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Subtherapeutic Posaconazole Prophylaxis in a Gastric Bypass Patient Following Hematopoietic Stem Cell Transplantation

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Subtherapeutic Posaconazole Prophylaxis in a Gastric Bypass Patient Following Hematopoietic Stem Cell Transplantation applyparastyle “fig//caption/p[1]” parastyle “FigCapt” CASE REPORT Subtherapeutic posaconazole prophylaxis in a gastric bypass patient following hematopoietic stem cell transplantation Emily A. Highsmith, PharmD, BCCCP, Department of Pharmacy, University Purpose. A case of invasive fungal infections (IFIs) with subtherapeutic of Texas MD Anderson Cancer Center, Houston, TX, USA posaconazole prophylaxis in a gastric bypass patient following hemato- poietic stem cell transplantation (HSCT) is reported. Downloaded from https://academic.oup.com/ajhp/article/78/14/1282/6245082 by BINASSS user on 15 July 2021 Vi P. Doan, PharmD, BCOP, Department of Pharmacy, University of Texas MD Anderson Cancer Center, Summary. A 52-year-old malnourished male with a medical history of Houston, TX, USA Roux-en-Y gastric bypass for obesity developed acute myelogenous leu- Todd W. Canada, PharmD, BCNSP, kemia and underwent allogeneic HSCT approximately 17 months later. He BCCCP, FASHP, FTSHP, FASPEN, was admitted 1 month after HSCT for failure to thrive and initiated on par- Department of Pharmacy, University of Texas MD Anderson Cancer Center, enteral nutrition due to worsening diarrhea and suspected gastrointestinal Houston, TX, USA graft-versus-host disease (GI GVHD). During admission, the patient was continued on daily oral posaconazole for antifungal prophylaxis and was found to have subtherapeutic posaconazole and deficient vitamin levels, likely secondary to his gastrojejunostomy and increased gastric transit time. The oral posaconazole was altered to twice-daily dosing in an effort to increase serum drug levels and prevent IFIs. Conclusion. Patients with a history of gastric bypass are at increased risk for malabsorption of oral posaconazole and nutrients, especially following HSCT with suspected GI GVHD. Keywords: gastric bypass, hematopoietic stem cell transplantation, intestinal absorption, posaconazole Am J Health-Syst Pharm. 2021;78:1282-1286 ariatric surgeries such as gastric patients require long-term immuno- Bbypass procedures are increas- suppression for prevention of graft- ingly common elective procedures. versus-host disease (GVHD), as well as In 2018, the American Society for prophylaxis for Pneumocystis jiroveci Metabolic and Bariatric Surgeries es- pneumonia, invasive fungal infections timated that 252,000 bariatric sur- (IFIs), and viral infections. geries were performed, representing a Previous literature has established 40% increase over a 5-year period.1 As perioperative management for bariatric obesity rates continue to rise, proced- procedures including nutritional man- ures such as Roux-en-Y gastric bypass agement, as well as evaluation of vita- (RYGB) or gastric sleeve will increase mins and serum trace element levels.3 in prevalence. Unfortunately, the published guidance Hematopoietic stem cell trans- for oral medication absorption fol- plantation (HSCT) is considered to lowing RYGB or ways to ameliorate de- be a curative therapy for a variety of creased absorption is scarce.4 malignancies, including leukemias, We describe a patient who was for- Address correspondence to Dr. Highsmith myelomas, and lymphomas. Over the merly obese before RYGB who devel- ([email protected]). past 6 decades, HSCT has dramatic- oped acute myelogenous leukemia and © American Society of Health-System ally increased in prevalence. In 2015, underwent HSCT with subtherapeutic Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals. over 21,000 transplantations were per- serum posaconazole levels during use of [email protected]. formed, and this number is expected to oral tablets and nutrient malabsorption DOI 10.1093/ajhp/zxab164 increase.2 Following allogeneic HSCT, with severe malnutrition. 1282 AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 14 | July 15, 2021 SUBTHERAPEUTIC POSACONAZOLE AFTER GASTRIC BYPASS CASE REPORT Case report DNA and negative for C. difficile toxin, KEY POINTS and the transplant team treated him A 52-year-old malnourished male • Patients with altered gastric with vancomycin 125 mg orally 4 times was hospitalized for significant gener- anatomy may be at risk for daily to suppress colonization and pre- alized weakness, fatigue, and failure to malabsorption of drugs and vent an active infection. The rest of the thrive. His medical history was signifi- nutrients. patient’s GI multiplex panel was nega- cant for positivity for hepatitis B core tive for pathogens. Because of profound • Patients with gastrointestinal antibody and obesity with a body mass thrombocytopenia (Table 1), high risk 2 graft vs host disease (GVHD) index of 53.3 kg/m , and he underwent