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

Benjamin A. Lipsky1,* and Uschi Stoutenburgh2

1 University of Washington School of Medicine, and General Internal Medicine Clinic, VA Puget Sound Health Care System (S-111-GIMC), 1660 S. Columbian Way, Seattle, WA 98108-1597; 2 Cubist Pharmaceuticals, Inc, Lexington, MA, USA


* Corresponding author. Tel: +1-206-764-2551; Fax: +1-206-764-2849; Email: benjamin.lipsky{at}med.va.gov

Received 2 September 2004; returned 1 October 2004; revised 9 November 2004; accepted 10 November 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives:

The predominant pathogens causing diabetic foot infections are Gram-positive cocci, many of which are now resistant to commonly prescribed antibiotics. Daptomycin is a new agent that is active against most Gram-positive pathogens. To compare the effectiveness of daptomycin against semi-synthetic penicillins or vancomycin, we analysed the subset of diabetic patients with an infected ulcer enrolled in two randomized, controlled investigator-blind trials of patients with complicated skin and soft-tissue infections presumptively caused by Gram-positive organisms.

Patients and methods:

Patients with a diabetic ulcer infection were prospectively stratified to ensure they were equally represented in the treatment groups, then randomized to either daptomycin [4 mg/kg every 24 h intravenously (iv)] or a pre-selected comparator (vancomycin or a semi-synthetic penicillin) for 7–14 days.

Results:

Among 133 patients with a diabetic ulcer infection, 103 were clinically evaluable; 47 received daptomycin and 56 received a comparator. Most infections were monomicrobial, and Staphylococcus aureus was the predominant pathogen. Success rates for patients treated with daptomycin or the comparators were not statistically different for clinical (66% versus 70%, respectively; 95% CI, –14.4, 21.8) or microbiological (overall or by pathogen) outcomes. Both treatments were generally well tolerated, with most adverse events of mild to moderate severity.

Conclusions:

The clinical and microbiological efficacy and safety of daptomycin were similar to those of commonly used comparator antibiotics for treating infected diabetic foot ulcers caused by Gram-positive pathogens. Daptomycin should be considered for treating these infections, especially those caused by resistant Gram-positive pathogens.

Keywords: diabetic ulcers , foot infections , soft tissue infections , antibiotic resistance , Gram-positive infections


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Foot ulcers are a common complication of diabetes mellitus, and these lesions frequently become infected.1,2 Most infections are mild to moderate in severity and can be managed on an outpatient basis with appropriate wound care and oral antibiotic therapy.3 Some infections, however, penetrate to fascia, muscle, joint and bone. These more severe diabetic foot infections usually require hospitalization, parenteral antibiotic therapy and surgical procedures.4 In all grades of infection, Staphylococcus aureus is the most frequently isolated microorganism.3,57 It may be the sole pathogen in acute infections, or part of the polymicrobial flora of chronic infections.3 Soft-tissue infections caused by strains of methicillin-resistant S. aureus (MRSA) are becoming increasingly prevalent in both institutional8 and community9 settings. Compared with other pathogens, diabetic foot infections caused by MRSA are associated with worse outcomes, including delayed healing and more frequent amputations.1015 These suboptimal outcomes highlight the need for new approaches, including using antibiotics highly active against MRSA when needed.

Daptomycin is the first agent of a novel class of cyclic lipopeptide antibiotics.16 Unlike other available agents, it offers once daily dosing and rapid in vitro bactericidal activity17 against MRSA,18,19 as well as penicillin-resistant streptococci19 and vancomycin-resistant enterococci.18,19 Recently, two Phase III trials that enrolled 1092 patients compared daptomycin with either vancomycin or a semi-synthetic penicillin for treating complicated skin and soft-tissue infections.20 Among those enrolled in the trials were diabetic patients with an infected ulcer. Because of the special characteristics of this subset of patients, and the potential severity of these infections, they were separately randomized during enrolment. This report specifically analyses the results of treating infected diabetic ulcers with daptomycin versus the comparators.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Two identical multicentre, international, investigator-blinded Phase III trials assessing the safety and efficacy of daptomycin for treating complicated bacterial skin and soft-tissue infections were conducted at 134 sites in the United States, Europe, South Africa, Australia, and Israel between 1999 and 2001. The institutional review board or independent ethics committee of each participating institution approved the protocols, and they were conducted in accordance with the principles of the Declaration of Helsinki, the Harmonized Tripartite Guidelines of Good Clinical Practice, and local laws and regulations.

