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Treatment of Bacterial Urinary Tract

Infections: Presence and Future
Kurt Naber

European Urology

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 european urology 49 (2006) 235–244

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Review - Infections

Treatment of Bacterial Urinary Tract Infections:

Presence and Future

Florian M.E. Wagenlehner *, Kurt G. Naber

Urologic Clinic, Hospital St. Elisabeth, Straubing, Germany

Article info Abstract

Article history: Bacterial urinary tract infections (UTIs) are frequent infections in the
Accepted December 12, 2005 outpatient as well as in the nosocomial setting. The stratification into
Published online ahead of uncomplicated and complicated UTIs has proven to be clinically useful.
print on January 4, 2006 Bacterial virulence factors on the one side and the integrity of the host
defense mechanisms on the other side determine the course of the
Keywords: infection. In uncomplicated UTIs Escherichia coli is the leading organism,
Urinary tract infections (UTI) whereas in complicated UTIs the bacterial spectrum is much broader
Uncomplicated and including Gram-negative and Gram-positive and often multiresistant
complicated UTI organisms. The therapy of uncomplicated UTIs is almost exclusively
Antibiotic resistance of antibacterial, whereas in complicated UTIs the complicating factors
uropathogens have to be treated as well. There are two predominant aims in the
Antibiotic treatment antimicrobial treatment of both uncomplicated and complicated UTIs:
New antiinfectives for (i) rapid and effective response to therapy and prevention of recurrence
treatment of UTI of the individual patient treated; (ii) prevention of emergence of resis-
tance to antimicrobial chemotherapy in the microbial environment. The
main drawback of current antibiotic therapies is the emergence and
rapid increase of antibiotic resistance. To combat this development
several strategies can be followed. Decrease the amount of antibiotics
administered, optimal dosing, prevention of infection and development
of new antibiotic substances. The aim of this review is to highlight the
current and to describe future treatment options for UTIs.
# 2005 Elsevier B.V. All rights reserved.

* Corresponding author. Urologic Clinic, Hospital St. Elisabeth, St. Elisabeth Str. 23, D-94315
Straubing, Germany. Tel. +49 9421 710 6702; Fax: +49 9421 710 1717.
E-mail address: Wagenlehner@AOL.com (Florian M.E. Wagenlehner).

