Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 16) pptx

• Fungus infections range from inconvenient skin conditions to life-threatening systemic diseases; the latter have become more frequent as opportunistic infections in patients immunocom

Viral, fungal, protozoal and

helminthic infections

SYNOPSIS

• Viruses present a more difficult problem of

chemotherapy than do higher organisms, e.g.

bacteria, for they are intracellular parasites

that use the metabolism of host cells Highly

selective toxicity is, therefore, harder to

achieve Identification of differences between

viral and human metabolism has led to the

development of effective antiviral agents,

whose roles are increasingly well defined.

• Fungus infections range from

inconvenient skin conditions to

life-threatening systemic diseases; the latter have

become more frequent as opportunistic

infections in patients immunocompromised

by drugs or AIDS, or receiving intensive

medical and surgical interventions in ICUs.

• Protozoal infections Malaria is the major

transmissible parasitic disease in the world.

The life cycle of the plasmodium that is

relevant to prophylaxis and therapy is

described Drug resistance is an increasing

problem and differs with geographical

location, and species of plasmodium.

• Helminthic infestations cause

considerable morbidity.The drugs that are

effective against these organisms are

summarised.

Viral infections

Antiviral agents are most active when viruses arereplicating The earlier that treatment is given,therefore, the better the result An important difficulty

is that a substantial amount of viral multiplicationhas often taken place before symptoms occur Apartfrom primary infection, viral illness is often theconsequence of reactivation of latent virus in thebody In both cases patients whose immune systemsare compromised may suffer particularly severeillness Viruses are capable of developing resistance

to antimicrobial drugs, with similar implications forthe individual patient, for the community and fordrug development An overview of drugs that haveproved effective against virus diseases appears inTable 14.1

Herpes simplex and varicella-zoster

ACICLOVIR

Aciclovir inhibits viral DNA synthesis only afterphosphorylation by virus-specific thymidine kinase,which accounts for its high therapeutic index.14

TABLE 1 4 1 Drugs of choice for virus infections

aciclovir(topical) aciclovir (topical and/or oral) aciclovir (topical and/or oral) famciclovir (oral) aciclovir aciclovir zidovudine didanosine ritonavir indinavir saquinavir nelfmavir interferon alfa-2a and 2b

zanamivir ganciclovir

tribavirin

Alternative

valaciclovir or famciclovir valaciclovir

valaciclovir valaciclovir penciclovir foscarnet zalcitabine stavudine lamivudine nevirapine abacavir efavirenz lamivudine amantadine foscarnet (for retinitis in HIV patients) oidofovir

Phosphorylated aciclovir inhibits DNA polymerase

and so prevents viral DNA being formed It

eff-ectively treats susceptible herpes viruses if started

early in the course of infection, but it does not

eradicate persistent infection Taken orally about 20%

is absorbed from the gut, but this is sufficient for the

systemic treatment of some infections It distributes

widely in the body; the concentration in CSF is

approximately half that of plasma, and the brain

concentration may be even less These differences are

taken into account in dosing for viral encephalitis

(for which aciclovir must be given i.v) The drug is

excreted in the urine (t l / 2 3 h) For oral and topical

use the drug is given x 5/d

Indications for aciclovir include:

Herpes simplex virus:

• skin infections, including initial and recurrent

labial and genital herpes (as a cream), most

effectively when new lesions are forming; skin

and mucous membrane infections (as tablets ororal suspension)

• ocular keratitis (as an ointment)

• prophylaxis and treatment in theimmunocompromised (oral, as tablets orsuspension)

• encephalitis, disseminated disease (i.v.)

Aciclovir-resistant herpes simplex virus has beenreported in patients with AIDS; foscarnet (see p 262)has been used in these cases

Varicella-zoster virus:

• chickenpox, particularly in theimmunocompromised (i.v.) or in theimmunocompetent with pneumonitis orhepatitis (i.v.)

• shingles in immunocompetent persons(as tablets or suspension, and best within

48 h of the appearance of the rash)

Immunocompromised persons will oftenhave more severe symptoms and requirei.v administration

Adverse reactions are remarkably few The thalmic ointment causes a mild transient stingingsensation and a diffuse superficial punctate ker-atopathy which clears when the drug is stopped.Oral or i.v use may cause gastrointestinal symp-toms, headache and neuropsychiatric reactions.Extravasation with i.v use causes severe localinflammation

oph-Valaciclovir is a prodrug (ester) of aciclovir, i.e.

after oral administration the parent aciclovir isreleased The higher bioavailability of valaciclovir(about 60%) allows dosing only 8-hourly It is used fortreating herpes zoster infections and herpes simplexinfections of the skin and mucous membranes

