Methicillin resistant Staphylococcus aureus in the critically ill

K. J. Hardy1,3, P. M. Hawkey*,1,3, F. Gao2 and B. A. Oppenheim1

1 Health Protection Agency, West Midlands Public Health Laboratory, and 2 Intensive Care Unit, Heartlands Hospital, Bordesley Green East, Birmingham, B9 5SS, UK. 3 The Department of Infection and Immunity, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

*Corresponding author. E-mail: peter.hawkey@heartsol.wmids.nhs.uk


    Abstract
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
Methicillin resistant Staphylococcus aureus (MRSA) is endemic within many hospitals worldwide. Critically ill patients on intensive care units have increased risk factors making them especially prone to nosocomially acquired infections. This review addresses the current situation regarding the evolution of MRSA and the techniques for identifying and epidemiologically typing it. It discusses specific risk factors, the morbidity and mortality associated with critically ill patients, and possibilities for future antibiotic treatments.

Br J Anaesth 2004; 92: 121–30

Keywords: complications, infections, methicillin resistant Staphylococcus aureus (MRSA); epidemiology; intensive care


    Introduction
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
Staphylococcus aureus has long been recognized as a major human pathogen responsible for a wide range of infections, from mild skin infections to wound infections and bacteraemia. Although the introduction of antibiotics over the last 50 yr has lowered the mortality rate from S. aureus infections, the bacteria have developed resistance mechanisms to all antimicrobial agents that have been produced.

The introduction of penicillin offered an opportunity to successfully treat serious staphylococcal infections. However, in the same year as the first clinical success with penicillin, an enzyme produced by S. aureus, penicillinase (later known as ß-lactamase) was described. This enzyme was responsible for the clinical failures that appeared soon after the introduction of penicillin.1 13 During the early 1950s, a series of semi-synthetic penicillins were developed that were stable to destruction by bacterial ß-lactamases. Methicillin was one of these compounds and was introduced into clinical practice in 1959. One year after its introduction, the first methicillin resistant S. aureus (MRSA) was detected and the first clinical failure of methicillin for the treatment of S. aureus described (Fig. 1).50 76



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Fig 1 The introduction of antibiotics and consequent evolution of resistance in S. aureus.

 

    Resistance and evolution
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
The site of action for ß-lactam antibiotics is the penicillin binding proteins (PBPs), which catalyse the transpeptidase reaction that cross links the peptidoglycan of the bacterial cell wall. The antibacterial effect of the ß-lactam antibiotics is a result of the inactivation of the high molecular weight PBPs (PBP1, 2, and 3); the high affinity of PBP1, 2, and 3 for ß-lactam antibiotics results in a stable complex being formed, which is lethal for cell growth (Fig. 2).



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Fig 2 Action of ß-lactam antibiotics on the peptidoglycan structure of the bacterial cell wall. (A) Cleavage of the peptide side chain releases the energy needed by transpeptidases to form the cross links of the peptidoglycan lattice. (B) Formation of the stable structure of the peptidoglycan lattice. (C) ß-Lactams inactivate the PBPs and prevent the cleavage of the peptide side chain, and therefore prevent the release of energy and consequently cross linking. Results in a structure, which is lethal for cell growth.

 
Staphylococcus aureus strains that express high-level resistance to methicillin produce an additional low affinity penicillin binding protein (PBP2a) encoded by the mecA gene.89 This is in contrast to the production of ß-lactamase that destroys non-stable ß-lactams such as penicillin and ampicillin. At normally inhibitory concentrations of methicillin, PBP2a retains its transpeptidase activity and takes over the role of the normal PBPs in cell wall synthesis.

It is believed that MRSA has evolved from methicillin sensitive S. aureus (MSSA) by the acquisition of a large genetic element known as the staphylococcal cassette chromosome mec (SCCmec). SCCmec carries the mec gene complex and various resistance genes against non ß-lactam antibiotics.55

Despite the SCCmec complex carrying resistance genes against non ß-lactam antibiotics, MRSA has until recently remained susceptible to vancomycin. Intermediate resistant strains were first reported in Japan in 1996 and have since been isolated in several countries around the world.44 Resistance to vancomycin in enterococci was identified in 1988 and since that time it has been anticipated that it would appear in S. aureus. Concerns were heightened when it was demonstrated in vivo that transfer of the vancomycin resistance gene, vanA could occur.69 However, it was not until 2002 that the first clinical vancomycin resistant S. aureus (VRSA) was isolated from a patient. The VRSA was isolated from the catheter tip of a renal dialysis patient in Michigan and contained both the mecA and vanA gene.12 Since this first report there has been one further report again in the USA, but unrelated to the first isolate identified (Fig. 1).11


