Foscarnet

Mechanism of Action

Foscarnet is an analog of pyrophosphate, a phosphorous oxyanion found in the DNA molecule. This analog acts like the pyrophosphate molecule by binding selectively and reversibly to the binding site on the DNA polymerase enzyme of the virus and inhibiting the DNA chain from elongating further. The role of the DNA polymerase enzyme is to cleave the pyrophosphate molecule from the DNA chain to add further nucleotides to the growing chain. Foscarnet binds and blocks that cleaving process. While foscarnet has selectivity for the viral DNA polymerase, it can also inhibit human DNA polymerase in much larger drug concentrations. However, such high concentrations are seldom necessary to treat these viral pathogens.[2]

Administration

Foscarnet is not an orally administered drug due to poor bioavailability, possibly due to the poor metabolism of the drug and its inclination to deposit within bone and cartilage.[2] Instead, the most common route is through intravenous administration. The dosing and rate of administration are determined based on the patient's age and weight and the specific viral infection (CMV versus HSV or VZV).

Some specific dosing regimens are as follows:

• AIDS-associated CMV retinitis (note: not first-line treatment):
  • Induction: 90 mg/kg/dose IV every 12 hours for 2 to 3 weeks, or alternately 60 mg/kg/dose IV every 8 hours for 2 to 3 weeks.
  • Maintenance treatment: 90 mg/kg/dose IV every 24 hours or 120 mg/kg/dose IV every 24 hours.
• Acyclovir-resistant mucocutaneous HSV infection:
  • 40 mg/kg/dose IV every 8 to 12 hours until healed; alternately apply 1% cream five times daily until healed (requires pharmacy compounding.)
  • Immunocompromised patients must maintain adequate hydration before and during IV treatment.[4]
• Ganciclovir-resitant CMV (off label):
  • Induction: 90mg/kg/dose IV for a minimum of 2 weeks, alternately 60 mg/kg/dose IV every 8 hours for a minimum of 2 weeks.
  • Maintenance treatment: 90 mg/kg/dose IV every 24 hours or 120 mg/kg/dose IV every 24 hours.[5][6]
  • Immunocompromised patients must maintain adequate hydration before and during IV treatment.
• Acyclovir-resistant varicella (chickenpox) or acyclovir-resistant herpes-zoster (shingles) (off label):
  • 90 mg/kg/dose IV every 12 hours.
  • Immunocompromised patients must maintain adequate hydration before and during IV treatment.

In adults with CMV infection and retinitis, for example, it is administered commonly at a rate of about 1mg/kg/minute.[5][6]

For all patients, the duration of therapy is dependent on the patient's immune status and the progress of the lesions. While the IV route is the most used method, intravitreal administration is also used on occasions by experienced healthcare providers for ophthalmic complications of viral pathogens.

In cases of renal compromise, including hemodialysis, significant dosing reductions are necessary; clinicians should consult package inserts and institutional protocols in such instances.

Adverse Effects

While there are multiple adverse effects of foscarnet, the most notable ones are nausea associated with the infusion of the drug, electrolyte derangements, and reduced renal function. Of these three significant adverse effects, the reports of renal insufficiency is a relatively more common event in patients receiving this drug. The acute decrease in renal function is reversible; therefore, it is crucial to address it once identified. Foscarnet affects the renal tubular cells via direct cytotoxic mechanisms, and the degree of drug-induced toxicity directly correlates to the dosage administered.[7] Along with the renal tubular damage, foscarnet can also cause crystal nephropathy with the deposition of crystals in the glomerular capillaries. These crystals are often a mix of sodium and calcium salts. The molecular aspects of foscarnet allow it to form complexes with these ions, leading to the deposition of these crystals in the glomerular network.[8] 

Due to these adverse effects on the renal system, monitoring renal function while on foscarnet therapy is essential. Within 1 to 2 weeks of administration of foscarnet, if there appears to be a rise in the plasma creatinine, then it could be a sign of renal tubular injury; this often presents as acute tubular necrosis, with granular or muddy brown casts in the urine and a triphasic event with an acute drop in GFR, followed by a rise in GFR and then an eventual resolution of kidney function.[9] In some instances, foscarnet can also cause nephrogenic diabetes insipidus.[10]

Electrolyte derangement is another adverse effect of foscarnet, which often presents with hypocalcemia and hypomagnesemia.[11] Hypocalcemia may be due to the formation of the foscarnet and calcium ion complex, or it may result from foscarnet-induced hypomagnesemia, which leads to both hypocalcemia (due to hypomagnesemia induced hypoparathyroidism state) and hypokalemia (due to excess renal potassium wasting). Due to these possible electrolyte abnormalities, it is essential to perform routine complete metabolic panels to prevent systemic adverse events such as cardiac arrhythmias and obtain a baseline EKG before initiation of treatment. 

