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BMJ Clinical Evidence logoLink to BMJ Clinical Evidence
. 2016 Feb 16;2016:0922.

MRSA: treating people with infection

Nikolas Rae 1,#, Anna Jarchow-MacDonald 2,#, Dilip Nathwani 3,#, Charis Ann Marwick 4,#
PMCID: PMC4755506  PMID: 26881888

Abstract

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) has a gene that makes it resistant to methicillin, as well as to other beta-lactam antibiotics, including flucloxacillin, beta-lactam/beta-lactamase inhibitor combinations, cephalosporins, and carbapenems. MRSA can be part of the normal body flora (colonisation), especially in the nose, but it can cause infection, particularly in people with prolonged hospital admissions, with underlying disease, or after antibiotic use. About 8% of S aureus in blood cultures in England, Wales, and Northern Ireland is resistant to methicillin.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of selected treatments for MRSA infections at any body site? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).

Results

At this update, searching of electronic databases retrieved 312 studies. After deduplication and removal of conference abstracts, 133 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 55 studies and the further review of 78 full publications. Of the 78 full articles evaluated, 15 systematic reviews and one subsequent RCT were added at this update. In addition, six studies were added to the Comment sections. We performed a GRADE evaluation for 12 PICO combinations.

Conclusions

In this systematic overview we categorised the efficacy for five interventions, based on information about the effectiveness and safety of cephalosporins (ceftobiprole, ceftaroline), daptomycin, linezolid, quinupristin-dalfopristin, pristinamycin (streptogramins), and tigecycline.

Key Points

Methicillin-resistant Staphylococcus aureus (MRSA) has a gene that makes it resistant to methicillin, as well as other beta-lactam antibiotics, including flucloxacillin, cephalosporins (excluding new anti-MRSA cephalosporins such as ceftobiprole and ceftaroline), and carbapenems. Newly introduced anti-MRSA cephalosporins, including ceftaroline and ceftobiprole, have increased affinity for penicillin-binding protein 2a (PBP2a), providing activity against MRSA. These agents are introduced in the overview, as they may offer alternative options, in select patients, to existing and other classes of new therapies.

  • MRSA can be part of the normal body flora (colonisation), especially in the nose, but it can cause infection, particularly in people with prolonged hospital admissions or with underlying disease, or after antibiotic use.

  • About 8% of S aureus in blood cultures in England, Wales, and Northern Ireland is resistant to methicillin.

  • We searched for RCTs and systematic reviews of RCTs comparing selected antibiotic treatments for MRSA infection compared with vancomycin, teicoplanin, and with each other.

Linezolid seems to have similar efficacy to 'standard' antibiotic treatment with glycopeptides (teicoplanin, vancomycin) at curing MRSA infection.

We found limited evidence that tigecycline may have similar cure rates to vancomycin, although there are concerns regarding the increased mortality observed in patients treated with tigecycline, particularly with severe infections.

We don’t know whether daptomycin, streptogramins (pristinamycin, quinupristin-dalfopristin), or anti-MRSA cephalosporins (ceftaroline and ceftobiprole) are effective at curing MRSA infection compared with vancomycin, teicoplanin, each other, and the other antibiotics included in this overview because we found no adequate RCTs.

Clinical context

General background

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are common worldwide. These include skin and soft tissue infections, bone and joint infections, pneumonia, bacteraemia, and endocarditis. Due to resistance to beta-lactam-based agents used to treat methicillin-susceptible strains, other antimicrobial agents are used in the treatment of MRSA infections. These agents have increased toxicity or adverse effects and appear less efficacious when compared to beta-lactam-based therapy for methicillin-sensitive S aureus (MSSA). Despite the widespread distribution of MRSA and the negative impact that serious bloodstream and other infections have on mortality and length of hospital stay, there is surprisingly little robust evidence to aid clinicians in the most effective choice of antimicrobial therapy.

Focus of the review

This updated overview largely focuses on newer anti-MRSA antimicrobials or those with an expanding role as an anti-MRSA agent. While many other agents possess activity against MRSA, susceptibility is variable and robust evidence for their use is lacking. The aim of this overview is to appraise evidence for agents indicated specifically for use in treatment of infections caused by MRSA, compared with standard therapy with glycopeptides (vancomycin or teicoplanin). This update is particularly important, as existing good-quality guidelines on this subject are already out of date. This overview will help to inform any forthcoming guidance on this subject.

Comments on evidence

While there are RCTs evaluating glycopeptides against other agents in the treatment of MRSA infection, there remains insufficient evidence to strongly recommend other agents over glycopeptide therapy. The RCTs evaluated were generally heterogeneous, consisted of small numbers of patients with MRSA infection, and were prone to bias, as well as being powered to detect non-inferiority rather than superiority, making it difficult to draw firm conclusions. The challenge of incorporating patients in clinical trials that reflect 'real world practice' remains. These people include patients with multiple comorbidity, obesity and severe disease. The limited available evidence suggests that linezolid appears to be similar in efficacy to glycopeptides and could be used as an alternative, with the strongest evidence in microbiologically-proven MRSA nosocomial pneumonia. There is some tentative evidence to support its use in skin and soft tissue infections (SSTI), bacteraemia, and endocarditis, but no convincing evidence of superior effectiveness. New agents, including the anti-MRSA cephalosporins, are promising additional options, although there is insufficient evidence to support their use presently. The exclusion criteria used in many studies, including comorbidities and severe illness, potentially impacts on the applicability of evidence derived from trials to patients encountered in clinical practice.

Search and appraisal summary

The update literature search for this overview was carried out from the date of the last search, November 2009, to June 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 312 studies. After deduplication and removal of conference abstracts, 133 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 55 studies and the further review of 78 full publications. Of the 78 full articles evaluated, 15 systematic reviews and one RCTs were added at this update. In addition, six studies were added to the Comment sections.

About this condition

Definition

Staphylococcus aureus mainly colonises the nasal passages, but it may be found regularly in most other anatomical sites. Carrier rates in adults vary from 20% to 50% with people being persistent carriers, intermittent carriers, or non-carriers. Methicillin-resistant S aureus (MRSA) is an organism resistant to methicillin by means of the mecA gene. This confers resistance to all beta-lactam antibiotics, including flucloxacillin, oxacillin, cephalosporins (excluding new anti-MRSA cephalosporins such as ceftobiprole and ceftaroline), and carbapenems. Antimicrobial resistance is defined as the failure of the antimicrobial drug to reach a concentration in the infected tissue that is high enough to inhibit the growth of the infecting organism. Like methicillin-sensitive S aureus (MSSA), MRSA can be part of the normal flora (colonisation) or it can cause infection. For MRSA to cause infection, it must be transmitted to the individual, colonise the individual, and gain entry to the host or target tissues. Infection is dependent on the balance between the host defences and the virulence of the infectious agent. Therefore, it is important to recognise the difference between colonisation and infection because they are entirely different entities in terms of clinical management. MRSA infection This is the growth of MRSA from a sterile body site (e.g., blood culture or cerebrospinal fluid, joint aspirate, or pleural fluid) or growth of MRSA from a non-sterile body site (e.g., wound, skin, urine, or sputum), usually in the presence of symptoms or signs of infection. The presence of viable bacteria in blood without a documented primary source of infection is termed 'primary bacteraemia', whereas 'secondary bacteraemia' is the presence of viable bacteria in the blood secondary to a localised focus of infection. The majority of MRSA strains in the UK are associated with the healthcare setting (healthcare-associated MRSA [HA-MRSA]). These are strains that are transmitted to and circulate between individuals who have had contact with healthcare facilities. These infections can present in the hospital or healthcare setting (hospital or healthcare onset) or in the community (community onset); for example, after hospital discharge. They also show a variable level of resistance to other groups of antibiotics such as quinolones and macrolides. MRSA is also becoming an increasingly important cause of community-acquired infection in people who have not been recently admitted to healthcare facilities or had medical problems. This is termed 'community-associated' or 'community-acquired' MRSA (CA-MRSA). CA-MRSA is defined as MRSA strains isolated from patients in an outpatient or community setting (community onset) or within 48 hours of hospital admission (hospital onset), who have no previous history of MRSA infection or colonisation, no history of hospital admission, surgery, dialysis, or residence in a long-term care facility within 1 year of the MRSA culture date, and absence of an indwelling catheter or percutaneous device at the time of culture. These infections are generally less severe and primarily cause skin and soft-tissue infections; although, cases of fulminant disseminated disease and necrotising pneumonia are increasingly reported.[1] We have primarily excluded this population from this overview. However, the boundaries between HA-MRSA and CA-MRSA are becoming blurred because of the movement of people and infections between hospitals and the community. For example, nosocomial outbreaks of CA-MRSA following admission of colonised or infected patients have been reported.[2] In the US, where CA-MRSA is now common, it is becoming increasingly difficult to distinguish between CA-MRSA and HA-MRSA on clinical and epidemiological assessment. Because HA-MRSA and CA-MRSA strains are often genotypically and phenotypically different, the microbiological characteristics of staphylococcal isolates may help to distinguish between healthcare-associated and community-associated infections.[3] Population Our population of interest in this overview is primarily people with HA-MRSA, although we have included people with CA-MRSA from studies in which most people (>50%) had HA-MRSA infections. The investigation of treatment strategies for community-acquired compared with nosocomial MRSA is ongoing and will not be covered here. We include adults with predominantly nosocomial or healthcare-acquired MRSA infection; we exclude children under 16 years. For MRSA colonisation please see our systematic overview, MRSA colonisation (eradicating colonisation in people without active invasive infection).

Incidence/ Prevalence

The incidence of MRSA infection varies from country to country.[4] The UK has a higher incidence when compared with Scandinavia, but a lower incidence than southern Europe (e.g., Spain, Italy and Greece).[5] The most objective measure of incidence is the percentage of S aureus found in blood cultures that are resistant to methicillin. At the time of writing for this overview, this figure stands at about 8% in England.[5] [6]

Aetiology/ Risk factors

A case-control study (121 people with MRSA infection, 123 people with MSSA infection) found that the following characteristics were associated with a significantly increased risk of MRSA infection: more comorbidities, longer length of hospital stay, greater exposure to antibiotics, previous hospitalisation, enteral feeding, and surgery.[7] A systematic review (search date 2006, 10 observational studies, 1170 people colonised, 791 colonised by MSSA, and 379 colonised by MRSA) found that MRSA colonisation was associated with a four-fold increased risk of infection compared with MSSA colonisation (OR 4.08, 95% 2.1 to 7.44).[8]

Prognosis

The virulence of MRSA has been found to be equal to that of MSSA in animal models. However, a meta-analysis of 31 cohort studies found that mortality associated with MRSA bacteraemia was significantly higher than that associated with MSSA bacteraemia (mean mortality not reported; OR 1.93, 95% CI 1.54 to 2.42).[9] [10] A prospective cohort study (1194 episodes of S aureus bacteraemia, 450 of these MRSA) found that MRSA infection was not an independent predictor of death and commented that the increased mortality associated with this invasive infection may be partly due to suboptimal treatment.[11]Another, retrospective cohort study (334 adults with S aureus bacteraemia, 77 due to MRSA) found that empirical treatment was inadequate significantly more often with MRSA bacteraemia than it was with MSSA bacteraemia (proportion of people with inadequate empirical treatment with antimicrobials: 54/257 [21%] in people with MSSA v 40/77 [52%] in people with MRSA; P <0.001). However, it found that MRSA was not associated with increased mortality rates at 30 days.[12] A recent pooled analysis of five prospective observational studies of 3395 patients with S aureus bacteraemia, of which 698 patients had MRSA, showed an increased mortality in patients with MRSA bacteraemia at 7 days (HR 1.35, 95% CI 1.03 to 1.75, P = 0.03), 30 days (HR 1.21, 95% CI 1.01 to 1.45, P <0.04) and 90 days (HR 1.34, 95% CI 1.15 to 1.56; P = 0.0002), even when confounding factors had been adjusted for.[13] We cannot assume that invasive infection with MRSA is necessarily associated with a poorer clinical outcome when compared to infections with MSSA. A range of confounding factors is likely to influence clinical outcome, including delay in receiving appropriate antimicrobials, less effective active antimicrobials (e.g., in comparison to beta-lactam therapy for MSSA infections), and other risk factors associated with MRSA colonisation.[9]

Aims of intervention

To improve the clinical and microbiological cure rate; to decrease length of stay in hospital, with minimal adverse effects of treatment.

Outcomes

Mortality; clinical and microbiological cure rates; length of hospital stay; adverse effects.

Methods

Search strategy BMJ Clinical Evidence search and appraisal date June 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to June 2014, Embase 1980 to June 2014, The Cochrane Database of Systematic Reviews 2014, issue 6 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the BMJ Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for MRSA: treating people with infection

