Use of Fosaprepitant for Management of Suspected Antimicrobial-Associated Nausea: A Case Report

Abstract

Intractable nausea can occur in numerous settings. We report on a 49-year-old woman with a past medical history of cystic fibrosis (CF) with chronic hypoxia, chronic nausea, complex infection history and frequent hospitalizations who was admitted to an academic medical center with a CF exacerbation. Her chronic nausea worsened with the use of antimicrobials, and she was unable to tolerate dopamine or serotonin antagonist antiemetics. Nausea persisted despite the use of benzodiazepines and antihistamines. She was given a one-time dose of fosaprepitant 150 mg intravenously (IV) with marked improvement of her nausea. During subsequent exacerbations, she again developed severe nausea which continued to respond well to a one-time dose of fosaprepitant 150 mg IV. Fosaprepitant is a substance P/neurokinin-1 (NK1) receptor antagonist that is FDA-approved for the prevention of chemotherapy-induced nausea and vomiting and has been used to prevent post-operative nausea and vomiting. Its use in other contexts has not been well established. This case suggests a role for fosaprepitant in the management of nausea outside the context of chemotherapy or general anesthesia.

Keywords:

• Cystic fibrosis
• fosaprepitant
• aprepitant
• nausea
• antimicrobial

Introduction

Nausea and vomiting are common symptoms in the palliative care population, frequently affecting the quality of life of patients with cancer and other life-limiting illnesses (1–3). In recent years, significant advancements have been made in controlling nausea and vomiting, particularly in cancer care. Despite the widespread availability and use of antiemetic medications, nausea and vomiting remain frequently reported by patients undergoing cancer treatment, particularly with chemotherapy and radiation therapy. Even when prophylactic antiemetic medications are used, nausea and vomiting remain common, with estimates of breakthrough nausea and vomiting in this population ranging from 35% to 75% (4–7). Patients with advanced forms of non-cancerous disease processes also report high rates of nausea and vomiting as they approach the end of life. For instance, across surveys of patients with end-stage forms of cardiac and renal disease, nausea and vomiting are commonly reported (8, 9).

The etiologies of nausea and vomiting in the palliative care population are wide-ranging and often multifactorial, including infection, bowel obstruction or impaired gut function, metabolic disturbances, intracranial pathology, and vestibular pathology. Medication side effects are another common cause of nausea and vomiting in the palliative care population. Numerous medications frequently used in advanced illness are known to cause nausea and vomiting, including antineoplastic agents, opioids, and, as demonstrated in this case, antimicrobials (1, 2).

Palliative care providers utilize a wide range of medications for the management of nausea and vomiting, including 5HT-3 (serotonin) receptor antagonists (e.g., ondansetron), dopamine receptor antagonists (e.g., prochlorperazine, haloperidol, olanzapine), and histamine receptor antagonists/anticholinergics (e.g., diphenhydramine, meclizine, scopolamine). Other antiemetics commonly described in advanced illness include corticosteroids, benzodiazepines, and cannabinoids (1, 2).

Aprepitant inhibits the effects of substance P, a neurokinin excitatory neurotransmitter implicated in both pain and nausea pathways that exerts its effect on the Neurokinin-1 (NK-1) receptor. Its intravenous (IV) formulation is a pro-drug called fosaprepitant, which is rapidly converted to aprepitant upon injection (10). Across several clinical trials, it has been found to be effective at preventing chemotherapy-induced nausea and vomiting (11–13). In 2008, fosaprepitant was FDA approved for the prevention of nausea and vomiting associated with the use of chemotherapy in adults and children over the age of 6 months (14). Recently published antiemetic guidelines from the American Society of Clinical Oncology call for the routine use of NK-1 receptor antagonists like fosaprepitant in the prevention of nausea and vomiting with highly emetogenic antineoplastic agents (15). Typical dosing regimen is an injection of 150 mg on day 1 of a chemotherapy regimen. Its use has also been described in the prevention of nausea and vomiting in the perioperative setting (10). Its package insert explicitly calls out a lack of evidence supporting its use outside of these specific settings (14).

