Later trials using purer forms of vancomycin found nephrotoxicity is an infrequent adverse effect (0.1% to 1% of patients), but this is accentuated in the presence of aminoglycosides. Rare adverse effects (<0.1% of patients) include: anaphylaxis, toxic epidermal necrolysis, erythema multiforme, red man syndrome, superinfection, thrombocytopenia, neutropenia, leukopenia, tinnitus, dizziness and/or ototoxicity, and DRESS syndrome. Vancomycin can induce platelet-reactive antibodies in the patient, leading to severe thrombocytopenia and bleeding with florid petechial hemorrhages, ecchymoses, and wet purpura. Vancomycin has traditionally been considered a nephrotoxic and ototoxic drug, based on observations by early investigators of elevated serum levels in renally impaired patients who had experienced ototoxicity, and subsequently through case reports in the medical literature. However, as the use of vancomycin increased with the spread of MRSA beginning in the 1970s, the previously reported rates of toxicity were recognized as not being observed. This was attributed to the removal of the impurities present in the earlier formulation of the drug, although those impurities were not specifically tested for toxicity. Subsequent reviews of accumulated case reports of vancomycin-related nephrotoxicity found many of the patients had also received other known nephrotoxins, in particular, aminoglycosides. Most of the rest had other confounding factors, or insufficient data regarding the possibility of such, that prohibited the clear association of vancomycin with the observed kidney dysfunction. In 1994, the use of vancomycin monotherapy was clearly documented in only three of 82 available cases in the literature. Prospective and retrospective studies attempting to evaluate the incidence of vancomycin-related nephrotoxicity have largely been methodologically flawed and have produced variable results. The most methodologically sound investigations indicate the actual incidence of vancomycin-induced nephrotoxicity is around 5% to 7%. To put this into context, similar rates of kidney dysfunction have been reported for cefamandole and benzylpenicillin, two reputedly non-nephrotoxic antibiotics. In addition, evidence to relate nephrotoxicity to vancomycin serum levels is inconsistent.