Clin Pharmacokinet 2007; 46 (4): 291-305

REVIEW ARTICLE 0312-5963/07/0004-0291/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Pharmacokinetic Characteristics of
Antimicrobials and Optimal
Treatment of Urosepsis
Florian M.E. Wagenlehner,1 Wolfgang Weidner1 and Kurt G. Naber2
1 Urologic Clinic, Justus-Liebig-University, Giessen, Germany
2 Technical University of Munich, Munich, Germany

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
1. Epidemiology of Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
2. Definition and Clinical Manifestation of Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
3. Pathophysiology of Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
3.1 Cytokines as Markers of the Septic Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
3.2 Procalcitonin is a Potential Marker of Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
4. Pathophysiological Conditions Altering Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
5. Treatment of Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
5.1 Adjunctive Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
5.2 Control of the Complicating Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
5.3 Antibacterial Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
5.3.1 General Principles of Antibacterial Therapy in Patients with Urosepsis . . . . . . . . . . . . . . . . 296
5.3.2 Parameters for Antibacterial Treatment in Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
5.4 Fluoroquinolone Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
6. Relationship between Renal Excretion and Bactericidal Titres of Different Fluoroquinolones . . . . . . 300
7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

Abstract Urosepsis accounts for approximately 25% of all sepsis cases and may develop
from a community-acquired or nosocomial urinary tract infection (UTI). Never-
theless, the underlying UTI is almost exclusively a complicated one with involve-
ment of the parenchymatous urogenital organs (e.g. kidneys, prostate) and mostly
associated with any kind of obstructive uropathy. If urosepsis originates from a
nosocomial infection, a broad spectrum of Gram-negative and Gram-positive
pathogens have to be expected, which are often multiresistant.
In urosepsis, as in other types of sepsis, the severity of sepsis depends mostly
upon the host response. The treatment of urosepsis follows the generally accepted
rules of the ‘Surviving Sepsis’ campaign guidelines. Early normalisation of blood
pressure and early adequate empirical antibacterial therapy with optimised dosing
are equally important to meet the requirements of early goal-directed therapy. In
most cases of urosepsis, early control of the infectious focus is possible and as
important. Optimal supportive measures need to follow the early phase of resusci-
tation. To lower mortality from urosepsis, an optimal interdisciplinary approach
between intensive care, anti-infective therapy and urology is essential, assisted by
easy access to the necessary laboratory and imaging diagnostic procedures.
292 Wagenlehner et al.

Although most antibacterials achieve high urinary concentrations, there are

several unique features of complicated UTI, and thus urosepsis, that influence the
activity of antibacterial substances: (i) renal pharmacokinetics differ in unilateral
and bilateral renal impairment and in unilateral and bilateral renal obstruction;
(ii) variations in pH may influence the activity of certain antibacterials; and
(iii) biofilm infection is frequently found under these conditions, which may
increase the minimal inhibitory concentrations (MIC) of the antibacterials at the
site of infection by several hundred folds. Assessment of antibacterial pharmaco-
dynamic properties in such situations should take into account not only the MIC as
determined in vitro and the plasma concentrations of the free (unbound) drug,
which are the guiding principles for many infections, but also the actual renal
excretion and urinary bactericidal activity of the antibacterial substance. In the
treatment of urosepsis, it is important to achieve optimal exposure to antibacterials
both in plasma and in the urinary tract. The role of drugs with low renal excretion
rates is therefore limited.
Since urosepsis quite often originates from catheter-associated UTI and uro-
logical interventions, optimal catheter care and optimal strategies to prevent
nosocomial UTI may be able to reduce the frequency of urosepsis.

1. Epidemiology of Urosepsis lations[7] or in patients with inadequate manage-

Urinary tract infections (UTIs) can manifest as
bacteriuria with limited clinical symptoms, sepsis or
severe sepsis, depending on localised or systemic
extension.
In 20–30% of all patients with sepsis, the infec-
tious focus is localised in the urogenital tract.[1,2]
Frequent causes of urosepsis are obstructive diseas-
es of the urinary tract, such as ureteral stones, anom-
alies, stenosis or tumour. Urosepsis may occur after
operations in the urogenital tract or after infections
of the parenchymatous organs.
Severe sepsis has a reported mortality rate rang-
ing from 20% to 42%.[3] Most severe sepsis reported
in the literature is related to pulmonary (50%) or
abdominal infections (24%), with UTIs accounting
for approximately 5%.[4] Sepsis is more common in
men than in women.[3] In recent years, the incidence
of sepsis has increased[3,5] but the associated mortal-
ity rate has decreased, suggesting improved man-
agement of patients.[3,5] In an evaluation of patients
with sepsis, it was shown that those with a designat-
ed urinary source of sepsis had a significantly lower
baseline risk of death (30%) than patients with other
causes of sepsis (54%).[6] Urosepsis may, however,
result in high mortality rates in special patient popu-
ment. The bacterial spectrum in urosepsis may con-
sist of 50% Escherichia coli, 15% Proteus spp., 15%
Enterobacter and Klebsiella spp., 5% Pseudomonas
aeruginosa and 15% Gram-positive organisms, ac-
cording to different surveillance studies.[8] If host
defence is impaired, less virulent organisms such as
enterococci or P. aeruginosa may also cause urosep-
sis.
Unfortunately, the published resistance rates
have not been determined specifically in patients
with urosepsis, but instead have been determined
mainly in patients with complicated/nosocomial
UTIs. However, there is no reason to believe that
isolates causing urosepsis would be less resistant.
The resistance patterns found in adults with compli-
cated/nosocomial UTIs also encompass an increas-
ing number of resistant and multiresistant patho-
gens. Resistance against the quinolones in E. coli,
for example, is rapidly rising to alarming levels
worldwide, making this class of drugs increasingly
inappropriate for empirical treatment of severe sep-
sis with a suspected source in the urinary tract.[9,10]
To guide adequate empirical antibacterial therapy in
urosepsis, the local susceptibility profile of compli-
cated UTIs must constantly be evaluated.

