Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 15) pdf

13
Chemotherapy
of
bacterial
infections
SYNOPSIS
We
live
in a
world
heavily
populated
by
microorganisms
of
astonishing
diversity. Most
of
these
exist
in our
external environment
but
certain
classes
are
normally harboured
within
our
bodies,
especially

colonising
mucosal
surfaces.
Depending
on the
circumstances,
infectious
disease
can
arise
from organisms
living
exogenously
or
endogenously,
and a
knowledge
of
common pathogens
at
specific
sites
often provides
a
good
basis
for
rational
initial therapy.
This

chapter
considers
the
bacteria
that
cause
disease
in
individual body
systems,
the
drugs
that
are
used
to
combat them,
and how
they
are
best
used.
It
discusses
infection
of:
Blood
Paransal
sinuses
and

ears
Throat
Bronchi,
lungs
and
pleura
Endocardium
Meninges
Intestines
Urinary tract
Genital tract
Bones
and
joints
Eye
Also
mycobacteria, that infect
many
sites
Table
I I. I (p. 21 I) is a
general reference
for
this chapter.
Infection
of the
blood
Septicaemia
is a
medical emergency. Accurate

microbiological
diagnosis
is of the
first
importance
and
blood cultures should
be
taken
before
starting
antimicrobial
therapy. Usually,
the
infecting organ-
ism^)
is not
known
at the
time
of
presentation
and
treatment
must
be
instituted
on the
basis
of a

'best
guess'.
The
clinical circumstances
may
provide
some clues. Patients
who
have been
in
hospital
for
some
time
before
presenting with septicaemia
may
need
antibiotic regimens
that
provide more reliable
cover
for
multiply
resistant
pathogens,
and
examples
of
suitable choices

are
given
in the
list below
in
brackets.
•
When septicaemia follows gastrointestinal
or
genital
tract surgery,
Escherichia
coll
(or
other
Gram-negative
bacteria), anaerobic bacteria, e.g.
Bacteroides,
streptococci
or
enterococci
are
likely
pathogens
and the
following combinations
are
effective:
cefuroxime
plus metronidazole

or
gentamicin plus benzylpenicillin plus
metronidazole (meropenem plus vancomycin).
•
Septicaemia related
to
urinary tract infection
usually involves
Escherichia
coli
(or
other Gram-
negative bacteria), enterococci: gentamicin plus
benzylpenicillin
or
cefotaxime
alone
(ciprofloxacin
plus vancomycin).
•
Neonatal septicaemia
is
usually
due to
streptococci or
coliforms: benzylpenicillin plus
gentamicin.
237
13
CHEMOTHERAPY

OF
BACTERIAL
INFECTIONS
•
Staphylococcal septicaemia
may
be
suspected
where
there
is an
abscess, e.g.
of
bone
or
lung,
or
with acute
infective
endocarditis
or
infection
of
intravenous
catheters: high dose flucloxacillin
is
indicated (vancomycin).
•
Toxic
shock syndrome occurs

in
circumstances that
include healthy women using vaginal tampons,
abortion
or
childbirth,
and
occasionally with skin
and
soft
tissue infection.
The
clinical problem
is
due to
systemic
effects
of
toxins produced
by
staphylococci: while this
is not
strictly
an
infection
of
the
blood,
flucloxacillin
is

used
to
eliminate
the
source. Elimination
of the
source
by
removal
of the
tampon
and
drainage
of
abscesses,
and
circulatory
support
are
also important.
Antimicrobials
should
be
given i.v. initially
in
septicaemia.
OTITIS
MEDIA
Mild
cases, characterised

by
pinkness
or
infection
of
the
eardrum,
often
resolve spontaneously
and
need only analgesia
and
observation. They
are
nor-
mally viral.
A
bulging, inflamed eardrum indicates
bacterial
otitis media usually
due to
Streptococcus
pneumoniae,
Haemophilus
influenzae,
Moraxella
(Bran-
hamella)
catarrhalis,
Streptococcus

pyogenes
(Group
A)
or
Staphylococcus
aureus.
Amoxicillin
or
co-amoxiclav
is
satisfactory,
but the
clinical
benefit
of
antibiotic
therapy
is
very small when tested
in
controlled
trials.
Chemotherapy
has not
removed
the
need
for
myringotomy when pain
is

very severe,
and
also
for
later
cases,
as
sterilised
pus may not be
completely
absorbed
and may
leave adhesions that impair
hearing. Chronic infection presents
a
similar problem
to
that
of
chronic sinus infection, above.
Infection
of
paranasal
sinuses
and
ears
SINUSITIS
Acute
infection
of the

paranasal sinuses causes
significant
morbidity. Since oedema
of the
mucous
membrane hinders
the
drainage
of
pus,
a
logical
first
step
is to
open
the
obstructed
passage
with
a
sympathomimetic vasoconstrictor, e.g. ephedrine
nasal
drops.
Antibiotic therapy produces
limited
additional clinical
benefit,
but the
common infecting

organism—Streptococcus
pneumoniae,
Haemophilus
influenzae,
Streptococcus
pyogenes,
Moraxella
(Branha-
mella)
catarrhalis—usually
respond
to
oral amoxicillin
(with
or
without clavulanic acid)
or
doxycycline,
if
the
case
is
serious enough
to
warrant antibiotic
therapy.
In
chronic sinusitis, correction
of the
anatomical

abnormalities (polypi, nasal septum deviation)
is
often
important.
Very
diverse organisms, many
of
them normal inhabitants
of the
upper respiratory
tract,
may be
cultured, e.g. anaerobic streptococci,
Bacteroides
spp.,
and a
judgement
is
required
as
to
whether
any
particular organism
is
acting
as a
pathogen. Choice
of
antibiotic

should
be
guided
by
culture
and
sensitivity testing; therapy
may
need
to
be
prolonged.
Infection
of the
throat
Pharyngitis
is
usually viral
but the
more serious
cases
may be
caused
by
Streptococcus
pyogenes
(Group
A)
which
is

always sensitive
to
benzylpenicillin.
Unfortunately,
streptococcal sore throats cannot
be
clinically
differentiated
from
non-streptococcal
with
any
certainty. Prevention
of
complications
is
more important than
relief
of the
symptoms
which
seldom last long. There
is no
general agreement
whether
chemotherapy
should
be
employed
in

mild
sporadic sore throat
and
expert reviews
on
the
subject
reflect
the
resulting
diversity
of
clinical
views.
1
'
2
-
3
The
disease usually subsides
in a few
days, septic complications
are
uncommon
and
rheumatic
fever
rarely
follows.

It is
reasonable
to
withhold
penicillin unless streptococci
are
cultured
or
the
patient develops
a
high
fever.
Severe spora-
dic
or
epidemic sore throat
is
likely
to be
strepto-
1
Cooper
R J,
Hoffman
J R,
Bartlett
J G et al
2001 Principles
of

appropriate antibiotic
use for
acute pharyngitis
in
adults:
background.
Annals
of
Internal Medicine 134: 506.
2
Del Mar C B,
Glasziou
P P,
Spinks
A B
2001 Antibiotics
for
sore
throat (Cochrane
Review).
The
Cochrane
Library
2.
Oxford:
Update
Software.
3
Thomas
M, Del Mar C,

Glasziou
P
2000
How
effective
are
treatments
other than antibiotics
for
acute sore throat? British
Journal
of
General Practice
50:
817.
238
INFECTION
OF THE
BRONCHI, LUNGS
AND
PLEURA
coccal
and
phenoxymethylpenicillin
by
mouth
(or
erythromycin/clarithromycin
or an
oral cephalo-

sporin
in the
penicillin allergic)
should
be
given
to
prevent these complications. Ideally,
it
should
be
continued
for 10
days,
but
compliance
is bad
once
the
symptoms have subsided
and 5
days
should
be
the
minimum objective.
If
there
is a
possibility that

the
pharyngitis
is due to
infectious
mononucleosis,
amoxicillin
must
not be
used
as the
patient
is
very
likely
to
develop
a
rash (see
p.
220).
In a
closed com-
munity,
chemoprophylaxis
of
unaffected
people
to
stop
an

epidemic
may be
considered,
for
instance
with phenoxymethylpenicillin
125 mg
12-hourly
orally,
for a
period
depending
on the
course
of the
epidemic.
In
scarlet
fever
and
erysipelas,
the
infection
is
invariably
streptococcal (Group
A) and
benzyl-
penicillin
should

be
used even
in
mild cases,
to
prevent rheumatic
fever
and
nephritis.
Chemoprophylaxis
Chemoprophylaxis
of
streptococcal (Group
A)
infection
with phenoxymethylpenicillin should
be
undertaken
in
patients
who
have
had one
attack
of
rheumatic
fever.
It is
continued
for at

least
5
years,
or
until aged
20,
whichever
is the
longer period
(although
some hold that
it
should continue
for
life,
for
histological study
of
atrial biopsies shows that
the
cardiac
lesions
may
progress despite absence
of
clinical
activity). Chemoprophylaxis
should
be
continued

for
life
after
a
second attack
of
rheumatic
fever.
A
single attack
of
acute nephritis
is not an
indication
for
chemoprophylaxis
but in the
rare
cases
of
nephritis
in
which recurrent haematuria
occurs
after
sore throats, chemoprophylaxis should
be
used. Ideally, chemoprophylaxis should continue
throughout
the

year
but,
if the
patient
is
unwilling
to
submit
to
this,
at
least
the
colder months should
be
covered (see also
p.
207).
Adverse
effects
are
uncommon. Patients taking
penicillin prophylaxis
are
liable
to
have penicillin-
resistant viridans type streptococci
in the
mouth,

so
that
during even minor dentistry,
e.g.
scaling, there
is
a
risk
of
bacteraemia
and
thus
of
infective
endo-
carditis
with
a
penicillin-resistant organism
in
those
with
any
residual rheumatic heart lesion.
The
same
risk
applies
to
urinary, abdominal

and
chest surg-
ery,
and
patients need special chemoprophylaxis
(see
Endocarditis). Patients taking penicillins
are
also liable
to be
carrying resistant staphylococci
and
pneumococci.
Other
causes
of
pharyngitis
Vincent's infection (microbiologically complex,
inc-
ludes anaerobes, spirochaetes) responds readily
to
benzylpenicillin;
a
single
i.m.
dose
of 600 mg is
often
enough except
in a

