MRSA: treating people with infection

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, especially in people with prolonged hospital admissions, with underlying disease, or after antibiotic use. About 20% of S aureus in blood cultures in England, Wales, and Northern Ireland is resistant to methicillin.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatment for MRSA infections at any body site? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 11 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: clindamycin, daptomycin, fusidic acid, glycopeptides (teicoplanin, vancomycin), linezolid, macrolides (azithromycin, clarithromycin, erythromycin), quinolones (ciprofloxacin, levofloxacin, moxifloxacin), quinupristin–dalfopristin, pristinamycin, rifampicin, tetracyclines (doxycycline, minocycline, oxytetracycline), tigecycline, trimethoprim, and trimethoprim–sulfamethoxazole (co-trimoxazole).

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, and carbapenems.

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

• About 20% of S aureus in blood cultures in England, Wales, and Northern Ireland is resistant to methicillin.

Glycopeptides (teicoplanin, vancomycin) and linezolid seem to have similar efficacy at curing MRSA infection. However, they have all been associated with adverse effects.

We found limited evidence that tigecycline may have similar cure rates as vancomycin, however effectiveness is not yet clear.

Trimethoprim–sulfamethoxazole (co-trimoxazole; TMP-SMX) may be as effective as vancomycin at curing MRSA infection in injecting drug users, with similar toxicity. However, we cannot draw conclusions on the effects of this drug in other populations.

We don’t know whether macrolides (azithromycin, clarithromycin, erythromycin), quinolones (ciprofloxacin, levofloxacin, moxifloxacin), tetracyclines (doxycycline, minocycline, oxytetracycline), clindamycin, daptomycin, fusidic acid, pristinamycin, quinupristin–dalfopristin, rifampicin, and trimethoprim are effective at curing MRSA infection, because we found no adequate RCTs.

• Ciprofloxacin has been used in combination with rifampicin or fusidic acid for MRSA bone and joint infections but we cannot confirm its effectiveness from adequate studies. Fusidic acid or rifampicin should not be used as monotherapy because resistance rapidly develops.

• Clindamycin may be used in preference to macrolides in susceptible MRSA infections, as bioavailability may be better and resistance less likely, however we found no adequate trials.

• Oral tetracyclines may be recommended for minor MRSA infections, however we found no adequate trials.

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 Staphylococcus 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, 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: 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 strains of MRSA 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. These MRSA strains are resistant to the isoxazolyl penicillins (such as meticillin, oxacillin, and flucloxacillin), beta-lactam/beta-lactamase inhibitor combinations, cephalosporins, and carbapenems. They also show a variable level of resistance to other groups of antibiotics such as quinolones, macrolides, and others. 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). This 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 review. 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. Since 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]Our population of interest in this review 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. Population: We include adults with predominantly nosocomial or healthcare-acquired MRSA infection; we exclude children under 16 years.

Incidence/ Prevalence

The incidence of MRSA varies from country to country.[4] The UK, Ireland, and southern Europe (e.g., Spain, Italy, and Greece) have a high incidence when compared with northern Europe and Scandinavia.[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 this review this stands at about 20% in the UK.[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 feedings, 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] A subsequent cohort study (438 people, predominantly men, with S aureus infection complicated by bacteraemia, 193 [44%] of whom had MRSA) also found higher S aureus-related mortality with MRSA compared with MSSA in people without pneumonia (HR [adjusted for age, comorbidities, and pneumonia] 1.8, 95% CI 0.2 to 3.0; P <0.01).[10] However, these studies had various methodological weaknesses including no specific data given on the adequacy of treatment administered or severity of illness, or other confounders not consistently available or considered. A more recent 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]Therefore, one cannot assume that invasive infection with MRSA per se is associated with a poorer clinical outcome. A range of confounders is likely to influence clinical outcome, and timeliness of treatment, among others, may be a factor.

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 of treatment.

Methods

Clinical Evidence search and appraisal November 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to November 2009, Embase 1980 to November 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributors for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs, RCTs and cohort studies (prospective and retrospective, with or without a control group) in any language, 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 required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We included studies that primarily addressed MRSA as the causative pathogen of the infection. We came across several studies of treatment of a range of gram-positive infections including MRSA. We have included these studies if MRSA was mentioned as one of the pathogens. We did not prospectively specify what percentage of the relevant population needed to have MRSA to include or exclude a study in our review. We have been explicit about these deficiencies in the studies included and their impact on the quality of the findings. To aid readability of the numerical data in our reviews, 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). 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 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 treatment for MRSA infections at any body site?
5 (73) [15]	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
7 (900) [13] [14]	Clinical or microbiological cure	Linezolid v vancomycin in infection at any body site	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), unclear/subjective outcome (clinical cure), and inclusion of co-intervention in one study (aztreonam)
more than 1 RCT (>62 people) [13] [14]	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), unclear/subjective outcome (clinical cure), and inclusion of co-intervention in one study (aztreonam)
more than 1 RCT (>80 people) [13] [14]	Clinical or microbiological cure	Linezolid v vancomycin in skin and soft-tissue infections	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), unclear/subjective outcome (clinical cure), and inclusion of co-intervention in one study (aztreonam)
12 (223) [15] [16]	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)[17]	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)[17]	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)
1 (51)[25]	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 (298)[25]	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 (47)[26]	Clinical or microbiological cure	Trimethoprim–sulfamethoxazole (co-trimoxazole) v vancomycin	4	–2	0	–2	0	Very low	Quality points deducted for sparse data and subgroup analysis. Directness points deducted for highly selected population (injecting drug users) and for use of unclear/subjective outcome (clinical cure)
1 (157) [24]	Clinical or microbiological cure	Tigecycline v vancomycin	4	–2	0	0	0	Low	Quality points deducted for sparse data and no statistical assessment

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.

Very low-quality evidence

Any estimate of effect is very uncertain.

MRSA colonisation

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