Current Drug Therapy

Vancomycin: A 50-something-year-old antibiotic we still don’t understand

Author and Disclosure Information

ABSTRACTBecause a significant proportion of Staphylococcus aureus strains as well as most coagulase-negative staphylococci are resistant to penicillin and semisynthetic beta-lactam drugs, the need for vancomycin and related antibiotics has never been greater. Effective use of vancomycin requires knowledge of dosing parameters and selection of target trough levels appropriate to the specific infection and to the pathogen being treated. For clinicians, it is vital to remain up-to-date with evolving definitions for vancomycin susceptibility, with new interpretations of efficacy, and with information on toxicity.

KEY POINTS

  • Giving vancomycin by continuous infusion appears to offer no advantage over giving it every 12 hours.
  • Therapeutic blood levels can be reached more quickly if a loading dose is given, but whether this offers a clinical advantage is unclear.
  • The trough vancomycin serum concentration should be greater than 10 mg/L to prevent the development of resistance, and trough levels of 15 to 20 mg/L are recommended if the minimum inhibitory concentration (MIC) is 1 mg/L or higher.
  • Whether S aureus is becoming resistant to vancomycin is not clear.
  • The variable most closely associated with clinical response to vancomycin is the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio), which should be greater than 400.


 

References

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.1

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.2

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.3 Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.1 It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.4

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al5 conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al6 compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.7

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al8 performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al9 compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

Pages

Next Article: