In this comparative, randomized, double-blind, multicentre study, moxifloxacin iv/oral was non-inferior to TZP–AMC in the treatment of cSSSIs, stratified according to severity and the need for initial baseline surgery. Such stratification prior to randomization has not, to the authors' knowledge, been carried out in other clinical trials and its omission from cSSSI studies has been identified as a potential design flaw.24
The four infections that determined eligibility were clearly defined: major abscess; DFI; wound infection; and infected ischaemic ulcer. DFI was assessed using several severity scores (data not shown) to ensure that patients with moderate-to-severe infections were recruited. The characteristics of the subgroup of patients with abscesses reflected that of a population with major abscesses, based on the size and location of abscesses seen. Such patients have been identified as potentially benefiting from hospital admission and initial iv therapy in addition to surgical intervention, especially if diabetes is a co-morbidity.6
The strict methodology used provided an in-depth and accurate assessment of patients and disease characteristics. Assessment by a blinded DRC, prospective use of the Wilson risk class and standardized photographic assessment of the lesions all helped eliminate investigator bias. The use of repeated photographs as a diagnostic tool has been validated in other clinical specialties, e.g. dermatology,25
and was used in the current study to improve diagnostic consistency.24
Indeed, a recent meta-analysis of cSSSI trials24
concluded that the legitimacy of using antimicrobials could be confirmed by such an approach. Retrospective stratification by cSSSI subgroup is common in clinical trials, but prospective stratification by disease type and severity, and detailed assessments of patients' wound types and clinical responses have not, to our knowledge, been reported in other cSSSI studies. Therefore, the RELIEF study adds a unique dimension to similar studies in this area and overcomes many shortcomings of previous trials.24
Moxifloxacin was shown to be clinically non-inferior to TZP–AMC. Thus, the current data confirm those from previous studies of cSSSIs.3,18,26
As well as good overall efficacy, moxifloxacin had comparable efficacy to TZP–AMC in the different subgroups of cSSSI, with particularly good efficacy in patients with abscesses. Cure rates were lower in patients with compromised vascular perfusion (DFI and ischaemic ulcers); however, the results in patients with a DFI are similar to those seen in other trials of antimicrobial treatments in cSSSIs.26
The analysis was not powered to look at differences in clinical efficacy in subgroups.
The type and distribution of baseline pathogens was as expected from previous studies, with the most commonly occurring pathogens being Gram-positive aerobes (in ~65% of PP patients), particularly methicillin-susceptible S. aureus
, β-haemolytic streptococci and E. faecalis
. The majority of the E. faecalis
strains were isolated from DFIs (n
59) and abscesses (n
24). E. faecalis
is known to be commonly isolated from patients with a DFI, though it is not clear whether this is contamination or colonization of the site. As in the present trial, previous studies have shown good clinical outcomes despite the use of agents that are not active against enterococci.27,28
Few anaerobic pathogens were isolated; it is possible these have a more important causative role to play in severe infections, such as necrotizing fasciitis.1
However, because this was a large multinational study, it is also possible that despite optimal transport containers and conditions, anaerobes did not survive the journey to the central laboratory as well as aerobes did. High bacteriological success rates were achieved in both arms, and success rates were generally similar between mono- and polymicrobial infections, as would be expected when using two broad-spectrum antibiotics. MRSA isolates were isolated relatively infrequently from patients with DFIs in this study (12.4%), although previous studies have isolated MRSA from 30%–50% of such infections.29–31
The reasons for this are unclear, but may be related to the exclusion criteria and/or differing epidemiology and geographical location of various study populations. Recent work has shown that across Europe, isolation rates of MRSA from cSSSIs can vary from 3% to 48%.32
Nonetheless, success rates against MRSA were similar and relatively good in both arms. As neither of the treatment regimens was specifically used for anti-MRSA activity, this clearance may be because the isolate was a colonizer rather than a pathogen or due to the role of extensive debridement; this is particularly likely in patients who received no anti-MRSA therapy but still experienced clinical cure. Given the limited activity of moxifloxacin and lack of activity of TZP–AMC against community-acquired MRSA (CA-MRSA), patients with known MRSA infections should not be treated with these regimens, despite the in vitro
susceptibility of some isolates to moxifloxacin. In contrast to the USA, the prevalence of CA-MRSA remains relatively low (1%–3%) in most European countries.33
Safety data are comparable to those from previous clinical trials of moxifloxacin,34
which can be considered safe and well tolerated in the patient population enrolled to the study. Specifically, similar numbers and types of AEs were seen in each treatment arm and no cardiac events that could be surrogates of arrhythmia occurred. C. difficile
-associated diarrhoea rates were notably low in the current study. The literature suggests that almost all classes of antibiotics may drive the selection of resistant strains of C. difficile
that can cause C. difficile
-associated diarrhoea outbreaks if infection control practices fail.35
Fluoroquinolones are probably not different in this respect from other classes of antibiotics.36
It is clear, however, that irrespective of the antibiotic being used, good antibiotic stewardship and scrupulous hygiene are key to limiting C. difficile
-associated diarrhoea and should be exercised in all clinical situations.37
Possible weaknesses of the study include the limited analysis of microorganisms; this could lead to underestimation of the polymicrobial character of the cSSSIs. Citron et al
commented on the large number and variety of organisms that were isolated from specimens in patients with moderate-to-severe DFIs, and found that most patients had polymicrobial cultures. However, the contribution to the pathogenicity of many of the microorganisms isolated from open lesions is still unclear.
While surgical intervention and/or drainage are clinically important features of cSSSI management,1,4
it is unclear how they may affect outcomes in antibiotic trials. Although only patients with residual infection after surgery were included, the role of antibiotic therapy after surgery is more difficult to assess and this may work in favour of equivalence or non-inferiority. The current study did, however, stratify for surgical intervention in order to reduce any confounding effects.
Most patients in this study were recruited from Eastern Europe, despite concerted efforts to recruit from Western Europe, which raises the question of whether the data are applicable across geographical populations. Differences may exist between Western and Eastern Europe in terms of the pathogens isolated, the severity of infections treated or referred to hospital, patients' access to healthcare and possible variation in the accepted standards of surgical care. However, these differences are speculative and their impact is unknown. A review of the 2008 report of the European Antibiotic Resistance Surveillance System39
suggests that differences tend to be between Southern and Northern Europe (particularly in the incidence of MRSA) rather than between Western and Eastern Europe.
Once-daily iv/oral moxifloxacin monotherapy was clinically and bacteriologically non-inferior to a commonly used broad-spectrum antibiotic therapy (4.0/0.5 g of piperacillin/tazobactam iv thrice daily followed by 875/125 mg of oral amoxicillin/clavulanate twice daily) in patients with cSSSIs, across the range of infection severities included in this study. Moxifloxacin sequential monotherapy, together with surgery, is an appropriate option for patients with cSSSIs, including those with polymicrobial infections, when used in accordance with the prescribing guidelines.