1. Background In the United States of America, UTIs are respon-

sible for over 7 million physician visits annually,
Urinary tract infections (UTIs) are among the most including more than 2 million visits for cystitis [1,2].
prevalent microbial diseases, and their financial Approximately 15% of all community-prescribed
burden on society is substantial. antibiotics in the United States are dispensed for
0302-2838/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.12.017
236 european urology 49 (2006) 235–244
UTI, at an estimated annual cost of over $1 billion [3].
Furthermore, the direct and indirect costs associated
with community-acquired UTIs in the United States
alone exceed an estimated $1.6 billion [2].
UTIs account for more than 100,000 hospital
admissions annually, most often for pyelonephritis
[1,2], and they also account for at least 40% of all
hospital-acquired infections and are in the majority
of cases catheter-associated [4–6]. Nosocomial bac-
teriuria develops in up to 25% of patients requiring a
urinary catheter for 7 days, with a daily risk of 5%
[6]. It has been estimated that an episode of
nosocomial bacteriuria adds $500 to $1,000 [7,8] to
the direct cost of acute-care hospitalization. In
addition the pathogens are fully exposed to the
nosocomial environment, including selective pres-
sure by antibiotic or antiseptic substances. There-
fore nosocomial UTIs comprise perhaps the largest
institutional reservoir of nosocomial antibiotic-
resistant pathogens [6].
Whereas community acquired UTIs are often
uncomplicated, almost all nosocomial UTIs are
complicated infections. Complicated UTI is a very
heterogenous entity, with a common pattern of the
following complicating factors:
- anatomical, structural or functional alterations of
the urinary tract (e.g. stents, urine transport
disturbances, instrumentation of the urinary tract,
stones, tumors, neurological disorders)
- impaired renal function, by parenchymal dis-
eases, or pre,-intra,-or post renal nephropathies
(e.g. acute, chronic renal insufficiencies, heart
insufficiency)
- accompanying diseases, that impair the patients
immune status (e.g. diabetes mellitus, liver insuf-
ficiency, immunosuppression, cancer, AIDS,
hypothermia).
For antimicrobial chemotherapy the bacterial s-
pectrum, it’s antimicrobial resistance patterns and
the development of both over the time is critical for
an effective chemotherapy.
The prevalence of uropathogens is different
comparing uncomplicated and complicated UTI.
2. Aims in the treatment of UTI
There are two predominant aims in the treatment of
both uncomplicated and complicated UTIs:
(i) rapid and effective response to therapy and
prevention of recurrence in the individual
patient treated.
(ii) prevention of emergence of resistance to che-
motherapy in the microbial environment or at
least prevention of further increase of resis-
tance.
2.1. Current treatment and prophylaxis of UTI
Two major strategies currently exist in the pharma-
cological treatment and prophylaxis of UTIs:
(i) Antimicrobial chemotherapy and
(ii) Vaccines.
2.1.1. Chemotherapy
The currently recommended chemotherapeutic
classes and dosages of antiinfectives for the treat-
ment of bacterial UTI are listed in Table 1. The target
and mechanism of actions of chemotherapeutic
drugs is shown in Fig. 1.
Antimicrobial susceptibility levels are often
gauged relative to what antibiotic concentration is
achievable in the blood. However tissue levels in
renal parenchyma, the deeper layer of the urinary
bladder wall or in the prostate may be more relevant
in the treatment of UTI. Because these concentra-
tions are difficult to assess in humans, urinary
concentrations or antimicrobial activity levels in the
urine are frequently consulted to evaluate the
activity of an antibiotic substance in the treatment
of UTI [9]. The urinary excretion and the determina-
tion of the activity of a substance in urine is
therefore important to assess if a substance is
suitable for treatment of UTI. The urinary excretion
of fluoroquinolones for example differs widely
between substances. A high urinary excretion
Fig. 1 – Target and mechanism of actions of current and
future antibacterial substances [modified after [50]. DHFA –
dihydrofolic acid; THFA – tetrahydrofolic acid; PABA –
para-amino-benzoic acid.
 european urology 49 (2006) 235–244 237

Table 1 – Groups and dosages of current chemotherapeutics for the treatment of UTI in adults

Antibiotic groups Antimicrobial substance Daily dosage

oral i.v./i.m.

b-lactams
Mecillinam Pivmecillinam 2  200*–400* mg –
Aminopenicillin + BLI Ampicillin/Sulbactam 2  750 mg 3  0.75–3 g
Amoxicillin/Clavulanic acid 3  625–1000 mg 3  1.2–2.2 g
Acylureidopenicillin + BLI Piperacillin/Tazobactam – 3  2.5–4.5 g
Cephalosporin Gr. 1 Cephalexin for prophylaxis only –
Cephalosporin Gr. 2 Cefuroxime axetil 2  250*–500 mg –
Cefuroxime – 3  0.75–1.5 g
Cefotiam – 2–3  1–2 g
Cephalosporin Gr. 3 Cefpodoxim proxetile 2  200 mg –
Cefixime 1  400 mg –
Ceftibuten 1  200*–400 mg –
Cephalosporin Gr. 3a Cefotaxime – 2–3  1–2 g
Cetriaxone – 1  1–2 g
Cephalosporin Gr. 3b Ceftazidime – 2–3  1–2 g
Cephalosporin Gr. 4 Cefepime – 22g
Carbapenem Gr. 1 Ertapenem – 11g
Carbapenem Gr. 2 Imipenem – 3–4  0.5–1 g
Meropenem – 3  0.5–1 g

Fluoroquinolones
Fluoroquinolone Gr. 1 Norfloxacin 2  400* mg –
Fluoroquinolone Gr. 2 Ciprofloxacin 2  500–750 mg 2–3  400 mg
Fluoroquinolone Gr. 3 Levofloxacin 1–2  500 mg 1–2  500 mg
Fluoroquinolone Gr. 4 Gatifloxacin 1  400 mg 1  400 mg

Pyrimethamines
Trimethoprim 2  200 mg
Trimethoprim + Sulfamethoxazole 2  160 mg + 2  800 mg

Fosfomycines
Fosfomycine Fosfomycin-trometamol 1  3* g

Nitrofuranes
Nitrofurane Nitrofurantoin 3  100* mg

Aminoglycosides
Aminoglycoside Gentamicin – 1  5–7 mg/BW
Tobramycin – 1  5–7 mg/BW
Amikacin – 1  15 mg/BW

Oxazolidinones
Oxazolidinone Linezolid 2  600 mg 2  600 mg

Glycopeptides
Glycopeptide Vancomycin – 2  1000 mg
Teicoplanin – 1  400 mg

BLI – beta-lactamase inhibitor; Gr. – group according to PEG [31]; BW – body weight (kg); *recommended for uncomplicated UTI.

