Treatment of methicillin-resistant Staphylococcus aureus (MRSA): 1

updated guidelines from the UK 2

Nicholas M. BROWN1, Anna GOODMAN2, Carolyne HORNER3*, Abi JENKINS4, 3

Erwin BROWN3 4

1Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 5

2Guy’s and St Thomas’ NHS Foundation Trust, London, UK 6

3British Society for Antimicrobial Chemotherapy, Birmingham, UK 7

4Formerly British Society for Antimicrobial Chemotherapy, Birmingham, UK 8

*Corresponding author: Tel: +44 121 236 1988; E-mail: chorner@bsac.org.uk 9

Short running title: Updated UK guidelines for treatment of MRSA 10

Keywords: evidence-based guidelines, new anti-staphylococcal agents. 11

12

Synopsis 13

These evidence-based guidelines are an updated version of the treatment of 14

methicillin-resistant Staphylococcus aureus (MRSA) guidelines issued in 2008. They 15

have been produced following a review of the published literature (2007-2018) 16

pertaining to the treatment of infections caused by MRSA. The guidelines update, 17

where appropriate, previous recommendations, taking into account changes in the 18

UK epidemiology of MRSA, ongoing national surveillance data, and the efficacy of 19

novel anti-staphylococcal agents licensed for use in the UK. Emerging therapies that 20

have not been licensed for use in the UK at the time of the review have also been 21

assessed. 22

Contents 23

Synopsis ..................................................................................................................... 2 24

1. Introduction ......................................................................................................... 5 25

2. Methods .............................................................................................................. 5 26

2.1 Scope and purpose ........................................................................................... 6 27

2.2 Stakeholder involvement .................................................................................. 6 28

2.3 Literature review ............................................................................................... 6 29

2.4 Consensus process and guideline development............................................... 7 30

3. Skin and soft tissue infections ............................................................................. 9 31

3.1 Impetigo ...................................................................................................... 10 32

3.2 Abscesses ................................................................................................... 11 33

3.3 Skin and soft tissue infections (SSTI) .......................................................... 15 34

4. Urinary tract infections .......................................................................................... 23 35

5. Bone and joint infections ................................................................................... 24 36

6. Bacteraemia ...................................................................................................... 27 37

7. Infective Endocarditis ........................................................................................ 29 38

8. Respiratory tract infections ................................................................................ 29 39

8.1 Necrotising pneumonia ............................................................................... 29 40

8.2 Nosocomial pneumonia ............................................................................... 30 41

8.3 Ear, nose and throat or upper respiratory tract infections ........................... 31 42

9. CNS and eye disease ....................................................................................... 31 43

9.1 Intracranial or spinal infections .................................................................... 31 44

9.2 CSF infections ................................................................................................ 32 45

9.3 Eye disease .................................................................................................... 33 46

10. Conclusions ........................................................................................................ 33 47

Acknowledgements .................................................................................................. 34 48

Funding .................................................................................................................... 34 49

Transparency declaration ......................................................................................... 34 50

References ............................................................................................................... 34 51

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54

1. Introduction 55

Current UK MRSA treatment guidelines are based on clinical evidence published 56

more than 10 years ago.1 Much has changed since then, including observed 57

changes in the nature, incidence and epidemiology of MRSA infections. In particular, 58

the incidence of MRSA in UK hospitals has fallen markedly since 2008 and serious 59

infection caused by MRSA is now less common.2 These changes have implications 60

for the empirical treatment of sepsis in hospitalised patients. Also, for reasons that 61

are unclear, community strains of MRSA, such as PFGE (pulsed-field gel 62

electrophoresis) strain-type USA300, have not become established in the UK, 63

despite frequent introductions.3 64

Unlike infections caused by antibiotic-resistant aerobic Gram-negative 65

bacteria, there is a broad range of antibiotics available to treat patients with 66

infections caused by MRSA. The clinical usage of agents such as linezolid and 67

daptomycin was limited when the previous MRSA guidelines were published;1 68

however, during the intervening period other agents have been licensed, or are close 69

to being licensed, and their places in therapeutic guidelines are unclear. This is 70

particularly relevant to the treatment of patients with some deep-seated or difficult-to-71

treat infections caused by MRSA, such as bone and joint infections, where the 72

durations of therapy are prolonged, and the morbidity remains high. 73

2. Methods 74

This guideline was developed in accordance with the AGREE II instrument.4 75

2.1 Scope and purpose 76

This guideline is intended to assist in the clinical care of patients with suspected or 77

confirmed MRSA infection in the UK. The 2008 MRSA guideline addressed both 78

prophylaxis and treatment of MRSA; however, prophylaxis has not been included in 79

the current guideline. The objectives of the guideline review can be summarised as 80

follows: (i) to improve the quality of care provided to patients with MRSA infection; (ii) 81

to provide an educational resource for all relevant healthcare professionals; (iii) to 82

encourage a multidisciplinary approach to the management of MRSA infection, and 83

(iv) to promote a standardised approach to the management of MRSA infection. 84

2.2 Stakeholder involvement 85

Updating the national guidelines relating to MRSA was a joint initiative of the BSAC, 86

British Infection Association (BIA), Healthcare Infection Society (HIS) and Infection 87

Prevention Society (IPS). BSAC and BIA alone were involved in the production of 88

this guideline. 89

2.3 Literature review 90

The Cochrane Library (including the Central Register of Controlled Trials), EMBASE, 91

and MEDLINE databases were comprehensively searched from 1 Jan 2006 – 26 92

March 2017 (Table S1, available as Supplementary data). A further search using the 93

same criteria, but covering the period 1 Jan 2016 – 31 August 2018, was undertaken 94

in order to identify any additional papers published since the initial search. A total of 95

108 articles were identified from the first literature search and 53 references in the 96

second search (Figure 1). 97

Only articles that contained original, relevant and interpretable data about the 98

management of MRSA infection and which were published in full in peer-reviewed 99

English language journals were acceptable. The following study designs were 100

eligible for inclusion: randomised control trials (RCTs), controlled clinical trials 101

(CCTs), interrupted time series (ITS) with at least three data points before and after 102

implementation of the intervention and controlled before and after studies (CBAs) 103

that were undertaken in three or more centres/hospitals. Exclusion criteria were 104

studies that did not have comparator groups, studies in which the results from 105

multiple studies were pooled and studies in which results for MRSA were not 106

specified. Studies with low numbers of participants (<10) in each treatment arm were 107

considered to have an unacceptable risk of bias and were excluded outright. Studies 108

with between 10-49 participants in each treatment arm were considered to have a 109

high risk of bias and were reviewed on an individual basis. Studies with between 50-110

199 patients in each treatment arm were considered to have an moderate risk of 111

bias, whereas studies with >200 patients in each treatment arm were considered to 112

have low risk of bias.5 The risk of bias was reflected in the grading of the evidence 113

for each study included. Systematic reviews/meta-analyses were excluded, but their 114

bibliographies were perused in order to identify studies not captured by the current 115

literature searches. Characteristics of the studies that met the inclusion criteria are 116

summarised in Table S3 (available as Supplementary data). 117

2.4 Consensus process and guideline development 118

The abstracts of all articles identified by the literature searches were screened by 119

two reviewers for clinical trials concerned with the treatment of patients with 120

infections caused by MRSA that had been published as full papers in peer-review 121

journals: any differences were resolved by discussion and consensus. The full 122

papers of studies meeting these criteria were obtained and they were assessed by 123

both reviewers, principally in terms of design criteria; again, any differences were 124

resolved by discussion and consensus. In the event of uncertainty or failure to agree, 125

studies were referred to the guideline development group. Studies identified as being 126

eligible for further consideration were referred to members of the guideline 127

development group who determined whether they should be included or excluded 128

and independently performed data extraction on the included studies. The full papers 129

of all studies which were deemed eligible for inclusion were reviewed in order to 130

identify those that fulfilled the criteria for inclusion; reasons for exclusion were 131

recorded (Table S2, which lists the excluded studies and reasons for their exclusion, 132

available as Supplementary data). Review authors independently performed data 133

extraction from the included studies (Table S3, available as Supplementary data) 134

recording information on study design, type of intervention, presence of controls, 135

type of targeted behaviour, participants, setting, methods (unit of allocation, unit of 136

analysis, study power), primary and secondary outcome measures and results. 137

Based on the analysis of the results, changes to previous recommendations were 138

made and new recommendations were proposed (Table 1). Previous guidelines 139

were used for comparison of the evidence identified in this review.1, 6 Some 140

recommendations were updated for pragmatic reasons in the absence of new 141

evidence to provide improved clarity to the reader in particular clinical situations, 142

such as MRSA meningitis. 143

The evidence grades used to support each recommendation were those 144

adopted by the Healthcare Infection Control Practices Advisory Committee, Centers 145

for Diseases Control and Prevention dating from 1999.7 Each recommendation was 146

categorised on the basis of scientific data available at the time, theoretical rationale, 147

applicability and economic impact. The categories were: 148

IA. Strongly recommended for implementation and strongly supported by well-149

designed experimental, clinical or epidemiological studies. 150

IB. Strongly recommended for implementation and supported by certain 151

experimental, clinical or epidemiological studies and a strong theoretical rationale. 152

IC. Required for implementation, as mandated by federal or state regulation or 153

standard or representing an established association standard. 154

II. Suggested for implementation and supported by suggestive (non-definitive) 155

clinical or epidemiological studies or a theoretical rationale. 156

Unresolved issue. No recommendation is offered. No consensus reached, or 157

insufficient evidence exists regarding efficacy. 158

Draft recommendations were written by the guideline development group. These 159

were circulated (17.12.19) to a comprehensive list of stakeholders and uploaded to 160

the BSAC website (www.bsac.org.uk) for a four-week consultation period. Final 161

alterations were made to the document in response to the consultation process. 162

3. Skin and soft tissue infections 163

Acute bacterial skin and soft tissue infection (SSTI) was the most common category 164

of infection in the new studies reviewed. Many of the studies were industry-165

sponsored, performed for licensing purposes and powered to demonstrate non-166

inferiority in comparison to current standard treatment, which was most often 167

vancomycin. There was marked heterogeneity in the types of infections studied. 168

Several studies enrolled patients with infections caused by bacteria other than just 169

MRSA. Several of the excluded studies could not be assessed due to the small 170

number of patients with proven MRSA infection. 171

In 2013 FDA guidance for the conduct of studies involving patients with acute 172

bacterial skin and skin structure infections (ABSSSI) was updated.8 The new FDA 173

guidance sought to provide more consistency in study design and recommended that 174

the primary efficacy endpoint in trials should be measured at 48-72h, rather than at 175

the end of therapy or at post-treatment review.8 Included studies have varied in their 176

compliance with this, according to their date of publication. 177

3.1 Impetigo 178

Only one new study was identified regarding the treatment of impetigo caused by 179

MRSA. Older evidence in this area is reviewed in the Public Health England (PHE) 180

primary care guidance9, a Cochrane Review10 and NICE Clinical Knowledge 181

Summaries (CKS): Impetigo (2015).11 Uncomplicated impetigo, defined as localised 182

non-bullous impetigo in an immunocompetent individual with no systemic signs of 183

infection, may respond to topical antiseptics, such as hydrogen peroxide 1% 184

cream.11 The guideline development group is concerned about the use of topical 185

fusidic acid and mupirocin owing to evidence of the emergence of resistant strains 186

following their application, notwithstanding their availability as treatment options with 187

proven efficacy. More extensive or complicated impetigo may require systemic 188

antibiotic therapy, but no new evidence relating to the optimal agent(s) specifically 189

for infection caused by MRSA was identified. 190

Retapamulin ointment has recently been licensed for the treatment of 191

impetigo. Topical retapamulin 1% administered twice daily for 5 days was shown to 192

be inferior to oral treatment with linezolid 600 mg 12-hourly for 10 days (or equivalent 193

dose adjusted for age in children) in a RCT including adults and children with either 194

infected wounds or impetigo caused by MRSA.12 The primary outcome was clinical 195

cure at follow up 7-9 days after the completion of therapy; 410 patients were enrolled 196

and 125 of these had impetigo. In the 404 patients who completed the study, the 197

clinical cure rate in the retapamulin group (161/268 (60.1%) was significantly lower 198

than that in the oral linezolid group (112/136 (82.4%) (difference -22.3%; 95% CI -199

31.9 - -12.6). However, outcome data were not provided for the subset of patients 200

with impetigo (79 in the retapamulin arm versus 46 in the linezolid arm) and therefore 201

no conclusions can be reached for impetigo specifically. Moreover, patients with both 202

bullous and non-bullous disease were included. 203

Recommendation 1: 204

(i) We recommend that impetigo caused by MRSA should be treated with an 205

alternative to topical fusidic acid or mupirocin, for example with a topical antiseptic 206

such as hydrogen peroxide 1% cream, where there is localised, non-bullous disease 207

and no systemic upset; topical fusidic acid or mupirocin should be limited to second-208

line options in the clinical setting and only when the MRSA isolate is known to be 209

susceptible. [Category II] 210

(ii) Complicated infection may require systemic antimicrobial therapy and the 211

choice of agent should be determined by susceptibility testing. [Category II] 212

3.2 Abscesses 213

There is robust evidence that antibiotic treatment is not required routinely in patients 214

with uncomplicated abscesses caused by methicillin-susceptible S. aureus (MSSA) 215

who undergo incision and drainage, provided there is no evidence of a systemic 216

inflammatory response (fever or cellulitis) or immunodeficiency.13 Hitherto, it has 217

been assumed that the same principles also apply to abscesses caused by MRSA. 218

Five new studies including patients with abscesses were identified during the 219

present systematic review.14-18 In each of these studies, patients with abscesses due 220

to a range of infective organisms were included, but there were sufficient patients 221

with MRSA in each arm of the studies to allow evaluation. 222

Chen et al. (2011) compared the use of oral clindamycin or cephalexin (an 223

antimicrobial agent with no activity against MRSA), in a RCT in 200 children with 224

uncomplicated abscesses presenting to an emergency department.14 The abscesses 225

were drained (either spontaneously or surgically), but hospital admission was not 226

required. Children with impaired immunity were excluded. The majority of wound 227

cultures (69%) grew MRSA and the majority of isolates (93%) were Panton Valentine 228

Leukocidin (PVL)-positive USA300 strains; 91% of MRSA isolates were clindamycin-229

susceptible. Success was high at both the primary endpoint (improvement at 48-72h) 230

and secondary outcome (resolution of infection at 7 days). For the subgroup of 231

patients with MRSA, 6/64 (9%) patients in the cephalexin arm and 2/71 (3%) in the 232

clindamycin arm were reported to have deteriorated at the 48-72h visit. This 233

difference was not statistically significant (p=0.15). Among patients who could be 234

evaluated at 7 days, cure was reported in 63/63 (100%) patients in the cephalexin 235

arm and 66/70 (94%) patients in the clindamycin arm (p=0.12). Therefore, in this 236

study, there was no evidence that antibiotics were beneficial. 237

Holmes et al. (2016) conducted a RCT powered for non-inferiority comparing 238

oral co-trimoxazole given for 3 days or the same drug given for 10 days in 239

immunocompetent children with abscesses requiring drainage presenting to an 240

emergency department in the US.16 The primary outcome was cure as assessed at a 241

10-14 day follow-up visit. Of the 265 children recruited, MRSA was isolated from 242

abscess cultures from 69 in each arm; all the MRSA isolates were susceptible to co-243

trimoxazole. Overall, there was no statistically significant difference in outcome 244

between the two groups at the primary endpoint. However, in the subset of patients 245

with MRSA, the treatment failure rate was 8/69 (12%) in the 3-day treatment arm 246

versus 1/69 (1%) in the 10-day arm (p=0.03). This failed to meet the predefined 247

criteria for non-inferiority, which was a difference of no more than 7%. 248

A large multicentre RCT included both adults and children in the US 249

presenting with small skin abscesses (≤5 cm in diameter).15 All patients underwent 250

incision and drainage and were then randomised to receive either clindamycin 251

(300mg 8 hourly for adults), co-trimoxazole (480mg twice daily for adults) or placebo 252

for 10 days; appropriate dose adjustment was made for children. The primary 253

outcome was clinical cure at the end of treatment. A total of 786 patients were 254

enrolled and MRSA was isolated from cultures in 388 of these. The overall clinical 255

cure rate in the evaluable population was statistically significantly higher in patients 256

treated with antibiotics [clindamycin 221/238 (92.9%), co-trimoxazole 215/232 257

(92.7%)], compared with those who received the placebo [177/220 (80.5%)] (p 258

<0.001). This was also the case in patients infected with MRSA [clindamycin 116/126 259

(92.1%), co-trimoxazole 110/117 (94%), placebo 93/96 (97%)] (p <0.001). There was 260

no statistically significant difference in cure rates between patients treated with 261

clindamycin or co-trimoxazole. In subset analysis the benefit of antibiotic treatment 262

was seen with infections caused by MSSA or MRSA, but not with infections where 263

no S. aureus was isolated. These findings challenge the view that antibiotics offer no 264

benefit over incision and drainage in small abscesses caused by S. aureus. 265

Talan et al. (2016) performed a similar large multicentre RCT in patients over 266

12 years of age in the US presenting with an uncomplicated abscess and treated as 267

outpatients following drainage.18 Patients were randomised to receive either high-268

dose oral co-trimoxazole (1,920 mg twice daily) or placebo for 7 days; 1,265 patients 269

were recruited and MRSA was isolated from specimens obtained following drainage 270

from 565 [394 of 410 MRSA isolates tested (96.1%) were PFGE strain type 271

USA300]. Overall clinical cure rates in the per protocol population at the primary 272

endpoint, the assessment at the end of treatment, demonstrated an advantage of 273

antibiotic therapy over placebo [co-trimoxazole 487/524 (92.9%) versus placebo 274

457/533 (85.7%)] (p<0.001). However, this difference was not observed at the FDA 275

guidance early end point assessment after 48-72h of treatment and results were not 276

presented for the subgroup of patients with MRSA. Talan et al. (2018) subsequently 277

performed further analysis of the data from this study.17 In the per protocol 278

population with infection caused by MRSA the response rate following treatment with 279

co-trimoxazole was statistically significantly higher than that with placebo [203/219 280

(92.7%) versus 202/249 (81.1%)] (difference 11.6%; 95% CI 5.2-18.0). In patients 281

with MSSA, a smaller statistically non-significant benefit was seen [co-trimoxazole 282

78/86 (90.7%) versus placebo 71/86 (82.6%)] (difference 8.1%; 95% CI -3.1-19.4), 283

whereas in patients from whom neither MRSA nor MSSA was recovered, there was 284

no benefit of antibiotic [co-trimoxazole 203/216 (94%) versus placebo 181/195 285

(92.8%)] (difference 1.2%; 95% CI -4.1-6.5). This suggests that antibiotic treatment 286

of abscesses after incision and drainage may be of benefit in the subset of patients 287

with infection caused by MRSA. 288

The aforementioned studies were performed in the US in a setting where 289

PVL-positive USA300 was the predominant MRSA strain in circulation. This is not 290

the case in the UK and therefore it is unclear if the findings can be extrapolated to 291

the UK, where the incidence of community strains of MRSA, especially USA300, is 292

low. A UK guideline for management of community-acquired MRSA published in 293

2010 recommended that immunocompetent patients with uncomplicated abscesses 294

(<5 cm in diameter) without cellulitis do not require antibiotic therapy after drainage.6 295

Recommendation 2: 296

(i) Abscesses require incision and drainage to control the source of infection. 297

[Category IA] 298

(ii) We recommend that antibiotic treatment should not be given routinely to 299

patients with abscesses that are drained, that are <5 cm in diameter and in the 300

absence of a systemic response (fever and/or cellulitis) and/or immunodeficiency. 301

[Category IA] 302

(iii) Antibiotics may be of benefit if the abscess is caused by PFGE strain type 303

USA300, in which case, should this strain become more common in the UK, a lower 304

threshold for antibiotic treatment should be adopted. [Category IB] 305

(iv) Antibiotics should be considered in combination with drainage in patients with 306

a known history of current MRSA colonisation. [Category II] 307

(v) Clindamycin or co-trimoxazole have been shown to be effective oral options if 308

treatment is warranted and the MRSA isolate is susceptible. [Category IA] 309

3.3 Skin and soft tissue infections (SSTI) 310

Glycopeptides are the current standard of care for the initial therapy of cellulitis 311

caused by MRSA. Since the previous guideline was published, linezolid and 312

daptomycin have become established alternatives, particularly in hospitalised 313

patients, although oral linezolid and parenteral daptomycin are frequently used to 314

facilitate discharge from hospital [the latter in the outpatient parenteral antimicrobial 315

therapy (OPAT) setting]. 316

Additional evidence which supports the use of linezolid as treatment of 317

patients with SSTI caused by MRSA was identified by the current systematic review. 318

One study meeting the guideline inclusion criteria demonstrated that linezolid was 319

not inferior to vancomycin.19 In this open-label randomised case control study, 320

patients with suspected MRSA infection were randomised to receive linezolid 600 321

mg twice daily (given either intravenously or orally) or IV vancomycin 15 mg/kg twice 322

daily (dose adjusted according to therapeutic drug monitoring) for 7-14 days. The 323

primary outcome was clinical success in the per protocol population at the end of the 324

study and was achieved in 191/227 (84%) patients in the linezolid arm and 167/209 325

(80%) patients in the vancomycin arm (p=0.249). 326

No new studies comparing daptomycin with vancomycin and fulfilling the 327

inclusion criteria were identified in the current systematic review. 328

Talan et al. (2016) performed a RCT comparing clindamycin 300 mg 6-hourly 329

with co-trimoxazole 1920 mg 12-hourly in patients >12 years of age presenting to 330

emergency departments in the USA with uncomplicated wound infections. Treatment 331

was administered for 7 days. The primary outcome was clinical cure as assessed at 332

7-14 days. The study was powered to demonstrate superiority of clindamycin over 333

co-trimoxazole and this required the lower value of the 95% CI of the difference in 334

clinical cure to be greater than zero. Overall, 500 patients were enrolled and 161 335

patients with proven MRSA infection were included in the per protocol population. 336

There were no statistically significant differences between the treatment arms and 337

clinical cure was seen in 70/78 (89.7%) patients treated with clindamycin and 78/83 338

(94%) of patients treated with co-trimoxazole (difference -4.2%; 95% CI -13.9-5.5).20 339

Several studies evaluated new agents with activity against MRSA as 340

treatment of patients with skin infections. These include the new anti-staphylococcal 341

cephalosporins, ceftaroline21 and ceftobiprole;22 new glycopeptides, dalbavancin,23 342

oritavancin,24-26 and telavancin;27 a new oxazolidinone, tedizolid;28, 29 two 343

pleuromutilin antibiotics, lefamulin30 and retapamulin;12 a new quinolone, 344

delafloxacin,31 and iclaprim.32, 33 At the time of writing, ceftobiprole, lefamulin and 345

iclaprim had not been licensed for this clinical indication. No studies meeting the 346

guideline inclusion criteria assessed the efficacy of omadacycline in this clinical 347

setting. 348

Cephalosporins with enhanced activity against Gram-positive bacteria, 349

including MRSA, were evaluated in two studies of patients with skin infections.21, 22 350

Ceftaroline was compared with the combination of vancomycin and aztreonam in a 351

pooled analysis of two identical RCTs in 1,378 patients with complicated SSTI 352

requiring admission to hospital (CANVAS 1 and 2).21 The trials were designed to 353

demonstrate non-inferiority of ceftaroline (600 mg 12-hourly) compared with 354

vancomycin (1 g 12-hourly adjusted according to local guidelines) given for 5-14 355

days. The primary outcome was clinical cure at a follow up visit 8-15 days after the 356

last dose of antibiotics. Clinical cure rates in the pooled analysis met the predefined 357

criteria for non-inferiority (lower limit of the 95% CI above -10%) and were 595/693 358

(85.9%) in the ceftaroline arm and 586/685 (85.5%) in the vancomycin/aztreonam 359

arm (difference 0.3% (95% CI -3.4 – 4.0). Clinical Cure was similar in 330 patients 360

infected with MRSA [155/179 (86.6%) versus 124/151 (82.1%) in the ceftaroline and 361

vancomycin/aztreonam modified intention-to-treat groups, respectively]. In a RCT 362

recruiting 784 patients powered to demonstrate non-inferiority, ceftobiprole (500 mg 363

12-hourly) was compared with vancomycin (1 g 12-hourly adjusted according to local 364

guidelines) in the treatment of complicated SSTI caused by Gram-positive 365

organisms, including MRSA.22 The antibiotics were administered for 7-14 days and 366

the primary outcome was clinical cure at an assessment visit performed 10-14 days 367

after the end of treatment. Overall, the clinical cure rate was 263/282 (93.3%) in the 368

ceftobiprole arm and 259/277 (93.5%) in the vancomycin arm (difference -0.2%; 95% 369

CI -4.4 – 3.9), which met the criteria for non-inferiority. There was no statistically 370

significant difference in outcome between the two groups in patients infected with 371

MRSA [cure rates of 56/61 (91.8%) in the ceftobiprole arm versus 54/60 (90%) in the 372

vancomycin arm (difference 1.8%; 95% CI -8.4-12.1)]. 373

Dalbavancin, a new lipoglycopeptide, was studied in two identical non-374

inferiority trials comprising 1,312 patients which were performed for licensing 375

purposes (DISCOVER 1 and DISCOVER 2) and the results were pooled.23 Patients 376

with SSTI requiring intravenous antibiotic therapy were given either dalbavancin 1 g 377

on day 1 followed by 500 mg on day 8, or vancomycin 15 mg/kg 12 hourly for at least 378

3 days with an option to switch to oral linezolid 600 mg twice daily to complete 10-14 379

days of therapy. The primary endpoint was early clinical response as measured at 380

48-72 h. Overall, dalbavancin was not inferior to vancomycin/linezolid with very 381

similar outcomes in the two treatment arms [cure rates of 525/659 patients (79.7%) 382

treated with dalbavancin compared with 521/653 patients (79.8%) treated with 383

vancomycin ± linezolid (difference -0.1%; 95% CI -4.5-4.2)]. In the secondary 384

analysis of the subset of patients with proven MRSA infection, cure rates assessed 385

at the end of treatment were similar [72/74 patients (97.3%) in the dalbavancin group 386

versus 49/50 patients (98%) in the vancomycin ± linezolid group]. 387

Two almost identical large international multicentre RCTs powered to 388

demonstrate non-inferiority compared a single dose of oritavancin (1,200 mg) with 389

vancomycin (1 g twice daily) given for 7-10 days in the treatment of patients with 390

SSTIs (SOLO-I and SOLO-II, recruiting 968 and 1,019 patients, respectively).25, 26 In 391

both studies oritavancin was demonstrated to be non-inferior to vancomycin with 392

equivalent clinical response rates in both arms. In the SOLO-I study, the early clinical 393

response in the modified intention to treat population was 391/475 (82.3%) for 394

oritavancin and 378/479 (78.9%) for vancomycin (difference 3.4%; 95% CI -1.6 – 395

8.4) and in SOLO-II the corresponding response rates were 403/503 (80.1%) for 396

oritavancin and 416/502 (82.9%) for vancomycin (difference -2.7%; 95% CI -7.5 – 397

2.0). In a pooled analysis, for those patients with proven infection caused by MRSA, 398

the early clinical response at 48-72h was 166/204 (81.4%) in the oritovancin arm 399

versus 162/201 (80.6%) in the vancomycin arm (difference 0.8%; 95% CI -6.9-8.4), 400

which met the predefined criteria for non-inferiority.24 401

Two large international, multicentre studies powered to demonstrate non-402

inferiority and comprising 1,867 adults with complicated SSTI requiring intravenous 403

therapy compared telavancin (10 mg/kg/day) with vancomycin (1g 12 hourly and 404

then adjusted according to therapeutic drug monitoring) (the ATLAS studies); the 405

results were pooled.27 Antibiotics were given for 10-14 days and the primary end-406

point was cure as assessed 10-14 days after the completion of treatment. In the 407

pooled analysis, telavancin met the criteria for non-inferiority; cure was reported in 408

658/745 (88.3%) clinically evaluable patients in the telavancin arm and 648/744 409

(87.1%) in the vancomycin arm (difference 1.2%; 95% -2.1 – 4.6). Among patients 410

with infection caused by MRSA, telavancin was non-inferior to vancomycin [cure rate 411

of 252/278 patients (90.6%) in the telavancin group versus 260/301 patients (86.4%) 412

in the vancomycin group (difference 4.1%; 95% CI -1.1-9.3)]. 413

Tedizolid was compared with linezolid in two studies powered to demonstrate 414

non-inferiority in patients with SSTI caused by Gram-positive bacteria (ESTABLISH-415

1 and ESTABLISH-2).28, 29 The primary outcome was early clinical response as 416

assessed at 48-72h according to FDA guidance. ESTABLISH-1 (n=667 patients) 417

compared oral tedizolid (200mg once daily for 6 days) with oral linezolid (600mg 418

twice daily for 10 days).29 ESTABLISH-2 (n=666 patients) was similar in terms of 419

dosage and duration of therapy, but compared tedizolid with linezolid both given 420

intravenously (with the option to de-escalate to oral therapy after administration of a 421

minimum of two intravenous doses).28 In both of the studies the pre-defined non-422

inferiority criterion was a lower 95% CI of higher than -10% and demonstrated that 423

tedizolid was non-inferior to linezolid. In ESTABLISH-1 the early clinical response 424

was 259/332 (78%) for tedizolid and 255/335 (76.1%) for linezolid (difference 1.9%; 425

95% CI -4.5 – 8.3) and in ESTABLISH-2 was 283/332 (85%) for tedizolid and 426

276/334 (83%) for linezolid (difference 2.6%; 95% CI -3.0 – 8.2). For patients with 427

infection caused by MRSA assessed at a follow up visit 7-10 days after the end of 428

treatment, response rates in ESTABLISH-1 were 75/88 (85.2%) versus 77/90 429

(85.6%) in the tedizolid and linezolid arms, respectively (p value not reported) and, in 430

ESTABLISH-2, 44/53 (83%) versus 44/56 (79%) in the tedizolid and linezolid arms, 431

respectively (difference 4.4%; 95% CI -10.8-19.5). 432

Pleuromutilin antibiotics (lefamulin and retapamulin) were assessed in two 433

RCTs. In the first trial30, patients with ABSSSI were randomly assigned to receive 434

either lefamulin 100 mg, or lefamulin 150 mg, or vancomycin (dosage adjusted 435

according to standard practice in individual institutions) for 5-14 days. The primary 436

outcome was clinical cure as assessed 10-14 days after the end of treatment. 437

Overall cure rates were 54/60 (90%) in the lefamulin (100 mg) arm, 48/54 (88.9%) in 438

the lefamulin (150 mg) arm and 47/51 (92.2%) in the vancomycin arm. MRSA was 439

identified in 105/210 patients recruited. Cure rates in the MRSA subgroup were 440

similar in all of the study arms [lefamulin (100 mg) 29/34 (85.3%), lefamulin (150 mg) 441

28/32 (87.5%) and vancomycin 32/39 (82.1%)]; a p value was not reported. 442

However, there is a high risk of bias due to the small number of patients with MRSA 443

in each treatment arm. At the time of writing, lefamulin is awaiting regulatory 444

approval. The retapamulin trial12 is discussed in Section 3.1 in relation to impetigo. 445

Topical retapamulin 1% administered twice daily for 5 days was shown to be inferior 446

to oral treatment with linezolid 600 mg 12-hourly for 10 days (or equivalent dose 447

adjusted for age in children) in a RCT including adults and children with either 448

infected wounds or impetigo caused by MRSA.12 The primary outcome was clinical 449

cure at follow up 7-9 days after the completion of therapy; 410 patients were enrolled 450

and 125 of these had impetigo. In the 404 patients who completed the study, the 451

clinical cure rate in the retapamulin group (161/268 (60.1%) was significantly lower 452

than that in the oral linezolid group (112/136 (82.4%) (difference -22.3%; 95% CI -453

31.9 - -12.6). 454

Delafloxacin 300 mg was shown to be non-inferior to vancomycin 15 mg/kg 455

plus aztreonam 2 g (each given 12-hourly for 5-14 days) in a RCT comprising 660 456

patients with ABSSSI. The primary outcome was clinical response at 48-72h in the 457

intention-to-treat population, and the predefined criterion for non-inferiority was that 458

the lower 95% CI of the difference between the treatment arms was greater than -459

10%. Clinical response was seen in 259/331 (78.2%) patients in the delafloxacin arm 460

and 266/329 (80.9%) patients in the vancomycin plus aztreonam arm (difference -461

2.6%; 95% CI -8.8 – 3.6). In the subgroup of patients with proven MRSA infection, 462

clinical response was seen in 190/220 (86.4%) patients in the delafloxacin arm and 463

in 199/225 (88.4%) patients in the vancomycin plus aztreonam arm (difference -2.0; 464

95% CI -8.39 - 4.16).31 465

Iclaprim, a novel diaminopyridimine antibiotic that inhibits dihydrofolate 466

reductase, has been studied in two similar licensing RCTs in patients with ABSSSI 467

(REVIVE-1 and REVIVE-2).32, 33 Iclaprim at a dose of 80 mg twice daily intravenously 468

was compared with vancomycin 15 mg/kg twice daily (dose adjusted according to 469

therapeutic drug monitoring), each given for 5-14 days. The primary endpoint was 470

early clinical response at 48-72h in the intention-to-treat population and the studies 471

were powered to demonstrate non-inferiority. In the two trials, a total of 1,198 472

patients were recruited and 272 had infection caused by MRSA. Iclaprim was non-473

inferior to vancomycin in the total patient population (clinical cure in the REVIVE-1 474

study was 241/298 (80.9%) in the iclaprim arm and 243/300 (81%) in the 475

vancomycin arm (difference -0.1%; 95% CI -6.42-6.17), while in the REVIVE-2 study, 476

clinical cure was 231/295 (78.3%) in the iclaprim arm and 234/305 (76.7%) in the 477

vancomycin arm (difference 1.58%; 95% CI -5.1 – 8.26)). Within the subgroup with 478

MRSA, clinical cure in the REVIVE-1 study was 59/73 (80.8%) in the iclaprim arm 479

and 50/61 (8281%) in the vancomycin arm [(difference -1.15%; 95% CI -17.9-15.8)], 480

while in the REVIVE-2 study, clinical cure was 61/69 (88.4%) iclaprim arm and 53/69 481

(76.8%) in the vancomycin arm [difference 11.6%; 95% CI -5.8-28.5)]. At the time of 482

writing, iclaprim had not been licensed for clinical use; further safety data on hepatic 483

toxicity are also awaited. 484

Recommendation 3: 485

(i) Glycopeptides (vancomycin or teicoplanin) remain the first-line treatment for 486

patients with severe cellulitis/soft tissue infection caused by MRSA. [Category IA] 487

Linezolid (oral or intravenous) [Category IA] and daptomycin [Category IB] are now 488

established alternative agents in clinical practice. Tigecycline is also licenced for use 489

in complicated SSTI when other antibiotics are not suitable. 490

(ii) Additional oral agents that may be used for de-escalation or in patients with 491

milder infection [as assessed by the absence of systemic upset in grading schemes 492

such as that proposed by Eron et al. 34 and depending on confirmation of 493

susceptibility] include co-trimoxazole, clindamycin and doxycycline. [Category IB] 494

(iii) Newer agents that may be considered in this clinical setting and that are 495

currently licensed in the UK include oritavancin, telavancin, delafloxacin [all Category 496

IB], ceftaroline, dalbavancin and tedizolid. [all Category IC] 497

4. Urinary tract infections 498

There is a lack of evidence on the management of MRSA urinary tract infections 499

(UTI). No new evidence was identified for the treatment of such infection, but the 500

previous guidelines were reviewed. The guideline development group feel that the 501

detection of MRSA in the urine should lead to an investigation of the cause. MRSA 502

might be shed in the urine as a result of a bacteraemia or the presence of the 503

bacterium in the urine may simply represent colonisation, particularly in patients with 504

long-term catheters. MRSA bacteriuria may also be secondary to an anatomic 505

abnormality of the urinary tract. 506

Recommendation 4: 507

(i) Prior to commencing treatment of a patient with MRSA UTI, the presence of 508

MRSA bacteraemia should be excluded. [Category IB] 509

(ii) A requirement of the agent chosen as treatment is that it must be excreted in 510

the urine. [Category IB] 511

(iii) Parenteral glycopeptides are the first-line choice for the management of 512

MRSA UTI. [Category IA] 513

(iv) Although daptomycin remains unlicensed for use in this setting, its high renal 514

excretion (80%) means that it is a commonly used alternative when a glycopeptide is 515

contraindicated. [Category II] Linezolid has lower renal excretion (30%) and is less 516

commonly used in this setting. [Category II] 517

(v) If MRSA bacteriuria is deemed to represent genuine lower UTI, the choice of 518

treatment should be based on the isolate’s antimicrobial susceptibility pattern. 519

Appropriate oral agents in this setting include, doxycycline, nitrofurantoin, 520

trimethoprim, quinolones or co-trimoxazole [Category IB]. 521

(vi) In the case of catheter-associated UTI, it would be appropriate to replace the 522

catheter, with or without the administration of a single dose of gentamicin [if the 523

strain is susceptible]. [Category II] 524

5. Bone and joint infections 525

Bone and joint infections caused by MRSA can be difficult to treat and may require 526

prolonged antimicrobial therapy. Our recommendations do not include the 527

management of the specialist conditions such as prosthetic joint infection and 528

diabetic foot infection. 529

Paul et al. performed a RCT of co-trimoxazole compared with vancomycin in 530

patients with a range of severe infections caused by MRSA35. Co-trimoxazole was 531

initially administered intravenously at a dosage of 1,920mg 12-hourly and this was 532

converted to an oral formulation at the same dosage at a time chosen by the treating 533

physician. The vancomycin dosing was 1g 12-hourly intravenously with target pre-534

dose serum concentrations of 10-20 mg/L; the duration of therapy was not reported. 535

The trial was powered for non-inferiority across a range of infections and therefore 536

not powered to determine utility of co-trimoxazole in bone or joint infection alone. 537

This trial included 39 and 32 patients with MRSA bone and joint infection, 538

randomised to co-trimoxazole or vancomycin, respectively (unpublished data). The 539

primary outcome was clinical treatment failure at seven days, and this occurred in 540

11/39 (28%, co-trimoxazole) and 7/32 (22%, vancomycin) patients, respectively. A 541

secondary outcome of mortality at 30 days did not differ between groups [2/39 (5%) 542

for co-trimoxazole and 1/32 (3%) for vancomycin]. These numbers are small, and 543

differences are not statistically significant. 544

Owing to its biofilm penetration rifampicin has been recommended in previous 545

UK guidelines1 as adjunctive therapy in patient with MRSA bone or joint infections, 546

particularly where metalwork is implanted. No evidence fulfilling the inclusion criteria 547

on the use of rifampicin to treat bone infection was identified during the current 548

systematic review. 549

There is increasing experience in the UK of the use of dalbavancin to treat 550

bone infection. Due to its long half-life and suitability for weekly administration, it is 551

used when other drugs cannot be easily administered. No evidence fulfilling the 552

inclusion criteria on the use of dalbavancin to treat bone infection was identified 553

during the current systematic review. 554

Recommendation 5: 555

(i) The treatment of patients with MRSA bone and joint infection should be based 556

on a multidisciplinary approach with surgery or drainage implemented where 557

indicated. [Category IA] The first-line antibiotic treatment of patients with such 558

infection is an intravenous glycopepide. [Category IA] The optimal duration of 559

treatment is not known but intravenous glycopeptide is usually administered for a 560

minimum of 2 weeks followed by further IV or oral antibiotics to complete a total 561

treatment course of a minimum of 4 weeks for patients with septic arthritis or 6 562

weeks for those with osteomyelitis. [Category II] 563

(ii) The use of glycopeptides should be combined with therapeutic drug 564

monitoring to ensure that non-toxic, therapeutic serum concentrations are achieved. 565

[Category IA] In some patients, high renal excretion can limit the utility of 566

glycopeptides and it is not possible to obtain therapeutic blood levels. Owing to the 567

lack of evidence, we cannot make recommendations for the use of daptomycin to 568

treat MRSA bone and joint infections; however, daptomycin (6 mg/kg dose) is 569

increasingly used as an alternative in such patients. [Category II] 570

(iii) Following initial treatment with a glycopeptide, oral antibiotics should be 571

administered on the basis of antimicrobial susceptibilities [Category IA]. Therapeutic 572

options include doxycycline, trimethoprim, co-trimoxazole, quinolones, rifampicin, 573

clindamycin, linezolid and co-trimoxazole [Category IA]. Rifampicin and quinolones 574

should not be used alone due to the risk of resistance developing but may be used in 575

combination with other agents to which the isolate is susceptible [Category IA]. 576

(iv) Fusidic acid is an option for adjunctive therapy1 but it is now less commonly 577

used due to a lack of strong evidence to support its use [Category IC]. 578

6. Bacteraemia 579

Three studies met our inclusion criteria in this clinical setting.35-37 Paul et al. 35 580

enrolled 91 patients with MRSA bacteraemia in a RCT. Of these patients 50 were 581

randomised to vancomycin (target pre-dose serum concentrations 10-20 mg/L) and 582

41 to co-trimoxazole (1,920mg 12-hourly IV initially then oral or IV). In the intention-583

to-treat analysis, 23/41 (56%) and 20/50 (40%) patients in the vancomycin and co-584

trimoxazole groups respectively experience clinical treatment failure at day 7 (effect 585

estimate 1.4 (95% CI 0.9-2.16). The secondary outcome of all-cause mortality at 30 586

days was non-significantly higher in the co-trimoxazole group (14/41 (34%) versus 587

9/50 (18%), effect estimate 1.9 (95% 0.9-3.9) leading the authors to advise that this 588

antibiotic is not used alone to treat patient with MRSA bacteraemia, although the 589

small numbers (and associated risk of bias) and the absence of a statistically 590

significant difference limit the impact of this recommendation. 591

In a second RCT, Thwaites et al.37 allocated patients with S. aureus 592

bacteraemia to adjunctive therapy with either rifampicin or placebo; patients also 593

received standard regimens. Of the 47 patients with infections caused by MRSA, 26 594

received rifampicin and 21 received placebo. Nine of 26 (35%) patients who were 595

given adjunctive rifampicin and 3/21 (14%) prescribed adjunctive placebo met the 596

primary outcome at 12 weeks (clinically defined treatment failure or disease 597

recurrence, or death) (p >0.05). The authors concluded that the addition of 598

adjunctive rifampicin to standard therapy did not improve clinical outcomes in 599

patients with S. aureus bacteraemia (SAB), but conclusions cannot be presumed to 600

extrapolate to MRSA. 601

In vitro and animal studies have suggested the potential for synergy when 602

vancomycin is combined with beta-lactam antibiotics for the treatment of patients 603

with MRSA bacteraemia.38, 39 Davis et al.36 report the results of a pilot RCT 604

(CAMERA) designed to investigate the effect of adjunctive beta-lactam in this 605

setting. Three hundred and eighty patients were screened and 60 were recruited. All 606

participants received intravenous vancomycin 1.5g 12-hourly, with 29 patients 607

receiving adjunctive placebo (control arm) and 31 patients receiving adjunctive 608

flucloxacillin 2g 6-hourly (combination arm), for 7 days. The duration of bacteraemia 609

was 3 days in the control arm and 1.94 days in the combination arm in the intention-610

to-treat analysis (p=0.06). As the results were inconclusive a larger trial (CAMERA-2) 611

is currently recruiting larger numbers to further test this hypothesis. 612

The evidence regarding teicoplanin in MRSA bacteraemia is limited. There is 613

no robust evidence of inferiority of teicoplanin compared with vancomycin. 614

Recommendation 6: 615

(i) The principal treatment of patients with uncomplicated MRSA bacteraemia is 616

vancomycin. [Category IA] As the infection is associated with high mortality rates 617

therapeutic drug monitoring is essential. 618

(ii) Linezolid is an alternative first-line treatment and should be used in 619

preference to vancomycin in cases in which therapeutic vancomycin serum 620

concentrations cannot be achieved, where the pathogen has reduced susceptibility 621

to glycopeptides or where there is vancomycin allergy or intolerance. [Category II] 622

Daptomycin, in dosages of ≥10mg/kg/day, has been used successfully when first-line 623

agents have been contraindicated, but there is currently insufficient published 624

evidence to enable it to be recommended routinely. [Category II] 625

(iii) There is no evidence to warrant the use of co-trimoxazole alone as a first-line 626

agent for patients with MRSA bacteraemia, although it may have a role in oral step-627

down where susceptibility allows. [Category II] 628

(iv) We recommend a minimum duration of 14 days of antibiotic treatment for 629

patients with uncomplicated MRSA bacteraemia and a minimum duration of 28 days 630

of treatment for those with complicated MRSA bacteraemia. [Category II] 631

7. Infective Endocarditis 632

Current BSAC endocarditis guidelines40 advise the use of vancomycin for 633

vancomycin-susceptible native or prosthetic valve MRSA endocarditis. If the patient 634

cannot tolerate vancomycin or if the isolate is not vancomycin-susceptible then 635

daptomycin is recommended as an alternative in combination with a second agent 636

chosen according to antibiotic susceptibility testing. The guidelines recommend a 637

minimum duration of 4 weeks for patients with native valve endocarditis and 6 weeks 638

for those with prosthetic valve endocarditis. 639

Recommendation 7: The reader is referred to the most recent version of the BSAC 640

endocarditis guidelines. 641

8. Respiratory tract infections 642

8.1 Necrotising pneumonia 643

MRSA necrotising pneumonia (e.g. in association with PVL) is a life-threatening 644

disease that requires urgent treatment. No new evidence that allows existing 645

guidelines to be updated/modified has been identified in the current systematic 646

review. The 2008 UK MRSA treatment guidelines1 recommended the use of 647

vancomycin or linezolid, but the authors expressed concerns regarding the efficacy 648

of both drugs. Previous PHE guidelines, which advised a combination of 649

clindamycin, linezolid and rifampicin, were subsequently withdrawn and should not 650

be used to guide treatment. 651

Recommendation 8.1: In the absence of novel evidence, we recommend that 652

patients with necrotising MRSA pneumonia should be treated with either vancomycin 653

or linezolid [Category II]. Given the severity of this infection, and in line with current 654

practice, we recommend that these antibiotics should be administered in 655

combination with a toxin-inhibiting agent, such as clindamycin or rifampicin, 656

according to antimicrobial susceptibility testing, if such results are available. 657

[Category II] 658

8.2 Nosocomial pneumonia 659

Wunderink et al.41 carried out a large RCT that enrolled 1184 patients with all-cause 660

nosocomial pneumonia in the initial recruitment. Patients were randomised to receive 661

either IV linezolid (600mg bd) or IV vancomycin (15mg/kg bd) for 7-14 days (or 21 662

days in the case of associated bacteraemia). The primary outcome measure for end-663

of-study clinical success was analysed according to those patients later identified as 664

having confirmed MRSA (a proportion of whom had MRSA combined with other 665

pathogens). This included 448 patients (linezolid n=224; vancomycin, n=224) for the 666

modified intention-to-treat analysis and 348 patients (linezolid, n=172; vancomycin, 667

n=176) in the per protocol population. In the per protocol population, 95/165 (58%) in 668

the linezolid arm and 81/174 (46.5%) in the vancomycin arm achieved clinical 669

success at end of study (p=0.042). Mortality at 60-days did not differ between the 670

modified intention-to-treat and the intention-to-treat groups. 671

Rubenstein et al.42 randomised 1532 patients with nosocomial pneumonia, of 672

whom 290 had evidence of MRSA infection, to IV telavancin 10mg/kg/day (n=136) or 673

vancomycin 1g bd (n=154) for 7-21 days. In both groups with MRSA infection, 75.5% 674

of patients (104/136 with telavancin and 115/154 with vancomycin) were assessed 675

as cured at the test of cure/follow up visit. Although these numbers are larger than 676

those in other studies in this clinical setting, they are not adequately powered to 677

demonstrate non-inferiority of telavancin over vancomycin in patients with MRSA 678

pneumonia. There was an increase in treatment-emergent adverse events on 679

telavancin (234/751, 31%) compared with vancomycin (197/752, 26%) overall in this 680

trial. 681

Recommendation 8.2: Patients with nosocomial MRSA pneumonia should be 682

treated with either vancomycin or linezolid. [Category IB]. More studies are required 683

to establish if telavancin can be used as an alternative. Daptomycin should be 684

avoided as it is inactivated by lung surfactant. [Category IB] 685

8.3 Ear, nose and throat or upper respiratory tract infections 686

MRSA associated ear, nose and throat or upper respiratory tract infections are rare, 687

although they may be complicated by skull penetration or brain abscess formation. 688

No new evidence which might inform our recommendations was identified in the 689

current systematic review. 690

Recommendation 8.3: MRSA associated ear, nose and throat or upper respiratory 691

tract infections should be treated with a glycopeptide or linezolid. [Category II] 692

9. CNS and eye disease 693

9.1 Intracranial or spinal infections 694

Infections in this category include brain abscess, subdural empyema, spinal epidural 695

abscess and vertebral osteomyelitis. No new evidence which might inform our 696

recommendations for the treatment of patients with MRSA infection in these clinical 697

settings was identified in the current systematic review. 698

Recommendation 9.1: Incision and drainage is the cornerstone of therapy for 699

patients with these infections, unless surgical intervention is contraindicated 700

[Category IA]; however, patients with small epidural abscesses can be treated with 701

antibiotics alone. [Category II] Vancomycin or linezolid are recommended in the 702

treatment of patients with any of these infections. [Category II] 703

9.2 CSF infections 704

No new evidence which might inform our recommendations for the treatment of 705

patients with CSF infection caused by MRSA was identified in the current systematic 706

review. 707

Shunt infection was not considered in this review. Oritavancin has demonstrated 708

efficacy in animals and may have a role to play in this clinical setting, but that role is 709

not currently clear. 710

Recommendation 9.2: 711

(i) The first-line choice of antibiotic for the management of patients with CSF 712

infection caused by MRSA (i.e. meningitis or ventriculitis) remains vancomycin, 713

despite its limited penetration into the CSF. [Category IA] Its efficacy can be 714

optimised by facilitating therapeutic serum concentrations through monitoring. 715

[Category II] In severe cases or when the patient fails to respond it may be 716

necessary to instil vancomycin directly into the ventricles. This, of course, will require 717

patients to be transferred to a neurosurgical centre. [CATEGORY II]. 718

(ii) Clindamycin does not penetrate into the CSF compartment and is 719

bacteriostatic. It should not be used therefore to treat patients CSF infection 720

irrespective of the pathogen’s susceptibility to it. [Category IC]. 721

(iii) Chloramphenicol possesses excellent CSF penetration, but it too is 722

bacteriostatic, thereby rendering it inappropriate as therapy of patients with CSF 723

infection caused by MRSA, even when the pathogen is susceptible. Linezolid is likely 724

to penetrate into the CSF, but its use as therapy in this setting is precluded by its 725

bacteriostatic activity. [Category IC] 726

(iv) It is not recommended that teicoplanin be used as first-line therapy owing to 727

limited evidence of its efficacy. [Category II] 728

9.3 Eye disease 729

MRSA eye disease is rare. In the event, no new evidence which might inform our 730

recommendations for the treatment of patients with eye infection caused by MRSA 731

was identified in the current systematic review. 732

Endophthalmitis can represent dissemination secondary to bacteraemia and this 733

should always be considered when a patient is diagnosed with this disease. 734

Recommendation 9.3: Superficial MRSA eye disease may be treated with 735

gentamicin or chloramphenicol drops according to susceptibility [Category II]. For 736

deeper eye infections close liaison between specialist ophthalmologists and 737

infectious diseases clinicians is critical. Options for treatment include intravitreal 738

vancomycin and quinolones. It is likely that oral linezolid penetrates the eye tissue, 739

but the efficacy for MRSA infections has not been established. 740

10. Conclusions 741

The incidence of MRSA has fallen considerably since the publication of the 2008 742

MRSA guidelines. At the current time empiric treatment for MRSA is no longer 743

advised in those without a known history of MRSA. This advice should be considered 744

in view of the epidemiology at the time this guideline is read. Since 2008 there has 745

been a change in clinical management of MRSA with linezolid and daptomycin 746

available more widely. Evidence was found to support the use of antibiotic treatment 747

in the case of USA300 strain MRSA abscesses and should this strain become more 748

common in the UK adjunctive antibiotics may be advised for the management of 749

abscesses in the future. 750

Acknowledgements 751

We thank Dr Vittoria Lutje for completing the literature searches and Prof. Phil Wiffen 752

for advice and guidance with the systematic review of the literature. We thank 753

colleagues who responded to the consultation and provided feedback about the 754

recommendations and BSAC Secretariat for their help coordinating the consultation 755

process. 756

Funding 757

This work was equally funded by the BSAC, British Infection Association (BIA), 758

Healthcare Infection Society (HIS), and Infection Prevention Society (IPS). 759

Transparency declaration 760

NB, EB, AJ and CH declare no conflict of interest. AG was an author of the ARREST 761

trial.37 762

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23. Boucher HW, Wilcox M, Talbot GH et al. Once-weekly dalbavancin versus 828 daily conventional therapy for skin infection. N Engl J Med 2014; 370: 2169-79. 829

24. Corey GR, Arhin FF, Wikler MA et al. Pooled analysis of single-dose 830 oritavancin in the treatment of acute bacterial skin and skin-structure infections 831 caused by Gram-positive pathogens, including a large patient subset with methicillin-832 resistant Staphylococcus aureus. Int J Antimicrob Agents 2016; 48: 528-34. 833

25. Corey GR, Good S, Jiang H et al. Single-dose oritavancin versus 7-10 days of 834 vancomycin in the treatment of gram-positive acute bacterial skin and skin structure 835 infections: the SOLO II noninferiority study. Clin Infect Dis 2015; 60: 254-62. 836

26. Corey GR, Kabler H, Mehra P et al. Single-dose oritavancin in the treatment 837 of acute bacterial skin infections. N Engl J Med 2014; 370: 2180-90. 838

27. Stryjewski ME, Graham DR, Wilson SE et al. Telavancin versus vancomycin 839 for the treatment of complicated skin and skin-structure infections caused by Gram-840 positive organisms. Clin Infect Dis 2008; 46: 1683-93. 841

28. Moran GJ, Fang E, Corey GR et al. Tedizolid for 6 days versus linezolid for 10 842 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a 843 randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2014; 14: 844 696-705. 845

29. Prokocimer P, De Anda C, Fang E et al. Tedizolid phosphate vs linezolid for 846 treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 847 randomized trial. JAMA 2013; 309: 559-69. 848

30. Prince WT, Ivezic-Schoenfeld Z, Lell C et al. Phase II clinical study of BC-849 3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and 850 skin structure infections. Antimicrob Agents Chemother 2013; 57: 2087-94. 851

31. Pullman J, Gardovskis J, Farley B et al. Efficacy and safety of delafloxacin 852 compared with vancomycin plus aztreonam for acute bacterial skin and skin 853

structure infections: a Phase 3, double-blind, randomized study. J Antimicrob 854 Chemother 2017; 72: 3471-80. 855

32. Holland TL, Riordan WO, McManus A et al. A phase 3, randomized, double-856 blind, multicenter study to evaluate the safety and efficacy of intravenous iclaprim 857 versus vancomycin for treatment of acute bacterial skin and skin structure infections 858 suspected or confirmed to be due to gram-positive pathogens (revive-2 study). 859 Antimicrob Agents Chemother 2018; 62: e02580. 860

33. Huang DB, O'Riordan W, Overcash JS et al. A Phase 3, Randomized, 861 Double-Blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous 862 Iclaprim Vs Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure 863 Infections Suspected or Confirmed to be Due to Gram-Positive Pathogens: REVIVE-864 1. Clin Infect Dis 2018; 66: 1222-9. 865

34. Eron LJ, Lipsky BA, Low DE et al. Managing skin and soft tissue infections: 866 expert panel recommendations on key decision points. J Antimicrob Chemother 867 2003; 52 Suppl 1: i3-17. 868

35. Paul M, Bishara J, Yahav D et al. Trimethoprim-sulfamethoxazole versus 869 vancomycin for severe infections caused by meticillin resistant Staphylococcus 870 aureus: randomised controlled trial. BMJ 2015; 350: h2219. 871

36. Davis J, Sud A, O'Sullivan MVN et al. Combination of Vancomycin and beta-872 Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot 873 Multicenter Randomized Controlled Trial. Clin Infect Dis 2016; 62: 173-80. 874

37. Thwaites GE, Scarborough M, Szubert A et al. Adjunctive rifampicin for 875 Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-876 blind, placebo-controlled trial. Lancet 2018; 391: 668-78. 877

38. Davis JS, Van Hal S, Tong SY. Combination antibiotic treatment of serious 878 methicillin-resistant Staphylococcus aureus infections. Semin Respir Crit Care Med 879 2015; 36: 3-16. 880

39. Dilworth TJ, Ibrahim O, Hall P et al. beta-Lactams enhance vancomycin 881 activity against methicillin-resistant Staphylococcus aureus bacteremia compared to 882 vancomycin alone. Antimicrob Agents Chemother 2014; 58: 102-9. 883

40. Gould FK, Denning DW, Elliott TS et al. Guidelines for the diagnosis and 884 antibiotic treatment of endocarditis in adults: a report of the Working Party of the 885 British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67: 886 269-89. 887

41. Wunderink RG, Niederman MS, Kollef MH et al. Linezolid in methicillin-888 resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled 889 study. Clin Infect Dis 2012; 54: 621-9. 890

42. Rubinstein E, Lalani T, Corey GR et al. Telavancin versus vancomycin for 891 hospital-acquired pneumonia due to Gram-positive pathogens. Clin Infect Dis 2011; 892 52: 31-40. 893

43. Moher D, Liberati A, Tetzlaff J et al. Preferred reporting items for systematic 894 reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097. 895

44. Aikawa N, Kusachi S, Mikamo H et al. Efficacy and safety of intravenous 896 daptomycin in Japanese patients with skin and soft tissue infections. J Infect 897 Chemother 2013; 19: 447-55. 898

45. Bradley J, Glasser C, Patino H et al. Daptomycin for complicated skin 899 infections: A randomized trial. Pediatrics 2017; 139: e20162477. 900

46. Covington P, Davenport JM, Andrae D et al. Randomized, double-blind, 901 phase II, multicenter study evaluating the safety/tolerability and efficacy of JNJ-Q2, a 902 novel fluoroquinolone, compared with linezolid for treatment of acute bacterial skin 903 and skin structure infection. Antimicrob Agents Chemother 2011; 55: 5790-7. 904

47. Dryden M, Zhang Y, Wilson D et al. A Phase III, randomized, controlled, non-905 inferiority trial of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus 906 aztreonam in patients with complicated skin and soft tissue infection with systemic 907 inflammatory response or underlying comorbidities. J Antimicrob Chemother 2016; 908 71: 3575-84. 909

48. Dunbar LM, Milata J, McClure T et al. Comparison of the efficacy and safety 910 of oritavancin front-loaded dosing regimens to daily dosing: an analysis of the 911 SIMPLIFI trial. Antimicrob Agents Chemother 2011; 55: 3476-84. 912

49. Dunne MW, Puttagunta S, Giordano P et al. A Randomized Clinical Trial of 913 Single-Dose Versus Weekly Dalbavancin for Treatment of Acute Bacterial Skin and 914 Skin Structure Infection. Clin Infect Dis 2016; 62: 545-51. 915

50. Ibrahim LF, Hopper SM, Babl FE et al. Who can have parenteral antibiotics at 916 home? A prospective observational study in children with moderate/severe cellulitis. 917 Pediatric infectious disease journal 2016; 35: 269‐74. 918

51. Joseph WS, Culshaw D, Anuskiewicz S et al. Tedizolid and Linezolid for 919 Treatment of Acute Bacterial Skin and Skin Structure Infections of the Lower 920 Extremity versus Non-Lower-Extremity InfectionsPooled Analysis of Two Phase 3 921 Trials. J Am Podiatric Med Assoc 2017; 107: 264-71. 922

52. Katz DE, Lindfield KC, Steenbergen JN et al. A pilot study of high-dose short 923 duration daptomycin for the treatment of patients with complicated skin and skin 924 structure infections caused by Gram-positive bacteria. Int J Clin Pract 2008; 62: 925 1455-64. 926

53. Kauf TL, McKinnon P, Corey GR et al. An open-label, pragmatic, randomized 927 controlled clinical trial to evaluate the comparative effectiveness of daptomycin 928 versus vancomycin for the treatment of complicated skin and skin structure infection. 929 BMC Infect Dis 2015; 15: 503. 930

54. Korczowski B, Antadze T, Giorgobiani M et al. A Multicenter, Randomized, 931 Observer-blinded, Active-controlled Study to Evaluate the Safety and Efficacy of 932 Ceftaroline Versus Comparator in Pediatric Patients With Acute Bacterial Skin and 933 Skin Structure Infection. The Pediatric infectious disease journal 2016; 35: e239-47. 934

55. Krievins D, Brandt R, Hawser S et al. Multicenter, randomized study of the 935 efficacy and safety of intravenous iclaprim in complicated skin and skin structure 936 infections. Antimicrob Agents Chemother 2009; 53: 2834-40. 937

56. Lipsky BA, Itani KM, Weigelt JA et al. The role of diabetes mellitus in the 938 treatment of skin and skin structure infections caused by methicillin-resistant 939

Staphylococcus aureus: results from three randomized controlled trials. Int J Infect 940 Dis 2011; 15: e140-6. 941

57. McCollum M, Sorensen SV, Liu LZ. A comparison of costs and hospital length 942 of stay associated with intravenous/oral linezolid or intravenous vancomycin 943 treatment of complicated skin and soft-tissue infections caused by suspected or 944 confirmed methicillin-resistant Staphylococcus aureus in elderly US patients. Clin 945 Ther 2007; 29: 469-77. 946

58. Weigelt J, Itani K, Stevens D et al. Linezolid versus vancomycin in treatment 947 of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005; 948 49: 2260-6. 949

59. McKinnon PS, Sorensen SV, Liu LZ et al. Impact of linezolid on economic 950 outcomes and determinants of cost in a clinical trial evaluating patients with MRSA 951 complicated skin and soft-tissue infections. Ann Pharmacother 2006; 40: 1017-23. 952

60. Mikamo H, Takesue Y, Iwamoto Y et al. Efficacy, safety and pharmacokinetics 953 of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan - 954 Results of a randomised, multicentre phase 3 study. J Infect Chemother 2018; 24: 955 434-42. 956

61. Moran GJ, Krishnadasan A, Mower WR et al. Effect of cephalexin plus 957 trimethoprim-sulfamethoxazole vs cephalexin alone on clinical cure of uncomplicated 958 cellulitis: A randomized clinical trial. JAMA 2017; 317: 2088-96. 959

62. Noel GJ, Draper MP, Hait H et al. A randomized, evaluator-blind, phase 2 960 study comparing the safety and efficacy of omadacycline to those of linezolid for 961 treatment of complicated skin and skin structure infections. Antimicrob Agents 962 Chemother 2012; 56: 5650-4. 963

63. O'Riordan W, Tiffany C, Scangarella-Oman N et al. Efficacy, safety, and 964 tolerability of gepotidacin (GSK2140944) in the treatment of patients with suspected 965 or confirmed gram-positive acute bacterial skin and skin structure infections. 966 Antimicrob Agents Chemother 2017; 61: e02095-16. 967

64. Stryjewski ME, Potgieter PD, Li YP et al. TD-1792 versus vancomycin for 968 treatment of complicated skin and skin structure infections. Antimicrob Agents 969 Chemother 2012; 56: 5476-83. 970

65. Talbot GH, Thye D, Das A et al. Phase 2 study of ceftaroline versus standard 971 therapy in treatment of complicated skin and skin structure infections. Antimicrob 972 Agents Chemother 2007; 51: 3612-6. 973

66. Chamny S, Miron D, Lumelsky N et al. Topical Minocycline Foam for the 974 Treatment of Impetigo in Children: Results of a Randomized, Double-Blind, Phase 2 975 Study. J Drugs Dermatol 2016; 15: 1238-43. 976

67. Duong M, Markwell S, Peter J et al. Randomized, controlled trial of antibiotics 977 in the management of community-acquired skin abscesses in the pediatric patient. 978 Ann Emerg Med 2010; 55: 401-7. 979

68. Rajendran PM, Young D, Maurer T et al. Randomized, double-blind, placebo-980 controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a 981 population at risk for community-acquired methicillin-resistant Staphylococcus 982 aureus infection. Antimicrob Agents Chemother 2007; 51: 4044-8. 983

69. Schmitz GR, Bruner D, Pitotti R et al. Randomized controlled trial of 984 trimethoprim-sulfamethoxazole for uncomplicated skin abscesses in patients at risk 985 for community-associated methicillin-resistant Staphylococcus aureus infection. Ann 986 Emerg Med 2010; 56: 283-7. 987

70. Wilcox MH, Tack KJ, Bouza E et al. Complicated skin and skin-structure 988 infections and catheter-related bloodstream infections: noninferiority of linezolid in a 989 phase 3 study. Clin Infect Dis 2009; 48: 203-12. 990

71. Fowler VG, Jr., Boucher HW, Corey GR et al. Daptomycin versus standard 991 therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J 992 Med 2006; 355: 653-65. 993

72. Stryjewski ME, Lentnek A, O'Riordan W et al. A randomized Phase 2 trial of 994 telavancin versus standard therapy in patients with uncomplicated Staphylococcus 995 aureus bacteremia: the ASSURE study. BMC Infect Dis 2014; 14: 289. 996

73. Kalimuddin S, Chan YFZ, Phillips R et al. A randomized phase 2B trial of 997 vancomycin versus daptomycin for the treatment of methicillin-resistant 998 Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum 999 inhibitory concentrations - results of a prematurely terminated study. Trials 2018; 19: 1000 305. 1001

74. Lin DF, Zhang YY, Wu JF et al. Linezolid for the treatment of infections 1002 caused by Gram-positive pathogens in China. Int J Antimicrob Agents 2008; 32: 241-1003 9. 1004

75. Jung YJ, Koh Y, Hong SB et al. Effect of vancomycin plus rifampicin in the 1005 treatment of nosocomial methicillin-resistant Staphylococcus aureus pneumonia. Crit 1006 Care Med 2010; 38: 175-80. 1007

76. Nicholson SC, Welte T, File TM, Jr. et al. A randomised, double-blind trial 1008 comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the 1009 treatment of patients with community-acquired pneumonia requiring hospitalisation. 1010 Int J Antimicrob Agents 2012; 39: 240-6. 1011

77. Wunderink RG, Mendelson MH, Somero MS et al. Early microbiological 1012 response to linezolid vs vancomycin in ventilator-associated pneumonia due to 1013 methicillin-resistant Staphylococcus aureus. Chest 2008; 134: 1200-7. 1014

78. Liu P, Capitano B, Stein A et al. Clinical outcomes of linezolid and 1015 vancomycin in patients with nosocomial pneumonia caused by methicillin-resistant 1016 Staphylococcus aureus stratified by baseline renal function: a retrospective, cohort 1017 analysis. BMC Nephrology 2017; 18: 168. 1018

79. Rello J, Nieto M, Sole-Violan J et al. Nosocomial pneumonia caused by 1019 methicillin-resistant Staphylococcus aureus treated with linezolid or vancomycin: A 1020 secondary economic analysis of resource use from a Spanish perspective. Medicina 1021 Intensiva 2016; 40: 474-82. 1022

80. Blumer JL, Ghonghadze T, Cannavino C et al. A Multicenter, Randomized, 1023 Observer-blinded, Active-controlled Study Evaluating the Safety and Effectiveness of 1024 Ceftaroline Compared With Ceftriaxone Plus Vancomycin in Pediatric Patients With 1025 Complicated Community-acquired Bacterial Pneumonia. The Pediatric infectious 1026 disease journal 2016; 35: 760-6. 1027

81. Cannavino CR, Nemeth A, Korczowski B et al. A Randomized, Prospective 1028 Study of Pediatric Patients With Community-acquired Pneumonia Treated With 1029 Ceftaroline Versus Ceftriaxone. The Pediatric infectious disease journal 2016; 35: 1030 752-9. 1031

82. Dezube R, Jennings MT, Rykiel M et al. Eradication of persistent methicillin-1032 resistant Staphylococcus aureus infection in cystic fibrosis. J Cyst Fibros 2018; 1033 http://dx.doi.org/10.1016/j.jcf.2018.07.005. 1034

83. Muhlebach MS, Beckett V, Popowitch E et al. Microbiological efficacy of early 1035 MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax 2017; 72: 1036 318-26. 1037

84. Jaksic B, Martinelli G, Perez-Oteyza J et al. Efficacy and safety of linezolid 1038 compared with vancomycin in a randomized, double-blind study of febrile 1039 neutropenic patients with cancer. Clin Infect Dis 2006; 42: 597-607. 1040

85. Harbarth S, von Dach E, Pagani L et al. Randomized non-inferiority trial to 1041 compare trimethoprim/sulfamethoxazole plus rifampicin versus linezolid for the 1042 treatment of MRSA infection. J Antimicrob Chemother 2015; 70: 264-72. 1043

86. Kohno S, Yamaguchi K, Aikawa N et al. Linezolid versus vancomycin for the 1044 treatment of infections caused by methicillin-resistant Staphylococcus aureus in 1045 Japan. J Antimicrob Chemother 2007; 60: 1361-9. 1046

87. Jindal NJ, S; Maitra, D. Efficacy of linezolid over vancomycin in treating 1047 methicillin resistant Staphylococcus aureus (MRSA) infections. Int J Pharma Bio Sci 1048 2015; 6: 1087-95. 1049

88. Garey KW, Lai D, Dao-Tran TK et al. Interrupted time series analysis of 1050 vancomycin compared to cefuroxime for surgical prophylaxis in patients undergoing 1051 cardiac surgery. Antimicrob Agents Chemother 2008; 52: 446-51. 1052

89. Stone PAC, J; AbuRahma, A; Safley, L; Emmett, M; Asmita M. Vascular 1053 Surgical Antibiotic Prophylaxis Study (VSAPS). Vasc Endovasc Surg 2010; 44: 521-1054 8. 1055

90. Stone PA, AbuRahma AF, Campbell JR et al. Prospective randomized 1056 double-blinded trial comparing 2 anti-MRSA agents with supplemental coverage of 1057 cefazolin before lower extremity revascularization. Ann Surg 2015; 262: 495-501. 1058

91. Tacconelli E, Cataldo MA, Albanese A et al. Vancomycin versus cefazolin 1059 prophylaxis for cerebrospinal shunt placement in a hospital with a high prevalence of 1060 meticillin-resistant Staphylococcus aureus. J Hosp Infect 2008; 69: 337-44. 1061

92. Tyllianakis ME, Karageorgos A, Marangos MN et al. Antibiotic prophylaxis in 1062 primary hip and knee arthroplasty: comparison between cefuroxime and two specific 1063 antistaphylococcal agents. J Arthroplasty 2010; 25: 1078-82. 1064

1065

Figure 1. Flow diagram illustrating stages of the literature search and systematic 1066 review.43 1067

1068

1069

1070 Records identified through

database searching

1 Jan 2006 to 26 March 2017 (n=108)

1 Jan 2016 to 31 August 2018 (n=53)

Additional records identified through other

sources (n=7)

Records screened

(n=168)

Records excluded

(n=92)

Full-text articles assessed for eligibility

(n=75)

Full-text articles excluded, with reasons

(n=49)

Studies included in review

(n=26)

Included

Eligibility

Identification

Screening

Table 1. Summary of MRSA treatment recommendations 1071

Clinical indication Recommendation

Skin and soft tissue infections

1 Impetigo

(i) We recommend that impetigo caused by MRSA should be treated with an alternative to topical fusidic acid or mupirocin, for example with a topical antiseptic such as hydrogen peroxide 1% cream, where there is localised, non-bullous disease and no systemic upset; topical fusidic acid or mupirocin should be limited to second-line options in the clinical setting and only when the MRSA isolate is known to be susceptible. [Category II]

(ii) Complicated infection may require systemic antimicrobial therapy and the choice of agent should be determined by susceptibility testing. [Category II]

2 Abscesses

(i) Abscesses require incision and drainage to control the source of infection. [Category IA]

(ii) We recommend that antibiotic treatment should not be given routinely to patients with abscesses that are drained, that are <5 cm in diameter and in the absence of a systemic response (fever and/or cellulitis) and/or immunodeficiency. [Category IA]

(iii) Antibiotics may be of benefit if the abscess is caused by PFGE strain type USA300, in which case, should this strain become more common in the UK, a lower threshold for antibiotic treatment should be adopted. [Category IB]

(iv) Antibiotics should be considered in combination with drainage in patients with a known history of current MRSA colonisation. [Category II]

(v) Clindamycin or co-trimoxazole have been shown to be effective oral options if treatment is warranted and the MRSA isolate is susceptible. [Category IA]

3 Skin and soft tissue infections

(i) Glycopeptides (vancomycin or teicoplanin) remain the first-line treatment for patients with severe cellulitis/soft tissue infection caused by MRSA. [Category IA] Linezolid (oral or intravenous) [Category IA] and daptomycin [Category IB] are now established alternative agents in clinical practice. Tigecycline is also licenced for use in complicated SSTI when other antibiotics are not suitable.

(ii) Additional oral agents that may be used for de-escalation or in patients with milder infection [as

assessed by the absence of systemic upset in grading schemes such as that proposed by Eron et al. 34 and depending on confirmation of susceptibility] include co-trimoxazole, clindamycin and doxycycline. [Category IB]

(iii) Newer agents that may be considered in this clinical setting and that are currently licensed in the UK include oritavancin, telavancin, delafloxacin [all Category IB], ceftaroline, dalbavancin and tedizolid. [all Category IC]

4 Urinary tract infections

(i) Prior to commencing treatment of a patient with MRSA UTI, the presence of MRSA bacteraemia should be excluded. [Category IB]

(ii) A requirement of the agent chosen as treatment is that it must be excreted in the urine. [Category IB]

(iii) Parenteral glycopeptides are the first-line choice for the management of MRSA UTI. [Category IA]

(iv) Although daptomycin remains unlicensed for use in this setting, its high renal excretion (80%) means that it is a commonly used alternative when a glycopeptide is contraindicated. [Category II] Linezolid has lower renal excretion (30%) and is less commonly used in this setting. [Category II]

(v) If MRSA bacteriuria is deemed to represent genuine lower UTI, the choice of treatment should be based on the isolate’s antimicrobial susceptibility pattern. Appropriate oral agents in this setting include, doxycycline, nitrofurantoin, trimethoprim, quinolones or co-trimoxazole [Category IB].

(vi) In the case of catheter associated UTI, it would be appropriate to replace the catheter, with or without the administration of a single dose of gentamicin [if the strain is susceptible]. [Category II]

5 Bone and joint infections

(i) The treatment of patients with MRSA bone and joint infection should be based on a multidisciplinary approach with surgery or drainage implemented where indicated. [Category IA] The first-line antibiotic treatment of patients with such infection is an intravenous glycopepide. [Category IA] The optimal duration of treatment is not known but intravenous glycopeptide is usually administered for a minimum of 2 weeks followed by further IV or oral antibiotics to complete a total treatment course of a minimum of 4 weeks for patients with septic arthritis or 6 weeks for those with osteomyelitis. [Category II]

(ii) The use of glycopeptides should be combined with therapeutic drug monitoring to ensure that non-toxic, therapeutic serum concentrations are achieved. [Category IA] In some patients, high renal excretion can limit the utility of glycopeptides and it is not possible to obtain therapeutic blood levels. Owing to the lack of evidence, we cannot make recommendations for the use of daptomycin to treat MRSA bone and joint infections; however, daptomycin (6 mg/kg dose) is increasingly used as an

alternative in such patients. [Category II]

(iii) Following initial treatment with a glycopeptide, oral antibiotics should be administered on the basis of antimicrobial susceptibilities [Category IA]. Therapeutic options include doxycycline, trimethoprim, co-trimoxazole, quinolones, rifampicin, clindamycin, linezolid and co-trimoxazole [Category IA]. Rifampicin and quinolones should not be used alone due to the risk of resistance developing but may be used in combination with other agents to which the isolate is susceptible [Category IA].

(iv) Fusidic acid is an option for adjunctive therapy1 but it is now less commonly used due to a lack of strong evidence to support its use [Category IC].

6 Bacteraemia

(i) The principal treatment of patients with uncomplicated MRSA bacteraemia is vancomycin. [Category IA] As the infection is associated with high mortality rates therapeutic drug monitoring is essential.

(ii) Linezolid is an alternative first-line treatment and should be used in preference to vancomycin in cases in which therapeutic vancomycin serum concentrations cannot be achieved, where the pathogen has reduced susceptibility to glycopeptides or where there is vancomycin allergy or intolerance. [Category II] Daptomycin, in dosages of ≥10mg/kg/day, has been used successfully when first-line agents have been contraindicated, but there is currently insufficient published evidence to enable it to be recommended routinely. [Category II]

(iii) There is no evidence to warrant the use of co-trimoxazole alone as a first-line agent for patients with MRSA bacteraemia, although it may have a role in oral step-down where susceptibility allows. [Category II]

(iv) We recommend a minimum duration of 14 days of antibiotic treatment for patients with uncomplicated MRSA bacteraemia and a minimum duration of 28 days of treatment for those with complicated MRSA bacteraemia. [Category II]

7 Endocarditis The reader is referred to the most recent version of the BSAC endocarditis guidelines.

8 Respiratory tract infections

8.1 Necrotizing pneumonia

In the absence of novel evidence, we recommend that patients with necrotising MRSA pneumonia should be treated with either vancomycin or linezolid [Category II]. Given the severity of this infection, and in line with current practice, we recommend that these antibiotics should be administered in combination with a toxin-inhibiting agent, such as clindamycin or rifampicin, according to antimicrobial susceptibility testing, if

such results are available. [Category II]

8.2 Nosocomial pneumonia Patients with nosocomial MRSA pneumonia should be treated with either vancomycin or linezolid. [Category IB]. More studies are required to establish if telavancin can be used as an alternative. Daptomycin should be avoided as it is inactivated by lung surfactant. [Category IB]

8.3 Ear, nose and throat or upper respiratory tract infections

MRSA associated ear, nose and throat or upper respiratory tract infections should be treated with a glycopeptide or linezolid. [Category II]

9 CNS and eye infections

9.1 Intracranial and spinal infections

Incision and drainage is the cornerstone of therapy for patients with these infections, unless surgical intervention is contraindicated [Category IA]; however, patients with small epidural abscesses can be treated with antibiotics alone. [Category II] Vancomycin or linezolid are recommended in the treatment of patients with any of these infections. [Category II]

9.2 CSF infections

(i) The first-line choice of antibiotic for the management of patients with CSF infection caused by MRSA (i.e. meningitis or ventriculitis) remains vancomycin, despite its limited penetration into the CSF. [Category IA] Its efficacy can be optimised by facilitating therapeutic serum concentrations through monitoring. [Category II] In severe cases or when the patient fails to respond it may be necessary to instil vancomycin directly into the ventricles. This, of course, will require patients to be transferred to a neurosurgical centre. [CATEGORY II].

