Foscarnet: Pyrophosphate Analogue Against CMV and Aciclovir Resistant Herpesviruses

Foscarnet is a non-nucleoside antiviral agent from the class of pyrophosphate analogues. It was approved in 1991 and is a reserve therapeutic agent for cytomegalovirus (CMV) infections, especially in immunosuppressed settings (HIV, after stem cell transplantation, after organ transplantation), as well as for aciclovir-resistant herpes simplex and varicella zoster virus infections. The well-known brand name is Foscavir.

Foscarnet has a niche in clinical practice as a second-line or third-line therapy because it must be administered exclusively intravenously and nephrotoxicity as well as electrolyte disturbances are frequently limiting factors. However, with aciclovir or ganciclovir-resistant viral strains, foscarnet is often the only option and can be life-saving. Careful indication assessment and intensive monitoring are prerequisites for safe use.

Mechanism of Action

Foscarnet is the trisodium salt of phosphonoacetic acid (PFA), a pyrophosphate analogue. Unlike aciclovir or ganciclovir, which are phosphorylated as nucleoside analogues in the cell and incorporated into viral DNA, foscarnet inhibits viral DNA polymerase directly through reversible binding to the pyrophosphate binding site.

The crucial advantage is that foscarnet does not require viral thymidine kinase for activation. Aciclovir and ganciclovir depend on the virus-specific thymidine kinase (TK) or phosphotransferase, which is why resistance can develop through mutations in these viral enzymes. Foscarnet works against such TK-deficient strains that are resistant to aciclovir or ganciclovir.

Foscarnet acts against cytomegalovirus, herpes simplex 1 and 2, varicella zoster virus, Epstein Barr virus and HHV-6, as well as against human hepatitis B and HIV (although without clinical relevance). Pharmacokinetically, foscarnet is not absorbed orally, intravenous half-life approximately 3 hours, elimination renal in unchanged form. It accumulates long-term in bone tissue, with unclear clinical significance.

Applications

• CMV Retinitis in AIDS Patients: First-line or in case of ganciclovir resistance
• Other CMV Diseases in Immunosuppressed Patients: Pneumonia, colitis, encephalitis, hepatitis in HIV or after transplantation
• Aciclovir-Resistant Herpes Simplex Infections: in HIV or stem cell transplantation, mucocutaneous or systemic
• Aciclovir-Resistant Varicella Zoster Virus Infections: in immunosuppressed patients
• Off-label: HHV-6 reactivation after stem cell transplantation

Dosage and Administration

CMV Retinitis Induction: 60 mg/kg every 8 hours or 90 mg/kg every 12 hours over 14 to 21 days. Maintenance Dose: 60 to 90 mg/kg once daily.

Aciclovir-Resistant HSV/VZV: 40 mg/kg every 8 hours over 14 to 21 days. For both indications, intravenous administration over at least one hour is required to avoid seizures and hypocalcemia from too rapid infusion.

Renal Insufficiency: Dose adjustment according to creatinine clearance is mandatory and is checked multiple times per week, as foscarnet itself is nephrotoxic and therefore creatinine clearance changes under therapy.

Hydration: Patients should receive 1 to 2 liters of 0.9 percent NaCl before each foscarnet infusion to reduce nephrotoxicity.

Side Effects

Very Common: Nephrotoxicity with acute renal insufficiency, electrolyte disturbances (hypocalcemia, hypomagnesemia, hypokalemia, hyperphosphatemia), anemia, nausea, vomiting, diarrhea, fever, genital ulcers (especially in uncircumcised men due to local accumulation in urine).

Common: Headaches, fatigue, seizures (especially with rapid infusion or electrolyte disturbances), neurological symptoms such as tremor, paresthesias, confusion. Bone marrow suppression with neutropenia and thrombocytopenia.

Serious: Acute renal failure up to dialysis requirement, severe seizures from hypocalcemia, cardiac arrhythmias from QT prolongation, pancreatitis, hepatotoxicity.

Important: Foscarnet is one of the most nephrotoxic antiviral agents. Close monitoring of creatinine, calcium, magnesium, phosphate and potassium multiple times per week is standard. If creatinine increases by more than 50 percent or new electrolyte disturbances develop, therapy adjustment or discontinuation is indicated.

Drug Interactions

• Other Nephrotoxic Agents (Aminoglycosides, Amphotericin B, Cyclosporin, Tacrolimus, NSAIDs, Vancomycin, High-Dose Aciclovir): Additive nephrotoxicity, combination should be avoided if possible or monitored closely
• Intravenous Pentamidine: Additive hypocalcemia and nephrotoxicity, combination should be avoided if possible
• QT-Prolonging Agents: Additive QT prolongation, ECG monitoring
• Ritonavir and Other HIV Protease Inhibitors: Increased nephrotoxic risk
• Calcium and Magnesium Supplementation: Mandatory for prevention and treatment of electrolyte disturbances

Special Instructions

Pregnancy and Breastfeeding: Contraindicated due to teratogenicity in animal studies. For life-threatening CMV disease in pregnancy, risk-benefit assessment.

Genital Ulcers: Foscarnet is excreted unchanged in high proportions renally and can cause local irritation in the genital area after micturition, especially in uncircumcised men. Careful genital and skin hygiene after urination reduces the risk.

Administration Only with Central Venous Catheter: Foscarnet is tissue-irritating and should be administered exclusively via central venous access, especially at higher doses.

Hospitalization: Foscarnet therapy is performed almost exclusively in hospital or day clinic settings due to the need for hydration, close monitoring and electrolyte correction.

You Might Also Be Interested In

• Ganciclovir, first-line in CMV therapy
• Valganciclovir, oral ganciclovir prodrug
• Aciclovir, classical herpesvirus therapy
• Cidofovir, further CMV reserve therapy
• Letermovir, new CMV prophylaxis after transplantation

Frequently Asked Questions

Sources

• Gelbe Liste, Foscarnet Active Substance Profile
• AWMF Guidelines CMV in HIV and After Transplantation
• BfArM, Federal Institute for Drugs and Medical Devices
• EMA Product Information Foscarnet Preparations