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iii28
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Intravenous therapy with a polymyxin (colistin or colisti-
methate sodium) has been used to treat infections due to multi-
resistant Gram-negative organisms. Although recent studies have
shown that it has acceptable effectiveness and fewer cases of
nephrotoxicity and neurotoxicity than previously reported, at
present its use is reserved mainly for ESBL-producing bacteria
that are also resistant to gentamicin and carbapenems.
30
Table 2 summarizes the important properties of antibiotics avail-
able in the UK for the treatment of cUTI. Once the organism
has been identied and susceptibilities are known, therapy
should be de-escalated if possible to a narrow-spectrum agent.
7
The main aim of therapy is to combat sepsis, relieve symp-
toms and prevent complications. In order to achieve a cure
and prevent re-infection or recurrence the obstruction must be
removed. Urinary devices such as indwelling catheters become
coated with a biolm, which acts as a reservoir for organisms,
protecting them from the action of antimicrobials and host
defences. Thus the organisms are likely to cause recurrence of
infection and become more resistant to antimicrobials after
each course of treatment. If possible, urinary catheters should
be removed and a condom catheter or another form of drainage
system be used instead. The use of physician reminders to
remove unnecessary urinary catheters may help.
2
If the patient
still requires a catheter, a new one should be inserted either
when collecting the specimen of urine in a patient with symp-
toms of a cUTI or soon after starting treatment for a sympto-
matic infection, so symptoms will settle in a shorter time and
increase the interval before the next relapse.
11
Where a urinary tract abnormality is not apparent a diagnos-
tic investigation should be carried out to look for other compli-
cating factors such as an abscess. Options include diagnostic
imaging, which may include pelvic and renal ultrasound, intrave-
nous pyelogram, CT or magnetic resonance imaging. Renal
investigations such as cystoscopy, retrograde pyelogram or uro-
dynamic studies may be required depending on the history
given.
7,11
How long should a patient receive antibiotics
for?
The optimal length of treatment for symptomatic cUTI has not
been extensively studied. As there are many different causes of
underlying abnormality, a simple recommendation cannot be
made. Most clinical trials have evaluated 714 days of treat-
ment, but a recent randomized multicentre study demonstrated
that levooxacin for 5 days was non-inferior to ciprooxacin for
10 days in cUTI and acute pyelonephritis.
31
Ten to fourteen
days of antibiotics are usually recommended for patients with
bacteraemia, hypotension and other signs of severe sepsis,
whereas a 7 day regimen should sufce for those with a lower
UTI.
3
A 3 day course is usually not sufcient and is thus not rec-
ommended for cUTI.
32
Clinical improvement should occur within
2448 h after starting treatment. If the patient has not
responded, the choice of antibiotic should be reviewed in the
light of the culture results. They may need an urgent investi-
gation to exclude an abscess that needs drainage. A patient
can be switched to an oral agent when they are clinically
improved providing they can tolerate it and the organism is
susceptible.
What preventative strategies can be used?
These have been well-reviewed in the Canadian Guidelines for
the management of cUTI in adults.
1
Extended courses of anti-
biotics should only be used in specic situations such as for
men with a relapsing infection from a prostatic source when
612 weeks of therapy have been given.
33
They are not rec-
ommended as long-term prophylaxis for the prevention of infec-
tion in, for example patients with spinal cord lesions undergoing
intermittent catheterization, as prophylaxis will select for
antibiotic-resistant organisms.
32
Rarely, a long-term course of
antimicrobials has been given as suppressive therapy to
prevent enlargement of stones that cannot be removed.
34
In
this situation the benet of giving the antibiotic must be
weighed against the likely side effects and the risk of selecting
for antibiotic-resistant organisms.
Sexually active women with recurrent UTI are recommended
to take prophylactic antibiotics at the time of intercourse and to
not use a spermicide-containing contraceptive. Results of studies
on the use of oral or vaginal oestrogen by post-menopausal
women with recurrent UTIs have been inconsistent and thus
the routine use of these agents has not been recommended.