Patient eligibility

Eligible patients were those with diabetes between the ages of 18 and 85 years who required hospitalization for an infected ulcer that was known or suspected (based on a Gram-stained smear) to be caused by a Gram-positive organism. Infection was defined as the presence of at least three of the following: elevated body temperature (greater than 38°C); leucocytosis (white blood cell count greater than 12.0 x 109/L) or a left-shifted leucocyte differential (10% or more band forms); local pain; tenderness to palpation; erythema; induration; or purulent secretions.

Patients with minor or superficial skin infections, uncomplicated cellulitis, myositis, multiple infected ulcers at distant sites, infected third-degree burn wounds, osteomyelitis, known bacteraemic shock, hypotension, or any disorder that could interfere with the treatment evaluation were excluded. Other exclusions were pregnancy, infection due to an organism known to be resistant to any study drug before study entry, body weight less than 40 kg, history of hypersensitivity reaction to any study drug, need for haemodialysis or peritoneal dialysis, impaired renal function (creatinine clearance less than 30 mL/min), immunosuppression, serum creatine phosphokinase (CPK) more than 50% above the upper limit of normal, or the use of any 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitor (statin) drugs. Patients were also excluded if they had received more than 24 h of systemic antibiotic therapy for the infected ulcer within the previous 48 h, unless the infecting Gram-positive organism was resistant to that therapy, or it was clinically ineffective. No non-study systemic or topical antimicrobials or antiseptics were allowed.

Patient evaluation

At the baseline (screening) visit, each patient provided a medical history, underwent a physical examination, and then had routine haematology tests, serum chemistries, a pregnancy test (where appropriate) and a urinalysis. Plain radiographs of the affected foot were obtained to exclude patients with osteomyelitis. Specimens were obtained for Gram staining and culture within 48 h before the initiation of study drug. Investigators were encouraged to take samples from the infected ulcer by tissue biopsy or debridement, or by needle aspiration of purulent secretions. Specimens were processed at the clinical microbiology laboratory at each site (all of which were certified by the National Committee for Clinical Laboratory Standards). All Gram-positive organisms isolated on culture were tested at the local laboratory for susceptibility to daptomycin, vancomycin and semi-synthetic penicillins, using Kirby–Bauer disc diffusion methods.21 In addition, all Gram-positive organisms were sent to one of two central reference laboratories for identification of the species level using standard procedures22 and for susceptibility testing by minimal inhibitory concentration (MIC) and disc diffusion methodologies.21,23 Daptomycin susceptibility was tested at the central reference laboratories and was carried out in accordance with the procedures subsequently published by the National Committee for Clinical Laboratory Standards in 2000.24

Randomization and treatment

Before randomization, each eligible patient was assigned to a comparator group (vancomycin or semi-synthetic penicillin) by the investigator, based on the investigator's assessment of the patient's clinical history and condition and the likelihood of infection with MRSA (Figure 1). This procedure was designed to ensure that a patient randomized to the comparator antibiotic would receive the most appropriate therapy (i.e. vancomycin if MRSA was suspected). Patients were then randomized to a 7–14 day course of daptomycin [4 mg/kg every 24 h intravenously (iv) over 30 min] or to their pre-selected comparator [vancomycin 1 g every 12 h iv over 60 min or a semi-synthetic penicillin (nafcillin, oxacillin, cloxacillin or flucloxacillin, per the investigator's choice) given in equally divided doses totalling 4–12 g/day iv]. For suspected or proven polymicrobial infection, the investigator was allowed to add aztreonam to cover Gram-negative bacteria, or metronidazole to cover obligate anaerobic bacteria, at his or her discretion. Investigators were encouraged to provide appropriate wound care, including debridement and pressure off-loading.