mouth needing dental
treatment,
when
relapse
may
follow.
Metronidazole
200
mg
8-hourly
by
mouth
for 3
days
is
also
effective.
Diphtheria
(Corynebacterium
diphtheriae).
Antitoxin
10
000-100
000
units
i.v.
in two
divided doses
0.5-2
h

apart
is
given
to
neutralise toxin already
formed
according
to the
severity
of the
disease.
Erythromycin
or
benzylpenicillin
is
also used,
to
prevent
the
production
of
more toxin
by
destroying
the
bacteria.
Whooping-cough
(Bordetella
pertussis).
Chemother-

apy
is
needed
in
children
who are
weak, have
damaged lungs
or are
under
3
years
old.
Erythro-
mycin
is
usually recommended
at the
catarrhal
stage
and
should
be
continued
for 14
days (also
as
prophylaxis
in
cases

of
special need).
It may
curtail
an
attack
if
given early enough
(before
paroxysms
have
begun)
but is not
dramatically
effective;
it
also
reduces infectivity
to
others.
A
corticosteroid, salbu-
tamol,
and
physiotherapy
may be
helpful
for
relief
of

symptoms,
but
reliable evidence
of
efficacy
is
lacking.
Infection
of the
bronchi,
lungs
and
pleura
BRONCHITIS
Most cases
of
acute bronchitis
are
viral; where
bacteria
are
responsible
the
usual pathogens
are
Streptococcus
pneumoniae
and/or
Haemophilus
influ-

enzae.
It is
questionable
if
there
is
role
for
anti-
microbials
in
uncomplicated acute bronchitis
but
239
13
CHEMOTHERAPY
OF
BACTERIAL
INFECTIONS
amoxicillin,
a
tetracycline
or
trimethoprim
are
app-
ropriate
if
treatment
is

considered necessary.
In
chronic bronchitis, suppressive chemotherapy,
generally needed only during
the
colder months
(in
temperate, colder regions),
may be
considered
for
patients with symptoms
of
pulmonary
insufficiency,
recurrent
acute exacerbations
or
permanently puru-
lent sputum. Amoxicillin
or
trimethoprim
is
suit-
able
for
treatment.
For
intermittent
therapy,

the
patient
is
given
a
supply
of the
drug
and is
told
to
take
it in
full
dose
at
the
first
sign
of a
'chest'
cold,
e.g.
purulent
sputum,
and to
stop
it
after
3

days
if
there
is
rapid
improvement. Otherwise,
the
patient should conti-
nue the
drug until recovery takes place.
If the
exacerbation
lasts
for
more than
10
days, there
is a
need
for
clinical reassessment.
PNEUMONIAS
The
clinical setting
is a
useful
guide
to the
causal
organism

and
hence
to the
'best
guess'
early choice
of
antimicrobial, although
in
seriously
ill
patients
cover
for
both 'typical'
and
'atypical' pathogens
should
be
included
from
the
beginning.
It is not
possible reliably
to
differentiate
between pneumonias
caused
by

'typical'
and
'atypical' pathogens
on
clinical
grounds alone.
Pneumonia
in
previously
healthy
people
(community acquired)
Disease
that
is
segmental
or
lobar
in its
distribu-
tion
is
usually caused
by
Streptococcus
pneumoniae
(pneumococcus).
Haemophilus
influenzae
is a

rare
cause
in
this group, although
it
more
often
leads
to
exacerbations
of
chronic bronchitis
and
does
cause
pneumonia
in
patients infected with HIV. Benzyl-
penicillin
i.v.
or
amoxicillin
p.o.
are the
treatments
of
choice
if
pneumococcal pneumonia
is

very likely;
alternatively,
use
erythromycin/clarithromycin
in a
penicillin-allergic
patient. Seriously
ill
patients
are
best given benzylpenicillin
(to
cover
the
pneumo-
coccus)
plus
ciprofloxacin
(to
cover
Haemophilus
and
'atypical' pathogens). Where penicillin-resistant
pneumococci
are
prevalent,
i.v.
cefotaxime
is a
reasonable

'best
guess' choice.
Pneumonia
following influenza
is
often
caused
by
Staphylococcus
aureus,
and
'best
guess'
therapy
is
usually achieved
by
adding
flucloxacillin
to one of
the
regimens above. When staphylococcal pneumo-
nia is
proven, sodium
fusidate
p.o.
plus
flucloxa-
cillin
i.v. should

be
used
in
combination.
'Atypical'
cases
of
pneumonia
may be
caused
by
Mycoplasma
pneumoniae
which
may be
epidemic,
or
more
rarely
Chlamydia
pneumoniae
or
psittaci
(psitta-
cosis/ornithosis)
Legionella
pneumophilia
or
Coxiella
burnetii

(Q
fever)
and a
tetracycline
or
erythromycin/
clarithromycin should
be
given
by
mouth. Treatment
of
ornithosis should continue
for 10
days
after
the
fever
has
settled
and in
mycoplasma pneumonia
and Q
fever
a
total
of 3
weeks treatment
may be
needed

to
prevent relapse.
At
the
earliest possible stage, once
a
clinical
im-
provement
has
been
seen,
initial
i.v.
administration
of
antibiotics
for
pneumonia should
be
switched
to
the
oral route.
Pneumonia
acquired
in
hospital
Pneumonia
is

usually
defined
as
being nosocomial
(Greek:
nosokomeian,
hospital)
if it
presents
after
at
least
2
days
in
hospital.
It
occurs primarily among
patients admitted with medical problems
or
recovering
from
abdominal
or
thoracic surgery
or
on
mechanical ventilators.
The
common pathogens

are
Staphylococcus
aureus,
Enterobacteriaceae,
Strepto-
coccus
pneumoniae,
Pseudomonas
aeruginosa,
and
Haemophilus
influenzae.
It is
reasonable
to
initiate
therapy with ciprofloxacin, meropenem
or
cef-
tazidime (plus vancomycin
if the
local
prevalence
of
MRSA
is
high) until
the
results
of

sputum culture
and
antimicrobial susceptibility tests
are
known.
Pneumonia
in
people
with
chronic lung
disease
Normal
commensals
of the
upper respiratory tract
proliferate
in
damaged lungs especially following
viral
infections, pulmonary congestion
or
pulmonary
infarction.
Mixed infection
is
therefore
common,
and
since
Haemophilus

influenzae
and
Streptococcus
pneumoniae
are
often
the
pathogens, amoxicillin
or
trimethoprim
are
reasonable choices,
but if
240
13
ENDOCARDITIS
response
is
inadequate co-amoxiclav
or a
quinolone
should
be
substituted.
Klebsiella
pneumoniae rarely causes lung infection
(Triedlander's pneumonia')
in the
alcoholic
and

debilitated elderly. Abscesses
form,
particularly
in
the
upper lobes:
cefotaxime
possibly with
an
amino-
glycoside
is
recommended.
Moraxella
(previously
Branhamella)
catarrhalis,
a
commensal
of the
oropharynx,
may be a
pathogen
in
patients with chronic bronchitis; because many
strains produce B-lactamase, co-amoxiclav
or
eryth-
romycin/clarithromycin
should

be
used.
Pneumonia
in
immunocompromised
patients
Pneumonia
is
common,
e.g.
in
acquired immuno-
deficiency
syndrome
(AIDS)
or in
those
who are
receiving immunosuppressive drugs.
Common pathogenic bacteria
may be
respons-
ible
(Staphylococcus
aureus,
Streptococcus
pneumoniae)
but
often
organisms

of
lower natural virulence
(Enterobacteriaceae,
viruses,
fungi)
are
causal
and
strenuous
efforts
should
be
made
to
identify
the
microbe including,
if
feasible,
bronchial washings
or
lung biopsy.
•
Until
the
pathogen
is
known
the
patient should

receive
broad-spectrum antimicrobial treatment,
such
as an
aminoglycoside plus
ceftazidime.
•
Aerobic Gram-negative bacilli, e.g.
Enterobacteriaceae,
Klebsiella
spp.,
are
pathogens
in
half
of the
cases, especially
in
neutropenic
patients,
and
respond
to
cefotaxime
or
ceftazidime.
Pseudomonas
aeruginosa
may
also

cause
pneumonia
in
these patients;
for
treatment
see
Reference
data
on
antimicrobial drugs
of
choice,
page 211,
Table
11.1.
• An
important respiratory pathogen
in
patients
with
deficits
in
cell-mediated immunity
is the
fungus
Pneumocystis
carinii,
which should
be

treated with co-trimoxazole
120
mg/kg/d
by
mouth
or
i.v.
in 2-4
divided
doses
for 14
days,
or
with pentamidine (see
p.
276).
Legionnaires'
disease
Legionella
pneumophila
responds
to
erythromycin
2-4
g/d
i.v.
in
divided doses
but
rifampicin

may be
added
in
more severe infections. Ciprofloxacin
is
also
effective.
Pneumonia
due to
anaerobic
microorganisms
Pneumonia
is
often
caused
by
aspiration
of
material
from
the
oropharynx,
or due to the
presence
of
other lung pathology such
as
pulmonary
infarction
or

bronchogenic carcinoma.
As
well
as
conventional
microbial
causes,
the
pathogens include anaerobic
and
aerobic streptococci,
Bacteroides
spp.
and
Fuso-
bacterium,
and the
diagnosis
may be
missed unless
anaerobic
cultures
of
fresh
material
are
performed.
Treatment
for
several weeks with

cefuroxime
plus
metronidazole
may be
needed
to
prevent relapse.
Pulmonary
abscess
is
treated according
to the
organism identified
and
with surgery
if
necessary.
Empyema
is
treated according
to the
organism
isolated
and
with aspiration
and
drainage.
Endocarditis
When suspicion
is

high
enough, three blood
cultures should
be
taken over
a few
hours
and
antimicrobial
treatment commenced;
it can be
adjusted
later
in the
light
of the
results. Delay
in
treating only exposes
the
patient
to the
risk
of
grave
cardiac
damage
or
systemic embolism. Streptococci,
enterococci

and
staphylococci
are
causal
in 80% of
cases,
with
viridans group streptococci
the
most
common pathogens.
In
intravenous drug users,
Staphylococcus
aureus
is the
most likely organism.
Culture-negative endocarditis
(up to 20% of
cases)
is
usually
due to
prior antimicrobial therapy
or to
special culture requirements
of the
microbe;
it is
best regarded

as
being
due to
streptococci
and
treated accordingly.
PRINCIPLES FORTREATMENT
•
High
doses
of
bactericidal drugs
are
needed
because
the
organisms
are
difficult
to
access
in
avascular
vegetations
on
valves
and the
protective
host
reaction

is
negligible.
•
Drugs
should
be
given parenterally
at
least
241
13
CHEMOTHERAPY
OF
BACTERIAL
INFECTIONS
initially
and
preferably
by
intravenous bolus
injection
which achieves
the
necessary high peak
concentration
to
penetrate
the
relatively
avascular vegetations.

