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J Antimicrob Chemother 2010; 65 Suppl 3: iii25 33

doi:10.1093/jac/dkq298

Complicated urinary tract infections: practical solutions for the


treatment of multiresistant Gram-negative bacteria
Ann Pallett 1* and Kieran Hand 2
1
Department of Microbiology, Southampton University Hospitals NHS Trust, Southampton General Hospital, Tremona Road,
Southampton SO16 6YD, UK; 2Department of Pharmacy, Southampton University Hospitals NHS Trust,
Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK

*Corresponding author. Tel: +44-23-8079-6767; Fax: +44-23-8070-2530; E-mail: Ann.Pallet@suht.swest.nhs.uk

Resistance in Gram-negative bacteria has been increasing, particularly over the last 6 years. This is mainly
due to the spread of strains producing extended-spectrum b-lactamases (ESBLs) such as CTX-M enzymes
or AmpC b-lactamases. Many of the isolates producing these enzymes are also resistant to trimethoprim,
quinolones and aminoglycosides, often due to plasmid co-expression of other resistance mechanisms.
CTX-M-producing Escherichia coli often occurs in the community and as E. coli is one of the commonest
organisms causing urinary tract infections (UTIs) the choice of agents to treat these infections is
diminishing. Novel combinations of antibiotics are being used in the community and broad-spectrum
agents such as carbapenems are being used increasingly as empirical treatment for severe infections.
Of particular concern therefore are reports in the UK of organisms that produce carbapenemases. As
resistance is becoming more widespread, prudent use of antimicrobials is imperative and, as asympto-
matic bacteriuria is typically benign in the elderly, antibiotics should not be prescribed without clinical
signs of UTI. The use of antibiotics as suppressive therapy or long-term prophylaxis may no longer be
defensible.

Keywords: ESBL, AmpC, carbapenemase, urinary catheter, bacteriuria, fosfomycin, cefixime, cefpodoxime, co-amoxiclav, clavulanate,
clavulanic acid, nitrofurantoin, pivmecillinam

Introduction What is a symptomatic UTI?


Urinary tract infections (UTIs) are among the most common Typical symptoms of a lower UTI include frequency and dysuria
infectious diseases occurring in either the community or health- without fever, chills or back pain whereas upper UTI usually pre-
care setting.1 Uncomplicated UTIs typically occur in the healthy sents with symptoms of pyelonephritis such as loin pain, flank
adult non-pregnant woman, while complicated UTIs (cUTIs) tenderness, fever or other signs of a systemic inflammatory
may occur in all sexes and age groups and are frequently associ- response.3 If both dysuria and frequency are present, the prob-
ated with either structural or functional urinary tract abnormal- ability of a UTI is .90% and antibiotic treatment is indicated.5
ities. Examples include foreign bodies such as calculi (stones), However, as exemplified by the case report shown in Figure 1,
indwelling catheters or other drainage devices, obstruction, diagnosis of UTI can be difficult especially in the confused
immunosuppression, renal failure, renal transplantation and elderly patient because of non-specificity and misleading symp-
pregnancy.2 UTI in the elderly is almost always complicated in toms and signs.6 As in this case, some patients may present with
men with prostatic hypertrophy and in post-menopausal signs of a chest infection or may have dual infection. The pres-
women who may have an increased post-void residual ence of delirium, urinary retention or incontinence, metabolic
volume.3 The likelihood of treatment failure and serious compli- acidosis or respiratory alkalosis may indicate a symptomatic
cations, particularly the development of antimicrobial resistance, UTI in this group. It is recommended that a urine sample be col-
is more common in cUTI. Although a broad range of pathogens lected before starting empirical antibiotic therapy for patients
can cause cUTI, Escherichia coli remains the most common; with cUTI but in the elderly it is more difficult to collect a non-
however, even this organism is becoming resistant to the contaminated sample,7 and an inout catheter may represent
agents that are normally prescribed.4 This leads to a number the optimum approach to obtaining a reliable specimen.6 A dip-
of management and therapeutic problems that will be discussed stick can be used to test for the presence of leucocyte esterase
below. Genetic susceptibility of individual patients to UTI has and nitrites as surrogate markers for bacteriuria in the non-
been well reviewed recently and will not be discussed in this catheterized patient, with negative tests associated with low
article.2 probability of bacteriuriaaround 20% in women with minimal