(75%) can be observed with gatifloxacin (80%),
levofloxacin (84%), lomefloxacin (75%) and ofloxacin
(81%). An intermediate excretion rate (40–74%) is seen
with ciprofloxacin (43%), enoxacin (53%), fleroxacin
(67%), and a low excretion rate (<40%) is seen with
gemifloxacin (28%), moxifloxacin (20%), norfloxacin
(20%), pefloxacin (14%) and sparfloxacin (10%) [9].
Whereas most of the drugs with high or intermediate
excretion achieved the clinical indication for the
treatment of UTI, of the drugs with low excretion only
the older substance norfloxacin achieved this indica-
tion, possibly because of the lack of comparator
substances at these days. The newer fluoroquinolone
substances gemifloxacin and moxifloxacin both have
passed phase III UTI studies with the comparator
agents ciprofloxacin, ofloxacin or levofloxacin with
generally unsatisfying results (data on file Bayer
Healthcare, SmithKline Beecham). As a result of these
studies the indication for the treatment of UTI in both
substances was not achieved up to date. Therefore
both pharmacokinetic parameters, serum concen-
tration and urinary excretion are currently used to
evaluate if an antibiotic substance might be suitable
for the treatment of UTI.
238 european urology 49 (2006) 235–244
The main drawback of current antibiotic therapies
is the emergence and rapid increase of antibiotic
resistance [10]. Since antibiotics have been intro-
duced into clinical medicine, antibiotic resistant
bacteria have evolved [11]. Antibiotic resistance
mechanisms have recently been alluded to in the
European Urology Update Series 2, 2004, page 125–135
[10]. The overall cause of increasing antibiotic
resistance is selective pressure by antimicrobial
substances in various environmental settings caus-
ing antibiotic resistant bacterial clones, followed by
the distribution of such clones facilitated by modern
medico-social circumstances [10]. The development
of new antimicrobial substances in the past has
counterbalanced this trend. However we are cur-
rently approaching a resistance level that might pose
a risk to loose effectiveness of antibiotic treatment in
the future. The epidemiology of antibiotic resistant
bacteria varies with type of infection, with medical
speciality, with region, and with time.
2.1.2. Vaccines
There are two different agents for immunisation
currently availabale. Uro-vaxom1 and Strovac1.
Both preparations are recommended for patients
with recurrent uncomplicated UTIs.
Uro-vaxom1 is an orally administered bacterial
extract consisting of immunostimulating compo-
nents derived fom 18 uropathogenic E. coli strains
[12]. A metaanalysis on five placebo controlled,
double-blind studies comprising 601 women
resulted in a pooled odds ratio of 2.28. UTIs per
year were reduced from 1 to a rate of 0.15–0.82 [13].
In a multicenter, double-blind study 453 female
patients were enrolled and Uro-vaxom1 resulted in
a 34% reduction of UTIs in patients compared to
placebo [14]. Therefore the oral immunotherapy
with Uro-vaxom is effective in the prevention of
recurrent UTI. Nevertheless a metaanalysis showed
that if antibiotic prophylaxis was compared with
placebo the reduction of recurrent UTIs was 81%
with antibiotics compared to placebo [15]. Unfortu-
nately there are no data comparing Uro-vaxom1
with antibiotics in the prevention of recurrent UTI.
Strovac1 is a whole cell bacterial extract derived
from uropathogenic E. coli strains, P. mirabilis, M.
morganii, K. pneumoniae and E. faecalis. The prepara-
tion is administered intramuscularly also for pre-
vention of recurrent UTI. In an prospective,
comparing study 41 patients with recurrent uncom-
plicated UTI were evaluated. The rate of reinfections
within 6 months was 41% in patients treated with
SulcoUrovac1 versus 96% in patients receiving
placebo [16]. Follow-up studies, however should be
carried out.
2.1.3. Probiotics
The use of probiotics entails prophylaxis and
treatment of UTI and is mainly concentrated on
Lactobacilli. Conflicting results have been observed
in clinical trials and animal studies mostly because
unspecific strains of Lactobacilli have been used.
Positive results have only been obtained using well
characterized strains [17]. Application for prophy-
laxis can be intravaginal or oral. For treatment
probiotics were mainly installed into the bladder.
Clinical studies using vaginally administered
Lactobacillus rhamnosis GR1 in combination with
either L. reuteri B 54 or RC 14 resulted in reduced
UTI recurrences. In one study of 52 women, UTI
recurrences were reduced from an average of 6 per
year to 1.6 with once weekly vaginal suppositories of
GR-1/B-54 [18].
A clinical randomized, placebo controlled study
of 64 women using daily oral intake of L. rhamnosus
GR-1 and L. reuteri RC-14 led to a significant reduction
