Incidence of Nephrotoxicity and Association With Vancomycin Use in Intensive Care Unit Patients With Pneumonia: Retrospective Analysis of the IMPACT-HAP Database

Cano, Ennie; Haque, Nadia Z.; Welch, Verna L; Cely, Cynthia; Peyrani, Paula; Scerpella, Ernesto G.; Ford, Kimbal D.; Zervos, Marcus J.; Ramirez, Julio A.; Kett, Daniel H.

doi:10.1016/j.clinthera.2011.12.013

Cited by 135 publications

(148 citation statements)

References 24 publications

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“…This is consistent with observations, including those in the guidelines (1), that for organisms for which the vancomycin MIC is Ն2 mg/liter, i.e., at an AUC of 800 mg · h/liter when maintaining a 400:1 ratio, toxicity begins to increase noticeably. We also believe that focusing on the AUC as the correct marker of toxicity risk is the explanation for the superficially contradictory observations that trough concentrations of Ͼ20 mg/liter are associated with increased nephrotoxicity when vancomycin is dosed intermittently (12,13,15,28,29), while constant concentrations of 20 to 30 mg/liter with continuous vancomycin infusions may be associated with less nephrotoxicity than intermittent dosing (16) or at least do not appear to be more toxic. Basic pharmacokinetic equations confirm that the smallest daily dose required to maintain the concentration above a minimum target is achieved by continuous infusion and that for the same minimum target, the daily dose divided into increasingly long intervals must be correspondingly larger, as must the daily AUC.…”

Section: Discussionmentioning

confidence: 98%

“…In the simulated population, we defined the peak as the concentration 2 h after the beginning of a 1-h infusion, i.e., C 2 , and the trough concentration as the concentration 12 h after the beginning of the infusion, i.e., C 12 .…”

Section: Figmentioning

confidence: 99%

“…Regarding toxicity, we used the prior work of Lodise et al (13), Cano et al (12), and others to define vancomycin trough concentration intervals of Ͻ10 mg/liter, 10 to Ͻ15 mg/liter, 15 to Ͻ20 mg/liter, and Ն20 mg/liter, which are associated with an increasing risk of nephrotoxicity. We determined the AUC 0-24 distribution in the subset of the simulated population within each trough concentration bracket and for each simulated dose.…”

Section: Figmentioning

confidence: 99%

“…Several papers have documented a higher incidence of nephrotoxicity associated with the more aggressive target trough concentrations, especially if the measured concentrations overshoot the upper target of 20 mg/liter (12)(13)(14)(15). In contrast, a large meta-analysis suggested that a constant vancomycin concentration of 25 mg/liter through continuous infusion is less nephrotoxic than standard intermittent dosing (16).…”

mentioning

confidence: 99%

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Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Neely

Youn

Jones

et al. 2014

Antimicrob Agents Chemother

317

351

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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.

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Section: Discussionmentioning

confidence: 98%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Neely

Youn

Jones

et al. 2014

Antimicrob Agents Chemother

317

351

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“…TDM of vancomycin mainly aims to balance therapeutic efficacy against the risk of nephrotoxicity. It has been shown in several studies -applying various analytical methods -that high vancomycin trough levels are associated with the incidence and extend of nephrotoxicity [4,5]. However, low trough levels of vancomycin may lead to increased occurrence of resistant strains of S. aureus and failure of treatment in complicated infections.…”

Section: Introductionmentioning

confidence: 99%

Quantification of vancomycin in human serum by LC-MS/MS

König¹,

Kobold²,

Fink³

et al. 2013

Clinical Chemistry and Laboratory Medicine

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Background: The aim of our work was to develop and validate a reliable LC-MS/MS-based measurement procedure for the quantification of vancomycin in serum, to be applied in the context of efforts to standardize and harmonize therapeutic drug monitoring of this compound using routine assays. Methods: Sample preparation was based on protein precipitation followed by ultrafiltration. In order to minimize differential modulation of ionization by matrix constituents extended chromatographic separation was applied leading to a retention time of 9.8 min for the analyte. Measurement was done by HPLC-ESI-MS/MS. For internal standardization the derivative vancomycin-glycin (ISTD) prepared by chemical synthesis was used, HPLC conditions ensured coelution of ISTD with the analyte. Results: In a bi-center validation total CVs of < 4% were observed for quality control material ranging from 5.3 mg/L to 79.4 mg/L; accuracy was ± 4%. No relevant ion suppression was observed. Comparative measurement of aliquots from 70 samples at the two validation sites demonstrated close agreement. Conclusions: Employing a closely related homologue molecule for internal standardization and the use of MS/ MS following highly efficient sample pre-fractionation by HPLC, the method described here can be considered to offer the highest level of analytical reliability realized so far for the quantification of vancomycin in human serum. Thus, the method is suitable to be used in a comprehensive reference measurement system for vancomycin.

