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Foscarnet


Foscarnet

Article Author:
Sriram Garikapati
Article Editor:
Minhthao Nguyen
Updated:
3/31/2020 9:06:14 AM
For CME on this topic:
Foscarnet CME
PubMed Link:
Foscarnet

Indications

Foscarnet is an FDA-approved antiviral therapy used in the treatment of cytomegalovirus (CMV) and CMV associated ophthalmic retinitis in individuals who are diagnosed with AIDS and are unable to tolerate gancyclovir, or as salvage therapy for those have drug-resistant CMV and fail gancyclovir. It also has approval for use as a treatment option in immunocompromised patients with Herpes simplex virus (HSV) who are resistant to acyclovir, the gold standard therapy for HSV.[1]

Foscarnet also has off-label use in certain instances, such as for gastrointestinal diseases such as esophagitis or colitis, outer retinal necrosis, allogeneic stem cell transplant, Varicella zoster virus (VZV) treatment, and even in the prevention of CMV infection itself.[2][1] Foscarnet is often used either as monotherapy or in combination with commonly used agents such as ganciclovir for CMV and acyclovir for HSV. When ganciclovir alone is ineffective, clinicians will often combine it with foscarnet, or if it shows strong side effects in a patient, foscarnet is used as monotherapy in place of ganciclovir.[3] While foscarnet is often indicated for use for the above mentioned viral infections in immunocompromised patients, it has no use in the treatment of HIV because it does not have antiretroviral properties.

Mechanism of Action

Foscarnet is an analog of pyrophosphate, which is 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 also can inhibit human DNA polymerase in much larger concentrations of the drug. However, such high concentrations are seldom necessary for the treatment of these viral pathogens.[2]

Administration

Foscarnet is not an orally administered drug due to poor bioavailability, possibly due to 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 age and weight of the patient and the specific viral infection (CMV versus HSV or VZV).

In adults with CMV infection and retinitis, for example, it is administered commonly at a rate of about 1mg/kg/minute, with an induction dose of 60 mg/kg/dose every 8 hours for 2 to 3 weeks, and later being maintained at doses of 90 to 120 mg/kg/dose infused once daily.[4][5]

In adults with acyclovir-resistant HSV infection, for example, IV induction is generally 40 mg/kg/dose every 10 hours for 2 to 3 weeks. In general, the administration of the drug is concomitant with the administration of normal saline. For all patients, the duration of therapy is dependent on the specific 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 the viral pathogens.[6]

Adverse Effects

While there are multiple adverse effects of foscarnet, the most notable ones are nausea associated with the infusion of this 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, which then leads to the deposition of these crystals in the glomerular network.[8] Due to these adverse effects on the renal system, it is important to monitor renal function while on foscarnet therapy. 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 be a result of a 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 to 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 why 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 also by slowing down the infusion rate of the drug.[12]

The less commonly reported adverse events due to foscarnet administration include seizures, genital ulcers (possibly due to a topical toxic effect as a result of the concentration of medication in the urine), and anemia. 

Contraindications

Foscarnet is often contraindicated for patients who have underlying diseases, which 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 who have serious hypersensitivity reactions such as angioedema or had a history of anaphylactic reactions to it. 

Monitoring

Given the list of adverse effects that may come with the administration of foscarnet, 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 every week 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 course of treatment, the frequency of monitoring may vary. It is also important to check the status of hydration before initiating the infusion of foscarnet to avoid symptoms like nausea. Lastly, the patient and the healthcare provider should both monitor for signs of hypersensitivity reactions with foscarnet so that complications are preventable. It is crucial to bear in mind the importance of dosing the drug appropriately depending on the patient’s medical history and the patient’s current tolerance status of the drug. 

Toxicity

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

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 a 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 to that, 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 emphasized in patient education of this drug. The education should come from all members of the team, 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 team needs to monitor renal function.[20][9] [Level3]

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).


