[Es secrion B_Annacto apy ‘ent (rade Wem) Mechanism of Gram-Postve — Gram-Negative ‘noerobes Yeast Adverse ects Beton Organisms Organisms Temas ‘probably dae w margiaton), moderate pentatonic bare ‘pseudoeschar, a proteinaceous existe ‘conte with prlence: resistance of ram-negaive acl fespocally Peedomoncs 399) develops seat hyperesmelalty Secondary to propylene siycol in ream bse Acetic ac Unkomn ND Preudonnas xD ND. Cerium nite, 22% Unknown pare pers ND pres ‘Methemoglobinenia (rae); icivaes| ver sled CChoeexidine Unknown ers prs ND + Prsible cena nerous ‘stem tonicity i bea snplieasen ‘ese sy a pes airy an par + ct nd spect no ti: MRSA, aebiilio-eia Stapcocas ras ND, nak Tie ts nee "Geamesive crim inde Hacmophir pp, Never sp Estates, and Psedomonas spas tere seid 10% 24-2, Parenteral Agents Used Topical in he Care of urns mmm 295 ANTIBACTERIAL AGENTS ieee 2 ose es pests Antiviral Agents Conk poaien Inmnenem ; Ee David W. Kimberiin Nolonin Peemalin Tella Th et omviral compos to Peis by tha Unicel Seta enya and Dug. Adminisraron (FDA) was, oturdine for the topical ee Seamer of bers siplex vine CSV ke fn 1063 TH ANTIFUNGAL AGENTS Shorly folloved by licensure of amantadine in 1966, as the Bt ‘Amphotericin B systemic antiviral compound, for the treatment of influenza A {grt Duro fo 190s, caly vitratine (1976) recto forthe systemic teatment of HSV central nevus system (CNS) infection. The licensure of acyelovir in 1982 opened the fll of clinical antiviral drug imervention snd heralded the era of rapid {evelopment of new drugs. Tn addition to anietroviral drugs for the treatment of the human immunodeficiency virus (HIV), three additional non-HIV ankiviral ‘rugs were licensed in the 1980s: trfluridine (1980), nibavisin (1985), land interferon (986), Ten non-HIV antiviral drugs were licensed in the 1980s: foscarnet (1991), rimantadine (1993), ganciclovir (1984), fameiclovir (1994, valgeyclovir (1995), topical penciclovir (1996), cidofovir (1996),” palivizumad (1998), zanamivir (1999), and ‘oseltamivir (1999). Additionally, lamivudine, which was originally ‘approved as an HIV medication, was licensed for the treatment of ‘chronic hepatitis B virus (HV) infection in 1998, Fewer new antvita fgents were brought to market in the fist years of the 21st century valganciclovir (2001), adefovi dipivoxl (2002), pegylated interferon PART IV Laboratory Dlagrsls ant Meapy fects Diseases.(2003), and entecavir (2006). ‘These antiviral agents have: demon- ‘rated efficacy in the teatment of infections caused by HSV, cytomegalovirus (CMY), yaricella-zoster vicus (VZV), HIV. respiratory syncytial virus (RSV), influenza A and B, hepatitis B and human popillomavirus (HPV), and Lassa virus.! Non-HIV. antiviral agents and interferons that are currently licensed by the FDA are the primary focus of this chapter. Monoclonal and polyclonal antibody preparations, also utilized in the treatment ‘and prevention of viral infections, are addressed in pathogen specific chapters and in Chapter 6, Passive Immunization. GENERAL CONSIDERATIONS IN ANTIVIRAL THERAPY Drugs can exert antiviral activity through a number of mechanisms. including the following: (1) impeding host-virus interactions; (2) interfering with tanscription or replication of the viral genome: (3) interrupting viral protein synthesis and assembly; or (4) modulating host response to infection (Table 295-1) Antiviral agents require the viral target to undergo active replication in onder to exert therapeutic effect, and thus have no impact on latent viruses. Because current antiviral agents are virostatic, rather than virucidal, infection can resume or recur afler cessation of antiviral therapy, especially in persons who are immunocompromised. Antiviral agents can be administered topically, orally, or inte venously, or by local injection. Therapeutic intervention strategies include administering antiviral drugs forthe following: (1) the teat- ment of active viral disease (eg., treatment of herpes. simplex ‘encephalitis (HSE)), 2) the prevention of viral infection o disease (ex, prophylaxis against HSV in renal tansplant recipients); and (3) the pre-emptive treatment of viral infection to prevent viral disease (ex, therapy against CMV in bone marrow transplant recipients)? Glinical efficacy is optimized if the drug is administered soon after ESE Autre Ageris CHAPTER 295 147A) the onset of infection, before the virus has spread widely or caused irreversible cell damage. Efficacy probably depends on achieving sufficient intracellular concentrations of the antiviral agent at the site of infection. However, in most eases, predictive relationships between drug concentrations attained, in vitro sensitivity, and clinical outcome have not been establishes. ‘Two factors chat can limit the utility of antiviral drugs are toxieity and the development of resistance to the antiviral agent on the part of the virus. The acceptability of a given drug's toxicity. profile correlates directly with the severity of the disease for which i is being utilized, Viral diseases with Title orno morbidity and mortality require very safe antiviral agents in order to provide a risk-to-benelit ratio that favors licensure and use of the compounds. On the other hand, {or life-threatening viral infections, one Would accept the use of an effective antiviral compound even if adverse effects were common. "The increasing frequency with which drug resistance is encountered resulis from the expanded indications for and use of antiviral therapy.’ Resistance should be suspected ifthe clinical or virologic resporse (0 therapy is ess than that antiejpated on the basis of prior experience. Factors favoring the emergence of resistance include high virus foad, such as that accompanying chronic and/or progressive infections; high intrinsic viral mutation rates; and selective drug eure, typically resuling ftom prolonged or repeated courses of ‘therapy-* Persistent or recurrent infgetions among. immuno- ‘compromised patients are more likely o be caused by drug.-resistant viruses, because these patients are more likely to receive antiviral therapeutics (selective pressure) and their immune systems are less capable of assising in viral clearance. Resistance usually results from mutations within the viral genome that occur during therapy, although sometimes antiviral agent-resistant subpopulations_are present at the onset of reatment.* Table 295-2 describes mechanisms of viral resistance and alternative agents to consider if a resistant isolate is encountered. tre a Aton Aral a ST ‘rar rniod ee hee as mig od a aloe ieee ee aS Alto dos ae [cin oo Entecavir HBV . oo HSV Foscarnet HSV, VZV, CMV A My e oo yay oe asy ccna ‘Trif_uridine HSV Ss cher anu a Viral assembly release, or deageegation Interferon RNA tumor viruses 4 a ‘Oseltamivir Influenza A and B “en ‘Zananivie Anfluenza A and B = (MY. cjomeznovins; HD hepa irs; HCY hepa Cin HIN ban neni vi HPV ran papillomas Sheps singer vrs RS, ‘epiiryspnytal is VZV val nr vir[lier seerion B Annee Theray oe Z Antal Wius(es) Mechanism of Resistance Clinical Cortlates of Resistance ‘Aternativ Atal Agents) Aeyelovir HSV,VZV__Unally due mutations in Pasiseat or poaresve infection Foscaret Valeyetovie thymidine Kinase gene esaing du o resist strain isolated In abvent or altered thymidine fiom paints with overly we rely de to ton ‘ompromisod immunity imDNA poecase gene {eg bone marow tansplane recipients ad dose with AIDS) ‘Roles of HSV fom hely inva described in tone receiving lng tern sees therapy ‘Armnadine Tnflenea A Mitton in RNA seautnce ‘Usually recovered fom dg Osttmvir Rianne ‘reading for MD piel recipients within 2 days of Zanarivie ‘eanonembrane doin Sing derpy, and hei infected housed cons stinial relevance undefined ‘Ciao (CMY, HSV Mutton in DNA ‘Only are lnc solites have Foscamct Polymerase pene son repaid to dts Fancielovir sally to mations in Persistent or progressive infacson Foscamet Peneilovir ‘tymigine kinase gene the to revs sais oated Agjelowt ‘esting in abseot or aleed ‘nom patients with severely ‘yin Kinase: can also be ‘compromise int ‘i to mitation in DNA (ere, bone mare anspant polymerase pete ‘recipients and toe wit AIDS}: Iles of HY fom heathy Inividas dese in those seeciving long-term suppressive therapy Foscamet Mutations in viral DNA (Onl ar clinical oats have Anjelove Polymerase gene "asm reported 0 te Coto Ganciclovir cmv Deceased nacelle Responsible for severe, apy Focaret Valpmcicovie Phosphorylation det progressive infection n pants Citta Ioations in the CMY’ UL97 tits severely composed pene with decreased Fmvnity te bose mateo ‘expression of CMY transplant eepiets snd those phosphovanserase enzymes sity ADS) trrmitation in vial DNA pis polymere sene Tanivedine HBV, Mutation in HEV Reappearance of HBV DNA. Adeovir Polymense gene in serum afer ts iia Entec Ssappearance although most patients cotinae to hve ower Sora HBV DNA an ALT Tests compared wath preveaiment evel IDS, sq bmmnstcesy andtme; ALT aie ener: CMY oom MBN, Rel 8 rs HSV, easier vr WZ, aller i SPECIFIC ANTIVIRAL AGENTS Nucleoside and Nucleotide Analogues ‘Acyclovir (Acyologuanasine, Zovirax, ACN) and Valacyclovir (vattrex) ‘Chemistry, Mechanism of Action, Spectrum, and Resistance. Acyclovir i a deoxyguanosine analogue with an aeyelic side chain that lacks the 3"hydoxyl group of natural nucleosides Following preferential upsake hy infected calls aeyelovie is monophosphorylated by virusencoded thymidine kinase; host cell thymidine kinase is approximately | million times less capable of converting acyclovir © its monophosphate derivative, Subsequent diphosphorylation and teiphosphorylation are catalyzed by host cell enzymes, resulting in acyelovi triphosphate concentrations that are 40 1 100 times higher in HSV-infected cells than in noninfected cells,” Acyclovir srphosphate prevents viral DNA. synthesis by ihibiting dhe via DNA polymerase. In vito, asyeloir tiphosphate competes wih ‘deoxy guanine triphosphate as substrate for viral DNA polymerase Because scycloieleiphospate lacks the V-ydroxylaroup requited for elongation of the DNA chain, the growing chain of DNA is terminated. Th the presence of the deoxynucleoside triphosphate complementary (0 the next template postion, the viral DNA polymerase is functionally inactivated” In addition, acyeovie Triphoophate is much beter substrate For the viral polymerase thin for cellule DNA polymerse, resting in ithe incorporation of acyclovir ino cellular DNA. The higher eoncenraion of the ace Ueiphosphate metabolite im infected cols plus the affinity for il polymerases rest inthe very low toxicity of aeyclovi in noninfected fost ells Acyclovir is most active in vitro against HSV, with activity agunst VZV ting about 10-4 less but sill substantial, Although Epstein-Barr virus (EBV) has only minimal thymidine kinase activity, PART W Lata Diagnosis and Thoapy of esis DseasesEBV DNA polymerase is susceptible to inhibition by acyclovir triphosphate, Therefore, EBV is moderately susceptible to acyclovir in vitro, Activity against CMV is limited because CMV does not encode for thymidine kinase, and CMV DNA polymerase is poorly Inhibited by acyclovir triphosphate. In vitro susceptibility of viruses to acyclovir depends on a number of factors, including cel line, viral inoculum, incubation conditions, and the specific assay system used. Currently, n0 standardized method of susceptibility testing is universally accepted, and therefore wide disparities in. specific inhibitory concentrations of antiviral agents are reported. Given the limitations of susceptibility testing and variations in reporting, the relative activity of an antiviral agent is more meaningful than is the absolute inhibitory concentration. The relative activities of drugs sed in the treatment of herpesvirus infections are summarized in Tle 295-3. Resistance of HSV to acyclovir has Jong been recognized. How: ‘ever, thas only become an important clinical problem during the last ecade, In some referral centers, 5% to 145 of HSV isolates from immunocompromised patients are resistant to acyclovin” resistance to aeyclovir ean result from mutations in either