Clinical relevance of increasing glycopeptide MICs against Staphylococcus aureus

International Journal of Antimicrobial Agents 31 (2008) 1–9

Clinical relevance of increasing glycopeptide MICs against Staphylococcus aureus Dr Ian M. Gould Department of Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK

Abstract Glycopeptides are among the most widely used agents for the treatment of serious infections caused by Gram-positive bacteria, with vancomycin recommended for the treatment of infections caused by β-lactam-resistant Staphylococcus aureus (MRSA). However, the utility of glycopeptides against MRSA has come into question owing to their poor tissue penetration, slow bactericidal activity and the emergence of strains with reduced susceptibility. A number of single-centre studies have demonstrated incremental increases in glycopeptide MICs for S. aureus strains over time – a phenomenon known as glycopeptide creep. High MICs have long been known to correlate with poorer clinical outcomes, but recent studies have shown that even small increases in MIC below the susceptibility breakpoint can affect the clinical efficacy of glycopeptides. The accurate measurement and ongoing surveillance of glycopeptide MICs at individual sites is therefore recommended to assist clinicians in their choice of empiric therapy for suspected serious S. aureus infections. Keywords: Glycopeptides; hVISA; MIC; MRSA; teicoplanin; vancomycin; VISA

1. Introduction The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial agent that inhibits the visible growth of a microorganism after overnight incubation in vitro; therefore, it can be used as a comparative measure of antimicrobial activity against a particular pathogen. Clinical microbiological guidelines categorize bacterial strains as susceptible, of intermediate resistance, or resistant to a particular antimicrobial agent on the basis of MICs. Accurate MIC measurement (susceptibility testing) and long-term surveillance are important in order to assess and monitor the susceptibility of strains detected in individual hospitals, which provides a guideline for the probable MIC of an individual isolate and thus assists the choice of empiric therapy. Glycopeptide antibiotics, which include vancomycin and teicoplanin, inhibit bacterial cell-wall synthesis. Vancomycin is one of the most widely used agents for the treatment of serious infections caused by Gram-positive bacteria [1], and is recommended for the treatment of infections caused by βlactam-resistant Staphylococcus aureus [2,3]. However, both agents have drawbacks that limit their clinical value, including poor tissue penetration, slow bactericidal activity and risk of nephrotoxicity with the doses needed to achieve suitable plasma trough levels [4].

Reduced susceptibility of S. aureus to vancomycin and teicoplanin has been definitively observed in recent years with the emergence of glycopeptide-resistant S. aureus (GRSA), glycopeptide-intermediate S. aureus (GISA) and heterogeneous GISA (hGISA) [5,6]. There is a growing body of evidence that shows the MICs of glycopeptides against S. aureus strains to be increasing incrementally, a process referred to as MIC creep. The clinical relevance of glycopeptide MIC creep has been investigated in a number of studies. Here, the evidence showing a relationship between increasing MIC and reduced glycopeptide efficacy against S. aureus is highlighted, with a focus on vancomycin.

2. How is MIC measured? There are a number of types of susceptibility test available, and the sensitivity and specificity of these can vary [7]; therefore, it is important to understand the techniques involved and how these techniques might be affected by properties of different antibiotics. All susceptibility testing methods act by exposing the bacterial strain to be tested to different concentrations of the antibiotic, usually in order to assess the minimum concentration at which the microbe is inhibited after 24 hours of incubation. An ideal test would allow precise determination of the MIC (e.g. it would not be