Famciclovir is a prodrug of penciclovir which is

similar to aciclovir; it is used for herpes zoster andgenital herpes simplex infections It need be given

only 8-hourly Penciclovir is also available as a cream

for treatment of labial herpes simplex

Idoxuridine was the first widely used antivirusdrug It is superseded by aciclovir and is variablyeffective topically for ocular and cutaneous herpessimplex with few adverse reactions

H U M A N I M M U N O D E F I C I E N C Y V I R U S ( H I V )

Human immunodeficiency

virus (HIV)

GENERAL PRINCIPLES

• No current antiviral agents or combinations

eliminate HIV infection, but the most effective

combinations (so-called highly-active

anti-retroviral therapy, HAART) produce profound

suppression of viral replication in many patients

which results in useful reconstitution of the

immune system This can be measured by a fall

in the plasma viral load and an increase in the

numbers of cytotoxic T-cells (CD4 count) in

patients' plasma Rates of opportunistic

infections such as Pneumocystis carinii pneumonia

and CMV retinitis are reduced in patients with

restored CD4 counts and their life-expectancy is

markedly increased Efficacy of viral suppression,

however, must be balanced against the risks of

unwanted effects from the multiple drugs used

Combination therapy reduces the risks of

emergence of resistance to antiretroviral drugs,

which is increasing in incidence even in patients

newly-diagnosed with HIV

• HAART comprises two nucleoside reverse

transcriptase inhibitors used with either a

non-nucleoside reverse transcriptase inhibitor or one

or two protease inhibitors

• The decision to begin antiretroviral therapy is

based on the CD4 cell count, the plasma viral

load and the intensity of the patient's clinical

symptoms Therapy is switched to alternative

combinations if these variables deteriorate

Available information about drugs and

combinations is accumulating monthly and the

choice of agents is best made after reference to

contemporary, expert advice

• Pregnancy and breast-feeding pose especial

problems; therapy at this time is aimed to

minimise toxicity to the fetus while reducing

maternal viral load and the catastrophic results of

HIV transmission to the neonate Prevention of

maternal-fetal and maternal-infant transmission

is the most cost-effective way of using

antiretroviral drugs in less developed countries

• Combination antiretroviral therapy isassociated with redistribution of body fat insome patients ('lipodystrophy syndrome'), andprotease inhibitors may disturb lipid andglucose metabolism Appropriate laboratorytests to monitor these effects should beperformed

• Impaired cell-mediated immunity leaves thehost prey to many (opportunistic) infectionsincluding: candidiasis, coccidioidomycosis,cryptosporidiosis, cytomegalovirus disease,

herpes simplex, histoplasmosis, Pneumocystis

carinii pneumonia, toxoplasmosis and

tuberculosis (with multiply-resistant organisms).Treatment of these conditions is referred toelsewhere in this text; for a comprehensive review

of the antimicrobial prophylaxis of opportunisticinfections in patients with HIV infection, readersare referred to Kovacs & Masur 2000 NewEngland Journal of Medicine 342:1416

Antiretroviral drugs may also be used in bination to reduce the risks of acquisition of HIVfrom accidental needlestick injuries from HIV-contaminated sharps such as needles The decision

com-to offer this postexposure prophylaxis (PEP), andthe optimal combination of drugs used, should bemade by experts and administration must beginrapidly (within a few hours of the injury)

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Zidovudine (Retrovir)

The human immunodeficiency virus replicates byconverting its single-standed RNA into double-stranded DNA which is incorporated into hostDNA; this crucial conversion, the reverse of thenormal cellular transcription of nucleic acids, is

accomplished by the enzyme reverse transcriptase.

Zidovudine, as the triphosphate, was the first HP/ drug to be introduced and has a high affinity forreverse transcriptase It is integrated by it into theviral DNA chain, causing premature chain ter-mination The drug must be present continuously toprevent viral alteration of the host DNA, which ispermanent once it occurs

anti-14

Pharmacokinetics Zidovudine is well absorbed

from the gastrointestinal tract (it is available as

capsules and syrup) and is rapidly cleared from the

plasma (t l / 2 1 h); concentrations in CSF are

approx-imately half those in plasma It is also available i.v

for patients temporarily unable to take oral

med-ications The drug is mainly metabolically

inacti-vated, but 20% is excreted unchanged by the

kidney

Uses Zidovudine is indicated for serious

manifes-tations of HIV infection in patients with acquired

immunodeficiency syndrome (AIDS) or

AIDS-related complex, i.e those with opportunistic

infec-tion, constitutional or neurological symptoms, or

with low CD4 counts; treatment reduces the

frequency of opportunistic infections and prolongs

survival when used in effective combinations It is

also indicated alone for pregnant women and their

offspring for prevention of maternal-fetal HIV

transmission

Adverse reactions early in treatment may include

anorexia, nausea, vomiting, headache, dizziness,

malaise and myalgia, but tolerance develops to

these and usually the dose need not be altered More

serious are anaemia and neutropenia which develop

more commonly when the dose is high, and with

advanced disease A toxic myopathy (not easily

distinguishable from HlV-associated myopathy) may

develop with long-term use Rarely, a syndrome of

hepatic necrosis with lactic acidosis may occur with

zidovudine (and with other reverse transcriptase

inhibitors)

