Vancomycin: ‘Tried and True’?

Vancomycin is likely the most well-known, most-studied antibiotic. It has become a core part of an empiric antimicrobial regimen in inpatient settings. Many studies have focused on the pharmacokinetics and pharmacodynamics of the drug. The published literature represents observational studies – not strong, prospective or randomized trials. This has led to multiple approaches for dosing and monitoring vancomycin therapy.

In January of this year, the American Society of Health System Pharmacist, the IDSA and the Society of Infectious Disease Pharmacists published a consensus paper addressing the therapeutic monitoring of vancomycin in adult patients. The intent of this consensus review – based on an extensive review of the literature from the past 50 years – was to provide recommendations for clinicians to optimize dosing strategies and monitor vancomycin.

History

Vancomycin was first discovered in the 1950s by Eli Lilly and Company. It was derived from nature, like most antimicrobials. The compound, now known as vancomycin, was isolated from Streptomyces orientalis, a very large glycopeptide chemical structure. Vancomycin’s place in therapy was evident from its inception: the treatment of serious staphylococci infections. Its popularity tarnished quickly, how ever, as the impurities from the preparation and fermentation broth were linked to ototoxicity and nephrotoxicity, earning the nickname “Mississippi Mud.”

It was not until the late 1970s that vancomycin reemerged as a key component in treating methicillin-resistant Staphylococcus aureus. It did not take staphylococci long to develop resistance to various antibiotics. Vancomycin was reformulated and retested in animal models for toxicity in the 1970s. It was found to have no ototoxicity and little nephrotoxicity. Since the 1970s, vancomycin did not need extravagant marketing strategies. The clinical need for an agent to fight MRSA was apparent and vancomycin quickly became the drug of choice. During the first several decades of use, staphylococci did not mount a resistance to vancomycin. It has only been within the last several years that vancomycin-intermediate

Staphylococcus aureus (VISA) and vancomycin- resistant Staphylococcus aureus (VRSA) has surfaced. This bug has overcome an otherwise steadfast drug. Many inpatient settings now focus on optimizing vancomycin dosing and monitoring to preserve its integrity to fight serious MRSA infections.

Several controversial issues still surround dosing: Is 15 mg/kg times actual body weight enough to achieve optimal drug levels? Can you dose aggressively enough to overcome higher MIC pathogens (MRSA MIC ≥ 2)? Does achieving target troughs affect clinical outcomes and does more aggressive vancomycin dosing induce toxicities?

Vancomycin dosing strategies

Dosing and drug monitoring for vancomycin is considered an art for many pharmacists. Dosing strategies were first established with the development of vancomycin. Pharmacodynamic studies against the bacterial pathogens have been limited to in vitro or animal models. It is accepted practice to dose vancomycin at 15 mg/kg times actual body weight for most infections; adjustments in dose is determined after evaluation of serum trough levels. More recent studies have suggested that for serious MRSA infection – such as bacteremia, endocarditis, osteomyelitis, meningitis and health-care associated pneumonia – the optimal, initial trough should be 15-20 mg/L. This may be difficult to obtain; dosing at the standard 15 mg/kg and dose as high as 25-30 mg/kg may need to be considered. The evidenced-based data in this area remains very thin.

Steady state is reached approximately after the third or forth dose of vancomycin. Therefore, levels should be obtained at that point of therapy. Vancomycin is considered a concentration-independent (time dependent killer) for staphylococci and streptococci, making intermittent IV infusions the preferred method of administration. Several smaller studies have evaluated if continuous infusion versus standard (Q8 or Q12 hour) dosing affect outcomes. The evaluated data do not suggest that continuous infusion has a significant impact. Dose adjustment in renal impaired patients is necessary. These dosing adjustments were established early on and have continued to be adjusted with the emergence of published data.

So, what is the best possible monitoring parameter? What is the optimal target serum trough level? Serum peak and trough levels have been studied to correlate their significance with outcomes. It is the consensus that serum peak levels provide little significance in clinical practice. Area under the curve/minimal inhibitory concentration has demonstrated efficacy in experimental models. This poses difficulties when applying this method in the clinical setting. This method requires multiple serum vancomycin levels be obtained to determine the AUC and calculate AUC/MIC. The trough serum levels have been the easiest level to obtain, interpret and apply in individual patients.