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Figure 1. Study design of daptomycin Phase III trials. Patients were first assigned to a comparator group based on the investigator's clinical assessment, then randomized to either remain on comparator or receive daptomycin.

 
Study end-points

Patients were assessed at ‘end-of-therapy’ (i.e. within 3 days of the last dose of study drug); ‘test-of-cure’ (i.e. within 6–20 days after completing the study drug); and ‘post-study’ (i.e. within 20–28 days after completing the study drug). At each assessment, a blinded investigator categorized the clinical outcome as one of the following: ‘cured’ if all clinically significant signs and symptoms of infection had resolved; ‘improved’ if clinical signs and symptoms had partially resolved relative to the baseline assessment, with no further need for antibiotic therapy; ‘failure’ if the response to therapy was inadequate, there were missing outcomes, or the patient was non-evaluable; or ‘unable to evaluate’ if the patient was lost to follow-up. The clinical success rate, defined as the percentage of patients deemed either ‘cured’ or ‘improved’ at the test-of-cure visit, was the primary efficacy variable. The microbiological success rate, defined as proven or presumed eradication of the baseline wound pathogens, was a secondary efficacy variable. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) as required by the International Conference on Harmonisation guidelines.25 Monitoring for adverse events was conducted throughout the study; treatment-emergent adverse events were rated as mild, moderate, or severe, using standard United States Food and Drug Administration (US FDA) criteria.26

Statistical analyses

The Phase III studies were powered to test the non-inferiority hypothesis, i.e. that the difference in success rates (comparator minus daptomycin) was less than 10%. Because we did not intend that comparisons within diagnostic subgroups be statistically powered, the presented data are descriptive of the results observed in the diabetic ulcer group. The differences in success rates are described by a 95% confidence interval around the difference in success rates (comparator minus daptomycin) based on the normal approximation to the binomial distribution.27


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Among the 1092 patients enrolled in the two studies, 133 (12%) had an infected diabetic ulcer. Of these, 103 were clinically evaluable, 47 of whom received daptomycin, and 56 of whom received a comparator (a semi-synthetic penicillin for 27 and vancomycin for 29). The majority of clinically evaluable patients (n=55) were from sites in the United States; other countries in which patients were enrolled were South Africa (n=14), Russia (n=8), the Czech Republic (n=7), Hungary (n=5), Germany (n=3), Australia (n=3), France (n=2), Spain (n=2), the UK (n=2), Austria (n=1) and Israel (n=1). The baseline demographic characteristics of patients with diabetic ulcers were similar to those of patients enrolled in other studies.2,28 Patients in the daptomycin and comparator groups were statistically equivalent with respect to all noted baseline variables, including mean age (60 and 63 years), sex (54% and 54% male) and race (80% and 78% white), respectively. Among the infections categorized as diabetic ulcers, 85% were confirmed to be located on the foot, but it is likely that most (if not all) of the others were also foot ulcers. At baseline, all of the isolated Gram-positive organisms tested at the central reference laboratories were susceptible to both daptomycin and vancomycin. In the clinically evaluable population, Gram-negative pathogens were identified in 22 patients in the daptomycin arm and 23 patients in the comparator arm. In addition to their assigned study drug, 41 clinically evaluable patients received aztreonam: 18 patients in the daptomycin arm and 23 in the comparator arm. Of the patients who had a Gram-negative pathogen and received aztreonam, 13 were in the daptomycin arm and 17 in the comparator arm.

As shown in Table 1, the overall clinical success rate was 66% for patients treated with daptomycin and 70% for patients treated with a comparator agent (95% CI, –14.4–21.8). Looking at individual comparators, the clinical success rates for patients randomized to daptomycin versus a semi-synthetic penicillin were 64.0% and 70.4%, respectively, whereas for those randomized to daptomycin versus vancomycin rates were 71.4% and 69.0%, respectively. None of these differences was statistically significant.


