dose daptomycin plus continuous infusion meropenem, in a patient with ... every 36 hours over 30 minutes; meropenem ranging from 0.25 g every 8 hours.
CASE REPORTS TDM-Guided Therapy with Daptomycin and Meropenem in a Morbidly Obese, Critically Ill Patient Federico Pea, Piergiorgio Cojutti, Rodolfo Sbrojavacca, Barbara Cadeo, Francesco Cristini, Alessandro Bulfoni, and Mario Furlanut
hoosing appropriate antibiotic dosages is extremely challenging when treating patients with severe, deep-seated infections with morbid obesity and multiple organ failure. We describe a case of severe cellulitis, successfully treated with high-dose daptomycin plus continuous infusion meropenem, in a morbidly obese patient with renal failure, in whom drug exposure over time was optimized by means of real-time therapeutic drug monitoring (TDM).
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Case Report
OBJECTIVE: To describe a case of severe cellulitis, successfully treated with highdose daptomycin plus continuous infusion meropenem, in a patient with morbid obesity and renal failure, in whom drug exposure over time was optimized by means of real-time therapeutic drug monitoring (TDM). CASE SUMMARY:
A 63-year-old man with morbid obesity (body mass index 81.6 kg/m2) and renal failure was admitted to the emergency department because of severe cellulitis. The patient had an admission Laboratory Risk Indicator for Necrotizing Fasciitis score of 9, and broad-spectrum antimicrobial therapy with daptomycin and meropenem was started. Because of rapidly changing renal function, dosage adjustments were guided by an intensive program of TDM (daptomycin ranging from 1200 mg every 48 hours over 30 minutes to 1200 mg every 36 hours over 30 minutes; meropenem ranging from 0.25 g every 8 hours over 6 hours to 500 mg every 4 hours by continuous infusion). Clinical response was observed within 72 hours. However, a sudden increase of serum creatine kinase (SCK) raised questions about the need for discontinuation of daptomycin. The drug concentrations were not toxic; therefore, we decided to continue therapy. Significant clinical improvement, with SCK normalization, was observed within a few days. Antimicrobial therapy was switched on day 29 to amoxicillin/clavulanate plus levofloxacin, and then discontinued at discharge on day 53.
A 63-year-old man with morbid obesity (175 cm, 250 kg, body mass index 81.6 kg/m2) and a history of chronic leg ulceraDISCUSSION: High-dose daptomycin plus continuous infusion meropenem may tions due to peripheral vascular disease ensure adequate empiric antimicrobial coverage in patients with possible early was sent to the emergency department by necrotizing fasciitis. However, in patients with morbid obesity and changing renal his family physician because of a 4-day function, significant challenges may arise because of the hydrophilic nature of history of increasing inflammation, erythethese drugs and the inaccuracy of standard methods of estimating renal function. ma, and intense pain in his left medial CONCLUSIONS: Real-time TDM may represent an invaluable approach in optimizing thigh, perineum, and scrotum. His vital drug exposure with high-dose daptomycin plus continuous infusion meropenem in patients with severe cellulitis, morbid obesity, and changing renal function. signs were temperature 36.6 ˚C, blood KEY WORDS: cellulitis, daptomycin, meropenem, serum creatine kinase, pressure 85/55 mm Hg, heart rate 72 therapeutic drug monitoring. beats/min, and respiratory rate of 20 Ann Pharmacother 2011;45:e37. breaths/min; laboratory testing showed PaCO2 46.4 mm Hg, and serum creatinine Published Online, 12 Jul 2011, theannals.com, DOI 10.1345/aph.1P745 (SCr) 4.6 mg/dL. He was diagnosed with severe cellulitis. An admission Laboratory hemoglobin 12 g/dL; sodium 134 mEq/L; SCr 4.6 mg/dL; Risk Indicator for Necrotizing Fasciitis (LRINEC)1 score of 9 serum glucose 123 mg/dL). Broad-spectrum antimicrobial denoted high risk of early necrotizing fasciitis (C-reactive therapy with daptomycin and meropenem was started, acprotein [CRP] 252 mg/L; total white blood cells 9900/µL; cording to our standardized treatment protocol. Initial intravenous loading doses, administered to rapidly achieve effecAuthor information provided at end of text. tive concentrations, were daptomycin 1200 mg over 30 mintheannals.com
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utes and meropenem 2 g over 30 minutes. Subsequently, maintenance doses of both antibiotics were determined by an intensive program of real-time TDM. This strategy was adopted because of the patient’s rapidly changing renal function and the severity of illness. At our institution, TDM of these antimicrobial agents is performed 3 times a week (Monday, Wednesday, Friday), and feedback to the clinician for dosage optimization is reported within the same day (real time). Each TDM result was used to estimate the timing and amount of the subsequent dose. Daptomycin and meropenem were measured separately with a 125S Beckman high-performance liquid chromatography (HPLC) system coupled with a Beckman 166 UV detector (Beckman