Is there a specific AUC target for vancomycin for serious infections such as osteomyelitis, endocarditis, or meningitis compared to less serious infections such as SSTI?

Comment by InpharmD Researcher

Only a specific target AUC/MIC range for serious MRSA infection has been recommended by the collective American infectious disease organizations (400 to 600 mg*h/L) as there is limited evidence for other serious or non-serious infection. Available literature for MRSA-associated bacteremia or septic shock revealed an AUC/MIC cutoff of 400 was correlated with lower rates of treatment failure. Various vancomycin AUC target goals were utilized in retrospective studies for other serious MRSA infections (see Table 1) ranging from approximately 250 to over 600 AUC.

Background

A vancomycin dosing guideline was published in 2020 specifically for the management of serious methicillin-resistant Staphylococcus aureus (MRSA) infection with a recommended target area under the concentration-time curve (AUC)/minimum inhibitory capacity (MIC) of 400 to 600 mcg*h/mL using the Bayesian model. Aside from MRSA, there is limited data available regarding the AUC target goal for other antibiotic-resistant organisms which has excluded recommended AUC goals for other infections. As a result, the 2022 vancomycin-focused guideline from the Japanese Society of Therapeutic Drug Monitoring (JSTDM) recommends altering the dosing regimen based on treatment response when treating non-MRSA infections, possibly yielding AUC/MIC <400 mcg*h/mL. For empiric therapy prior to determining the MIC, a target AUC of 400 mcg*h/mL or greater is recommended (presuming MIC is 1 mcg/mL). AUC should not exceed 600 mcg*h/mL due to the increased risk of acute kidney injury (AKI). [1], [2]

A Q&A briefing on the Sanford Guide website regarding the 2020 guidelines addresses similar concerns regarding the AUC/MIC 400 to 600 limit. Due to limited data, the AUC target range only applies to serious MRSA infections. Other serious and nonserious infections are excluded from the recommendations. [3]

A 2021 meta-analysis analyzed the efficacy and safety of vancomycin AUC cutoff in five clinical trials, although the primary infection was MRSA-associated bacteremia or septic shock. No other infection was evaluated. Target AUC/MIC breakpoints varied between studies ranging from 393 to 451. The meta-analysis authors utilized an AUC/MIC cutoff of 400 (400 ± 15%, 392.7 to 451) to indicate success which found a higher AUC/MIC ratio was correlated with lower rates of treatment failure (odds ratio [OR] 0.28; 95% CI 0.18 to 0.45; p<0.0001). In contrast, an AUC/MIC cutoff of 600 was associated with higher rates of acute kidney injury. [4]

A 2020 review reported data on vancomycin AUC monitoring specifically within the pediatric population, although evidence is limited. Retrospective studies did not reveal a relationship between the vancomycin AUC24 ≥ 400 mg*h/L in patients with MRSA bacteremia. But given the lack of prospective pediatric data, the authors suggest extending the guideline recommendation of 400 to 600 AUC/MIC to the pediatric population. [5]

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;77(11):835-864. doi:10.1093/ajhp/zxaa036
[2] Matsumoto K, Oda K, Shoji K, et al. Clinical Practice Guidelines for Therapeutic Drug Monitoring of Vancomycin in the Framework of Model-Informed Precision Dosing: A Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. Pharmaceutics. 2022;14(3):489. Published 2022 Feb 23. doi:10.3390/pharmaceutics14030489
[3] Antimicrobial Therapy Inc. Sanford Guidelines: Therapeutic Vancomycin Monitoring Using AUC. Accessed August 2, 2022. https://www.sanfordguide.com/vanco-auc-faq/
[4] Tsutsuura M, Moriyama H, Kojima N, Mizukami Y, Tashiro S, Osa S, Enoki Y, Taguchi K, Oda K, Fujii S, Takahashi Y, Hamada Y, Kimura T, Takesue Y, Matsumoto K. The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing. BMC Infect Dis. 2021 Feb 6;21(1):153. doi: 10.1186/s12879-021-05858-6. PMID: 33549035; PMCID: PMC7866743.
[5] Burns AN, Goldman JL. A Moving Target-Vancomycin Therapeutic Monitoring. J Pediatric Infect Dis Soc. 2020;9(4):474-478. doi:10.1093/jpids/piaa078
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is there a specific AUC target for vancomycin for serious infections such as osteomyelitis, endocarditis, or meningitis compared to less serious infections such as SSTI?