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (4)
Optimisation of Urosepsis Treatment 293

2. Definition and Clinical Manifestation
of Urosepsis
In urosepsis, as in other types of sepsis, the
severity of sepsis depends mostly upon the host
response. Urosepsis predominantly depends on local
factors, such as urinary tract calculi, obstruction at
any level in the urinary tract, congenital uropathies,
neurogenic bladder disorders or endoscopic ma-
noeuvres. Patients who are more likely to develop
urosepsis include elderly patients, diabetics, immu-
nosuppressed patients such as transplant recipients,
patients receiving cancer chemotherapy or corticos-
teroids, and patients with acquired immunodeficien-
cy syndrome. However, all patients can be affected
by bacterial species capable of inducing inflamma-
tion within the urinary tract.
For therapeutic purposes, the diagnostic criteria
of sepsis should identify patients at an early stage of
the syndrome, prompting urologists and intensive
care specialists to search for and treat infection,
apply appropriate therapy, and monitor for organ
failure and other complications. In the case of
urosepsis, the clinical evidence of UTI is based on
the symptoms, physical examination, sonographic
and radiological features, and laboratory data such
as bacteriuria and leukocyturia. The following defi-
nitions apply (table I):
• Sepsis is a systemic response to infection. The
symptoms of systemic inflammatory response
syndrome (SIRS), which were initially consid-
ered to be ‘mandatory’ for the diagnosis of sep-
sis,[11,13] are now considered to be alerting symp-
toms.[12] Many other clinical or biological symp-
toms must be considered.
• Severe sepsis is sepsis associated with organ
dysfunction.
• Septic shock is persistence of hypoperfusion or
hypotension despite fluid resuscitation.
• Refractory septic shock is defined by absence of
a response to therapy.
3. Pathophysiology of Urosepsis
Microorganisms reach the urinary tract by way of
the ascending, haematogenous or lymphatic routes.
For urosepsis to be established, the pathogens have
to reach the bloodstream. The risk of bacteraemia is
increased in severe UTIs, such as pyelonephritis and
acute bacterial prostatitis, and is facilitated by ob-

Table I. Clinical diagnostic criteria of sepsis and septic shock[11,12]

Disorder Definition
Infection Presence of organisms in a normally sterile site that is usually, but not necessarily, accompanied
by an inflammatory host response
Bacteraemia Bacteria present in the blood as confirmed by culture. May be transient
Systemic inflammatory response Response to a wide variety of clinical insults, which can be infectious, as in sepsis, but may be
syndrome non-infectious in aetiology (e.g. burns, pancreatitis). This systemic response is manifested by two
or more of the following conditions:
temperature >38°C or <36°C
heart rate >90 beats/min
respiratory rate >20 breaths/min or PaCO2 <32mm Hg (<4.3 kPa)
white blood count >12 000 cells/mm3 or <4000 cells/mm3 or ≥10% immature (band) forms
Sepsis Activation of the inflammatory process due to infection
Hypotension Systolic blood pressure <90mm Hg or reduction of >40mm Hg from baseline in the absence of
other causes of hypotension
Severe sepsis Sepsis associated with organ dysfunction, hypoperfusion or hypotension. Hypoperfusion and
perfusion abnormalities may include but are not limited to lactic acidosis, oliguria or acute
alteration of mental status
Septic shock Sepsis with hypotension despite adequate fluid resuscitation along with the presence of perfusion
abnormalities that may include but are not limited to lactic acidosis, oliguria, or acute alteration in
mental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensive
at the time when perfusion abnormalities are measured
Refractory septic shock Septic shock that lasts >1h and does not respond to fluid administration or pharmacological
intervention
PaCO2 = partial pressure of carbon dioxide in arterial blood.

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (4)
294
struction. SIRS is then triggered: an initially pro-
inflammatory reaction, activated by mediators such
as bacterial toxins, is accompanied by a counter-
regulatory anti-inflammatory response syndrome
(CARS). Pro-inflammatory cytokines from stimu-
lated macrophages (e.g. tumour necrosis factor
[TNF]-α, interleukin [IL]-1 and IL-6) damage organ
function, directly or indirectly, via secondary
mediators. Inducible nitric oxide synthetase causes
loss of vessel tone in arterioles and venules of the
systemic circulation and thus leads to low systemic
vascular resistance and venous pooling of the in-
travasal volume. The mean arterial blood pressure
falls. In the pulmonary circulation, pulmonary vas-
cular resistance may rise because of lowered left
ventricular compliance and consecutive dilatation.
Besides increased capillary permeability, rheologic
disturbances and arteriovenous shunts, which di-
minish organ perfusion, inflammatory mediators
such as TNFα, nitric oxide, endotoxin or IL-1 can
damage cells directly by interfering with oxidative
cellular metabolism.[14]
3.1 Cytokines as Markers of the
Septic Response
Cytokines are heavily involved in the pathogene-
sis of sepsis syndrome. They are peptides that regu-
late the amplitude and duration of the host inflam-
matory response. They are released from various
cells, including monocytes, macrophages and endo-
thelial cells, in response to various infectious stimuli
such as peptidoglycans or lipopolysaccharides bind-
ing to Toll-like receptors 2 or 4.[15-17] When they
become bound to specific receptors on other cells,
cytokines change their behaviour in the inflammato-
ry response. The complex balance between pro- and
anti-inflammatory responses is modified in severe
sepsis. An immunodepressive phase follows the ini-
tial pro-inflammatory mechanism. Other cytokines,
such as interleukins, are involved. TNF-9 pt, IL-1,
IL-6 and IL-8 are cytokines that are associated with
sepsis. A genetic predisposition probably explains
the unfavourable outcome of sepsis in certain pa-
tients. The mechanisms of organ failure and death in
patients with sepsis remain only partially under-
stood.[4]
© 2007 Adis Data Information BV. All rights reserved.
Wagenlehner et al.
3.2 Procalcitonin is a Potential Marker
of Sepsis
Procalcitonin is the propeptide of calcitonin but
is devoid of hormonal activity. Normally, pro-
calcitonin levels are undetectable in healthy
humans. During severe generalised infections (bac-
terial, parasitic and fungal) with systemic manifesta-
tions, procalcitonin levels may rise to >100 ng/mL.
In contrast, during severe viral infections or inflam-
matory reactions of non-infectious origin, pro-
calcitonin levels show only a moderate increase or
no increase. The exact site of procalcitonin produc-
tion during sepsis is not known. Procalcitonin moni-
toring may be useful in patients who are likely to
develop SIRS of infectious origin. High pro-
calcitonin levels, or an abrupt increase in pro-
calcitonin levels in these patients, should prompt a
search for the source of infection. Procalcitonin may
be useful in differentiating between infectious and
non-infectious causes of a severe inflammatory sta-
tus.[18]
4. Pathophysiological Conditions
Altering Renal Function
Impairment of renal function can be acute or
chronic, or unilateral or bilateral. Postrenal obstruc-
tion is one of the most frequent causes of urosepsis
in urological cases. In this instance, the obstruction
is the cause of the sepsis on one side and severely
influences the pharmacokinetics of drugs such as
antibacterials in the urinary tract on the other side. In
this context, the pharmacokinetics of drugs at the
affected site are also significantly influenced by
total renal function and thus by the function of the
contralateral kidney. Furthermore, the pharmacoki-
netics of a drug in the kidney are influenced by the
arterial plasma concentration, the renal plasma con-
centration, the renal tissue concentration and the
urine concentration. The renal tissue concentration
is complex and is a function of renal blood flow,
glomerular filtration, tubular secretion and reabsorp-
tion, pyelovenous- and lymphous backflow, and the
number of intact nephrons. The renal tissue concen-
tration of a drug is therefore difficult to assess;
representative concentrations have been investigat-
ed, and one of those could be the concentrations in
the renal lymph which might resemble interstitial
Clin Pharmacokinet 2007; 46 (4)
Optimisation of Urosepsis Treatment
concentrations.[19] Renal lymph concentrations in
unobstructed normal kidneys and unobstructed but
infected kidneys have been determined for a variety
of β-lactam antibacterials, aminoglycosides and ni-
trofurantoin. Concentrations in the renal lymph were
generally lower than the corresponding arterial plas-
ma concentrations, which suggests that there is no
concentration effect in the renal interstitial space.[20]
In acute total unilateral ureteral obstruction, how-
ever, there is still some glomerular filtration and
renal plasma flow present. In an experimental study
in dogs,[19] it was shown that the glomerular filtra-
tion rate and the effective renal plasma flow in the
obstructed kidney in the first hours decreased to an
average of 14% and 12%, respectively, compared
with the unobstructed kidney. The persisting turno-
ver of urine is due primarily to pyelovenous back-
flow and also, but less importantly, due to drainage
into the hilar lymph. The concentrations of a clear-
ance substance such as certain antibacterials in the
renal hilar lymph are higher than the corresponding
arterial plasma concentrations in the acute phase of
unilateral obstruction (from the first hours to the
first week) and become equal to the arterial plasma
concentrations in chronic obstructive disease (long-
er than 1 week).[21]
The glomerular filtration rate is influenced by the
balance of inward and outward pressures at the
glomerular arterioles and Bowman’s capsule. In-
ward forces are significantly increased with pos-
trenal obstruction and are the cause of a reduced
filtration rate.[19,22] An increasing number of neph-
rons will cease filtering if the ureteral pressure ex-
ceeds one-third of the mean blood pressure. Acute
unilateral occlusion of a ureter results in a character-
istic triphasic relationship between renal blood flow
and ureteral pressure. The first phase, lasting ap-
proximately 1.5 hours, shows a rise in both ureteral
pressure and renal blood flow, followed by a second
phase with a decline in renal blood flow and a
continued increase in ureteral pressure lasting from
approximately 1.5 to 5 hours, followed by a third
phase resulting in a further decline in renal blood
flow accompanied by a progressive decrease in ure-
teral pressure. Phase I is characterised by initial
afferent arteriole vasodilatation followed by efferent
arteriole vasoconstriction in phase II and afferent
arteriole vasoconstriction in phase III. This third
© 2007 Adis Data Information BV. All rights reserved.
295
