Methicillin-resistant Staphylococcus aureus infection epidemiology and clinical response from tigecycline soft tissue infection trials

    Methicillin-resistant Staphylococcus aureus infection epidemiology and clinical response from tigecycline soft tissue infection trials Laura Puzniak, Alvaro Quintana, Michele Wible, Tim Babinchak, Paul C. McGovern PII: DOI: Reference:

S0732-8893(14)00110-2 doi: 10.1016/j.diagmicrobio.2014.03.001 DMB 13567

To appear in:

Diagnostic Microbiology and Infectious Disease

Received date: Revised date: Accepted date:

1 May 2013 25 February 2014 2 March 2014

Please cite this article as: Puzniak Laura, Quintana Alvaro, Wible Michele, Babinchak Tim, McGovern Paul C., Methicillin-resistant Staphylococcus aureus infection epidemiology and clinical response from tigecycline soft tissue infection trials, Diagnostic Microbiology and Infectious Disease (2014), doi: 10.1016/j.diagmicrobio.2014.03.001

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ACCEPTED MANUSCRIPT Methicillin-resistant Staphylococcus aureus infection epidemiology and clinical response

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from tigecycline soft tissue infection trials

Laura Puzniaka*, Alvaro Quintanaa, Michele Wiblea, Tim Babinchakb†, Paul C. McGovernc† Pfizer Inc, Collegeville, PA, USA

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Phoenixville, PA, USA

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Berwyn, PA, USA

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Former employee of Pfizer Inc

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*Corresponding author.

Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426-3930 USA

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Tel: +1-314-249-0285; fax: +1-646-441-4626.

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E-mail address: [email protected].

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Running title: Tigecycline and MRSA

Keywords: Tigecycline, methicillin-resistant Staphylococcus aureus, complicated skin and skin structure infections, diabetic foot infections Some findings from this work were presented as a poster at the 49 th Annual IDSA Meeting in 2011 (McGovern PCM, Wible M, Quintana A, Babinchak T. Methicillin-resistant Staphylococcus aureus epidemiology and clinical response in tigecycline clinical trials).

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ABSTRACT

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Given increasing resistance, therapeutic options to treat MRSA soft tissue infections should be evaluated. This pooled analysis evaluated data from subjects enrolled in 6 tigecycline clinical

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trials with documented MRSA complicated skin and skin structure infections or diabetic foot infections (DFIs). Baseline characteristics were compared between subjects with and without

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molecularly classified community-acquired (CA) MRSA, specifically staphylococcal cassette chromosome mec (SCCmec) IV. Clinical response was compared by CA-MRSA designation

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and treatment group. A total of 378 subjects with MRSA soft tissue infections were identified, including 79 with DFI. A total of 249 (65.9%) were molecularly classified as CA-MRSA. Clinical

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response rates for MRSA soft tissue infection were similar between tigecycline and vancomycin

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(treatment difference, 1.0%; 95% CI: –9.3, 12.0) as well as by infection type, SCCmec, and PVL status. Tigecycline demonstrated comparable efficacy for treatment of MRSA soft tissue

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infections regardless of infection type, SCCmec, or PVL status.

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ACCEPTED MANUSCRIPT 1. Introduction Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA)

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are a common cause of soft tissue infections (Moran et al., 2006; Namdari et al., 2012).

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Selection of an effective therapeutic regimen to treat MRSA soft tissue infections is complicated by growing rates of resistance, increasing prevalence of community-acquired MRSA (CA-

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MRSA), patients with multiple comorbidities, and polymicrobial infections (Chua et al., 2011;

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David and Daum, 2010; Davis et al., 2007; King et al., 2006; Mediavilla et al., 2012; Mendes et al., 2008). In addition, limited data are available on clinical efficacy and safety of newer

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antimicrobial agents for microbiologically proven MRSA infections (Logman et al., 2010). There is an increasing heterogeneity among MRSA isolates with the rising incidence of

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CA-MRSA phenotypes both in the community and within the hospital setting (David and Daum, 2010). As a result, there are differences in patient clinical presentation, antimicrobial

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susceptibility, and virulence that can affect treatment efficacy. Molecularly, CA-MRSA is often

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classified by the presence of the staphylococcal chromosomal cassette mec (SCCmec) type IV or V and frequently carries the gene for Panton-Valentine leukocidin (PVL). Risk factors often

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associated with CA-MRSA include younger age, African American race, low socioeconomic status, abscesses, and athletes, military, or incarcerated individuals (David and Daum, 2010; King et al., 2006; Mediavilla et al., 2012; Peppard et al., 2009). Therefore, the lines of delineation for CA-MRSA and healthcare-associated MRSA are beginning to blur due to the rising incidence of molecularly classified CA-MRSA isolates spreading within the hospital setting (David and Daum, 2010). Tigecycline is an expanded broad spectrum glycylcycline with in vitro activity against gram-positive and gram-negative pathogens involved in soft tissue infections (Namdari et al., 2012). In an analysis of soft tissue infection isolates from the Tigecycline Evaluation and

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ACCEPTED MANUSCRIPT Surveillance Trial between 2004 and 2009, there were no tigecycline resistant isolates to MRSA and all the minimum inhibitory concentrations (MICs) were at or below susceptibility breakpoints

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(Namdari et al., 2012). In an analysis of 1989 CA-MRSA isolates, defined as MRSA isolates

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without nosocomial exposures, from 33 medical centers, including 1884 (94.7%) PVL positive isolates, the tigecycline susceptibility rate was 98.2% (Mendes et al., 2008).

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Tigecycline is indicated for the treatment of cSSSI, including those caused by MRSA. It

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is not indicated for the treatment of diabetic foot infections (DFI). Given the increasing resistance rates and limited new antibiotics, it is important to evaluate the utility of therapeutic

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options that can treat MRSA infections. The objective of this study was to examine the infection epidemiology and clinical response of subjects with MRSA from phase 3 and 4 tigecycline soft

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tissue infection clinical trials.

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2. Methods

Subject data from 6 phase 3 and 4 global trials that were conducted worldwide between

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2002 and 2008 and included hospitalized subjects with a proven MRSA cSSSI or DFI without

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evidence of osteomyelitis were included in the pooled analysis of soft tissue infections. Subjects with chronic DFI > 1 week in duration were excluded from the cSSSI trials. The details of the trial design and drug regimen have been previously described (Breedt et al., 2005; Florescu et al., 2008; Matthews et al., 2012; Sabol et al.; Sacchidanand et al., 2005; Vasilev et al., 2008; Lauf et al., 2013). Four of these trials were randomized double blind studies (Breedt et al., 2005; Florescu et al., 2008; Sabol et al.; Sacchidanand et al., 2005); there was also a randomized open-label trial (Matthews et al., 2012) and an open-label noncomparator Gram-negative resistant pathogen trial that included a small number of subjects concomitantly infected with MRSA (Vasilev et al., 2008). All subjects in these trials received 100 mg loading dose of tigecycline, followed by 50 mg every 12 hours, except for the DFI trial, where the subjects

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ACCEPTED MANUSCRIPT received 150 mg tigecycline every 24 hours (Lauf et al., 2013). Subjects received therapy for up to 14 days (Breedt et al., 2005; Matthews et al., 2012; Sacchidanand et al., 2005) or up to 28

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days (Florescu et al., 2008; Sabol et al.; Vasilev et al., 2008). In the comparator-based trials, the

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comparator arm was a treatment regimen and the regimen varied based on the protocol; however, all protocols used vancomycin as the anti-MRSA agent dosed 1 gram every 12 hours

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with dosage adjustment per site’s current local guidelines.

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Subjects from the modified intent-to-treat population (received at least 1 dose of study medication) who had a documented MRSA infection were included in the descriptive analysis of

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MRSA epidemiology. A subset of subjects, the microbiologically evaluable (ME) population that met all the evaluability and inclusion/exclusion criteria of the respective trials, including no use

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of concomitant effective antibiotic therapy, a test of cure response of cure or failure, and a documented MRSA isolate from corresponding skin lesion or blood cultures at baseline were

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analyzed for clinical response. Cure was defined as resolution of clinical signs and symptoms

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with no additional antibiotic therapy or source control. Failure was defined as lack of clinical response or need for additional antibiotic therapy as well as study withdrawal due to an adverse

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event or death due to the infection. All blood cultures and aerobic and anaerobic cultures from the primary site of infection were assessed using the Covance Central Laboratory Services (Indianapolis, IN, USA). SCCmec and PVL typing were determined by multiplex polymerase chain reaction (McAleese 2005). For the purposes of this analysis, subjects were classified as CA-MRSA infections by the presence of SCCmec type IV. 2.1. Statistical analysis Descriptive analyses were performed on the pooled population to evaluate the distribution of baseline characteristics between subjects with and without molecularly classified 5

ACCEPTED MANUSCRIPT CA-MRSA. Statistical comparisons between groups were performed using the chi-square test or Fisher exact test for categorical variables and 1-way analysis of variance for continuous

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variables with significance at P ≤ 0.05.

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Risk difference and 95% confidence intervals (CI) were calculated to evaluate the differences in clinical response between treatment groups and were based on molecular

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classification of MRSA; 95% CI were calculated using the Wilson score method corrected for

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continuity.

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3. Results

There were 378 of 2,783 (13.6%) subjects from 6 tigecycline trials with a MRSA soft

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tissue infection, including 79 subjects with DFI. Of these, 249 (65.9%) had a CA-MRSA infection (SCCmec type IV), 127 (33.6%) had a non–CA-MRSA infection, and 2 (0.5%) subjects had a

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missing MRSA SCCmec. All subjects had MRSA that was susceptible to tigecycline and vancomycin. However, there were 111 (29.5%) patients with polymicrobial infections and of

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those, 9 patients had Pseudomonas aeruginosa resistant to tigecycline (4 of 9 were presumed

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or documented to have persistence) and 3 to the comparator (2 of 3 were presumed or documented to have persistence) and one had Proteus mirabilis resistant to the comparator which was presumed eradication. There were 7 MDR organisms in the tigecycline arm (5 Acinetobacter baumanii, 1 E. coli, and 1 S. maltophilia) and 1 in the comparator arm (Proteus mirabilis). Six (75.0%) of these MDR pathogens were either presumed or documented to have persistence at the test of cure visit. Significant differences were noted in demographic and baseline characteristics between subjects with CA-MRSA infection and in those subjects with MRSA infection not due to CAMRSA (Table 1). Subjects with CA-MRSA more commonly had major skin abscess due to spontaneous infection or trauma that was monomicrobial and PVL positive compared with 6

ACCEPTED MANUSCRIPT subjects with no CA-MRSA. Baseline body mass index (P = 0.130), prior antibiotic failure (P = 0.114), and subjects with baseline secondary MRSA bacteremia (P = 0.389) were not different

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between subjects with and without CA-MRSA. Mean therapy duration (10.0 ± 5.6 days vs. 11.2

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± 5.2 days; P= 0.050) and mean hospital length of stay (13.9 ± 13.0 days vs. 20.2 ± 15.1 days; P = <0.001) was shorter in subjects initially hospitalized for CA-MRSA compared with subjects

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with no CA-MRSA.

Significant demographic and baseline differences between subjects with CA-MRSA and

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non–CA-MRSA appear to be due to differences in subjects with cSSSI infections. For all characteristics except PVL positive isolates, there were no significant differences between DFI

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subjects with and without CA-MRSA (data not shown). In subjects with DFI, there was a higher

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incidence of PVL positive isolates among subjects with CA-MRSA (31.8% vs. 5.7%; P = 0.004). A total of 287 subjects were in the ME population, including 70 with DFI. The overall cure

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rate in the ME population for this study was 75.6% (217/287). The majority of patient-level

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microbiological successes for the ME population was presumed (66.2%) based on the patient’s clinical success. A small number of patients 10 (3.5%) had documented eradication of baseline organisms. The overall microbiological success rate (69.7%) aligned with the clinical success rate. Tigecycline and vancomycin had similar clinical responses overall (treatment difference [TD] %: 1.0, 95% CI: –9.3, 12.0) and within both the cSSSI (TD: 1.5, 95% CI: –9.9, 13.8) and DFI (TD: 0.5, –22.5, 25.3) subgroups. Clinical cure rates were similar between tigecycline and vancomycin based on CA-MRSA, PVL status, and CA-MRSA/PVL status (Table 2), although tigecycline clinical response to non–CA-MRSA was numerically higher than its clinical response

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ACCEPTED MANUSCRIPT to CA-MRSA (83.3% vs. 70.9%). Cure rates were also similar between tigecycline and vancomycin within indications (i.e. cSSSI or DFI) and by monomicrobial or polymicrobial

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infection. Two out of 4 tigecycline subjects and 4 out of 6 vancomycin subjects with secondary

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MRSA bacteremia were considered cured.

Six tigecycline subjects and 1 vancomycin subject with baseline MRSA died during the

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clinical trials. Four of the 6 tigecycline subjects had MRSA isolates that were characterized as

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CA-MRSA. Two subjects had polymicrobial infection, including Gram-negative pathogens; none of these 6 MRSA isolates were tigecycline-resistant (MIC < 0.25 mcg/mL). None of these deaths

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were considered related to the test article by the study investigators.

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4. Discussion

Tigecycline has been studied in 6 randomized clinical trials involving soft tissue

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infections, and aggregate data on the efficacy of tigecycline against MRSA is helpful for several reasons. First, soft tissue infections involving S. aureus, especially MRSA, are commonly

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encountered infections in the community and hospital setting. Second, the efficacy of tigecycline

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and use for tigecycline against MRSA infections has been the subject of discussion (Liu et al., 2011; Prasad et al., 2012). This secondary analysis is the largest analysis of the clinical efficacy of tigecycline against microbiologically confirmed MRSA soft tissue infections. Importantly, the data demonstrate that the clinical efficacy of tigecycline was similar to vancomycin in the treatment of MRSA soft tissue infections requiring initial hospitalization and that the clinical response was consistent regardless of infection type, monomicrobial or polymicrobial status, and SCCmec type, or PVL status. The dataset included only a small number of subjects with secondary MRSA bacteremia at baseline; therefore evaluation of this subpopulation is limited Multiple significant differences were observed in baseline subject and infection characteristics between subjects with and without molecularly classified CA-MRSA. Cure rates 8

ACCEPTED MANUSCRIPT in the ME population were similar between treatment groups for subjects with CA-MRSA and numerically higher in tigecycline-treated subjects with non CA-MRSA. Of note, the baseline

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subject and infection characteristics of those subjects with CA-MRSA are consistent with

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characteristics for CA-MRSA described in the literature and therefore appear to be representative of patients in the ongoing CA-MRSA epidemic (David and Daum, 2010; King et

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al., 2006; Mediavilla et al., 2012; Peppard et al., 2009). Furthermore, the distribution by CAMRSA and non CA-MRSA appears to be consistent with what has been reported in the

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literature, however, SCCmec type IV is now observed as both a cause of CA-MRSA and HA-

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MRSA. (David and Daum, 2010; King et al., 2006; Mediavilla et al., 2012; Mendes 2008) Clinical responses for MRSA DFI were similar between tigecycline- and vancomycin-

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treated subjects, although this subset consists of only 70 subjects of which 44 received tigecycline. The lower clinical response for MRSA DFI compared with MRSA cSSSI for both

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treatment groups are likely due to the underlying disease process and higher number of

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polymicrobial infections; however, the clinical responses are consistent with other DFI trials (Lipsky et al., 2005; Lipsky et al., 2007; Lipsky and Stoutenburgh, 2005). Tigecycline is not

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approved for the treatment of DFI nor for once daily dosing. The failure of tigecycline to demonstrate non-inferiority and the differences with standard tigecycline dosing in the DFI trial are potential limitations to the inclusion of the DFI data in this pooled analysis (Lauf et. al., 2013, ). However, once-daily tigecycline can be supported by its pharmacokinetics (Muralidhara et al 2005) and a post hoc analysis suggested subject discontinuation as an issue impacting the overall DFI trial results (Lipsky et al., 2012; Lauf et. al., 2013) . Therefore, despite these limitations, the data are relevant to the full understanding of tigecycline efficacy in MRSA soft tissue infections. Guidelines have provided different recommendations on the use of tigecycline to treat MRSA soft tissue infections (Brink et al., 2010; Lipsky et al., 2012; Liu et al., 2011; Luna et al., 9

ACCEPTED MANUSCRIPT 2010; Nathwani et al., 2008). In the recently updated Infectious Diseases Society of America (IDSA) clinical practice guidelines for the treatment of MRSA infection, tigecycline was not

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included for the treatment of MRSA infections (Liu et al., 2011). The rationale for exclusion was

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due to the increase in all-cause mortality and the number of available alternatives to treat MRSA infection. The Surgical Infection Society guideline on cSSSI included tigecycline, in particular for

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the treatment of rapidly progressive soft tissue infections due to S. aureus and MRSA (May et

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al., 2009).

Given the availability of other orally available or more narrow spectrum therapy against

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MRSA, tigecycline may be more appropriate for patients hospitalized for the treatment of polymicrobial soft tissue infections or for patients with monomicrobial soft tissue infections and

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other considerations (e.g. antibiotic allergy, renal dysfunction). Approximately 30% of the soft tissue infections in this analysis were polymicrobial infections. Clinical response was lower in

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polymicrobial infections relative to the monomicrobial MRSA infections but similar between

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tigecycline and vancomycin. Tigecycline use in the empiric therapy of suspected polymicrobial soft-tissue infection, including MRSA (e.g. surgical site infections), or directed therapy against

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polymicrobial soft tissue infections, including MRSA (Nathwani et al., 2008), especially when other resistant pathogens are known or when patients have previously failed other antibiotic regimens may be an appropriate treatment consideration (Brink et al., 2010). There was an increase in all-cause mortality in the tigecycline phase 3 and 4 clinical program (McGovern et al., 2013); however, in both the cSSSI and DFI indications, there was a nonsignificant difference in mortality (Wyeth Pharmaceuticals Inc., 2013) and MRSA did not emerge as a risk factor in the analyses of mortality across all indications pooled. In this analysis of MRSA soft tissue infections, there were numerically more deaths reported in the tigecycline group (6) relative to vancomycin (1). In only 2 of the 6 tigecycline subjects in this analysis, death

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ACCEPTED MANUSCRIPT could possibly be related to the infection under study, whereas more deaths appeared related to complications of underlying medical comorbidities.

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In addition to the limitation of the DFI trial data, this analysis has several limitations.

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First, this is a secondary, retrospective analysis of pooled data from 6 clinical trials with varying protocols and indications conducted over multiple years. However, consistency of the clinical

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response across the various analyses suggests that this had a minor impact on the

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interpretation of the results. Second, due to limitations of the data, we were unable to assess early clinical response at day 3 as recommended by the new FDA guidance on Acute Bacterial

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Skin and Skin Structure Infection. Finally, this represents the largest analysis of clinical response to microbiologically confirmed MRSA soft tissue infections treated with tigecycline;

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however, the power to detect statistically meaningful clinical differences may be limited. In conclusion, this analysis evaluated the efficacy and mortality of tigecycline for the

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treatment of MRSA soft tissue infections from 6 global clinical trials. Subjects with CA-MRSA

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soft tissue infections from tigecycline clinical trials had characteristics similar to patients described in the CA-MRSA epidemic. Tigecycline demonstrated comparable efficacy in the

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treatment of MRSA soft tissue infections regardless of infection type, monomicrobial or polymicrobial infection, and SCCmec type and PVL status. Tigecycline is an appropriate therapy option for MRSA soft tissue infections.

Acknowledgments This study was funded by Pfizer Inc. Tim Babinchak and Paul C. McGovern are former employees of Pfizer Inc. Programming support was provided by Jeff Goodrich of Pfizer Inc. Medical writing support was provided by Charlotte Kenreigh of Engage Scientific Solutions and was funded by Pfizer Inc. 11

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ACCEPTED MANUSCRIPT Table 1

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Demographic and baseline characteristics of subjects with MRSA soft tissue infections in the modified intent-to-treat population

48.0 ± 15.9

Male gender, n (%)

165 (66.3)

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Mean age ± SD, y

Non–CA-MRSA (N = 127) 54.7 ± 15.9

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Characteristic

CA-MRSA (N = 249)

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Ethnic origin, n (%)

70 (55.1)

107 (84.3)

African American

44 (17.7)

3 (2.4)

22 (8.8)

7 (5.5)

10 (4.0)

5 (3.9)

8 (3.2)

5 (3.9)

MA

165 (66.3)

ED

Asian Other

(N = 247)

(N = 125)

28.7 (7.6)

30.2 (10.8)c

CE

PT

Body Mass Index (kg/m2) mean (SD)

AC

Infection subtype, n (%)a

81 (32.5)

41 (32.3)

Major abscesses

92 (36.9)

17 (13.4)

Infected ulcers

14 (5.6)

17 (13.4)

Burns

5 (2.0)

4 (3.1)

44 (17.7)

35 (27.6)

Cause of the original infection, n (%)a Spontaneous infection

0.035

0.130

< 0.001

Deep or extensive cellulitis

Diabetic foot infection

< 0.001

< 0.001

White

Hispanic

P value

< 0.001 108 (43.4)

30 (23.6)

Previous surgery

20 (8.0)

36 (28.3)

Trauma

37 (14.9)

12 (9.4)

18

ACCEPTED MANUSCRIPT New/acute onset

26 (10.4)

18 (14.2)

Worsening of prior infection

18 (7.2)

17 (13.4)

Country, n (%)a

4 (1.6)

Ukraine

12 (4.8)

Bulgaria

1 (0.4)

Russian Federation

9 (3.6)

PT

Infection, n (%)

PVL, n (%) Bacteremia

AC

Polymicrobial

CE

Monomicrobial

14 (11.0) 4 (3.1)

(N = 248)

(N = 125)

119.2 ± 50.6

103.1 ± 49.2

90 (36.1)

68 (53.5)

0.001

(N = 204)

(N = 92)

0.007

19 (9.3)

19 (20.7)

ED

Peripheral vascular disease, n (%)

4 (3.1)

MA

Mean creatinine clearance ± SD, mL/min Diabetes, n (%)

12 (9.4)

NU

Romania

41 (32.3)

RI P

162 (65.1)

SC

United States

T

< 0.001

0.004

< 0.001 190 (76.3)

75 (59.1)

59 (23.7)

52 (40.9)

162 (65.1)

5 (3.9)

< 0.001

9 (3.6%)

7 (5.5%)

0.389

P value was calculated on all categories. a

Only the 5 most frequent categories shown;

CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus; PVL, Panton-Valentine leukocidin; SD, standard deviation, DFI Diabetic foot infection).

19

ACCEPTED MANUSCRIPT

Table 2

T

Clinical response at the test of cure visit in the ME population with MRSA infections

n/N (%)

95% CIa

n/N (%)

95% CIa

CR

difference (%)

Total ME

133/175 (76.0)

57.0, 82.0

84/112 (75.0)

56.3, 81.3

1.0

–9.3, 12.0

cSSSI

104/131 (79.4)

59.5, 84.5

67/86 (77.9)

58.4, 83.4

1.5

–9.9, 13.8

DFI

29/44 (65.9)

49.4, 74.4

17/26 (65.4)

49.0, 91.3

0.5

–22.5, 25.3

Monomicrobial

95/120 (79.2)

59.4, 84.4

60/76 (78.9)

59.2, 84.2

0.2

–11.6, 13.2

Polymicrobial

38/55 (69.1)

51.8, 76.8

ED

95% CIb

24/36 (66.7)

50.0, 75.0

2.4

–17.6, 23.5

CA-MRSA

73/103 (70.9)

53.2, 78.2

56/75 (74.7)

56.0, 81.0

-3.8

–17.2, 10.5

Non–CA-MRSA

60/72 (83.3)

AC

IP

Treatment

62.5, 87.5

26/35 (74.3)

55.7, 93.6

9.0

–7.7, 28.4

PVL+

46/62 (74.2)

55.6, 80.6

39/51 (76.5)

57.4, 82.4

–2.3

–18.8, 15.1

PVL–

87/113 (77.0)

57.7, 82.7

43/59 (72.9)

54.7, 79.7

4.1

–9.7, 19.3

54.7, 79.7

38/50 (76.0)

57.0, 82.0

–3.1

–20.1, 14.7

PT

CA-MRSA status

Vancomycin

MA NU S

Tigecycline

CE

Population

Treatment

PVL status

Combined CA-MRSA and PVL status CA-

43/59 (72.9)

20

ACCEPTED MANUSCRIPT

–3.8

–25.8, 21.3

0.0

–69.0, 94.5

55.1, 93.4

9.1

–8.2, 28.8

30/44 (68.2)

51.1, 76.1

18/25 (72.0)

54.0, 93.0

3/3 (100)

25.0, 100

1/1 (100)

25.0, 100

57/69 (82.6)

62.0, 87.0

25/34 (73.5)

T

CA-

CR

MRSA/PVL+

Non–CA-

IP

MRSA/PVL–

Non–CA-

MA NU S

MRSA/PVL+

MRSA/PVL–

95% CI for individual treatment groups is calculated by using the methods of Clopper-Pearson.

b

95% CI for differences between treatment groups is calculated by using the Wilson score method corrected for continuity.

ED

a

AC

CE

PT

CI, confidence interval; ME, microbiologically evaluable; cSSSI, complicated skin and skin structure infection; CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus; DFI, diabetic foot infection; PVL, Panton-Valentine leukocidin.

21