• The
infusion site should
be
examined daily
and
changed regularly
to
prevent opportunistic
infection,
which
is
usually with coagulase-
negative staphylococci
or
fungi.
Alternatively,
use may be
made
of a
central subclavian venous
catheter sited with meticulous attention
to
aseptic
technique.
•
Prolonged therapy
is
needed, usually
4
weeks,

and in the
case
of
infected
prosthetic
valves
at
least
6
weeks.
The
patient should
be
reviewed
one
month
after
completing
the
antimicrobial
treatment.
Valve
replacement
may be
needed
at
any
time during
and
after

antibiotic therapy
if
cardiovascular function
deteriorates
or if the
infection
proves impossible
to
control.
•
Dosage must
be
adjusted according
to the
sensitivity
of the
infecting organism. This
is
established
by the
Minimum Inhibitory
Concentration
test
(p.
203), rather
than
by
testing
dilutions
of the

patient's serum against
the
organism
(the
Serum Bactericidal Titre which
was
formally
recommended,
but
which
has not
been proved
useful).
DOSE
REGIMENS
The
following regimens
are
those commonly
rec-
ommended:
1.
Initial (best guess) treatment should comprise
benzylpenicillin
1.2-2.4
g
4-hourly, plus
gentamicin
in low
dose,

e.g.
80 mg
12-hourly,
by
i.v.
injection
(synergy allows this dose
of
gentamicin
and
minimises
risk
of
adverse
effects).
Regular serum gentamicin assay
is
vital:
trough concentrations should
be
below
1
mg/1
and
peak concentrations about
3
mg/1;
if
Staphylococcus aureus
is

suspected, high-dose
flucloxacillin
plus
either gentamicin
or
sodium
fusidate
should
be
used. Patients allergic
to
penicillin should
be
treated with vancomycin.
2.
When
an
organism
has
been identified
and its
sensitivity
to
drugs determined:
•
Viridans group streptococci:
benzylpenicillin
plus gentamicin i.v.
for at
least

4
weeks
or, if
the
organism
is
very sensitive,
for 2
weeks,
followed
by
amoxicillin
p.o.
for 2
weeks.
Some
patients
with
uncomplicated
endocarditis caused
by
very sensitive strains
may be
managed
as
outpatients;
for
these
patients
ceftriaxone

may be
suitable, with
its
prolonged
t
1
/
2
allowing convenient once-daily
administration.
•
Enterococcus
faecalis
(Group
D):
benzylpenicillin
1.8-3g
4-hourly plus gentamicin i.v.
for 4-6
weeks.
The
prolonged gentamicin
administration carries
a
significant risk
of
adverse drug
reactions,
but is
essential

to
assure eradication
of the
infection.
•
Staphylococcus aureus:
flucloxacillin
2 g
4-hourly
by
i.v.
injection
for at
least
4
weeks plus either
gentamicin
by
i.v.
injection
or
sodium
fusidate
by
mouth
for
the
first
1-2
weeks.

•
Staphylococcus epidermidis
and
other coagulase
negative staphylococci infecting native heart
valves should
be
managed
as for
Staphylococcus aureus
if the
organism
is
sensitive.
These
organisms,
however,
have
a
predilection
for
prosthetic valves
and
such
cases
should
be
treated with vancomycin plus
rifampicin
for at

least
6
weeks with
gentamicin
for the
first
2
weeks.
•
Coxiella
or
Chlamydia:
tetracycline
by
mouth
for
at
least
4-6
weeks.
Valve
replacement
is
advised
in
most cases,
but
some
may
continue

indefinitely
on
tetracycline.
•
Fungal endocarditis:
amphotericin plus
flucytosine
are
used.
Valve replacement
is
usually essential.
•
Culture-negative endocarditis:
benzylpenicillin
plus gentamicin i.v.
are
given
for 4-6
weeks.
PROPHYLAXIS
Transient
bacteraemia
is
provoked
by
dental proce-
dures, surgical incision
of the
skin, instrumentation

of
the
urinary tract, parturition
and
even seemingly
innocent
activities such
as
brushing
the
teeth
or
chewing
toffee.
Experience shows that people with
acquired
or
congenital heart
defects
are at
risk
from
bacteraemia
and may be
protected
by
antimicro-
bials used prophylactically (although there
is no
scientific

proof
of the
efficacy
of
this).
The
drugs
are
given
as a
short course
in
high dose
at the
time
of
242
13
the
procedure
to
coincide with
the
bacteraemia
and
avoid emergence
of
resistant organisms. There
follow
general recommendations

4
'
5
'
6
on
antimicro-
bial prophylaxis;
not
every contingency
is
covered
because prophylaxis
may be
needed
for
patients
with cardiac
defects
whenever surgery
or
instru-
mentation
is
undertaken
on
tissue that
is
heavily
colonised

or
infected,
e.g.
in
surgery
or
instrumen-
tation
of the
upper respiratory
or
genitourinary
tracts,
or
obstetric, gynaecological
or
gastrointestinal
procedures.
Different
national Working Parties have
recommended
differing
prophylactic measures,
4
'
5
'
6
and the
physician should consult special sources

and
exercise
a
clinical judgement that relates
to
individual circumstances.
All
oral drugs should
be
taken under supervision.
Dental
procedures
Under
local
or no
anaesthesia
•
Adults
who are
not
allergic
to
penicillins
and who
have
not
taken penicillin more than once
in the
previous month (including those
with

a
prosthetic valve,
but not if
they have
had
endocarditis
in the
past)
should
receive
amoxicillin
3 g by
mouth
1 h
before
the
procedure.
•
Patients
allergic
to
penicillins
or who
have taken
penicillin more than once
in the
previous month
should receive clindamycin
600 mg by
mouth

1 h
before
the
procedure.
Under
general anaesthesia
•
Patients
who are not
allergic
to
penicillins
and
who
have
not
taken penicillin more than once
in
the
previous month should receive amoxicillin
1 g
i.m.
or
i.v.
at
induction then
0.5 g by
mouth
6
h

later. Alternatively amoxicillin
3 g may be
taken
by
mouth together with probenecid
1 g by
4
Simmons
N
A1993 Recommendations
for
endocarditis
prophylaxis.
Journal
of
Antimicrobial Chemotherapy
31:
437.
5
Littler
W A,
McGowan
D A,
Shanson
D C
1997 Changes
in
recommendations about amoxycillin prophylaxis
for
prevention

of
endocarditis. Lancet 350:1100.
6
Dajani
A S,
Taubert
K
Wilson
W et al
1997 Prevention
of
bacterial
endocarditis. Recommendations
by the
American
Heart Association. Journal
of the
American
Medical
Association
277:1794.
MENINGITIS
mouth
4 h
before
the
procedure (probenecid
delays renal excretion
and
thus maintains

a
high
blood concentration
of
amoxicillin),
or
amoxicillin
3 g may be
followed
by
another
3 g
dose
as
soon
as
possible
after
the
procedure.
•
Special
risk
patients, i.e. with prosthetic valves
or
with previous endocarditis,
should
receive
amoxicillin
1 g

i.m.
or
i.v.
and
gentamicin
120 mg
at
induction, then amoxicillin
0.5 g by
mouth
6 h
later. Patients
who are
penicillin-allergic
or
have
received penicillin more that once
in the
previous month should receive vancomycin
1 g
i.v.
over
100 min
then gentamicin
120 mg
i.v.
at
induction
or 15 min
before

the
procedure;
or
teicoplanin
400 mg
i.v. plus gentamicin
120 mg
i.v.
at
induction
or 15 min
before
the
procedure;
or
clindamycin
300 mg
over
at
least
10 min at
induction
or 15 min
before
the
procedure then
clindamycin
150 mg
i.v.
or by

mouth
6 h
later.
Special
sources should
be
consulted
for
pro-
phylactic regimens recommended
for
children
and
for
other procedures, such
as
instrumentation
of the
urogenital
or
gastrointestinal tracts.
Meningitis
Speed
of
initiating treatment
and
accurate bacterio-
logical
diagnosis
are the

major
factors
determining
the
fate
of the
patient. When meningococcal disease
is
suspected (and unless
the
patient
has a
history
of
penicillin anaphylaxis) treatment with benzyl-
penicillin should
be
started
by the
general practi-
tioner
before
transfer
to
hospital;
benefit
to the
patient outweighs
the
reduced chance

of
identi-
fying
the
causative organism. Newly introduced
diagnostic methods such
as the
Polymerase Chain
Reaction
(PCR)
for
bacterial
DNA in CSF or
blood
enable accurate
and
rapid
diagnosis
even when
the
causative organisms have been destroyed
by
antibiotics.
Drugs must
be
given i.v.
in
high
dose;
the

regimens below provide
the
recommended therapy,
with alternatives
for
patients allergic
to
first
choices.
Intrathecal therapy
is now
considered unnecessary,
and can be
dangerous, e.g. encephalopathy with
penicillin.
243
13
CHEMOTHERAPY
OF
BACTERIAL
INFECTIONS
INITIALTHERAPY
Initial
therapy should
be
sufficient
to
kill
all
pathogens, which

are
likely
to be:
All
ages over
5
years
For
Neisseria
meningitidis
and
Streptococcus
pneu-
moniae
benzylpenicillin
2-4 g
4-6-hourly
should
be
given, followed,
in the
case
of
Neisseria
meningitidis,
by
rifampicin
for 2
days prior
to

discharge
from
hospital
(to
eradicate persisting organisms). Some
prefer
to use
cefotaxime
2-3 g
6-8-hourly
in all
cases
until
the
results
of
susceptibility tests
are
known,
and
this
may be the
generally preferred choice
if
penicillin
resistance
in
pneumococci
and
meningococci rises

in
prevalence.
Optimal therapy
for
penicillin-resistant
pneumococcal
meningitis
may
comprise
cefotaxime
2-3 g
6-8-hourly
plus vancomycin
1 g
12-hourly plus
rifampicin
600 gm
12-hourly.
Children
under
5
years
Neisseria
meningitidis
is now
commonest
and
Haemo-
philus
influenzae,

formerly
a
frequent
pathogen,
is
much
less
often
isolated
(as a
result
of
immunisa-
tion
programmes).
Streptococcus
pneumoniae
is
also
less commonly found than
in
older patients.
Give
a
cephalosporin,
e.g.
cefotaxime.
When
Haemophilus
influenzae

is
isolated give rifampicin
for
4
days
before
discharge
from
hospital
to
clear
naso-pharyngeal
carriage.
Neonates
For
Escherichia
coli:
give
cefotaxime
or
ceftazidime
perhaps with gentamicin.
For
Group
B
streptococci:
give benzylpenicillin plus gentamicin. Consult
a
specialist
text

for
details
of
doses
for
neonates.
Ampicillin
must
be
added
if
Listeria
monocyto-
genes
is
suspected.
Dexamethasone
given
i.v.
and
early appears
to
reduce
long-term neurological sequelae, especially
sensorineural
deafness,
in
infants
and
children.