in uropathogens and yeast in the vagina [19]. It can
possibly be concluded from such findings that UTI
might also be preventable by oral intake of specific
lactobacilli.
Few studies have shown positive results in the
treatment of UTI by probiotics. One such animal
study showed that after therapeutic application of
Lactobacillus murinus bladder counts of treated mice
were significantly lower although no significant
differences were detected in P. mirabilis kidney
colonisation of treated and non-treated animals [20].
3. Future strategies in the treatment of
bacterial UTI
The current research goals comprise the following
targets:
- known substances are improved in terms of higher
bioavailability, longer half life, better PK/PD
performance, other formulations (i.e. extended/
gastric release formulation; liposomal formula-
tion).
- known substances are evaluated for other indica-
tions (i.e. UTI).
- new derivatives of known substance classes are
developed in order to enlarge the bacterial
spectrum, improve bioavailability, improve anti-
microbial action (i.e. younger generation sub-
stances).
- new substance classes which should have new
molecular targets are developed.
- new strategies to improve susceptibility of bac-
teria are developed (i.e. efflux-pump inhibitors).
 european urology 49 (2006) 235–244
- new strategies to slow down the emergence of
antimicrobial resistance are developed.
- alternative antimicrobial substances are under
discovery (e.g. bacteriophages, bacteriophage
enzymes).
- new compounds for vaccination in uncompli-
cated, and possibly as well as in complicated
UTI are developed.
Bacteria exhibit an enormous repertoire of dif-
ferent resistance mechanisms. Unspecific mechan-
isms such as reduced permeability or efflux alter the
tolerance to antibiotic substances less than specific
mechanisms, such as inactivation of the antibiotic
for example. However the antibiotic spectrum tar-
geted is much more extensive. On the other hand
unspecific mechanisms can also be induced by non
antibiotic substances such as salicylates. Low-level
resistance can thus be confered and give bacteria a
selection-advantage [10].
What parameters should be assessed for new
drugs to become included in the treatment of UTI?
Although there are no exact quantitative prereque-
sites, the following qualities should be considered:
- coverage of the respective bacterial spectrum
(uncomplicated versus complicated UTIs)
- antimicrobial activity in urine in an acidic as well
as alkaline environment
- sufficient urinary excretion of the drug
3.1. Emerging chemotherapeutics
Emerging compounds are discussed in Table 2
regarding the following parameters: Substance, class,
mode of action, bacterial spectrum, pharmacoki-
netics with emphasis on urinary excretion, opinion
about success. The target and mechanism of actions
of future chemotherapeutic drugs are shown in Fig. 1.
3.2. Emerging novel strategies
Bacteriophage lytic enzymes are highly evolved
molecules produced by bacterial viruses to digest
the bacterial cell wall for bacteriophage progeny
release [21]. These enzymes have been used success-
fully in animal models to treat bacterial infections in
blood and mucosal surfaces. Phages or their enzymes
are very specific for the pathogen without disturbing
the normal flora. These novel antimicrobial strategies
have shown very interesting in vitro results [22,23].
The further development might be promising,
because this strategy involves highly conserved
evolutionary mechanisms that have proven to be
efficacious in nature over millions of years.
239
3.3. Emerging vaccines
Vaccination theoretically is the best strategy to
prevent bacterial infections. There are however some
pitfalls in the vaccination against UTIs: Complicated
UTIs show a highly heterogenous bacterial spectrum.
In uncomplicated UTIs E. coli is the predominant
pathogen. However infections and recurrent infec-
tions are usually caused by a variety of E. coli strains.
All uropathogenic E. coli as a common feature
have a FimH-chaperone-adhesin on the tip of their
type 1 fimbriae. A FimH adhesion-based vaccine,
which showed promising results in animal and in
vitro studies [24,25], so far could not enter larger
vaccination trials in humans.
A somewhat different approach is made by using
a vaginal vaccine containing 10 heat killed uro-
pathogenic bacteria. A placebo-controlled phase II
clinical trial was performed in 54 women. Women
receiving immunisation experienced an infection in
45%, whereas the placebo treated women experi-
enced an infection in 89% [26]. Based on this result
vaginal mucosal vaccine seem to be effective.
P. mirabilis is a difficult to treat pathogen causing
complicated UTIs especially in patients with per-