the gene or the viral DNA polymerase gene. In addition to wildype (TK*) virus, three categories of TK mutants have been described, based on the extent of viral TK expression and TK substrate specificity. The most common of these are the thymidine kinase- negative (TIC) mutants, which are completely devoid of TK activity. Thymidine Kinase-partil (TKp) variants are very low producers of TK, having only 1% to 15% of normal TK activity. This degree of decrease in TK impairs their ability to phosphorylate acycloxir effectively, The third category of TK mutants are the TK-alteed (Ka) viruses: they are unable t0 phosphorylate acyclovir but can still Posphorylate thymidine. Although these acyciovir-resistant isolates ‘exhibit diminished virulence in animal models, among HIV-infected patients they can cause severe, progressive, debilitating mucosal disease and, rarely, visceral dissemination," Acycloviresistant strains of HSV have also eon recovered from cancer chemotherapy tents, bone marrow and sold organ transplant recipients, children With congenital immunodeficiency syndromes, and neonates, Aldiough itis uncommon, genital herpes caused by acyelovir-tesistant isolates has also been reported in immunocompetent hosts, who usualy have received chronic aeyclovir therapy." ‘Acyelovirresistant strains of VZV have also been reported. Resistance is due to mechanisms the same as those deseribed for HSV isolates, with TK" isolates being the most common. Most acyclovir- resistant VZV strains have been isolated trom HIV-infected children and adults who have profound depletion of CDA cells (100/mm") and hve previously received acyclovir therapy for prolonged periods of time." Changes in the susceptibility of VZV isolates to acyclovir can develop after only 4 10 12 weeks.” Foscamet is the drug of choice for both HSV and VZV infections caused by acyelovirresistant strats.” Valacyclovir is the L-valyl ester of acyclovir that is rapidly comerted to acyclovir afler oral administration by first-pass Antvral gents CHAPTER 205 147300008) metabolism in the iver its mechanism of ation, antiviral spectrum, and resistance age the same as those ofits parent drug. aeyelovie Pharmacokinetics. Acyclovir is available asa topical formula. tion, as oral formulations (capsules, tablets, and suspension), ands 2 sterile powder for intravenous shfusion, The topical formulation licensed in the United States is an ointment, whereas a cream is svailable in Europe. Although thes topical products ae nt absorbed sstemically, a substantial concentration of the dag reaches the bas epidermis in eutaneous infections. Only 15% 10. 30% of the oral Formulations of acyclovir is absorbed: peak concentrations of approximately 05 ugfnk are atained 1.5 to 25 bout aftr a 20-me dose." Higher doses est in higher serum concentrations, ad Foo oes not appear to aller the extent of absorption substantial, Steady State concentrations of acyclovir after intravenous doses of 2.5 to 15 mg/kg range from 6.7 © 20.6 yam. The disposition of acyclovir is ot affected by the duration or frequency of dosing, ‘Systemically. administered acyclovir is widely distributed, taining high concentrations in the kidneys, lg, liver, hear, and skin vesiles: concentrations atined in the cerebrospinal uid (CSP) are approximately 50% of those in the plasma,” Aeyelevir realy tosses the placenta and also accumlates in breast ik. Protein Winding ranges from 9% w 33% and is independent of plasma drug concentration. Less than 20% of acyclovir is metabolized ‘0. biologically inactive: metabolite; more than 60% of administered drug is excreted intact in the urine. Tae halite of aeylove is 20 $ hours in older chien and sults and 25 to 5 hous in neonates with ormal creatinine clearance (CxCI)." Elimination of acyclovie is prolonged in patiens with renal dysfunction, with « AAERS of Spproximately 20 hours in persons with endstage eeaal disease.” Dosage modifications are necessary for those with CrCl < 50 mLmin por 1.73 m? (for dosing. guidelines for various degrees of renal {ysfunetion, sce Table 295-4), Acyelovi is readily hemesilyeable, “he mean plas halle in patients during hemodialysis about $ hours, requiring that patients receive an additonal dose of acylovir after each dialysis (Table 295-5)" The halflife of seyelove is 13, to IShours diring continuous ambulatory peritoneal dialysis (CAPD), and no supplemental dose is necessry after adjustment of the desing terval ‘Alter eral administation of valcyclovir, pid and complete comversion to aeyelovie aceies wilh fstpass iotestnal ad hepatic rnetabolsm. The bioavailability of valaeyelovir exceeds 50%, which is thwee w five tines greater than that of aeyclovi Peak serum concentration, atained about 1.5 hours aficra dose has been given, tre proportional wo the amount of drog adminisered, they range fiom 08 to 85 upiml. for doses of 100 to 2000 mg.” The area under the drug concenttion time curve approximates that seen after inavenous aeyelovi. All other pharmacokinetic characteristics are similar to those of acyelovi. Toxicity and Drug Interactions. Acyclovie has consistently demonstrated a favorable safety profile. The topical formulation ‘an cause transient burning, expecially when applied to ulerated rnucosal lesions. Oral seyelovir # sometimes associated with mild Aeysivir Poncilovir Vidarabine Foscamet Ganciclovir ev + He 4 cu . 2 + EBV + i E + + ‘OMY, evonezaoei EBV, Epsen-Rar vis; ASV, mes lex vs VZV, vic oder vn - igh pe f avi, + mete dg of ath + inal ‘eae acs vn et ac[ers secrion B Antec Therry Ceo ed {retnine Clearance (mLnin pr 178m) Suggest Modifications of Standard Intravenous Dose ‘Suggested Mosiication of Standard Or Dose 350 No modesto acexry Te modicato bore 25-50 “Maintain unit dose, bt increase the dosing interval by 50% __No modification necessiry 1035 “Maina uni dose, bat double the dosing itera "Mains anit dose, but double the desing nerd “040 Reduce dose by 50%, and double the dosing serv “Maintain unit doe, br wip the dosing a ros Wags alan Les a” intra TABLE 295-5. Dosage Adjustments Necessary al Agents in Individuals with Renal Dystunation ‘reatnine Clarence Necessiating ‘esd for Suplementay Dose Dose Adustment nmin per 1.73) Fallowing Hemodaisis Apelor = Aeovir z <0 mantatne a 1.5 mpl lulated CxCI of $3 mlm, or urine Pron of 100 m/l (equivalent 10 2+ proteinuria). The maintenance ‘ose of eidofovir mast he reduced from 5 mgfke to 3 mgrke for an increase in serum creatinine of 0.3 10 04 mg/dL above baseline Cidofovir therapy must be discontinued if serum creatinine increases 0.5 mg. above baseline. In animal studies, cidofovir has been shown to be carcinogenic and teratogenic, and to eause hypospermia ‘Owing to poor eral bioavailability 2% 0 265), eidofovie ean only be administered intravenously or topically, Intravitreal ‘administration has been associated with acalar hypotony ‘Clinical Uses and Recommended Doses. Cidofovirhas been cvalated forthe treatment of CMY cetinitis inpatients with acquired Immunodeficiency syndrome (AIDS), and it delays retinal disease progression, One study ‘treated patients who had failed or were Intolerant of traditional therapy (ganciclovir o¢ foscamet) with a 2-week induction course of cidofovir (5 mg/kg administered weekly) followed by randomization to maintenance with either a dose of S mglkg or 3 mg/kg every other week" At the higher maintenance dose of eidotovit, disease progression was delayed for 115 days, ‘compared with 49 days inthe lower-dose cohort. Cidofovr his also been used successfilly in the management of disease caused by acyclovirresistant HSV isolates" ‘The safety and efficacy of eidofovir in children have not been studied, The tse ofeidofovir in children with AIDS warrants eaution because of the risk of long-term carcinogenicity and reproductive tonicity Tncralesional injection of cidofovie has been reported in several small, uncontrolled studies in patients sith laryngeal papillomatosis eaused by HPV infection.” Some patienls have experienced ‘dramatic improvement in thei disease although the anecdotal ature fof the wials prevents definitive conclusions regarding efficacy. Recent ncontolled studies have epotd less impressive therapeutic responses to cidofovie therapy.”"* raising further questions about cidofovir's efficacy and safely in laryngeal ppillomatosis. Case reports and small case series suggest that cidofovr may be beneficial in the management of adenovirus infections! and BK. virus infections" in immunocompromised patients. Cidovir is currently being cvaluated for the therupy of BK-induced nephropathy in a randomized controlled tial, conducted by the National Insite of Allergy" and Infectious Diseases (NIAID) Collaborative Antiviral Sudy Grovp. "The recommended induction dese of cidofovie for patients with ‘CMY disease with a serum creatinine of 1.5 mp/L, a calculated CrCl >55 mL/min, and a urine protein < 100 mgd (equivalent to <2+ proteinuria) is 5 mg/kg administered once per week for 2 consecutive weeks, The recommended maintentnce dose of idolovir is 5 mg/kg administered once every 2 weeks. Entecavir Baraclude) Chemistry, Mechanism of Action, Spectrum, and Resistance. Eniecavir is « guanosine micleside analogue, which, folowing phosphorylation tothe active triphosphate form, exhibits potent activity against HBV polymerase.” Entecavir triphosphate Inhibiss HBV polymerase base priming, everse transription of the negative strand from the pregenomic messenger RNA, and synthesis ‘of postive-stand HBV DNA. Its approximately 30-fod moe poten ‘an lamivudine in vito.” Entecavir phosphate isa eak inhibitor of cellular DNA. polymerases, and does not demonstrate activity, ‘against HIV-1 replication." ‘Current data suggest that emergence of resistance to enlecavie ‘does not commonly occur in nucleoside-nave patents. However, approximately 7 of lamivudine-tefractory patients with HBV infection develop entecavir resistance-associated substitutions st 169, ATIS4, $202, and/or M250 when pre-exising lamivudine resistance mutations reLIS0M andlor rtM204V/E are present. "= Entecavir is active against lamivudine and adefovirresistant mutants.” Emergence of entocavir resistance mutations is usually associated with virologic rebound during therapy. ‘Pharmacokinetics. Entecavr peak plasma concentrations oesut between 05 anid 15 hours following oral administration in adults Steady state is achieved following 6 to 10 days of once-duily ‘administration, with approximately ewofbld accumulation. At steady Mate, Cou 8 42 ngfmnL and Cina is 0.3 ng/ml. Due to decreases fof approximately 20% in area under the curve (AUC) when administered with food, entecavr sould only be given at eas 2 hours before or after a meal. The intracellular halflife of entecavie ‘eiphosphate is 15 hours. Approximately two-thirds to three-quarters ‘of drug is excreted unchanged in the urine Pharmacokinetic studies of entecuvir have not been conducted in children younger than 16 years of age Toxicity and Drug interactions. Coadminisration of enecavir in vitro with several HIV nucleoside reverse transcriptase inhibitors (OXRTIs) had no negative impact on entecavir'sant-HBV activity Con versely entecavr did not have a detrimental effect on the activity of the NRIs" anti-HIV aetivity. Eotecave i nota substrate, inhibitor, or inducer of the cytochrome P-4S0 enzyme system. AS such, enecait ‘pharmacokinetics are unlikely tobe affected by drugs that alec or are metabolized by the eytochrome P-450 system, Steady-state pharmaco Kinetics of entecavir are not altered when the drug is coadministred With lamivudine, adefovir dipivoxl, and tenofovir disopeoxi fumarate ‘As with other therapies for chronic HBV infections, severe acute exacerbations of hepatitis B have been reported in patients who have liscontinued entecavir therapy. Therefore, hepatic function should be ‘losely monitored with both clinical and laboratory follow-up for at least several months in patients who discontinue HBV therapy. Glinical Uses and Recommended Dosage. Entocwir is indicated forthe treatment of chronic HBV infection in adults with, evidence of active viral replication and either evidence of