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reliant on 2-fold dilution) and would enable measurement and comparison of all antibiotics. Traditionally, agar disk diffusion has been used to measure glycopeptide susceptibility, but it is not now regarded as ideal as it does not measure the MIC directly. A number of paper disks, each impregnated with a calibrated concentration of antibiotic, are placed onto an agar plate inoculated with bacteria. A visible zone of growth-inhibition of susceptible bacteria will form around some disks according to their antibiotic concentration and the MIC or the organism. This method, however, is not suitable for large antibiotic molecules, such as glycopeptides and daptomycin, because they diffuse too slowly into agar [1]. The Etest has been developed as an accurate agar plate method. An Etest strip, which contains a gradient of antibiotic, is placed on an inoculated agar plate and the pattern of bacterial growth is examined after 24 hours. In using a gradient of antibiotic, the Etest has greater precision than disc diffusion methods, allowing better ascertainment of the actual MIC. It is also suitable for glycopeptides and other large antibiotic molecules [8]. An alternative method for measuring glycopeptide MIC is broth microdilution – the gold-standard test for measuring antibiotic MICs. Bacteria are grown in commercially available microtitre plates that contain a liquid medium and a range of dilutions of the test antibiotic. The lowest antibiotic concentration that completely inhibits bacterial growth after 24 hours is taken as the MIC. Automated susceptibility testing systems are also widely used, but the performance of these for measuring glycopeptide MICs has been questioned [9–11]. In a study assessing the MICs of methicillin-resistant S. aureus (MRSA) isolates to vancomycin, only 44% of strains with MIC = 2 µg/ml detected by broth microdilution were detected by the VITEK automated systems [10]. Similarly, in a study comparing Etest and VITEK for measuring teicoplanin susceptibilities, VITEK did not detect the 3 of 130 strains identified as being of intermediate resistance by Etest, and instead classified these as fully susceptible [11]. Thus, such systems might not have the required sensitivity to accurately determine MICs. Authorities such as the European Committee on Antimicrobial Susceptibility Testing (EUCAST) define threshold MICs or so-called ‘breakpoints’ to categorize bacterial isolates as susceptible, of intermediate resistance, or resistant. Considerations in the setting of these breakpoints include the population-distribution of MICs and the association between MIC and clinical efficacy. Breakpoints are used to give clinical meaning to MIC values and to provide clinicians with simple and practical guidance for antibiotic selection. However, the use of breakpoints in surveillance analyses could obscure changes in susceptibility that occur within the categories, which might have clinical relevance. Further, laboratories usually do not report absolute MICs in patient reports and only categorize isolates as susceptible, of intermediate resistance, or resistant; consequently, the true resistance patterns of S. aureus strains to antibiotics may be

underestimated in many populations and, in particular, subtle shifts in MIC may not be obvious.

3. Glycopeptide treatment of S. aureus infections – clinical outcomes The SENTRY surveillance program revealed S. aureus to be the leading cause of skin and soft-tissue infections (SSTIs), and the second most common causative organism for bacteraemia in Europe [12,13]. MRSA is of particular concern, as it is associated with greater mortality than methicillin-susceptible S. aureus (MSSA) [14,15]. Although vancomycin is the most widely used agent against Grampositive infections, against S. aureus, other agents have demonstrated equivalent and/or superior efficacy to vancomycin in clinical trials of MRSA and MSSA infections [16–23].

3.1 Skin and soft-tissue infections For the treatment of complicated SSTIs daptomycin showed equivalent efficacy to standard therapy, which comprised vancomycin for suspected MRSA infections and β-lactams for suspected MSSA infections (success rates for the clinically evaluable group were 83.4% for daptomycin patients and 84.2% for comparator patients) [16]. Among patients who were successfully treated with intravenous therapy alone, duration of therapy was significantly shorter for those treated with daptomycin compared with those receiving comparator agents (63% versus 33% requiring only 4–7 days of therapy, respectively, P<0.0001) [16]. For the treatment of SSTIs caused by MRSA, linezolid has shown equivalent or greater efficacy to vancomycin in a number of trials. For example, a small randomized, openlabel trial has demonstrated equivalent efficacy of the two agents, with clinical cure rates of 79.4% for linezolid and 73.3% for vancomycin (statistical significance not assessed) [17]; also, a larger, multicentre, multinational, randomized, open-label trial of patients with MRSA SSTIs requiring hospitalization showed significantly greater microbiological success for linezolid vs vancomycin (88.6% vs 66.9%; P<0.0001) 7 days after the end of treatment [18]. Linezolid has also been associated with significantly shorter hospital stays for complicated SSTIs than vancomycin [24].