    Epidemiology
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
MRSA was first recognized in Europe in the early 1960s, and the number of resistant isolates and outbreaks reported increased throughout the decade. Then during the early 1970s there was a decline in the frequency of MRSA in Europe, the reasons for which are not entirely known. It may have been a result of improvements in infection control and antibiotic use.6 The second wave of MRSA occurred in the late 1970s, first in Australia, the Irish Republic, and the USA, since then the rates of MRSA have increased in virtually all countries, with a few exceptions, such as the Netherlands and Denmark.24 30

Epidemic MRSA (EMRSA) strains have been described, the first of which, EMRSA-1, was isolated in a London hospital in 1981, then spreading to other hospitals in London and the South East.27 Seventeen EMRSA strains have been described,5 but the two most predominant EMRSA strains in the UK are EMRSA-15 and -16. The number of reports of EMRSA-15 and -16 have continued to rise over the last decade and are responsible for greater than 95% of all MRSA bacteraemias in the UK (Fig. 3).51 65 EMRSA-16 is concentrated in the South East whilst EMRSA-15 is widespread throughout the country. Once endemic in a hospital EMRSA-15 and -16 are very hard to control, with previously successful preventative measures in controlling outbreaks being unsuccessful.6



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Fig 3 Staphylococcus aureus bacteraemia laboratory reports and methicillin susceptibility for England and Wales, 1992–2001. (Courtesy of Public Health Laboratory Service.)

 
ICU and hospital epidemiology
Rates of MRSA on different ICUs are difficult to compare because of differing surveillance methods, lack of uniformity in diagnostic criteria, and lack of adequate systems to compare the severity of illness. In many studies, ICUs have the highest incidence of MRSA followed by surgical wards and medical wards, with the community having the lowest rates.7 16 The ICUs have been proposed as having a central role in the intra- and inter-hospital spread of MRSA.45 It has also been noted however, that when rates of MRSA increase in an ICU there is a parallel increase in the rates on general medical wards. Patients in hospital are frequently transferred both within the hospital and between different hospitals allowing for spread both within and between hospitals, with some of the large hospitals being termed ‘super spreaders’ (Fig. 4). The strains carried by these patients are normally EMRSA. In contrast, patients from nursing homes may be the commonest source of MRSA imported to hospitals but their strains often differ from the epidemic strains.



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Fig 4 MRSA acquisition and transmission between ICU, the hospital and the community. Patients are admitted to ICU colonized with MRSA, but a larger percentage of patients are transferred from ICU back to the general wards colonized with MRSA. This pattern is then continued out into the community.

 

    Identification of MRSA
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
The laboratory plays an important role in the detection of MRSA, which necessitates the availability of rapid and reliable tests. However, timely detection of MRSA is still problematic with the majority of techniques taking longer than 48 h to produce a result. Isolation of MRSA using solid media is the most commonly used technique, with many different selective media now being available, most containing oxacillin and sodium chloride.22 The sensitivity of detecting carriers is significantly enhanced when using broth enrichment, but with the disadvantage that it takes longer to obtain a result and therefore delays implementation of infection control procedures.21

Development of rapid and accurate tests is crucial for the control of MRSA in hospitals and to initiate the appropriate antimicrobial treatment in critically ill patients. Advancement of molecular techniques in recent years has led to many assays being developed to detect the mecA gene, which now represents the ‘gold standard’ for detecting methicillin resistance. Despite many of these techniques outperforming conventional culture, they still require an overnight enrichment culture of clinical samples.52 87

Techniques have recently been developed that have increased the possibilities of same day testing, combining a high degree of sensitivity and accurate identification. These methods have been described for both swabs and blood cultures, but have so far not been extensively used in routine laboratories.31 61 Despite their high costs, they may prove to be cost effective by reducing transmission rates. Bedside testing, which would be the most useful option is still not available.