Do trough levels really correlate with emergence of resistance and therapeutic failure?

The early target for vancomycin concentrations were 5-10 mg/L, then it climbed to 8-15 mg/L. Now, 15-20 mg/L is the recommended attainment for treating MRSA infections. This trend for obtaining higher levels is to achieve significant antibiotic exposure while overcoming the higher MIC values of some MRSA pathogens. In 2005, the CDC evaluated a data set of vancomycin susceptibility reports of S. aureus isolates (n= 241,605). They reported 16.2% of the isolates had a MIC of 2 mg/L. Several studies have been conducted to evaluate the outcomes of higher MIC pathogens. The summary of these studies suggest that with higher MRSA, MIC value pathogens, bacterial eradication, treatment duration, recurrence of infection and infection-related mortality due to presumed treatment failure were all impacted, showing statistical significance and/or correlation.

Another significant concern with treating higher MRSA MIC pathogens with vancomycin, is the emergence of more resistant pathogens, such as VISA and VRSA. Again, multiple studies evaluated the correlation between MIC values and producing strains of VISA. The consensus around this topic suggest that S. aureus exposure to vancomycin concentrations >10 mg/L must be maintained to avoid development of resistant pathogens.

Vancomycin toxicity

Of all the areas of research around vancomycin, the toxicity profile has not been extensively studied. There is a lack of data to suggest a direct causal relationship between toxicity and higher doses or concentration of vancomycin. In regards to nephrotoxicity, the data have not filtered out confounding factors such as obesity, impact of critical illness-variation in volume of distribution, significant changes in renal function and impact of concomitant nephrotoxic agents. It is still recommended to monitor serum trough levels to reduce the incidence of nephrotoxicity in aggressively dosed patients. Closely monitoring patients with unstable renal function, anticipated prolonged course of vancomycin (more than 5 days), or target trough of 15-20 mg/L is a prudent clinical approach to patient care. More than one drug level should be obtained in patients receiving prolonged course or variable renal function. Dose adjustments should be calculated based on targeted serum drug levels.

The stigma of ototoxicity related to vancomycin has been left in history. Since the newer formulation of vancomycin was brought to market-ototoxicity has been rarely reported.

Infusion related toxicities are fairly common in the literature. The most common adverse effects reported include, fever, chills and phlebitis (particularly with peripheral administration). The all too common “Red man syndrome,” which is associated with tingling and flushing of the face, neck and upper torso, is an infusion-related reaction. To avoid this, the infusion rates are extended: 500 mg over 30 minutes, 1000 mg over one hour and doses ≥1500 mg should be administered over 1.5 to 2 hours.

As like any other medication, vancomycin has the potential to have unwanted side effects. The safest approach for patients is to take into account clinical status, dose and monitoring plans, and evaluation for infusion related toxicities.

Vancomycin has remained a tried and true antibiotic. Very few antibiotics have kept its place in treatment for as long as vancomycin. The “vancomycin MIC creep” is proving to be an issue in clinical practice for treating serious MRSA infections. A clinician should not just look at a susceptibility pattern of MRSA, see an “S” for sensitive and assume your patient will be successfully treated. Critical evaluation of site of infection, MIC data, aggressive dosing with close monitoring and follow up is now warranted with vancomycin therapy. Just as many antibiotics, vancomycin will soon be outsmarted by S. aureus completely and its use will dissipate but using it wisely in the present, will preserve its use for now.

Kimberly Boeser, PharmD, is the Infectious Disease Clinical Pharmacologist at the University of Minnesota Medical Center, Fairview in Minneapolis, where she coordinates the antimicrobial stewardship program.

For more information:

• Rybak M, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health System Pharmacist, the Infectious Disease Society of America and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009;66:82-98.
• Tenover FC, et al. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis. 2007;44:1208-2015.