phase is not seen in bilateral ureteral obstruction,
which leads to a progressive rise in ureteral pressure
despite a decrease in renal blood flow. The single
nephron glomerular filtration rate declines in unilat-
eral and bilateral ureteral occlusion, which is secon-
dary to an increase in afferent arteriolar resistance in
unilateral occlusion and secondary to a rise in in-
tratubular pressure in bilateral occlusion.[23] These
differences between unilateral and bilateral obstruc-
tion are most probably due to substances that accu-
mulate in bilateral obstruction or unilateral obstruc-
tion of a solitary kidney but do not accumulate in
unilateral obstruction with a functioning contralater-
al kidney. One important factor of these changes is
the atrial natriuretic peptide that plays an important
role in renal homeostasis.[23]
The urinary concentrations of most antibacterials
are usually much higher than the plasma concentra-
tions. Most aminoglycosides, tetracyclines and sul-
fonamides are excreted exclusively by glomerular
filtration; most β-lactams and quinolones addition-
ally undergo tubular secretion and reabsorption.
Apart from renal clearance, protein binding, ex-
trarenal excretion and metabolism are also impor-
tant for urinary concentration.
Mathematical models were calculated for an an-
tibacterial substance with glomerular filtration and
extrarenal elimination (trimethoprim) and one with
exclusive renal elimination (cephalexin) in the case
of unilateral and bilateral renal impairment and in
the case of acute and chronic unilateral obstruction
in conjunction with normal and differently impaired
contralateral renal function.[24] The following results
can be summarised:
1. In the case of severe unilateral renal insufficiency
(glomerular filtration 1 mL/minute) but normal con-
tralateral renal function (glomerular filtration
60 mL/minute), the urinary antibacterial concentra-
tions of both kidneys are high, whereby the impaired
kidney achieves half the urinary concentration of the
intact kidney.
2. In the case of bilateral renal insufficiency, the
urinary concentrations significantly decrease down
to plasma concentrations in the case of severe im-
pairment (glomerular filtration 2 mL/minute). This
difference in unilateral and bilateral renal insuffi-
ciency can be explained by the intact-nephron theo-
ry. The single nephrons (e.g. the concentration abili-
Clin Pharmacokinet 2007; 46 (4)
296
ty) remain intact in the case of physiological prer-
enal conditions. In bilateral renal insufficiency,
there is an increased offer of solutes per nephron,
which results in diuresis with impaired powers of
concentration.[25]
3. In acute unilateral obstruction, the urinary con-
centrations of the obstructed kidney are almost as
high as those of the normal unobstructed kidney,
which is also due to the maximal urinary concentra-
tion in acute obstruction.
4. Even in chronic unilateral obstruction, rather high
urinary concentrations are achieved depending on
the function of the contralateral kidney.
5. Treatment of Urosepsis
Effective treatment improves organ perfusion
and eliminates the infectious focus. Treatment of
urosepsis comprises three basic strategies: adjunc-
tive measures, control or elimination of the compli-
cating factor and antimicrobial therapy.[26-28] All
three strategies need to be started as early as possible
(e.g. within the first hour).
5.1 Adjunctive Measures
Management of the fluid and electrolyte balance
is a crucial aspect of patient care in sepsis syndrome,
particularly when the clinical course is complicated
by shock. An early goal-directed therapy has been
shown to reduce mortality.[28,29] Volaemic expan-
sion and vasopressor therapy have a considerable
impact on the outcome. Early intervention with ap-
propriate measures to maintain adequate tissue per-
fusion and oxygen delivery by prompt institution of
fluid therapy, stabilization of arterial pressure and
providing sufficient oxygen transport capacity are
highly effective and can be surveilled by the central
venous oxygen saturation.
Hydrocortisone is useful in patients with relative
insufficiency in the pituitary gland-adrenal cortex
axis.[30] As yet, however, there has been no well
designed, large study confirming the benefit of hy-
drocortisone in severe sepsis.
Tight blood glucose control by administration of
insulin doses of up to 50 units/hour has been shown
to be beneficial in critically ill patients after sur-
gery.[31]
© 2007 Adis Data Information BV. All rights reserved.
Wagenlehner et al.
Recombinant activated protein C (drotrecogin α)
is a new drug that has been approved for therapy of
severe sepsis. This expensive treatment has been
proven to be more effective in patients with more
severe disease, as assessed by Acute Physiology and
Chronic Health Evaluation (APACHE) II scores of
≥25 or the presence of ≥2 organ dysfunctions.[32]
The best strategy has been summarised and grad-
ed according to a careful evidence-based methodol-
ogy in the recently published ‘Surviving Sepsis’
campaign guidelines.[33,34]
5.2 Control of the Complicating Factor
Drainage of any obstruction in the urinary tract
and removal of foreign bodies, such as urinary cath-
eters or stones, may themselves cause resolution of
symptoms and lead to recovery. These are key com-
ponents of the strategy. This condition is an absolute
emergency.[35]
5.3 Antibacterial Therapy
5.3.1 General Principles of Antibacterial Therapy in
Patients with Urosepsis
Antibacterials are among the most important and
commonly prescribed drugs in the management of
patients with severe infections.[36] Inappropriate use
of antibacterials may cause therapeutic failure in the
individual patient and additionally may contribute
towards promoting the emergence of resistant
pathogens, which might also readily spread in the
hospital setting.[37] It has been shown that cross-
contamination and cross-infection are also frequent
with UTIs.[38] Adequate initial antibacterial therapy
ensures an improved outcome in septic shock[39,40]
and is also critical in severe UTI. Inappropriate
antibacterial therapy in community-acquired bacter-
aemia due to UTI in adults has been linked to a
higher mortality rate,[41] as has also been shown with
other infections.[42,43] Empirical antibacterial ther-
apy therefore needs to follow certain rules,[44] which
may be based upon the expected bacterial spectrum,
the institutional specific resistance rates and the
individual patient’s requirements. Initial empirical
treatment should provide broad antibacterial cover-
age and should later be adapted on the basis of
culture results. To cover a broad spectrum, combina-
tion therapy may be applied.[45] If enterobacteria are
Clin Pharmacokinet 2007; 46 (4)
Optimisation of Urosepsis Treatment
expected, a third-generation cephalosporin (e.g. cef-
triaxone or cefotaxime) can be used in combination
with an aminoglycoside. In the case of Pseu-
domonas spp., acylaminopenicillins (e.g. azlocillin),
piperacillin in combination with a β-lactamase-in-
hibitor, a Pseudomonas-active cephalosporin (e.g.
ceftazidime) or a carbapenem should be chosen.[26]
In any case, microbiological sampling (urine, blood,
tissue culture) prior to initiation of treatment is
compulsory in order to tailor the initial empirical
therapy according to laboratory results. Additional-
ly, the correct dosing and duration of therapy are
equally important.
5.3.2 Parameters for Antibacterial Treatment
in Urosepsis
Adequate treatment of UTI depends on the an-
tibacterial being able to inhibit the growth or kill
bacteria that are present in the urinary tract. In any
infection of the kidney or bladder, a significant part
of the bacteria (sometimes more than 106/mL) is
also found free in the bladder lumen. Therefore,
high urinary excretion of the antibacterial is also
needed.[46-48] Accordingly, antibacterials that are
primarily eliminated via renal excretion and achieve
high urinary concentrations (100- to 1000-fold con-
comitant serum concentrations) [e.g. ampicillin/
sulbactam, cefuroxime, gatifloxacin, levofloxacin]
theoretically represent optimal choices for the treat-
ment of UTIs. But besides favourable pharmacoki-
netics, an agent suitable for the treatment of severe
complicated UTI should also provide optimal phar-
macodynamic properties at the site of infection,
i.e. urinary bactericidal activity. Thus, even for
agents that are modestly eliminated by renal mecha-
nisms, high intrinsic potency (minimum inhibitory
concentration [MIC]) against the most common
uropathogens (e.g. ciprofloxacin), is also an impor-
tant consideration in antibacterial selection.[49]
Agents whose antibacterial activity is compro-
mised by changes in the urinary pH, such as fluoro-
quinolones, should be administered in doses high
enough to compensate for the possible negative in-
fluence on activity by the urinary pH.
If the infection involves renal tissues or the pa-
tient has urosepsis, adequate serum concentrations
are necessary to produce high tissue concentrations,
thereby necessitating administration of high-dose
intravenous antibacterials. Even in uncomplicated
© 2007 Adis Data Information BV. All rights reserved.
297
pyelonephritis and uncomplicated cystitis, there
is interstitial and intracellular invasion of the
uropathogens.[50-53] The antibacterial concentrations
in tissue are dependent on the plasma concentra-
tions, the specific tissue architecture, the pharma-
cokinetic parameters of the antibacterial drug (the
charge and size of the molecule, protein binding, pH
in the infectious focus) and the distribution of the
infection in the tissue (stroma, epithelium).
Moreover, biofilm infection plays a considerable
role in urosepsis, not only in association with urina-
ry catheters but also in scar tissue, stones, prostatitis
and the obstructed urinary tract.[54-57] For most
uropathogens, the ability to form biofilms has been
demonstrated.[58-64] Goto et al.[65,66] investigated kill-
curves of P. aeruginosa in a biofilm-catheter infec-
tion model. β-lactam antibacterials (piperacillin,
ceftazidime) were not able to eradicate the biofilm
cells, even when concentrations 128 times the mini-
mal bactericidal concentrations were administered.
With fluoroquinolones (ciprofloxacin, levoflox-
acin), eradication was possible, but only in concen-
trations that reached 32- to 64-fold the minimal
bactericidal concentrations.[65,66] Therefore, in gen-
eral, high dosages of antibacterials need to be ap-
plied in conjunction with the attempt to eliminate
the biofilm and the biofilm-causing complicating
factor. If there is a chance to remove the biofilm, this
should be done, e.g. by removing infected stones or
catheters.
While pharmacodynamic studies in UTI are rela-
tively scarce, at least one recent study has docu-
mented that therapeutic success following β-lactam
therapy depends on the time during which the anti-
microbial concentration remains above the MIC
(T>MIC). A recent data analysis by Frimodt-Møl-
ler[47] reported that there was a significant correla-
tion between the cumulative T>MIC in serum and
bacteriological cure, wherein a cumulative T>MIC
of 30 hours provided a maximal cure rate of
80–90%. The investigators postulated that the rea-
son why β-lactams have often not provided success-
ful outcomes in the treatment of UTIs compared
with other antibacterial classes is most likely im-
proper dosing (i.e. dose too low and infrequent
dosage interval).
For drugs with concentration-dependent time-kill
activity, such as the aminoglycosides and the fluoro-
Clin Pharmacokinet 2007; 46 (4)
298
quinolones, a positive outcome appears to be more
dependent on the maximum concentration (Cmax)/
MIC or the area under the concentration-time curve
(AUC)/MIC ratio. While it remains unclear which
ratio is a better predictor of outcome, a high ratio is
desirable in either case. The pharmacodynamics of
ciprofloxacin were investigated in one animal model
UTI study in mice infected with E. coli.[47] While the
data were limited to three points, there was an
obvious correlation between reduced bacterial
counts and the AUC/MIC ratio. Despite the paucity
of pharmacodynamic data to guide therapy in UTIs,
it has been noted that among the available qui-
nolones, the Cmax/MIC in serum and AUC/MIC in
serum ratios are highest for ciprofloxacin against
P. aeruginosa.[67] For other Gram-negative infec-
tions, the pharmacodynamic properties of the availa-
ble quinolone agents are more similar. This model
was unable to evaluate the aminoglycosides using
pharmacodynamic principles because these agents
are characterised by high binding to the renal cor-
tex.[47]
Further pharmacodynamic research is needed in
order to determine the optimal dosages of all an-
tibacterials used to treat serious UTIs. Appropriate
dosing is especially important to minimise the de-
velopment of resistance and to maintain antibacteri-
al efficacy. For patients with serious UTIs, high-
er than approved doses may be needed, especial-
ly against difficult-to-treat pathogens such as
P. aeruginosa.[49] For example, intravenous or oral
ciprofloxacin 750mg twice daily or levofloxacin
500mg twice daily may be more appropriate than
conventional dosing.[68]
In this respect, the mutant-prevention concentra-
tion (MPC) could be a suitable parameter for inclu-
sion in the selection of appropriate agents for diffi-
cult-to-treat infections. The MPC is a novel suscep-
tibility parameter designed to minimise the selection
of first-step resistant mutants present in large
(≥1010 CFU/mL) or heterogeneous bacterial popu-
lations, and is a measurement distinct from MIC
testing.[69] Ciprofloxacin and levofloxacin have been
tested by the MPC methodology and compared
against clinical isolates of P. aeruginosa.[70]
Ciprofloxacin was substantially less likely to select
for quinolone resistance in P. aeruginosa than was
levofloxacin. In a separate report, Hansen and
© 2007 Adis Data Information BV. All rights reserved.
Wagenlehner et al.
Blondeau,[69] compared the MPC results for
ciprofloxacin, levofloxacin and garenoxacin against
clinical isolates of urinary tract pathogens (E. coli,
Citrobacter freundii, E. cloacae, K. pneumoniae and