3.2 Bacteraemia and infective endocarditis For the treatment of bacteraemia/infective endocarditis (IE) attributable to MSSA, vancomycin has shown inferior efficacy to β-lactams for a range of endpoints including mortality, persistent/recurrent infection and length of intensive care unit (ICU) stay (Table 1) [19,22,25,26]. Thus, β-lactams remain the agents of choice for MSSA and vancomycin is only advocated in patients with hypersensitivity to β-lactams.

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Table 1 Vancomycin vs β-lactam outcome in patients with MSSA bacteraemia/IE Reference

Study design

Endpoint measured

Outcome (vancomycin vs β-lactam)

Gentry et al. 1997 [19]

Retrospective study of 54 patients with MSSA IE

• Complication rate • ICU stay

1.72% vs 0.74%; P<0.05 11.7 vs 1.89 days; P<0.05

Chang et al. 2003 [25]

Prospective observational study of 98 patients with MSSA bacteraemia

• Bacteraemia persistent for >3 days • Bacteraemia persistent for >7 days • Bacteraemia relapse • Bacteriologic failure

21% vs 6%* 11% vs 0%* 7% vs 0%* 19% vs 0%; P=0.058

Lodise et al. 2007 [26]

72 intravenous drug users with MSSA IE treated in a US hospital

• Infection-related mortality

39.3% vs 11.4%; P<0.005

Stryjewski et al. 2007 [22]

Prospective study of 123 haemodialysis patients with MSSA bacteraemia

• Treatment failure at 12 weeks • Death at 12 weeks • Recurrent infection at 12 weeks

31% vs 13%; P=0.02 10% vs 4%; P=0.32 21% vs 9%; P=0.08

*Significance not reported.

For MRSA bacteraemia/IE, vancomycin is considered the gold-standard treatment. However, there have been recent reports of treatment failures against vancomycinsusceptible strains [27,28]. In one study, glycopeptide therapy failed in 19/25 patients with infections caused by MRSA that conformed to definitions of VISA or hVISA by population analysis profiling [27]. S. aureus bacteraemia was detected in fifteen of these patients after 7 days of glycopeptide therapy, and S. aureus was isolated in 4 patients from a sterile site after 21 days. A separate study showed vancomycin treatment to fail in 5/5 MRSA patients with VISA, compared with 1/48 patients with vancomycinsusceptible MRSA [28]. Alternative treatments to vancomycin may be considered for the empiric therapy of suspected MRSA bacteraemia/IE before the MIC and the presence of VISA or hVISA have been determined. Daptomycin has shown equivalent efficacy to vancomycin against MRSA bacteraemia/IE and might provide an alternative treatment option. In a pre-specified analysis of a phase III bacteraemia/IE trial, daptomycin had a higher success rate (44%) than vancomycin plus gentamicin (33%) in the treatment of fully vancomycin susceptible MRSA bacteraemia, although the difference was not statistically significant [23]. Daptomycin is also as effective as standard therapy against MSSA bacteraemia/IE [29]. An antibiotic that has high clinical efficacy against both MSSA and MRSA infections is of particular value as an alternative to vancomycin, given that suspected S. aureus infections are often treated empirically and the consequences of inappropriate antimicrobial use, such as vancomycin for an infection later confirmed to be MSSA, can be severe. For example, one study showed that in critically ill patients with bloodstream infections, inappropriate therapy was associated with a mortality rate of 61.9%, compared with 28.4% for patients treated appropriately (P<0.001) [30]. Linezolid is not licensed for the treatment of S. aureus bacteraemia/IE and has been associated with excess

mortality compared with vancomycin or a combination of oxacillin/dicloxacillin in patients with Gram-negative catheter-related bloodstream infections [31].