Didanosine (DDI) has a much longer intracellular

duration than zidovudine and thus prolonged

antiretroviral activity Didanosine is rapidly but

incompletely absorbed from the gastrointestinal

tract and is widely distributed in body water;

30-65% is recovered unchanged in the urine which

it enters both by glomerular filtration and tubular

secretion (t l / 21h) Didanosine may cause pancreatitis

with an incidence of 7% at a dose of 500 mg/d; a

reduced dose may be tolerated after symptoms have

resolved Other adverse effects include peripheral

neuropathy, hyperuricaemia and diarrhoea, any of

which may give reason to reduce the dose or

discontinue the drug It reduces gastric acidity, which

impairs absorption of a number of drugs frequentlyused in patients with AIDS including dapsone,ketoconazole, quinolones and indinavir

Zalcitabine (DDC) (t 1 / 2 1h) is similar Adverseeffects include peripheral neuropathy, hepatitis andpancreatitis which are reason to discontinue the drug.Oral ulceration, gastrointestinal symptoms and bonemarrow suppression have also been reported

Lamivudine (3TC) is a reverse transcriptase inhibitor

with a relatively long intracellular half-life (14 h;plasma t1/2 6 h) In combination with zidovudine,lamivudine appears to reduce viral load effectivelyand to be well tolerated, although bone marrowsuppression may be produced Rarely, pancreatitismay occur Lamivudine has also been used fortreatment of chronic hepatitis B infection, but res-istant strains of virus have been reported

Abacavir (t1/2 2 h) may be the most potent reversetranscriptase inhibitor It is usually well-tolerated,but adverse effects may include hypersensitivityreactions especially during the first 6 weeks oftherapy

Stavudine (t1/21 h) Hepatic toxicity and pancreatitishave been reported, and a dose-related peripheralneuropathy may occur

PROTEASE INHIBITORS

Protease inhibitors constitute a new class of agentfor HIV infection In its process of replication, HIVproduces protein and also a protease which cleavesthe protein into component parts that are sub-sequently reassembled into virus particles; proteaseinhibitors disrupt this essential process

Protease inhibitors have been shown to reduceviral RNA concentration (Viral load'), increase theCD4 count and improve survival when used incombination with other agents and comparedagainst placebo They are extensively metabolised

by isoenzymes of the cytochrome P450 system,notably by CYP 3A4 which is involved in the

metabolism of many drugs Plasma t l / 2 for each ofthese is in the range 2-4 h The drugs have broadlysimilar therapeutic effects and include:

Amprenavir, indinavir, lopinavir, nelfmavir,

ritonavir and saquinavir

Adverse effects A variety of effects has been

asso-ciated with these agents, including gastrointestinal

disturbance, headache, dizziness, sleep disturbance,

raised liver enzymes, neutropenia, pancreatitis, and

rashes

I N F L U E N Z A A

Anti-HIV drugs are the subject of intenseresearch and development and several new agentsbelonging to one or other of the above classes are to