persistent levations in serum aminotransferses or histologically active liver disease. Enecavir is superior to lamivudine in the weatment of ‘chronic HBV infection," and is the most potent ant-HBV agent ‘available. When entecavir (05 mg once daily) was compared With lamivudine (100 mg once daily) for 32 weeks in nueleoside-naive patients with compensated liver disease, more patiens receiving feneeavir experienced improvement in histologic Knodell necro inflammatory scores in both hepatitis B e antigen (HBeAg)-postve (72% versus 62%, P <0.05) and HBeAg-negative (TO% versus 615, P-<005) patients Similarly, more patients developed normal alanine teunsferase (ALT) concentrations. during therapy with entecavie compared with lamivudine (68% versus 605) for HBeAg-positve patients, P16 years of age is 0.5 mz ‘once daily. In HBV-infected persons 216 years of age wiho have a bistory of HBV viremia while receiving lamivudine or who have a known lamivudine resistance mutation, the entecavir dase should be increased to 1.0 mg once daily. The optimal duration of therapy with entecavir is not know, Hemodialysis removes approximately 13% of the entecavir dose cover 4 houts, whereas CAPD removes approximately 0.3% of the dose over 7 days, In patients with renal impairment, the apparent foral clearance of entecavir decreases as CrCl decreases, Dosage ‘adjustment is recommended for patients with CrCl <5) mLimin, including patients on hemodialysis or CAPD, Dosage is 0.25 mi ‘once daily for CrCl 30 to <50 mlJmin, 0.15 mg once daily for CrCl 1010 < 30 mL/min, and 005 mg once daily for CCl < 10 mL/min or CAPD. A. dose should be administered after hemodialysis. These ‘doses are doubled for individuals refractory to lamividine. Fameiclovr Famvir) and Topical Penciclovir (Denavir) Chemistry, Mechanism of Action, Spectrum, and Resistance. Famciclovir is the inactive diacetyl ester prodrug of peaciclovir, an acyelic nucleoside anafogue with a spectrum of aetivity ‘agaist herpesviruses similar to that of acyclovi. hs activation by vial ‘and host ell enzymes and its mechanism of action are also akin to that ‘of acyclovir, excep that iis neither an obligate DNA chai terminator nor an inactivator of the DNA polymerase. However, laboratory Mies suggest that penciclovir triphosphate retards the rate of Subsequent nucleotide incorporation, Penciclovir is. approximately T0Ocfold less potent than acyclovir in inhibiting herpesvirus DNA, polymerase activity, However, it remains an effective antiviral agent because of high intracellular concentrations and long. halite Because peneielovir, like acyclovir, must be activated by the vita encaded TK enzyme, TK-delicient viral strains are rsisiant to both acyclovir and penciclovir. However, strains of HSV and VZV can remain susceptible to penciclovir when resisunce 10 acyclovir is ‘conferred by alteration of the TK enzyme or by DNA polymerase mutations." In addition to HSV and VZN, penciclovir has demonstrable in vitro activity against EBV and HBV. Penciclovir Persists in high intracellular concentrations much longer than Acyclovir its antiviral effect is more sustained, and the drug ean be audinistered less frequently than acyclovie Pharmacokinetics. After oral alministtation of fameiclovi, the bioavailability of penciclovr is about 70%. Food delays absorption but does not affect the final plasma drug concentration. Peak concentrations of drug after intravenous administration of 10 mg/kg fare approximately sixfold higher than those attained after oral doses of 250 mg. Drug halflife is 2.5 hows; almost 75% of administered drug is recovered unchanged in the urine, and) dose reduction is recommended for those with compromised renal function. 12-hour dosing interval is recommended for those with CrCl between 30 and 50 mL/min per 1.73 m?, and a 24-hour interval for those with CxC] < 30 mL/min per 1.73 mm." Measurable penciclovir concentrations are not detectable in plasma or urine after topical administration of peneiclovir cream. “Toxicity and Drug Interactions. Famciclovir is. as well tolerated as acyclovir. Complaints of nausea, diarthea, and headache ‘occurred in clinical wials, but at feequencies similar to those evel AgesenarreR 205 7ST reported by placebo recipients." No clinically significant drug fnleractions have been reported to date, although concentrations of famciclovir among volunteers increase by about 20% in patents ‘ectiving concomitant cimetidine or theophylline administration," Glinical Uses and Recommended Dosage. ‘The efficacy of famciclovir in the treatment of uncomplicated herpes zoster was studied in 2 placebo-comtolled, double-blind trial of 419 immuno- ‘competent adults. Treatment was begun within 72 hours of the appearance of lesions, and therapy was continued for 7 days Fameiclovir therapy decreased the median time to full crusting by 2 days. The effects of fameiclovie were greater when therapy was initiated within 48 hours of the onset of rash; it was also. more pronounced in patients 50 years of age or older. There were no ‘overall differences in the duration of pain before healing of rash between the fameiclovir-treated and the placebo groups. In addition, there was no difference in the incidence of postherpetic neuralgia between the treatment groups. Among patieats who developed postherpetic neuralgia, however, the meslian duration of symptoms ‘was shorter in patients treated with fameiclovir than in those given placebo (63 days and 119 days, respectively) ‘A double-blind, controlled wal in 545 immunocompetent adults ‘with uncomplicated berpes zoster weated within 72 hours of the initial appearance of lesions compared three doses. of fameiclovie with aeyelovir at « dose of 800 mg 5 times per day. Times to full lesion emusting and times to loss of acute pain were comparable for all groups, and there were no statistically significant differences in the times to resolution of postherpatic neuralgia between famiclov and acyelovir-treated groups. Placebo-controlled. studies of famciclovir for the episodic treatment of genital HSV" and for suppression of genital HSV recurrences!" have also been performed. Famciclovir was well tolerated and efficacious in these investigations.” Fumciclovic was approved by the FDA forthe treatment of herpes zoster in 1994, and was subsequently approved for the treatment ‘and suppression ‘of genital HSV disease. The indications for and recommended dosages of famciclovir are presented in Table 295-8, ‘Topical penciclovir forthe treatment of recurrent herpes labialis reduces the time to healing and the duration of pain by about half a day." "” Application of medicine should begin as early as possible, preferably during the prodromal phase, and should be continued every 2 hours during waking hours for 4 days Ganciclovir (DHPG, Cytovene, GCV) and Valganciclovir Walcyte, VeCV) Chemistry, Mechanism of Action, Spectrum, and Resistance. Ganciclovir is a nucleoside analogue that differs from selovir by having an extra hydroxymethyl group on the acyclic side chain." Its greatest in vitro activity is against CMV (soe Table 295.3), although it is aso as aetive as zeyclovir against HSV-1 and HSV-2 and almost as active against’ VZV. As with acyclovir LE 295-8. Fame ons and Dosages Infcton Dosage Duration Zoster 500mg id Taye Recent genital HSV (episodic heaps) 125 mg bid S days Recent genital HSW (suppressive 250mg bid Upw 1 year ‘therapy Recut genital HSV i compromised 500mg bid Tdays oats ‘Recuentocolabal HSV in compromised 500mg bid 7days HSV ees siglo vn[M40 section B_ Antintetie Teapy tnd penciclovir, the frst step in ganciclovir phosphorylation is carried out by a virus-encoded enzyme, and the final steps by cellular ‘enzymes. Because CMV lacks the gene for thymidine kinase. the fenzyme that catalyzes the initial phosphorylation of ganciclovir in ‘CMV-infected cells isthe phosphokransferase encoded by the (197 gene.” Intracellular ganciclovir triphosphate concentrations are at least 10-fold higher in CMV-infected cells than in noninfected cell." and intracellular ganciclovir triphosphate has a halflife of more than 24 hours. Ganciclovir triphosphate serves as a competitive inhibitor of berpesvial DNA polymerases, although i also as some activity against cellular DNA polymerases. This potential for incorporation into host cellular [DNA accounts for ganciclovir's Significant toxicity. Incorporation of ganciclovir teiphosphate ino the rowing viral DNA chain rsulis in slowing and subsequent cessation ‘of DNA chain elongation ‘Valganciclovir was approved by the FDA in 2001, Because itis ‘well absorbed ufler oral administration, it may representa favorable ‘option o intravenously administered ganciclovir forthe treatment and Suppression of CMV infections in immunacompromised. hosts, Valganciclovir isan L-valine ester produg of ganciclovir and has the ‘sme mechanism of action and antivial spectrum as ganciclovir,” Ganciclovir resistance among CMV isolates is. conferred by ‘mutations in ether the UL97 gene or the CMV DNA polymerase gone. (OF these two mechanisms of antiviral resistance, sunciclovir resistant (CMY isolates with mutations inthe UL? open reading frame are the ‘predominant phenotype.” Specific mutations within the UL9T region can be rapidly detected in plasma and serum by digect sequencing of polymerase chain reaction amplified CMV DNA." Resistant strains ‘of CMY should be suspected when progressive disease and continued recovery of virus occur despite ganciclovir therapy. In one sty, 87 (of 72 patients with AIDS had progressive infection associated with isolation of gunciclovir-resistant strains of CMV after 3 months of ‘continuous ganciclovir therapy.” Resistance may be more likely to ‘cur in patients «eated with oral ganciclovir than in those weaved ‘with intravenous ganciclovir, possibly owing tothe selective pressure applied by the lower concentrations. of deug achieved with oral Administration," By. contrast, CMV. isolates from solid organ ‘ransplant recipients who have been exposed to ganciclovir appear less likely to develop resistance tothe drug!” Fosearnet may be useful in ‘he Heatment of CMV infections caused by gunciclovieresistant isolates!" Occasionally, strains of HSV that are resistant to acyclovir because of TK deficiency ae also much less sensitive to gancieiovi.” Ganciclovieresistant isolates of HSV due to mutations in DNA. polymerase have been demonstrated in the laboratory but have not yet ‘become a clinical prablem. The mechanism of resistance to ganciclovir and valganciclovir are the same." Since selective pressure resulting from exposure to lower concentrations of drug appears to increase the likelihood of resistance eveloping. among CMY isolates," itis believed that the higher serum and tissue concentrations of ganciclovir achieved with ‘administration of valganeiclovir will produce less emergence of resistance compared with oral ganciclovir. Small studies. have indicated that rates of resistance among valganciclovir recipients are similar to those of intravenous ganciclovir recipients and are less ‘han those of patients taking oral ganciclovir Pharmacokinetics. Pesk scrim concentrations of ganciclovir atuained afier 5 my’ky administered intravenously range from 8 (0 11 jf. Concentrations suficient wo inhibit susceptible rains of (CMY are atained in aqueous humor, subretnal fluid, CSE, and brain tissue. Most of an administered dose of ganciclovie is eliminated Unchanged in the urine; the elimination halF-ife is 2 to 3 hours.” Dose reduction, roughly proportional to the degree of reduction in ‘CxCl, is necessary in persons with impaired renal function (see Table 295-5)" For CrCl 50 w <80 mLimin, half of the usual dose Should be given every 12 hours, Ths same dase should be given every 24 hours for CiC1 25 10 <50 mL/min per 1.73 my, and 25% of the ‘usual dose should be given every 24 hours for CrCl-<25 mLJmin per 1.73 me. Because ganciclovir i efficiently removed by hemodialysis, 1 supplemental dose is recommended after dialysis." ‘The pharmacokinetics of ganciclovir inthe neonatal popustion ae similar to those of adults After intravenous administation of 6 maske