Patient intolerance due to nausea and other gastrointestinal symptoms is a well-known and often reported adverse event of foscarnet and is a primary reason it is difficult to administer to patients. Administration of foscarnet is often with concurrent IV and oral hydration to suppress nausea. Nausea can also be mitigated by providing the patient with antiemetics and slowing down the drug infusion rate.[12]

The less commonly reported adverse events due to foscarnet administration include seizures, genital ulcers (more common in males - possibly due to a topical toxic effect resulting from medication concentration in the urine), and anemia. There are also reports of QT prolongation and torsades de pointes.

Contraindications

Foscarnet is often contraindicated for patients with underlying diseases that increase the effect of the adverse reaction profile of the drug. With the health care provider’s medical discretion, the drug is either used with extreme caution or not used at all in patients who have abnormal EKG readings due to chronic cardiac problems, chronic kidney disease with decreased renal function, underlying electrolyte abnormalities (which have to be corrected to be able to administer foscarnet) or seizure disorders. Foscarnet is also contraindicated in patients with serious hypersensitivity reactions such as angioedema or a history of anaphylactic reactions to it. 

Significant and contraindicated drug interactions include concurrent use with cidofovir, pimozide, and thioridazine.

Monitoring

Given the list of adverse effects that may come with foscarnet administration/therapy, it is important to monitor specific parameters. The three main components to monitor are 24-hour creatinine clearance, EKG, and baseline electrolyte measurements. It is also important to get a baseline complete blood count to monitor hematocrit, hemoglobin, and WBC count. The different electrolytes to keep track of are calcium, potassium, sodium, magnesium, and phosphorus weekly during maintenance therapy. Certain symptoms such as muscle twitching and anxiety warrant earlier monitoring of electrolyte levels.[13] Monitoring calcium ion status, especially, is useful for detecting renal dysfunction during the early period of foscarnet administration.[14] 

Depending on the patient’s specific medical history and treatment course, the frequency of monitoring may vary. It is also essential to check the hydration status before initiating the infusion of foscarnet to avoid symptoms like nausea. Lastly, both the patient and the healthcare provider should monitor for signs of hypersensitivity reactions with foscarnet to prevent complications. It is crucial to bear in mind the importance of dosing the drug appropriately depending on the patient’s medical history and current drug tolerance status. 

Toxicity

To prevent irreversible damage, the patient should have frequent bloodwork and constant monitoring for renal impairment, electrolyte derangement, and/or seizures in overdose situations. 

Renal toxicity is one of the major concerns around administering foscarnet. The risk is reducible by concurrent administration of 0.9% normal saline (about 0.5 L to 1.0 L) or dextrose 5% water solution. While a history of chronic renal disease can increase the risk of foscarnet toxicity, it is also important to withhold the administration of other potentially nephrotoxic drugs such as ACE inhibitors, angiotensin II receptor blockers amphotericin B, vancomycin, or aminoglycosides to reduce the risk of additional renal damage.[15][16] While there is no particular antidote for foscarnet overdose, it can be prevented by adequate prophylactic hydration or urgent hemodialysis to decrease drug plasma levels.    

Enhancing Healthcare Team Outcomes

Managing the administration of foscarnet to immunocompromised individuals infected with HSV, CMV, or VZV viruses requires an interprofessional team effort by health care professionals comprised of physicians, nurses, lab technicians, infectious disease specialists, pharmacists, and social workers. Such a team would be able to enhance the optimal outcomes in the administration of this drug. Prompt action in the diagnosis of infection and administration of the drug is fundamental to the optimal efficacy of this therapy.[17] [Level 5]

In addition, since this is a drug that is not available orally and is administered most commonly via intravenous routes, it is of utmost importance to have the team involved with consistent monitoring of the drug’s effect on the patient’s condition, especially during dosing changes.[18] [Level 2]  Potential obstacles to ineffective therapy with foscarnet include inefficient interprofessional communication between team members (nurses and physicians, physicians and pharmacists, etc.), inconsistency in surveillance of the patient’s progress with the therapy, or concurrent usage of drugs that may interfere with foscarnet therapy.[19] [Level 3]

Compliance and overdose are two aspects of the medication that require emphasis in patient education of this drug. The education should come from all team members, such as physicians, specialists, nurses, and pharmacists. Since appropriate dosing of this drug is very crucial, the physician, nurse, and pharmacist must always be on the same page with the individualized aspect of therapy: the patient’s past medical history, inpatient and outpatient medication list, and changes in dosages of the foscarnet therapy regimen should always be available and consistent between all of them. With renal dysfunction being one of the major concerns of this drug, the interprofessional team needs to monitor renal function.[20][9] [Level 3]

Upon completion of the treatment regimen, the patient’s primary care physician or infectious disease physician must schedule follow-up visits to assess remission status versus recurrence; this is a crucial part of treatment as it catches any early recurrence of disease and prevents the need to reinitiate therapy (thereby exposing the patient to more side effects).