# The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

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Pallett and Hand

signs or symptoms of a UTI and ,10% in symptomatic nursing sign and occasionally there may be suppuration around the cath-
home residents.5,6 In symptomatic non-catheterized elderly eter.11 Even if there are no localizing signs, because the urine
patients, a positive result is less reliable with the presence of leu- culture is frequently positive the patient is assumed to have a
cocyte esterase having ,50% positive predictive value. However, UTI. However, a prospective study using serological markers
some experts consider that the detection of nitrites in the symp- identified only one-third of the patients with bacteriuria in a
tomatic patient should prompt initiation of treatment.6 long-term care facility as having a UTI, which suggests that
The quantitative criterion appropriate for the microbiological the diagnosis of UTI in this situation is that of exclusion. The
identification of significant bacteriuria is generally considered febrile episodes often settle spontaneously (Figure 2).11
to be at least 108 cfu/L. In some specific groups it is less: for A number of excellent guidelines reviewing the diagnosis and
men 106 cfu/L; and for women with symptoms of UTI it is treatment of ASB in adults are available.5,12 In essence, in the
105 cfu/L.5 Asymptomatic bacteriuria (ASB) is common in the absence of genitourinary symptoms, bacteriuria should not be
elderly, rising with age to .50% in women and .35% in men treated except in pregnancy or for surgical manipulation of the
over the age of 80 years. Other co-morbidities such as diabetes urinary tract. Unnecessary treatment will lead to selection of
mellitus or an indwelling catheter also contribute to increased resistant organisms and puts patients at risk of adverse drug
frequency of this condition.8 Algorithms have been developed effects including infection with Clostridium difficile. Likewise
to optimize antimicrobial use for suspected UTI in the nursing there is good evidence that screening for ASB is not necessary
home, recommending that in the absence of minimal signs of in pre-menopausal patients who are not pregnant, older patients
UTI, urine should not be cultured and antimicrobials should not living in the community or long-term care facilities and patients
be prescribed.9 Indeed a call has been made by US clinicians with spinal cord injury or indwelling catheters.
for a performance measure for not treating asymptomatic It is suggested by some groups that screening for ASB should also
bacteriuria.10 be carried out prior to implant surgery, to determine the choice of
The diagnosis of cUTI is particularly difficult in patients who antibiotic for peri-operative prophylaxis (Figure 3). Treatment of
have an indwelling catheter and present with a fever. Such a ASB prior to implant surgery is not recommended unless the
patient is described in the case report shown in Figure 2. Costo- patient is symptomatic as this will select for resistance and will
vertebral tenderness or angle pain may be a helpful localizing make choice of the antibiotic agent for prophylaxis more difficult.

Case 1

An 85-year-old lady presented to casualty with fever, confusion and signs of a chest
infection. Blood cultures were taken and as the urine was dipstick positive it was
sent for culture.

She was admitted and commenced on co-amoxiclav. An Enterobacter sp. resistant to


amoxicillin, co-amoxiclav and cefalexin was cultured from the urine but the blood
cultures were negative and she improved clinically.

No further antibiotics were needed and the lady was discharged home.

Figure 1. Case report 1: uncomplicated UTI in an elderly patient.

Case 2

An 85-year-old man lives in a nursing home and has been catheterized for
incontinence. He becomes generally unwell but does not have any specific urinary
symptoms.

A specimen of urine is sent for culture and broad-spectrum antibiotics are given for a
possible chest infection or UTI. An E. coli is grown from the urine and is resistant to
all first-line antibiotics including gentamicin and nitrofurantoin and is identified as
an ESBL producer. His chest infection and clinical condition improve so antibiotic
treatment is stopped.

The elderly gentleman now becomes febrile after his catheter blocks. He is adamant
that he does not want to be admitted to hospital.

A stat dose of gentamicin is given intramuscularly followed by a course of cefixime


and co-amoxiclav and the blocked catheter is changed.

Figure 2. Case report 2: UTI in a catheterized elderly patient.