4. S. aureus with reduced susceptibility to glycopeptides In response to growing concern in the early 1990s about the emergence of glycopeptide resistance in enterococci, infection-control guidelines advocated that all S. aureus strains undergo susceptibility testing [32]. In recent years, GISA and hGISA isolates have emerged, and a small number of cases of GRSA have also been reported [5,6]. Years of glycopeptide under-dosing – owing to fears of toxicity – coupled with the poor penetration of glycopeptides into tissues (e.g. lung and endocardial tissue), is thought to have played a part in the emergence of reduced susceptibility by exposing S. aureus to subinhibitory concentrations of vancomycin [9,33,34]. Glycopeptides are also only weakly bactericidal, and this might also have contributed to the development of strains with reduced susceptibility. In 2006, the Clinical and Laboratory Standards Institute (CLSI) lowered the S. aureus vancomycin susceptibility breakpoint from 4 µg/ml to 2 µg/ml in response to evidence that vancomycin has reduced efficacy against isolates with MIC ≥ 4 µg/ml [35,36]. The resistance breakpoint was also lowered (from 32 µg/ml to 16 µg/ml), reflecting clinical judgement that S. aureus strains with MIC ≥ 16 µg/ml are fully resistant to vancomycin. The reduction of these breakpoints has also resulted in the redefinition of intermediate resistance as those strains with MIC between 4 µg/ml and 8 µg/ml. The current CLSI breakpoints are shown in Table 2. It has been suggested, however, that these breakpoints are still too high and further reduction might further help us to examine how susceptibilities are changing over time [9].

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Table 2 CLSI susceptibility breakpoints for vancomycin [35] Pathogen

Susceptibility

MIC breakpoint (µg/ml)

VSSA

Susceptible

≤2

hVISA

Heteroresistant

1–2a

VISA

Intermediate

4–8

VRSA

Resistant

≥16b

a

Consists of subpopulations (≤ 1 in 1,000,000) that may grow in media with > 2 µg/ml of vancomycin b Requires backup primary testing with 6 µg/ml of vancomycin on an overnight plate

mixed susceptibilities need to be quantified. Liu and Chambers [5] discuss a number of approaches, including population analysis profiling, but conclude that without a standardized, validated method for detecting hVISA, the prevalence and clinical significance of hVISA cannot be accurately addressed. Furthermore, strains assayed prior to the introduction of reduced CLSI MIC breakpoints in 2006 would be subject to less stringent categorization than they would be today. It is clear from retrospective studies and testing of previously isolated strains that the presence of VISA and hVISA was overlooked prior to 1996. Also, with the variation in effectiveness of susceptibility tests used, and without consensus on how hVISA MICs should be measured, it is difficult to gauge the true extent of vancomycin resistance and reduced susceptibility today.

4.1 VRSA 5. Vancomycin MIC creep Seven cases of vancomycin-resistant S. aureus (VRSA) isolated from patients with bacteraemia and IE have been documented to date: the first was reported in 2002 [37]. VRSA strains are still rare, but on the basis of other trends, their incidence is likely to increase. A mathematical model based on susceptibility data from a single hospital (1997–2003) predicted that, although all strains were susceptible to vancomycin in the study period, VRSA strains would emerge by 2009 if the rate of susceptibility decrease continued [38].

4.2 VISA and hVISA The first case of VISA was reported in Japan in 1997 [5], but retrospective literature searches and testing of previously isolates strains show that VISA strains arose much earlier [1]. Approximately 100 cases have now been reported [39], from diverse geographic locations (Europe, South America, Asia and the US) [1]. hVISA is regarded as a precursor to VISA [5]: it comprises a heterogeneous population of S. aureus cells with an overall MIC in the susceptible range (i.e. < 2 µg/ml), but with non-susceptible subpopulations (i.e. with an overall MIC ≥ 4 µg/ml) detectable after selection with vancomycin. The first case of hVISA was reported in Japan in 1996 [5], but current prevalence is unknown. A meta-analysis of 14 studies published between 1997 and 2001 calculated an overall prevalence of 1.67% (192 out of 7920 strains tested) [5]. This consisted of 2.16% among MRSA strains and 0.05% among MSSA strains. However, individual studies within this meta-analysis reported prevalences ranging from 0% to 74%, highlighting the high inter-site variability in vancomycin susceptibility. A complicating factor in reporting the prevalence of VISA and hVISA is that the sensitivity and specificity of susceptibility tests for detecting hVISA and VISA vary [7]. hVISA, which consists of a population of cells with mixed susceptibilities, is particularly difficult to measure, as these