References

[1] Razonable RR, Antiviral drugs for viruses other than human immunodeficiency virus. Mayo Clinic proceedings. 2011 Oct;     [PubMed PMID: 21964179]
[2] Wagstaff AJ,Bryson HM, Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs. 1994 Aug;     [PubMed PMID: 7527325]
[3] Tan BH, Cytomegalovirus Treatment. Current treatment options in infectious diseases. 2014;     [PubMed PMID: 25999800]
[4] Chilukuri S,Rosen T, Management of acyclovir-resistant herpes simplex virus. Dermatologic clinics. 2003 Apr;     [PubMed PMID: 12757254]
[5] Jacobson MA, Maintenance therapy for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: foscarnet. The American journal of medicine. 1992 Feb 14;     [PubMed PMID: 1310573]
[6] Diaz-Llopis M,España E,Muñoz G,Navea A,Chipont E,Cano J,Menezo JL,Romero FJ, High dose intravitreal foscarnet in the treatment of cytomegalovirus retinitis in AIDS. The British journal of ophthalmology. 1994 Feb;     [PubMed PMID: 8123619]
[7] Trifillis AL,Cui X,Drusano GL, Use of human renal proximal tubule cell cultures for studying foscarnet-induced nephrotoxicity in vitro. Antimicrobial agents and chemotherapy. 1993 Nov;     [PubMed PMID: 8285643]
[8] Maurice-Estepa L,Daudon M,Katlama C,Jouanneau C,Sazdovitch V,Lacour B,Beaufils H, Identification of crystals in kidneys of AIDS patients treated with foscarnet. American journal of kidney diseases : the official journal of the National Kidney Foundation. 1998 Sep;     [PubMed PMID: 9740154]
[9] Deray G,Martinez F,Katlama C,Levaltier B,Beaufils H,Danis M,Rozenheim M,Baumelou A,Dohin E,Gentilini M, Foscarnet nephrotoxicity: mechanism, incidence and prevention. American journal of nephrology. 1989;     [PubMed PMID: 2554731]
[10] Farese RV Jr,Schambelan M,Hollander H,Stringari S,Jacobson MA, Nephrogenic diabetes insipidus associated with foscarnet treatment of cytomegalovirus retinitis. Annals of internal medicine. 1990 Jun 15;     [PubMed PMID: 2160217]
[11] Guillaume MP,Karmali R,Bergmann P,Cogan E, Unusual prolonged hypocalcemia due to foscarnet in a patient with AIDS. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1997 Oct;     [PubMed PMID: 9356819]
[12] Jayaweera DT, Minimising the dosage-limiting toxicities of foscarnet induction therapy. Drug safety. 1997 Apr;     [PubMed PMID: 9113493]
[13] Gearhart MO,Sorg TB, Foscarnet-induced severe hypomagnesemia and other electrolyte disorders. The Annals of pharmacotherapy. 1993 Mar;     [PubMed PMID: 8384030]
[14] Ota R,Hirata A,Noto K,Yokoyama S,Hosomi K,Takada M,Matsuoka H, Relationship between serum calcium and creatinine in hematopoietic stem cell transplantation patients treated with foscarnet
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[15] Zaman MM,Burney S,Landman D,Quale JM, Rapid development of renal insufficiency with the simultaneous administration of amphotericin B and foscarnet. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1996 Feb;     [PubMed PMID: 8838205]
[16] Kwan LP,Mok MM,Choy BY,Chan TM, Acute kidney injury in a renal transplant recipient due to concomitant use of vancomycin and foscarnet. Nephrology (Carlton, Vic.). 2017 Oct;     [PubMed PMID: 28921753]
[17] Ordemann R,Naumann R,Geissler G,Kroschinsky F,Bornhäuser M,Schwerdtfeger R,Ehninger G, Foscarnet--an alternative for cytomegalovirus prophylaxis after allogeneic stem cell transplantation? Annals of hematology. 2000 Aug;     [PubMed PMID: 10985362]
[18] Mylonakis E,Kallas WM,Fishman JA, Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2002 May 15;     [PubMed PMID: 11981729]
[19] Takahashi M,Takahashi K,Inose R,Sugimoto T,Koh H,Hino M,Nagayama K, Safety profile of the concomitant use of foscarnet and aerosolized pentamidine in allogeneic hematopoietic stem cell transplantation recipients. Transplant infectious disease : an official journal of the Transplantation Society. 2020 Feb;     [PubMed PMID: 31883423]
[20] Pierce B,Richardson CL,Lacloche L,Allen A,Ison MG, Safety and efficacy of foscarnet for the management of ganciclovir-resistant or refractory cytomegalovirus infections: A single-center study. Transplant infectious disease : an official journal of the Transplantation Society. 2018 Apr;     [PubMed PMID: 29380479]