Anti-infection Strategies

Mechanism of Action

Adamantanes are tricyclic amines that inhibit the M2 protein whose ion channel function is important in several stages of viral replication.

Pharmacokinetics

Amantadine and rimantadine are orally administered and well absorbed. Amantadine is eliminated essentially unchanged by the kidneys, whereas rimantadine undergoes extensive hepatic metabolism before renal excretion.

Toxicity

Adamantanes are usually well tolerated. Most side effects are mild gastrointestinal symptoms, such as lack of appetite or nausea, or central nervous system (CNS) complaints, such as anxiety, dizziness, confusion, insomnia, and difficulty concentrating. Most effects spontaneously resolve even if treatment is maintained. CNS adverse events are increased with the concomitant use of antidepressants, antihistamines, and anticholinergic medications. Rimantadine is usually better tolerated than amantadine.

Spectrum

At concentrations compatible with clinical use, adamantanes are only effective against influenza A and not influenza B.

Resistance

Most circulating influenza A/H3N2 viruses have developed resistance to adamantanes because of point mutations in the M2 protein. Since the 2009 pandemic, most A/H1N1 circulating strains are also resistant to adamantanes.

Mechanism of Action

Oseltamivir phosphate is a prodrug that is converted by the hepatic esterases to the sialic acid analog oseltamivir carboxylate. The prodrug allows for the increased bioavailability by masking the molecule’s polarity. Zanamivir is also a sialic acid analog. Both are potent inhibitors of influenza A and B neuraminidases and competitively inhibit the neuraminidase active site, therefore preventing cleavage of sialic acid residues and the release of virions.

Pharmacokinetics

Oseltamivir is available in oral formulation with an oral bioavailability of around 75%. Elimination after conversion to oseltamivir carboxylate is almost entirely renal. Zanamivir is available in inhaled or intravenous (IV) formulations but not in an oral formulation because of a bioavailability of around 5%.

Toxicity

Oseltamivir is usually well tolerated. Dose-related gastrointestinal symptoms (nausea, epigastric pain, vomiting) are usually self-resolving, even in the absence of drug discontinuation. In the pediatric population particularly, neuropsychiatric adverse events, such as nightmares and delirium, have been reported. Intravenous and inhaled zanamivir are usually well tolerated, with headaches, gastrointestinal symptoms, and fatigue frequently reported, although there is a potential risk for bronchospasm during the use of the inhaled form.

Spectrum

Neuraminidase inhibitors (NAIs) are active against all neuraminidases of both influenza A and B. Oseltamivir is more effective in vitro and in clinical studies against influenza A than B viruses. Zanamivir has been shown to be more active against influenza B than oseltamivir in the clinical setting.

Resistance

NAIs are the only antivirals effective against influenza B. Because of uniform resistance of influenza A to adamantanes, NAIs are the first-line agents for influenza, regardless of the type and/or subtype. Mutations conferring resistance to NAIs most commonly involve the neuraminidase, and because they are close to the active site, they tend to alter viral fitness, explaining why mutant viruses have not become dominant in the absence of antiviral pressure. Risk factors for resistance to NAIs are immunosuppression and current or previous antiviral treatment.

Oseltamivir

The H275Y mutation in the neuraminidase is the most frequent mutation conferring resistance in N1 viruses, whereas mutations E119V and R292K are more frequently found in N2 viruses. Most point mutations confer only resistance to one NAI: for example, H275Y and E119V mutations confer resistance to oseltamivir only. Cross-resistance to two or more NAIs has been reported. For example, R292K mutations confer resistance to oseltamivir and, to a lesser extent, zanamivir in H3N2 viruses, whereas the E119D mutation has been shown to confer various degrees of resistance to all NAIs.

Zanamivir

Resistance to zanamivir is rarer than resistance to oseltamivir. It may be because of the intrinsic properties of the drug or the fact that mutations significantly reduce viral fitness, rather than because of the lower frequency of use. Mutations conferring resistance to oseltamivir do not usually affect zanamivir, although cross-resistance has been reported. Similarly, mutations conferring resistance to zanamivir do not usually confer resistance to oseltamivir.

Prevention

Because of increased mortality and morbidity in the adult and pediatric SOT setting, annual immunization with the injectable inactivated vaccine (IIV) is recommended for SOT patients. Children younger than 9 years should receive two doses 4 weeks apart, whereas those over 9 years should receive one dose. Children 6 to 36 months of age should receive two half-doses 4 weeks apart. The live-attenuated vaccine is contraindicated because of the risk of vaccine-derived influenza. Even though immunization is not fully protective, it has been shown to reduce disease severity in adult SOT patients.

If the IIV is contraindicated or unlikely to be effective (therapy for acute rejection, early transplantation, patient unlikely to mount an immune response before the end of the season), some experts consider antiviral prophylaxis starting at the beginning of the influenza season and continued for up to 12 weeks. However, the only randomized controlled trial (RCT) performed showed a reduction in influenza-diagnosed cases but not in influenza disease among adult SOT recipients.

Postexposure Prophylaxis

In case of exposure, prophylaxis for at least 7 days has been shown to be about 80% efficient to prevent influenza in adult SOT recipients.

Treatment

All infected patients should be treated, and early treatment has been shown to improve outcome. Recommended treatment duration is 5 days, although longer courses (up to 10 days) can be considered in case of suboptimal response or persistent viral shedding.

Mechanism of Action

Ribavirin is a guanosine analog inhibiting replication of a wide range of DNA and RNA viruses.

Pharmacokinetics

Ribavirin exists in aerosolized, oral, and IV formulations. Aerosol formulations seem to be the most efficient administration route in animal studies. Oral bioavailability ranges from 45% to 60%. Elimination requires both renal and, to a lesser extent, hepatic metabolism.

Toxicity

Dose-related hemolytic anemia is reported after systemic administration, especially in the case of concomitant kidney disease. Oral administration can lead to hyperbilirubinemia, increased uric acid, and iron. Ribavirin can also cause myalgia, pruritus, rash, as well as neuropsychiatric side effects. Intravenous administration is associated with headaches, hypocalcemia, and hypomagnesemia. Inhaled ribavirin can cause conjunctivitis, rash, and bronchospasm but is usually not associated with anemia.

Spectrum

Ribavirin has efficacy against a wide range of DNA and RNA viruses, such as respiratory syncytial virus (RSV), influenza, human metapneumovirus, parainfluenza virus (PIV), coronaviruses, adenoviruses, and herpesviruses.

Resistance

Resistance to ribavirin has not been documented in respiratory viruses so far.

Prophylaxis

Although prophylactic palivizumab has not been evaluated in pediatric liver transplantation (PLT), this strategy seems to be frequently used in pediatric transplant recipients less than 2 years old on a monthly basis during RSV season.

Treatment

RSV infection has been associated with high mortality rates after pediatric SOT. Supportive care with reduction of immunosuppression when possible is recommended. Because of the lack of data, there is no consensus on the use of ribavirin in SOT. Most SOT data come from adult lung transplant recipients and mostly with the aerosolized formulation. Expert opinions support the use of aerosolized ribavirin with IV immunoglobulins (IVIGs) and possibly IV steroids for severe RSV infection only.