gancielovie, peak concentrations of 7.0 ugiml. are achieved. ‘The mean elimination halflife is 2-4 hous. ‘Oral biovailbility of ganciclove i poor wih < 10% of the drug being absorbed following oral administration. Despite this, anor dose of 1000 mg ganciclovir proces a peak plasma concentaton of 1 upiml, a evel tha is above the inhibitory concentration of mot (CMV clinical isolates nraiteal drug concentration achieved ding inwavenous induction therapy averages | ygimL, wheteas subnet concentation is comparable with plasma" Concenation of fanccloviin the CNS ranges fam 24% to 70% of tos in the pasa, ‘With bran concentration approximately 38% of plasma evel alganciclovi is rapidly converisd to ganciclovir, with a mean plasma halite of about 30 minutes The absolute bioavailability of Valgancielovir exceeds 60% and is enhanced by about 30% with concomitan administration of food.” Oral valganiclovir produces exposures of ganciclovir exceeding those atgned wit oral ganeiclovi an similar to those reported after standard intravenous administration of ganciclovir’ Patients with impaied renal inetion require dossee ‘eduction roushly proportional to their reuetion in CxCL." Toxicity and’ Drug Interactions. Tho most important txie effect of ganciclovir is myelosuppression. Dose-elated neutropenia, defined as a> S0% decrease in absolute neutophil count from baseline or <1000/mm'. is the most. consistent hematologic disturbance." The incidence of neutropenia during & 2-week course fs about 40%, Ieis dose-limiting in. about 134 of course, and is, reversible on cesstion of daug./® The likelihood of neutropenia ‘curring following oral administration of gancicloie i lower with 14% to 24% of patients developing an absolute neutrophil count of = 1000Vmm'. Hematopoietic growth factors may. he sel in preventing or counteracting neutropenia." Thrombocytopenia, (©5000. plstelewinin') occurs. in approximately 20% of tated Patients. Anemia oocurs in only about 26 of ganeiclovie recipients “Approximately 8% of ganciclovir recipients expeience some com bination ot headsche, cousin, altered mental sas, hallciation, nightmares, annity. ataxia, tremors, and. seizures. About 2% of recipients develop fever, rash, and abnormal levels of serum hepatic enzymes. Intraocular injection of ganciclovir can eause transient, increases in intraocular pressure with associated intense pain and amaurosis lasting up 1030 minutes." Tn pretinical est systems, sancilovi is mutagenic, carinosenic, and teratogenic. Additional, it causes imeversible reproductive toxicity in animals ‘The most common side effects associated with valgnciclvir therapy incluge diarrhea (41%). nausea (30%), neutropenia (27%), anemia (26%), and headache (22%). Long-term (up 10 5 yeas), treatment with valganciclovris well tolerated inpatients with AIDS, and the type and ineidence of adverse evens experienced long-term appear be similar to those observed at 1 yeas. Clinical Uses and Recommended Dosage. Ganciclovir i indicated for the tweatment and prevention of life- and sight threatening CMV" infections occurring in_ immunosuppressed patients It is approved inthe United States forthe treatment and Suppression of retinitis caused hy CMV in immuanocompromised patients and for the prevention of CMV disease in transplant recipients, bits frequently used fora numberof eter serious CMV infections. In almost 90% of patients with CMV retinitis, there is improvement o stabilization of the ecular disease and then cieating of te condition, o” & more than 100-fld reduction in vial tes, fom twine, blood, and throat after 110 2 weeks of gancielevi therapy Relapse of retinitis is virtually inevitable in patients with AIDS: ths, zzanciclove should be continued long-erm fox CMV suppression afer induction therapy. Patients in whom ganciclovir therapy has filed may benefit from treatment with a combination of foscamet and zzanciclovie! Paticnts with AIDS who have CNS disease caused by CMY have also been tested successfully with a combination of zanciclovi and foscarnet"” As many a8 25% of ganciclovir reipients develop resistance within 9 months of the initiation of therapy." PART IV Leburcty Dagnss and Therapy facts DisasasPationts with AIDS and recipients of solid organ transplants who ‘have gastrointestinal disease attributed to CMV appear to benefit fom, sunciclovir therapy." Gancielovie monotherapy does not appear to benefit hone marrow transplant recipients with CMY gastrointestinal iafbetions."= Timited and uncontrolled data suggest that ganciclovir therapy may be useful in patients with AIDS and CMV pneumonia” By contrast, bone marrow transplant recipients with CMV pneumonia ail, to respond to ganciclovir therapy alone but may benefit from therapy with intravenous CMV hyperimmunoglobulin and ganciclovir iver together ‘Ganciclovir has been evaluated in the treatment of neonates congenitally infovied with CMY. Ina phase Il ranomized controled tak ganciclovir therapy (6 ma/ke per dose administered q12 hours intravenously for 6 weeks) protected infants from hearing deterioration beyond I year of lie" Transient positive effects on growth were also seen, as was a decreased tine o resolution of serum hepatic transaminase flevation. Approximately two-thirds of treated. patients, however, ‘developed neutropenia, with half ofthese requiring dose modification, (Ganciclovir is usefl for prevention of CMY infstions in high-risk Jimmunocompromised subjects, including bone marrow and solid ‘organ transplant recipients (see Table 295-7), Strategie that have been tsed to reduce the frequency of postransplantation disease include routine administration of gancilewi o all ransplant recipients at risk ‘a pre-emptive administration to those who have @ postive cultare {for CMV after transplantation. Pre-emptive therapy has been demon. strted to reduce CMY disease effectively in recipients of liver,” Tu, heart," and bone marrow transplants," CMV-seropesitive recipients of heart, lung. oF liver transplants who receive routine ropilanis with gancilevir for I mont also have significant reductions in postranspiant CMV infection and disease." Pro-emptive ‘administration of ganciclovir improves survival in bone marrow transplant recipients," whereas routine initiation of prophylactic {ganciclovir prior to hone marrow tansplantation in patients who are EMV-seropositive does not have an impact on survival" Ukimately, however, the est stiategy has not been determined for preventing Primary CMV infections in seroncgative solid orpan transplant recipients ‘who receive an organ from a CMV-seropositive donot ‘The usta therapeutic and prophylactic dose of ganciclovir is mgr per day IV divided q12 hors for 2to 3 weeks. For continued suppressive therapy to prevent relapse of infection (eg. in patients ‘with AIDS) or long-term prophylaxis, either of the following may be used: (1) 5 mys as a single daily dose each day of the week: or (2) 6 migke administered as a single dose $ days a week. Prophylactic ‘oral ganciclovie (1000 mg td) significantly reduces the risk of CMV Alisase in persons with advanced AIDS." ‘Valaanciclovi has similar indications co ganciclovir. However, ‘based on limited controlld trials published to date itis curentty only approved for the induction and maintenance therapy of CMV retinitis!” The recommended dose of valganciclovir for induction therapy is 900 mg twice daly for 2 wecks, The recommended dose for maintenance therapy is 990 mg once daly. Orally administered valgancilovir appears to be as effective as intravenous ganciclovir for induction testment and is convenient and effective For the long-term ‘management of CMV retinitis in patients with AIDS. The greater systemic exposure to ganciclovir delivered by valganciclovir when used prophylactically is safe and is associated with delayed development of viremia in solid organ transplant recipients, compared with oral ganciclovir! Valgancilovir is also effective as pre-emptive therapy!” 2 and treatment for CMV {isease™ in solid organ transplant recipients Lamivudine (Epivr, 70) ‘Chemistry, Mechanism of Action, Spectrum, and Resistance, Lamivudine is a nucleoside analogus that is phosphorylated (0 lamivudine wiphosphate by cellular Kinases, Lamivudine inhibits the reverse tanseripase of both HBV and HI, and is indicated forthe treatment of HIV and chronic HBV infection, Amira Agents CHAPTER 295 LLamivudine-resistant HBV. mutants occur in up 10 one-third of subjects by th endof 1 year of therapy, an in p to two-thids by he fend of 4 years of drug exposure!” The most common mation affets the tyrosine-methionine-aspartate-aspartate (YMDD) motif in the eatalytie domain of the HBV polymerase, resulting ina change from methionine to valine (MS22V) or isoleucine (M522). Pharmacokinetics. Lamivudine at a dose of 4 mg/ke admin, istered tice daily produces an AUC), of 5.16 mg/L and ty. of 1.76 Fours This fn children is less than the Za in adults G5 hours).*” ‘Toxicity ‘and Drug Interactions. Adverse reactions include pancreatitis. paresthesia, peripheral neuropathy, neutropenia, anemia, Fashes, nausea, vomiting. ad hait loss Clinical Uses and Recommended Dosage. In the treatment ‘of chronie HBV infection, lamivudine decreases serum HBV DNA by 5 to log copies per mL in most patienss. Among patients who are Positive for HeAg, approximately 20%% achieve HBeAg serocon- version and undetectable serum HBV DNA at the end of | year of lamivudine therapy." Slightly more than half of patients experience improvement in histologic liver abnormalities. Similar Tindings have boon seen in children." Lamivudine resistance is visually manifest as breakthrough infection defined as reappearance ‘of HBV DNA in serum aftr ils initial disappearance." and occurs in approximately two-thids of patients within 3 yeas of therapy. Most patients continue to have lower serum HBV DNA and ALT levels compared with pretreatment values, perhaps due to decreased fitness of the lamivadine-resistant mutants, Upon cessation of Tumivdine therapy. most patients experience an increase in serum HBV DNA concentrations." [Lamivodine i indicated for th treatment of HIV infection and of clonic HBV infection. OF note, Epivi-HBV tablets and oral soltion tontain a lower dose of lamivudine than do Epivie tablets and oral Solution used for HIV infection. Therefore, the formulation and dosage of lamivuine in Epivir HBV are not appropriate for patents ‘dually infected with HIV and HBV: rapid emergence of HIV resistance is likely @ result hecause of the subtherapeutic dose for HIV, The recommended oral dose of lamivudine In adult’ HBV- infected patients is 1X) mg once daily. For HBV-infocted children 2 0 7 years of age, the dose is 3 mg/kg (maximum dose 100 mg) administered once daly Ribavirin (Vrazole; Rebetron Combination Therapy) Chemistry, Mechanism of Action, Spectrum, and Resistance. Ribavirin isa symbetic nucleoside analogue develope in 1972 that most lose resembles guanosine in structure." Ribavirin is rapidly absorbed aeross cell membranes and enzymatically converted by host cell enzymes into is phosphate derivatives and the deribosylated base" These metabolites interfere with the capping land elongation of messenger RNA. Ribavirin also appears to reduce {zuanine nucleosides via feedback inhibition. Although more potent fagtinst RNA vinises,ibavirin is active in vitro against a wide range fof both RNA and DNA viruses, inchuding myxovinuses, paramyxo Viruses, arenaviruses, bunyaviruses, herpesviruses, adenoviruses, powviruses, and regoviruses, "Tr is approved in the United States for the treatment of RSV infections and, in combination with interferon, for hepatitis C vias infections. The concentrations of dg required to inhibit in vio replication of influenza, parainfluenza, and RSV range from 3 10 10 wit, "=" Viral resistance to eibavrin has hot heen observed, although Sindbis views mutants with diminished ‘susceptibility to ribavirin have beea reported.” Pharmacokinetics. Ribavirin can be administered orally. inravenously, or by axovel, Only the aerosolized formulation of drug (Virazole) and the oral formulation (in combination in interferon-t (Rebetol