5
The use of oral lactulose however, to reduce constipation in
elderly patients, may be helpful and some studies have shown
Case 4
A 56-year-old man takes ciprooxacin for travellers diarrhoea whilst in India. On his
return home he becomes acutely unwell with fever, loin pain and signs of sepsis and
is admitted to hospital.
After taking blood cultures and sending urine to the laboratory, gentamicin and
piperacillin/tazobactam are started as per hospital guidelines. He improves clinically.
An ESBL-producing E. coli is cultured from the blood cultures and the urine specimen
and is found to be susceptible to gentamicin and carbapenems, but resistant to all
-lactams, trimethoprim and ciprooxacin. His antibiotics are switched to intravenous
ertapenem and he is discharged on this once-daily, administered by the district
nurse for a total of 10days.
Figure 4. Case report 4: systemic sepsis and bacteraemia in a patient returning from foreign travel.
Treatment of complicated urinary tract infection
iii29
JAC
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Table 2. Antibiotics commonly used to treat infections caused by resistant Gram-negative bacteria including AmpC- and ESBL-producing organisms
Antibiotic Place in therapy Key advantages Contraindications Side effects/disadvantages
NIT: 100 mg oral q6h for
7 days minimum
treatment of complicated and
uncomplicated lower UTI
widely available and extensive
clinical experience
renal impairment
(GFR,60 mL/min)
nausea and vomiting (common)
peripheral neuropathy with long-term use
(rare) resistance rare in E. coli although
more common in other
Enterobacteriaceae
no iv formulation
G6PD
inherent resistance in Proteus
spp. and Pseudomonas
spp.
FOF 3 g sachet oral once
every 3 days for
14 days for cUTI
treatment of complicated and
uncomplicated lower UTI
(unlicensed)
resistance rare even in Spain
where it is used extensively
not suitable for
pyelonephritis or severe
urinary sepsis due to poor
systemic absorption
not licensed or marketed in the UK and thus
difcult to obtain urgently
headache or diarrhoea in 10% of patients oral capsules and iv formulation
also available
GEN 35 mg/kg iv daily
in divided doses or
57 mg/kg iv once
daily (consult local
guidelines)
option for once-daily outpatient
iv therapy for complicated
UTI
resistance relatively uncommon severe renal impairment nephrotoxicity
vestibular and auditory toxicity
risk of resistance in certain ESBL strains
serum levels required to determine safe and
effective continuing dosing
TMC 12 g iv q12h treatment of cUTI and other
infections caused by ESBL-
and
good in vitro activity against
multiresistant ESBLs including
AmpC-producing bacteria
penicillin allergy inactive against Gram-positive bacteria,
Bacteroides spp. and Pseudomonas spp.
provenance outside the
AmpC-producing bacteria
susceptible to this agent
narrow spectrum urinary tract to be established
limited clinical experience in the UK
ETP 1 g iv once daily option for outpatient iv therapy
for cUTI caused by
susceptible ESBL-producing
bacteria
once-daily administration history of penicillin
anaphylaxis
does not cover infections caused by
Pseudomonas spp.
more vulnerable than other carbapenems to
resistance combinations of impermeability
with an ESBL or AmpC
seizure rate attributed to ertapenem 0.2%
from clinical trials
36
IPM (plus cilastatin)
500 mg1 g iv q6h
q8h (maximum
4 g/day)
treatment of cUTI and other
infections caused by ESBL-
and AmpC- producing
bacteria
broad spectrum of activity
including Enterococcus faecalis,
Pseudomonas spp. and
ESBL-producing bacteria
history of penicillin
anaphylaxis
seizure risk 1.5%2% (more common with
higher doses, renal impairment and in
patients with a history of epilepsy)
36
renal failure (GFR,5 mL/
min) Cilastatin is required to inhibit
dehydropeptidase enzyme present on the
brush border of proximal renal tubular cells
that hydrolyses and inactivates IPM
MEM 5001000 mg
iv q8h
treatment of cUTI and other
infections caused by ESBL-
and AmpC-producing
bacteria
relatively low seizure risk
(0.08%)
37
history of penicillin
anaphylaxis
increased hepatic enzymes (bilirubin and
transaminases) (.1% incidence)
somewhat less active carbapenem against
Gram-positive organisms
broad spectrum of activity
including Pseudomonas spp.
