The clinical significance of hVISA and VISA has been difficult to assess. It is unknown whether these strains are fully virulent or perhaps even more virulent than vancomycin-susceptible strains of S. aureus
and whether levels of resistance are responsible for treatment failures. A variety of complicating factors make it difficult to ascertain whether the reported deaths in patients with VISA infections are directly attributable to the organism. For example, a patient in Illinois with VISA mitral valve endocarditis died while bacteremic from VISA but had refused surgical intervention (6
Treatment failures with vancomycin may occur fairly commonly even with vancomycin-susceptible S. aureus
(VSSA) strains. Moise and Schentag (27
) reviewed 23 cases of vancomycin treatment failures in lower respiratory tract S. aureus
infections, representing a treatment failure rate of 40% in their institution over a 1-year period. In each case, the vancomycin MIC for the organism was within the susceptible range and the vancomycin concentration in serum was shown to be in the therapeutic range. Several of these patients received multiple courses of vancomycin as their infections relapsed upon discontinuation of the antibiotic. The isolates recovered in this study were not tested to determine if they might be hVISA.
Since the recognition of hVISA and VISA, it has been suggested that hVISA strains are responsible for clinical failures to vancomycin treatment of otherwise apparently susceptible S. aureus
strains. Ariza et al. (1
) reported that 86% (12 of 14) of orthopedic surgery patients with MRSA infections whose isolates tested positive for hVISA experienced treatment failure compared to 20% (1 of 5) of patients with MRSA-positive and hVISA-negative infections. For all of these MRSA strains, the vancomycin MICs were between 1 and 4 μg/ml. However, the interpretation of the results of this study was complicated by the presence of implanted orthopedic devices in 12 of the 13 failures and in 13 of the 14 hVISA-infected patients. The only hVISA-negative patient who experienced treatment failure had an implanted device; none of the four hVISA-negative patients who were cured had devices in place.
Moore et al. (28
) found that hVISA was associated with treatment failure in a patient with endocarditis. Paired S. aureus
isolates (the pretreatment and relapse clinical isolates) from this patient were tested. Both strains had similar genotypes, and the vancomycin MICs for both strains were ≤2 μg/ml; however, population analysis determined that the second isolate exhibited heterogeneous resistance to vancomycin. The strains were further tested with a rabbit model of endocarditis in which the pretreatment isolate was eradicated by vancomycin while the relapse hVISA isolate was not, suggesting that vancomycin treatment failure in this case was due to heterogeneous resistance.
The properties of the drug itself may be sufficient to account for these observed treatment failures. In vitro, its activity falls between that of classically bacteriostatic drugs, such as tetracyclines, and that of bactericidal drugs, such as penicillins. Vancomycin is less rapidly bactericidal than antistaphylococcal penicillins, such as nafcillin, and is therefore less efficacious for the treatment of methicillin-susceptible staphylococcal (MSSA) infections (33
). Patients with MRSA endocarditis treated with vancomycin have a delayed clinical response to the drug, as evidenced by prolonged bacteremia and sustained fever, compared to that of patients with MSSA endocarditis treated with beta-lactams (25
Whether vancomycin failure is due to an intrinsic property of the drug, the virulence of the organism itself, or perhaps some combination of both continues to be an area of much controversy. Further studies are needed to evaluate the relevance of hVISA in patients with clinical failure to vancomycin. In order to conduct such studies, a means of accurately identifying these strains is essential.