There
is
not,
however, general agreement about
the
use of
dexamethasone
for
meningitis
in
adults.
Chloramphenicol remains
a
good alternative
for
'blind'
therapy
in
patients giving
a
history
of
B-lactam
anaphylaxis.
SUBSEQUENTTHERAPY
When
the
infecting
organism
has

been identified,
specific
therapy
is
chosen
as
follows. Intravenous
administration should continue until
the
patient
is
capable
of
taking drugs
by
mouth,
and
whether
continuation therapy
should
be
given
by
mouth
or
i.v.
is a
matter
of
debate. Antimicrobials (except

aminoglycosides) enter well into
the CSF
when
the
meninges
are
inflamed; relapse
may be due to
resto-
ration
of the
blood-CSF barrier
as
inflammation
is
reduced.
The
following
are
recommended (adult
doses).
Neisseria
meniningitidis: benzylpenicillin
2.4 g
4-6-hourly
or
cefotaxime
2-3 g
6-8-hourly
is

given.
Treatment
should
continue
for a
minimum
of 5
days.
Streptococcus
pneumoniae:
cefotaxime
2-3 g
6-8-
hourly
is
given
or
benzylpenicillin
2.4 g
4-6-hourly
if
the
organism
is
penicillin-sensitive. Treatment
should continue
for 10
days
after
the

patient
has
become
afebrile
and the
physician should
be
aware
of
the
possibility
of
relapse.
Haemophilus
influenzae:
cefotaxime
2-3 g
6-8-
hourly
or
chloramphenicol
100
mg/kg/d
is
given.
Treatment
should continue
for 10
days
after

the
temperature
has
settled. Subdural empyema,
often
presenting
as
persistent
fever,
is
relatively common
after
haemophilus
meningitis
and may
require
surgical
drainage.
Chemoprophylaxis
The
three common pathogens (below)
are
spread
by
respiratory
secretions. Asymptomatic nasopharyn-
geal
carriers seldom develop meningitis
but
they

may
transmit
the
pathogens
to
close personal
con-
tacts.
Rifampicin
by
mouth
is
effective
at
reducing
carriage
rates.
Meningococcal
meningitis
often
occurs
in
epi-
demics
in
closed communities,
but
also
in
isolated

cases.
Close personal contacts should receive oral
rifampicin
600 mg
12-hourly
for 2
days. Single
doses
of
oral
ciprofloxacin
(500
mg) or
i.m.
ceftriaxone
(2
g) are
alternatives,
the
latter
of
particular value
for
pregnant women.
244
13
Haemophilus
influenzae
type
b has an

infectivity
similar
to
that
of the
meningococcus.
Rifampicin
600
mg
daily should
be
given
for 4
days.
Pneumococcal
meningitis
tends
to
occur
in
iso-
lated
cases
and
chemoprophylaxis
of
contacts
is not
recommended.
Infection

of the
intestines
(For
Helicobacter
pylori
see p.
630.) Antimicrobial
therapy should
be
reserved
for
specific
conditions
with identified pathogens where
benefit
has
been
shown;
not all
acute diarrhoea
is
infective
for it can
be
caused
by
bacterial toxins
in
food,
dietary

in-
discretions, anxiety
and by
drugs. Even
if
diarrhoea
is
infective,
it may be due to
viruses;
or, if it is
bacterial,
antimicrobial agents
may not
reduce
the
duration
of
symptoms
and may
aggravate
the
condition
by
permitting opportunistic infection
and
encouraging
Clostridium
difficile
associated

diarrhoea. Maintenance
of
water
and
electrolyte
balance, either
by
i.v.
infusion
or
orally with
a
glucose-electrolyte solution together with
an
anti-
motility drug (except
in
small children)
are the
mainstays
of
therapy
in
such cases
(see
Oral
rehydration therapy,
p.
643).
Some

specific
intestinal infections
do
benefit
from
chemotherapy:
Campylobacter
jejuni.
Erythromycin
or
cipro-
floxacin
by
mouth will eliminate
the
organism
from
the
stools
and a
5-day course
is
worth giving early
in the
illness
if it is
severe.
Shigella.
Mild disease requires
no

specific
anti-
microbial
therapy
but
toxic shigellosis with high
fever
should
be
treated with ciprofloxacin
or
amoxi-
cillin
by
mouth.
Salmonella.
An
antimicrobial should
be
used
for
severe salmonella gastroenteritis,
or for
bacteraemia
or
salmonella enteritis
in an
immunocompromised
patient.
The

choice lies between
ciprofloxacin,
amoxi-
cillin
or
co-trimoxazole, according
to the
sensitivity
of
the
pathogen.
Typhoid
fever
is a
generalised
infection
and
requires treatment with
ciprofloxacin.
Chloramphe-
nicol, amoxicillin
or
co-trimoxazole
are
less
effec-
tive
alternatives.
The
i.v.

route should
be
used
at
NFECTION OFTHE
INTESTINES
least initially, followed
by
oral administration.
A
longer period
of
treatment
may be
required
for
those
who
develop complications such
as
osteomyelitis
or
abscess.
A
carrier
state
develops
in a few
individuals
who

have
no
symptoms
of
disease
but who can
infect
others.
7
Organsims
reside
in the
biliary
or
urinary
tracts.
Ciprofloxacin
in
high
dose
by
mouth
for
3-6
months
may be
successful
for
what
can be

a
very
difficult
problem. Cholecystectomy
or
investigation
of
urinary tract abnormalities
may
be
needed.
Escherichia
coli
is a
normal inhabitant
of the
bowel
but
some enterotoxigenic strains
are
patho-
genic
and are
frequently
a
cause
of
travellers'
diarrhoea.
A

quinolone,
e.g.
ciprofloxacin,
is the
drug
of
choice
in
most high-risk parts
of the
world
for
a
severe attack (see Travellers' diarrhoea,
p.
644).
Antimicrobials
are not
generally given
for
prophyl-
axis
but,
when
it is
indicated,
a
quinolone should
be
used.

Verotoxic
Escherichia
coli
(VTEC;
O157)
may
cause
severe bloody diarrhoea
and
systemic
effects
such
as the
haemolytic uraemic syndrome
(HUS);
antibiotic therapy
has
been shown
in
some trials
to
worsen
the
prognosis, perhaps
by
releasing more
toxin
from
dying bacteria.
An

antimicrobial should
generally
therefore
be
avoided
for
bloody diarrhoea
unless
the
diagnosis
has
been confirmed bacte-
riologically
not to be
VTEC.
Vibrio
cholerae.
The
cause
of
death
in
cholera
is
electrolyte
and
fluid
loss
in the
stools

and
this
may
exceed
1
1/h.
The
most important
aim of
treatment
is
prompt replacement
and
maintenance
of
water
and
electrolytes
with
oral
or
intravenous electrolyte
solutions. Doxycycline, given early, significantly
reduces
the
amount
and
duration
of
diarrhoea

and
eliminates
the
organism
from
the
faeces
(thus
lessening
the
contamination
of the
environment).
Carriers
may be
treated
by
doxycycline
by
mouth
in
high dose
for 3
days.
Ciprofloxacin
may be
given
for
resistant organisms.
7

The
most
famous
carrier
was
Mary
Mallon (Typhoid
Mary')
who
worked
as a
cook
in New
York
City,
USA, using
various
assumed
names
and
moving through several
different
households.
She
caused
at
least
10
outbreaks with
51

cases
of
typhoid
fever
and 3
deaths.
To
protect
the
public,
she was
kept
in
detention
for 23
years.
245
13
CHEMOTHERAPY
OF
BACTERIAL
INFECTIONS
Suppression
of
bowel
flora
is
thought
by
some

to
be
useful
in
hepatic encephalopathy. Here,
absorption
of
products
of
bacterial breakdown
of
protein (ammonium, amines)
in the
intestine lead
to
cerebral
symptoms
and
even
to
coma.
In
acute
coma,
neomycin
6 g/d
should
be
given
by

gastric
tube;
as
prophylaxis,
1-4 g/d may be
given
to
patients with
protein
intolerance
who
fail
to
respond
to
dietary protein restriction (see also lactulose,
p.
640).
Selective
decontamination
of the gut
reduces
the
risk
of
nosocomial infection
from
gut
organisms
(including

fungi)
in
patients
who are
immuno-
compromised
or
receiving intensive care (notably
mechanical
ventilation).
The
commonest regimen
involves
combinations
of
nonabsorbable
(framy-
cetin, colistin, nystatin
and
amphotericin)
and
i.v.
(cefotaxime)
antimicrobials
to
reduce
the
number
of
Gram-negative bacilli

and
yeasts while maintaining
a
normal anaerobic
flora.
An
alternative
is to
administer oral
ciprofloxacin
alone.
Peritonitis
is
usually
a
mixed infection
and
anti-
microbial
choice must take account
of
coliforms,
anaerobes
and
streptococci;
a
combination
of
gentamicin, benzylpenicillin plus metronidazole
or

of
cefuroxime
plus metronidazole,
or
meropenem
alone
is
usually
appropriate.
Surgical
drainage
of
peritoneal collections
and
abscesses
is
usually
required
as
well.
Chemoprophylaxis
in
surgery:
see p.
208.
Antibiotic-associated
colitis:
see p.
210.
Infection

of the
urinary
tract
(excluding
sexually transmitted infections)
Common pathogens include:
Escherichia
coli
(commonest
in all
patient
groups)
Proteus
spp.
Klebsiella
spp.
Other
Enterobacteriaceae
Pseudomonas
aeruginosa
Enterococcus
spp.
Staphylococcus
saprophyticus.
Patients with abnormal urinary tracts (e.g. renal
stones, prostatic hypertrophy, indwelling urinary
catheters)
are
likely
to be

infected
with
a
more
varied
and
antimicrobial-resistant microbial
flora.
Identification
of the
causative organism
and of its
sensitivity
to
drugs
are
important
because
of the
range
of
organisms
and the
prevalence
of
resistant
strains.
For
infection
of the

lower urinary tract
a low
dose
may be
effective,
as
many antimicrobials
are
con-
centrated
in the
urine. Infections
of the
substance
of
the
kidney require
the
doses needed
for any
systemic
infection.
Elimination
of
infection
is
hastened
by a
large urine volume (over
1.5