Population shifts in vancomycin MIC against S. aureus strains over time – ‘MIC creep’ – have been noted in a number of single-centre studies in the past decade [8,38,40]. Steinkraus et al. [8] used Etests to investigate whether MIC creep was occurring in vancomycin and comparator antibiotics between 2001 and 2004 in a single US hospital. Overall, MICs significantly increased over the 5-year period for vancomycin, linezolid and oxacillin, and declined slightly for daptomycin (Table 3) [8]. For vancomycin (Figure 1) and linezolid, this MIC creep occurred within the range of MICs considered susceptible, but further creep could conceivably shift MICs into the nonsusceptible zone. This highlights the importance of using sensitive MIC surveillance methods that are capable of capturing small incremental changes, because these could have clinical significance over time. Examining the components of vancomycin MIC creep reveals that there has been a large increase in the proportion of strains with MIC = 1 µg/ml – more than 3-fold in studies by Steinkraus et al. (Figure 2A) [8] and Wang et al. (Figure 2B) [40]. At the same time, the proportion of strains with MIC ≤ 0.5 µg/ml has been decreasing to a similar extent (Figure 2A,B), such that the mean and median MIC has shifted over time [8,40]. Outside the susceptible range, a small increase in the proportion of strains with MIC ≥ 2 µg/ml was observed by Wang et al. [40] (0.2% in 2001 to 0.8% in 2004; Figure 2B), although Steinkraus et al. [8] did not isolate any non-susceptible strains. MICs ≥ 2 µg/ml have been reported elsewhere, however, with the highest prevalence reported from a study of hospitals in Las Cruces, NM, USA: 35/43 of strains had an MIC ≥ 2 µg/ml and 12 of these had MICs of 3 µg/ml [41]. In the Wang et al. study [40], MIC creep was also examined individually in MSSA and MRSA, and an increase in the proportion of strains with MIC = 1 µg/ml was apparent for both between 2000 and 2004. It should be noted that

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Table 3 Deviation of antibiotic MIC over time from the 2001 median [8] Isolates with MIC ≤ 2001 median MIC (%), by year

Vancomycin Linezolid Daptomycin Oxacillin

2001 Median MIC (µg/ml)

2001

2002

2003

2004

2005

P-value

0.75 0.5 0.25 128

84 72 54 67

76 82 55 48

48 77 53 38

29 60 51 28

24 41 66 36

<0.0001 <0.0001 0.1361 <0.0001

Fig. 1. Vancomycin ‘MIC creep’ over 5 years in the New Hanover Regional Medical Center, NC, USA [8]

although the prevalence of strains with MIC = 1 µg/ml was higher for MRSA than MSSA at all timepoints, the proportion of MSSA strains with MIC = 1 µg/ml increased the most dramatically over the 5-year period. Vancomycin is not recommended for the treatment of MSSA owing to poor outcomes. Suboptimal treatment of MSSA infections with vancomycin can provide the selective pressure for strains with reduced susceptibility to evolve. Thus it appears that the rate of vancomycin creep varies greatly between sites, perhaps owing to the different selective pressures present (e.g. magnitude of vancomycin use, dosage, appropriateness of use) and/or inter-study differences in patient populations and susceptibility testing methodology. This may explain why MIC creep has not been noted in large studies such as SENTRY, where the pooling of data from multiple sites could have obscured trends in individual sites [1]. Site-specific surveillance is crucial for guiding clinicians on the probable susceptibility of S. aureus infections to vancomycin in their patients, and for helping to predict future local trends. There are a number of reasons why vancomycin MICs may be increasing. As discussed, years of exposing strains to subinhibitory concentrations of vancomycin is thought to be a key factor and, within an individual patient, prior exposure to vancomycin appears to be important. An examination of 700 S. aureus bacteraemia isolates from three New York hospitals showed that exposure to vancomycin in the previous 3 months was associated with significantly higher incidence of MIC = 2 µg/ml than no previous exposure (50.8% vs 28.4%; P=0.001) [42]. Supporting this, a recent

Figure 2. Vancomycin MIC creep over 5 years in two US hospitals: (A) New Hanover Regional Medical Center, NC [8] and (B) UCLA Medical Center, CA [40]

multivariate analysis of 105 patients with MRSA bacteraemia identified prior vancomycin exposure as one of three significant independent predictors of MIC values ≥ 1.5 µg/ml [43]. The other two independent predictors were prior antibiotic exposure and whether the isolate was collected while the patient was in ICU. Finally, empiric use of vancomycin may also influence MIC creep in MSSA by exposing strains to inappropriate treatment.