To facilitate the control of outbreaks and enable us to have an understanding of the changing epidemiology of MRSA, it is necessary for us to be able to distinguish between the different types of MRSA. There are several typing schemes available but no consensus regarding which method is the best.94 DNA-based typing methods are more discriminatory than the previously used phenotypic methods, with pulse field gel electrophoresis (PFGE) being the most widely used.17 90


    Risk factors for colonization and infection
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
Many strategies have been applied to identify both the risk factors that lead to colonization and those that lead to subsequent infection.23 In many cases, identification of a single risk factor is not possible because of patients being simultaneously exposed to several. Intensive care patients have risk factors making them especially prone to nosocomially acquired infection.

Previous MRSA colonization
The risk of MRSA infection in patients is much higher if they are previously colonized with MRSA.4 Between 30 and 60% of critically ill patients colonized with MRSA will develop infection.16 85 In a study of patients developing MRSA bacteraemia, 83% of patients had been colonized previously.9 Case control studies examining S. aureus colonization have shown nasal colonization to be a significant risk factor for the development of wound infection.56 However, despite colonization rates being perceived to be higher on ICU, there are no comparative studies and along with colonization many risk factors predispose critically ill patients to infection. An example of this is the high rates of colonization in nursing homes but the low rates of infection.

Length of ICU and hospital stay
In several studies, the amount of time spent on ICU has been considered the most significant risk factor in acquisition of MRSA infection.60 The odds ratio for acquiring infection increased more than 2.5 times with a stay of longer than 2 weeks, and more than four times after 3 weeks in a study by Ibelings and Bruining.48 When compared with MSSA infection, patients infected with MRSA had a significantly longer length of stay on ICU both before and after infection.15

Severity of illness and intensity of care
An increasing APACHE II score has been associated with the risk of acquiring MRSA, but once the APACHE II score is greater than 21–25 a reduction is seen in the incidences of infection. Patients with the higher APACHE II scores are more likely to die of their underlying disease before acquiring MRSA, whereas less severely ill patients are exposed to a greater number of risk factors.48

The intensity of care and staff deficits have been associated with MRSA colonization and infection; an increasing intensity of work was associated with a greater risk of MRSA acquisition in ICUs.29 92 The effect of staff deficit has been significantly associated with MRSA clusters, whilst in sporadic cases staff deficit did not influence the occurrence of MRSA.37

Intravascular devices
The insertion of intravascular devices has been identified as an independent risk factor associated for MRSA bacteraemia.73 Asensio and colleagues4 found invasive procedures including the insertion of intravascular devices to be independently associated with MRSA colonization and infection, similar to Law and Gill60 who found a 9-fold increase in MRSA acquisition if a patient had an indwelling catheter.

Antibiotic consumption
The administration of antibiotics has the effect of altering the normal human microbial flora, decreasing the number of susceptible organisms and consequently increasing the numbers of resistant organisms. Hospitalized patients have been shown to have skin flora differing from that of healthy adults with significantly higher levels of resistant bacteria.59 Consumption of antibiotics is greatest on ICU, with reports linking the high usage to increasingly high numbers of resistant bacteria.

Several studies have identified that an increased risk of MRSA infection is associated with the administration of antibiotics.29 36 73 Comparison of patients colonized with MSSA and MRSA reveals that the number of antibiotics received and the duration of the therapy are statistically associated with an increased risk of MRSA acquisition. Association of antibiotic prescribing and MRSA rates is also supported by comparisons of prescribing regimes in different countries. Germany, which has much lower resistance rates than the USA, has a higher relative use of narrow spectrum antibiotics and a lower relative use of broad-spectrum antibiotics. Cephalosporins are the most frequently prescribed antimicrobials on ICUs in the USA but are used to a lesser extent in Germany.29 38 Further evidence is also provided by the Dutch who have strict prescribing policies and very low rates of MRSA. Despite this evidence, several studies have failed to find a significant association when using logistic regression between antibiotic exposure and MRSA acquisition.41 When individual antibiotic classes are examined, both cephalosporins and quinolones have been significantly associated with predisposing patients to MRSA colonization. Both increasing incidences of MRSA colonization and outbreaks of MRSA have been correlated with increasing quinolone and cephalosporin usage.42 62 A multicentre study of 50 Belgian hospitals identified an increasing incidence of MRSA with increasing use of ceftazidime, cefsulodin, co-amoxiclav, and fluoroquinolones.20 In a study of risk factors on ICU, Graffunder and Venezia36 found both levofloxacin and macrolides to be independently associated with MRSA infection, along with longer length of stay before infection, previous surgery, and enteral feeding tubes.