I/d)
and
by
frequent micturition.
Drug treatment
of
urinary tract
infection
falls
into
several
categories:
Lower
urinary
tract
infection
Initial treatment with
an
oral cephalosporin
(e.g.
cefalexin),
trimethoprim, amoxicillin
or co-
amoxiclav
is
usually
satisfactory,
although current
resistance rates
of

20-50% among common patho-
gens
for
trimethoprim
and
amoxicillin threaten
their value
for
empirical therapy. Therapy should
normally last
3
days
and may
need
to be
altered
once
the
results
of
bacterial
sensitivity
are
known.
Upper
urinary
tract
infection
Acute
pyelonephritis

may be
accompanied
by
septicaemia
and it is
advisable
to
start with genta-
micin plus amoxicillin i.v.
or
alternatively
cefotaxime
i.v.
alone.
If
oral therapy
is
considered suitable,
ciprofloxacin
or
norfloxacin
is
recommended
for 2
weeks. This
is an
infection
of the
kidney substance
and so

needs adequate blood
as
well
as
urine
concentrations.
Recurrent
urinary tract infection
Attacks
following rapidly with
the
same organism
may
be
relapses
and
indicate
a
failure
to
eliminate
the
original
infection.
Attacks with
a
longer interval
between them
and
produced

by
differing
bacterial
types
may be
regarded
as due to
reinfection,
most
often
by
ascending
infection
from
the
perineal skin.
Repeated
short courses
of
antimicrobials should
overcome most recurrent infections but,
if
these
fail,
246
13
GENITALTRACT INFECTIONS
7-14 days
of
high-dose treatment

may be
given,
following
which
continuous
low-dose
prophylaxis
may
be
needed.
Asymptomatic
infection
('asymptomatic
bacteriuria')
This
may be
found
by
routine urine testing
of
pregnant women
or
patients with known structural
abnormalities
of the
urinary tract. Such infection
may
explain micturition
frequency
or

incontinence
in the
elderly. Appropriate antimicrobial therapy
should
be
given, chosen
on the
basis
of
susceptibility
tests,
and
normally
for
7-10
days. Amoxicillin
or a
cephalosporin
is
preferred
in
pregnancy, although
nitrofurantoin
may be
used
if
imminent delivery
is
not
likely (see below).

Prostatitis
The
commonest pathogens here
are
Gram-negative
aerobic
bacilli, although Chlamydia
may
also
be
involved.
A
quinolone
such
as
ciprofloxacin
is
commonly
used,
although trimethoprim
or
erythro-
mycin
are
also
effective.
Being lipid soluble, these
drugs penetrate
the
prostate

in
adequate concen-
tration; they
may
usefully
be
combined. Response
to
a
single,
short course
is
often
good,
but
recurrence
is
common
and a
patient
can be
regarded
as
cured only
if
he has
been symptom-free without resort
to
antimicrobials
for a

year. Four weeks
of
oral therapy
is
often
given
for
recurrent attacks.
Chemoprophylaxis
Chemoprophylaxis
is
sometimes undertaken
in
patients
liable
to
recurrent attacks
or
acute exacerba-
tions
of
ineradicable infection.
It may
prevent
progressive renal damage
in
children
who are
found
to

have
asymptomatic
bacteriuria
on
routine
screening. Nitrofurantoin (50-100
mg/d),
nalidixic
acid
(0.5-1.0
g/d)
or
trimethoprim (100
mg/d)
are
satisfactory.
The
drugs
are
best given
as a
single
oral
dose
at
night.
Tuberculosis
of the
genitourinary
tract

is
treated
on the
principles described
for
pulmonary infection
(p.
249).
SPECIAL
DRUGS
FOR
URINARYTRACT
INFECTIONS
General
antimicrobials
are
used
for
urinary tract
infections
and
described elsewhere.
A few
agents
are
used solely
for
infection
of the
urinary tract:

Nitrofurantoin,
a
synthetic antimicrobial,
is
active
against
the
majority
of
urinary pathogens except
pseudomonads.
It is
well absorbed
from
the
gastro-
intestinal
tract
and is
concentrated
in the
urine (t
1
/,
1 h); but
plasma concentrations
are too low to
treat
infection
of

kidney tissue. Excretion
is
reduced when
there
is
renal
insufficiency,
rendering
the
drug both
more toxic
and
less
effective.
The
main
use of
nitrofurantoin
is now for
prophylaxis. Adverse
effects
include nausea
and
vomiting (much reduced
with
the
macrocrystalline preparation)
and
diar-
rhoea.

Peripheral neuropathy occurs especially
in
patients with significant renal impairment,
in
whom
the
drug
is
contraindicated. Allergic
reactions
include
rashes,
generalised urticaria
and
pulmonary infiltration with lung consolidation
or
pleural
effusion.
It is
safe
in
pregnancy, except near
to
term because
it may
cause neonatal haemolysis,
and it
must
be
avoided

in
patients with glucose-6-
phosphate dehydrogenase
deficiency
(see
p.
123).
Nalidixic
acid:
see
page
233.
Genital
tract
infections
A
general account
of
orthodox literature
is
given
below,
but
treatment
is
increasingly
the
prerogative
of
specialists,

who,
as is so
often
the
case,
get
the
best results. Interested readers
are
referred
to
specialist texts. Sexually transmitted infections
are
commonly
multiple. Screening
of
contacts plays
a
vital
part
in
controlling spread
and
reducing
reinfection.
GONORRHOEA
The
problems
of
(3-lactam

and
quinolone
resistance
in
Neisseria
gonorrhoeae
are
increasing,
and
selection
of
a
particular drug will depend
on
sensitivity
testing
and a
knowledge
of
resistance patterns
in
different
geographical locations.
Effective
treatment
247
13
CHEMOTHERAPY
OF
BACTERIAL

INFECTIONS
requires exposure
of the
organism
briefly
to a
high
concentration
of the
drug. Single-dose regimens
are
practicable
as
well
as
being obviously desirable
for
social
reasons, including compliance.
The
following
schedules
are
effective:
Uncomplicated anogenital infections: amoxicillin
with probenecid
by
mouth;
spectinomycin i.v,
cefotaxime

i.m.
or
ciprofloxacin
by
mouth
may be
used
for
penicillin-allergic patients.
Pharyngeal gonorrhoea responds less reliably,
and
i.m.
cefotaxime
is
recommended.
Coexistent
infection.
Chlamydia
tmchomatis
is
fre-
quently present with
Neisseria gonorrhoeae;
tetra-
cycline
by
mouth
for 7
days
or a

single oral dose
of
azithromycin
Ig
will treat
the
chlamydial
urethritis.
Nongonococcal
urethritis
The
vast
majority
of
cases
of
urethritis with
pus
in
which gonococci cannot
be
identified
are due to
sexually-transmitted organisms, usually
Chlamydia
trachomatis
and
sometimes
Ureaplasma
urealyticum.

Tetracycline
or
azithromycin
by
mouth
is
effective.
Pelvic
inflammatory
disease
Several
pathogens
are
involved including
Chla-
mydia trachomatis, Neisseria gonorrhoeae
and
Myco-
plasma
hominis
and
there
may be
superinfection
with bowel
and
other urogenital tract bacteria.
A
combination
of

antimicrobials
is
usually required,
e.g.
metronidazole
plus
doxycycline
by
mouth.
SYPHILIS
Treponema
pallidum
is
known
to be
invariably sensitive
to
penicillin.
Primary
and
secondary
syphilis
are
effectively
treated
by
benzylpenicillin
or
procaine penicillin
i.m. daily

for
10-21 days. Tetracycline
or
erythro-
mycin orally
may be
used
for
penicillin-allergic
patients.
Tertiary
syphilis
should have
the
same treatment,
ensuring that
it
continues
for 3
weeks.
Congenital syphilis
in the
newborn should
be
treated with benzylpenicillin
for 10
days
at
least.
Some

advocate that
a
pregnant woman with syphilis
should
be
treated
as for
primary syphilis,
in
each
pregnancy,
in
order
to
avoid
all
danger
to
children.
Therapy
is
best given between
the
third
and
sixth
month,
as
there
may be a

risk
of
abortion
if it is
given earlier.
Results
of
treatment
of
syphilis with penicillin
are
excellent.
Follow-up
of all
cases
is
essential,
for 5
years
if
possible.
The
Herxheimer
(or
Jarisch-Herxheimer)
reaction
is
probably caused
by
cytokine (mainly tumour

necrosis
factor)
release
following
massive slaughter
of
spirochaetes.
Presenting
as
pyrexia,
it is
common
during
the few
hours
after
the
first
penicillin
injection;
other
features
include tachycardia, head-
ache, myalgia
and
malaise which last
up to a
day.
It
cannot

be
avoided
by
giving graduated doses
of
penicillin.
Prednisolone
may
prevent
it and
should
probably
be
given
if a
reaction
is
specially
to be
feared,
e.g.
in a
patient
with
syphilitic
aortitis.
CHANCROID
The
causal agent,
Haemophilus ducreyi,

normally
responds
to
erythromycin
for 7
days
or a
single
dose
of
ceftriaxone
or
azithromycin.
GRANULOMA
INGUINALE
Calymmatobacterium
granulomatis
infection
is
treated
with ampicillin
or
co-trimoxazole
or a
tetracycline
for
2
weeks.
BACTERIALVAGINOSIS
(BACTERIAL