Please see Table 1 for your response.

 

Summary of Retrospective Studies on Vancomycin AUC monitoring

Citation

Design/Population

Vancomycin AUC monitoring 

 Results

Alosaimy, 20211

Retrospective cohort

Adult patients (N= 154) treated with ≥72 hours of vancomycin for MRSA cSSTI

 AUC ≥ 435 mg*hr/L

Timely clinical success (TCS; resolution of signs and symptoms of infection within 72 hours) was achieved in 69.7% in the target-AUC group versus 52.5% in the below-target AUC group, (p= 0.013).  

Target-AUC attainment was associated with increased odds of TCS (adjusted odds ratio [aOR] 2.208; 95% confidence interval [CI] 1.047–4.659).

Dea, 20202

Retrospective observational study 

Adults (N= 722) treated with IV vancomycin with ≥1 measured concentration for SSTI

 AUC > 253

Clinical cure was significantly different between the AUC ≤253 (6/9 [67%]) and AUC >253 (214/234 [91%]) cohorts (p= 0.043).

There were no differences in hospital length of stay or duration of vancomycin therapy.

Nephrotoxicity occurred in seven patients with all having AUC >253.

Casapao, 20153

 

Retrospective observational cohort

Adults (N= 139) received at least 72 h of vancomycin therapy in response to a MRSA endocarditis

 AUC0 –24/MICBMD ≥ 600

Failure was more pronounced in patients with an AUC0–24/MIC of <600 versus those with AUC0-24/MIC of >600 (69.8% versus 54.7%, respectively;p= 0.073).

In the logistic regression analysis, an AUC/MIC as determined of <600 was independently associated with failure (aOR 2.3; 95% CI 1.01 to 5.37; p= 0.047). 

Gawronski, 20134

Retrospective chart review

Adult inpatients (N= 59) with concomitant MRSA bacteremia and MRSA osteomyelitis treated with vancomycin

 AUC/MIC > 293

Mean time to clearance was 2 days shorter when the AUC/MIC was >293 (4 days vs 6 days; p= 0.01).

Mean infection-related length of stay was 13 versus 18 days in patients with an AUC24/MIC ratio >293 or ≤293, respectively (p= 0.25).

In patients with an AUC24/MIC ≤293, 39% versus 17% had recurrent bacteremia (p= 0.09) and were readmitted compared with patients with an AUC/MIC > 293.

Brown, 20125

Retrospective chart review

Adults patients (N= 38) with confirmed complicated bacteremia and infective endocarditis due to MRSA

 AUC24/MIC > 211

Patients with an AUC24/MIC of <211 had a >4-fold increase in attributable mortality versus patients who received vancomycin doses that achieved an AUC24/MIC of ≥211 (38% vs. 8%, respectively;p = 0.02).

Vancomycin AUC/MIC ratio of <211 was an independent predictor of attributable mortality (OR 10.4; p= 0.01).

MRSA, methicillin-resistant Staphylococcus aureus; cSSTIs, complicated skin and soft tissue infections; IV, intravenous
References:

[1] Alosaimy S, Murray KP, Zasowski EJ, et al. Vancomycin Area Under the Curve to Predict Timely Clinical Response in the Treatment of Methicillin-resistant Staphylococcus aureus Complicated Skin and Soft Tissue Infections. Clin Infect Dis. 2021;73(11):e4560-e4567. doi:10.1093/cid/ciaa1039
[2] Dea L, Johns ST, Ma A. 192. The Use of Area Under the Curve to Determine Therapeutic Vancomycin Dosing in Skin and Soft Tissue Infections. Open Forum Infect Dis. 2020;7(Suppl 1):S224. Published 2020 Dec 31. doi:10.1093/ofid/ofaa439.502
[3] Casapao AM, Lodise TP, Davis SL, et al. Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis. Antimicrob Agents Chemother. 2015;59(6):2978-2985. doi:10.1128/AAC.03970-14
[4] Gawronski KM, Goff DA, Brown J, Khadem TM, Bauer KA. A stewardship program's retrospective evaluation of vancomycin AUC24/MIC and time to microbiological clearance in patients with methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis. Clin Ther. 2013;35(6):772-779. doi:10.1016/j.clinthera.2013.05.008
[5] Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its association with attributable mortality during hospitalization. Antimicrob Agents Chemother. 2012;56(2):634-638. doi:10.1128/AAC.05609-11