Instruments, Berkeley, CA), using 2 different HPLC techniques,2-4 with some modifications. Briefly, for daptomycin extraction, methanol 200 µL was added to 100 µL of calibrators, quality control samples, or patient samples, then mixed for 5 seconds and left at room temperature for 15 minutes. The samples were then ultra-centrifuged at 11,000 g for 10 minutes, and 20 µL of the clear supernatant was injected into the HPLC system. Separation through an Ultrasphere C8 column (Octyl–150 mm × 4.6 mm–5 µm Beckman Instruments) at 30 °C was carried out with a solution of ammonium dihydrogen phosphate (0.5%)/acetonitrile (70/30 v/v) at a flow rate of 1.8 mL/min in isocratic conditions (daptomycin retention time was 9.8 min). For meropenem extraction, 25 µL of a 1-µg/µL cefepime solution, as internal standard, was added to 1 mL of
calibrators, quality control samples, or patient samples. The samples were then mixed and transferred into an extraction cartridge conditioned with 2 mL of methanol and then 2 mL of phosphate buffer 0.05M at pH 4. After washing the extraction cartridge with 2 mL of phosphate buffer 0.05M at pH 4, the samples were eluted with 800 µL of a solution of phosphate buffer 0.05M pH 6/methanol (9/1 v/v). Twenty microliters of the eluate was then injected into the HPLC system. Separation through an Ultrasphere C18 column (ODS–250 mm × 4.6 mm–5 µm, Beckman Instruments) was carried out with a solution of phosphate buffer/acetonitrile (91/9 v/v) at a flow rate of 1.2 mL/min in isocratic conditions (cefepime and meropenem retention times were 3.8 and 9.1 min, respectively). The precision and accuracy of both assays were assessed by performing replicate analyses of quality control samples against calibration standards. Intra- and interassay coefficients of variation were always less than 10%. The low limit of detection, for both daptomycin and meropenem, was 0.5 mg/L. Target concentrations were a trough (Cmin) of 60 mg/L for daptomycin and steady-state concentrations (Css) of 8-12 mg/L for continuous infusion meropenem. Temporal trends in plasma concentrations of daptomycin and meropenem are depicted in Figure 1. Clinical response was observed within 72 hours, with a decrease in CRP from 252 to 129.8 mg/L. Blood culture and wound swabs obtained before starting therapy showed no microorganisms.
Figure 1. Temporal trends of daptomycin trough (Cmin), peak (Cmax), and random (Crandom) concentrations, meropenem concentrations (Css), serum creatinine (SCr), and serum creatine kinase (SCK). Die = per day. Arrows show the time of redosing for daptomycin, which varied between 36 and 48 hours, according to each TDM result. TDM = therapeutic drug monitoring.
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TDM-Guided High-Dose Antimicrobial Therapy
On day 3, a more than 3-fold increase from baseline of serum creatine kinase (SCK) (from 657 U/L to 2241 U/L) (Figure 1) raised questions about the need for discontinuation of daptomycin. However, in light of the patient’s rapid clinical improvement and the low incidence of daptomycin-induced muscular toxicity with normal plasma drug concentrations,5 we decided to continue antimicrobial therapy with both agents. SCK started dropping on day 4 and normalized on day 7, when CRP further decreased to 55.5 mg/L. On day 12, the patient was transferred to the medical ward. Given his progressive recovery of renal function (SCr 1.62 mg/dL on day 7), repeated dosage increases for both drugs were needed to maintain the desired concentrations. The dosage of daptomycin was progressively varied from 1200 mg every 48 hours to 1200 mg every 36 hours, whereas that of meropenem was progressively increased from 0.25 g every 8 hours infused over 6 hours to 500 mg every 4 hours by continuous infusion. By day 9, the patient’s SCr had normalized (1.3 mg/dL) and remained so until discharge, similar to what occurred with the SCK. On day 29, antimicrobial therapy was switched to amoxicillin/clavulanate plus levofloxacin and then stopped on day 53, when the patient was discharged in good clinical condition. Discussion Severe cellulitis with possible early necrotizing fasciitis may be a life-threatening condition requiring prompt intravenous therapy with broad-spectrum antimicrobial agents.6 The combination of daptomycin and meropenem ensures adequate antimicrobial coverage in these cases. However, the accuracy of dosing strategies with these hydrophilic antimicrobials is challenging when treating deep-seated infections in critically ill patients who are morbidly obese and have changing renal function.7 For these reasons, with our patient, an intensive program of TDM was applied, in which each TDM result was used to estimate, in real time, the timing and the amount of the subsequent dose. The ranges of TDM for daptomycin and meropenem were chosen on the basis of published pharmacokinetic studies5,8,9 examining concentrations of both drugs in relation to efficacy and toxicity. For daptomycin, optimal theoretical pharmacodynamic determinants of its concentration-dependent antibacterial activity were defined as Cmax >60 mg/L coupled with Cmin
