogens were eradicated in 84% of patients with superficial incisional SSI and in approximately 50% of those with deep SSI. Daptomycin was effective in eradicating 100% of superficial SSI and 67% of deep SSI caused by MRSA. Importantly, all isolates tested—including MRSA—were susceptible to daptomycin, and isolates persisting after one course of daptomycin treatment remained susceptible to the drug.

The overall clinical success rate of 92% for daptomycin in treating SSI was similar to the clinical success rate of 84% for patients with infected wounds (surgical or traumatic) seen in previous studies of daptomycin for the treatment of complicated skin and skin-structure infections [16,18]. The results presented here further suggest that wound classification based on the CDC criteria may be an important stratification variable, given that clinical and microbiologic success rates were higher in the superficial SSI category (100% and 84%, respectively) than in the deep SSI category (83% and 48%, respectively).

The efficacy of daptomycin shown in this study against SSI caused by gram-positive pathogens has important clinical relevance, given the risk of superficial and deep incisional surgical site infections in common surgical procedures, especially in long-duration, contaminated surgery and in patients with compromised physical status (higher American Society of Anesthesiologists [ASA] preoperative assessment score) [4,19,20]. The type of infecting organism is another important variable in evaluating efficacy, especially in the context of the increasing prevalence of MRSA in nosocomial infections. In a retrospective analysis of nearly 500 patients with S. aureus SSI, methicillin resistance was associated with a higher mortality rate 90 days after surgery than were MSSA infections [5]. Additional factors, including age of 70 years or greater, surgery lasting four hours or more, postoperative antibiotic treatment for more than one day, and discharge to a long-term care facility, were significantly associated with MRSA SSI in a univariable analysis of data from another retrospective study. However, only discharge to a long-term care facility and postoperative antibiotic treatment for more than one day remained significantly associated with MRSA SSI on multivariable analysis [21].

The current study of SSI found marked efficacy at the end of daptomycin therapy against MRSA isolated at baseline. These results are consistent with the findings by Arbeit et al. [16] in a broader range of complicated skin and skin-structure infections with MRSA isolates. In addition, the activity against MRSA in SSI reported here compares favorably with the microbiological success rates for vancomycin reported in the literature [22 –24]. The encouraging clinical and microbiological success rates reported in this analysis translated to a median time to defervescence of five days and a mean duration of treatment of 11.2 days.

The results of this study are similar to those recently reported in a postmarketing analysis of the use of daptomycin in the treatment of SSI. In this analysis, the overall clinical success rate at the end of therapy in 231 patients was 94%; 98% of patients with a superficial SSI and 89% of patients with a deep SSI achieved clinical success [25].

The safety profile of daptomycin in this study was unremarkable and consistent with a surgical population and with prior clinical experience [16]). Adverse effects commonly associated with other classes of antimicrobials (e.g., nephrotoxicity, local irritation, ototoxicity, hypersensitivity, and gastrointestinal effects) were infrequent.

The limitations of this study include its open-label design, lack of a comparator group, and the paucity of data collected about the original operations giving rise to the infections under study. However, this trial was not designed to be a rigorous, controlled assessment of the efficacy of daptomycin for the treatment of SSI. Instead, the objective was to provide further understanding of the use of daptomycin for the treatment of SSI and, specifically, to explore the different responses of superficial and deep SSI characterized by the CDC criteria. An additional limitation of the study is that the use of adjunctive surgical procedures was not standardized. For reasons that are not clear, debridement was performed more frequently for superficial than for deep SSIs; this difference may have contributed to the differences in outcomes of the two treatment groups. Nevertheless, the results of this trial provide useful information about the response of two major categories of SSI categories to daptomycin therapy and may offer important guidance to other studies on the antimicrobial treatment of these infections.

In conclusion, the present study indicated daptomycin is safe and effective in the treatment of superficial and deep SSI caused by gram-positive pathogens, including MRSA. The differential outcomes in superficial and deep SSI suggest that wound classification should be considered a stratification variable in future studies of antibacterial treatment of SSI.

Footnotes

Acknowledgments

Doctors Beth A. Kamp and Brian Falcone provided expert writing and editorial assistance. Preparation of the manuscript was funded by Cubist Pharmaceuticals, Inc.

Author Disclosure Statement

This study was supported by Cubist Pharmaceuticals, Inc., of Lexington, Massachusetts. AGK, SY, and WJM are employees of Cubist.

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