Fluoroquinolones are readily excreted in sweat and achieve minimum inhibitory concentrations on the skin, therefore suppressing normal flora and allowing a higher density of skin colonization with multiple resistant bacteria.40 46 There is also evidence to suggest that the excretion of ß-lactam antibiotics in sweat may in part explain the resistance of staphylococcus to ß-lactam antibiotics.47


    Clinical consequences of MRSA
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
MRSA can cause a wide range of infections from superficial skin infections to severe SSI and bacteraemias. Many of the studies compare the clinical consequences of MRSA with MSSA.

Bacteraemia, SSI, and pneumonia
Mandatory reporting of all MRSA bacteraemias to the Department of Health was implemented in England in April 2001; rates during the first year of surveillance ranged from 0 to 0.66/1000 occupied bed days, with an overall rate of 0.17/1000 occupied bed days. Single speciality trusts had lower rates than general or specialist trusts, with London having the highest regional rates.2 Although data have only been collected for 1 yr, 14 trusts have had significant increases in their MRSA rates over this time. Previous surveillance of hospital acquired bacteraemias (HAB) demonstrated that the rates on ICU are much higher when compared with overall trends: 9.1 HAB/1000 patient days as opposed to 0.6 HAB/1000 patient days. Over 40% of the HAB were caused by staphylococci, 26% of which were S. aureus and 54% of these were methicillin resistant.79 The percentage of S. aureus bacteraemias caused by MRSA isolates has increased from 2% in 1992 to greater than 40% in 2001, in addition to those attributable to MSSA isolates, the numbers of which have remained relatively constant (Fig. 3). Similar results were also seen in surveillance of surgical site infections (SSI) in England and Wales with staphylococci being responsible for 47% of SSI, of which 82% were S. aureus and 62% were methicillin resistant.80 This is similar to the results from the European Prevalence of Infection in Intensive Care study (EPIC) where MRSA accounted for 57% of all ICU acquired S. aureus.93

MRSA pneumonia causes a significant degree of mortality amongst ICU patients, with rates of greater than 50% reported by several studies.35 75 Patients with MRSA develop bacteraemia and septic shock more frequently than patients with MSSA pneumonia.

Mortality and morbidity
The degree of morbidity and mortality attributable to MRSA is difficult to assess. Many studies have compared the mortality of MRSA and MSSA bacteraemia with conflicting results. A meta-analysis of 31 studies by Cosgrove and colleagues18 concluded that bacteraemia as a result of MRSA is associated with an increased mortality compared with MSSA bacteraemia with an odds ratio of 1.93 (95% CI, 1.54–2.42; P<0.01). When looked at independently, only seven of the studies had found a significant difference between the mortality rates of MSSA and MRSA bacteraemia; this may be because many of the studies were small and lacked the power to find an association. Adjustment for confounding variables is problematic; one such adjustment is needed for the severity of illness. There is a belief that patients with MRSA bacteraemia are sicker and will consequently have a higher mortality because of their underlying illness. Several studies including one by Blot and colleagues9 that have adjusted for underlying disease still found MRSA bacteraemia to have a higher attributable mortality than MSSA bacteraemia.

EPIC data found that mortality was greatest in countries with a higher ICU acquired infection rate, and was higher again in those countries with high MRSA ICU acquired infection rates.93 Univariate analysis of the data confirmed that ICU acquired infections are among the most important independent risk factors associated with mortality. Lower respiratory tract infection with MRSA has the greatest risk for increased mortality.

An examination of death certificates from 1993 to 1998 in the UK where staphylococcal infection was mentioned showed that there was an increase over the 5-yr period, with the increasing proportion being attributable to MRSA.19 On the certificates where staphylococcal infection was the underlying cause of death, the percentage where MRSA was mentioned increased from 8% in 1993 to 44% in 1998.

The 2001 report of the National Confidential Enquiry into Perioperative Deaths (NCEPOD) has found that there were four out of 222 (1.8%) deaths after general surgery with documented MRSA infection.3 Clearly, MRSA infection is a hazard for surgical patients.


