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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
are
replicating.
The
earlier that treatment
is
given,
therefore,
the
better
the
result.
An
important
difficulty
is
that
a
substantial amount
of
viral multiplication
has
often
taken place
before
symptoms occur. Apart
from
primary infection, viral illness
is
often
the
consequence
of
reactivation
of
latent virus
in the
body.
In
both cases patients whose immune systems
are
compromised
may
suffer
particularly severe
illness. Viruses
are
capable
of
developing resistance
to
antimicrobial drugs, with similar implications
for
the
individual patient,
for the
community
and for
drug development.
An
overview
of
drugs that have
proved
effective
against virus
diseases
appears
in
Table
14.1.
Herpes simplex
and
varicella-zoster
ACICLOVIR
Aciclovir
inhibits viral
DNA
synthesis only
after
phosphorylation
by
virus-specific thymidine kinase,
which accounts
for its
high therapeutic index.
257
14
VIRAL,
FUNGAL, PROTOZOAL
AND
HELMINTHIC INFECTIONS
TABLE
1 4. 1
Drugs
of
choice
for
virus
infections
Organism
Varicella-zoster
chickenpox
zoster
Herpes simplex
keratitis
labial
genital
encephalitis
disseminated
Human
immunodeficiency
virus
(HIV)
Hepatitis
B, C or D
Influenza
A
Cytomegalovirus
(CMV)
Respiratory
syncytial virus
Drug
of
choice
aciclovir
aciclovir
or
famciclovir
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
or
oral
suspension)
•
ocular keratitis
(as an
ointment)
•
prophylaxis
and
treatment
in the
immunocompromised (oral,
as
tablets
or
suspension)
•
encephalitis, disseminated disease
(i.v.).
Aciclovir-resistant
herpes simplex virus
has
been
reported
in
patients with AIDS; foscarnet (see
p.
262)
has
been used
in
these cases.
Varicella-zoster
virus:
•
chickenpox, particularly
in the
immunocompromised
(i.v.)
or in the
immunocompetent with pneumonitis
or
hepatitis
(i.v.)
•
shingles
in
immunocompetent persons
(as
tablets
or
suspension,
and
best within
48
h of the
appearance
of the
rash).
Immunocompromised persons will
often
have more severe symptoms
and
require
i.v.
administration.
Adverse reactions
are
remarkably
few.
The
oph-
thalmic ointment causes
a
mild transient stinging
sensation
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 local
inflammation.
Valaciclovir
is a
prodrug (ester)
of
aciclovir,
i.e.
after
oral administration
the
parent aciclovir
is
released.
The
higher bioavailability
of
valaciclovir
(about
60%)
allows dosing only 8-hourly.
It is
used
for
treating herpes zoster infections
and
herpes simplex
infections
of the
skin
and
mucous membranes.
Famciclovir
is a
prodrug
of
penciclovir which
is
similar
to
aciclovir;
it is
used
for
herpes zoster
and
genital 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 antivirus
drug.
It is
superseded
by
aciclovir
and is
variably
effective
topically
for
ocular
and
cutaneous herpes
simplex
with
few
adverse reactions.
258
14
HUMAN
IMMUNODEFICIENCY VIRUS (HIV)
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
is
associated with redistribution
of
body
fat in
some patients ('lipodystrophy syndrome'),
and
protease inhibitors
may
disturb lipid
and
glucose metabolism. Appropriate laboratory
tests
to
monitor these
effects
should
be
performed.
•
Impaired cell-mediated immunity leaves
the
host prey
to
many (opportunistic) infections
including: candidiasis, coccidioidomycosis,
cryptosporidiosis, cytomegalovirus disease,
herpes simplex, histoplasmosis,
Pneumocystis
carinii
pneumonia, toxoplasmosis
and
tuberculosis (with multiply-resistant organisms).