and ESBL-producing bacteria
P
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H
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0
b y g u e s t o n A u g u s t 6 , 2 0 1 4h t t p : / / j a c . o x f o r d j o u r n a l s . o r g /D o w n l o a d e d f r o m
DOR 500 mg iv q8h treatment of cUTI and other
infections caused by ESBL-
and AmpC-producing
bacteria
most potent agent in
carbapenem class
history of penicillin
anaphylaxis
headache very common
limited clinical experience in the UK
reduce dose in renal impairment (GFR,50
mL/min)
broad spectrum of activity
including Pseudomonas spp.
and ESBL-producing bacteria
relatively low seizure risk
38
TGC 100 mg iv loading
dose followed by
50 mg iv q12h
licensed for complicated skin
and soft tissue infections and
complicated intra-abdominal
infections only
treatment option in severe
penicillin allergy
cannot be given to children
,8 years of age due to
discolouration of teeth
limited urinary excretion of active drug
nausea very common (up to one-third of
patients) salvage therapy for infection with
resistant ESBL-producing
organisms
relatively low serum concentrationscaution
in bacteraemia
29
extensive distribution
concentration in tissues inherent resistance in Pseudomonas spp. and
acquired resistance in Proteus spp. no dosage adjustment in renal
failure reduce dose in severe hepatic impairment
CST 12 million units iv
q8h (1500025000
units/kg iv q8h if
,60 kg)
cUTI and bacteraemia caused
by susceptible Gram-negative
bacteria resistant to other
agents
treatment option in severe
penicillin allergy
Myasthenia gravis inherent resistance in Gram-positive bacteria,
anaerobes, Proteeae, Serratia spp.,
Providencia spp. salvage therapy for infection with
resistant ESBL-producing
organisms
neurotoxicity (most commonly apnoea and
sensory disturbances in 7% of patients)
nephrotoxicity (8%20% in seriously ill
hospitalized patients); reduce dose in renal
impairment (GFR,20 mL/min); monitor
renal function and discontinue if
nephrotoxicity occurs.
effective against wide range of
resistant Gram-negative
bacteria including
Acinetobacter spp.
q6h, every 6 h; q8h, every 8 h; q12h, every 12 h; CST, colistin; DOR, doripenem; ETP, ertapenem; FOF, fosfomycin; GEN, gentamicin; GFR, glomerular ltration rate; G6PD,
glucose-6-phosphate dehydrogenase deciency; IPM, imipenem; iv, intravenous; MEM, meropenem; NIT, nitrofurantoin; PMEC, pivmecillinam; TGC, tigecycline; TMC, temocillin.
T
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1
J
A
C
b y g u e s t o n A u g u s t 6 , 2 0 1 4h t t p : / / j a c . o x f o r d j o u r n a l s . o r g /D o w n l o a d e d f r o m
that cranberry products (juice, tablets or capsules) may reduce
the frequency of recurrent UTI in women.
5,8,33,35
In the future
other preventative strategies may include the development of
vaccines. The use of intentional colonization with benign organ-
isms that are also susceptible to a wider range of antibiotics may
need to be considered.
33
There is an urgent need for research into the effectiveness of
combinations of oral antibiotics in the treatment of complicated
UTI in ambulatory care and the impact on the epidemiology of
resistance. There is also an immediate requirement for increased
availability of fosfomycin in the UK.
Transparency declarations
This article is part of a Supplement sponsored by the BSAC.
A. P. has received funds for speaking at symposia and attending advi-
sory boards organized on behalf of Novartis, Wyeth/Pzer and AstraZe-
neca. K. H. has received funds for speaking at symposia and attending
advisory boards organized on behalf of Novartis, Wyeth/Pzer and
Astellas.
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