This report describes the case of a patient with advanced cystic fibrosis complicated by frequent hospitalizations, recurrent infections with multi-drug resistant organisms, and chronic nausea who experienced acute worsening of nausea with the use of complex antimicrobial regimens. She was unable to tolerate or failed to respond to numerous first-line antiemetics, but experienced significant improvement in nausea after the administration of fosaprepitant.

Case

In the fall of 2022, a 49-year-old medically complex woman was admitted to a tertiary academic medical center for the management of an exacerbation of cystic fibrosis. Her past medical history was most notable for cystic fibrosis, chronic pancreatic insufficiency, malnutrition, cystic fibrosis related diabetes mellitus, sinus disease, chronic nausea, as well as chronic hypoxic respiratory failure for which she would intermittently use supplemental oxygen at home. She presented to the Emergency Department with 1 week of worsening cough, congestion, shortness of breath, and low-grade fevers (home temperature 99°F). In the month prior, she had two other hospitalizations for complications related to cystic fibrosis. She had a complex ­microbiologic history, including known prior infections with Methicillin-sensitive Staphylococcus aureus (MSSA), Extended Spectrum Beta-Lactamase-producing Escherichia coli, Pseudomonas aeruginosa, Mycobacterium abscessus, Scedosporium, and Aspergillus. On admission, she was found to have recurrent MSSA bacteremia suspected secondary to pneumonia. Just prior to admission, she was receiving an outpatient course of antifungals including oral posaconazole, IV micafungin, and inhaled amphotericin. In close consultation with the Pulmonology service, she remained on micafungin and inhaled amphotericin, and also started treatment with cefepime and omadacycline. She was eventually transitioned from cefepime to IV ceftaroline and ceftazidime/avibactam, and several days into her course tedizolid was added.

Her CF treatment course had been chronically complicated by nausea, often worsened in the setting of antimicrobial treatment. Unfortunately, she developed intolerable adverse effects or failed to respond to numerous first-line antiemetics. She had utilized prochlorperazine for nausea relief for roughly 6 years, but developed involuntary mouth movements and fidgeting. She was evaluated by neurology in December 2021, who concluded that these movements likely represented tardive dyskinesia. Neurology subsequently recommended against the future use of any dopamine antagonist antiemetic, including specific precautions against the use of metoclopramide, prochlorperazine, promethazine, and antipsychotics. She was treated with ondansetron (5-HT3 antagonist), however with this medication she also developed involuntary muscle movements thought to represent extrapyramidal side effects. At various points in her care, she received steroids for nausea and at times reported improvement in symptoms, however she found that steroids caused intolerable side effects including anxiety and “jumpiness.” She did not respond to a trial of scopolamine. She did find some relief with lorazepam 1 mg and diphenhydramine 25 mg, which she would take at home as needed. She additionally was prescribed dronabinol which she took through the final stages of her CF care, although its benefits for her were less clear.

During this hospitalization, she developed acute on chronic nausea 1 week after initiation of ceftaroline and ceftazidime/avibactam. She would refuse doses of these antimicrobials out of concern that additional doses would worsen her nausea. In addition to her home dronabinol (5 mg twice daily), she was prescribed scheduled lorazepam 1 mg IV every 6 h and diphenhydramine 25 mg IV every 6 h as needed for nausea, as this regimen was found to be helpful during prior hospitalizations. Notably, she did not exhibit mental status changes with regular doses of lorazepam.

Inpatient palliative care was consulted to address her worsening nausea that was not responding to her prior regimen. The recommendation was to escalate her lorazepam to every 4 h scheduled and diphenhydramine to 50 mg every 6 h as needed for nausea. Her severe nausea persisted, and the palliative care team recommended a trial of fosaprepitant. She was given fosaprepitant 150 mg IV once, and the following day reported rapid and significant improvement in her nausea. She was initially planned for a brief course of oral aprepitant to follow her initial dose, however the patient was unable to access oral aprepitant due to insurance coverage issues. Her nausea persisted, but at a more tolerable level, and she was eventually discharged to continue her antimicrobial course at home.