Treatment
of
these conditions
is
referred
to
elsewhere
in
this text;
for a
comprehensive review
of
the
antimicrobial prophylaxis
of
opportunistic
infections
in
patients with
HIV
infection, readers
are
referred
to
Kovacs
&
Masur
2000
New
England
Journal
of
Medicine 342:1416.
Antiretroviral
drugs
may
also
be
used
in
com-
bination
to
reduce
the
risks
of
acquisition
of HIV
from
accidental needlestick
injuries
from
HIV-
contaminated sharps such
as
needles.
The
decision
to
offer
this postexposure prophylaxis
(PEP),
and
the
optimal combination
of
drugs
used,
should
be
made
by
experts
and
administration must begin
rapidly (within
a few
hours
of the
injury).
NUCLEOSIDE
REVERSE
TRANSCRIPTASE
INHIBITORS
Zidovudine
(Retrovir)
The
human immunodeficiency virus replicates
by
converting
its
single-standed
RNA
into double-
stranded
DNA
which
is
incorporated into
host
DNA; this crucial conversion,
the
reverse
of the
normal
cellular transcription
of
nucleic acids,
is
accomplished
by the
enzyme
reverse
transcriptase.
Zidovudine,
as the
triphosphate,
was the
first
anti-
HP/
drug
to be
introduced
and has a
high
affinity
for
reverse transcriptase.
It is
integrated
by it
into
the
viral
DNA
chain, causing premature chain
ter-
mination.
The
drug must
be
present continuously
to
prevent viral alteration
of the
host
DNA,
which
is
permanent once
it
occurs.
259
14
VIRAL,
FUNGAL, PROTOZOAL
AND
HELMINTHIC INFECTIONS
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
/
2
1h).
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
frequently
used
in
patients with
AIDS
including dapsone,
ketoconazole, quinolones
and
indinavir.
Zalcitabine
(DDC) (t
1
/
2
1h) is
similar. Adverse
effects
include peripheral neuropathy, hepatitis
and
pancreatitis which
are
reason
to
discontinue
the
drug.
Oral
ulceration, gastrointestinal symptoms
and
bone
marrow
suppression have also been reported.
Lamivudine
(3TC)
is a
reverse transcriptase inhibitor
with
a
relatively long intracellular
half-life
(14 h;
plasma
t
1
/
2
6 h). In
combination with zidovudine,
lamivudine
appears
to
reduce viral load
effectively
and to be
well tolerated, although bone marrow
suppression
may be
produced.
Rarely,
pancreatitis
may
occur. Lamivudine
has
also been used
for
treatment
of
chronic hepatitis
B
infection,
but
res-
istant strains
of
virus have been reported.
Abacavir
(t
1
/
2
2 h) may be the
most potent reverse
transcriptase inhibitor.
It is
usually well-tolerated,
but
adverse
effects
may
include hypersensitivity
reactions especially during
the
first
6
weeks
of
therapy.
Stavudine
(t
1
/
2
1
h).
Hepatic toxicity
and
pancreatitis
have been reported,
and a
dose-related peripheral
neuropathy
may
occur.
PROTEASE
INHIBITORS
Protease inhibitors constitute
a new
class
of
agent
for
HIV
infection.
In its
process
of
replication,
HIV
produces protein
and
also
a
protease which cleaves
the
protein
into
component
parts
that
are
sub-
sequently reassembled into virus particles; protease
inhibitors disrupt this essential process.
Protease inhibitors have been shown
to
reduce
viral
RNA
concentration
(Viral
load'), increase
the
CD4
count
and
improve survival when used
in
combination with other agents
and
compared
against 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
of
these
is in the
range
2-4 h. The
drugs have broadly
similar therapeutic
effects
and
include:
260
14
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.
INFLUENZA
A
Anti-HIV
drugs
are the
subject
of
intense
research
and
development
and
several
new
agents
belonging
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
(t
1
/
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; it
acts
by
interfering with
the
uncoating
and
release
of
viral genome into
the
host cell.