    Control Of MRSA
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
Hand hygiene
The main source of cross transmission of nosocomial infections is on the hands of health care workers, a source of cross transmission that can be prevented (Table 1). Several studies have demonstrated that the hand-washing compliance of health care workers in most institutions is low.54 Pittet and colleagues found compliance with hand-washing protocols of only 48% in a teaching hospital in Geneva.72 Worryingly, in accordance with other studies, the compliance was lowest when the procedure was high risk and when the activity index was highest.86 The implementation of a hand hygiene campaign and the use of bedside alcohol rinses at this hospital saw improved hand hygiene compliance from 48% in 1994 to 66.2% in 1997, and coincided with a reduction of nosocomial infections and MRSA transmission.71 This is in accordance with a statistical model, which showed that the rate of carriage of resistant organisms could be reduced by a third if hand hygiene compliance increased from 40 to 70%.81 The availability of alcohol-based hand rubs reduces the amount of time spent hand washing, which may become prohibitive during busy periods especially on ICU. This factor is thought to be one of the main reasons why German ICUs have a greater compliance with hand hygiene than American ICUs, which have not adopted alcohol-based rubs.38


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Table 1 Routes of transmission and control measures for the reduction of MRSA colonization and infection on the Intensive Care Unit
 
Screening and isolation of patients
Within hospitals, the main reservoirs of MRSA are colonized or infected patients. The likelihood of becoming colonized or infected with MRSA on ICU has been shown to be directly associated with the number of patients infected or colonized with MRSA on ICU at the time of admission.63 Identifying colonized patients early through screening is important to enable the implementation of isolation and infection control. Screening patients on admission to ICU is recommended to establish if the patients are colonized with MRSA, and then weekly or more frequently thereafter to identify and monitor carriage (Fig. 5). The most commonly screened sites for detection of MRSA carriage are nose and perineum, with most carriers being first identified through nasal swabs; several studies showing identification rates of greater than 80%.16 34



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Fig 5 MRSA screening protocol on the Intensive Care Unit.

 
The isolation of patients is thought to be one of the most effective control measures (Fig. 5), although in studies where this has been shown to be effective there have also been other control measures introduced concurrently. The Dutch have successfully used isolation policies resulting in very low rates of MRSA; however, this is in combination with very strict antibiotic prescribing policies.7 91

Eradication from patients
Eradication of MRSA from patients has proved problematic, with many believing that there is no evidence for systemic or topical antimicrobial therapy specifically to eradicate MRSA colonization. Topical treatment with mupirocin has been shown to only marginally reduce the levels of MRSA colonization. A high success rate in initial decolonization was seen by Dupeyron and colleagues,28 but 25.9% of these patients became recolonized. However, Harbarth and colleagues39 found an eradication rate of only 44% in a test group treated with mupirocin compared with the control group that had an eradication rate of 23%. There have also been reports of mupirocin resistance in situations where it has been used for prolonged periods.64 Mupirocin has been shown to be useful in outbreak situations disrupting transmission in conjunction with other infection control procedures.43

The environment and cleaning
Although it is well recognized that the hands of health care workers are the main source of transmission for MRSA and colonized or infected patients the main reservoirs, the question of whether the environment plays a significant role remains unresolved.84 Some studies have shown the environment to play a role during outbreaks and endemic situations, whilst others have reported limited environmental contamination.10 Levels of environmental contamination have been reported to be higher in rooms of colonized or infected patients when compared with levels in unoccupied rooms.78 Variations in frequencies of environmental contamination have also been identified, depending on the site infected or colonized.10 Boyce and colleagues10 also demonstrated that environmental contamination of a patient’s room was sufficient to contaminate the gloves of health care workers who had contact with the environment but no direct patient contact.

The survival of S. aureus in the environment may be a critical factor in its transmission, with Jawad and colleagues49 demonstrating that S. aureus are resistant to desiccation particularly when dried in protein rich menstrum. Many studies have investigated the survival time of S. aureus, and although not directly comparable all show that S. aureus has the potential to survive for long periods under conditions found in the hospital environment.25 Staphylococci has been shown to survive for at least 1 day on five common hospital materials, with some still viable after 56 and 90 days on polyester and polyethylene plastic respectively.26 57 68

Contamination of the environment with MRSA and its ability to survive for long periods of time emphasizes the necessity for cleaning. Cleaning is often a forgotten infection control measure despite evidence that outbreaks have only been brought under control once MRSA has been eliminated from the environment. Rampling and colleagues74 showed that elimination of MRSA from the environment was only possible when emphasis was placed on dust control; previous cleaning of the ward had only provided temporary measures.