In the days following her discharge, she was seen multiple times by her outpatient pulmonologist who set up an ongoing antimicrobial treatment plan, including IV omadacycline, tedizolid, and clofazimine. She developed clostridium difficile colitis, and was additionally started on oral vancomycin. Her nausea continued, but she reported to her outpatient palliative care provider that it was improved from her hospitalization and manageable at home with as needed lorazepam 1 mg and diphenhydramine 50 mg oral tabs.

Over the ensuing weeks, she was again hospitalized several more times for exacerbations of her cystic fibrosis. With each hospitalization, she was treated with a complex antimicrobial regimen, and each time she experienced a severe exacerbation of her chronic nausea that was treated with lorazepam and diphenhydramine. In consultation with the palliative care service, she was treated with fosaprepitant 150 mg IV three additional times during these hospitalizations. With the two subsequent administrations of fosaprepitant, she reported rapid and marked improvement in her nausea. Documentation about her response to the third additional instance of fosaprepitant administration is less clear, as her respiratory condition and oxygenation began deteriorating around the same time. She was subsequently transitioned to comfort care, and passed away in the hospital 5 days later.

Discussion

Core to the management of nausea and vomiting in palliative care is an understanding of the physiology and signaling pathways associated with these symptoms. Palliative care providers routinely evaluate for underlying causes contributing to a patient’s nausea and vomiting, and attempt to match a recommended treatment course to the suspected etiology and related signaling pathway (1–3). For instance, nausea and vomiting aggravated by head movement or “motion sickness” may have an underlying vestibular component and respond to well to medications targeting histamine or acetylcholine pathways (1, 2). Nausea and vomiting associated with anxiety may have cortical contributions and respond to medications targeting GABA pathways (1, 2). Nausea and vomiting related to biochemical disturbances and the use of various medications are often associated with the chemoreceptor trigger zone (CTZ) of the brain (1, 2). The CTZ represents a particular anatomic structure at the base of the fourth ventricle not separated from the rest of the body by the blood-brain barrier and thus thought to be responsive to biochemical derangements in the systemic circulation (1, 2). Dopamine and serotonin pathways are associated with the chemoreceptor trigger zone and are frequently targeted when selecting medication regimens for related phenomena (1, 2).

NK-1 pathways have similarly been implicated in nausea and vomiting originating in the chemoreceptor trigger zone, although medications targeting this pathway have primarily been used in specific settings including the prevention of nausea and vomiting related to chemotherapy or in the peri-operative period (2, 10). While fosapreitant is generally well tolerated, reported common adverse effects include fatigue, constipation, diarrhea, hiccups, neutropenia, and dyspepsia. Infusion site reactions, hypersensitivity reactions, and drug-drug interactions, including interference with warfarin and hormonal contraceptive regimens, have been reported (11–14). Fortunately, this patient reported no such adverse reactions and tolerated the use of fosaprepitant well across multiple rounds of administration.

This case describes a patient with nausea related to the concurrent use of multiple antimicrobials suggesting involvement of the chemoreceptor trigger zone in the development of her nausea. While this patient was not receiving chemotherapy, the mechanism underlying fosaprepitant’s demonstrated effectiveness in preventing nausea and vomiting related to chemotherapy likely overlaps with the nausea and vomiting associated with the use of other classes of medications by way of the chemoreceptor trigger zone. This patient was unable to tolerate multiple first-line antiemetics that would typically have been prescribed, including those targeting dopamine and serotonin pathways. She was, however, able to tolerate the use of fosaprepitant, and after its administration reported rapid and significant improvement in her nausea.

Conclusion

This case raises the possibility of a role for the use of fosaprepitant, and possibly other substance P/neurokinin-1 receptor antagonists, in the management of established nausea and vomiting related to medication use beyond chemotherapeutics alone. Future research is needed to further elucidate the safety and effectiveness of medications such as fosaprepitant in the management of existent nausea beyond its established role in the prevention of nausea and vomiting related to chemotherapy.

Ethics approval

This case is presented anonymously, without clearly identifying patient information. No IRB approval was required for this case presentation.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.