be expected

InfluenzaA

Interactions Involvement of protease inhibitors

with the cytochrome P450 system provides scope

for interaction with numerous substances Agents

that induce P450 enzymes (e.g rifampicin, St

John's wort) accelerate their metabolism, and

reduce plasma concentration; enzyme inhibitors

(e.g ketoconazole, cimetidine) raise their plasma

concentration; competition with other drugs for the

cytochrome enzymes can lead to variable results

Ritonavir is itself a powerful inhibitor of CYP 3A4

and CYP 2D6 This effect is utilised when ritonavir

in small quantity is combined (in capsules) with

lopinavir to inhibit its metabolism and increase its

therapeutic efficacy The present account should be

sufficient to warn the physician, and thereby the

patient, to take particular heed when seeking to

co-administer any drug a with protease inhibitor

NON-NUCLEOSIDE REVERSE

TRANSCRIPTASE INHIBITORS

Efavirenz has a long duration of action and need

be taken only once per day (t l / 2 52 h) Rash is

relatively common during the first 2 weeks of

therapy, but resolution usually occurs within a

further 2 weeks; the drug should be stopped if the

rash is severe or if there is blistering, desquamation,

mucosal involvement or fever Neurological adverse

reactions occur and may be reduced by taking the

drug; gastrointestinal side effects, hepatitis and

pancreatitis have also been reported

Nevirapine is used in combination with at least two

other antiretroviral drugs, usually for progressive or

advanced HIV infection, although it appears effective

also in pregnancy It penetrates the CSF well, and

undergoes hepatic metabolism (t1/2, 28 h) It is taken

once daily, increasing to twice daily if rash is not seen

Rash and hepatitis are the commonest side effects

Amantadine

Amantadine is effective only against influenza A; itacts by interfering with the uncoating and release ofviral genome into the host cell It is well absorbedfrom the gastrointestinal tract and is eliminated inthe urine (t1/2 3 h) Amantadine may be used orally forthe prevention and treatment of infection withinfluenza A (but not influenza B) virus Those mostlikely to benefit include the debilitated, persons withrespiratory disability and people living in crowdedconditions, especially during an influenza epidemic.Adverse reactions include dizziness, nervousness,lightheadedness and insomnia Drowsiness, hal-lucinations, delirium and coma may occur in patientswith impaired renal function Convulsions may beinduced, and amantadine should be avoided inepileptic patients

Amantadine for Parkinson's disease: see page 404

Zanamivir (Relenza)

Zanamivir is a neuraminidase inhibitor which blocksentry of the influenza A and B viruses to target cellsand the release of their progeny It is administered

as 5 mg of a dry powder twice daily in 5-day coursevia a special inhaler Controlled trials have shownthat the duration of symptoms is reduced from about

6 to 5 days, with a smaller reduction in the mean timetaken to return to normal activities In high-riskgroups the reduction in duration of symptoms is alittle greater, and fewer patients need antibiotics.Zanamivir was one of the first medicines to be thesubject of a technology appraisal by the NationalInstitute for Clinical Excellence (NICE) in the UK.NICE recommends that it be reserved for: at-riskpatients (those with chronic respiratory or cardio-vascular disease, immunosuppression or diabetesmellitus, or over the age of 65); when virological

14

surveillance in the community indicates that

influen-za virus is circulating; and only for those who present

within 48 h of the onset of influenza-like symptoms

Unwanted effects are uncommon, but bronchospasm

may be precipitated in asthmatics and

gastro-intestinal disturbance and rash are occasionally

seen

Cytomegalovirus

when other drugs are unsuitable Nephrotoxicity iscommon, but is reduced by hydration with i.v.fluids before each dose and co-administration withprobenecid A variety of other side effects has beenreported, including bone marrow suppression,nausea and vomiting, and iritis and uveitis

Respiratory syncytial virus (RSV)

Ganciclovir

Ganciclovir is similar to aciclovir in its mode of

action, but is much more toxic It is given i.v or

orally and is eliminated in the urine, mainly

unchanged (t l / 2 4 h) Ganciclovir is active against

several types of virus but because of toxicity, its i.v

use is limited to life- or sight-threatening

cytomegalo-virus (CMV) infection in immunocompromised

patients, and (by mouth) for maintenance

suppres-sive treatment of retinitis in patients with AIDS,

and to prevent CMV disease in patients receiving

immunosuppressive therapy following organ

trans-plantation (especially liver transplants)

Ganciclovir-resistant cytomegalovirus isolates have been

reported

Adverse reactions include neutropenia and

throm-bocytopenia which are usually but not always

reversible after withdrawal Concomitant use of

potential marrow-depressant drugs, e.g

cotrimox-azole, amphotericin B, zidovudine, should be

avoided Other reactions are fever, rash,

gastro-intestinal symptoms, confusion and seizure (the last

especially if imipenem is coadministered)

Foscarnet is used i.v for retinitis due to CMV in

patients with HIV infection when ganciclovir is

contraindicated; it has also been used to treat

aciclovir-resistant herpes simplex virus infection

(see p 258) It causes numerous adverse effects,

including renal toxicity, nausea and vomiting,

neurological reactions and marrow suppression

Cidofovir is given by i.v infusion (usually every

1-2 weeks) for CMV retinitis in patients with AIDS

Ribavirin (Tribavirin) is a synthetic nucleoside

which may be administered by inhalation via aspecial ventilator for RSV bronchiolitis in infantsand children Efficacy for this indication iscontroversial, and it is usually reserved for the mostsevere cases, and those with co-existing illnesses,such as immunosuppression Systemic absorption

by the inhalational route is negligible It is effective

by mouth (t1/2 45 h) in treating Lassa fever and,when combined with interferon alfa-2b, for chronichepatitis C infection (see below) Systemic ribavirin

is an important teratogen, and it may cause cardiac,haematological, gastrointestinal and neurologicalside effects