manent catheters or stents. The urease produced by
this organism leads to stone formation and catheter
blockage. The primary surface antigen is the MR/P
fimbria is a good candidate for vaccination. In vitro
studies with a MrpH vaccine showed promising
results [27].
4. Prevention of emergence of antibiotic
resistance
The most important draw-back in the treatment of
UTIs is the development of antimicrobial resistance.
The prevention of emergence of resistance in
human medicine entails several strategies:
- decrease of antibiotic consumption
- antibiotic cycling
- new dosing strategies for antibiotics
- combination of two classes of antibiotics
All strategies not specifically designed for anti-
microbial therapy of UTI may have to be adjusted
accordingly.
4.1. Decrease of antibiotic consumption
To lower antibiotic consumption in UTI three
strategies are developed and are evidence based
by several good clinical studies: (i) asymptomatic
240
Table 2 – Emerging compounds are discussed regarding substance-name, antibiotic class and characteristics (mode of
action, bacterial spectrum, pharmacokinetics with emphasis on urinary excretion, opinion about success)
Antibiotic substance
Daptomycin (intravenous)
Tigecycline (intravenous)
Cefozopran (intravenous)
Ceftobiprole (intravenous)
Doripenem (intravenous)
Not indicated
Ciprofloxacin XR
(extended release) (oral)
Balofloxacin (oral)
european urology 49 (2006) 235–244
Antibiotic class Characteristics
Lipopetide-antibiotic Exerts its antibacterial activity by disrupting multiple aspects of the
bacterial membrane function.
Specific activity against Gram-positive pathogens including MRSA
and VRE, not active against Gram-negative bacteria.
Urinary excretion is 78%.
Clinically relevant toxicities are limited to skeletal muscle effects, at
higher dose levels, peripheral nerve effects.
The high urinary excretion promises activity in UTI, however the large
molecule might hinder distribution into urinary tract tissues. The
specific Gram-positive activity restricts the substance to treatment
of a relative small proportion of UTIs [32–37].
Glycylcyline Exerts its antibacterial activity by inhibiting protein synthesis.
Good activity against Gram-positive pathogens including MRSA and
VRE, and against E. coli, Klebsiella spp., Enterobacter spp. and C. freundii,
including ESBL producing organisms. Less active against P. aeruginosa,
Proteus spp., M. morganii and S. marcsecens because of efflux-mechanisms.
Urinary excretion is approximately 14%.
Side effects observed in general were mild.
The substance covers an interesting bacterial spectrum for the treatment
of UTI, although difficult to treat organisms, such a P. aeruginosa or
Proteus spp. are more resistant because of efflux pump activity.
The relatively low urinary excretion might be a potential drawback
in the treatment of UTI [38].
Cephalosporin Strong activity against P. aeruginosa. Because of the specific activity
against P. aeruginosa this compound is of potential interest for
the treatment of complicated UTI [39].
Cephalosporin Anti-MRSA cephalosporin. Against Gram-negative bacteria comparable
activity to group 3 and 4 cephalosporins. The spectrum of activity
towards P. aeruginosa resembles that of ceftazidime. Limited activity
against putative ESBL poducers but good activity against putative
high-level AmpC producers.
Urinary excretion is about 90%.
Because of the wide range of activity against most uropathogens and the
high urinary excretion, the substance is of potential interest in
the treatment of UTI [40].
Carbapenem Exerts activity against Gram-positive bacteria except MRSA and
enterococci and Gram-negative bacteria including imipenem
resistant P. aeruginosa.
Urinary excretion is 75%.
Doripenem is highly excreted in urine and shows excellent activity
against P. aeruginosa. Therefore it is of potential interest for treatment
of complicated UTI [41].
b-lactamase inhibitors Novel b-lactamase inhibitors are under development for the potential
treatment of UTI. Because of the increasing prevalence of
ESBL-producing enterobacteria in UTIs, novel b-lactamase inhibitors
might be promising.
Fluoroquinolone Exerts identical antibacterial activity as ciprofloxacin targeting
predominantly Gram-negative pathogens with good activity
against P. aeruginosa.
Urinary excretion is 40%.
Ciprofloxacin XR is a once daily formulation, overall comparable to
twice daily ciprofloxacin [42–44].
Fluoroquinolone Exerts good antibacterial activity against Gram-positive pathogens,
but in comparison to other fluoroquinolones decreased activity against
Gram-negative pathogens.
Urinary excretion is 86%.
Balofloxacin is in the treatment of UTI probably not superior to
other fluoroquinolones [45].
 european urology 49 (2006) 235–244 241