oF peginteferon c-2a (Copegus) are approved for use in the United States. About 40% of orally administered ribavirin is absorbed following doses ranging from 600 vo 2400 mg, peak plasma feancentrations range from 1.3 to 3.2 jim. Peak concentations after intravenous therapy are approximately [0-fold greater. Riboviin nd its metabolites concentrate in red blogd eels, The levels in CSE[Ee section Bsns Therapy ‘ae approximately 70% of the plasms concentration of the deg,"* ‘About ove-quarter to one-third of systemically administered ribavirin is recovered unchanged in urine, and an additional 6% t0 30% is excreted as metabolites, The terminal half-life of ribavirin is 18 10 36 hours, but some drug persists in red blood ells for several weeks ater administration.” ‘Aerosolzed delivery of sbavitin (by mask, oxygen tet, oxygen ood, oF endotracheal tube) is accomplished’ with a smali-particle aerosol generator (SPAG). Although ribavirin is absozbed systemically after aerosolized delivery. the concentration of drug in the respiratory tract is much higher than in plasma, Levels in respiratory secretions are often > 1000 ng/mL. Plasma conocatrations increase with the duration of treatment, fom a mean plasma conceotration of (0.19 wef after 25 hours t 1.10 pater 8 hours of aerosolized ribuviin ‘The half-life of ribavirin in tracheal seeetions ranges from 14 0 25 hours “Toxicity and Drug Interactions. Ribavirin administered by the ‘ral and intravenous routes causes dose-related, reversible anemia ™ ‘Av ow doses of the drug, anemia is doe to extavasculee hemolysis, ‘whereas at high Joss itis due to bone marrow suppression. Increases in serum biliubin, iron, and uric acid also occur with systemic ribavirin therapy. Aerosolizd ribavirin is Sometimes associated with ld. conjunctival m and rash, Transient wheezing and cceasionally reversible deterioration in pulmonary function ean also accompany the use of aerosolized ribavirin, but whether this effect is due tothe treatment or the underlying RSV infection is eiffiult 9 Getermine."” No adverse hematologic effects are associated. with ‘administration of ribavirin by aerosol. When used in mechanically ‘ventilated infants, ribavirin can precipitate, plugging the ventilator ‘valves and ting, unless earful attention is paid to modifying the Circuitry and frequently changing in-line filter." Although no Pertinent human data exis, because ribavirin is teratogenic and bryolethal in a numberof small animal species iis containdicated in women who are or may become pregnant during exposure to the drug.” Acrosolization of ribavirin potentially exposes healthcare penonnel tothe daug, with expostre being greatest when ribavirin 1s delivered by tent and least when delivered by mechanical ‘entation *” Ribavirin was detected in low concentration (O44 ya ri) inthe erythrocytes of only 1 of 29 healtheare workers evaluated {nwo studies in which drug was being administered t0 children by ‘entlator oF oxygen tent oF oxygen hood without 2 seavenger system Ribavirin was not detected in any urine or serum samples. Clinical Uses and Recommended Dosage. In the United States, ribavirin aerosol was approved for use in spontaneously breathing infants in 1986 forthe treatment of lower respiratory tract Infoetions caused by RSV. However, considerable controversy exists about its clinical efficacy, and opinions diverge as othe ereumstances under which its use is appropriate. Initial placebo-controlie ils found that ribavirin improved respiratory signs and. symptoms, increased oxygenation, and decreased RSV titers in rbavinn-teaed patients "8°" Subsequent studies, however, have not shown Glinical benefit in reducing the severity of RSV disease."”—"" ‘Additionally, one study suggested that ribavirin use in mechanically \entlated. patients prolonged intensive care unit stay and/or hospitalization” As'a resuly, the American Academy of Pediatics Committ on Infectious Diseases changed iss recommendations for teatment of infants and chilren at igh risk for serious RSV disease from nbuvirin “should be used” (in 1993)2"" to “may be ‘considered (in 199), to “decisions shouldbe based onthe particular Clinical circumstance and physician's experience (in 2000) and Shoes Systemic ribavirin as demonstrated efficacy in the management ‘of lifethreatening infections caused by Lassa fever and hemorrhagic fever with renal syndrome.*"*" Orally and intravenously administered bavirin substantially reduce the mortality and morbidity dicctly attributable to each of these infections, and oral ribavirin has been recommended for propylans aginst Lassa fever in exposed comtaets. Clinical benefit has slo been observed inthe lweatment of Argentine and Bolivian hemorehagic fever" and Jaboratory-acquied Sabi virus infection “The usual dosage of aerosolized sbaviin is 20 magia. of drug ins inthe SPAG reservoir and administered for 12 2 hours pot day for 3 1 6 days. A more hihly concentrated dose of 60 mem ministered for 2-hour pedods, 3 ties a day, is well tla, permits easier accessibility for patent eare, and. may result in Iss frvironmental expostre of healtheate personnel without compen: ‘ising efficacy. The usual systemic dose of ribavirin i 4 I) i adults loading dose of 30 mgikg per dy (in tree divided doses), Tollowed by 15 mg/k per day. was use ina child. Tifluriine (TFT, Tifluorothymidine, Viroptic) ‘Tiflurdine isa pyrimidine nucleoside ative in vitro against HSV-1 and HSV-2 (including acyelovir-esistant strains), CMV, and certain adenoviruses" DNA polymerase activity and viral DNA synthesis ‘are inhibited. after phosphorylation to wifluridine_criphosphate Selection of tsifluridine-resistanc HSV strains with altered TK substrate specificity can be accomplished in the laboratory ‘Triflucdine is only approved for topical use in the management of primary keratoconjunctivits and recurrent keratitis caused by HSY. It Js more active than idoxuridine in HSV ocalar infections" and isthe ‘teatment of choice forthe topical treatment of HSV keratitis. Adverse effects include local discomfort, irritation, edema, and, less ‘commonly, hypersensitivity reactions as well as superficial punctate or epithelial Keratopaty. It is supplied asa 1% ophthalmic solution, one drop tobe instilled in each eye, upto nine times a dy. Vidarabine (ARA-A, Adenine Arabinoside, Vira-A Ophthalmic Ointment) Licensed for use inthe United States in 1977 asa systemic treatment for lfethreatening HSV and VZV infections, intaenous vdsrabing has not been available inthe United States since 1982 det the more favorable toxicity prof of intravenous acyclovir, However, topical preparation remains on the market fr the Weatment of HSV kertis Nidarabine is psphorylted by cellar enzymes wo the active triphosphate form. Thus, unlike acyelovi, conversion of viarabine to is active ineaceluar derivative doesnot require viral enzymes ta stp of the phosphorylation process this nck of pectfty accounts for at least some ois tone. Vidarabine triphosphate then seo a compete inhibitor of viral and, to lesser extent, cellule DNA. Polymers. 1 functions as a chai terminator ater incorporation tno the growing chain ofboth Viral and cellular DNA?” Vidarabing Usiphosphate aso inhibits ribonucleoside reductase, RNA polyadenylation, and S-adenosylhomocyseine hydrolase (SAH). an ‘zyme involved in tansmethslaton reactions. Inhibition of SAH an the resulting inhibition of adenosine deaminase may conta to Vidarabine'santivel and toxic eects" Resistance to viarsbine is conferred by mations in the vita DNA polymerase gene, ‘The degree of maximal resistance 10 vidarabine in polymerase mutants is fowfld, much lower han the 100-fold resistance to ayclovethat can result fo similar mutations Acyclovieesistant clinical HSV isolates vieually always retain in ito suscepaility to vdarabine > "Aktbough ifaridine i he ania agent of choice forthe topical treatment of HSV heraitis,vidarabie Is suitable alternate in puliens in whom tiflrdine cannot be used.” Topical vdarabine Js superior io idoxuriine inthe treatment of HSV ocular infestons.* Tricyclic Amines Amantadine (Symmetrel) and Rimantadine (Flumadine) Chemistry, Mechanism of Action, Spectrum, and Resistance, ‘Amantadine (I-adamantanamine hydrochloride) and rimantadine (0- ‘methyl-I-adamantanemethylamine hydrochloride) are. symmetric PART 1 Labortoy Deano and Tear of rtecbous oasestieyetic amines with cagelike siruetures that are closely related structurally to one another. Amantadine was the frst antiviral azent te licensed for systemic use in the United States. The activity of {amantadine and rimantadine is limited 10 influenza A. viruses, Rimantadine is 4- to 10-fold more active than amantadine. Inhibitory concentrations of susceptible influenza A isolates range from O.L to 04 g/mL for amantadine" and from 0.01. to 4 gil. for rimantadine-"" The target of the inhibitory action for boi amantadine and rimantadine isthe influenza A virus M2 protein. ‘The M2 proven isan integral transmembrane protein that functions as anion channel and is activated by pH" The M2 channel permits ions to enter the virion during the process of viral uncoating, This rests in destabilization of protein-protcn hands, allowing the viral nucleic acid tobe transported into the nucleus In addition, the M2 shamel acts to modulate the pH. of intracellular comparanent, Pull the Golgi apparatus." In some species, this stabilizes the influenza A virus hemagglutinin during intracellular anspor." ‘These activities of the M2 ion channel ae blocked by both ranting and amantadine." Resistance to amantadine and rimatdine results from a point mutation in the RNA sequence encoding forthe (M2 protein transmembrane domain "" The pH channel is effectively Locked by decreasing both the amplitude and the frequency of M2 ion channel opening. Resistance typically appears in the tated subject and his of her close contacts within 2 to 3 days ofthe initiation of therapy; as many’ as one-third of treated adults and children shed resistant strains of influenza by the fifth day of treatment"! The clinical significance of isolating resistant strains from treated subject, is not clear, ecause infection resolves despite the development of resistance #2" The transmission of resistant stains housshold tantacts can oceut, and the failure of drug prophylaxis can result! Therefore, contact between treated patients and susceptible subjects at high risk should be avoided." The tcyelie amines are not active against the influenza type A (HISN1) avian influenza vieuses. Pharmacokinetics. Amantadine is well absorbed. alter oral akinistration, with >80% of an orally administered dose being excreted unchanged in the urine. Rimantadine is also well absorbed. In contrast with amantadine, however, mantadine is metabolized extensively, with < 15% ofthe drug being excreted unchanged inthe tine" Food does noe appear to interfere withthe sbsorpion of ether drug. The time to the atainment of peak concentrations of both drugs ‘aries widely, ranging from 2 to 6 hours. Peak serum concentrations (044 to 08 ugimL) of both drugs are similar after 100-me oral doses. Children with eystic fibrosis have mean plasma concentrations of amantadine of approximately 0.6 ug/L after 6 mgfke per day.” The cancentrations of amantadine and rimantadine in nasal secretions ate 50% to 100% of those attained in serum; limited data suggest that thet is also good penetration into pulmonary tissue in infants The halflife of amantadine ranges from 12 t0 18 hours and that of Fimantadine ranges from 24 10 36 hours. Because of substantial diferenesin drug metabotism, compromised renal Function afects the climination halflife of amantadine more markedly than that of Fimanfadine. Substantial dose adjustments of amantadine are necessary in persons with CrCl <80 mLdmin per 1.73 m (Table 295-9)" By ‘contrast, dose adjustments forFimantadine are not necessary unless the GiC1 is <10 mLJmin, because clearance is decreased by only 40%, ‘even among those with severely compromised renal function.