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Table 1. Clinical success rates for patients with infected diabetic ulcers by antibiotic treatment group (clinically evaluable population)

 
Microbiological results were available for 103 evaluable patients (Table 2); cultures were negative in 10 patients. Among the 93 subjects with a positive culture, 43 were in the daptomycin group and 50 were in the comparator group. In patients with a positive baseline culture, 64/93 (69%) had a single Gram-positive pathogen, and 29/93 (31%) had two or more Gram-positive pathogens. S. aureus was the predominant pathogen in both treatment groups, with 10 (18.2%) of 55 isolates being methicillin-resistant. Among the patients with an MRSA isolate, one was treated with daptomycin and seven with vancomycin. Two MRSA patients were randomized to a semi-synthetic penicillin but were switched to vancomycin after treatment with 5 days of flucloxacillin in one case and 6 days of nafcillin in the other; both were clinical successes. Success rates for clinical outcome and microbiological eradication by baseline infecting organism were similar for most pathogens, and for the patients in the daptomycin and comparator groups (Table 3). The success rate data reported are only those for the Gram-positive pathogens included in the US FDA's indication for daptomycin: S. aureus (methicillin-susceptible and methicillin-resistant), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies equisimilis, and vancomycin-susceptible Enterococcus faecalis.


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Table 2. Gram-positive pathogens isolated from infected diabetic ulcers at baseline in the clinically evaluable population

 

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Table 3. Clinical and microbiological success rates by infecting pathogena

 
The incidence of adverse events (Table 4) was comparable between the treatment groups. The most common events in both groups were gastrointestinal; most adverse events were deemed unrelated to the study medications, were of mild to moderate intensity, and rarely required that the drug be discontinued. Of the 56 adverse events that were possibly or probably related to treatment, 37 (66%) occurred in the 72 patients in the comparator group, and 19 (34%) occurred in the 61 patients in the daptomycin group. Adverse events associated with aztreonam occurred in 13 patients in the daptomycin group and 16 in the comparator group, whereas adverse events associated with metronidazole were reported in four patients in the daptomycin group and seven receiving a comparator. Adverse events rated as severe occurred in six patients in the comparator group and one in the daptomycin group. The daptomycin-treated patient had elevated serum CPK levels during the second week of treatment, associated with upper extremity pain and weakness. Daptomycin was discontinued and all clinical and laboratory abnormalities rapidly resolved. This was one of two cases (0.4%) of CPK elevations leading to discontinuation of daptomycin among all 534 patients treated in the Phase III trials of daptomycin.


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Table 4. Adverse events possibly or probably related to the study druga

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A diversity of organisms may cause foot infections in diabetic patients, but S. aureus is consistently the predominant, and often sole, pathogen.5 Any antibiotic regimen selected to treat these infections must therefore include an antistaphylococcal agent. With the increasing prevalence of antibiotic-resistant Gram-positive pathogens, particularly MRSA, in the community as well as hospitals, antibiotic regimens previously demonstrated to be effective for treating diabetic foot infections will often be inadequate.2,28 Thus, selected patients at risk for infection with resistant Gram-positive bacteria would be appropriate candidates for antibiotics active against these pathogens. Daptomycin is one such agent, and the results of this study demonstrated that it was as effective in treating diabetic foot infections caused by Gram-positive bacteria as either vancomycin or the semi-synthetic penicillins.

