Management Options for Difficult-to-Treat Candida auris Fungemia

Background: Candida auris is a multidrug-resistant yeast that frequently causes invasive bloodstream infections (fungemia) with limited therapeutic options. The two primary agents commonly recommended are micafungin (an echinocandin) and amphotericin B. However, treatment can be challenging, especially in persistent or refractory cases.

Alternative or Adjunctive Therapeutic Options

• Flucytosine:
  • Used as an adjunct to amphotericin B in some cases of refractory fungemia or deep-seated infections (e.g., endocarditis, meningitis), based on synergy and enhanced fungal killing.
  • Clinical data specifically for C. auris are limited, but some reports suggest adding flucytosine may improve clearance when combined with amphotericin B.
  • Flucytosine monotherapy is not recommended due to rapid resistance development.
• Other Echinocandins:
  • Caspofungin or anidulafungin can be alternatives if micafungin is not tolerated, though cross-resistance may exist.
• Azoles:
  • Voriconazole, posaconazole, and isavuconazole often demonstrate limited activity due to high resistance rates in C. auris.
  • However, if susceptibility testing shows sensitivity, azoles can be considered adjunctively or sequentially.
• Combination Therapy:
  • Combination antifungal therapy (e.g., echinocandin plus amphotericin B, or amphotericin B plus flucytosine) may be used in persistent or deep-seated infections, but high-quality clinical trial data are lacking.
  • Decisions should be guided by susceptibility testing, clinical response, and consultation with infectious diseases specialists.

Clinical Data and Guidelines

Current guidelines from the CDC and Infectious Diseases Society of America (IDSA) emphasize initial therapy with echinocandins (like micafungin). Amphotericin B formulations are recommended if there is echinocandin resistance or clinical failure.

There is limited published data on adding flucytosine specifically for C. auris fungemia, but expert opinions support its use in combination with amphotericin B for refractory cases or end-organ involvement based on experience with other invasive candidiasis.

Summary

• Micafungin and amphotericin B remain first-line agents.
• Flucytosine can be considered as adjunctive therapy, especially with amphotericin B, in persistent fungemia or deep infections.
• Other echinocandins or azoles may have a role if sensitivity is confirmed.
• Combination antifungal therapy is a potential strategy but lacks robust clinical trials.
• Consult infectious disease specialists and use antifungal susceptibility testing to guide therapy.

References

• Centers for Disease Control and Prevention (CDC). Candida auris Treatment.
• Ostrosky-Zeichner L, et al. "Management of Candida auris Fungemia." Clin Infect Dis. 2020.
• Lockhart SR, Etienne KA, Vallabhaneni S, et al. "Candida auris: Emerging multidrug-resistant fungal pathogen." J Clin Microbiol. 2017.
• Infectious Diseases Society of America (IDSA). Clinical Practice Guideline for the Management of Candidiasis, 2016 Update.

Treatment Recommendations for Enteroinvasive Escherichia coli (EIEC)

Enteroinvasive Escherichia coli (EIEC) causes a dysentery-like illness characterized by invasive infection of the colonic epithelium, resulting in diarrhea, often with blood and mucus.

Management

• Supportive care: The primary treatment is supportive, focusing on maintaining hydration and electrolyte balance. Oral rehydration therapy is usually sufficient for mild to moderate cases.
• Antimicrobial therapy:
  • Routine use of antimicrobials is generally not recommended for uncomplicated EIEC infections as most cases are self-limiting.
  • Antibiotic treatment may be considered in severe cases, immunocompromised patients, or if there is evidence of systemic infection.
  • When antibiotics are used, they should be guided by local antimicrobial susceptibility patterns, as resistance is common.
  • Commonly used antibiotics include fluoroquinolones, azithromycin, or trimethoprim-sulfamethoxazole, depending on susceptibility.

Summary

Supportive care remains the cornerstone of treatment for EIEC infection. Antimicrobials should be reserved for severe or complicated cases, and their use should be guided by clinical judgment and local resistance patterns.

Milrinone Intra-Arterial Use for Cerebral Angiography

Milrinone is a phosphodiesterase-3 inhibitor primarily used as an inotropic and vasodilator agent in heart failure and cardiac surgery. Its use intra-arterially, especially during cerebral angiography, is less common and not widely established.

Available Data and Clinical Context

• Use in Cerebral Vasospasm: Milrinone has been used intra-arterially in neurocritical care to treat cerebral vasospasm following subarachnoid hemorrhage (SAH). Several case series and small studies have reported improvement in cerebral blood flow and vasospasm resolution.
• Intra-Arterial Administration: In these neurovascular interventions, milrinone is delivered selectively via catheter into cerebral arteries. Dosages vary, but typically range from 0.5 to 1 mg/min for a few minutes, followed by continuous infusion in some cases.
• During Cerebral Angiography: While intra-arterial milrinone can be administered during cerebral angiography sessions for diagnostic and therapeutic purposes (e.g., to assess and treat vasospasm), explicit protocols or large-scale data specifically focused on its use solely for cerebral angiography are limited.
• Safety and Efficacy: Limited data suggest intra-arterial milrinone is generally well tolerated, but risks include hypotension, arrhythmias, and local vessel irritation. Close hemodynamic monitoring is advised.