Important outcomes Clinical or microbiological cure, length of hospital stay, mortality, adverse effects
Number of studies (participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of selected treatments for MRSA infections at any body site?
8 (4838)[30] Mortality Linezolid v vancomycin in infection at any body site 4 –1 0 0 0 Moderate Quality point deducted for methodological weaknesses (no blinding)
5 (73) [34] Mortality Linezolid v vancomycin in bacteraemia 4 –3 0 0 0 Very low Quality points deducted for sparse data, methodological weaknesses (no blinding), and subgroup analysis
9 (at least 2174) [30] Clinical or microbiological cure Linezolid v vancomycin in infection at any body site 4 –1 0 –1 0 Low Quality point deducted for methodological weaknesses (no blinding); directness point deducted for unclear/subjective outcome (clinical cure)
at least 3 (at least 1090) [29] [17] Clinical or microbiological cure Linezolid v vancomycin in nosocomial pneumonia 4 –3 0 –2 0 Very low Quality points deducted for incomplete reporting, methodological weaknesses (no blinding), and subgroup analysis; directness points deducted for population issues (inclusion of people with non-MRSA infections in some studies) and unclear/subjective outcome (clinical cure)
6 RCTs (at least 1289) [33] Clinical or microbiological cure Linezolid v vancomycin in skin and soft-tissue infections 4 –2 0 –2 0 Very low Quality points deducted for methodological weaknesses (no blinding) and subgroup analysis; directness points deducted for population issues (inclusion of people with non-MRSA infections in some studies) and unclear/subjective outcome (clinical cure)
12 (223) [34] [35] Clinical or microbiological cure Linezolid v vancomycin in bacteraemia 4 –2 0 –2 0 Very low Quality points deducted for incomplete reporting and methodological weaknesses (no blinding); directness points deducted for population issues (inclusion of people with non-MRSA infections in some studies, inclusion of children in some studies) and unclear/subjective outcome (clinical cure)
1 (182)[37] Clinical or microbiological cure Linezolid v teicoplanin 4 –2 0 –2 0 Very low Quality points deducted for sparse data and inclusion of people without MRSA; directness points deducted for low follow-up and use of unclear/subjective outcome (clinical cure)
1 (182)[37] Mortality Linezolid v teicoplanin 4 –2 0 –1 0 Very low Quality points deducted for sparse data and inclusion of people without MRSA; directness point deducted for highly selected population (on intensive care)
4 (270) [17] [24] Clinical or microbiological cure Daptomycin v vancomycin 4 –3 0 –1 0 Very low Quality points deducted for methodological issues (no blinding, lack of statistical power in subsequent RCT) and for subgroup analysis; directness point deducted for use of unclear/subjective outcome (clinical cure)
1 (298)[45] Mortality Quinupristin–dalfopristin v vancomycin 4 –1 0 –1 0 Low Quality point deducted for inclusion of people without MRSA; directness point deducted for lack of subgroup analysis in people with MRSA only (hence, limited generalisability to this population group)
1 (51)[45] Clinical or microbiological cure Quinupristin–dalfopristin v vancomycin 4 –2 0 –1 0 Very low Quality points deducted for sparse data and subgroup analysis; directness point deducted for use of unclear/subjective outcome (clinical cure)
1 (157) [50] Clinical or microbiological cure Tigecycline v vancomycin 4 –2 0 0 0 Low Quality points deducted for sparse data and no statistical assessment
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Type of evidence: 4 = RCT; Consistency: similarity of results across studies; Directness: generalisability of population or outcomes; Effect size: based on relative risk or odds ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

MRSA colonisation

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Nikolas Rae, Ninewells Hospital and Medical School, Dundee, UK.

Anna Jarchow-MacDonald, Ninewells Hospital and Medical School, Dundee, UK.

Dilip Nathwani, Ninewells Hospital and Medical School, Dundee, UK.

Dr Charis Ann Marwick, Population Health Sciences, School of Medicine, University of Dundee, Dundee, UK.

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BMJ Clin Evid. 2016 Feb 16;2016:0922.

Ceftobiprole, ceftaroline (cephalosporins)

Summary

We found no direct information from RCTs on the effects of cephalosporins (ceftobiprole and ceftaroline only) compared with vancomycin, teicoplanin, and the other antibiotics in this overview in people with MRSA infection.

Benefits

Ceftaroline versus teicoplanin, vancomycin, and other antibiotics listed in this overview

We found four systematic reviews evaluating the effects of ceftaroline in the treatment of MRSA infections (search dates 2008,[14] 2011,[15] [16] and 2012[17]). None of the RCTs evaluating ceftaroline identified by the reviews met BMJ Clinical Evidence reporting criteria.

Ceftobiprole versus teicoplanin, vancomycin, and other antibiotics listed in this overview

We found four systematic reviews (search dates 2007,[18] 2008,[14] [19] and 2012[20]). None of the RCTs evaluating ceftobiprole identified by the reviews met BMJ Clinical Evidence reporting criteria.

Harms

Ceftaroline versus teicoplanin, vancomycin, and other antibiotics listed in this overview

We found no systematic review or RCT meeting BMJ Clinical Evidence reporting criteria.

Ceftobiprole versus teicoplanin, vancomycin, and other antibiotics listed in this overview

We found no systematic review or RCT meeting BMJ Clinical Evidence reporting criteria.

Comment

While there were no RCTs comparing standard of care vancomycin with anti-MRSA cephalosporins that met BMJ Clinical Evidence reporting criteria, there are two studies that we feel should be highlighted.

One double-blinded RCT[21] evaluated treatment with ceftobiprole against vancomycin/ceftazidime for 7 to 14 days for complicated skin and soft tissue infections. Of 828 patients enrolled, 123 had MRSA infection. Clinical cure was similar between the groups (78/87 [90%] with ceftobiprole v 31/36 [86%] with vancomycin plus ceftazidime, 95% CI –8.0% to +19.7%). Adverse effects reported were similar (304/543 [56%] with ceftobiprole v 159/279 [57%] with vancomycin plus ceftazidime). There was a difference between the groups with regards to hypersensitivity reactions (29/279 [10%] with vancomycin plus ceftazidime v 28/543 [5%] with ceftobiprole). There were four deaths reported, three in the ceftobiprole group. None of the deaths was felt to be associated with the study treatment.

CANVAS 1 and 2[22] were two phase 3 double-blinded, randomised efficacy and safety studies comparing ceftaroline with vancomycin plus aztreonam for 5 to 14 days for the treatment of complicated skin and soft tissue infections. In the treatment of patients with MRSA infection, clinical cure was similar in both groups (142/152 [93%] with ceftaroline v 115/122 [94%] with vancomycin plus aztreonam, microbiologically evaluable population, 95% CI not given). Adverse effects were similar between the two groups (309/692 [45%] with ceftaroline v 326/686 [47%] with vancomycin plus aztreonam, no 95% CI reported). Over a third of enrolled patients had large abscesses, which would probably have improved with incision and drainage alone. However, using figures for cellulitis alone, clinical cure was similar (213/219 [93%] for ceftaroline v 222/243 [91%] with vancomycin plus aztreonam, 95% CI –3.4% to +6.7%). Three patients treated with ceftaroline died, although these were felt to be unrelated to the study, while no patients died in the vancomycin plus aztreonam group.

Clinical guide

The anti-MRSA cephalosporins (ceftaroline and ceftobiprole) are a new addition to the antimicrobial armamentarium. These agents exhibit enhanced affinity to penicillin-binding protein 2a (PBP2a), the major factor correlating with methicillin resistance in Staphylococcus aureus. Their broad spectrum in addition to anti-MRSA activity make them an attractive prospect in infections that are commonly polymicrobial, such as complicated skin and soft tissue infections (including diabetic foot infections) and hospital-acquired pneumonia. At present there is no evidence for their use beyond these indications. The use of cephalosporins has been strongly associated with Clostridium difficile infection (CDI).[23] Although there is presently little evidence to link the use of anti-MRSA cephalopsorins and CDI, experience with earlier cephalosporins should be borne in mind when considering the use of these agents.

Substantive changes

Ceftobiprole, ceftaroline (cephalosporins) New option. Seven systematic reviews added,[17] [14] [15] [16] [18] [19] [20] none of which identified any RCTs meeting BMJ Clinical Evidence reporting criteria. Categorised as 'unknown effectiveness'.

BMJ Clin Evid. 2016 Feb 16;2016:0922.

Daptomycin

Summary

CLINICAL OR MICROBIOLOGICAL CURE Daptomycin compared with vancomycin in skin and soft tissue infections: We don't know how daptomycin and vancomycin compare at increasing clinical cure, bacterial clearance, and clinical effectiveness rates in people with MRSA skin and soft tissue infections ( very low-quality evidence ).