It is
well absorbed
from
the
gastrointestinal tract
and is
eliminated
in
the
urine
(t
1
/
2
3 h).
Amantadine
may be
used orally
for
the
prevention
and
treatment
of
infection
with
influenza
A
(but
not
influenza
B)
virus. Those most
likely
to
benefit
include
the
debilitated, persons with
respiratory
disability
and
people living
in
crowded
conditions, especially during
an
influenza epidemic.
Adverse reactions include dizziness, nervousness,
lightheadedness
and
insomnia. Drowsiness, hal-
lucinations, delirium
and
coma
may
occur
in
patients
with impaired renal
function.
Convulsions
may be
induced,
and
amantadine should
be
avoided
in
epileptic patients.
Amantadine
for
Parkinson's disease:
see
page 404.
Zanamivir (Relenza)
Zanamivir
is a
neuraminidase inhibitor which blocks
entry
of the
influenza
A and B
viruses
to
target cells
and the
release
of
their progeny.
It is
administered
as
5 mg of a dry
powder twice daily
in
5-day course
via
a
special inhaler. Controlled trials have shown
that
the
duration
of
symptoms
is
reduced
from
about
6
to 5
days, with
a
smaller reduction
in the
mean time
taken
to
return
to
normal activities.
In
high-risk
groups
the
reduction
in
duration
of
symptoms
is a
little greater,
and
fewer
patients need antibiotics.
Zanamivir
was one of the
first
medicines
to be the
subject
of a
technology appraisal
by the
National
Institute
for
Clinical
Excellence
(NICE)
in the UK.
NICE
recommends that
it be
reserved for: at-risk
patients (those with chronic respiratory
or
cardio-
vascular
disease, immunosuppression
or
diabetes
mellitus,
or
over
the age of
65); when virological
261
14
VIRAL,
FUNGAL, PROTOZOAL
AND
HELMINTHIC
INFECTIONS
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
is
common,
but is
reduced
by
hydration with
i.v.
fluids
before
each dose
and
co-administration with
probenecid.
A
variety
of
other
side
effects
has
been
reported, 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 a
special
ventilator
for RSV
bronchiolitis
in
infants
and
children.
Efficacy
for
this
indication
is
controversial,
and it is
usually reserved
for the
most
severe cases,
and
those with co-existing illnesses,
such
as
immunosuppression. Systemic absorption
by the
inhalational route
is
negligible.
It is
effective
by
mouth (t
1
/
2
45 h) in
treating Lassa
fever
and,
when combined with interferon
alfa-2b,
for
chronic
hepatitis
C
infection (see below). Systemic ribavirin
is an
important teratogen,
and it may
cause cardiac,
haematological, gastrointestinal
and
neurological
side
effects.
Palivizumab
may be
given
by
monthly
i.m.
injec-
tion
in the
winter
and
early spring
to
infants
at
high
risk
of
suffering
RSV
infection. Transient
fever
and
local
injection site reactions
are
seen,
and
rarely
gastrointestinal disturbance, rash, leucopenia
or
disturbed liver
function
may
occur.
Drugs
that
modulate
the
host
immune
system
Interferons
Virus
infection
stimulates
the
production
of
pro-
tective
glycoproteins (interferons) which
act:
(1)
directly
on
uninfected cells
to
induce enzymes that
degrade viral RNA;
(2)
indirectly
by
stimulating
the
immune system. Interferons will also
modify
cell
regulatory mechanisms
and
inhibit neoplastic
262
14
SUPERFICIAL MYCOSES
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, hypertension, 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 infection
ranging
from
comparatively trivial cutaneous
infec-
tions
to
systemic disease that demands prolonged
treatment with potentially toxic agents.
In
hospital,
Candida
infections have risen over
10-fold
over
the
past decade,
and
associated usage
of
antifungal
drugs
has
risen markedly.