* Neither amantadine nor rimantadine is readily hemodialyzed: thus, ‘xkltional doses after dialysis are not required.” No pharmacokinetic ‘data exist for either amantadine or rimantadine in neonates, and the drugs are not icensed for use in children younger than I year of age. “Toxicity and Drug Interactions. Generally rimantadine is beter tolerated than amantaine: the types of averse reactions associated with both drugs are qualitatively similar but less frequent with Fimantaine. ‘The most common minor complaints associated with the sdministration of oth drugs are dose-related gastrointestinal and CNS, ssturbanees. CNS side effects, including nervousness, insomnia, Aificlty in concentrating, and confusion, occur in as many 2s one third of recipients of amantadine but in significantly fewer recipients Anat Agents cwarven 298 48310) TABLE 2 oo TT action ry ry 392 Adjustment Gratin (1 Clearance (comin per 1.73 m?) ‘Nona Ce Grancr ‘Usual daily dose for child younger 4.4 mg/kg per day in 1-2 aided than 10 eats of age with doses ‘Usual dally de for oer children 200 moday in 1-2 divided doses ‘nd ads Rouen Cx Cuan 0-30 Alternate usual daily dese with halt ‘of sal daily dose: drug very day 40-60 Half of usual diy dose: rug given ‘ich day 30-40 ‘Usual daly dose, bu drug given only tvie/neck 200 Half usual dally dose, drag given S timesweck 10-20 ‘Usual daily dose aerating with Tul usual dally dose, dug sven very 7 days ‘of rimantadine. Inability to continue prophylactic amantadine because ‘of these toxie reactions is reported in 54 to 10% of subjects." By ‘contrast, rimantadine prophylaxis is rarely discontinued because of side effects High plasma concentrations of amantadine can cause severe neuro- toxiciy, including tremor, hallucinations, seizures, and coma; cardiac arrhythmnias and death can also occu.” Patients with chronie seizure disorders can have increased frequency of seizures associated with either amantadine or rimantadine therapy. Long-term amantadine therapy can cause vision loss, hypotension, urinary retention, pet pheral edema, and congestive heat failure. Amantadine overdose can be associated with signs of excess anticholinergic activity, including ‘dry mouth, pupillary dilation, urinary retention, and toxie psychosis. Antihistamine and anticholinergic drugs can interact adversely ‘with amantadine, causing an increase in CNS symptoms. Drugs that ‘decrease the renal clearance of amantadine can also precipitate CNS symptoms, Clinically important interactions between rimantadine and ‘her drugs have no! been reported. Clinical Uses and Dosage. Until the 2005-2006 infivenza season, amantadine and rimantadine were useful in the prevention and treatment of infections caused by influenza A= However, extremely high rates of resistance emerged rapidly in 2005, and at the current time neither amantadine nor rimantadine are recommended for tecutment oF prophylaxis of influenza Prior to 2005, after experimentally induced or naturally occurring infections, both drugs reduced the risk of clinical illness due to various subtypes of influenza A by 70% to 90% compared with placebo2*=""=* Qutbreaks of infection within households, schools, rursing homes, and hospitals have been controlled with amantadine or rimantadine°"" Seasonal prophylaxis of high-risk hosts was recommended for those who cannat tolerate influenza vaccine because of toxicity or allergies and those in whom vaccine is unlikely to induce protective immunity because of severe immunosuppression (see Table 205-7).>" Prophylaxis was also prescribed if the vaccine may be ineffective because the epidemic strain differs substantially from the ‘vaccine stain of influenza A of forthe 2 weeks Following vaccination if influenza Ais already active in the community Seasonal prophy- axis as to be initiated as soon as influenza is identified in the con ‘munity and continued throughout the epidemic period. Prophylactic treatment of contacts of known cases of influenza A was tobe started as Soon as the contact is recognized and continued for 4 10 8 weeks.[Ms section B Aniinicetve Merny Prior to 2005, amantadine and rimantadine were also been shosen tbe effective inthe treatment of influenca A infections in adulls and children, provided that weatment is initiated within 48 hours of the ‘onset of symptoms" Compared with placeho, drug therapy results in reduced duration of viral excretion, fever, and other s¥stemic complaints, as well as an earlier resumption of normal activities, Rimantadine is only approved for prophylactic use in children, "The usual therapeutic and prophylactic dose of amantadine in children with normal renal function is 5 mg/kg per day given in 1 2 divided doses. Rimantadine is given inthe same dose but only once a day. The therapeutic dose of amantadine and timantadine for adults i 200 my/day, The prophylactic dose is 100 mg/day of amantadine and 200 mg/day of rimantadine, Inorganic Pyrophosphate Analogues Foscarnet (PFA, Foscavi Chomistry, Mechanism of Action, Spectrum, and Resistance. Foscamet is an inorganic pyrophosphate analogue that inhibits all known human herpesviruses, including most ganciclevit resistant CMV isolates and aeyclovieesistant HSV and VZV stains (Gee Table 295.3)" Is also active against HIV. This antiviral agent, directly inhibits DNA polymerase by blocking the pyrophosphate binding site and preventing cleavage of pytophosphate. from deoxynucleotide triphosphates." Is a noncompetitive inhibitor of viral DNA polymerases or HIV reverse transcripase and is not incorporated into the growing viral DNA chain, Its approximately 100-fold more active against vital enzymes than host cellular cnzymes" Although the drug concentrations required for inhibition ‘of Viral replication vary markedly, they generally range from 10 (0 130M for HSV, 1000 300 uM for CMV and 100 25 uM for HIV"? Resistance occurs as & result of DNA polymerase mutations; stains of CMY, HSY, and VZV with threefold to fivefold reduced sensitivity 0 foscamet have heen reported"? These isolates may respond 10 therapy with acyclovir or cidofovir Pharmacokinetics. Foscarnet is poorly absorbed after oral administration, with a bioavailability of only about 20%.” This tims foscarnet’s delivery to the intravenous route. Maximal. serum concentration attained after a dose of 60 mafky is approximately 500 umol/L. Data regarding tssue distibaton ave limited, but CS concentrations are about two-thirds of those in serum" Eighty perwent of an administered dose of fosearnet is eliminated unchanged, inthe urine: the hal-ie is 48 hours, and dosage adjustments are necessary even in the presence of minimal desrees of renal dysfunction (see Table 295-5). The deuree of dose reduction is proportional tothe degre of reduetion in CxCI; when CxCl is 50% of hormual, the dose should be reduced by about 50% (Figure 298-1, Hemodialysis efficiently eliminates foseamet. and therelgre an extra dose of drug is recommended after 2 3-hour dialysis run There are ‘no pharmacokinetic data for foscaret in neonates. Toxicity and Drug Interactions. ‘The most common and serious adverse effects of foscamet therapy ae nephrotoxicity and metabolic erangements, Azotemia, proteinuria, seute tubular necrosis, cryse tallria, and inerstal nephritis can occur and serum ereatnine conceriratons increas, usually durin the ccond week of therapy 8 as many as 50% of patents. In most affected patients, renal function ‘ears fo normal within 2to 4 weeks of stopping therapy, Risk factors for developing renal dysfunction include pre-existing renal disease, concurtent use of ether nephrosoxic drugs, dehydration, rapid injection ff large doses, and continous intravenous infusion of drug." Elccioyte disturbances, including symplomatic hypocalcemia and hypercalcemia and hypophosphatemia and hyperphosphatemis, can be caused by fosearmet therapy. Hypocaleemia i due to direct chelation ‘of fonized calcium by te du, and pation can have sympeoms such ss paresthesiss, tetany, seizures, and arthythmias"® Metabolic istrbanees can be minimized if foscamet is administered by slow infusion, with rates not exceeding 1 mg/kg per minute. Common CNS 2B s Big ee) S 0 02 04 06 08 1 12 14 46 Creatinine cloarance (link) Figure 295-1. Flecarrmendeci dosage of foscarme in patios wit ‘varying degrees of real imoatrnent. Tangles indicate maintenance ‘dove Pg per day; squares indicate induction dace (mag pet 8. ‘Adapted fom MacGregor AR, Graziani AL, Wess Reta. Success roscamet therapy or cytomegalovirus fetits in an AIDS patent undergoing hemodlass: atonal for erp dosing and plasma vel rmonitorng, J infect Os 1991;164.785-767, with permission, symptoms associated with foscamet therapy are headache, trenoe ieviabilty, seizures, and hallucinations. Fever, nausea, vomiting abnormal serum bepatic enzymes. anemia, granuloeytonenia, at ental ulcerations have also been reported. ‘The genital ulcerations ‘appear fo be associated with high urinary concentrations of drus."* Concomitant use of amphotericin B, eyelosporine, gentamicin, and other nephrotoxic dugs nereases the likelihood of renal dysfunction sssocated with foscaret therapy. Hypocalemia is more common ‘with coadministration of pentamidine, and anensia and neutropenia are Tore common when patients are treated with hoth foscamet and ‘idovudine. Clinical Uses and Recommended Dosage. the most important indication for fosearet is for therapy for sight-hreatening chorioretinitis caused by CMV in patients with AIDS.” Several controlled trials have demonstrated that foscamet is as effective as ganciclovir in managing this infection and may offer a survival advantage beeanse ofits inherent activity against HIV." In refractory cases of chovioretiniis,fescamet and guncilovir therapy have been sven in combination." Foscamet is also effective inthe treatment of CMY ‘infections caused by ganciclovirresistant stains ot CMV.” Limited data in patients with AIDS suggest that foxcamet may be cof henefit when administered to those. with gastrointestinal and pulmonary infections caused by CMY."*"" The usual dosage resinen Of foscaret for CMV infection is 180 mks per day in three divided oses for 4 to 21 days, followed by a daily maintenance dose of 90 40 120 mg/kg. About 90% of patients have stabilization of their retinitis, and the time to progression of inection is prolonged to about 3 months Infections caused by acyclovirresistant strains of HSV and VZV have also been successfully controled with foscaret 2 The dosage of foscamet used for these infection is 120 marke per day in three divided! doses. In paiens with AIDS, foscamet therapy should be inves within 7 10 10 days of suspicion of infection caused by avyeloviesesistant HSV or VZV." Therapy should be continued until lesions have resolved Interferons and Pegylated interferons Chemistry, Mechanism of Action, Spectrum, and Resistance. Inverferons urea family of nonspecific regulatory proeins associated with @ variety of antiviral, antproliferative, and immunomodulating ‘ctivities 2" There are two major types of interferons, Type I (and B) interferons are secreted by all nucleated cells after viral infection; PART 1 Laboratory Dayo an Therapy of fects Diseasesierfxon Bis prodominanty produced by vns-infected leukooyes, an interferons by fbyoblate There ae about 20 subeypes of iterfren-a tat share high degree of amino sci sequence homology but have efferent antiviral and biologie effets on human cals in ite Type IL oF immune) interferon is the product of setgen- of mitogenstinlatedIymphocstes. In addition to being Dace by iferet cells, the major types of inrferon are mano Ioialy dint and ave unique bolo effects and physiochemical sper Interferons reactive inst ahd range of irises in feteral, RNA ies are more sensitive than DNA vies Interferons da not hve direct antviell activity, ha rather exert satvraleffers by inducing producGon of mow than two dove tlctor proteins in expose cells. Antiviral cHets ane mediated by inition of viral penetration or uncoating, synthesis or meth aon of RNA, vial preci tension, or vial sembly and release" “The main inhibitory effet for specie viruses sitfer amon vires families, snd individual viwses an be inte at more than one sep. Antiviral activity can also be failifated by the complex interactions