Benefits

Daptomycin versus vancomycin

Complicated skin and skin structure infections:

We found one systematic review (search date 2012[17]) and one subsequent RCT.[24] We also found a systematic review (search date 2008) that carried out a network meta-analysis using a Bayesian random effects model to evaluate the comparative effects of various antibiotics.[25] The review did not present data from a standard pair-wise analysis. Results from the network meta-analysis are mentioned in the Comment section in support of the results from the direct evidence.

The systematic review reporting pair-wise analysis found no significant difference between daptomycin and vancomycin in clinical success at test of cure in people with proven MRSA infection (3 RCTs [2 publications]; 48/77 [62%] with daptomycin v 57/82 [70%] with vancomycin, OR 0.69, 95% CrI 0.30 to 1.57).[17] It should be noted that the review included RCTs evaluating treatments in suspected or proven MRSA skin and tissue infections. The reported meta-analysis is based on data for the subgroup of people within the RCTs with proven MRSA infection.

The subsequent RCT (111 adults with proven or suspected MRSA skin and tissue infections) found no significant difference between daptomycin and vancomycin in the proportion of people with infections proven to be caused by MRSA and achieving a successful clinical response at the test-of-cure visit (45/55 [82%] with daptomycin v 16/19 [84%] with vancomycin, P = 0.593).[24] Additionally, the RCT found no significant difference between treatments in microbiological success rates against MRSA at the test-of-cure visit (31/55 [56%] with daptomycin v 9/19 [47%] with vancomycin, P = 0.250). The study was open label in design, randomised people in a 4:1 ratio (daptomycin:vancomycin), and was not statistically powered to compare the efficacy of the two treatments.

Harms

Daptomycin versus vancomycin

Complicated skin and skin structure infections:

The review gave no information on adverse effects of daptomycin versus vancomycin.[17]

The subsequent RCT found no significant difference between daptomycin and vancomycin in the proportion of people experiencing an adverse effect (62/88 [71%] with daptomycin v 19/22 [86%] with vancomycin, P = 0.934), or a drug-related adverse effect (19/88 [22%] with daptomycin v 6/22 [28%] with vancomycin, P = 0.71).[24]

Comment

In light of the paucity of data in infections other than skin and soft tissue infections, we have included one open-label RCT[26] evaluating daptomycin 6 mg/kg once daily versus standard therapy (vancomycin 1 g or anti-staphylococcal penicillin [with gentamicin 1 mg/kg twice daily for the first four days]) in Staphylococcus aureus bacteraemia with or without endocarditis. In the MRSA group there was no statistically significant difference for clinical success between daptomycin and vancomycin at 42 days after completion of therapy (20/45 [44%] for daptomycin v 14/44 [32%] for vancomycin, P = 0.28). There was no difference in median length of time to clearance of MRSA bacteraemia (8 days for daptomycin v 9 days for vancomycin, P = 0.25). There was no difference between daptomycin and standard therapy in the proportion of people experiencing any serious adverse effect (62/120 [52%] with daptomycin v 52/116 [45%] standard therapy, P = 0.3). It should be noted that these data include methicillin-sensitive S aureus (MSSA) infections where the standard therapy group used an anti-staphylococcal penicillin rather than vancomycin as the comparator. There were significant differences in new elevations of creatine kinase (23/92 [25%] with daptomycin v 12/96 [12%] with standard therapy, P = 0.04), peripheral neuropathy (11/120 [9%] with daptomycin v 2/116 [2%] with standard therapy, P = 0.02), and renal dysfunction (7% with daptomycin v 18% with standard therapy [absolute numbers not reported], P = 0.009).

The authors of the review noted that one of the RCTs included in the meta-analysis was at risk of performance bias, detection bias, and attrition bias.[17]

The review carrying out a network meta-analysis found no significant difference between daptomycin and vancomycin in success rate based on clinical and microbiological cure (estimated difference in MRSA eradication rate for daptomycin compared with vancomycin: +3.4%, 95% CrI –17.3% to +18.0%).[25] The network included 14 RCTs (1840 people) and evaluated six antibiotics (linezolid, vancomycin, daptomycin, tigecycline, dalbavancin, and telavancin).

Clinical guide

Clinical experience with daptomycin is increasing, particularly in the treatment of soft tissue infections, bacteraemia, and endocarditis caused by MRSA.[27] Due to its inactivation by pulmonary surfactant, guidelines advise against using daptomycin for MRSA pneumonia. MRSA infection, in particular bacteraemia, caused by isolates with a minimum inhibitory concentration (MIC) to vancomycin of 2 mg/L or greater have inferior outcomes when treated with vancomycin.[28] In this situation, daptomycin provides a potential alternative to glycopeptide therapy, although there is limited robust evidence.

Reduced susceptibility to daptomycin can develop on therapy, particularly in deep-seated infections such as osteomyelitis or endocarditis.[26] This should be considered when MRSA bacteraemia persists despite therapy with daptomycin.

The optimal dose of daptomycin has not been definitively established. The efficacy of the drug seems to be dose dependent, especially in severe and deep-seated infections, as was again shown by the EU-CORE study in a subgroup of 906 patients with MRSA infections.[27]

Substantive changes

Daptomycin Two systematic reviews[17] [25] and one subsequent RCT[24] added. Categorised as 'unknown effectiveness'.

BMJ Clin Evid. 2016 Feb 16;2016:0922.

Linezolid

Summary

MORTALITY Linezolid compared with vancomycin: Linezolid and vancomycin seem equally effective at reducing mortality in adults with MRSA infections ( moderate-quality evidence ). Linezolid compared with vancomycin in bacteraemia: We don't know how effective linezolid or vancomycin are, compared with each other, at improving survival in adults with MRSA bacteraemia ( very low-quality evidence ). Linezolid compared with teicoplanin: We don't know how effective linezolid or teicoplanin are, compared with each other, at reducing mortality (very low-quality evidence). CLINICAL OR MICROBIOLOGICAL CURE Linezolid compared with vancomycin in infection at any body site: Linezolid may be more effective at increasing clinical cure, bacterial clearance, and clinical effectiveness rates in people with MRSA infection or gram-positive infection, including MRSA, at any body site ( low-quality evidence ). Linezolid compared with vancomycin in nosocomial pneumonia: Linezolid may be more effective at increasing clinical cure, bacterial clearance, and clinical effectiveness rates in people with microbiologically proven MRSA infection or gram-positive infection, including MRSA, in the subgroup of people with nosocomial pneumonia (very low-quality evidence). Linezolid compared with vancomycin in skin and soft-tissue infection: We don't know how effective linezolid or vancomycin are, compared with each other, at improving clinical cure rate or microbiological success rate in skin and soft-tissue infection (very low-quality evidence). Linezolid compared with vancomycin in bacteraemia: We don't know how effective linezolid or vancomycin are, compared with each other, at improving clinical cure rate or microbiological success rate in adults or children with MRSA bacteraemia (very low-quality evidence). Linezolid compared with teicoplanin: We don't know how effective linezolid or teicoplanin are, compared with each other, at increasing clinical cure rate or microbiological success rate in people treated for microbiologically confirmed MRSA infection (very low-quality evidence). Note: linezolid has been associated with adverse effects, including blood disorders.

