Vancomycin Research & Studies

Vancomycin and related glycopeptides are drugs of last resort for the treatment of severe infections caused by Gram-positive bacteria such as Enterococcus species, Staphylococcus aureus, and Clostridium difficile. Vancomycin was long considered immune to resistance due to its bactericidal activity based on binding to the bacterial cell envelope rather than to a protein target as is the case for most antibiotics. However, two types of complex resistance mechanisms, each comprised of a multi-enzyme pathway, emerged and are now widely disseminated in pathogenic species, thus threatening the clinical efficiency of vancomycin. Vancomycin forms an intricate network of hydrogen bonds with the d-Ala-d-Ala region of Lipid II, interfering with the peptidoglycan layer maturation process. Resistance to vancomycin involves degradation of this natural precursor and its replacement with d-Ala-d-lac or d-Ala-d-Ser alternatives to which vancomycin has low affinity. Through extensive research over 30 years after the initial discovery of vancomycin resistance, remarkable progress has been made in molecular understanding of the enzymatic cascades responsible. Progress has been driven by structural studies of the key components of the resistance mechanisms which provided important molecular understanding such as, for example, the ability of this cascade to discriminate between vancomycin sensitive and resistant peptidoglycan precursors. Important structural insights have been also made into the molecular evolution of vancomycin resistance enzymes. Altogether this molecular data can accelerate inhibitor discovery and optimization efforts to reverse vancomycin resistance. Here, we overview our current understanding of this complex resistance mechanism with a focus on the structural and molecular aspects.

Vancomycin use is often associated with nephrotoxicity. It remains uncertain, however, to what extent vancomycin is directly responsible, as numerous potential risk factors for acute kidney injury frequently coexist. Herein, we critically examine available data in adult patients pertinent to this question. We review the pharmacokinetics/pharmacodynamics of vancomycin metabolism. Efficacy and safety data are discussed. The pathophysiology of vancomycin nephrotoxicity is considered. Risk factors for nephrotoxicity are enumerated, including the potential synergistic nephrotoxicity of vancomycin and piperacillin-tazobactam. Suggestions for clinical practice and future research are given.

A case of vancomycin-induced neutropenia is presented with a review of other reported cases in the literature. A 59-year-old white female was started on vancomycin therapy for a chronic infection of a total left hip replacement. After 38 days of treatment, the patient developed a severe leukopenia with a white blood cell count of 1700/mm3 and the presence of only occasional neutrophils. Upon discontinuation of vancomycin, the leukocyte and neutrophil counts promptly increased with full recovery in one week. Subsequently, the patient was restarted on a five-day course of vancomycin at a lower dose that proved uneventful with no recurrence of neutropenia. It is unclear whether the neutropenia would have recurred with a longer course of vancomycin. A review of the literature suggests that an immunologic mechanism may be responsible for the reaction. Physicians and other health professionals should be aware that neutropenia is a potential reaction of patients receiving prolonged vancomycin treatment.

Vancomycin, virtually discarded after development of antistaphylococcal penicillins, has recently been receiving renewed attention. There are several clinical situations in which it appears to offer advantages over other available antimicrobial agents: infections due to methicillin-resistant staphylococci; bacterial endocarditis in patients allergic to penicillin; staphylococcal enterocolitis; staphylococcal infection in patients undergoing hemodialysis; infections caused by penicillin-resistant diphtheroids; and prophylaxis of bacterial endocarditis in patients with prosthetic valves or penicillin allergy. Its penetration into the cerebrospinal fluid suggests that vancomycin may be useful in treating certain infections of the central nervous system. Although its ototoxic and nephrotoxic potential cannot be ignored, these problems can be minimized by keeping the serum concentration at the proper level.