Glycopeptides have been the mainstay of treatment for MRSA infections and staphylococcal infections in patients with true penicillin allergy. Glycopeptides are less bactericidal than β-lactam agents, and penetration into tissues is poor. Vancomycin has been reported to clear bacteraemia in patients with endocarditis more slowly than β-lactams, i.e. 7 days vs. 3.4 days in nafcillin-treated patients , and has been found to be associated with higher infection-related mortality than β-lactams in treatment of endocarditis caused by MSSA . For these and other reasons, a number of recent reports have called into question the efficacy of this class of antimicrobials in the treatment of severe MRSA infections. Higher rates of relapse, complications, treatment failure and mortality in cases of MRSA bacteraemia and endocarditis have been associated with vancomycin therapy. Increasing the dose of vancomycin may not safely overcome its limited bactericidal activity, and its combination with a second antistaphylococcal agent does not improve its therapeutic efficacy (mortality being the outcome measure). MRSA strains with lower vancomycin MIC values have been associated with increased rates of treatment success with vancomycin as compared with strains that have higher vancomycin MIC values, whereas increased MICs of vancomycin for S. aureus may be predictive of increased treatment failure (30-day mortality) and longer duration of bacteraemia in patients receiving vancomycin therapy [6,7].
Decreasing activity of glycopeptide antimicrobials
Despite more than 50 years of treatment with vancomcyin, fully vancomycin-resistant strains (vancomycin-resistant S. aureus (VRSA)) are still an anecdotal phenomenon, with fewer than ten strains having been described, mainly in the USA, but also abroad [8,9]. These strains have been associated with only limited clinical consequences, because they have not been associated with invasive disease.
VRSA and vancomycin-intermediate S. aureus (VISA) are usually cross-resistant to teicoplanin . VISA and heteroresistant VISA strains of S. aureus that contain subpopulations of daughter cells displaying intermediate sensitivity to vancomycin, but for which the MICs of vancomycin fall within the susceptible range, can be difficult to detect in the microbiology laboratory, because the phenotypes are unstable and can be lost on subsequent passages.
The role of tolerance to vancomycin in S. aureus has not been well clarified. It is more frequently associated with MRSA than with MSSA and in isolates from patients with endocarditis . Whether tolerance is a prerequisite for attenuated vancomycin efficacy and the development of glycopeptide resistance warrants further study. Part of the intermediate glycopeptide resistance seen in VISA may be due to tolerance . Several small series and case studies have reported poor clinical response to vancomycin in the treatment of bacteraemia/endocarditis caused by vancomycin-tolerant S. aureus and the need for additional agents for a bactericidal effect [13–15].
Teicoplanin is used in several European countries as the main glycopeptide. The MIC90 of teicoplanin is greater than that of vancomycin. The protein-binding ability of teicoplanin is approximately 92%; however, bactericidal activity depends on the total drug level of teicoplanin rather than on the concentration of the free drug. Teicoplanin is usually seriously underdosed, and a loading dose is needed. Trough concentrations should be maintained at c. 20 mg/L. Teicoplanin-intermediate S. aureus may now be more common than VISA, but its clinical impact has not been studied systematically.
There is growing evidence of a vancomycin MIC creep in various MRSA isolates. For example, a study from UCLA Medical Center showed that, among the 6002 clinically relevant MRSA isolates tested, there was a shift in vancomycin MICs from ≤0.5 to 1.0 mg/L during the 5-year study period. The percentage of S. aureus isolates with a vancomycin MIC of >1 mg/L in 2004 was significantly higher than the percentage of isolates in 2000 (70.4% vs. 19.9%; p <0.01). This shift in vancomycin MIC value was more notable in MSSA . In another recent study from the south of the USA, 90% of the strains demonstrated vancomycin MICs of >2.0 mg/L according to Etest, and 12% demonstrated a vancomycin MIC of 3.0 mg/L .
Most unfortunately, there is a poor correlation between MICs obtained by Etest and those obtained by microdilution procedures, and MICs may vary significantly between two different determinations. It is important to realize the important limitations of the clinical laboratory in detecting reduced susceptibility and resistance to vancomycin, and the reader is referred to the review in this issue by Struelens et al. for further discussion. On the other hand, it should be realized that vancomycin creep is not a universal phenomenon, and that vancomycin MICs have been found to be stable over time by other investigators [18,19].
There is some evidence for the clinical impact of increased vancomycin MICs. The vancomycin success rate in treating MRSA bacteraemia was found to be much higher for isolates with MICs of ≤0.5 mg/L (56%) than for isolates with MIC values of 1.0–2.0 mg/L (10%) [7,20]. Also, in a recent study from Spain, mortality associated with MRSA bacteraemia was significantly higher when vancomycin was used empirically for treatment of infection with strains with a high vancomycin MIC (>1 mg/L) . Other recent reports have linked clinical failure with vancomycin treatment of infections involving strains with MICs of 2–4 mg/L or heteroresistant VISA strains [6,7,20–23]. The CLSI therefore lowered the vancomycin breakpoint for S. aureus susceptibility from 4 to 2 mg/L in 2006.
Clinical MRSA strains with high vancomycin MIC values (2 mg/L) require aggressive empirical therapy to achieve trough concentrations ≥15 mg/L.
This can be achieved with continuous perfusion of vancomycin, a concept that has become popular in many European countries, in particular in the intensive-care unit (ICU) setting. However, not all studies were able to show that achieving a vancomycin trough in excess of 15 mg/L improved success rates .
In summary, vancomycin is recommended for empirical therapy in healthcare settings with an increased incidence of methicillin-resistant staphylococci or when risk factors for MRSA infections are present, such as MRSA-positive surveillance cultures. Although high-level resistance remains rare, data from some centres suggest an evolutionary change in S. aureus, as evidenced by reduced susceptibility to vancomycin. This, together with the problem of heteroresistance to vancomycin, as well as poor tissue penetration after systemic administration, presents potential obstacles to the successful treatment of S. aureus infections with this glycopeptide. Although it has been suggested that these problems may be overcome by administration of vancomycin in much higher doses by continuous perfusion, the efficacy and safety of this approach remain to be determined.
The subgroup of patients with infections due to strains with vancomycin MIC values of >1 mg/L can be managed by alternative therapy, with the combination of vancomycin and other drugs, or by providing doses of vancomycin high enough to achieve trough levels >15 mg/L. However, the risk with higher dosages is an increase in nephrotoxicity.