Table 2 (Continued )
Antibiotic substance Antibiotic class Characteristics

Garenoxacin Des-F(6)-quinolone Exerts good antibacterial activity against Gram positive pathogens.
(oral and intravenous) Activity against Gram-negative pathogens is comparable to fluoroquinolones,
such as ciprofloxacin or levofloxacin, activity against P. aeruginosa is poor.
It seems that garenoxacin exerts also activity against fluoroquinolone
resistant strains. The ability to induce resistance in vitro is apparently
less than with fluoroquinolones such as levofloxacin.
Urinary excretion is 30 to 40%.
In view of the increasing quinolone resistance, substances of this class
with decreased cross resistance and less susceptibility to resistance
emergence are needed. Des-F(6)-quinolone derivatives like garenoxacin
are promising substances for the treatment of UTI [46].
Not indicated Dihydrofolate Novel dihydrofolate reductase inhibitors are under discovery. The novel
reductase inhibitors compounds are more active against Gram-positive pathogens.
Because of the long lasting activity of trimethoprim, novel dihydrofolate
reductase inhibitors are generally of interest in the treatment of UTI.

Not indicated MurA inhibitors Exert activity against Gram-positive and Gram-negative organisms to a
variable degree. They target the bacterial enzyme MurA and thus inhibit
cell wall synthesis.
In view of the increasing antimicrobial resistance novel acting antibiotics
are of interest for all kinds of bacterial infections [47].
Not indicated Bacterial efflux Exert activity in combination with other antimicrobials against bacterial
pump inhibitors species that overexpress efflux pumps, such as P. aeruginosa. Efflux
pump inhibitor agents have provided proof-of-principle of potentiation
of other animicrobials both in vitro and in vivo. The initial practical
application of improving activity against P. aeruginosa confirms that
existing antibiotics can be potentiated by inhibition of efflux pumps, and
suggests that efflux pump inhibitors may be a possible future treatment
option that would address an unmet medical need. In addition efflux
pumps contribute to a large extent to the emergence of resistance
against different antibiotic classes. Efflux pump inhibitors can narrow
the mutant selection window and thus slow down emergence of
antibiotic resistance [48].
Not indicated Siderophore-b-lactam Novel strategy for the potential treatment of Gram-negative bacterial
conjugates infections, including P. aeruginosa. Siderophore substances are covalently
bound to aminopenicillins. Because of the bacterial spectrum covered,
siderophore-b-lactam conjugation is a novel strategy of interest for the
treatment of UTIs [49].