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Empirical Anti-MRSA vs Standard Antibiotic Therapy and Risk of 30-Day Mortality in Patients Hospitalized for Pneumonia

et al. 2020

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IMPORTANCEUse of empirical broad-spectrum antibiotics for pneumonia has increased owing to concern for resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA). The association of empirical anti-MRSA therapy with outcomes among patients with pneumonia is unknown, even for high-risk patients.OBJECTIVE To compare 30-day mortality among patients hospitalized for pneumonia receiving empirical anti-MRSA therapy vs standard empirical antibiotic regimens. DESIGN, SETTING, AND PARTICIPANTSRetrospective multicenter cohort study was conducted of all hospitalizations in which patients received either anti-MRSA or standard therapy for community-onset pneumonia in the Veterans Health Administration health care system from January 1, 2008, to December 31, 2013. Subgroups of patients analyzed were those with initial intensive care unit admission, MRSA risk factors, positive results of a MRSA surveillance test, and positive results of a MRSA admission culture. Primary analysis was an inverse probability of treatment-weighted propensity score analysis using generalized estimating equation regression; secondary analyses included an instrumental variable analysis. Statistical analysis was conducted from June 14 to November 20, 2019.EXPOSURES Empirical anti-MRSA therapy plus standard pneumonia therapy vs standard therapy alone within the first day of hospitalization.MAIN OUTCOMES AND MEASURES Risk of 30-day all-cause mortality after adjustment for patient comorbidities, vital signs, and laboratory results. Secondary outcomes included the development of kidney injury and secondary infections with Clostridioides difficile, vancomycin-resistant Enterococcus species, or gram-negative bacilli. RESULTS Among 88 605 hospitalized patients (86 851 men; median age, 70 years [interquartile range, 62-81 years]), empirical anti-MRSA therapy was administered to 33 632 (38%); 8929 patients (10%) died within 30 days. Compared with standard therapy alone, in weighted propensity score analysis, empirical anti-MRSA therapy plus standard therapy was significantly associated with an increased adjusted risk of death (adjusted risk ratio [aRR], 1.4 [95% CI, 1.3-1.5]), kidney injury (aRR, 1.4 [95% CI, 1.3-1.5]), and secondary C difficile infections (aRR, 1.6 [95% CI, 1.3-1.9]), vancomycin-resistant Enterococcus spp infections (aRR, 1.6 [95% CI, 1.0-2.3]), and secondary gram-negative rod infections (aRR, 1.5 [95% CI, 1.2-1.8]). Similar associations between anti-MRSA therapy use and 30-day mortality were found by instrumental variable analysis (aRR, 1.6 [95% CI, 1.4-1.9]) and among patients admitted to the intensive care unit (aRR, 1.3 [95% CI, 1.2-1.5]), those with a high risk for MRSA (aRR, 1.2 [95% CI, 1.1-1.4]), and those with MRSA detected on surveillance testing (aRR, 1.6 [95% CI, 1.3-1.9]). No significant favorable association was found between empirical anti-MRSA therapy and death among patients with MRSA detected on culture (aRR, 1.1 [95% CI, 0.8-1.4]).CONCLUSIONS AND RELEVANCE This study suggests that empirical anti-MRSA th...

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Incidence of Nephrotoxicity and Association With Vancomycin Use in Intensive Care Unit Patients With Pneumonia: Retrospective Analysis of the IMPACT-HAP Database

Cited by 135 publications

References 24 publications

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Quantification of vancomycin in human serum by LC-MS/MS

Empirical Anti-MRSA vs Standard Antibiotic Therapy and Risk of 30-Day Mortality in Patients Hospitalized for Pneumonia

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