VAGINITIS,ANAEROBICVAGINOSIS)
Bacterial
vaginosis
is a
common
form
of
vaginal
discharge
in
which neither
Trichomonas vaginalis
nor
Candida
albicans
can be
isolated
and
inflammatory
cells
are not
present. There
is
evidence
to
associate
the
condition with overgrowth
of
several normal

commensals
of the
vagina including
Gardnerella
vaginalis,
Gram-negative curved bacilli,
and
anaero-
bic
organisms, especially
of the
Bacteroides
genus,
the
latter being responsible
for the
characteristic
fishy
odour
of the
vaginal discharge.
The
condition
responds well
to a
single
2 g
oral dose
of
metro-

248
13
MYCOBACTERIAL
INFECTIONS
nidazole, with topical clindamycin
offering
an
alternative.
Candida
vaginitis:
see
page 263.
Trichomonas
vaginitis:
see
page 234.
Infection
of
bones
and
joints
Osteomyelitis
may be
acute
or
chronic
and the
causative
bacteria arrive
in the

bloodstream
or are
implanted directly (through
a
compound
fracture,
chronic
local infection
of
local tissue,
or
surgical
operation).
Staphylococcus
aureus
is the
commonest
isolate
in all
patient groups
but
Haemophilus
influen-
zae
is
frequently seen
in
children (much reduced
now by the Hib
vaccine),

and
Salmonella
species
in the
tropics. Chronic osteomyelitis
of the
lower
limbs (especially when underlying chronic skin
infection
in the
elderly) frequently involves obligate
anaerobes (such
as
Bacteroides
species)
and
coliforms.
Strenuous
efforts
should
be
made
to
obtain bone
for
culture because superficial
and
sinus
cultures
are

poorly predictive
of the
underlying
flora,
and
prolonged therapy
is
required
for
chronic osteo-
myelitis
(usually
6-8
weeks, sometimes longer).
The
outcome
of
chronic osteomyelitis
is
improved
if
dead bone
can be
removed surgically.
Definitive
therapy
is
guided
by the
results

of
culture
but
commonly used regimens include
flucloxacillin
with
or
without
fusidic
acid
(for
Staphylococcus
aureus),
cefotaxime
or
co-amoxiclav
(in
children),
and
ciprofloxacin
(for
coliforms).
Short
courses
of
therapy
(3
weeks)
may
suffice

for
acute
osteomyelitis.
Septic arthritis
is a
medical emergency
if
good
joint
function
is to be
retained.
Staphylococcus
aureus
is the
commonest pathogen,
but a
very wide range
of
bacteria
may be
involved including streptococci
coliforms
and
Neisseria.
Aspiration
of the
joint
allows
specific

microbiological
diagnosis,
dif-
ferentiation
from
noninfectious causes such
as
crystal
synovitis,
and has
therapeutic benefit,
e.g.
for
the hip
joint where
formal
drainage
is
recommended. Initial therapy
is as for
chronic
osteomyelitis.
Eye
infections
Superficial
infections, caused
by a
variety
of
organisms,

are
treated
by
chloramphenicol,
fusidic
acid,
framycetin, gentamicin, ciprofloxacin,
ofloxacin
or
neomycin
in
drops
or
ointments. Ciprofloxacin,
ofloxacin,
gentamicin
or
tobramycin
are
used
for
Pseudomonas
aeruginosa,
and
fusidic
acid principally
for
Staphylococcus
aureus.
Preparations

often
contain
hydrocortisone
or
prednisolone,
but the
steroid
masks
the
progress
of the
infection,
and
should
it
be
applied with
an
antimicrobial
to
which
the
organism
is
resistant (bacterium
or
virus)
it may
make
the

disease worse
by
suppressing protective
inflammation.
Local chemoprophylaxis without
corticosteroid
is
used
to
prevent secondary bacte-
rial
infection
in
viral conjunctivitis.
A
variety
of
antibiotics
may be
given
by
direct
injection
to the
chambers
of the eye for
treatment
of
bacterial
endophthalmitis

.
Chlamydial conjunctivitis.
In the
developed world,
the
genital
(D-K)
serotypes
of the
organism
are
responsible
and the
reservoir
and
transmission
is
maintained
by
sexual contact. Endemic trachoma
in
developing countries
is
usually caused
by
serotypes
A,
B and C. In
either case, oral tetracycline
is

effec-
tive.
Pregnant
or
lactating women
may
receive
sys-
temic erythromycin.
Neonatal
ophthalmia
should
be
treated with systemic erythromycin
and
topical
tetracycline.
Herpes
keratitis
(see
p.
258).
It is
essential that
a
corticosteroid
should never
be put on the
eye;
the

disease
is
exacerbated
and
permanent
blindness
can
result.
Mycobacterial infections
PULMONARYTUBERCULOSIS
Drug therapy
has
transformed tuberculosis
from
a
disabling
and
often
fatal
disease into
one in
which
almost
100% cure
is
obtainable, although
the
recent
emergence
of

multiple drug resistant strains
of
Mycobacterium
tuberculosis
(MDRTB)
in
developed
249
13
CHEMOTHERAPY
OF
BACTERIAL
INFECTIONS
countries will disturb this optimistic view. Chemo-
therapy
was
formerly
protracted,
but a
better
understanding
of the
mode
of
action
of
antituber-
culous drugs
has
allowed

the
development
of
effective
short-course regimens.
Principles
of
antituberculosis
therapy
• A
large number
of
actively multiplying
bacilli
must
be
killed:
isoniazid
achieves this.
•
Treat
persisters,
i.e.
semidormant bacilli that
metabolise slowly
or
intermittently:
rifampicin
and
pyrazinamide

are the
most
efficacious.
•
Prevent
the
emergence
of
drug resistance
by
multiple therapy
to
suppress
single-drug-
resistant mutants that
may
exist
de
novo
or
emerge during therapy
in all
large bacterial
populations:
isoniazid
and
rifampicin
are
best.
•

Combined formulations
are
used
to
ensure that
poor compliance does
not
result
in
monotherapy
with consequent drug resistance.
Most contemporary regimens employ
an
initial
phase with administration
of at
least three drugs
to
reduce
the
bacterial load
as
rapidly
as
possible
(usually
for 2
months), followed
by a
continuation

phase with usually
two
drugs given
for 4
months.
All
short-course regimens include isoniazid, pyra-
zinamide
and
rifampicin.
After
extensive clinical
trials,
the
following
three have been found
satisfactory:
1.
An
unsupervised
regimen
of
daily dosing
comprising isoniazid
and
rifampicin
for
6
months, plus pyrazinamide
for the

first
2
months.
2.
A
supervised
(directly observed) regimen
for
patients
who
cannot
be
relied upon
to
comply
with treatment, comprising thrice-weekly
dosing with isoniazid
and
rifampicin
for
6
months, plus pyrazinamide
for the
first
2
months (isoniazid
and
pyrazinamide
are
given

in
higher dose than
in the
unsupervised
regimen).
With
both
the
above regimens, ethambutol
by
mouth
or
streptomycin i.m. should
be
added
for
the
first
2
months
if
there
is a
likelihood
of
drug-
resistant organisms,
or if the
patient
is

severely
ill
with extensive active lesions.
3. A
less
costly,
yet
still
effective,
regimen
favoured
by
some countries comprises supervised daily
administration
of
isoniazid, rifampicin,
pyrazinamide
and
either ethambutol
or
streptomycin
for 2
months
followed
by 6
months
of
unsupervised daily isoniazid
and
thiacetazone.

All
the
regimens
are
highly
effective,
with
relapse rates
of
1-2%
in
those
who
continue
for 6
months; even
if
patients
default
after,
say,
4
months,
tuberculosis
can be
expected
to
recur
in
only

10-15%.
Drug resistance seldom develops with
any
of
these regimens.
Although compliance
is
often
a
concern with
multiple drug therapy given
for
long periods, espe-
cially
in the
Developing World, directly observed
therapy (DOT)
has
surprisingly
not
been proven
to
improve relapse rates
in
many trials. Combination
therapy
is
assumed
to
improve compliance: some

commonly
used combinations include
Rifater
(rifampicin,
isoniazid plus pyrazinamide),
and
Rifinah
or
Rimactazid
(rifampicin
plus isoniazid).
Special problems
Resistant organisms. Initial resistance occurs
in
about
4% of
isolates
in the UK,
usually
to
isoniazid.
Multiple-drug-resistant tuberculosis,
i.e.
resistant
to
rifampicin
and
isoniazid
at
least, should

be
treated
with three
or
four
drugs
to
which
the
organisms
are
sensitive
and
should extend
for
12-24
months
after
cultures become negative. Treatment
of
such cases
requires expert management. Atypical myco-
bacteria
are
often
resistant
to
standard drugs; their
virulence
is low but

they
can
produce serious
infection
in
immunocompromised patients which
may
respond,
e.g.
to
clarithromycin
or a
quinolone,
often
in
combination.
Chemoprophylaxis
may be
either
•
primary,
i.e.
the
giving
of
antituberculosis drugs
to
uninfected
but
exposed individuals, which

is
seldom
justified;
or
•
secondary,
which
is the
treatment
of
infected
but
symptom-free
individuals, e.g. those known
to
be
in
contact with
the
disease
and who
develop
a
positive tuberculin reaction. Secondary
chemoprophylaxis
may be
justified
in
children
under

the age of 3
because they have
a
high risk
250
13
of
disseminated
disease;
isoniazid alone
for
6
months
may be
used since there
is
little risk
of
resistant organisms emerging because
the
organism load
is
low.
Pregnancy. Drug treatment should never
be
inter-
rupted
or
postponed
during