Palivizumab may be given by monthly i.m

injec-tion in the winter and early spring to infants at highrisk of suffering RSV infection Transient fever andlocal injection site reactions are seen, and rarelygastrointestinal disturbance, rash, leucopenia ordisturbed liver function may occur

Drugs that modulate the host immune system

Interferons

Virus infection stimulates the production of tective glycoproteins (interferons) which act: (1)directly on uninfected cells to induce enzymes thatdegrade viral RNA; (2) indirectly by stimulatingthe immune system Interferons will also modifycell regulatory mechanisms and inhibit neoplastic

pro-S U P E R F I C I A L M Y C O pro-S E pro-S

growth They are classified as alfa, beta or gamma

according to their antigenic and physical properties

Alfa interferons (subclassified -2a, -2b and -Nl) are

effective against conditions that include hairy cell

leukaemia, chronic myelogenous leukaemia,

recur-rent or metastatic renal cell carcinoma, Kaposi's

sarcoma in AIDS patients (an effect that may be partly

due to its activity against HIV) and condylomata

acuminata (genital warts)

Interferon alfa-2a and -2b also improve the

man-ifestations of viral hepatitis, but responses differ

according to the infecting agent (see p 658) Whereas

patients with hepatitis B and C may respond to

interferon alfa, those with hepatitis C have a higher

rate of relapse and may need prolonged therapy

Interferon alfa-2b has been used in combination with

ribavirin for moderate to severe, chronic hepatitis C

infection, but not in patients who are heavy imbibers

of alcohol because of the risks of liver damage

Successful treatment results in the serum

concentra-tion of viral RNA becoming undetectable by

poly-merase chain reaction (PCR) Hepatitis D requires a

much larger dose of interferon to obtain a response

and yet relapse may occur if the drug is withdrawn

Adverse reactions are common and include an

influenza-like syndrome (naturally-produced

inter-feron may cause symptoms in natural influenza

infection), fatigue and depression which respond to

lowering the dose Other effects are anorexia

(suf-ficient to induce weight loss), convulsions,

hypo-tension, hyperhypo-tension, cardiac arrhythmias and

bone marrow depression Interferons inhibit the

metabolism of theophylline, increasing its effect

Inosine pranobex

This drug is reported to stimulate the host immune

response to virus infection and has been used for

mucocutaneous herpes simplex and genital warts

(but aciclovir is superior) It is administered by mouth

and metabolised to uric acid, so should be used with

caution in patients with hyperuricaemia or gout

Fungal infections

Widespread use of immunosuppressive

chemo-therapy and the emergence of AIDS have contributed

to a rise in the incidence of opportunistic infectionranging from comparatively trivial cutaneous infec-tions to systemic disease that demands prolongedtreatment with potentially toxic agents In hospital,Candida infections have risen over 10-fold over thepast decade, and associated usage of antifungaldrugs has risen markedly

Superficial mycoses

DERMATOPHYTE INFECTIONS

(ringworm, tinea)Longstanding remedies such as Compound BenzoicAcid Ointment (Whitfield's ointment) are stillacceptable for mild infections but a topical imidazole(clotrimazole, econazole, miconazole, sulconazole),which is also effective against Candida, is now usuallypreferred Tioconazole is effective topically for nailinfections If multiple areas are affected, especially ifthe scalp or nails are included, and if topicaltherapy fails, oral itraconazole or terbinafine areused Griseofulvin has largely been superseded forthese indications

CANDIDA INFECTIONS

Cutaneous infection is generally treated with topicalamphotericin, clotrimazole, econazole, miconazole ornystatin Local hygiene is also important An under-lying explanation should be sought if a patient fails torespond to these measures, e.g diabetes, the use of abroad-spectrum antibiotic or of immunosuppressivedrugs

Candidiasis of the alimentary tract mucosaresponds to amphotericin, fluconazole, ketoconazole,miconazole or nystatin as lozenges (to suck, for oralinfection), gel (held in the mouth before swallowing),suspension or tablets

Vaginal candidiasis is treated by clotrimazole,econazole, isoconazole, ketoconazole, miconazole

or nystatin as pessaries or vaginal tablets or creaminserted once or twice a day with cream or ointment

on surrounding skin Failure may be due to aconcurrent intestinal infection causing reinfectionand nystatin tablets may be given by mouth

14

8-hourly with the local treatment Alternatively, oral

fluconazole therapy may be used, and this is now

available without prescription ('over the counter'

medication) in the UK The male sexual partner may

use a similar antifungal ointment for his benefit

and for hers (reinfection)