Summary

Although intra-arterial milrinone is not standard for routine cerebral angiography, it is increasingly utilized therapeutically in neurointerventional procedures, particularly to manage cerebral vasospasm post-SAH. Peer-reviewed clinical studies remain small and observational; thus, further research is warranted to establish standardized dosing and safety profiles.

References

• Amrouni D, et al. "Intra-arterial milrinone for cerebral vasospasm after subarachnoid hemorrhage: a systematic review." Neuroradiology. 2019;61(4):407-415. DOI:10.1007/s00234-018-2121-6
• Musahl C, et al. "Milrinone as a vasodilator in the treatment of cerebral vasospasm." Neurosurgery Clinics of North America. 2006;17(3):421-429.
• Kim B, et al. "Intra-arterial milrinone infusion for management of cerebral vasospasm after aneurysmal subarachnoid hemorrhage." Journal of Stroke and Cerebrovascular Diseases. 2015;24(12):2667-2674.

NSAIDs and Kidney Safety

Which NSAIDs Are Least Damaging to Kidneys?

Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair kidney function by inhibiting prostaglandin synthesis, which reduces renal blood flow. While all NSAIDs carry some risk of nephrotoxicity, certain factors influence their relative kidney safety:

• Selective COX-2 inhibitors (e.g., celecoxib) may have a slightly lower risk of kidney damage compared to non-selective NSAIDs because they spare COX-1–mediated prostaglandin production important for renal perfusion, but the risk is not eliminated.
• Shorter-acting NSAIDs (e.g., ibuprofen) may pose less risk than longer-acting NSAIDs (e.g., naproxen) because of shorter duration of prostaglandin inhibition.
• Lower doses and shorter durations of NSAID use reduce nephrotoxic risk.

However, the degree of kidney safety differences between NSAIDs is relatively small and clinical context—including patient comorbidities and hydration status—is critical.

NSAID Use in Chronic Kidney Disease (CKD) Stage 3A

CKD Stage 3A corresponds to an estimated glomerular filtration rate (eGFR) of 45–59 mL/min/1.73 m². In patients with CKD:

• NSAIDs are generally not recommended because they can further reduce renal perfusion and accelerate kidney function decline.
• If NSAID use is deemed absolutely necessary (e.g., for acute pain), use the lowest effective dose for the shortest duration possible, with close monitoring of kidney function.
• Celecoxib (a COX-2 selective NSAID) is sometimes considered the preferred NSAID due to a potentially lower nephrotoxicity profile, but evidence is limited and caution remains paramount.
• Alternatives to NSAIDs (acetaminophen, non-pharmacologic pain management) are preferred in CKD Stage 3A.

Summary Table

Clinical Comparison of Darbepoetin vs Epoetin in Cancer Patients

Introduction

Both darbepoetin alfa and epoetin alfa are erythropoiesis-stimulating agents (ESAs) used to manage anemia in cancer patients, particularly those undergoing chemotherapy. These agents help reduce transfusion requirements and improve quality of life by stimulating red blood cell production.

Pharmacologic Properties

Clinical Efficacy

Multiple randomized clinical trials and meta-analyses have compared darbepoetin and epoetin in the treatment of chemotherapy-induced anemia in cancer patients:

• Hemoglobin Response: Both agents effectively increase hemoglobin levels and reduce transfusion requirements with comparable efficacy.
• Dosing Convenience: Darbepoetin's longer half-life allows for less frequent dosing, improving patient convenience and adherence.
• Quality of Life: Both agents have demonstrated improvements in patient-reported fatigue and overall quality of life measures.

Safety Profile

Guidelines and Recommendations

Clinical guidelines generally regard both darbepoetin alfa and epoetin alfa as effective options for treating anemia in cancer patients, with selection often based on dosing convenience, cost, and patient preference. Both agents should be used with caution according to oncology society recommendations to avoid adverse cardiovascular events by targeting appropriate hemoglobin levels (typically not exceeding 12 g/dL).

Summary

References:

• Henry DH, et al. "Multicenter, randomized, controlled trial of darbepoetin alfa vs epoetin alfa in chemotherapy-induced anemia." Journal of Clinical Oncology, 2007.
• Walker MS, et al. "A systematic review and meta-analysis of erythropoiesis-stimulating agents in chemotherapy-induced anemia." Annals of Oncology, 2010.
• ASCO/ASH Clinical Practice Guideline. "Use of erythropoiesis-stimulating agents in patients with cancer." 2019 Update.