bacteriuria must not be treated in general (there are
some exceptions), (ii) short-term therapy of uncom-
plicated UTI by suitable antimicrobial agents, and iii)
low dose prophylaxis in uncomplicated recurrent
UTI, respectively development of effective vaccines.
4.2. Antibiotic cycling
For antibiotic cycling there are practically no reliable
studies available concerning treatment of UTI. There
is, however, a more or less general agreement that the
overuse of one group of antibiotics selecting for
similar resistance genes should be avoided especially
in a hospital of institutional setting. Therefore good
guidelines recommend in general alternative sub-
stances as well, to allow antibiotic cycling.
4.3. Antibiotic dosing
The key idea of the third strategy, however yet
clinically untested, is based on the use of antibiotic
concentrations that require bacterial cells to obtain
two concurrent resistance mutations for growth.
That concentration has been called mutant preven-
tion concentration (MPC) because no resistant bac-
terial colony is recovered even when high numbers of
bacterial cells are plated. Resistant mutants are
selected exclusively within a vulnerable concentra-
tion range (mutant selection window) that extends
from the point where growth inhibition begins,
approximately by the minimal inhibitory concentra-
tion, up to the mutant prevention concentration [28].
If the antibiotic dose given is high enough also to kill
the mutant population, the selection of clinically
resistant mutants could be restricted [29]. A further
idea in this respect is to narrow the mutant selection
window by developing appropriate substances,
for example those which lower the MPC, or those
that lower these concentrations of other drugs (e.g.
efflux pump inhibitors). Therefore drugs with the
most favourable pharmacokinetic/pharmacody-
namic characteristics should be used as first-line
242 european urology 49 (2006) 235–244
agents in order to preserve the potential of a specific
drug class and, most importantly, to provide the
patient with an optimally effective regimen. On the
other hand the dosing of an antibiotic should be
aimed high enough to reach the MPC.
4.4. Combination of two classes of antibiotics
For some organisms or in some infections it is
difficult to find antibiotics that can be dosed high
enough to prevent emergence of antibiotic resis-
tance. A typical example is antibiotic treatment of M.
tuberculosis where combination therapy with two or
more antibiotic substances of different classes is
recommended. In order to become resistant against
two antibiotic substances, two concurrent muta-
tions are required for bacterial growth, which has a
very low probability to occur [28]. Clinical studies in
UTIs however are very scarce. In one study combi-
nation therapy with a macrolide and ciprofloxacin
showed higher efficacy in eliminating uropathogens
than the single therapy with ciprofloxacin [30]. The
success of the macrolide in this study however was
more attributed to the specific biofilm inhibiting
effect of the macrolide [30].
5. Conclusion
There are a number of new derivatives of classes in
use. In most cases these derivatives are subject to
cross resistance inherent to the whole substance
class. Therefore new classes of antibiotics with
unrelated mode of action are a more valuable deve-
lopment. The indications for treatment of such novel
substances should be selected very carefully, in order
to conserve new substance classes as long as possible.
For a variety of reasons however new substance
classes will be increasingly difficult to launche.
Therefore new derivatives of classes in use should
be thoroughly screened for their potential to induce
resistance. Substances with a low potential to select
resistant strains will be highly welcome. Very impor-
tant in that respect will be combinatory agents that
impede general widespread mechanisms of resis-
tance, such as efflux pump inhibitors. Novel anti-
microbial strategies, such as the use of bacteriophagal
enzymes urgently need to be evaluated further.
The best strategy in infection in general is the
prevention of the disease. In UTI there is a variety of
concepts involved:
- Hygienic issues and catheter materials are pre-
dominantly important in complicated, health-care
associated UTIs.
- The low dose antibiotic prophylaxis in recurrent
UTIs is effective, however the emergence of
antibiotic resistant pathogens might be under-
estimated, although the idea of antibiotic prophy-
laxis is to use low dosages that do not fall within
the mutant selection window and thus theoreti-
cally should not cause emergence of resistance.
- Vaccination will be an important issue in the
future. The most experience has been made with
vaccines in recurrent uncomplicated cystitis,
because a single species E. coli causes more than
90% of episodes. Desirable would be more
attempts for vaccination in complicated UTIs,
especially with difficult to treat organisms like P.
aeruginosa.
The ongoing process in the treatment of infec-
tious diseases is highly dynamic. The substantial
difference to non-infectious diseases is that the
management of an infection in a single patient al-
lways has an effect on the environment. Consider-
ing this, the management of infectious diseases
must be highly responsible.
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