Fluconazole is often given orally or i.v to heavily

immunocompromised patients (e.g during periods

of profound granulocytopenia) and to severely ill

patients on intensive care units to reduce the

incidence of systemic candidiasis

Systemic mycoses

The principal treatment options are summarised in

Table 14.2

Pneumocystosis, caused by Pneumocystis carinii

(now classified as a fungus), is an important cause

of potentially fatal pneumonia in the

irnmuno-suppressed It is treated with co-trimoxazole in high

dose (120 mg/kg daily in 2-4 divided doses for 14

days by mouth or i.v infusion) Intolerant or resistant

cases may benefit from pentamidine or, if mild to

moderate, from atovaquone, or trimetrexate (given

with calcium folinate) Co-trimoxazole by mouth or

intermittent inhaled pentamidine are used for

prophylaxis in patients with AIDS

Drugs that disrupt the fungal cell membrane

potyenes: e.g amphotericin

azotes: imidazoles, e.g ketoconazole triazoles, e.g.

fluconazole

allylamine: terbinafine

Drug that inhibits mitosis: griseofulvin

Drug that inhibits DMA synthesis: flucytosine

TABLE 14.2 Drugs of choice for some fungal infections Infection

Aspergillosis Blastomycosis '

Candidiasis mucosal

systemic Coccidiodoidomycosis '

Cryptococcosis chronic suppression Histoplasmosis chronic suppression 3 Mucormycosis

Paracoccidioidomycosis Pseudallescheriasis Sporotrichosis cutaneous deep

Drug of first choice amphotericin itraconazole or amphotericin

fluconazole or amphotericin amphotericin or flucytosine fluconazole or amphotericin

amphotericin + flucytosine fluconazole or itraconazole itraconazole or amphotericin itraconazole amphotericin

itraconazole or amphotericin ketoconazole or itraconazole itraconazole amphotericin

Alternative

itraconazole ketoconazole 2 or

fluconazole itraconazole or ketoconazole or

fluconazole itraconazole or ketoconazole 2 or

fluconazole fluconazole or itraconazole amphotericin (weekly) ketoconazole 2 amphotericin no

dependable alternative ketoconazole 2

potassium iodide Itraconazole or fluconazole

Drugs that disrupt the

fungal cell membrane

1 Patients with severe illness, meningitis.AIDS or some other causes of immunosuppression should receive amphotericin.

2 Continue treatment for 6-12 months.

3 For patients with AIDS.

This Table is drawn substantially from the Medical Letter on Drugs and Therapeutics (200l,USA).We are grateful to the Chairman of the Editorial Board for permission to publish the material (PNB, MIB).

membranes The resulting deformity of the brane allows leakage of intracellular ions andenzymes, causing cell death Those polyenes thathave useful antifungal activity bind selectively toergosterol, the most important sterol in fungal (butnot mammalian) cell walls

D R U G S T H A T D I S R U P T T H E F U N G A L C E L L M E M B R A N E

and must be given by i.v infusion for systemic

infection; about 10% remains in the blood and the fate

of the remainder is not known but it is probably

bound to tissues The tl / 2 is 15 d, i.e after stopping

treatment, drug persists in the body for several weeks

Amphotericin is at present the drug of choice for

most systemic fungal infections (see Table 14.2) The

diagnosis of systemic infection should whenever

possible be firmly established because toxicity from

conventional amphotericin is significant and the

lipid-associated formulations are very expensive;

tissue biopsy and culture may be necessary New

molecular diagnostic methods based on the

polymerase chain reaction to detect aspergillus DNA

may soon revolutionise management of invasive

infection A conventional course of treatment for

filamentous fungal infection lasts 6-12 weeks during

which at least 2 g of amphotericin is given (usually

1 mg/kg/day), but lower total and daily (e.g

0.6 mg/kg) doses are used for Candida infections

with correspondingly lower rates of adverse drug

reactions

Lipid-associated formulations of amphotericin

offer the prospect of reduced risk of toxicity while

retaining therapeutic efficacy In an aqueous medium,

a lipid with hydrophilic and hydrophobic properties

will form vesicles (liposomes) comprising an outer

lipid bilayer surrounding an aqueous centre The

AmBisome formulation incorporates amphotericin

in a lipid bilayer (diameter 55-75 nm) from which

the drug is released Amphotericin is also

for-mulated as other lipid-associated complexes, e.g

Abelcet ('amphotericin B lipid complex'), and

Amphocil ('amphotericin B colloidal dispersion')

Experience with these formulations is growing;