Benefits

Linezolid versus vancomycin

We found 10 systematic reviews[29] [30] [17] [31] [32] [25] [33] [34] [35] [36] comparing treatment of nosocomial MRSA with linezolid versus vancomycin at various body sites. Here, we have broken down reporting of reviews by body site.

Any body site:

We found two reviews reporting on infection at any body site (search dates 2006 [7 RCTs, reported in 8 publications][29] and 2012 [9 RCTs][30]). Between them, the reviews identified 10 RCTs, with six RCTs common to both reviews. The reviews reach the same conclusions. However, the review with the more recent search date carried out a meta-analysis, and so we report from the second identified review.[30] It should be noted that eight of the RCTs identified by the second review are open-label in design (but comparing the same route of administration) and as such do not meet reporting criteria for this BMJ Clinical Evidence overview. However, due to the paucity of blinded RCTs on the treatment of MRSA, we have decided to present the data.

The review found that significantly more people in the linezolid group than in the vancomycin group achieved clinical treatment success and microbiological treatment success at the test-of-cure visit and at the end-of-treatment visit (see table 1 ).[30] However, the review found no significant difference between linezolid and vancomycin in rate of mortality (see table 1 ).

Table 1.

Studies comparing linezolid with vancomycin or teicoplanin

Ref Intervention Participants Outcomes Results
Linezolid v vancomycin for MRSA infection of any body site
[30]Systematic review Linezolid 600 mg every 12 hours (iv or oral) v vancomycin 1 g or 15 mg/kg Adults with MRSA infection, 8 RCTs, 4838 patients Mortality 192/2475 (8%) with linezolid v 180/2363 (8%) with vancomycin; OR 1.03, 95% CI 0.82 to 1.28, P = 0.81
Adults with MRSA infection, 8 RCTs, 2174 patients Clinical treatment success at the test-of-cure visit 928/1131 (82%) with linezolid v 786/1043 (75%) with vancomycin; OR 1.77, 95% CI 1.22 to 2.56, P = 0.003, I2 = 47%
Adults with MRSA infection, 5 RCTs, 1112 patients Clinical treatment success at the end-of-treatment visit 485/588 (82%) with linezolid v 384/524 (73%) with vancomycin; OR 2.26, 95% CI 1.32 to 3.89, P = 0.003, I2 = 52%
Adults with MRSA infection, 9 RCTs, 1555 patients Microbiological treatment success at the test-of-cure visit 579/803 (72%) with linezolid v 463/752 (62%) with vancomycin; OR 1.78, 95% CI 1.22 to 2.58, P = 0.003, I2 = 52%
Adults with MRSA infection, 5 RCTs, 1025 patients Microbiological treatment success at the end-of-treatment visit 445/537 (83%) with linezolid v 307/488 (63%) with vancomycin; OR 3.26, 95% CI 2.03 to 5.23, P <0.00001, I2 = 44%
Linezolid v vancomycin for MRSA nosocomial pneumonia
[29]Systematic review Linezolid (600 mg every 12 hours iv or orally for 7–21 days) v vancomycin (1 g every 12 hours iv for 7–21 days) Subgroup analysis of adults with MRSA nosocomial pneumonia (number of RCTs and people in this analysis not reported) Proportion of people with clinical cure OR 3.45, 95% CI 1.90 to 6.26; favours linezolid; absolute results per group not reported
Subgroup analysis of adults with MRSA nosocomial pneumonia (number of RCTs and people in this analysis not reported) Proportion of people with bacterial clearance (timeframes not reported) OR 2.60, 95% CI 1.31 to 5.15; favours linezolid; absolute results per group not reported
[17]Systematic review Linezolid 600mg iv or iv/po every 12 hours v vancomycin 750 mg–1 g iv every 12 hours 2 RCTs, 1090 people with nosocomial or ventilator-associated MRSA Clinical success at test of cure 114/209 (55%) with linezolid v 106/231 (46%) with vancomycin; OR 1.37, 95% credible interval [CrI] 0.72 to 2.44; results presented here are for pair-wise analysis of RCTs within network meta-analysis
Linezolid v vancomycin for MRSA skin and soft-tissue infection
[33]Systematic review 600 mg linezolid (iv or oral) every 12 hours v 1 g or 15 mg/kg vancomycin iv every 12 hours 6 RCTs, 2659 patients suspected or proven to have MRSA SSTI Clinical cure 794/1361 (58%) with linezolid v 695/1298 (54%) with vancomycin; RR 1.09, 95% CI 1.03 to 1.17, P = 0.0058
6 RCTs, 1289 people who had a positive MRSA culture at baseline Microbiological cure rate 421/655 (64%) with linezolid v 338/634 (53%) with vancomycin; RR 1.17, 95% CI 1.04 to 1.32, P = 0.010, I2 = 46%
Linezolid v vancomycin for MRSA bacteraemia
[34]Systematic review Linezolid v vancomycin 144 people with secondary S aureus bacteraemia, subgroup analysis in 73/144 (51%) people with MRSA Survival for MRSA bacteraemia 24/36 (67%) with linezolid v 24/37 (65%) with vancomycin; OR 1.08, 95% CI 0.41 to 2.85
[35]Systematic review Linezolid (10 mg/kg to 600 mg iv every 8–12 hours) v vancomycin (10 mg to 1 g iv every 6–24 hours) 7 RCTs, subgroup analysis in adults and children with MRSA bacteraemia Proportion of people with clinical cure (timeframe not reported) 65/92 (71%) with linezolid v 41/68 (60%) with vancomycin; RR 1.22, 95% CI 0.97 to 1.53, P = 0.10
Linezolid v teicoplanin for MRSA infection of any body site
[37]RCT Linezolid (600 mg every 12 hours) v teicoplanin (400 mg every 12 hours for 3 doses, then 400 mg every 24 hours iv) 202 people with suspected or confirmed gram-positive infections in an intensive care population; 82 people had confirmed MRSA Clinical cure rate Data for MRSA infection not reported; for all people: 71/90 (79%) with linezolid v 67/92 (73%) with teicoplanin; RR 1.10, 95% CI 0.92 to 1.27, P = 0.39
202 people with suspected or proved gram-positive infections in an intensive care population; 82 people had proved MRSA Mortality Data for MRSA infection not reported; for all people: 18% with linezolid v 25% with teicoplanin, P = 0.3
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iv, intravenous; ref, reference.

Nosocomial pneumonia:

We found four systematic reviews evaluating the effects of linezolid compared with vancomycin in the treatment of nosocomial pneumonia.[29] [17] [31] [32] Two of the reviews (search dates 2009[31] and 2012[32]) reported on linezolid versus glycopeptides as a class of antibiotic, combining results for vancomycin and teicoplanin, and so the results from these reviews are not discussed in the benefits and harms section (see Comment). The remaining two reviews (search dates 2006[29] and 2012[17]) report results from different analyses on different outcomes, and so we present the results of both reviews.

The first systematic review found that linezolid significantly improved clinical cure rates and bacterial clearance compared with vancomycin in the subgroup of people with MRSA nosocomial pneumonia (see table 1 for results).[29] However, specific details regarding the follow-up and number of patients in the linezolid and vancomycin groups were not provided, making it difficult to draw definitive conclusions.