Superficial
mycoses
DERMATOPHYTE
INFECTIONS
(ringworm, tinea)
Longstanding remedies such
as
Compound Benzoic
Acid
Ointment (Whitfield's ointment)
are
still
acceptable
for
mild infections
but a
topical imidazole
(clotrimazole,
econazole, miconazole, sulconazole),
which
is
also
effective
against
Candida,
is now
usually
preferred.
Tioconazole
is
effective
topically
for
nail
infections.
If
multiple areas
are
affected,
especially
if
the
scalp
or
nails
are
included,
and if
topical
therapy
fails,
oral itraconazole
or
terbinafine
are
used. Griseofulvin
has
largely been superseded
for
these indications.
CANDIDA
INFECTIONS
Cutaneous infection
is
generally treated with topical
amphotericin, clotrimazole, econazole, miconazole
or
nystatin.
Local
hygiene
is
also important.
An
under-
lying explanation should
be
sought
if a
patient
fails
to
respond
to
these measures,
e.g.
diabetes,
the use of a
broad-spectrum antibiotic
or of
immunosuppressive
drugs.
Candidiasis
of the
alimentary tract mucosa
responds
to
amphotericin, fluconazole, ketoconazole,
miconazole
or
nystatin
as
lozenges
(to
suck,
for
oral
infection),
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
cream
inserted once
or
twice
a day
with cream
or
ointment
on
surrounding skin. Failure
may be due to a
concurrent
intestinal infection causing reinfection
and
nystatin tablets
may be
given
by
mouth
263
14
VIRAL,
FUNGAL, PROTOZOAL
AND
HELMINTHIC INFECTIONS
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
mem-
brane
allows leakage
of
intracellular ions
and
enzymes, causing
cell
death. Those polyenes that
have
useful
antifungal activity bind selectively
to
ergosterol,
the
most important sterol
in
fungal
(but
not
mammalian)
cell
walls.
POLYENE
ANTIBIOTICS
These
act by
binding tightly
to
sterols present
in
cell
Amphotericin (amphotericin
B)
Amphotericin
is
negligibly absorbed
from
the gut
264
14
DRUGSTHAT DISRUPTTHE FUNGAL CELL
MEMBRANE
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
t
l
/
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 ampho-
tericin
is
used. Renal impairment
is
invariable,
although reduced
by
adequate hydration
and
ampho-
tericin
need
not be
stopped until serum creatinine
has
risen
to
180-200
micromol/1;
the
same dose
may
then
be
resumed
after
3-5
days. Amphotericin
nephrotoxicity
is
reversible,
at
least
in its
early
stages. Hypokalaemia
(due
to
distal renal tubular
acidosis)
may
necessitate replacement therapy. Other
adverse
effects
include: anorexia, nausea, vomiting,
malaise, abdominal, muscle
and
joint
pains,
loss
of
weight, anaemia, hypomagnesaemia
and
fever.
Aspirin,
an
antihistamine
(H
l
receptor)
or an
anti-
emetic
may
alleviate symptoms. Severe
febrile
re-
actions
are
mitigated
by
hydrocortisone
25-50
mg
before
each infusion. Lipid-formulated preparations
are
much less
often
associated with adverse reactions,
but
fever,
chills, nausea, vomiting, nephrotoxicity,
electrolyte
disturbance
and
occasional hepatotoxicity
have been reported.
Nystatin
(named
after
New
York
State Health Laboratory)
Nystatin
is too
toxic
for
systemic
use.
It is not
absorbed
from
the
alimentary canal
and is
used
to
prevent
or
treat
superficial
candidiasis
of the
mouth, 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
anthelminthic
members
of
this group
are
described
in the
appro-
priate sections. Antifungal azoles comprise
the
following:
•
Imidazoles
(ketoconazole, miconazole,
fenticonazole,
clotrimazole, isoconazole,
tioconazole)
interfere with
fungal
oxidative
enzymes
to
cause lethal accumulation
of
hydrogen
peroxide; they also reduce
the
formation
of
ergosterol,
an
important constituent
of the
fungal
cell
wall which thus becomes permeable
to
intracellular
constituents.
Lack
of
selectivity
in
these actions results
in
important adverse
effects.
•
Triazoles
(fluconazole, itraconazole) damage
the
265
14
VIRAL,
FUNGAL, PROTOZOAL
AND
HELMINTHIC INFECTIONS
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
H
2
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.
Fluconazole
Fluconazole
is
absorbed
from
the
gastrointestinal
tract
and is
excreted largely unchanged
by the
kidney
(i
l
/
2
30 h). It is
effective
by
mouth
for
oropharyngeal
and
oesophageal candidiasis,
and
i.v.
for
systemic
candidiasis
and
cryptococcosis (including crypto-
coccal
meningitis;
it
penetrates
the CSF
well).
It is
used prophylactically
in a
variety
of
conditions
predisposing
to
systemic
Candida
infections, includ-
ing at
times
of
profound neutropenia
after
bone
marrow
transplantation,
and in
patients
in
Intensive
Care
Units
who
have intravenous lines
in
situ,
are
receiving antibiotic therapy
and
have undergone
bowel
surgery.
It may
cause gastrointestinal
dis-
comfort,
headaches, elevation
of
liver enzymes
and
allergic
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.
admin-
istration. Absorption
from
the gut is
about
55% and is
variable.
It is
improved
by
ingestion with
food,
but
decreased
by
fatty
meals
and
therapies that reduce
gastric acidity,
and is
often
reduced
in
patients with
AIDS;
to
assure adequacy
of
therapy, serum concen-
trations should
be
assayed during prolonged
use for
critical
indications.
It is
heavily protein bound
and
virtually
none
is
found
within
the
CSF. Itraconazole
is
almost
completely oxidised
by the
liver
(it is a
substrate
for CYP
3A),
and
excreted
in the
bile; little
unchanged drug enters
the
urine
(t
1
/
2
25 h,
increasing
to
40 h
with continuous treatment). Itraconazole
is
used
for a
variety
of
superficial mycoses,
as a
prophylactic
agent
for
aspergillosis
and
candidiasis
in
the
immunocompromised,
and
i.v.
for
treatment
of
histoplasmosis.
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
brought
under control
by an
amphotericin preparation.
It
266
14
[...]... transmission of the infection because the patient becomes noninfective and the parasite fails to develop in the mosquito (site 4) In summary, drugs may be selected for: • treatment of clinical attacks • prevention of clinical attacks • radical cure Drugs used for malaria, and their principal actions are classified in Table 14.3 DRUG-RESISTANT MALARIA Drug-resistant parasites constitute a persistent... Erythrocyte cycle (site 2 in Fig 14.1) Merozoites enter red cells where they develop into schizonts which form more merozoites which are released when the cells burst giving rise to the features of the clinical attack The merozoites reenter red cells and the cycle is repeated Chloroquine, quinine, mefloquine, halofantrine, proguanil, pyrimethamine, and tetracyclines (blood schizontocides) kill these... Helminths have complex life-cycles, special knowl276 HELMINTHIC INFECTIONS edge of which is required by those who treat infections Table 14.5 will suffice here Drug resistance has not so far proved to be a clinical problem, though it has occurred in animals on continuous chemoprophylaxis Drugs for helminthic infections Albendazole is similar to mebendazole (below) Diethylcarbamazine kills both microfilariae . patient's
renal
function
deteriorates.
Further clinical trials
are
needed
to
establish
the
best
clinically
and
cost
effective
ways
to use
. 4).
In
summary, drugs
may be
selected for:
•
treatment
of
clinical attacks
•
prevention
of
clinical attacks
•
radical cure.
Drugs used
for
malaria,