The choice of an antibiotic regimen for treating diabetic foot infections should be based on several factors, including its proven clinical efficacy, convenience, cost (of the drug and its administration) and safety. With the data available from this study, there are now three main antibiotic options to consider if infection with MRSA is suspected: vancomycin, linezolid and daptomycin. Vancomycin had not been specifically studied for treating diabetic foot infections before this study, but it has a long clinical track record for treating complicated soft-tissue infection.29 Acquisition costs for generic vancomycin are relatively low, but total costs must take into consideration that it usually must be administered twice daily, often requires monitoring of drug levels to ensure efficacy and avoid toxicity,30 and is only slowly bactericidal against staphylococci and enterococci.31 Overuse of vancomycin has resulted in the emergence of resistant strains of enterococci32 and staphylococci,33 diminishing its utility and leading the US Centers for Disease Control to discourage unnecessary use.34 Furthermore, recent studies of soft-tissue infection have shown that, compared with vancomycin, newer agents, such as linezolid, may be more clinically active and even cost-effective.35,36

Linezolid has demonstrated efficacy for treating diabetic foot infections in a large randomized, controlled trial.7 Clinical cure rates with linezolid and the aminopenicillin-penicillinase inhibitor comparators were statistically equivalent overall (81% versus 71%, respectively) but were significantly higher for linezolid-treated patients with an infected foot ulcer (81% versus 68%; P=0.018).7 Linezolid was associated with more drug-related adverse effects, however, and routine blood count monitoring is recommended for more than a 2 week course of therapy.37,38 Fortunately, most soft-tissue diabetic foot infections do not require a prolonged course of antibiotics. Both the linezolid study and the current one with daptomycin demonstrate that 2 weeks of antibiotic therapy is usually a sufficient duration for soft-tissue infections of mild to moderate severity. The oral formulation of linezolid allows convenient initial or switch therapy, but it must be given twice daily, and there have been reports of clinical failures in bacteraemic patients with linezolid-susceptible MRSA.39,40 These rare cases highlight the continual need for clinical vigilance and for developing alternative treatment options.

Daptomycin is a newly licensed, rapidly bactericidal,41 concentration-dependent antibiotic.42 A recent study of over 6700 Gram-positive isolates (staphylococci, streptococci, enterococci, Bacillus spp., Corynebacterium spp. and Listeria spp.) from Europe, North America and South America demonstrated that 99.4% had an MIC of ≤ 2 mg/L, well below the usual therapeutic serum levels.19 Furthermore, in a European study of S. aureus isolates with genotypic resistance to oxacillin and ciprofloxacin, daptomycin MICs were ≤ 0.5 mg/L.18 Daptomycin must be administered parenterally, but only once daily, thus reducing drug administration costs and making it particularly convenient for outpatient parenteral antibiotic therapy.

In this study, daptomycin achieved a clinical success rate of 66%, similar to the 70% for the comparators, and similar to results of other reported trials treating diabetic foot infection in hospitalized patients.2,28 The number of evaluable patients enrolled (103 total) was greater than in most previous studies of diabetic foot infections, and, unlike most other studies, the evaluating investigator was blinded to therapy. Consistent with other studies,5,7 S. aureus was the most frequently isolated pathogen. For methicillin-susceptible S. aureus (MSSA), clinical success rates were 79% in each arm, and eradication rates were 63% in the daptomycin group and 68% in the comparator group. The prevalence of MRSA was too low to draw any conclusions about the relative efficacy of daptomycin and comparators against this pathogen. Daptomycin was well tolerated, with only one severe drug-related adverse event, a reversible elevation of serum CPK levels. In randomized, controlled trials, clinically significant CPK elevations have been rare, asymptomatic, and reversible upon discontinuing treatment. Limitations of this study include the fact that there were few patients infected with MRSA, and a small proportion of patients with an infected diabetic ulcer did not have a confirmed location to the foot.

The role of daptomycin in treating diabetic foot infections will need further exploration, but based on these results, as well as its in vitro spectrum of activity, its efficacy and safety in treating complicated skin and soft-tissue infections, its good tolerability, and its once-daily dosing, it should be considered for those requiring parenteral therapy, particularly if MRSA infection is suspected.


    Acknowledgements
 
We thank Megan Robertson, Stuart Murray and Kevin Flynn for their help in preparing the manuscript. This study was supported by Cubist Pharmaceuticals, Lexington, MA. U.S. is an employee of Cubist and B.A.L. has been an investigator and consultant to Cubist.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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