6. Relationship between MIC and glycopeptide efficacy There is a growing body of evidence indicating that glycopeptide MIC has a real impact on patient outcomes. Recent studies have shown higher MICs to be correlated with lower vancomycin success against MRSA. In a small study examining MRSA bloodstream isolates from 30 patients, there was a 56% success rate of vancomycin against strains with vancomycin MIC of 0.5 µg/ml compared with a 9.5% success against strains with vancomycin

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Figure 3. Vancomycin success by MIC in two studies [44,45]

MIC = 1–2 µg/ml (Figure 3A; P=0.01) [44]. Similarly, success rates were considerably higher for strains with vancomycin MIC of 0.5 µg/ml when compared with vancomycin MICs of 1 µg/ml and 2 µg/ml in a study of MRSA isolated from 63 patients (Figure 3B; P=0.004) [45]. Achievement of serum unbound vancomycin trough concentrations of 4–5 × MIC or a 24-hour area under the concentration curve to MIC ratio (AUC24/MIC) of 400 is considered optimal for bacterial eradication and clinical success [46]. As MIC increases, greater doses are required to achieve the corresponding increases in exposure to vancomycin necessary to maintain the target AUC24/MIC ratio. Attaining target AUC24/MIC is important as it may affect clinical outcomes. In a study of 32 patients with S. aureus lower respiratory tract infections, median time to bacterial eradication was significantly shorter in patients attaining AUC24/MIC ≥ 400 than in those who did not attain this level (10 days vs > 30 days; P=0.0402) [46]. However, increasing vancomycin dose to attain the target trough level in patients with higher MICs may not compensate in terms of outcomes, even against strains within the vancomycin-susceptible range. Data from a study of 79 patients by Hidayat et al. [47] show that a higher MIC is associated with a less favourable end response, notwithstanding achievement of target trough levels (clinical response 85% vs 62% for MIC ≤ 1 µg/ml and MIC = 2 µg/ml groups, respectively, P=0.02). In a separate study of 34 MRSA bacteraemia patients treated with vancomycin, in whom trough levels of 8–12 µg/ml were attained, higher vancomycin MICs were associated with a delay in bacterial eradication [48]. Median time to eradication was 6 days for strains with MIC = 0.5 µg/ml, compared with 9.5 days for MIC = 1 µg/ml and >15 days for MIC = 2 µg/ml. By the end of vancomycin therapy, bacteraemia was completely eradicated in a similarly high proportion of patients with MICs of 0.5 µg/ml and 1 µg/ml (77% and 71%, respectively), but in only 21% of patients with an MIC of 2 µg/ml. Higher vancomycin MICs have also been associated with higher mortality rates [49,50]. In a multivariate regression

analysis of 414 episodes of MRSA bacteraemia diagnosed in a single hospital over 15 years, the risk of death significantly increased with increasing MIC (Figure 4) [49]. Inappropriate empiric therapy was associated with a risklevel similar to that of having MIC = 2 µg/ml. A separate study of 50 haemodialysis patients with MRSA bacteraemia treated with vancomycin showed an in-hospital mortality rate of 24% for patients with strains of MIC ≤ 0.5 µg/ml compared with 35% for those with MIC = 2 µg/ml [50]. Patients within the higher MIC group stayed longer on average in hospital (24 vs 17 days) and in the ICU (16 vs 5 days). This translated to considerably higher mean hospitalization costs for the MIC = 2 µg/ml vs MIC ≤ 0.5 µg/ml group ($26,792 vs $47,624). It is important to note that the studies summarized here clearly show that amongst vancomycin-susceptible S. aureus strains, those with higher MICs are associated with poorer clinical outcomes. As discussed, not all susceptibility methods are sensitive enough to detect MICs lower than 2 µg/ml. These data highlight the importance of determining precise MICs, even below the susceptibility breakpoint, as changes below this threshold can have clinical significance.