(ii) Clindamycin does not penetrate into the CSF compartment and is bacteriostatic. It should not be used therefore to treat patients CSF infection irrespective of the pathogen’s susceptibility to it. [Category IC].

(iii) Chloramphenicol possesses excellent CSF penetration, but it too is bacteriostatic, thereby rendering it inappropriate as therapy of patients with CSF infection caused by MRSA, even when the pathogen is susceptible. Linezolid is likely to penetrate into the CSF, but its use as therapy in this setting is precluded by its bacteriostatic activity. [Category IC]

(iv) It is not recommended that teicoplanin be used as first-line therapy owing to limited evidence of its efficacy. [Category II]

9.3 Eye disease

Superficial MRSA eye disease may be treated with gentamicin or chloramphenicol drops according to susceptibility [Category II]. For deeper eye infections close liaison between specialist ophthalmologists and infectious diseases clinicians is critical. Options for treatment include intravitreal vancomycin and quinolones. It is likely that oral linezolid penetrates the eye tissue, but the efficacy for MRSA infections has not been established.

1072

Supplementary Table S1. Search criteria used for evidence identification. 1073

Search Engine # Search term

Cochrane Library 1 MeSH descriptor: [Methicillin-Resistant Staphylococcus aureus] explode all trees

2 (((Methicillin or Meticillin) near/2 Resist* near/2 (Staph* or S? aureus)) or MRSA):ti,ab

3 Combine #1 or #2

4 MeSH descriptor: [Staphylococcus aureus] this term only

5 MeSH descriptor: [Methicillin Resistance] explode all trees

6 Combine #4 and #5

7 Combine #3 or #6 Publication Year from 2007

EMBASE 1 Methicillin Resistant Staphylococcus aureus/ OR (((Methicillin ORMeticillin) adj2 Resist* adj2 (Staph* OR S? aureus)) OR MRSA).ti,ab.

2 Crossover-Procedure/ OR Double-Blind Procedure/ OR Randomized Controlled Trial/ OR Single-Blind Procedure/ OR (Random* OR Factorial* OR Crossover* OR (Cross Over*) OR Cross-Over* OR Placebo* OR (Doubl* adj Blind*) OR (Singl* adj Blind*) OR Assign* OR Allocat* OR Volunteer*).mp. OR ("Interrupted Time Series" OR "ITS Studies" OR "ITS Study" OR "Controlled Before After" OR "Controlled Before and After" OR "CBA Studies" OR "CBA Study").ti,ab.

3 Combine 1 AND 2

4 Exp Animals/ OR Exp Invertebrate/ OR Animal Experiment/ OR Animal Model/ OR Animal Tissue/ OR Animal Cell/ OR Nonhuman/

5 Human/ OR Normal Human/ OR Human Cell/

6 Combine 4 AND 5

7 Combine 4 NOT 6

8 Combine 3 NOT 7

9 Limit 8 to (Exclude Medline Journals AND YR="2007 -Current")

MEDLINE 1 Methicillin-Resistant Staphylococcus aureus/ OR (Exp Staphylococcus aureus/ AND Exp Methicillin Resistance/) OR (((Methicillin ORMeticillin) adj2 Resist* adj2 (Staph* OR S? aureus)) OR MRSA).ti,ab.

2 Interrupted Time Series Analysis/ OR Controlled Before-After Studies/ OR ("Interrupted Time Series" OR "ITS Studies" OR "ITS Study" OR "Controlled Before After" OR "Controlled Before and After" OR "CBA Studies" OR "CBA Study").ti,ab. OR (Randomized Controlled Trial OR Controlled Clinical Trial OR Pragmatic Clinical Trial).pt. OR (Randomi?ed OR Randomly OR Placebo OR Trial OR Groups).ab. OR Drug Therapy.fs. NOT (Animals NOT (Humans AND Animals)).sh.

3 Combine 1 AND 2

4 Limit 3 to YR="2007 -Current"

Supplementary Table S2. Summary of studies excluded from review (n=49). 1074

Infection Type Population Intervention Comparator Reason for Exclusion Reference

SSTI Adult Daptomycin 4mg/kg/day Vancomycin 1g bd

Bias in study design (4:1 daptomycin: vancomycin ratio); less than 50 participants infected with MRSA in vancomycin group

Aikawa et al. 201344

SSTI Paediatric Daptomycin once daily at age-dependent doses

Standard of care No MRSA subgroup analysis Bradley et al. 201745

SSTI Adult JNJ-Q2 (novel fluoroquinolone) 250mg bd

Linezolid 600mg bd Less than 50 participants infected with MRSA in each group

Covington et al. 201146

SSTI Adult Ceftaroline (600 mg every 8 h) Vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g every 8h)

Less than 50 participants infected with MRSA in each group

Dryden et al. 201647

SSTI Adult

Oritavancin Daily dose 200mg for 3-7 days; single 1200mg dose or 800mg dose with option for 400mg on day 5

Oritavancin Daily dose 200mg for 3-7 days; single 1200mg dose or 800mg dose with option for 400mg on day 5

No comparator agent Dunbar et al. 201148

SSTI Adult Dalbavancin 1500mg single dose

Dalbavancin 1000mg dose followed by 500mg 7 days later

No comparator agent Dunne et al. 201649

SSTI Paediatric Ceftriaxone 50 mg/kg once daily via OPAT

Hospitalised: IV flucloxacillin 50 mg/kg every 6 hours

A small number of participants (n=6) infected with MRSA

Ibrahim et al. 201650

SSTI Adult Tedizolid 200mg od Linezolid 600mg bd No values for MRSA subgroup Joseph et al. 201751

SSTI Adult Daptomycin 10mg/kg/day Vancomycin 1g bd Less than 50 participants infected with MRSA in each group

Katz et al. 200852

SSTI Adult Daptomycin 4mg/kg/day Vancomycin Less than 50 participants infected with MRSA in each group

Kauf et al. 201553

SSTI Paediatric Ceftaroline (dose adjusted for age and weight)

Vancomycin or cefazolin, plus optional aztreonam

Less than 10 participants infected with MRSA

Korczowski et al. 201654

SSTI Adult Iclaprim 0.8 mg/kg body weight 1.6 mg/kg body weight

Vancomycin 1g bd Less than 10 participants infected with MRSA in each group

Krievins et al. 200955

SSTI

Diabetic foot Adult

Linezolid 600mg bd

(oral or IV) Vancomycin 1g bd

Pooled results of three previously published RCTS

Lipsky et al. 201156

SSTI Adult Linezolid 600mg bd Vancomycin 1g bd Less than 50 participants infected with MRSA in each group

McCollum et al. 200757

SSTI Adult Linezolid 600mg bd Vancomycin 1g bd Based on Weigelt et al. 2005,58 included in previous guideline

McKinnon et al. 200659

SSTI Adult Tedizolid 200mg od Linezolid 600mg bd Less than 50 participants infected with MRSA in each group

Mikamo et al. 201860

SSTI ≥12 years Cephalexin 500mg qds plus co-trimoxazole

Cephalexin 500mg qds plus placebo

Data not interpretable: unclear about number of MRSA at the

Moran et al. 201761

320mg/1600mg bd beginning of study

SSTI Adult Omadacycline 100mg od Linezolid 600mg bd Less than 50 participants infected with MRSA in each group

Noel et al. 201262

SSTI Adult Gepotidacin: 750mg bd; 1000mg bd, or 1000mg tds

Gepotidacin: 750mg bd; 1000mg bd, or 1000mg tds

No comparator agent O'Riordan et al. 201763

SSTI Adult TD-1792 (cefilavancin) 2mg/kg od

Vancomycin 1g bd Less than 50 participants infected with MRSA in each group

Strykewski et al. 201264

SSTI Adult Ceftaroline 600 mg bd Vancomycin 1g bd Less than 10 participants infected with MRSA in each group

Talbot et al. 200765

Impetigo Paediatric Topical minocycline

(1% or 4%)

Topical minocycline

(1% or 4%) No comparator agent

Chamny et al. 201666

Abscess Paediatric Co-trimoxazole

(10-12mg/kg/day) Placebo No MRSA subgroup analysis

Duong et al. 201067

Abscess Adult Cephalexin 500mg qds Placebo Intervention and comparator are both placebo for MRSA

Rajendran et al. 200768

Abscess Adult Co-trimoxazole

(320mg/1600mg) bd Placebo No MRSA subgroup analysis

Schmitz et al. 201069

Abscess ≥12 years Co-trimoxazole

(320mg/1600mg) bd Placebo No MRSA subgroup analysis

Talan et al. 201618

SSTI, CR-BSI ≥ 13 years, ≥40kg

Linezolid 600mg bd Vancomycin 1g bd Less than 50 participants infected with MRSA in each group

Wilcox et al. 200970

Bacteraemia, endocarditis

Adult

Daptomycin 6mg/kg od (participants with left-sided endocarditis also received 1mg/kg gentamicin tds)

Low-dose gentamicin (1mg/kg tds) plus either an anti-staphylococcal penicillin (nafcillin, oxacillin, or flucloxacillin 2g qds) or vancomycin 1g bd

Less than 50 participants infected with MRSA in each group

Fowler et al. 200671

Bacteraemia Adult Telavancin 10 mg/kg od

Vancomycin 1g bd or anti-staphylococcal penicillin (nafcillin 2g qds, oxacillin 2g qds, or cloxacillin 2 g qds)

Less than 10 participants infected with MRSA in each group

Strykewski et al. 201472

Bacteraemia Adult Daptomycin 6 mg/kg body weight of daptomycin infused over 30 min every 24 h

Vancomycin 15 mg/kg body weight of vancomycin infused every 12 h over 2 h with appropriate dose adjustments

Less than 10 participants infected with MRSA in each group

Kalimuddin et al. 201873

SSTI or pneumonia

Adult Linezolid 600mg bd Vancomycin 1g bd Less than 50 participants infected with MRSA in each group

Lin et al. 200874

HAP Adult Vancomycin 1g bd with rifampicin 300mg bd

Vancomycin 1g bd Less than 50 participants infected with MRSA in each group

Jung et al. 201075

CAP Adult Ceftobiprole 500mg with placebo

Ceftriaxone 2g 30 min infusion with linezolid 600mg bd

Less than 10 participants infected with MRSA in each group

Nicholson et al. 201276

HAP Adult Linezolid 600mg bd Vancomycin 1g bd Less than 50 participants infected with MRSA in each group

Wunderink et al. 200877

HAP Adult Linezolid 600mg bd Vancomycin 1g bd

Reassessment of Wunderink et al. 201241 Assessment of renal function; no new efficacy data

Liu et al. 201778

HAP Adult Linezolid 600mg bd Vancomycin 15 mg/kg per dose

Economic analysis of Wunderink et al., 2012 No new efficacy data

Rello et al. 201679

CAP Paediatric Ceftaroline (dose adjusted for age and weight)

Ceftriaxone with vancomycin (dose adjusted for age and weight)

Less than 10 participants infected with MRSA in each group

Blumer et al. 201680

CAP Paediatric Ceftaroline (dose adjusted for age and weight)

Ceftriaxone (dose adjusted for age and weight)

Less than 10 participants infected with MRSA in each group

Cannavino et al. 201681

Cystic fibrosis Adults Nebulized vancomycin (250 mg in 5 cc sterile water, twice per day)

Nebulised placebo (quinine 0.1 mg/mL in 5 cc sterile water, twice per day)

Colonisation of CF participants - not treatment

Dezube et al. 201882

Cystic fibrosis Ages 4-45 years

Oral co-trimoxazole, or if sulfa-allergic, minocycline plus oral rifampicin; chlorhexidine mouthwash for 2 weeks; nasal mupirocin and chlorhexidine body wipes for 5 days and environmental decontamination for 21 days.