The second review found that, although linezolid was associated with a higher rate of clinical success at test of cure than vancomycin, the difference between groups did not reach statistical significance (microbiological modified intention to treat median OR 1.37, 95% CrI 0.72 to 2.44).[17] This review included two RCTs with MRSA pneumonia comparing linezolid with vancomycin. It should be noted that the review also included RCTs evaluating treatments in suspected or proven MRSA skin and tissue infections, although these data are reported separately from the analysis of MRSA pneumonia data.

Skin and soft-tissue infection:

We found two systematic reviews evaluating the effects of linezolid compared with vancomycin in the treatment of skin and soft tissue infections (search dates 2008[25] and 2013[33]). Both reviews identified the same five RCTs evaluating linezolid versus vancomycin in MRSA skin and soft tissue infections acquired while in hospital. The review with the latest search date[33] also included data from a sixth RCT that enrolled people with gram-positive bacterial infection and reported data for the subgroup of people with MRSA infection.

The review with the later search date synthesised data in a pair-wise meta-analysis.[33] The review found that linezolid significantly improved clinical cure rate and microbiological cure rate compared with vancomycin in people with a positive MRSA culture at baseline (see table 1 ). It should be noted that all the RCTs included in the analysis were open-label in nature.

The second review carried out a network meta-analysis using a Bayesian random effects model to evaluate the comparative effects of various antibiotics.[25] The review did not present data from a standard pair-wise analysis. Results from the network meta-analysis are mentioned in the Comment section in support of the results from the direct evidence.

Bacteraemia:

We found two systematic reviews (search date not reported in one review[34] and search date 2009[35]) that presented subgroup analyses in people with bacteraemia. The first review included five RCTs (144 people with secondary Staphylococcus aureus bacteraemia, 73/144 [51%] with MRSA).[34] The second review included seven RCTs in adults and children with bacteraemia, one of which was identified by the first review (160 people with MRSA bacteraemia).[35]

The first systematic review found no significant difference between linezolid and vancomycin in mortality for MRSA bacteraemia (see table 1 for results). It also found no significant difference between groups in clinical cure; however, the follow-up for this outcome was low (<80% of the randomised study population) and so we have not reported it further. The review did not separately report microbiological outcomes for the subgroup of people with MRSA infection. Two of the identified RCTs were blinded, and three were not.[34] The second systematic review found that there was no significant difference between linezolid and vancomycin in clinical cure (time frame not reported; see table 1 for results). The results of this systematic review should be interpreted with caution, because it had several limitations: four RCTs included children aged less than 12 years, which do not meet our reporting criteria, details of blinding were available in only one RCT, and no sensitivity analysis was undertaken.[35]

Linezolid versus teicoplanin

Any body site:

We found one systematic review (search date 2010).[36] The review identified one RCT comparing linezolid with teicoplanin and meeting BMJ Clinical Evidence reporting criteria.[37] The RCT found no significant difference in clinical or microbiological cure in the subgroup of people treated for microbiologically confirmed MRSA infection. No figures were reported in the RCT, but the review reported data for microbiological cure in all people (see table 1 ). Data for the subgroup of people with MRSA infection were not reported in either the RCT or the review. Due to the paucity of data we have reported the results for the full population. The RCT found no significant difference in clinical cure between linezolid and teicoplanin for all gram-positive infections (see table 1 ). It found no significant difference between groups in microbiological success for all gram-positive infections; however, the follow-up for this outcome was low (<80% of the randomised study population), so we have not reported it further. The RCT also found that there were significantly fewer deaths in the linezolid group compared with the teicoplanin group for all people regardless of MRSA infection, although the cause of death was usually multifactorial.

Linezolid versus any other antibiotic listed in this overview

We found no systematic review or RCTs satisfying BMJ Clinical Evidence inclusion criteria.

Harms

Linezolid versus vancomycin

The systematic review evaluating treatment of MRSA at any body site found no significant difference between linezolid and vancomycin in the proportion of people experiencing at least one adverse event (8 RCTs, 665/2569 [26%] with linezolid v 576/2465 [23%] with vancomycin, OR 1.20, 95% CI 0.98 to 1.48, P = 0.08).[30] Additionally, there was no significant difference between groups in the proportion of people experiencing at least one serious adverse event (5 RCTs, 114/1072 [11%] with linezolid v 100/1000 [10%] with vancomycin, OR 1.00, 95% CI 0.74 to 1.36, P = 0.99). Compared with vancomycin, treatment with linezolid was associated with significantly more gastrointestinal-related adverse events (5 RCTs, 174/1535 [11%] with linezolid v 55/1443 [4%] with vancomycin, OR 3.28, 95% CI 2.38 to 4.51, P <0.00001, I2 = 44%) but significantly fewer episodes of abnormal renal function (4 RCTs, 54/1300 [4%] with linezolid v 123/1231 [10%] with vancomycin, OR 0.39, 95% CI 0.28 to 0.55, P <0.00001).

One systematic review did not report on adverse effects of treatment.[29] Three RCTs identified by the systematic review reported adverse effects. In the first RCT, 10 people in each group discontinued treatment owing to adverse effects.[38] There was a higher rate of drug-related adverse effects in the linezolid group compared with the vancomycin group (460 people; drug-related adverse effects: 44/240 [18%] with linezolid v 18/220 [8%] with vancomycin, P = 0.001). These were mostly gastrointestinal disturbance for linezolid. There were two cases each of anaphylaxis and renal disturbance in the vancomycin group. In the second RCT, there was no significant difference in the rate of treatment discontinued owing to adverse effects or drug-related adverse effects (1080 people; drug-related adverse effects: 131/592 [22%] with linezolid plus aztreonam v 121/588 [21%] with vancomycin plus aztreonam, P = 0.516).[39] Gastrointestinal disturbance and thrombocytopenia were significantly more common with linezolid, and rash, anaphylaxis, allergic reaction, and phlebitis occurred significantly more often in the vancomycin group. In the third RCT, there was no significant difference in the rate of treatment discontinued owing to adverse effects or drug-related adverse effects.[40]

Another systematic review found a significantly higher rate of new-onset thrombocytopenia with linezolid compared with vancomycin (5/36 [14%] with linezolid v 0/70 [0%] with vancomycin, P = 0.02).[34] It found no significant difference between groups in rates of any adverse effect, rates of serious adverse effects (as assessed by investigators), or rates of discontinuation from treatment (any adverse effect: 59/74 [80%] with linezolid v 48/59 [70%] with vancomycin, P = 0.16; serious adverse effects: 35/74 [47%] with linezolid v 26/70 [37%] with vancomycin, P = 0.22; discontinuation from treatment: 27/74 [37%] with linezolid v 27/70 [39%] with vancomycin, P = 0.80). [34]

The third systematic review comparing linezolid with vancomycin for gram-positive infections found that there was no significant difference between groups in overall adverse effects or anaemia (overall adverse effects: P = 0.64; anaemia: P = 0.48; absolute results not reported). However, it found that renal inadequacy was significantly lower with linezolid compared with vancomycin (0.47% with linezolid v 2.51% with vancomycin, P = 0.0003; absolute results not reported), and that thrombocytopenia was significantly higher with linezolid compared with vancomycin (4.39% with linezolid v 1.35% with vancomycin, P = 0.01; absolute results not reported).[35]