7. Activity of antibiotic agents against VISA and hVISA The in vitro activities of a number of antibiotic agents against VISA and hVISA strains have been examined, although the clinical efficacy of such agents has not yet been established in the published literature. In the SENTRY surveillance program, lower MIC values were measured for daptomycin (0.12–2 µg/ml) compared with vancomycin (1–8 µg/ml) against hVISA and VISA, as well as vancomycin-susceptible MRSA and MSSA [51]. In time–kill experiments in two GISA and one hGISA strain, daptomycin at 2 × MIC demonstrated bactericidal activity throughout the 24-hour measurement period and displayed 99.9% kill by 8 hours in all three strains [52]. Arbekacin and tigecycline also showed activity against these strains over

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Figure 4. Vancomycin MIC and risk of mortality [49]. *Inappropriate therapy defined as empirical therapy to which the MRSA strain was resistant

24 hours, whereas in contrast, vancomycin displayed no activity at the 24-hour timepoint. There has been some concern that S. aureus strains with reduced susceptibility to vancomycin may also have reduced susceptibility to daptomycin. In the MIC surveillance study by Steinkraus et al. [8], daptomycin MICs did not increase over the 5-year period, despite vancomycin MICs incrementally increasing, suggesting that cross-resistance was not occurring. If we look above the susceptibility breakpoint, all VRSA strains identified to date have been susceptible to daptomycin [53], but a proportion of VISA isolates have shown reduced daptomycin susceptibility [53–55]. Reduced susceptibility in some VISA strains may be a result of adaptive modifications such as thickened cell walls, reducing antibiotic penetration – other resistance mechanisms such as vanA-mediated resistance should not influence susceptibility to agents with a different mode of action to vancomycin. In a recent study of 81 patients with MRSA bacteraemia, prior vancomycin exposure within 30 days was associated with significantly higher vancomycin MICs and reduced vancomycin killing activity in vitro [56]. In contrast, there was only a trend towards higher daptomycin MICs with previous vancomycin exposure, and daptomycin retained its full in vitro bactericidal activity [56]. That previous vancomycin exposure does not affect a reduction in the bactericidal activity of daptomycin is supported by a separate study of VISA isolates [55]. Other antibiotics have also shown activity in VISA and hVISA; in a comparison of eight licensed antibiotics, linezolid and quinupristin/dalfopristin were the only agents to demonstrate potent activity against VISA and hVISA [57]. The MICs for linezolid were consistently low (0.25–2 µg/ml), whereas the MICs for quinupristin/dalfopristin were more variable (0.25–16 µg/ml).

8. Summary Glycopeptides were the gold-standard treatment for MRSA infections, but in recent years MRSA/MSSA strains with reduced susceptibility to glycopeptides have emerged,

including seven cases of VRSA and over 100 cases of VISA and hVISA. Furthermore, MIC creep has been reported in strains categorized as susceptible to vancomycin in a number of single-centre studies, and has been observed in both MSSA and MRSA. MIC creep has consequences for efficacy, with poorer outcomes against MRSA observed with higher vancomycin MICs, even below the susceptibility breakpoint. The empirical use of vancomycin against Gram-positive infections should be carefully considered in the context of local vancomycin MIC data and, where possible, local MIC trends should be taken into account. Where vancomycin MIC is >1 µg/ml, alternative therapies should be considered to avoid the possibility of treatment failure. Precise determination of MIC, as well as regular surveillance are therefore of key importance because even small changes in MIC can have clinical significance.

Acknowledgements The author would like to thank RA Higgins of Chameleon Communications International for editorial support in the preparation of the manuscript, with financial support from Novartis Pharma AG. Competing interests: Dr Gould has received financial support from the following companies who have treatment for MRSA infections: Johnson & Johnson; Novartis; Pfizer; Phico therapeutics; Wyeth. Ethical approval: not required.

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