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Treatment of complicated urinary tract infection JAC
Case 3

A 73-year-old lady was seen in the pre-assessment clinic for an elective hip
replacement. Urine was dipstick positive and sent for culture with results as follows:
>20 white blood cells per L seen; no epithelial cells; E. coli resistant to amoxicillin,
co-amoxiclav and trimethoprim but susceptible to ciprofloxacin and nitrofurantoin
was isolated (>105 cfu/mL).

The orthopaedic surgeon prescribed ciprofloxacin. The patient was asked to go to


her general practitioner for a repeat specimen to confirm that urine was culture
negative before surgery would be undertaken.

The patient did not have any symptoms but a urine specimen was sent for culture.
E. coli was isolated again but was now only susceptible to nitrofurantoin and
gentamicin. It was identified as an ESBL producer.

As the patient did not have any symptoms, therapy was not indicated and
gentamicin was included in the prophylactic cover for the hip surgery.

The patient was transferred to a rest home for rehabilitation but a few days later she
developed urinary symptoms. The ESBL-producing E. coli was cultured again from
her urine.

The patient is given a 1 week course of cefixime with co-amoxiclav and the
symptoms settle.

Figure 3. Case report 3: patient with asymptomatic bacteriuria.

Antibiotic-resistant organisms that cause cUTI include Gram- Klebsiella spp. and E. coli can also confer a wide range of resist-
positive cocci such as methicillin-resistant Staphylococcus aureus ance to penicillins and most cephalosporins apart from the
(MRSA), methicillin-resistant coagulase-negative staphylococci fourth-generation agents cefepime and cefpirome (neither of
(MRCoNS), vancomycin-resistant enterococci (VRE) and Gram- which is available currently in the UK). These enzymes are resist-
negative organisms particularly those species that produce ant to inhibition by clavulanic acid.18 Some of these bacteria
AmpC enzymes or extended-spectrum b-lactamases (ESBLs). remain susceptible to trimethoprim and the quinolones.
Urea-splitting organisms such as Proteus spp., Morganella morganii The oral options available for the treatment of cUTI caused by
and Providencia stuartii are often found in patients with indwel- ESBL or AmpC-producing bacteria are limited, particularly if sus-
ling devices. Pseudomonas spp. with their intrinsic resistance ceptibility testing indicates concurrent resistance to trimetho-
are also problematic.11 Candida species are frequently found as prim and quinolones.19 Most organisms remain susceptible to
a colonizing organism and account for ,5% of cUTIs. There nitrofurantoin; however, this agent is licensed for lower UTIs
are only isolated reports of other fungi causing cUTI.7 only and the authors personal experience has shown that resist-
In the past few years the number of cUTIs due to resistant ance may develop on treatment. One alternative is an agent
Gram-negative bacteria has risen, mainly due to the spread of used more widely in the rest of Europefosfomycin. Fosfomycin
ESBL-producing bacteria and these are causing a number of is approved by the Food and Drug Administration in the United
management problems. Before 2003 most ESBLs seen were in States for treatment of uncomplicated lower UTI and single-dose
Klebsiella spp. and were mutants of TEM and SHV penicillinases. therapy (3 g oral powder) was found to be equivalent to a 7 day
They occurred mainly in specialist units and were often hospital course of norfloxacin in a randomized open-label study.20 For
acquired.13 Recently there has been a growing problem of CTX-M treatment of cUTI, dose regimens of 3 g every 2 3 days for up
ESBLs in E. coli as well as Klebsiella and many occur in the com- to 21 days have been used but due to limited systemic absorp-
munity. Prior antibiotic therapy with agents such as cephalospor- tion, fosfomycin should not be used for pyelonephritis or severe
ins or previous international travel are recognized risk factors for urinary sepsis. Fosfomycin is licensed in the UK but a licensed for-
the acquisition of these organisms.14,15 Most producers are mulation is not currently marketed. Supplies are available from
resistant to a wide range of cephalosporins and penicillins includ- pharmaceutical importers but a delay of 24 48 h for a commu-
ing piperacillin/tazobactam and many are also resistant to nity pharmacy to obtain stock limits the usefulness of this agent
non-b-lactam agents such as fluoroquinolones, trimethoprim in a primary care setting.
and gentamicin due to other co-expressed resistance mechan- Failures have been reported when pivmecillinam has been
isms.16 CTX-M-producing E. coli are often pathogenic and a used alone to treat infections caused by ESBL-producing organ-
high proportion of infections result in bacteraemia with resultant isms and in vitro studies have shown significantly raised MICs
mortality.17 at a higher inoculum of 106 cfu/spot.21,22 However, there is evi-
Other resistant urinary bacteria include Enterobacter cloacae dence that the addition of clavulanic acid results in a decrease
that express a chromosomal AmpC b-lactamase. This enzyme in MIC bringing it down from an intermediate/resistant range
is inducible on exposure to b-lactams such as cephalosporins. to within the susceptible range (the modal value was reduced
Plasmid-mediated AmpC b-lactamase in bacteria such as from 8 16 to 0.030.06 mg/L).21 A combination of agents

