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

333

351

eThe current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P ‫؍‬ 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with troughonly data allowed 97% (93 to 102%; P ‫؍‬ 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of >400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.

mentioning

confidence: 99%

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Neely

Youn

Jones

et al. 2014

333

351

“…Later studies have corroborated this pattern with minimal variations with other types of infections and clinical outcomes (12)(13)(14). Obtaining adequate magnitudes would allow us to ensure clinical and microbiological efficacy.…”

Section: Discussionmentioning

confidence: 83%

“…AUC 0 -24 /MIC values of Ն400 have demonstrated clinical and microbiological efficacy against lower respiratory tract infections by methicillinresistant Staphylococcus aureus (7), which have been later validated by international recommendations and guidelines (8)(9)(10)(11). On the other hand, lower values have shown not only poor infection eradication but also require longer treatments and a higher mortality rate (12)(13)(14). In order to reach an appropriate PK/PD value, it has been proposed that trough levels between 15 and 20 g/ml for complicated infections are required (8,9,15).…”

mentioning

confidence: 97%

Pharmacokinetic Assessment of Vancomycin Loading Dose in Critically Ill Patients

Álvarez

Plaza‐Plaza

Ramírez

et al. 2017

The vancomycin loading dose (LD) of 25 to 30 mg/kg is a frequently practiced strategy to achieve effective concentrations from the first-treatment dose. However, considering only the body weight for dosing might be inadequate in critically ill patients due to pharmacokinetics changes. We sought to assess achieving optimal trough serum levels of vancomycin and AUC 0 -24 /MIC in the first 24 h of treatment by using an LD based on population pharmacokinetic parameters of critically ill patients. We performed a concurrent cohort study over 22 months of patients with severe sepsis who received intravenous vancomycin. The patients were treated with three different strategies to initiate vancomycin: without an LD (group A), with an LD of 25 to 30 mg/kg (group B), and with an LD based on population pharmacokinetic parameters of the critically ill patient (group C). An optimal trough serum concentration was achieved in 5, 9, and 83% of patients in groups A, B, and C, respectively. The number of patients that reached optimal AUC 0 -24 was 2 of 18 (11%), 5 of 11 (46%), and 11 of 12 (92%) in groups A, B, and C, respectively. The statistical analysis for both parameters revealed significant differences in group C with respect to other groups. The administration of the LD calculated from population pharmacokinetic parameters from the beginning of therapy is a more efficient strategy to obtain adequate trough serum concentrations and AUC 0 -24 /MIC in critical patients.

“…Bacterial density over time was determined by taking a sample from each model at predetermined time points (0, 1, 2, 4,6,8,10,12,14,18,24,26,30,36,38,42,48,50,56,60,62,66, and 72 h) and serially diluting it in normal saline. Aliquots of diluted samples were plated for quantitative culture utilizing Trypticase soy agar plates (100-mm diameter) with 5% sheep blood.…”

Section: Methodsmentioning

confidence: 99%

“…In general, a total drug daily AUC/ MIC ratio of at least 400 is required for a successful response; however, this pharmacodynamic threshold can range between 200 and 650, depending on the method used to estimate the MIC and the AUC (21)(22)(23)(24)(25). Given that vancomycin protein binding is approximately 50% in human serum, the target is roughly half (ϳ200) when corrected for free-drug concentrations.…”

Section: It Is Well Established That Vancomycin Is An Antibiotic Withmentioning

confidence: 99%

In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure

Hamada

Kuti

Nicolau

2016

Vancomycin is considered a first-line antibiotic for complicated skin and skin structure infections (cSSSI) because of the risk of methicillin-resistant Staphylococcus aureus (MRSA). The vancomycin exposure of tissue can vary widely in patients with cSSSI, yet most models test only the average exposure. The in vitro pharmacodynamic model was used to simulate three tissue exposure levels attained by administering vancomycin at 1 g every 12 h (q12h), based on the median (50th), 25th, and 10th percentile tissue area under the concentration-time curve (AUC) values observed during an in vivo microdialysis study of diabetic patients. Four clinical isolates (two of MRSA [vancomycin MIC, 1 and 2 g/ml] and two of methicillin-susceptible S. aureus [MSSA] [MIC, 1 and 2 g/ml]) were evaluated. Experiments were performed over 72 h in duplicate. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) during the final 24-h dosing interval (48 to 72 h) (AUBC 48 -72 ) was calculated. Reductions in the 72-h number of CFU/ml and AUBC 48 -72 at the different exposure levels were compared. Target tissue vancomycin exposure levels for the 50th (AUC 0 -12 , 102.0 ؎ 9.1 g · h/ml), 25th (AUC 0 -12 , 44.3 ؎ 1.8 g · h/ml), and 10th (AUC 0 -12 , 25.3 ؎ 3.1 g · h/ml) percentiles were obtained in all studies. No differences in the 72-h number of CFU or AUBC were observed between exposure levels when all of the isolates were analyzed together. However, for the two MRSA isolates, the 10th percentile exposure level achieved a lower 72-h number of CFU/ml (؊1.4 ؎ 0.4 log 10 CFU/ml, P ‫؍‬ 0.007) and a greater AUBC 48 -72 (97.1 ؎ 20.0 log 10 CFU · h/ml, P ‫؍‬ 0.011) than the higher exposure levels. The majority of the tissue exposure levels achieved with a vancomycin dosing regimen of 1 g q12h resulted in substantial killing of MSSA and MRSA; however, the lowest exposure levels observed in a minority of the population may explain the poor vancomycin response. C omplicated skin and skin structure infections (cSSSI) are among the most common infections in hospitalized patients (1, 2). These infections are frequently caused by Gram-positive bacteria, including Staphylococcus aureus and Streptococcus pyogenes (2). Methicillin-resistant S. aureus (MRSA) can be present in as many as 60% of cases (3, 4) and has been linked with outcomes worse than those of methicillin-susceptible S. aureus (MSSA) infections (5, 6). As a result of this epidemiology and the long history of vancomycin use, it is considered a first-line antibiotic for the empirical treatment of cSSSI (2, 7).In addition to possessing in vitro microbiological activity against the causative pathogen, the treatment antibiotic must be able to penetrate to the site of infection with sufficient exposure to kill the organism. Comorbidities often present in patients with cSSSI, including diabetes mellitus and peripheral vascular disease, can result in altered and varied tissue perfusion to the site of infection, making it increasingly difficult to predict a...