Observation only - No antibiotics or other intervention

Colonisation of CF participants - not treatment

Muhlebach et al. 201783

Various

≥13 years, ≥40kg Neutropenic participants with cancer

Linezolid 600mg bd Vancomycin 1g bd Less than 10 participants infected with MRSA in each group

Jaksic et al. 200684

SSTI, BJI, pneumonia, bacteraemia

Adult Co-trimoxazole 160mg/800mg tds with rifampicin 600mg od

Linezolid 600mg bd Less than 50 participants infected with MRSA in each group

Harbath et al. 201485

Pneumonia, SSTI and sepsis

Not stated Linezolid 600mg bd Vancomycin 1g bd Less than 50 participants infected with MRSA in each group

Kohno et al. 200786

Pneumonia, SSTI, sepsis

Not stated Linezolid 600mg bd Vancomycin 1g bd Less than 10 participants infected with MRSA in each group

Jindal et al. 201587

Prophylaxis for cardiac surgery

Adult Cefuroxime 1.5g Vancomycin 1g Prophylaxis Garey et al. 200888

Prophylaxis for vascular surgery

Adult Cefazolin with vancomycin Cefazolin plus daptomycin Prophylaxis Stone et al. 201089

Prophylaxis for vascular surgery

Adult Cefazolin

Weight-based dosing

Cefazolin with vancomycin Cefazolin with daptomycin

Weight-based dosing

Prophylaxis Stone et al. 201590

Prophylaxis for cerebral shunt placement

Adult Cefazolin 1.5g Vancomycin 1g Prophylaxis Tacconelli et al. 200891

Prophylaxis for primary hip and

Adult Cefuroxine 1.5g (3 doses) Fusidic acid 500mg (3 doses)

Prophylaxis Tyllianakis et al. 201092

knee arthroplasty Vancomycin 500mg (3 doses)

Key: Adult defined as ≥18 years; CAP, community-acquired pneumonia; CR-BSI, catheter-related bloodstream infection; CF, cystic 1075

fibrosis; HAP, hospital-acquired pneumonia; OPAT, outpatient parenteral antimicrobial therapy; SSTI, skin and soft tissue infection. 1076

Supplementary Table S3. Summary of studies included for review (n=26). 1077

Infection Type

Population Intervention

Outcome

Comparator

Outcome

Primary Test/

Assessment of Cure

Conclusion

(as stated in the reference)

Treatment Difference

(95% CI intervals) [p value]

Reference

SSTI Adult

Dalbavancin 1g (d1), 500mg (d8)

Treatment success 72/74 (97.3%)

Vancomycin 15 mg/kg bd (at least 3 days) followed by oral linezolid 600mg bd

Treatment success 49/50 (98%)

48-72 hours

Once-weekly IV dalbavancin was not inferior to twice-daily IV vancomycin followed by oral linezolid for the treatment of ABSSSI

No values Boucher et al. 201423

SSTI Paediatric

Cephalexin 40mg/kg/day

6/64 (9%) worse outcome

Clindamycin 20mg/kg/day

2/71 (3%) worse outcome

48-72 hours

There was no significant difference between cephalexin and clindamycin for treatment of uncomplicated paediatric SSTI caused predominantly by CA-MRSA

[p=0.15] Chen et al. 201114

SSTI Adult

Oritavancin 1200mg stat

Clinical response 84/104 (80.8%)

Vancomycin 1g bd

Clinical response 80/100 (80%)

48-72 hours

A single dose of oritavancin was not inferior to twice-daily vancomycin administered for 7 to 10 days for the treatment of ABSSSI caused by Gram-positive pathogens

0.8

(-10.1, 11.7)

Corey et al. 201426

SSTI Adult

Oritavancin 1200mg stat

Clinical response 82/100 (82%)

Vancomycin 1g bd

Clinical response 82/101 (82.2%)

48-72 hours

A single 1200-mg dose of oritavancin was not inferior to 7–10 days of vancomycin in treating ABSSSI caused by Gram-positive pathogens

0.8

(-9.9, 11.5)

Corey et al. 201525

SSTI Adult

Ceftaroline 600mg bd

Clinical cure 155/179 (86.6%)

Vancomycin 1g bd + Aztreonam 1g bd

Clinical cure 124/151 (82.1%)

8-15 days after treatment

Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens

No values Corey et al. 201021

Surgical drainage of abscess

Paediatric

Co-trimoxazole 3/7 10 mg/kg per day divided twice a day

Treatment failure 8/69 (12%)

Recurrent infection 8/60 (13%)

Co-trimoxazole 10/7 10 mg/kg per day divided twice a day

Treatment failure 1/69 (1%)

Recurrent infection 2/67 (3%)

10-14 days after treatment

Patients with MRSA skin abscesses are more likely to experience treatment failure and recurrent skin infection if given 3 rather than 10 days of co-trimoxazole after surgical drainage

Treatment Failure: 10.1, (12.1, 18.2) [p=0.03] Recurrent infection: 10.3, 0.8, 19.9) [p=0.046]

Holmes et al. 201616

SSTI Adult

Linezolid 600mg bd (oral or IV)

Clinical success at end of study

191/227 (84%)

Vancomycin 15 mg/kg twice daily

Clinical success at end of study

167/209 (80%)

7-10 days after treatment

Linezolid is an effective alternative to vancomycin for the treatment of cSSTl caused by MRSA.

[p=0.249] Itani et al. 201019

SSTI Adult

Ceftobiprole 500mg bd

Clinical cure 56/61 (91.8%)

Vancomycin 1g bd

Clinical cure 54/60 (90%)

10-14 days after treatment

The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria

1.8%

(-8.4, 12.1)

Noel et al. 200822

SSTI Adult

BC-3781 (Lefamulin) 100mg or 150mg bd

Clinical success

Vancomycin 1g bd

Clinical success 32/39 (82.1%)

10-14 days after treatment

These results provide the first proof of concept for the systemic use of a pleuromutilin antibiotic for the

No values Prince et al. 201330

100mg: 29/34 pts (85.3%) 150mg: 28/32 pts (87.5%)

treatment of ABSSSI

SSTI Adult

Telavancin 10mg/kg/day

Clinical cure 252/278 (90.6%)

Vancomycin 1g bd

Clinical sure 260/301 (86.4%)

10-14 days after treatment

Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with cSSTI, including those infected with methicillin-resistant S. aureus

4.1

(-1.1, 9.3)

Strykewski et al. 200827

SSTI Adult

Oritavancin 1200mg stat

Clinical Response 162/204 (81.4%)

Vancomycin 1g bd

Clinical Response 162/201 (80.6%)

48-72 hours

Whereas both oritavancin and vancomycin achieved similarly high rates of clinical response by pathogen, including methicillin-susceptible and -resistant Staphylococcus aureus. oritavancin provides a single dose alternative to 7-10 days of twice-daily vancomycin to treat ABSSSl.

0.8 (-6.9 to 8.4) Corey et al. 201624

SSTI Adult Delafloxacin 300mg

190/220 (86.4%)

Vancomycin 15mg/kg bd plus aztreonam 2g bd

199/225 (88.4%)

48-72 hours

Delafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48–72h following the start of therapy and was well tolerated as monotherapy in the treatment of ABSSSI.

-2.0 (-8.4, 4.16) Pullman et al. 201731

SSTI Adult

Iclaprim 80mg bd

Clinical response 61/69 (88.4%)

Vancomycin 15mg/kg bd

Clinical Response 53/69 (73.8%)

48-72 hours

Iclaprim achieved non-inferiority compared with vancomycin at its primary endpoint of early clinical response

11.6

(-5.80, 28.48)

Holland et al. 201832

SSTI Adult

Iclaprim 80mg bd

Clinical Response 59/73 (80.8%)

Vancomycin 15mg/kg bd

Clinical Response 50/61 (82%)

48-72 hours

The primary endpoint of this study was a ≥20% reduction in lesion size (early clinical response compared with baseline among patients randomized to iclaprim or vancomycin at the early time point, 48 to 72 hours

–1.15

(–17.9, 15.8)

Huang et al. 201833

SSTI Adult

Tedizolid 200mg od

75/88 (85.2%)

Linezolid 600mg bd

77/90 (85.6%)

48-72 hours

Tedizolid was a statistically noninferior treatment to linezolid in early clinical response at 48 to 72 hours after initiating therapy for an ABSSSI.

No value Prokocimer et al. 201329

SSTI ≥12 years

Clindamycin (7-day course of clindamycin (one 300-mg capsule, 4 times daily, with 3 placebo capsules, twice daily for first and third doses)

Clinical cure (70/78 89.7%)

Co-trimoxazole (4 single-strength capsules, 80 mg/400 mg, twice daily, with 1 placebo capsule, twice daily for second and fourth doses)

Clinical cure 78/83 (94%)

7-14 days after treatment

In settings where MRSA is prevalent, clindamycin and co-trimoxazole produce similar cure and adverse event rates among patients with an uncomplicated wound infection

4.2 (13.9, 5.5) Talan et al. 201620

SSTI ≥12 years

Tedizolid 200mg od

Clinical response 44/53 (83%)

Linezolid 600mg bd

Clinical response 44/56 (79%)

48-72 hours

Intravenous to oral once-daily tedizolid 200 mg for 6 days was non-inferior to twice-daily linezolid 600 mg for 10 days for treatment of patients with ABSSSI

4·4

(–10·8 to 19·5)

Moran et al. 201428

Abscess ≥12 years

Co-trimoxazole (320 mg or 1600 mg bd)

487/542 (92.9%)

Placebo

457/533 (85.7%)

7-14 days after treatment

In settings in which MRSA was prevalent, co-trimoxazole treatment resulted in a higher cure rate among patients with a drained cutaneous abscess than placebo.

[p<0.001] Talan et al. 201618

Abscess ≥12 years

Co-trimoxazole (7-days (4 single-strength pills, 80 mg/400 mg each, twice daily)

Clinical cure 203/219 (92.7%)

Placebo (4 pills twice daily)

Clinical cure 202/249 (81.1%)

7-14 days after treatment

Treatment with co-trimoxazole was associated with improved outcomes regardless of lesion size or guideline antibiotic criteria

11.6 (5.2, 18.0) Talan et al. 201817

Abscess Adult/Paediatric

Incision/drainage plus clindamycin 300mg tds

Cure rate

116/126 (92.1%)

Incision/drainage plus co-trimoxazole (160:800mg bd plus placebo for midday dose)

Incision/drainage plus placebo

93/96 (76%)

End of treatment

As compared with incision and drainage alone, clindamycin or co-trimoxazole in conjunction with incision and drainage improves short-term outcomes in patients who have a simple abscess

[p<0.001] Daum et al. 201715

Cure rate

110/117 (94%)

HAP Adult

Telavancin 10mg/kg/day

Clinical cure 104/139 (74.8%)

Vancomycin 1g bd

Clinical cure 115/154 (74.7%)

7-14 days after treatment

Telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens

0.4 (–9.5, 10.4) Rubenstein et al. 201142

Pneumonia Adult

Linezolid 600mg bd

Clinical success 95/165 (58%)

Vancomycin 15mg/kg bd

Clinical success 81/174 (46%)

End of study

For the treatment of MRSA nosocomial pneumonia, clinical response at end of study in the per-protocol population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar

[p=0.042] Wunderink et al. 201241

Bacteraemia Adult

Standard therapy plus rifampicin (600mg or 900mg)

Treatment failure 9/26 (35%)

Standard therapy plus placebo

Treatment failure 3/21 (14%)

Time to bacteriologically confirmed treatment failure, disease recurrence or death

Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia

[p>0.05] Thwaites et al. 201837

Bacteraemia Adult

Vancomycin 1.5g bd

29 patients Mean duration of bacteraemia 3.00 (3.35)

Vancomycin 1.5g bd plus flucloxacillin 2g qds

31 patients Mean duration of bacteraemia 1.94 (1.79))

Duration of MRSA bacteraemia (days)

Combining an anti-staphylococcal β-lactam with vancomycin may shorten the duration of MRSA bacteraemia

[p=0.06] Davis et al. 201636

Traumatic lesions and impetigo

>2 months

Retapamulin ointment (1%) bd plus oral placebo

Clinical success 41/72 (56.9%)

Linezolid bd-tds plus placebo ointment

Clinical success 32/35 (84.2%)

7-9 days after therapy

Clinical success rate at follow-up in the per-protocol MRSA population was significantly lower in the retapamulin versus the linezolid group

-22.3 (-31.9,-12.6)

Tanus et al. 201412

SSTI, BJI, Endovascular, pneumonia, bacteraemia, other

Adult

Co-trimoxazole 320/1600 bd

BJI: 11/39 (28%) B: 20/50 (40%)

Vancomycin 1g bd

BJI: 7/32 (22%)

B: 23/41 (56%)

Treatment failure at 7 days

High dose co-trimoxazole did not achieve non-inferiority to vancomycin in the treatment of severe MRSA infections. The difference was particularly marked for patients with bacteraemia

B: 1.4

(0.91, 2.16)

Paul et al. 201535

Key: Adult defined as ≥18 years; B, bacteraemia, BJI, bone and joint infection; CAP, community-acquired pneumonia; CR-BSI, 1078

catheter-related bloodstream infection; CF, cystic fibrosis; HAP, hospital-acquired pneumonia; OPAT, outpatient parenteral 1079

antimicrobial therapy; ABSSSI, acute bacterial skin and skin structure infection; cSSSI, complicated skin and skin structure 1080

infection, SSTI, skin and soft tissue infection. Clinical success is defined as clinical cure plus improved. 1081

1082