Top 10 issues in hospital medicine for 2008, issue 7: emerging problems in the treatment of MRSA

We live with the fear that suddenly, one day, we will wake up to find vancomycin resistant Staphylococcus aureus (VRSA) in our community. Although rare reports of the sudden appearance of high level vancomycin resistance due to the vanA gene known to cause vancomycin resistance in enterococci have surfaced, the reality is that the major threats are different: vancomycin is gradually wearing out its welcome, by multiple mechanisms, while new strategies evolve. Hospitalists must be aware of these mechanisms and evolving strategies.

The mechanisms:

There are inherent weaknesses in vancomycin compared to beta lactam antibiotics. This relates to less effective killing action and a narrower therapeutic window for vancomycin. This is not a new problem, and accounts for higher mortality in MRSA infections (in which vancomycin is usually administered) than in MSSA infections (in which beta lactam antibiotics are used). This issue is reviewed here.

Vancomycin treatment failures increase in proportion to increasing MICs even well within the “sensitive” range below 2 mcg/ml.

Transient heteroresistance to vancomycin, in which small subpopulations of organisms show vancomycin MICs in the intermediate range, is common and may lead to treatment failure in patients whose isolates test “sensitive”.

Vancomycin tolerance, defined as a wide discrepancy between the MIC and MBC, may lead to treatment failure in patients whose isolates test “sensitive”.

Traditional vancomycin dosing regimens have resulted in low trough levels. This can lead to treatment failure, since vancomycin’s effectiveness is time dependent rather than peak concentration dependant.

Poor penetration of vancomycin in lung tissue, requiring trough levels several fold above MIC.

These concerns have led to a lowering of the vancomycin sensitivity breakpoints for MRSA.

Evolving strategies:

Aiming for higher vancomycin trough levels. Although newer vancomycin preparations have been considered relatively non toxic, recent trends in higher dosing may be producing nephrotoxicity.

Use of other older antibiotics such as trimethoprim/sulfa, clindamycin and tetracyclines. In contrast to HA-MRSA, CA-MRSA isolates are usually sensitive to these antibiotics. Their use as an alternative to vancomycin in serious MRSA infections has been limited, has not been validated in high level studies, and is controversial.

Newer agents. Linezolid has been suggested as an alternative to vancomycin for pneumonia. The jury is still out. Daptomycin has been found non-inferior in intravascular infections. It is not effective against pneumonia. Tygecycline has efficacy against MRSA but is not approved for a wide variety of clinical indications. Limitations are that it is bacteriostatic and may not be effective against infections in which bacteriocidal activity is required. Moreover, serum levels tend to be low, a possible limitation in bacteremic infections.

Acknowledgment: Several issues raised here were covered by Dr. James Pile in his presentation at SHM 2008, which was the inspiration for this post.