AmBisome is the most established, and it is

sig-nificantly less toxic but much more expensive than

conventional amphotericin It may be more

effective for some indications, probably because

higher doses may safely be given more quickly (e.g

3 mg/kg/day) It is the first choice for patients with

impaired renal function, but treatment is often

begun with the conventional formulation in those

with normal kidneys Therapy can be transferred to

AmBisome if the patient's renal function deteriorates

Further clinical trials are needed to establish the best

clinically and cost effective ways to use these drugs

Adverse reactions Gradual escalation of the dose

limits toxic effects but these may have to be accepted

in life-threatening infection if conventional tericin is used Renal impairment is invariable,although reduced by adequate hydration and ampho-tericin need not be stopped until serum creatinine hasrisen to 180-200 micromol/1; the same dose maythen be resumed after 3-5 days Amphotericinnephrotoxicity is reversible, at least in its earlystages Hypokalaemia (due to distal renal tubularacidosis) may necessitate replacement therapy Otheradverse effects include: anorexia, nausea, vomiting,malaise, abdominal, muscle and joint pains, loss ofweight, anaemia, hypomagnesaemia and fever

ampho-Aspirin, an antihistamine (H l receptor) or an emetic may alleviate symptoms Severe febrile re-actions are mitigated by hydrocortisone 25-50 mgbefore each infusion Lipid-formulated preparationsare much less often associated with adverse reactions,but fever, chills, nausea, vomiting, nephrotoxicity,electrolyte disturbance and occasional hepatotoxicityhave been reported

anti-Nystatin

(named after New York State Health Laboratory)Nystatin is too toxic for systemic use It is notabsorbed from the alimentary canal and is used toprevent or treat superficial candidiasis of themouth, oesophagus or intestinal tract (as suspension,tablets or pastilles), for vaginal candidiasis (pessaries)and cutaneous infection (cream, ointment or powder)

AZOLES

The antibacterial, antiprotozoal and anthelminthicmembers of this group are described in the appro-priate sections Antifungal azoles comprise thefollowing:

• Imidazoles (ketoconazole, miconazole,

fenticonazole, clotrimazole, isoconazole,tioconazole) interfere with fungal oxidativeenzymes to cause lethal accumulation of hydrogenperoxide; they also reduce the formation ofergosterol, an important constituent of the fungalcell wall which thus becomes permeable tointracellular constituents Lack of selectivity inthese actions results in important adverse effects

• Triazoles (fluconazole, itraconazole) damage the

14

fungal cell membrane by inhibiting a

demethylase enzyme; they have greater

selectivity against fungi, better penetration of the

CNS, resistance to degradation and cause less

endocrine disturbance than do the imidazoles

Ketoconazole

Ketoconazole is well absorbed from the gut (poorly

where there is gastric hypoacidity, see below); it is

widely distributed in tissues but concentrations

in CSF and urine are low; its action is terminated

by metabolism by cytochrome P450 3A (CYP 3A)

(i l / 2 8 h) Ketoconazole is effective by mouth for

systemic mycoses (see Table 14.2) but has been

superseded by fluconazole and itraconazole for

many indications largely on grounds of improved

pharmacokinetics, unwanted effect profile and

efficacy Impairment of steroid synthesis by

keto-conazole has been put to other uses, e.g inhibition of

testosterone synthesis lessens bone pain in patients

with advanced androgen-dependent prostatic cancer

Adverse reactions include nausea, giddiness,

head-ache, pruritus and photophobia Impairment of

testosterone synthesis may cause gynaecomastia and

decreased libido in men Of particular concern is

impairment of liver function, ranging from transient

elevation of hepatic transaminases and alkaline

phosphatase to severe injury and death

Interactions Drugs that lower gastric acidity, e.g

antacids, histamine H2 receptor antagonists, impair

the absorption of ketoconazole from the

gastro-intestinal tract Like all imidazoles, ketoconazole

binds strongly to several cytochrome P450

iso-enzymes and thus inhibits the metabolism (and

increases effects of) oral anticoagulants, phenytoin

and cyclosporin, and increases the risk of cardiac

arrhythmias with terfenadine A disulfiram-like

reaction occurs with alcohol Concurrent use of

rifampicin, by enzyme induction of CYP 3A,

markedly reduces the plasma concentration of

ketoconazole

Miconazole is an alternative Clotrimazole is an

effective topical agent for dermatophyte, yeast, and

other fungal infections (intertrigo, athlete's foot,

ringworm, pityriasis versicolor, fungal nappy rash)

Econazole and sulconazole are similar Tioconazole is

used for fungal nail infections and isoconazole and

fenticonazole for vaginal candidiasis.

predisposing to systemic Candida infections,

includ-ing at times of profound neutropenia after bonemarrow transplantation, and in patients in IntensiveCare Units who have intravenous lines in situ, arereceiving antibiotic therapy and have undergonebowel surgery It may cause gastrointestinal dis-comfort, headaches, elevation of liver enzymes andallergic rash, but is generally very well tolerated.Animal studies demonstrate embryotoxicity and flu-conazole ought not to be given to pregnant women.High doses increase the effects of phenytoin, cyclo-sporin, zidovudine and warfarin

Itraconazole

Itraconazole is available for oral and i.v istration Absorption from the gut is about 55% and isvariable It is improved by ingestion with food, butdecreased by fatty meals and therapies that reducegastric acidity, and is often reduced in patients withAIDS; to assure adequacy of therapy, serum concen-trations should be assayed during prolonged use forcritical indications It is heavily protein bound andvirtually none is found within the CSF Itraconazole isalmost completely oxidised by the liver (it is asubstrate for CYP 3A), and excreted in the bile; littleunchanged drug enters the urine (t1/2 25 h, increasing

admin-to 40 h with continuous treatment) Itraconazole isused for a variety of superficial mycoses, as aprophylactic agent for aspergillosis and candidiasis inthe immunocompromised, and i.v for treatment ofhistoplasmosis It is licensed in the UK as a second

line agent for Candida, Aspergillus and Cryptococcus

infections, and it may be convenient as 'follow on'therapy after systemic aspergillosis has been broughtunder control by an amphotericin preparation It

appears to be an effective adjunct treatment for

allergic bronchopulmonary aspergillosis

Adverse effects are uncommon, but include

tran-sient hepatitis and hypokalaemia Prolonged use may

lead to cardiac failure, especially in those with

pre-existing cardiac disease Co-administration of a

calcium channel blocker adds to the risk

Interactions Enzyme induction of CYP 3A, e.g by

rifampicin, reduces the plasma concentration of

itraconazole Additionally, its affinity for several P450

isoforms, notably CYP 3A4, causes it to inhibit the

oxidation of a number of drugs, including phenytoin,

warfarin, cyclosporine, tacrolimus, midazolam,

triazolam, cisapride and terfenidine (see above),

increasing their intensity and/or duration of effect

Voriconazole and posaconazole appear to be more

active than itraconazole against Aspergillus.

ALLYLAMINE

Terbinafine

Terbinafine interferes with ergosterol biosynthesis,

and thereby with the formation of the fungal cell

membrane It is absorbed from the gastrointestinal

tract and undergoes extensive metabolism in the

liver (t l / 2 14 h) Terbinafine is used topically for

dermatophyte infections of the skin and orally for

infections of hair and nails where the site (e.g hair),

severity or extent of the infection render topical use

inappropriate (see p 315) Treatment (250 mg/d)

may need to continue for several weeks It may

cause nausea, diarrhoea, dyspepsia, abdominal

pain, headaches and cutaneous reactions

or more Treatment must continue for a few weeksafter both visual and microscopic evidence havedisappeared Fat in a meal enhances absorption ofgriseofulvin; it is metabolised in the liver and induces

hepatic enzymes (t l / 2 15 h)

Griseofulvin is effective against all superficialringworm (dermatophyte) infections but is ineffec-tive against pityriasis versicolor, superficial candidi-asis and all systemic mycoses

Adverse reactions include gastrointestinal upset,rashes, photosensitivity, headache, and also variouscentral nervous system disturbances

Flucytosine

Flucytosine (5-fluorocytosine) is metabolised in thefungal cell to 5-fluorouracil which inhibits nucleicacid synthesis It is well absorbed from the gut,penetrates effectively into tissues and almost all is

excreted unchanged in the urine (t l / 2 4 h) The dose

should be reduced for patients with impaired renalfunction, and the plasma concentration should bemonitored The drug is well tolerated when renal

function is normal Candida albicans rapidly

becomes resistant to flucytosine which ought not to

be used alone; it may be combined with amphotericin(see Table 14.2) but this increases the risk of adverseeffects (leucopenia, thrombocytopenia, enterocolitis)and it is reserved for serious infections where the

risk-benefit balance is favourable (e.g Cryptococcus

neoformans meningitis).

Griseofulvin

Griseofulvin prevents fungal growth by inhibiting

mitosis The therapeutic efficacy of griseofulvin

depends on its capacity to bind to keratin as it is being

formed in the cells of the nail bed, hair follicles and

skin, for dermatophytes specifically infect keratinous

tissues Griseofulvin does not kill fungus already

Malaria

Over 90 million cases of malaria occur each year; insocioeconomic impact, it is the most important ofthe transmissible parasitic diseases

Quinine as cinchona bark was introduced intoEurope from South America in 1633 It was used for

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