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Pallett and Hand

containing clavulanic acid (for example co-amoxiclav) with other

Clavulanic acid can induce AmpC enzymes e.g. in


Enterobacter spp. possibly negating the effect
high risk for selecting for superadded infections

community-use as directed therapy for non-


readily available extended-spectrum oral antibiotics that resist
hydrolysis by common b-lactamases, such as pivmecillinam,

of inhibiting the ESBL. These are rarer in


cefixime or cefpodoxime (Figure 3), has been used to treat

Table 1. Combinations of oral antibiotics that have been used specifically for the treatment of uncomplicated UTIs caused by ESBL-producing bacteria (please note: these
UTIs caused by CTX-M ESBL-producing E. coli.23 These combi-

Side effects/disadvantages

such as C. difficile and Candida spp.


nations are unlicensed and reports of such use in the literature
are rare. They are not effective against AmpC-producing Entero-
bacteriaceae as the clavulanate induces the production of AmpC
enzymes, which attack the cephalosporin. Combinations of cefe-

q8h, every 8 h; q12h, every 12 h; AMC, amoxicillin/clavulanate; AMX, amoxicillin; CFM, cefixime; CPD, cefpodoxime; NIT, nitrofurantoin; PMEC, pivmecillinam.
pime or cefpirome (both are in intravenous form only and not
available in the UK) with clavulanate could be considered,

AmpC producers.
as these agents are more stable to AmpC enzymes.23 In
summary, these combinations should not be used as empirical
therapy but could be considered once the organism and type
of resistance are known. Table 1 summarizes some of the impor-
tant properties of antibiotic combinations used off-licence for the
treatment of infections caused by ESBL-producing pathogens.

combinations are not licensed for use in this form and are not effective for the treatment of AmpC-producing Enterobacteriaceae)
It may be possible to use intravenous agents that can be
given once a day such as gentamicin (also suitable for intramus-

concurrent or recent
Contraindications
cular injection) and ertapenem on an outpatient basis.24,25

infection with
penicillin allergy
Gentamicin is contraindicated in significant renal impairment,

C. difficile
which is more common in the elderly, and regular monitoring
of pre-dose serum concentrations is required to assess further
dosing. When infection is more severe (Figure 4) and the
patient possibly has bacteraemia, intravenous therapy should
be given. The choice of antibiotic will depend on the severity

organisms when NIT not effective


and site of the infection and whether the susceptibility pattern

salvage therapy for infection with

clavulanic acid inhibits ESBLs and


of the organism is known. A treatment strategy should be

CFM, CPD and PMEC are more

co-expressed b-lactamases
based on the local susceptibility pattern, so where the local

stable than AMX to other


resistant ESBL-producing
pathogens remain susceptible, for instance in areas where
Key advantages

CTX-M ESBL-producing E. coli is predominant, gentamicin may


be used as empirical therapyin combination with other
agents to treat a severe infection. Amikacin has been used as or not tolerated
an alternative where gentamicin-resistant isolates remain sus-
ceptible to it.
It is important to note that delay in adequate therapy will
lead to adverse outcomes and potentially increased mortality.26
Carbapenems, such as meropenem and imipenem, are broad-
spectrum agents that can be used as empirical therapy for
severe sepsis that may be caused by ESBL- or AmpC-producing
resistant ESBL-producing

