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

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