The review evaluating linezolid versus vancomycin in the treatment of skin and tissue infections found that a significantly smaller proportion of people receiving linezolid developed red man syndrome compared with those receiving vancomycin (2 RCTs, 0/617 [0%] with linezolid v 16/555 [3%] with vancomycin; RR 0.04, 95% CI 0.01 to 0.29).[33] Additionally, linezolid was associated with significantly lower risk of pruritus (3 RCTs, 9/1209 [1%] with linezolid v 24/1143 [2%] with vancomycin; RR 0.36, 95% CI 0.17 to 0.75) and rash (3 RCTs, 8/1209 [1%] with linezolid v 27/1143 [2%] with vancomycin; RR 0.27, 95% CI 0.12 to 0.58). However, linezolid was associated with a significantly higher risk of thrombocytopenia (2 RCTs, 24/672 [4%] with linezolid v 0/628 [0%] with vancomycin; RR 13.06, 95% CI 1.72 to 99.22) and nausea (2 RCTs, 58/1129 [5%] with linezolid v 23/1103 [2%] with vancomycin; RR 2.45, 95% CI 1.52 to 3.94). It should be noted that these analyses were not limited to those people with infections attributed to MRSA.

Linezolid versus teicoplanin

The RCT comparing linezolid with teicoplanin found no significant difference in the rate of adverse effects overall or for any particular adverse effect.[37]

Linezolid versus any other antibiotic listed in this overview

We found no RCTs.

Comment

We found one retrospective cohort study comparing linezolid with teicoplanin in gram-positive infection.[41] However, the study did not present a direct comparison between linezolid and teicoplanin monotherapy in people with MRSA infection.

Two systematic reviews reporting on nosocomial pneumonia synthesised data for 'glycopeptides' as a class of antibiotic, combining results for vancomycin and teicoplanin.[31] [32] One review found that linezolid was significantly more effective than glycopeptides at improving microbiological eradication in nosocomial pneumonia (6 RCTs, n = 539 [MRSA-evaluable population], RR 1.18, 95% CI 1.01 to 1.38, P = 0.04).[32] However, the second review found no significant difference between linezolid and vancomycin in clinical success rate of nosocomial pneumonia (5 RCTs, 300 patients, RR 1.23, 95% CI 0.97 to 1.57, P = 0.09),[31] although all studies in this review were already included in the first review.[32] These studies included open-label RCTs.

The review carrying out a network meta-analysis found that linezolid was associated with a higher success rate (based on clinical and microbiological cure) than vancomycin (estimated difference in MRSA eradication rate [favouring linezolid] 9.7%, 95% CrI 4.4% to 15.8%). The network included 14 RCTs (1840 people) and evaluated six antibiotics (linezolid, vancomycin, daptomycin, tigecycline, dalbavancin, and telavancin).[25]

Three methodological aspects must be considered when interpreting the results of these studies. First, most were open label, which could be a problem in view of the subjective nature of the main outcome measure in most RCTs, clinical cure. Second, people with MRSA, and those with particular types of MRSA infection, usually formed a subgroup within a larger investigation of presumed gram-positive infection. Third, the population size was often small and microbiological clearance of MRSA was not consistently measured. One meta-analysis of trials evaluating parenteral antimicrobial therapy for skin and soft-tissue infections found that, although 88% (15/17 trials) had reported infection with MRSA, only 10/17 (59%) reported separate cures for the pathogens.[42] Furthermore, FDA guidance recommended that at least 70% of the clinically evaluable population should be microbiologically evaluable; however, very few studies complied with this recommendation.

Although testing for microbiological eradication may provide definitive confirmation that the MRSA infection has been resolved, use of this endpoint is confounded by people who remain colonised with MRSA. This may be a potential source of bias, as it could lead to an underestimate of the treatment effect.

Clinical guide

Linezolid was not found to be consistently better than glycopeptides across all groups analysed, which undermines the reliability of significant results from individual studies. Theoretically, the superior tissue penetration of linezolid should give it an advantage when treating infections where high antibiotic levels are difficult to achieve, such as in the lungs and poorly perfused lower limbs. However, as is common for trials of antimicrobials, most RCTs are only powered to demonstrate non-inferiority to standard therapy.

Due to concerns regarding toxicity, in particular myelosuppression, lactic acidosis, and peripheral and optic neuropathy, duration of therapy with linezolid should not extend for more than 28 days. While the majority of these adverse effects are reversible, there have been reports of permanent deficits.[43]

On the basis of the available data for nosocomial pneumonia caused by MRSA, linezolid appears to show a small tendency towards greater efficacy (clinical cure and microbiological clearance) compared with vancomycin. There is no definitive evidence to support greater efficacy of linezolid in soft tissue infections. Linezolid appears to have similar efficacy to glycopeptides for bacteraemia, although evidence for its use in endocarditis is lacking. The adverse effects profile is similar between the two groups, but an oral preparation with high bioavailability gives linezolid an additional advantage over glycopeptides, particularly in patients not requiring inpatient treatment.[44]

Substantive changes

Linezolid Seven systematic reviews added.[30] [17] [31] [32] [25] [33] [36] Categorisation unchanged (trade-off between benefits and harms).

BMJ Clin Evid. 2016 Feb 16;2016:0922.

Quinupristin-dalfopristin, pristinamycin (streptogramins)

Summary

MORTALITY Quinupristin-dalfopristin compared with vancomycin for MRSA nosocomial pneumonia: We don't know how effective quinupristin-dalfopristin and vancomycin are, compared with each other, in improving mortality ( low-quality evidence ). CLINICAL OR MICROBIOLOGICAL CURE Quinupristin-dalfopristin compared with vancomycin for MRSA nosocomial pneumonia: We don't know how effective quinupristin-dalfopristin and vancomycin are, compared with each other, in improving clinical cure rates ( very low-quality evidence ). NOTE We found no direct information from RCTs on the effects of pristinamycin in people with MRSA infection.

Benefits

Quinupristin-dalfopristin versus vancomycin

MRSA nosocomial pneumonia:

We found two systematic reviews (search dates 2008[14] and 2012[17]). Both reviews identified one RCT evaluating quinupristin-dalfopristin and meeting BMJ Clinical Evidence reporting criteria.[45] The multi-centre RCT (298 people with nosocomial pneumonia, 51 of whom had MRSA, age range not reported) compared quinupristin-dalfopristin with vancomycin.[45] It found no significant difference in the clinical cure rate (defined as the disappearance of signs and symptoms) with quinupristin-dalfopristin (7.5 mg/kg 3 times daily intravenously [iv] for 5–14 days) compared with vancomycin (1 g twice daily iv for 5–14 days) in the subgroup of people with MRSA pneumonia (clinical cure: 6/31 [19%] with quinupristin-dalfopristin v 8/20 [40%] with vancomycin; difference –21%, 95% CI –46% to +5%). It found no significant difference in mortality between quinupristin-dalfopristin and vancomycin at 30 days' follow-up for all people with nosocomial pneumonia regardless of MRSA infection (38/150 [25%] with quinupristin-dalfopristin v 32/148 [22%] with vancomycin, P = 0.45).[45] The number of people in the RCT with confirmed MRSA was small and was not sufficient to detect a clinically significant difference in the cure rate.[45]

Quinupristin-dalfopristin versus any other antibiotic listed in this overview

We found no systematic review or RCTs satisfying BMJ Clinical Evidence inclusion criteria.

Pristinamycin versus any other antibiotic listed in this overview

We found no systematic review or RCTs meeting BMJ Clinical Evidence inclusion criteria.

Harms

Quinupristin-dalfopristin versus vancomycin

MRSA nosocomial pneumonia:

The RCT found no significant difference between groups in adverse effects (non-venous adverse effects: 145/150 [97%] with quinupristin-dalfopristin v 138/148 [93%] with vancomycin, P = 0.18; venous adverse effects: 36/150 [24%] with quinupristin-dalfopristin v 29/148 [20%] with vancomycin, P = 0.36).[45] There was also no significant difference in withdrawal rates because of adverse effects (23/150 [15%] with quinupristin-dalfopristin v 14/148 [9%] with vancomycin, P = 0.12).[45]

Quinupristin-dalfopristin versus any other antibiotic listed in this overview

We found no RCTs.

Pristinamycin versus any other antibiotic listed in this overview

We found no RCTs.

Comment

Clinical guide

Streptogramins, while established drugs, have been relatively seldom used in clinical practice. Pristinamycin, an agent available in an oral preparation (albeit not licensed for use in the UK at present), may be a suitable agent in patients requiring prolonged oral therapy. There have been some reports (mainly uncontrolled studies or retrospective observational studies) of its use in management of MRSA skin and soft-tissue infections and osteoarticular infections. However, RCT evidence of efficacy for this indication is lacking, and it is not referred to in current UK guidance.[46] [47]

Substantive changes

Quinupristin-dalfopristin, pristinamycin (streptogramins) Two systematic reviews added,[17] [14] both of which identified one RCT[45] that was already reported in the overview. Categorised as 'unknown effectiveness'.

BMJ Clin Evid. 2016 Feb 16;2016:0922.

Tigecycline

Summary

CLINICAL OR MICROBIOLOGICAL CURE Tigecycline compared with vancomycin: We don't know how effective tigecycline and vancomycin are, compared with each other, at increasing cure rates in hospitalised people with serious MRSA infection ( low-quality evidence ).

Benefits

Tigecycline versus vancomycin

MRSA infection at any body site:

We found three systematic reviews (search dates 2010[48] and 2012[17] [49]). Only one of the RCTs included in these reviews meets BMJ Clinical Evidence reporting criteria, and this RCT is reported separately.[50] We also found a systematic review (search date 2008) that carried out a network meta-analysis using a Bayesian random effects model to evaluate the comparative effects of various antibiotics.[25] The review did not present data from a standard pair-wise analysis. Results from the network meta-analysis are mentioned in the Comment section in support of the results from the direct evidence.

The RCT (157 hospitalised people with serious MRSA infection; complicated skin or soft-tissue infection [108 people], complicated intra-abdominal infection [21 people], primary bacteraemia [15 people], hospital-acquired pneumonia [10 people], or community-acquired pneumonia [2 people]; median age 51 years) compared tigecycline (100 mg intravenously [iv] loading dose followed by 50 mg every 12 hours) with vancomycin (1 g iv every 12 hours).[50] The RCT found similar clinical cure rates with tigecycline and vancomycin at 12 to 37 days after the last dose (intention-to-treat [ITT] analysis: proportion of people with clinical cure: 85/118 [72%] with tigecycline v 29/39 [74%] with vancomycin; significance not reported; proportion of test-of-cure attendees with clinical cure: 75/100 [75%, 95% CI 65% to 83%] with tigecycline v 27/33 [82%, 95% CI 65% to 93%] with vancomycin). Microbiological cure rates were also similar between groups (ITT analysis: proportion of people with microbiological cure [eradication of the organism, documented or presumed]: 74/100 [74%] with tigecycline v 27/33 [82%] with vancomycin; significance not reported).[50]

Tigecycline versus any other antibiotic listed in this overview

We found no systematic review or RCTs satisfying BMJ Clinical Evidence inclusion criteria.

Harms

Tigecycline versus vancomycin

MRSA infection at any body site:

The RCT found similar rates of drug-related adverse effects in both groups (45% with tigecycline v 33% with vancomycin; absolute numbers and P value not reported).[50] Adverse events affecting the digestive system (nausea, vomiting, and diarrhoea) were significantly more common with tigecycline than with vancomycin (58/117 [50%] with tigecycline v 12/39 [31%] with vancomycin, P <0.05). Treatment discontinuation for adverse events was similar between treatment groups (8/117 [7%] with tigecycline v 2/39 [5%] with vancomycin; reported as not significant). Eight people died, but the deaths were not thought to be treatment related (all-cause mortality during the study [timescale not defined]: 6/117 [5%] with tigecycline v 2/39 [5%] with vancomycin).

Tigecycline versus any other antibiotic listed in this overview

We found no RCTs.

Comment

One double-blinded study of hospitalised patients with serious MRSA infections found similar cure rates between tigecycline and vancomycin, but was not powered to demonstrate superiority of either agent.[50] The population in the study was heterogeneous, and its effectiveness for any specific infection site is difficult to ascertain.

The review carrying out a network meta-analysis found no significant difference between tigecycline and vancomycin in success rate based on clinical and microbiological cure (estimated difference in MRSA eradication rate for tigecycline compared with vancomycin –4.3%, 95% CrI –26.0% to +13.8%).[25] The network included 14 RCTs (1840 people) and evaluated six antibiotics (linezolid, vancomycin, daptomycin, tigecycline, dalbavancin, and telavancin).

While the evidence is not definitive, there have been concerns raised about the increase in mortality observed in patients treated with tigecycline. A recent meta-analysis of 14 RCTs showed lower efficacy of tigecycline against comparators (modified intention-to-treat population, odds ratio [OR] 0.81, 95% CI 0.72 to 0.92, P = 0.001), with higher all-cause mortality (odds ratio [OR] 1.33, 95% CI 1.03 to 1.72, P = 0.03).[51] The difference in efficacy in skin and soft tissue infections did not reach statistical significance (modified intention-to-treat population, odds ratio [OR] 0.88, 95% CI 0.64 to 1.19, P = 0.40). It should be noted that this meta-analysis is highly heterogeneous in terms of both microbiology and underlying pathology. We are unable to say to what extent these findings reflect treatment of MRSA infections with tigecycline, but the concerns regarding its efficacy in a wide range of infections should be considered.

Clinical guide

Tigecycline was previously recommended as an alternative treatment for MRSA skin and soft tissue infections.[10] Owing to subsequent concerns regarding increased mortality in patients treated with tigecycline,[51] [52] in clinical practice tigecycline is often reserved for situations where other agents are inappropriate due to resistance or intolerance. When there is no other therapeutic option and based on a good clinical risk benefit analysis, tigecycline could be used for treatment of skin and soft tissue infections caused by MRSA. Due caution and vigilance should be exercised during therapy.

Substantive changes

Tigecycline Four systematic reviews added,[17] [48] [49] [25] which all identified one relevant RCT[50] that was already reported in the overview. Categorised as 'unknown effectiveness'.

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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