bacteria. Ertapenem and temocillin are reserved mainly for


uncomplicated UTI due to

organism not requiring

treatment of appropriate infections of known aetiology, as they


Place in therapy

hospital admission

are both inactive against Pseudomonas spp. Temocillin is also


inactive against Gram-positive bacteria and Bacteroides spp.
Carbapenemase-producing E. coli and Klebsiella pneumoniae
have been isolated but are still uncommon in the UK, although
ertapenem and temocillin resistance is slightly more
common.25,27 International travel, particularly to the Indian sub-
continent, is a risk factor for the acquisition of bacteria producing
a newly described carbapenemase known as New Delhi
metallo-b-lactamase (NDM).28
Clavulanic acid in the form of
CPD 100 200 mg oral q12h

Although tigecycline has activity against ESBL-producing bac-


teria it is unstable in the urinary tract and thus is not a first-line
PMEC 400 mg oral q8h
CFM 200 mg oral q12h

antibiotic for treatment of these infections unless the source of


AMC 375 mg q8h
Treatment regimen

the organisms is known to be a different site. Tigecycline has a


large volume of distribution as evidenced by relatively low
serum levels and is therefore not recommended for urinary
tract-related bloodstream infection. It is also unreliable
PLUS

against Proteus and Pseudomonas spp., which are inherently


OR

OR

resistant. 24,29

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Treatment of complicated urinary tract infection JAC
Case 4

A 56-year-old man takes ciprofloxacin 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 ciprofloxacin. His antibiotics are switched to intravenous
ertapenem and he is discharged on this once-daily, administered by the district
nurse for a total of 10 days.

Figure 4. Case report 4: systemic sepsis and bacteraemia in a patient returning from foreign travel.

Intravenous therapy with a polymyxin (colistin or colisti- underlying abnormality, a simple recommendation cannot be
methate sodium) has been used to treat infections due to multi- made. Most clinical trials have evaluated 714 days of treat-
resistant Gram-negative organisms. Although recent studies have ment, but a recent randomized multicentre study demonstrated
shown that it has acceptable effectiveness and fewer cases of that levofloxacin for 5 days was non-inferior to ciprofloxacin for
nephrotoxicity and neurotoxicity than previously reported, at 10 days in cUTI and acute pyelonephritis.31 Ten to fourteen
present its use is reserved mainly for ESBL-producing bacteria days of antibiotics are usually recommended for patients with
that are also resistant to gentamicin and carbapenems.30 bacteraemia, hypotension and other signs of severe sepsis,
Table 2 summarizes the important properties of antibiotics avail- whereas a 7 day regimen should suffice for those with a lower
able in the UK for the treatment of cUTI. Once the organism UTI.3 A 3 day course is usually not sufficient and is thus not rec-
has been identified and susceptibilities are known, therapy ommended for cUTI.32 Clinical improvement should occur within
should be de-escalated if possible to a narrow-spectrum agent.7 24 48 h after starting treatment. If the patient has not
The main aim of therapy is to combat sepsis, relieve symp- responded, the choice of antibiotic should be reviewed in the
toms and prevent complications. In order to achieve a cure light of the culture results. They may need an urgent investi-
and prevent re-infection or recurrence the obstruction must be gation to exclude an abscess that needs drainage. A patient
removed. Urinary devices such as indwelling catheters become can be switched to an oral agent when they are clinically
coated with a biofilm, which acts as a reservoir for organisms, improved providing they can tolerate it and the organism is
protecting them from the action of antimicrobials and host susceptible.
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 What preventative strategies can be used?
be removed and a condom catheter or another form of drainage
system be used instead. The use of physician reminders to These have been well-reviewed in the Canadian Guidelines for
remove unnecessary urinary catheters may help.2 If the patient the management of cUTI in adults.1 Extended courses of anti-
still requires a catheter, a new one should be inserted either biotics should only be used in specific situations such as for
when collecting the specimen of urine in a patient with symp- men with a relapsing infection from a prostatic source when
toms of a cUTI or soon after starting treatment for a sympto- 6 12 weeks of therapy have been given.33 They are not rec-
matic infection, so symptoms will settle in a shorter time and ommended as long-term prophylaxis for the prevention of infec-
increase the interval before the next relapse.11 tion in, for example patients with spinal cord lesions undergoing
Where a urinary tract abnormality is not apparent a diagnos- intermittent catheterization, as prophylaxis will select for
tic investigation should be carried out to look for other compli- antibiotic-resistant organisms.32 Rarely, a long-term course of
cating factors such as an abscess. Options include diagnostic antimicrobials has been given as suppressive therapy to
imaging, which may include pelvic and renal ultrasound, intrave- prevent enlargement of stones that cannot be removed.34 In
nous pyelogram, CT or magnetic resonance imaging. Renal this situation the benefit of giving the antibiotic must be
investigations such as cystoscopy, retrograde pyelogram or uro- weighed against the likely side effects and the risk of selecting
dynamic studies may be required depending on the history for antibiotic-resistant organisms.
given.7,11 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
How long should a patient receive antibiotics on the use of oral or vaginal oestrogen by post-menopausal
women with recurrent UTIs have been inconsistent and thus
for?
the routine use of these agents has not been recommended.5
The optimal length of treatment for symptomatic cUTI has not The use of oral lactulose however, to reduce constipation in
been extensively studied. As there are many different causes of elderly patients, may be helpful and some studies have shown