betwee ilerferons and wher components ofthe mine system, resulting in modieaton of host response to infection.” Iierorony devteses severe snfeton ia chien with chronic granulomas disease Pharmacokinetic. Inerferons ar aninstred by ingamuscular or subcutaneous Toutes, of by aiet injection ino vital lesions. ‘Absorpion of intereron-y is more than 80% complete ater invamuscular oe subcutaneous injection: plasma levels peak at 10 8 hours Plasma halite is appoximaely 2 to 4 hous, but the ati tate peaks at 2 hours and then slowly decrees to bascline over about 6 days2”” Neglsible plasma fevels of imerferon are detected ae intramuscular or subeutaneoos injection, and concen trations of iaterfeon-y are variable. After parenteral administration, cy Tow concentrations of interferon are detectable in boy tists An inching the CSF Inerteon eliminate by inaction in saious body fluids and metabolism in a number of omsans, including the Kidneys, iver, hea, sKeletal muscle, and Tangs ‘eli amounts are exerted in the wre “Toxicity and Drug Interactions. Inerferons cause immediate and late-onset adverse effets tha are dove tlated™ AL intercon doses at and above 1 to 2 milion TU, most persons develop an infec tks illness, with fever. cil, headabe, nals, hal au gastrointestinal diatrbances. These symptoms fpically appear ding the fist week of therapy and remit with continued therapy They rarely necessitate discontinuing therapy of modying dosage ‘Major therapy limited toxics. of systemically administred interferon are neuropsyehissic complications and. bone. marrow suppression." About 10% to 20% of interferon recipients dovelog Deuropsychiatrc problems, with greatest frequency inthe elderly ‘howe mith pre-existing CNS injuries, ins, oF psychosis ad those ity cons Symptons dually develop 2to 3 mans alter he initiation of therapy’ and itcle sommolenes, confusion, behavioral Usturbances, depression, neurasthenia with profound. fae, fnoresia, weight Toss, and cdsionallyseirures and coma Neatropenia an thrombocytopenia re the most commen sign Of hone marrow suppression they occur mos requ n patents with pre-existing poral hypenension Most persons have 40% decline inatolue neutopilcount within he st werk of therapy threo, therapy should be avoided. in those. with a noutrophil_count <150Q/m before therapy. The dose ofotereroy sould be reduced by 50% ifthe soup count drops 10 35 yM and 0.004 UM to > 100 uM, respectively (I uM = 0.284 w/a). Inhuman challenge studies, only 3% of pstreatment isolates were resistant to oseltamivir. However, a phase IV study from Japan identi- fied neuraminidase mutation confering resistance to neuraminidase inhibitors in 18% of treated children.“® The specific mutations were ‘Arg292Lys, Glul19Val, and Asn294Ser; sensitivity testing to oseltamivir carboxylate revealed that the neuraminidases of viruses ‘with these mutations were about 100-fld, 500-fld, or 300-fold more resistant than their pretreatment neuraminidases, respectively. (Oseltamiviersisant viruses were firs detected at day 4 of treatment. Pharmacokinetics. Osclamivir has goo! oral bioavalail at least 7566 of orally administered drug reaches the systemic eircuation inthe Form of oseltamivir carboxylate, The Cyax and the AUC for the active compound following a multiple 75-rmg bid oral dosing regimen are ‘M8 ng/ml. and 2719 ng himL, respectively. CCoadministrtion with food has no significant effect on the peak plasma concentration, Neither oseltamivir nor oseltamivir earboxylate is metabolized by cytochrome P-50 isoforms, Protein binding of oseltamivir carboxylate is only 34%, whereas the protein binding ofthe prodrug is 429%, The halF-life of oseltamivir after oral administration is 1 to 3 hours, ‘whereas the halflife of oseltamivir carboxylate is 6 to 10 hours" The Frimary route of elimination of oselumivir is by conversion to the active drug, with more than 90% of the prodrug being metabolized to osellamivie carboxylate, Oseltamivie carboxylate is not further metabolized, and it s entirely eliminated by renal excretion through lomeruar filtration and anionic tubwlar secretion. Serum concentni= lions of oseltamivir curboxylate inreave in the presence of declining renal function, and dose adjustment is recommended for patients with 8 CxCI below 30 mL/min, Administration of oseltamivir 1 patents with real failure (CeCl-< 10 min) has not been evaluated. Toxicity and Drug Interactions. ‘The most common advene effet reported with oseltamivir use is nausea, with of without vomiting. In eongolled clinical trials, approximately 10% of patents reported nausea without vomiting, and an addtional 10% experienced vomiting. The nauses and vomiting episodes were generally mild to moderate and usually occurred on the first 2 days of osekamivir fdministraion, Fewer than 1% of study subjects discontinued Participation in the clinical tials prematurely because of nausea nor vomiting. Food my help to alleviate these gastrointestinal sie effets in some patients." Insomnia and vertigo were aso reported more frequently among oseltamivir recipients than those receiving placebo, 'No drug interactions have been described to date fo oseltamivir or oseltamivir carboxylate. Neither the prodrug nor the active metabolite is metabolized by eytochrome P-450 isoforms. No dose adjustment, ‘te required when oseltamivir is coadministered with probenecid, Although oseltamivir has been demonstrated to be effective and well tolerated in treating patents as young as 1 year of age.” preclinical findings in juvenile rats raise concerns regarding use in Infants less than 1 year of age. A single dose of 1000 mg/ks ‘oseltamivir phosphate (about 250 times the recommended dase in children) in 7-day-old rats resulted in deaths associated with unusually high exposure to. oth oseltamivir and oseltamivir phosphate. Further studies showed levels of oseltamivir phosphate inthe brain be approximately 1500 times those seen in adult anima. Its likely that these high exposures are related to an immature blood-brain barrier. Studies showed no deaths or other significant effects in older juvenile rats given the same or higher doses of oseltamivir. The amount of oseltamivir phosphate not associated with adverse effeetsin the bran of juvenile rats corresponds to approximately 800-fld the exposure expected in a I-year-old child, The clinical significance of these preclinical data 10 human infants is uncertain, although reassuring data from small rials have been published. * Nevertheless, labeling information hes been modified de to these animal data to State that oseltamivir is not indicated for either treatment of prophylaxis of influenza in pediatric patients younger than | year of ‘age because of uncertainties regarding the rate of development ofthe human blood-brain barier and the unknown clinical significance of ‘nonclinical animal toxicology data for human infants" Clinical Uses and Recommended Doses. Oscltamivie is Ticensed for the eatment of influenza infection in patients I year of tage and oller, and is indicated for the prophylaxis of influenza in patients 13 years of age and olde. The efficacy of osetamivi forthe freatment of influenza has been established in «wo large phase I suds, one conducted at 60 centers throughout the United States.”” and the other conducted at 63 centers in Europe, Canada, and China "* ‘A total of [355 patients were enrolled into these two tials of whom {849 (63%) were subsequently confirmed to be infected with influenza, ‘The vast majority (85%) of patients were infected with influenza A Patients ha! to be enrolled within 36 houts of the onset of symptoms ‘The duration of illness among oselamivir recipients was reduced by approximately 1.3 days in both studies compared with placebo recipients." Among patents treated within 24 hours ofthe onset fof symptoms, illness duration was reduced by almost 2 days." (Oseltamivie recipients also had a more rapid return to normal Health ‘nd activity compared with patients receiving placebo." No serious drug-related adverse events were noted. ‘The proportions of ‘oseltamivir recipients who experienced nausea were 17% and 12% {or the United States and iterational studies, respectively. The frequency of physician-diagnosed secondary complications leading ‘antibiotic prescriptions was. slso reduced amnong_ oseltamivir recipients Similar results were observed in a randomized double blind, placebo-contolled study conducted in children with influenza infection.” PART IV Latratary Diagnosis nd Therapy of ects Diseases‘Compared with placebo, administration of oseltamivir for 6 weeks ‘during the peak of influenza season significantly reduced the risk of contracting influena,”” The protetiveeliccy forthe prevention of| culture-proven influenza approached 90F%,""°" which is comparable With that achievable with amantadine and rimantadine for influenza A ‘With the recognition beginning in Hong Kong in 1997 of type A (HSNI) avian influenza viruses capable of directly causing human disease, concer has steadily mounted worldwide about the possibilty ‘of an avian influenza pandemic. Changes in the A (HSN1) virus in 2003 resulted in the generation of wiat is termed the Z strain, which has spread to counties aeross Asia, and into Eastern and Western Burope."= This strain is characterized by pathogenicity in a larger number of animal species than are affected by other A (HSNI) strains, and by resistance tothe tricyclic amine class of antiviral agents, which include amantadine and rimantadine. Between December 2003 and December 30, 2005, a total of 142 Inboratory-confirmed aman cases of avian influenza A (HSN1) infections were reported to the World Health Organization.” OF these, 74 (5206) were fatal. All cases were reported from five countries in Asia (Cambodia, China, Indonesia, ‘Thailand, and. Vietnam), although reports of deaths from avian inluenza A in Turkey were also reported in easly 2006. The majority of cases appear to have been sequired from direct contat with infected poultry, but isolated eases of human-to-human spread of & (NSHI) has occurred in Vietnam and ‘Thailand. These clusters of human-to-human spread have resulted in deaths, suggesting thatthe A (HSN1) viruses spread from human to human have retained their pathogenicity ‘Antiviral susceptibility of strains of influenza A (HSNI) has been pecformed utilizing licensed influenza antiviral medications that include amantadine, rimantadine, and oseltamivix."* Influenza A (HSN1) is resistant to both amantadine and rimantadine. As of 2006, influenza A (HSN1) is. generally sensitive to oseltamivir at concentrations easily achievable in the plasta, although cases of oseltamivir resistance have been reported in Vietnam.” ‘The recommended oral dose of oseltamivir for the treatment of {influenza in adults and adolescents 13 years and older is 75 me bid for 5 days. For children 1 to 13 yeats of age, dose is based upon weight: (1) 215 kg (£33 Ibs), 30 mg bid: (2) > 15 kg to 23 kg (>33 Ib to 51 Ib), 45 mg bids 3) >23 kg to 40 kg (51 Toto 88 ib), 60 mg bid: and G4) >40 kg (88 Ih), 75 mg bid, Duration of treatment is 5 days ‘Treatment should begin within 2 days of the onset of symptoms of {nflucnea. Osoltamivie may'be taken with oF without food when taken with food, tolerability may be enhanced in some patients ‘The recommended oral dose of oseltamivir for the prophylaxis of influenza in adults and adolescents 13 years and older is 75 mg once daily for atleast 7 days. Therapy should begin within 2 days of close coniact with an infected person. Safety and efficacy have been demonstrated for up t0 6 weeks."” 