Airborne transmission
The role of airborne transmission in staphylococcal infections has been recognized since the 1960s, but there are conflicting reports over its significance.66 A study by Bauer and colleagues8 did not find any evidence of a role for airborne transmission, but Shiomori and colleagues82 suggested that airborne spread might have a role to play in the colonization of the nasal cavity or respiratory tract infections. They showed that MRSA particles in the respirable range were liberated into the air during bed making, and therefore have the potential to reach the lung and cause infection.83

Is control worth it?
Controversy exists over whether measures to control MRSA are effective, particularly in endemic situations. Guidelines have been established in several countries, some of which, like the Netherlands, have an aggressive approach to management of MRSA, to others, which opt for containment.

The cost of infection control measures is high, but studies comparing the costs involved in treating patients infected with MRSA all demonstrate that implementing infection control measures is cost effective. Selective screening and isolation of carriers on admission to ICU in a study by Chaix and colleagues14 was shown to be beneficial compared with no isolation.


    Treatment
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
Glycopeptides, including vancomycin and teicoplanin are still the mainstay treatment for MRSA, with usage being directly related to the incidence of MRSA, but the emergence of vancomycin resistant strains has lead to a need for other antimicrobial compounds to be considered for the treatment of MRSA.32 Several new compounds have emerged in recent years including linezolid and quinopristin-dalfopristin. Quinopristin-dalfopristin is a combination of quinopristin 30% and dalfopristin 70% and is bactericidal against a range of Gram positive bacteria, although not active against Enterococcus faecalis.58 It can only be administered parenterally and has a modest tissue penetration. Success rates against MRSA are in the range 64–76%, but therapy has been associated with superinfections with E. faecalis. Occurrences of adverse events are high compared with comparable compounds, with therapy discontinued in 15.3–19.1%. Linezolid, the first oxazolidinone was approved for clinical use in the UK in 2001. It is a novel synthetic antibiotic that acts at a unique site in the protein synthesis process, with antibacterial activity against a wide range of Gram positive bacteria including MRSA. For the treatment of MRSA nosocomial pneumonia, linezolid is as effective as vancomycin both in terms of clinical and microbiological outcomes.77 One of the advantages of linezolid is that it is available in an oral formulation therefore potentially allowing an earlier discharge of patients. However, resistant isolates have already been described in patients who had previously had MRSA that was sensitive to linezolid, and the cost of linezolid is nearly 10 times greater than the cost of vancomycin.95

Several other antibacterial agents are currently in development. Tigecycline (GAR-936) is a derivative of minocycline, a member of a new group of antibiotics, the glycylcyclines. It is in the late stages of clinical trials and has shown good activity against a broad spectrum of resistant organisms, including MRSA and VISA strains.70 Two new novel carbapenems are in trial: CP5609, which has shown potent activity and good efficacy compared with vancomycin in vitro against MRSA;67 and CS-023, which has better activity against MRSA than other carbapenems and has shown to be safe and well tolerated.33 BAL9141 and S-3578 are novel cephalosporin derivatives that have a broader spectrum of activity than vancomycin and linezolid and have been proposed as candidates for treating both systemic and local MRSA infections.53 88


    Conclusions
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
Intensive care patients are at great risk of infection from MRSA. They have increased risk factors, including extended stays in hospital, high antibiotic consumption and numerous i.v. devices inserted. The severity of their underlying disease also means that the consequences of infection with MRSA cause significant morbidity or mortality.

Controversy exists over whether MRSA can be brought under control and if the effort to try and control MRSA is a waste of resources. However, on ICU where MRSA contributes to the high degree of morbidity and mortality, control measures have been shown to be cost effective. The control of MRSA must be a team effort involving all health care professionals with the implementation of strict infection control programmes and rational antibiotic prescribing.

At present, the mainstay of treatment for MRSA is vancomycin, but the recent discovery of vancomycin resistant MRSA demonstrates how MRSA is constantly evolving and suggests that the future may not be bright.


    Acknowledgement
 
The authors wish to thank Wyeth for the support of K. J. Hardy.


    References
 Top
 Abstract
 Introduction
 Resistance and evolution
 Epidemiology
 Identification of MRSA
 Risk factors for colonization...
 Clinical consequences of MRSA
 Control Of MRSA
 Treatment
 Conclusions
 References
 
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