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Pallett and Hand


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 treatment of complicated and widely available and extensive renal impairment nausea and vomiting (common)
7 days minimum uncomplicated lower UTI clinical experience (GFR,60 mL/min) peripheral neuropathy with long-term use
resistance rare in E. coli although (rare)
more common in other no iv formulation
Enterobacteriaceae G6PD
inherent resistance in Proteus
spp. and Pseudomonas
spp.

FOF 3 g sachet oral once treatment of complicated and resistance rare even in Spain not suitable for not licensed or marketed in the UK and thus
every 3 days for uncomplicated lower UTI where it is used extensively pyelonephritis or severe difficult to obtain urgently
14 days for cUTI (unlicensed) oral capsules and iv formulation urinary sepsis due to poor headache or diarrhoea in 10% of patients
also available systemic absorption

GEN 3 5 mg/kg iv daily option for once-daily outpatient resistance relatively uncommon severe renal impairment nephrotoxicity
in divided doses or iv therapy for complicated vestibular and auditory toxicity
5 7 mg/kg iv once UTI risk of resistance in certain ESBL strains
daily (consult local serum levels required to determine safe and
guidelines) effective continuing dosing

TMC 1 2 g iv q12h treatment of cUTI and other good in vitro activity against penicillin allergy inactive against Gram-positive bacteria,
infections caused by ESBL- multiresistant ESBLs including Bacteroides spp. and Pseudomonas spp.
and AmpC-producing bacteria provenance outside the
AmpC-producing bacteria narrow spectrum urinary tract to be established
susceptible to this agent limited clinical experience in the UK

ETP 1 g iv once daily option for outpatient iv therapy once-daily administration history of penicillin does not cover infections caused by
for cUTI caused by anaphylaxis Pseudomonas spp.
susceptible ESBL-producing more vulnerable than other carbapenems to
bacteria resistance combinations of impermeability
with an ESBL or AmpC
seizure rate attributed to ertapenem 0.2%
from clinical trials36

IPM (plus cilastatin) treatment of cUTI and other broad spectrum of activity history of penicillin seizure risk 1.5% 2% (more common with
500 mg1 g iv q6h infections caused by ESBL- including Enterococcus faecalis, anaphylaxis higher doses, renal impairment and in
q8h (maximum and AmpC- producing Pseudomonas spp. and renal failure (GFR , 5 mL/ patients with a history of epilepsy)36
4 g/day) bacteria ESBL-producing bacteria 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 treatment of cUTI and other relatively low seizure risk history of penicillin increased hepatic enzymes (bilirubin and
iv q8h infections caused by ESBL- (0.08%)37 anaphylaxis transaminases) (.1% incidence)
and AmpC-producing broad spectrum of activity somewhat less active carbapenem against
bacteria including Pseudomonas spp. Gram-positive organisms
and ESBL-producing bacteria
Treatment of complicated urinary tract infection
DOR 500 mg iv q8h treatment of cUTI and other most potent agent in history of penicillin headache very common
infections caused by ESBL- carbapenem class anaphylaxis limited clinical experience in the UK
and AmpC-producing broad spectrum of activity reduce dose in renal impairment (GFR, 50
bacteria including Pseudomonas spp. mL/min)
and ESBL-producing bacteria
relatively low seizure risk38