'No dose adjustment is necessary for patients with CxCl > 30 mL min. In patients with CrCl <30 mL/min, itis recommended thatthe dose of oseltamivir be reduced to 75 mg once daly forS day's. Caution is advised when one administers oseltamivir 10 patients with CrCl <10 mL/min, because the use ofthe compound has not been evaluated in this population. At present, oseltamivir is only licensed by the FDA for use in adulis for the treatment of influenza A and B infections, Zanamivir Relenza) Chemistry, Mechanism of Action, Spectrum, and Resistance. Zanamivir also interferes with the function’ of the influenza neuraminidase enzyme, with subsequent interference with the deaggregation and release ofthe viral progeny. Zansamivir has poor oral bioavailability and is therefore administered by oral inhalation Although the amount of zanamivir that is delivered to the respiratory ‘ract during inhalation depends on patient factors, such as inspiratory flow, the supplied delivery device delivers 4 mg of zanamivir ‘when tested in vitro under conditions that approximate inhalation pressures achievable in vivo, Antiviral activity in vitro is dependent Antiviral Agents CHAPTER 295 fon the assay utilized and the viral strain evaluated. The ICsp and IC) ranged from 0.005 10 16.0 uM and 0.05 to > 100 4M, respectively (uM = 0.3 ugimab), "Antiviral resistance can be induced in vito by performing passage of the virus in the presence of increasing concentrations of zanamivie."™"" Decreased susceptibility to zanamivir was associated ‘with mutations resulting in amino acid changes in the viral neuraminidase and/or hemagglutinin. Resistance has_also. been documented in clinical specimens isolated from a zanamivir ecipient. ‘fier 2 weeks of therapy with zanamivir, an immunocompromised patient infected with influenza B shed a resistant isolte that was ‘Shown to have mutations in both the viral hemagelutinin and the viral neuraminidase.” The neuraminidase mutation resulted in 1000-fold reduction in enzyme activity. Cross-esistance between zanamivir and oseltamivir has been demonstrated as well in resistant isolates generated in vitro. Accurate estimation ofthe risk of emergence of (oseltamivir resistance inthe clinical setting will omy be determined by careful phase IV posilcensure monitoring Pharmacokinetics. More than 75% of an orally inhaled dose of ‘zanamivir is deposited inthe oropharynx, most of which is swallowed Approximately 13% ofthe dose distributes tothe sways and lungs, and the. remainder is retained in the delivery device." Inhaled ‘zanamivir provides local concentrations in respiatory tract mucosa, that greatly exceed inhibitory concentrations for influenza. A and B Viruses"; median zanamivir concentrations exceed 1000 ng/ml. in sputum 6 hours after inhalation and remain detectable for 24 hours.” Between 4% and 17% of an inhaled dose of zanamivir is absorbed systemically. Peak serum concentrations range from 17 to 142 ng/ml Within 2 hours of a 10-mg dose." The plasma half-life of zanamivir after oral inhalation ranges from 2.5 to 5.1 hours." Less than 10% of absorbed zanamivir is bound to plasma protein, No metabolites of zanamivir have been identified, and all absorbed drug is excreted Unchanged in the urine. Although serum zanamivir concentrations ease with decreasing CrCl, no adjustment in dosing is necessary in ‘cases of renal insufficiency. Unabsorbed drug is excreted inthe feces ‘Toxicity and Drug Interactions. Zanamivir is well tolerated." ‘The most serious adverse event associated with its use i respiratory distress. Decline in pulmonary function and bronchospasm have been reported in some patients receiving zanamivir" Mang, but not all, of these patients had underlying airways disease, such as asthma oF chronic obstructive pulmonary disease. Although influenza itself ean cause such deteriorations, eanamivir is generally not recommended for the treatment of patients with underlying airways disease because of the risk of adverse events andthe lack of demonstrated efficacy inthis population, Zanamivir should be discontinued in any patient who develops bronchospasm or a decline in respiratory function. No drug interactions with zanamivir have been reported Zanamivir does not affect cytochrome P-450 isoenzymes in human liver microsomes. Clinical Uses and Recommended Doses. The efficacy of ‘zanamivir in the management of influenza A and B virus infections has been demonstrated in three placebo-controlted stu." A total of 1588 patients were enrolled in these three investizations, of ‘whom 1167 (73%) were infected with influenza. Patients reccived zanamivir, 10 mg inhaled bid, versus placebo inhaled bid. The zanamivirsreated patents improved 1,0to 2.5 days faster than di the placebo recipients. Combined analysis of these tials indicated that Zanamivir reduces the duration of symptoms by approximately 1.5 days. Similar findings have been demonstrated in influenca-infected pediatric subjects"! Efficacy has been documented for both influenza ‘A and influenza B. Zanamivie therapy also reduces the frequency of ‘antibiotic prescriptions for lower respiratory complications by 40%, although it does not reduce prescriptions for presumed. uppet respiratory tract complications." Inhaled zanamivir, 10 mg once daily administered for 4 weeks os seasonal prophylaxis, reduces the likelihood of laboratory-confirmed influenza infection (with or without symptoms) by 31%, influenza disease by 67%, and influenza disease with fever by 849%." A study of zanamivir administered once daily to healthy household contacts offlitsse seeriow 8 Aonectne erpy influenca-infectod index subjects demonstrated a 79% reduction in influenza illness. “Zanativi is indicated forthe weatment of uncomplicated illness ve to influenza A and B virus of ao more than 2 days" duration, The recommended dose of zanamivir for the teatment of influenza in ‘duls and pediatie patients ages 7 years and older is two inhalaions (5 mg each administered bid fr $ days. "To doses should be taken on the fist day of weaument whenever possible, provided tha there is, at east 2 hours between doses. On subsequent ds, the doses should be approximately 12 hour apart Patients scheduled to use an inhaled Tronehodiaior at the same Gime as zanamivir should use their hronchedilsor before aking zaman, No dose adjustments are indicate in patients with implied renal function Antiparasitic Agents Craig M. Wilson and David 0. Freedman “This chapter provides a overview of antiparasitic thecapy organized broadly int: (1) gems ative aguinst luminal prosozouns: (2) agents active against the kintoplastd protozcans; 3) agents ative against the malarial parasites: (4) andbacerial agents with antprotozoan activity; and’ (5) anthelmintics. These divisions are somewhat bit, hecause some drugs are pertinent to moe than one category Appendix 296-1 is a reproduction with permission of the Drug for Parasitic Injections, Aust 2004 eon, published bythe Medical Letter Ine. and is organized by organism! Currently recommended dosing indications for individual drugs are given inthe table a5 they ‘may sary by omgunism. Most of the drugs and their paricular indications in speciic disease states are discussed more extensively in the ehaprers devoted to those organisms. Certain drugs, particularly the antibacterial agents with antiprotozoan activity. and. recom- ‘mendations for prophylaxis against specific parasites, are discussed in more dealin individual chapters inthe text. few drugs tha ae not available inthe United States but are used extensively in her ‘counties are discussed. ‘Commercial production and distribution of several widely use antiparasitic agents have ceased in the United States over the past Several years, because of commercial nonprofiabiiy fr their man- facturens in the domestic market* These agents include niclosamid, ‘quinaerine, dioxanide Turoate, and furazolidone. Specialized com: Pounding pharmacies may import bulk powder of all of these ‘compounds previously approved hy the United States Food and Drug ‘Administration (FDA), Panorama Compoonding Pharma and Medic ‘Center Pharmacy have well-established reputations within the topical «disease communi: Dithycarbamazine (DEC), mearsprol,nifrtine, Sodium stibosluconae, suramin, dehydroemstng, and bthenol ae now ‘only available through the Centers for Disease Control and Prevention (CDC). Telephone numibers fr the above-mentioned companies and the ‘CDC ae given in Appendix 296-1. Inravenous quinidine for weament of severe malaria is n0 longer stocked routinely by most hospitals cause it has fle into disuse as a eadiae agent “Thore are multiple other informative resourees about antiparasitic ‘horapy, eluding & more detailed discussion of pharmacokinetics and averse reactions.” Martindale: The Complete Drug Reference comains comprohensive information on antiparasitic drs available ‘worldwide, including brand names.” For particular recommendations regarding ‘malaria prophylaxis and advice for physicians. on ‘ease management, the telephone numbers are given in Chapter 271 (Plasmodiaon Species (Malaria). ‘TREATMENT OF LUMINAL PROTOZOA “Therapy for luminal protozoa as changed litle in the past decade However, some ances have heen made in the management of luminal protozoa that are inereasngly being recognized as pathogens, inially in patients with the acquired immunodeficiency syndrome {AIDS} and then in her community sotings, such as in eronp childcare. In addition, tnidazote and ntazoxanide have recently bee approved for use and wil be discussed further Below. Metronidazole and Tinidazole Metronidazole and tnidazole are synthetic nitroimidazoles with seletve activity agains organisms that utilize anaerobic metabolism (ee Chapter 292, Antimicrobial Agents). Metronidazole has been shown © be efficacious for the following. protozoa infections: Entamoeba hisiolytca.® E. polec” Giardia lambli,’Trickomenas vaginalis” Blastocystis hominis,” and Balantidium col The approval of tnidazole was based on studies done predominantly inthe 1970s and 1980s prior to ts use in European countries, Tnidezae is approved for use against giardiasis ond amebiasis in als and chien greater than 3 years of age and for trichomoniass in adults For amebiasis, these drugs are active against the trophoroite stage of the parasite life eyele and can bo used to treat the Iominal and tse phases of the infection, including. liver abscesses, Patients with Invasive colonic disease or liver abseess are also treated with jodoquinol or ther laminaly ative amebicies to elininate resid cyst forms of the parait. Mtronidxzole and tnidazol are the oa elective therapy svilable in the United States for trichomoniass, ‘with cure rates approaching 959% with single-dose regimens of both rugs" Tinidazole has in vitro activity against metronidazole resistant strains of 7. vaginalis” Both drugs are elfoctive against siardiasis"" Generally, tiniazole is as effective as metonidernie for most clinical indications and is modestly better tolerate, Tinidazole i used a8 a single-dose regimen for giardiasis and trichomoniasis and the recommended course for amebiasis s shor. Despite this, a course of tiniazole is considerably more expensive than generic metronidazole forall indications.” Tnidazoe is not available in suspension but can be formulated by crushing the Uublets Ornidazole is another nitromidazole with a similar pharmacokinetic profile to tinidayole and also ‘with extensive ‘linia experience in non-United States settings." Both metronidazole and tinidavole are generally well tolerste, With tinidazole being modestly. more favorable compared with ‘metronidazole at the high single-dose regimens or at the higher ses used for amebiasis. Sido effects of both digs include nasea, vomiting, epigasric discomfort, snorexia, and metalic or bier taste. Seizures and peripheral neuropathy have een reported uncommonly with both drugs. Patients taking either deg should avoid aleobol {including that found commoaly in suspensions of children’s medicines) because ofthe dislliram-lke effect Furazolidone FFurazolidone is nitofuran derivative most commonly used inthe treatment of giardiasis in children because of ts availability in a liquid preparation, although it i no longer commercially tvilable in the United States. This agent has heen used for & varity of bacterial pathogens of the intestine, including. Wbrio cholerae. The gastrointestinal tract side effects of nausea and Vomiting are the most commen complaints associated with furazolidone therapy. Allergic reactions, including pulmonary inflation, hypotension, umticaria, fever, and vesicular fash, occur PART 1 Lataatay lags an Therapy fects Dieses