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: [email protected] 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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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
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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
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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
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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