for bleeding, and patient refusal, a or increased gastric transit RYGB in May 2018. Before RYGB, the feeding tube was not initially placed. time are at increased risk for Downloaded from https://academic.oup.com/ajhp/article/78/14/1282/6245082 by BINASSS user on 15 July 2021 patient reported his weight to be 165 kg Parenteral nutrition (PN) was initiated altered intestinal absorption. with a weight loss of approximately on hospital day 5 for failure to thrive 100 kg over the course of a year. He was • The use of therapeutic drug and suspected GI GVHD via endoscopy diagnosed with acute myelogenous leu- monitoring may help guide and sigmoidoscopy performed the kemia in April 2019, for which he under- clinicians to optimal dosing re- same day. The patient’s tissue biopsies went allogeneic HSCT with cells from a gimens in patients exhibiting were negative for GI GVHD with the matched sibling in October 2019. Before malabsorption or altered clear- transplant team empirically treating the initiation of the HSCT conditioning ance. patient with an 8-day course of tapering regimen and throughout his admission methylprednisolone administered in October 2019, he experienced min- IV. Repeat endoscopy and sigmoid- imal appetite and increased vomiting oscopy were performed in December and diarrhea and continued to lose 2019, and tissue biopsies were again weight. He was enrolled on a protocol negative for GI GVHD. PN was discon- where he received a myeloablative temporal wasting was evident. He con- tinued 5 days after placement of an en- intensity conditioning regimen that tinued to receive posaconazole 300 mg teral feeding tube, and the patient was consisted of busulfan (area under the orally daily. started on continuous enteral feeding curve target of 6,000), fludarabine, His hospital course was significant due to chronic poor oral intake. aldesleukin, and natural killer cells on for a large volume (>1 L/day) of watery Given the suspicion of GI GVHD, day –8 before stem cell infusion. His diarrhea while receiving an oral diet, malabsorption with a history of RYGB, GVHD prophylaxis regimen included which was concerning given that this and risk for fungal infection with con- posttransplant administration of cyclo- can indicate gastrointestinal infec- comitant use of corticosteroids, serum phosphamide on days 3 and 4, followed tion or GVHD (GI GVHD). The patient posaconazole trough levels were by administration of tacrolimus starting tested positive for Clostridioides difficile obtained to assess oral absorption. on day 5. He received posaconazole 300 mg intravenously (IV) daily for 14 days as IFI prophylaxis per our Table 1. Select Laboratory Values on Readmission institution’s standard of care. The pa- Analyte Value Reference Rangea tient was partially engrafted 19 days following HSCT but remained an- White blood cell count, /μL 7,400 4,000-11,000 emic and thrombocytopenic (Table 1). Red blood cell count, ×106/μL 2.72 4.5-6 His posaconazole dose was switched Hemoglobin, g/dL 7.9 14-18 to 300 mg of the oral tablets (three 100-mg tablets) daily for 20 days fol- Hematocrit, % 23.1 40-54 lowing HSCT. His hospital course was Mean corpuscular volume, fL 85 82-98 complicated by Burkholderia cepacia Platelet count, ×103/μL 18 140-440 septicemia requiring admission to the intensive care unit and treatment with Blood urea nitrogen, mg/dL 48 6-23 subsequent discharge on post-HSCT Serum creatinine, mg/dL 1.01 0.67-1.17 day 28. Two days after discharge, the Alanine aminotransferase, U/L 14 ≤41 patient experienced significant gener- Aspartate aminotransferase, U/L 21 ≤40 alized weakness, fatigue, dizziness, and hypothermia accompanied by rigors Total bilirubin, mg/dL 0.5 <1.2 and was readmitted to the hospital. Albumin, g/dL 3.2 3.5-5.2 Upon readmission, the patient’s weight aReference values are institution specific. was 53 kg and significant muscle and AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 14 | July 15, 2021 1283 CASE REPORT SUBTHERAPEUTIC POSACONAZOLE AFTER GASTRIC BYPASS The posaconazole assay measured absorbing all medications. We suspected Discussion total drug concentration as opposed absorption issues with other oral medica- to the concentration of available free tions, such as valacyclovir, letermovir, and Posaconazole is a second-generation drug. Figure 1 illustrates the patient’s entecavir, but were unable to measure triazole medication commonly used posaconazole trough levels, all of which serum levels of these agents. Fortunately, for prophylaxis and treatment of IFIs. were subtherapeutic (<700 ng/mL) the patient did not develop infections re- It is a potent cytochrome P-450 iso- on an oral tablet dosage, despite ini- lated to the organisms for which these zyme 3A4 (CYP3A4) inhibitor and tial intravenous dosing of 300 mg medications provide prophylaxis, which prolongs the QT interval, requiring daily followed by 300 mg orally daily may support
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