By Lina Meng, PharmD, BCPS, BCIDP

Infectious Diseases and Antimicrobial Stewardship Pharmacist, Stanford Antimicrobial Safety and Sustainability Program, Stanford Health Care, Stanford, CA

Dr. Meng reports no financial relationships relevant to this field of study.

SYNOPSIS: The key change from the 2009 vancomycin guidelines is the switch from trough-based to area under the curve (AUC)-based dosing and monitoring. This article will highlight key differences between the 2009 and 2020 guidelines, limitations of the new guidelines, and implementation issues.

SOURCE: Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2020 Mar 19. pii: zxaa036.

The switch from trough-based dosing to area under the curve (AUC)-based dosing for vancomycin was driven by recent evidence showing that trough values are a poor surrogate for AUC values, and may lead to unnecessary nephrotoxicity when targeting trough values of 15 mg/dL to 20 mg/dL.

The 2020 guidelines now recommend targeting a vancomycin AUC to minimum inhibitory concentration (MIC) measured by a broth microdilution (BMD) (AUC: MICBMD) ratio of 400-600 for both adults and children. (See Table 1.) This narrow range balances efficacy with toxicity thresholds. Data point to increased nephrotoxicity risk at vancomycin AUCs ranging 563 mg∙h/L to 1,300 mg∙h/L, but converge around 650 mg∙h/L.

Table 1. Comparison of 2009 and 2020 Vancomycin Guideline Recommendations (Adults)1,2

 

2009 Guidelines2

2020 Guidelines1

Recommended monitoring parameter

Target troughs 15-20 mg/L as surrogate marker for PK/PD target (AUC24/MICBMD ≥ 400) if MIC
≤ 1 mg/L for complicated infections (bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia caused by S. aureus)

Avoid troughs < 10 mg/L

Target AUC24/MICBMD 400-600 in suspected or definitive serious MRSA infections (assume vancomycin MICBMD of 1 mg/L), preferably in the first 24-48 hours of therapy. Do not decrease dose if MICBMD < 1 mg/L.

Method of therapeutic drug monitoring

No routine monitoring of peaks

Trough prior to next dose at steady state (before 4th dose)

Preferred: Bayesian software, using 1-2 vancomycin concentrations, with at least one trough, but preferable two levels

Alternatively, collection of two concentrations (peak and trough), preferably during the same dosing interval, utilizing first-order PK equations

Dosing weight

Actual body weight

Actual body weight

Loading dose (complicated infections in seriously ill patients)

25-30 mg/kg

20-35 mg/kg, max: 3,000 mg

Obese: 20-25 mg/kg, max 3,000 mg

Continuous infusion regimens

No recommendations

Continuous infusions as alternative if AUC cannot be achieved with intermittent dosing; target level 20-25 mg/L

PK = pharmacokinetic; PD = pharmacodynamic; AUC = area under the curve; MIC = minimum inhibitory concentration;
BMD = broth microdilution; MRSA = methicillin-resistant Staphylococcus aureus

The preferred method of estimating vancomycin AUC is by using Bayesian software programs based on one to two (preferably two) serum concentrations. Bayesian software uses individual patient data together with a population pharmacokinetic (PK) model (ideally in a similar patient population) to predict an optimal dosing regimen. Some advantages include:

  • ability to use pre-steady-state vancomycin concentrations;
  • fewer drug levels;
  • Bayesian models continuously learn; incorporates real-time individual patient data and can inform subsequent dosing.

Alternatively, the AUC may be calculated using two steady-state concentrations, usually a peak and trough concentration, drawn during the same dosing interval, and using first-order PK equations.

In contrast to the 2009 guidelines, the updated 2020 guidelines include expanded guidance on special populations, including obese, dialysis, and pediatric patients.

COMMENTARY

The generally accepted PK/pharmacodynamic (PD) parameter for vancomycin’s efficacy (AUC/MICBMD ≥ 400) is based nearly exclusively on retrospective, observational studies in methicillin-resistant Staphyloccocus aureus (MRSA) bacteremia, except for a few in pneumonia and one in infective endocarditis.1 Studies on osteomyelitis and meningitis are notably missing. Thus, the 2020 guidelines only address serious infections caused by MRSA. The authors cautioned against extrapolating to infections due to methicillin-susceptible S. aureus (MSSA) strains, coagulase-negative staphylococci, enterococci, streptococci, and other pathogens. It is important to achieve PK/PD targets early in the course of vancomycin therapy, often prior to culture and MIC results. However, if vancomycin is continued in a patient for a non-MRSA infection, these guidelines do not directly address their management. Most patients ultimately do not have a MRSA infection. In one study on AUC-based vancomycin dosing, 42% of the study population had an infection with a gram-positive organism, but only 10% were MRSA.5 For non-S. aureus isolates, investigators targeted an AUC of 400 mg∙h/L regardless of the MIC. In a separate publication, the lead guideline author recommended targeting a vancomycin AUC of 400-600 mg∙h/L regardless of MIC or organism treated.6