pregnancy.
On the
general principle
of
limiting exposure
of the
fetus,
the
standard three-drug, 6-month course
(1
above)
is
best. Streptomycin should
be
excluded
from
any
regimen (danger
of
fetal
eighth cranial nerve
damage).
Nonrespiratory tuberculosis.
The
principles
of
treat-
ment,
i.e.
multiple therapy

and
prolonged
follow-
up, are the
same
as for
respiratory tuberculosis.
In
only
a few
cases
is
surgery
now
necessary.
It
should
always
be
preceded
and
followed
by
chemotherapy.
Many
chronic tuberculous lesions
may be
relatively
inaccessible
to

drugs
as a
result
of
avascularity
of
surrounding tissues; treatment
frequently
has to be
prolonged
and
dosage
high,
especially
if
damaged
tissue cannot
be
removed
by
surgery,
e.g.
tuber-
culosis
of
bones.
Meningeal tuberculosis.
It is
essential
to use

iso-
niazid
and
pyrazinamide which penetrate well into
the
CSF.
Rifampicin
enters inflamed meninges well
but
noninflamed meninges less
so. An
effective
regimen
is
isoniazid,
rifampicin,
pyrazinamide
and
streptomycin. Treatment
may
need
to
continue
for
much longer than modern short-course chemo-
therapy
for
pulmonary tuberculosis.
Adrenal
steroid

and
tuberculosis.
In
pulmonary
tuberculosis
a
corticosteroid
may be
given
to
severely
ill
patients.
It
reduces
the
injurious reac-
tion
of the
body
to
tuberculoprotein
and
buys time
for
the
chemotherapy
to
take
effect.

It
also causes
the
patient
to
feel
better much more quickly.
In
the
absence
of
effective
chemotherapy,
an
adrenal
steroid
will
cause tuberculosis
to
extend
and it
should never
be
used alone,
e.g.
for
another
disease,
if
tuberculosis

is
suspected.
Tuberculosis
in the
immunocompromised. Immu-
nocompromised patients require special measures
because
they
may be
infected
more readily when
exposed, their
infections
usually involve large
MYCOBACTERlAL
INFECTIONS
numbers
of
tubercle bacilli (multibacillary disease),
and in the
case
of
patients with AIDS,
are
more
likely
to be
infected
with multiply antibiotic resistant
strains. Usually

at
least
four
drugs
are
started,
and
patients
are
isolated until bacteriological results
are
obtained
and
they have
shown
clinical improve-
ment.
If
infections
are
proved
to
involve antibiotic
susceptible mycobacteria, therapy
can
continue
with
a
conventional 6-month regimen with
careful

follow-up.
Particular problems
may
occur with
multiple drug interactions during antituberculous
treatment
of
patients receiving antiretroviral therapy.
ANTITUBERCULOSIS DRUGS
Isoniazid
Isoniazid (INH, INAH, isonicotinic acid hydrazide)
is
selectively
effective
against
Mycobacterium
tuber-
culosis
because
it
prevents
the
synthesis
of
comp-
onents that
are
unique
to
mycobacterial

cell
walls.
Hence
it is
bactericidal against actively multiplying
bacilli
(whether within macrophages
or at
extra-
cellular
sites)
but is
bacteriostatic against
non-
dividing bacilli;
it has
little
or no
activity against
other bacteria. Isoniazid
is
well absorbed
from
the
alimentary
tract
and is
distributed throughout
the
body water, readily crossing tissue barriers

and
entering cells
and
cerebrospinal
fluid.
It
should
always
be
given
in
cases where there
is
special risk
of
meningitis
(miliary
tuberculosis
and
primary
infection).
Isoniazid
is
inactivated
by
conjugation
with
an
acetyl group
and the

rate
of the
reaction
is
bimodally distributed
(see
Pharmacogenetics,
p.
123).
The
t
l
/
2
is 1 h in
fast
and 4 h in
slow acetylators; steady-
state plasma concentration
in
fast
acetylators
is
less
than
half
that
in
slow acetylators
but

standard oral
doses
(300 mg/d)
on
daily regimens give adequate
tuberculocidal
concentrations
in
both groups.
Adverse
effects.
Isoniazid
is in
general well
tolerated.
The
most severe adverse
effect
is
liver
damage which
may
range
from
moderate elevation
of
hepatic enzymes
to
severe hepatitis
and

death.
It
is
probably caused
by a
chemically reactive meta-
bolite^),
e.g.
acetylhydrazine. Most cases develop
within
the
first
8
weeks
of
therapy
and
liver
function
tests
should
be
monitored monthly during
this period
at
least.
251
13
CHEMOTHERAPY
OF

BACTERIAL
INFECTIONS
Isoniazid
is a
structural analogue
of
pyridoxine
and
accelerates
its
excretion,
the
principal
result
of
which
is
peripheral neuropathy with numbness
and
tingling
of the
feet,
motor involvement being
less common. Neuropathy
is
more
frequent
in
slow
acetylators, malnourished people,

the
elderly
and
those with
HIV
infection, liver disease
and
alcohol-
ism. Such patients should receive pyridoxine
10
mg/d
by
mouth, which prevents neuropathy
and
does
not
interfere
with
the
therapeutic
effect;
some
prefer
simply
to
give pyridoxine
to all
patients.
Other
adverse

effects
include mental disturbances,
incoordination, optic neuritis
and
convulsions.
Isoniazid inhibits
the
metabolism
of
phenytoin,
carbamazepine
and
ethosuximide,
increasing
their
effect.
Rifampicin
Rifampicin
has
bactericidal activity against
the
tubercle
bacillus, comparable
to
that
of
isoniazid.
It
is
also used

in
leprosy.
It
acts
by
inhibiting
RNA
synthesis, bacteria
being sensitive
to
this
effect
at
much lower concen-
trations than mammalian cells;
it is
particularly
effective
against mycobacteria that
lie
semidormant
within cells.
Rifampicin
has a
wide range
of
antimicrobial activity. Other
uses
include
leprosy,

severe Legionnaires' disease (with erythromycin
or
ciprofloxacin),
the
chemoprophylaxis
of
meningo-
coccal
meningitis,
and
severe staphylococcal
inf-
ection (with flucloxacillin
or
vancomycin).
Rifampicin
is
well absorbed
from
the
gastro-
intestinal tract.
It
penetrates well into most tissues.
Entry
into
the CSF
when meninges
are
inflamed

is
sufficient
to
maintain therapeutic concentrations
at
normal oral doses
but
transfer
is
reduced
as
inflammation
subsides
in 1 or 2
months.
Enterohepatic recycling takes place,
and
eventually
about
60% of a
single dose
is
eliminated
in the
faeces;
urinary excretion
of
unchanged drug
also
occurs.

The
t
l
/
2
is 4 h
after
initial doses,
but
shortens
on
repeated dosing because rifampicin
is a
very
effective
enzyme inducer
and
increases
its
own
metabolism
(as
well
as
that
of
several other
drugs,
see
below).

Adverse
reactions.
Rifampicin
rarely causes
any
serious toxicity. Adverse reactions include flushing
and
itching with
or
without
a
rash,
and
thrombo-
cytopenia.
Rises
in
plasma
bilirubin
and
hepatic
enzymes
may
occur when treatment starts
but are
often
transient
and are not
necessarily
an

indication
for
stopping
the
drug;
fatal
hepatitis, however,
has
occurred. Hepatic
function
should
be
checked
before
starting treatment
and at
least
for the
first
few
months
of
therapy. Intermittent dosing,
i.e.
less
than twice weekly, either
as
part
of a
regimen

or
through poor compliance, promotes certain
effects
that probably have
an
immunological
basis,
namely,
an
influenza-like syndrome (malaise, headache
and
fever,
shortness
of
breath
and
wheezing), acute
haemolytic
anaemia
and
thrombocytopenia
and
acute
renal
failure
sometimes
with
haemolysis.
Red
discolouration

of
urine, tears
and
sputum
is a
useful
indication that
the
patient
is
taking
the
drug.
Rifampicin
also causes
an
orange discolouration
of
soft
contact lenses.
Interactions.
Rifampicin
is a
powerful enzyme
inducer
and
speeds
the
metabolism
of

numerous
drugs, including warfarin, steroid contraceptives,
narcotic
analgesics, oral antidiabetic agents, pheny-
toin
and
dapsone. Appropriate increase
in
dosage,
and
alternative methods
of
contraception,
are
required
to
compensate
for
increased drug metabolism
(see
also paracetamol
overdose,
p.
287).
Rifabutin
(t
1
/
2
36 h) has

similar activity
and
adverse
reactions,
and is
used
for
prophylaxis
of
Myco-
bacterium
avium
infection
in
patients with
AIDS,
and
for
treatment
of
tuberculous
and
nontuberculous
mycobacterial
infection
in
combination with other
drugs.
Pyrazinamide
Pyrazinamide

is a
derivative
of
nicotinamide
and
is
included
in
first-choice
combination regimens
because
of its
particular ability
to
kill intracellular
persisters,
i.e.
mycobacteria that
are
dividing
or
semidormant,
often
within cells.
Its
action
is
depen-
dent
on the

activity
of
intrabacterial pyrazinami-
dase which converts pyrazinamide
to the
active
pyrazinoic acid;
this
enzyme
is
most
effective
in an
acidic
environment such
as the
interior
of
cells.
It is
inactive
against
Mycobacterium
bovis.
Pyrazinamide
is
well absorbed
from
the
gastrointestinal

tract
and
metabolised
in the
liver, very little unchanged drug
252
13
MYCOBACTERIAL
INFECTIONS
appearing
in the
urine
(i
l
/
2
9 h). CSF
concentrations
are
almost identical
to
those
in the
blood, hence
the
drug
is
valuable
in
tuberculous

meningitis.
Experience
in
several countries indicates that
pyrazinamide
is
safe
to use in
pregnancy.
Adverse
effects
include hyperuricaemia
and
arth-
ralgia, which
is
relatively
frequent
with
daily
but
less
so
with intermittent
dosing
and,
unlike gout,
affects
both large
and

small joints. Pyrazinoic acid,
the
principal metabolite
of
pyrazinamide, inhibits
renal
tubular secretion
of
urate. Symptomatic
treatment
with
an
NSAID
is
usually
sufficient
and it
is
rarely necessary
to
discontinue pyrazinamide
because
of
arthralgia. Hepatitis, which
was
particularly
associated with high
doses,
is not a
problem with modern short-course schedules.

Sid-
eroblastic anaemia
and
urticaria also occur.
Ethambutol
Ethambutol, being bacteriostatic,
is
used
in
con-
junction
with other antituberculosis drugs
to
delay
or
prevent
the
emergence
of
resistant bacilli.
It is
well absorbed
from
the
gastrointestinal tract
and
effective
concentrations
occur
in

most body tissues
including
the
lung;
in
tuberculous meningitis,
suffi-
cient
may
reach
the CSF to
inhibit mycobacterial
growth
but
insignificant amounts cross into
the
CSF
if the
meninges
are not
inflamed. Excretion
is
mainly
by the
kidney,
by
tubular secretion
as
well
as by

glomerular
filtration
(t
l
/
2
4 h); the
dose should
be
reduced when renal function
is
impaired.
Adverse
effects.
In
recommended oral doses
(15
mg/kg
per
day)
(taking account
of
reduced
renal
function),
ethambutol
is
relatively nontoxic.
The
main problem

is
optic
neuritis
(unilateral
or
bilateral)
causing loss
of
visual
acuity,
central scoto-
mata, occasionally also peripheral vision loss
and
red-green
colour blindness.
The
changes reverse
if
treatment
is
stopped promptly;
if
not,
the
patient
may go
blind.
It is
prudent
to

note
any
history
of
eye
disease
and to get
baseline tests
of
vision
before
starting treatment with ethambutol.
The
drug
should
not be
given
to a
patient whose vision
is
much reduced
and who may not
notice
further
minor deterioration. Patients
should
be
told
to
make

a
point
of
reading small print
in
newspapers
(with
each
eye
separately)
and if
there
is any
deterioration
to
stop
the
drug immediately
and
seek advice. Patients
who
cannot understand
and
comply (especially children) should
be
given alter-
native therapy,
if
possible.
The

need
for
repeated
specialist ophthalmological monitoring
is
contro-
versial. Peripheral neuritis occurs
but is
rare.
Streptomycin:
see
page 225.
Thiacetazone
Thiacetazone
is
tuberculostatic
and is
used with
isoniazid
to
inhibit
the
emergence
of
resistance
to
the
latter drug.
It is
absorbed

from
the
gastrointes-
tinal
tract, partly metabolised
and
partly excreted
in
the
urine
(t
1
/
2
13
h).
Adverse
reactions include gastrointestinal symp-
toms, conjunctivitis
and
vertigo. More serious
effects
are
erythema multiforme, haemolytic anaemia,
agranulocytosis, cerebral oedema
and
hepatitis.
Alternative
or
reserve drugs

are
used where there
are
problems
of
drug intolerance
and
bacterial
resistance. They
are in
this class because
of
either
greater
toxicity
or of
lesser
efficacy
and
include:
ethionamide
(gastrointestinal irritation, allergic
reactions),
capreomycin
(nephrotoxic),
and
cycloserine
(effective
but
neurotoxic).

Quinolone
antibiotics
such
as
ciprofloxacin
and the
more recently intro-
duced
macrolides such
as
clarithromycin
and
azithro-
mycin
also have
useful
activity against mycobacteria.
LEPROSY
Effective
treatment
of
leprosy
is
complex
and
requires much experience
to
obtain
the
best results.

Problems
of
resistant leprosy
now
require that
multiple drug therapy
be
used
and
involve:
•
for
paucibacillary
disease:
dapsone
and
rifampicin
for
6
months
•
for
multibacillary
disease:
dapsone,
rifampicin
and
clofazimine
for 2
years. Follow-up

for 4-8
years
may
be
necessary.
Dapsone,
a
bacteriostatic sulphone
(related
to
sulphonamides,
and
acting
by the
same mechanism,
see
p.
231),
has for
many years been
the
standard
drug
for the
treatment
of all
forms
of
leprosy.
253

13
CHEMOTHERAPY
OF
BACTERIAL
INFECTIONS
Irregular
and
inadequate duration
of
treatment
with
a
single drug have allowed
the
emergence
of
resistance, both primary
and
secondary,
to
become
a
major
problem. Dapsone
is
also used
to
treat
dermatitis
herpetiformis,

and is
given
for
Pneumo-
cystis
carinii
and
(with pyrimethamine) malaria
prophylaxis.
The
t
1
/
2
is 27 h.
Adverse
effects
range
from
gastrointestinal symptoms
to
agranulocytosis,
haemolytic
anaemia
and
generalised allergic reac-
tions that include
exfoliative
dermatitis.
Rifampicin

(see above)
is
bactericidal,
and is
safe
and
effective
when
given once monthly. This long
interval renders
feasible
the
directly observed
administration
of
rifampicin which
the
above
regimens require.
Clofazimine
has a
leprostatic action
and an
anti-
inflammatory
effect
that prevents erythema nodo-
sum
leprosum.
It

causes gastrointestinal symptoms.
Reddish discolouration
of the
skin
and
other
cutaneous lesions also occur,
and may
persist
for
months
after
the
drug
has
been
stopped.
The
t
l
/
2
is
70
days.
Other antileprotics include ethionamide
and
pro-
thionamide. Thalidomide (see Index), despite
its

notorious past, still
finds
a use
with corticosteroid
in the
control
of
allergic lepromatous reactions.
OTHER
BACTERIAL
INFECTIONS
Burns. Infection
may be
reduced
by
application
of
silver
sulphadiazine
cream. Substantial
absorption
can
occur
from
any raw
surface
and use of
aminoglycoside, e.g. neomycin, preparations
can
cause

ototoxicity.
Gas
gangrene.
The
skin between
the
waist
and
the
knees
is
normally
contaminated
with
anaerobic
faecal
organisms. However assiduous
the
skin
preparation
for
orthopaedic operations
or
thigh
amputations, this will
not
kill
or
remove
all the

spores. Surgery done
for
vascular
insufficiency
where
tissue
oxygenation
may be
poor
is
likely
to
be
followed
by
infection.
Gas
gangrene
(Clostridium
perfringens)
may
occur;
it may be
prevented
by
benzylpenicillin
or
metronidazole prophylaxis.
Wounds. Systemic chemoprophylaxis
is

necessary
for
several days
at
least
in
dirty
wounds
where
sutures have
to be
left
below
the
skin,
and in
penetrating wounds
of
body cavities. Flucloxacillin
is
probably
best,
but in the
case
of
penetrating
abdominal wounds, metronidazole should
be
added,
and

consideration given
to
adding
an
agent
active
against aerobic Gram-negative bacteria, e.g.
gentamicin (see also Tetanus).
Abscesses
and
infections
in
bone
and
serous
cavities
are
treated according
to the
antimicrobial
sensitivity
of the
organism concerned
but
require
high doses because
of
poor penetration.
Local
instillation

of the
drug
may be
needed.
Actinomycosis.
The
anaerobe
Actinomyces
israelii
is
sensitive
to
several drugs,
but not
metronidazole,
and
access
is
poor because
of
granulomatous
fibro-
sis. High doses
of
benzylpenicillin
or
amoxicillin
are
given
for

several weeks;
the
infections
are
often
mixed
with other anaerobic bacteria
so
metronida-
zole
is
often
given
in
addition
to
ensure activity
against
all
components
of the
mixture. Co-amoxiclav
may
be a
convenient alternative. Surgery
is
likely
to
be
needed.

Leptospirosis.
To be
maximally
effective,
chemo-
therapy should
be
started within
4
days
of the
onset
of
symptoms. Benzylpenicillin
is
recommended;
a
Herxheimer
reaction
may be
induced (see Syphilis).
General
supportive management
is
important,
including attention
to
fluid
balance
and

observation
for
signs
of
hepatic, renal
or
cardiac
failure.
Lyme
disease. Keeping
the
skin covered
and use of
insect
repellants
are
effective
to
prevent
tick
bites
and
tick
removal shortly
after
attachment (within
24
h)
will prevent
infection.

In
most manifestations
of the
disease,
Borrelia
burgdorferi
responds
to
amoxicillin
or
doxycycline
orally
for up to 21
days
but
when
the
central
nervous system
is
invaded large doses
of
cefotaxime
should
be
given i.v.
for 14
days.
GUIDETO
FURTHER

READING
Adachi
J A,
Ostrosky-Zeichner
L,
DuPont
H L,
Ericsson
C D
2000
Empirical
antimicrobial
therapy
254
13
for
traveler's diarrhea. Clinical Infectious Diseases
31:1079-1083
Arroll
B,
Knealy
T
2001 Antibiotics
for
acute
bronchitis. British Medical Journal 322: 939-940
Bisno
A L
2001 Acute pharyngitis.
New

England
Journal
of
Medicine 344:
205
Brown
P D,
Lerner
S
A1998 Community-acquired
pneumonia. Lancet
352:1295-1302
Campion
E W
1999 Liberty
and the
control
of
tuberculosis.
New
England Journal
of
Medicine
340:
385-386
Del
Mar C et al
1997
Are
antibiotics indicated

as
initial
treatment
for
children with acute
otitis
media?
A
meta-analysis. British Medical Journal 314:
1526-1529
Dixon
T C et al
1999 Anthrax.
New
England Journal
of
Medicine 341:
815-826
Goldenberg
D
L1998 Septic arthritis. Lancet 351:
197-202
Gorbach
S L
1999 Antibiotics
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difficile.
New
England Journal

of
Medicine
341:1690-1691
Jacobson
R R,
Krahenbuhl
J L
1999 Leprosy. Lancet
353:
655-660
Joint
Tuberculosis Committee
of the
British Thoracic
Society 1998 Chemotherapy
and
management
of
tuberculosis
in the
United Kingdom:
recommendations. Thorax
53: 536
MYCOBACTERlAL
INFECTIONS
Lew
D P,
Waldvogel
F
A1997 Osteomyelitis.

New
England Journal
of
Medicine 336: 999-1007
Marik
P E
2001 Aspiration pneumonitis
and
aspiration
pneumonia.
New
England Journal
of
Medicine 344:
665-671
Mead
P S,
Griffin
P M
1998
Escherichia coli
0157;H7.
Lancet
352:1207-1212
Mylonakis
E,
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