TGC 100 mg iv loading licensed for complicated skin treatment option in severe cannot be given to children limited urinary excretion of active drug
dose followed by and soft tissue infections and penicillin allergy ,8 years of age due to nausea very common (up to one-third of
50 mg iv q12h complicated intra-abdominal salvage therapy for infection with discolouration of teeth patients)
infections only resistant ESBL-producing relatively low serum concentrationscaution
organisms in bacteraemia29
extensive distribution
concentration in tissues inherent resistance in Pseudomonas spp. and
no dosage adjustment in renal acquired resistance in Proteus spp.
failure reduce dose in severe hepatic impairment

CST 1 2 million units iv cUTI and bacteraemia caused treatment option in severe Myasthenia gravis inherent resistance in Gram-positive bacteria,
q8h (15 00025 000 by susceptible Gram-negative penicillin allergy anaerobes, Proteeae, Serratia spp.,
units/kg iv q8h if bacteria resistant to other salvage therapy for infection with Providencia spp.
,60 kg) agents resistant ESBL-producing neurotoxicity (most commonly apnoea and
organisms sensory disturbances in 7% of patients)
effective against wide range of nephrotoxicity (8% 20% in seriously ill
resistant Gram-negative hospitalized patients); reduce dose in renal
bacteria including impairment (GFR, 20 mL/min); monitor
Acinetobacter spp. renal function and discontinue if
nephrotoxicity occurs.

q6h, every 6 h; q8h, every 8 h; q12h, every 12 h; CST, colistin; DOR, doripenem; ETP, ertapenem; FOF, fosfomycin; GEN, gentamicin; GFR, glomerular filtration rate; G6PD,
glucose-6-phosphate dehydrogenase deficiency; IPM, imipenem; iv, intravenous; MEM, meropenem; NIT, nitrofurantoin; PMEC, pivmecillinam; TGC, tigecycline; TMC, temocillin.

JAC
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Pallett and Hand

that cranberry products (juice, tablets or capsules) may reduce 14 Laupland KB, Church DL, Vidakovich J et al. Community-onset
the frequency of recurrent UTI in women.5,8,33,35 In the future extended-spectrum b-lactamase (ESBL) producing Escherichia coli:
other preventative strategies may include the development of importance of international travel. J Infect 2008; 57: 4418.
vaccines. The use of intentional colonization with benign organ- 15 Woodford N, Ward ME, Kaufmann ME et al. Community and hospital
isms that are also susceptible to a wider range of antibiotics may spread of Escherichia coli producing CTX-M extended-spectrum
need to be considered.33 b-lactamases in the UK. J Antimicrob Chemother 2004; 54: 73543.
There is an urgent need for research into the effectiveness of 16 Livermore DM, Canton R, Gniadkowski M et al. CTX-M: changing the
combinations of oral antibiotics in the treatment of complicated face of ESBLs in Europe. J Antimicrob Chemother 2007; 59: 16574.
UTI in ambulatory care and the impact on the epidemiology of 17 Tumbarello M, Sanguinetti M, Montuori E et al. Predictors of mortality
resistance. There is also an immediate requirement for increased in patients with bloodstream infections caused by extended-spectrum-
availability of fosfomycin in the UK. b-lactamase-producing Enterobacteriaceae: importance of inadequate
initial antimicrobial treatment. Antimicrob Agents Chemother 2007; 51:
1987 94.
18 Jacoby GA. AmpC b-lactamases. Clin Microbiol Rev 2009; 22: 16182.
Transparency declarations 19 Prakash V, Lewis JS, Herrera ML et al. Oral and parenteral therapeutic
This article is part of a Supplement sponsored by the BSAC. options for outpatient urinary infections caused by Enterobacteriaceae
A. P. has received funds for speaking at symposia and attending advi- producing CTX-M extended-spectrum b-lactamases. Antimicrob Agents
sory boards organized on behalf of Novartis, Wyeth/Pfizer and AstraZe- Chemother 2009; 53: 1278 80.
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