While Bayesian software programs allow for accurate, individualized dosing with as few as one vancomycin concentration (possible with a population PK model with richly sampled PK data from a similar population as your institution’s), obstacles to implementation include high cost, specialized training required, and informatics resources to integrate software with existing electronic medical records. Many hospitals have created homegrown spreadsheet calculators to calculate AUC values based on two concentrations using the linear-trapezoid rule. Both dosing methods are accurate and precise, with a median error of < 2%.7,8 These methods of vancomycin dosing will take additional resources to implement in the inpatient and outpatient parenteral antibiotic therapy (OPAT) setting.

The 2020 guidelines dance around the dosing issues around MRSA isolates with a vancomycin MICBMD = 2 mg/L. On one hand, they argue that automated susceptibility testing methods are imprecise, but they state that alternative therapy should be considered since AUC/MIC targets may not be safely achieved. This conflicts with Infectious Diseases Society of America (IDSA) MRSA treatment guideline recommendations that for susceptible MRSA isolates, “the patient’s clinical response should determine the continued use of vancomycin, independent of the MIC.”9

Overall, these guidelines address many of the gaps in the 2009 guidelines. Additional research is needed for optimal vancomycin dosing in patients receiving extracorporeal membrane oxygenation, those with infections of the central nervous system, and infections due to non-MRSA organisms such as Streptococcus spp. and coagulase-negative Staphylococcus. Optimal dosing regimens still are unknown for obese populations and patients with renal insufficiency.

Implementation of vancomycin appropriateness criteria and early vancomycin de-escalation efforts, such as with the use of negative nasal MRSA polymerase chain reaction in suspected MRSA pneumonia,10 may circumvent unresolved vancomycin monitoring issues. Avoidance of vancomycin is another alternative, as emerging data suggest a promising role for early stepdown to oral antibiotics in serious gram-positive infections traditionally treated with intravenous therapy.11-13

REFERENCES

  1. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2020 Mar 19. doi: 10.1093/ajhp/zxaa036
  2. Rybak MJ, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66:82-98.
  3. Crass RL, Dunn R, Hong J, et al. Dosing vancomycin in the super obese: Less is more. J Antimicrob Chemother 2018;73:3081-3086.
  4. Rodvold KA, Blum RA, Fischer JH, et al. Vancomycin pharmacokinetics in patients with various degrees of renal function. Antimicrob Agents Chemother 1988;32:848-852.
  5. Neely MN, Kato L, Youn G, et al. A prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother 2018;62. doi: 10.1128/AAC.02042-17
  6. Heil EL, Claeys KC, Mynatt RP, et al. Making the change to area under the curve-based vancomycin dosing. Am J Health-Syst Pharm 2018;75:1986-1995.
  7. Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev 2014;77:50-57.
  8. Neely MN, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother 2014;58:309-316.
  9. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-e55.
  10. Smith EA, Gold HS, Mahoney MV, et al. Nasal methicillin-resistant Staphylococcus aureus screening in patients with pneumonia: A powerful antimicrobial stewardship tool. Am J Infect Control 2017;45:1295-1296.
  11. Willekens R, Puig-Asensio M, Ruiz-Camps I, et al. Early oral switch to linezolid for low-risk patients with Staphylococcus aureus bloodstream infections: A propensity-matched cohort study. Clin Infect Dis 2019;69:381-387.
  12. Jorgensen SCJ, Lagnf AM, Bhatia S, et al. Sequential intravenous-to-oral outpatient antibiotic therapy for MRSA bacteraemia: One step closer. J Antimicrob Chemother 2019;74:489-498.
  13. Spellberg B, Chambers HF, Musher DM, et al. Evaluation of a paradigm shift from intravenous antibiotics to oral step-down therapy for the treatment of infective endocarditis: A narrative review. JAMA Intern Med 2020; Mar 30. doi: 10.1001/jamainternmed.2020.0555. [Epub ahead of print].