P. aeruginosa). The ciprofloxacin, levofloxacin and
garenoxacin MPC results in this study for E. coli,
C. freundii, E. cloacae, K. pneumoniae and
P. aeruginosa, respectively, were 0.5, 1, 1, 1 and
4 mg/L; 1, 2, 4, 2 and 16 mg/L; and 1, 8, >8, 4 and
≥32 mg/L. By comparison, the MIC required to
inhibit the growth of 90% of organisms (MIC90)
results ranged from ≤0.06 to 4 mg/L for the Enter-
obacteriaceae organisms and from 1 to 4 mg/L for
P. aeruginosa. Therefore, MPC testing may provide
remarkably different results in some substances and
bacterial strains that are tested. Incorporation of
MPC strategies into current fluoroquinolone dosing
in UTI represents a realistic approach for preventing
the further selection of resistant organisms associat-
ed with UTIs.[69]
5.4 Fluoroquinolone Clinical Trials
A limited number of US and international clinical
trials have been published and provide evidence to
support the effectiveness of the fluoroquinolones in
the treatment of complicated and hospital-acquired
UTIs.[71-95] However, no clinical trials have assessed
the fluoroquinolones specifically in urosepsis pa-
tients, using current diagnostic criteria. Moreover,
the findings of these trials are often difficult to
compare or interpret because of differing or incom-
plete definitions of the ‘complicated’ condition. Al-
though these trials vary in their study design, many
support the use of fluoroquinolones in the treatment
of serious/complicated UTIs; the most experience
has been garnered with ciprofloxacin.[71-75,77-84]
The majority of the published trials of ciproflox-
acin in serious UTI employed the conventional
twice-daily tablet,[71,77-83] while one recent prelimi-
nary report demonstrated the effectiveness of a new
once-daily extended-release tablet formulation.[84]
Three of these studies were conducted primarily in
Germany and used a relatively low dose of
ciprofloxacin (250mg twice daily) but with good
outcomes.[80-82] The majority of these published
clinical trials of oral ciprofloxacin revealed excel-
lent bacteriological (>84%) and clinical cure rates
(>90%). As expected, all of these trials demonstrat-
Clin Pharmacokinet 2007; 46 (4)
Optimisation of Urosepsis Treatment
ed that ciprofloxacin was at least equivalent to a
comparator regimen (e.g. ofloxacin, gatifloxacin).
In general, ciprofloxacin was effective for serious
UTIs due to P. aeruginosa.
One study[71] demonstrated that ciprofloxacin
was significantly bacteriologically superior to a
comparator agent in a population with long-term
bladder catheterisation. Fang et al.[71] demonstrated
a superior bacteriological response at the early fol-
low-up visit (5–9 days post-therapy) with ciproflox-
acin 500 mg twice daily compared with the aminog-
lycoside regimen (p = 0.0005). The response rates
were similar between the two treatment groups at
the long-term follow-up visit (28–30 days post-ther-
apy). In this trial, 75% of P. aeruginosa isolates
were eradicated at short-term follow-up by both the
ciprofloxacin and aminoglycoside regimens, al-
though there was a high rate of recurrence in both
treatment groups. While ciprofloxacin provided
short-term superiority, recurrence was high in both
treatment groups, likely due to the presence of bi-
ofilms and the fact that catheters could not be re-
moved from these patients. These findings stress the
difficulty of treating patients who have permanent
indwelling urinary catheters.
Cox et al.[83] recently evaluated the efficacy of
ciprofloxacin (500mg twice daily) versus gatiflox-
acin (400mg once daily) for 7–10 days in 288 adult
patients with complicated UTI. Approximately one-
third of patients had more than one ‘complicating’
factor (e.g. impaired bladder emptying) at study
entry. E. coli and K. pneumoniae were the predomi-
nant causative baseline pathogens for almost two-
thirds of patients. As in many clinical trials, patients
whose pretreatment pathogen was resistant to either
drug therapy were excluded from the efficacy-
evaluable population. Bacteriological and clinical
outcomes were comparable between the two treat-
ments. At the test of cure visit (5–9 days post-
therapy), the overall bacteriological eradication of
organisms was 90% for ciprofloxacin versus 100%
for gatifloxacin. The lower rate of eradication in the
ciprofloxacin group was largely due to several per-
sistent Enterococcus faecalis organisms. The rates
of superinfections were comparable between the
two treatments (one with ciprofloxacin vs two
with gatifloxacin) and were typically due to qui-
nolone-resistant bacteria (Alcaligenes faecalis and
© 2007 Adis Data Information BV. All rights reserved.
299
P. aeruginosa). All five ciprofloxacin-treated pa-
tients with a baseline P. aeruginosa infection
achieved bacteriological eradication; no evaluable
gatifloxacin-treated patient was infected with a
pseudomonal strain. Clinical success at the test-of-
cure (4–11 days post-therapy) exceeded 90% in both
treatment groups for those with complicated UTIs.
Excluding indeterminate responses, the clinical cure
rate at long-term follow-up was slightly lower: 83%
for ciprofloxacin versus 86% for gatifloxacin. This
contemporary study demonstrates the continued ef-
ficacy of fluoroquinolones for treatment of serious
UTIs, including ciprofloxacin’s efficacy against
P. aeruginosa.
Mombelli et al.[75] investigated the efficacy of
oral ciprofloxacin (500mg twice daily) versus intra-
venous ciprofloxacin (200mg twice daily) as empiri-
cal therapy for 141 patients with community-ac-
quired and nosocomial complicated UTIs or severe
pyelonephritis. Only patients with severe sepsis (de-
fined as the presence of infection-related organ dys-
function) were excluded. Resistance to ciproflox-
acin was found for 11 baseline organisms (8%),
including five Enterococcus spp. and one each of
P. aeruginosa, E. coli, Enterobacter spp., Staphylo-
coccus aureus, coagulase negative staphylococci,
and Candida albicans. This study found that empiri-
cal oral ciprofloxacin was bacteriologically and
clinically as effective as intravenous ciprofloxacin
for management of serious UTIs, including bacter-
aemia, in patients without severe sepsis, obstruction
or renal foci of suppuration. The rates of bacterio-
logical failure or unsatisfactory clinical response
were extremely low (2% and 3%, respectively, for
intravenous administration vs 3% and 4%, respec-
tively, for oral administration). Importantly, no in-
fection-related deaths occurred, and no patient had
to be switched early from empirical to alternative
therapy because of clinical worsening. However,
treatment was ultimately altered following the avail-
ability of susceptibility findings in 7% of patients
randomised to intravenous ciprofloxacin versus
14% of oral ciprofloxacin recipients (p = 0.31).
There are several unique aspects/findings of this
trial: (i) the enrolled patients had serious UTIs,
including 53 patients with proven bacteraemia; (ii)
males constituted >40% of the study population and
nosocomial acquisition was reported for 23%; and
Clin Pharmacokinet 2007; 46 (4)
300 Wagenlehner et al.

Table II. Mean single-dose pharmacokinetic parameters of different fluoroquinolones at relatively high dosages
Fluoroquinolone Dose Route of Cmax t1/2 (h) Mean urinary AUC36h Reference
(mg) administration (mg/L) excretion (%) (μg • h/mL)
Ciprofloxacin XR 1000 Oral 3.3 8.2 41 19.5 99
Levofloxacin 500 Oral 6.2 6.4 80 47.8 99
Gatifloxacin 400 Oral 3.4 6.5 81 33.3 100
Gemifloxacin 800 Oral 4.3 8.0 39 31.4 103,104
Moxifloxacin 400 Oral 4.3 9.1 20 39.3a 96
Trovafloxacinb 200 Intravenous 2.3 12.3 10 29.2 105
a AUC∞.
b Alatrofloxacin.
AUC36h = area under the concentration-time curve from 0 to 36 hours; AUC∞ = AUC from time zero to infinity; Cmax = maximum
concentration; t1/2 = elimination half-life; XR = extended release.

(iii) patients with resistant organisms were not auto-
matically excluded. It is also noteworthy that the
majority of ciprofloxacin resistance was against
Gram-positive organisms and that, despite this, most
patients had an adequate initial clinical and bacterio-
logical response. In fact, the clinical response to
ciprofloxacin was satisfactory in six of seven pa-
tients with ciprofloxacin-resistant pathogens, in-
cluding two episodes of bacteraemia. Although this
study was not large, it provides compelling evidence
that both intravenous and oral ciprofloxacin are ef-
fective in the initial treatment of patients with seri-
ous UTIs, including nosocomially acquired infec-
tions.
6. Relationship between Renal Excretion
and Bactericidal Titres of
Different Fluoroquinolones
In many infections, antibacterial susceptibility
levels are often gauged relative to what antibacterial
concentration is achievable in the blood. In the
treatment of complicated UTI, however, the urinary
concentrations – or, more precisely, the urinary an-
tibacterial activity – are more important. Fluoroqui-
nolones differ in their pharmacokinetic properties[96]
and antibacterial activity.[97] The urinary concentra-
tion has to be considered and correlated with the
respective antibacterial activities. This can be done,
for example, in an ex vivo model by determining the
urinary bactericidal titres (UBTs). In this model, the
pharmacokinetic and pharmacodynamic parameters
of an antibacterial in urine are linked together. Vari-
ous fluoroquinolones have thus been compared with
each other.
Selected pharmacokinetic studies of fluoroqui-
nolones used at relatively high dosages are shown in
table II. The UBTs of these fluoroquinolones have
been investigated.[98-102] Although these studies are
not directly comparable, they emphasise the impor-
tance of special urinary parameters such as the UBT
for the assessment of antibacterial substances suita-
ble for the treatment of UTI.
In a randomised cross-over study in 12 volun-
teers, single oral doses of extended-release
ciprofloxacin 1000mg versus levofloxacin 500mg
were compared to assess UBTs.[102] UBTs were
determined for eight strains with the following
MICs (mg/L) for ciprofloxacin/levofloxacin: E. coli
ATCC 25922 (0.008/0.03), K. pneumoniae (0.008/
0.03), P. mirabilis (0.03/0.06), E. coli [nalidixic acid
resistant] (0.125/0.25), P. aeruginosa (0.5/2),
S. saprophyticus (0.25/0.25), S. aureus (0.125/
0.125), E. faecalis (1/1). The areas under the UBT-
time curve within the first 24 hours showed statisti-
cally significant differences only for P. mirabilis in
favour of extended-release ciprofloxacin, and for
S. aureus and S. saprophyticus in favour of lev-
ofloxacin. Because levofloxacin shows double the
excretion rate of ciprofloxacin (levofloxacin ap-
proximately 80%, ciprofloxacin approximately
40%),[99] double the dose of ciprofloxacin is neces-
sary to achieve urinary activity (UBTs) comparable
to that achieved with levofloxacin.
Another randomised cross-over study in 12 vol-
unteers compared single oral doses of gatifloxacin
400mg and ciprofloxacin 500mg.[100] Again, ga-
tifloxacin showed double the excretion rate of
ciprofloxacin (gatifloxacin approximately 80%,

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (4)
Optimisation of Urosepsis Treatment
ciprofloxacin approximately 40%). UBTs were de-
termined for 10 strains with the following MICs
(mg/L) for gatifloxacin/ciprofloxacin: E. coli ATCC
25922 (0.008/0.008), E. coli 523 (0.06/0.06),
K. pneumoniae (0.03/0.016), P. mirabilis (0.125/
0.016), P. aeruginosa (1/0.125), E. faecalis 60 (0.5/
1) and E. faecalis 55 (8/32), S. aureus (0.03/0.125)
and S. saprophyticus (0.125/0.25). The areas under
the UBT-time curve calculated for 120 hours
showed generally superior results for gatifloxacin
compared with ciprofloxacin, with the exception
of Proteus and Pseudomonas spp. Therefore, the
inferior urinary excretion rate of ciprofloxacin (half
that of gatifloxacin) is levelled out only in those
species where the pharmacodynamic advantage of
ciprofloxacin is 8-fold higher than that of gatiflox-
acin (MIC).
A different cross-over study in volunteers com-
pared single oral doses of levofloxacin 250mg, ga-
tifloxacin 400mg, moxifloxacin 400mg and
trovafloxacin 200mg.[101] Urinary concentrations
were highest with gatifloxacin followed by
levofloxacin, moxifloxacin and trovafloxacin. Uri-
nary bactericidal activity was determined against
levofloxacin-susceptible and moderately-suscepti-
ble strains with the following MICs: E. coli (0.125
and 4 mg/L), K. pneumoniae (0.125 and 4 mg/L),
P. aeruginosa (0.5 and 4 mg/L) and E. faecalis (0.25
and 4 mg/L). Gatifloxacin and levofloxacin exhibit-
ed prolonged urinary bactericidal activity (≥6 hours)
against all study isolates, whereas moxifloxacin
failed to show prolonged urinary bactericidal activi-
ty against both Pseudomonas strains, and trovaflox-
acin failed to show this activity against all moderate-
ly susceptible strains, with the exception of E. fae-
calis.
Therefore those fluoroquinolones with very lim-
ited urinary excretion (<40%) [moxifloxacin,
trovafloxacin] showed inferior results in this ex vivo
pharmacokinetic/pharmacodynamic study design.
Fluoroquinolones with intermediate urinary excre-
tion rates (ciprofloxacin) showed comparable results
only in those strains where the MICs are favourable
in comparison with highly excreted fluoroqui-
nolones (levofloxacin, gatifloxacin). Otherwise, the
administered daily dose needs to be increased ac-
cordingly.
© 2007 Adis Data Information BV. All rights reserved.
301
In clinical studies, newer fluoroquinolones were
compared with ciprofloxacin 500mg twice daily as a
standard treatment in the oral treatment of compli-
cated UTI. Whereas levofloxacin 250mg once dai-
ly[106] and gatifloxacin 400mg once daily[107] (both
of which are excreted into the urine at a rate of about
80%) showed clinical and microbiological results
equivalent to those achieved with ciprofloxacin,
equivalence could not be achieved when moxiflox-
acin 400mg once daily (urinary excretion 20%)[108]
or gemifloxacin 320mg once daily (urinary excre-
tion 30%)[109] were compared with ciprofloxacin.
All four newer fluoroquinolones showed almost
complete bioavailability after oral administration,
with subsequent good corresponding plasma con-
centrations. The lower urinary concentrations, and
hence lower urinary antibacterial activity, of mox-
ifloxacin and gemifloxacin had the consequence that
these two compounds did not achieve approval for
treatment of complicated UTI by the regulatory bod-
ies.
Therefore the ex vivo studies assessing urinary
bactericidal activity proved to be relevant to the
prediction of results in clinical studies.
In severe UTI, adequate initial antibacterial ther-
apy is critical,[41] therefore empirical treatment
needs to cover also moderately susceptible bacteria.
Pea et al.[68] assessed the urinary pharmacokinetics
and theoretical pharmacodynamics of levofloxacin
in intensive care unit (ICU) patients treated with
500mg intravenously twice daily. Using this high
dosage, urinary concentrations were maintained at
least 50-fold higher than the MIC90 of most sensi-
tive uropathogens during the overall dosing interval
in ICU patients with normal renal function. The
investigators concluded that considering the major
pharmacodynamic determinants of the concentra-
tion-dependent bactericidal activity of levofloxacin
as applicable at the urinary level (Cmax/MIC >12.2
and/or AUC24/MIC >125 hours), this high dosage
regimen may ensure optimal exposure for the treat-
ment of catheter-related and severe lower UTIs not
only against sensitive microorganisms, but probably
also whenever microorganisms that are usually con-
sidered as intermediate susceptible or resistant to
levofloxacin may be involved. The resistance levels
of fluoroquinolones against uropathogens, however,
are constantly rising to levels where fluoroqui-
Clin Pharmacokinet 2007; 46 (4)
302
nolones may no longer be considered for empirical
treatment of UTIs.[9,10] Therefore, in the treatment of
severe UTIs, high dosages should generally be
mandatory.
7. Prevention
Septic shock is the most frequent cause of death
in patients hospitalised for both community-ac-
quired and nosocomial infection (20–40%). Sepsis
initiates the cascade that progresses to severe sepsis
and then septic shock in a clinical continuum. Pre-
vention of urosepsis can mainly be achieved by
preventing nosocomial UTI.[110] The most effective
methods to prevent nosocomial urosepsis are basi-
cally the same as those used to prevent other
nosocomial infections:
• Isolation of all patients infected with multi-resis-
tant organisms to avoid cross-infection.
• Prudent use of antibacterial agents, both in pro-
phylaxis and in treatment of established infec-
tions, to avoid selection of resistant strains. An-
tibacterial agents should be chosen according to
the predominant pathogens at a given site of
infection in the hospital environment.
• Reduction in hospital stay. It is well known that
long inpatient periods prior to surgery lead to a
greater incidence of nosocomial infections.
• Early removal of indwelling urethral catheters, as
soon as the patients’ condition allows it.
• Nosocomial UTIs are promoted by bladder
catheterisation as well as by ureteral stenting.
• Use of closed catheter drainage and minimisation
of breaks in the integrity of the system, e.g. for
urine sampling or bladder wash-out.
• Use of the least invasive method to release urina-
ry tract obstruction until the patient is stabilised.
• Attention to simple everyday techniques to as-
sure asepsis, including routine use of protective
disposable gloves, frequent hand disinfection,
and use of infectious disease control measures to
prevent cross-infections.
• Appropriate perioperative antimicrobial prophy-
laxis.
8. Conclusion
Sepsis syndrome in urology remains a serious
situation with a mortality rate as high as 20–40%.
© 2007 Adis Data Information BV. All rights reserved.
Wagenlehner et al.
The recent ‘Surviving Sepsis’ campaign led to the
formation of guidelines aimed at reducing mortality
by 25% in the next few years. Early recognition of
the symptoms may decrease mortality through time-
ly treatment of urinary tract disorders, e.g. obstruc-
tion, urolithiasis. Adequate life-support measures
and appropriate antibacterial treatment, including
optimized dosing, provide the best conditions for
improving patients’ survival. Prevention of sepsis
syndrome is dependent on good practice to avoid
nosocomial infections and use of antibacterial pro-
phylaxis and therapy in a prudent and well accepted
manner.
Acknowledgements
No sources of funding were used to assist in the prepara-
tion of this review. The authors have no conflicts of interest
that are directly relevant to the content of this review.
References
1. Book M, Lehmann LE, Schewe JC, et al. Urosepsis: current
therapy and diagnosis [in German]. Urologe A 2005; 44 (4):
413-24
2. Brun-Buisson C. The epidemiology of the systemic inflammato-
ry response. Intensive Care Med 2000; 26 Suppl. 1: S64-74
3. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of
sepsis in the United States from 1979 through 2000. N Engl J
Med 2003; 348 (16): 1546-54
4. Hotchkiss RS, Karl IE. The pathophysiology and treatment of
sepsis. N Engl J Med 2003; 348 (2): 138-50
5. Brun-Buisson C, Meshaka P, Pinton P, et al. EPISEPSIS: a
reappraisal of the epidemiology and outcome of severe sepsis
in French intensive care units. Intensive Care Med 2004; 30
(4): 580-8
6. Knaus WA, Sun X, Nystrom O, et al. Evaluation of definitions
for sepsis. Chest 1992; 101 (6): 1656-62
7. Rosser CJ, Bare RL, Meredith JW. Urinary tract infections in
the critically ill patient with a urinary catheter. Am J Surg
1999; 177 (4): 287-90
8. Menninger M. Urosepsis, Klinik, Diagnostik und Therapie. In:
Hofstetter A, editor. Urogenitale Infektionen. Berlin, Heidel-
berg, New York: Springer, 1998: 521-8
9. Wagenlehner FM, Weidner W, Naber KG. Emergence of antibi-
otic resistance amongst hospital-acquired urinary tract infec-
tions and pharmacokinetic/pharmacodynamic considerations.
J Hosp Infect 2005; 60 (3): 191-200
10. Wagenlehner F, Naber KG. Antibiotics and resistance of
uropathogens. European Urology (Update Series) 2004; 2:
125-35
11. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and
organ failure and guidelines for the use of innovative therapies
in sepsis: the ACCP/SCCM Consensus Conference Commit-
tee. American College of Chest Physicians/Society of Critical
Care Medicine. Chest 1992; 101 (6): 1644-55
12. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/
ACCP/ATS/SIS International Sepsis Definitions Conference.
Crit Care Med 2003; 31 (4): 1250-6
13. Bone RC, Sprung CL, Sibbald WJ. