Foscarnet is used for the treatment of CMV retinitis in immu- nosuppressed patients (187). Forcarnet also has emerged as a replacement for acyclovir for herpes simplex infections that have become acyclovir-resistant (389). Approved for use by the FDA, foscarnet is an organic analog of inorganic pyrophos- phate (Fig. 3.41). The unique mechanism of foscarnet makes it more effective against TK-negative viral strains. In addition, foscarnet has efﬁcacy against VZV strains that are acyclovir resistant although this use of foscarnet is not FDA-approved. Other possible applications of foscarnet include HIV and HHV-8 (213,390–393).
Fig. 3.41 Associated names, structure, and applicability of foscarnet.
Mechanism of Action
As an organic analog of inorganic pyrophosphate, foscarnet inhibits viral DNA polymerase by blocking its pyrophosphate binding site (Fig. 3.42). Foscarnet also inhibits HIV reverse transcriptase in the same manner. The nucleotide triphos- phates are unable to cleave from the pyrophosphate and there is inhibition of further primer-template extension (392).
Another asset of foscarnet is that it does not require phospho- rylation by viral thymidine kinase (TK) for intracellular acti- vation. This makes foscarnet effective against TK-negative viral strains.
Clinical Studies and Reports that Support the Use of Foscarnet
A diverse number of clinical studies and reports support the use of foscarnet as a major replacement therapy when acyclovir- resistant strains of speciﬁc viruses are present (186,211,
391–405) (Table 3.40).
Currently, foscarnet is administered intravenously (Table 3.41) or by injection. Foscarnet does not cure CMV retinitis, but may help in preventing a worsening of symptoms. Foscarnet must be administered regularly as it works best when the blood titer does not vary. Foscarnet has been used for CMV infections in the lungs, esophagus, and intestines and for VZV infections that do not respond to acyclovir.
Anemia. Foscarnet may cause or worsen anemia, dehy- dration, or kidney disease. Sores or ulcers in the mouth or throat are rare.
Most common side effects. Some of the more common effects may not need medical attention and may go away as the body adjusts to foscarnet. These include:
Abdominal or stomach pain. Anxiety.
Loss of appetite. Nausea and vomiting.
Unusual tiredness or weakness. Headache.
Anemia without neutropenia.
Electrolytic imbalances. Patients may experience in- creased thirst and a change in frequency of urination. Foscarnet may cause genital ulcerations. Washing the genitals after urination may decrease the extent of this problem.
Nausea and vomiting. Headache.
Central nervous system disturbances. Convulsions, muscle twitching, and tremors are less common.
Renal dysfunction. Renal dysfunction is usually re- versible provided there is frequent monitoring of se- rum creatinine levels and adequate hydration.
Renal toxicity. Risk of renal toxicity is increased when other nephrotoxic medications are concurrently admin- istered. Dose adjustments should be made if changes in renal function occur.
Tingling, pain, or numbness. A tingling sensation around the mouth or pain or numbness in hands or feet while receiving medication may indicate a drop in normal calcium levels.
Foscarnet-resistance. Six patients with AIDS have been reported to have foscarnet-resistant HSV. Five of these cases had been previously treated with foscarnet (391,392). Some of these cases responded to acyclovir, but there are reports of resistance to both acyclovir and foscarnet (406).
Monotherapy failure with foscarnet or ganciclovir.
Combination therapy of both foscarnet and ganciclovir is indicated.
Aminoglycoside antibiotics coadministration. Coad- ministration of foscarnet with aminoglycoside antibiot- ics increases the risk of renal toxicity.
Amphotericin B coadministration. Coadministration with foscarnet increases the risk of renal toxicity.
Other drug contraindications or dosage concerns:
• Combination pain medicine containing acetaminophen and aspirin or other salicylates (with large amounts taken regularly);
• Deferoxamine (with long-term use);
• Gold salts (medicine for arthritis);
• Inﬂammation or pain medicine, except narcotics;
• Other anti-infectives (e.g., noted above);
• Streptozocin; or
Use of these medications may increase chances for renal dysfunction.
Use of pentamidine injection with foscarnet may lower the level of calcium and magnesium in the blood. This increases the chance for kidney problems.
Pregnant women. Not indicated for use in pregnant wom- en. Foscarnet causes birth defects in studies in animals.
Breast-feeding. It is not known to what degree foscar- net appears in breast milk and what effect there might be on the breast-feeding infant.
Children. No studies of risk or efﬁcacy in children.
Hydration. Unless otherwise indicated, patients should drink several glasses of water each day to help pre- vent some unwanted effects foscarnet may have on the kidneys.
1-Docosanol (n-docosanol) is an alcohol that exerts an inhibi- tory effect on the replication of viruses, such as herpes simplex and respiratory syncytial virus. Combination of docosanol and antiviral nucleoside analogs (e.g., acyclovir) can have a syner- gistic effect with few toxic side effects (Fig. 3.43).
Fig. 3.43 Associated names, structure, and applicability of n-docosanol.
Mechanism of Action
n-Docosanol is a 22-carbon, straight-chain, saturated alcohol formulated for topical applications as a cream. The mecha- nism of action is unclear. Pope et al. have reported that n- docosanol inhibits viral entry (407). Spruance reports that n- docosonal is a suspension as it is insoluble in water, does not inactivate the virus directly, and is not cytotoxic (408). For n- docosonal to be most effective, it should be applied before infection occurs (409,410). Spruance further reports that n- docosonal may be an anti-inﬂammatory agent in the murine model and a clinical trial supports the idea (411).
Topical docosanol is used to treat symptoms of herpes simplex viral infections on the lips and around the mouth. Topical docosanol does not cure herpes simplex but relieves the pain and may help lesions heal faster.
IMPLICATIONS FOR NEW ANTIVIRAL AGENTS
As new viral diseases emerge and medicines that task the immune system become more common practice, challenges for developing new and better antivirals as alternative treatment strategies gain more importance. DNA-based viruses are a frequent cause of infection as they are able to develop long- term latency after the initial infection and are opportunistic when the patient’s immune system is challenged (196).
Detection of viral diseases at an early stage via various diagnostic tests enables clinicians to make immediate deci- sions on treatment options. It is inappropriate to treat a dis- ease with antivirals if the disease is not virus-based. Toxicity of many antivirals is a concern as it may place several compo- nents of a patient population at risk to the point that the risks outweigh the beneﬁts.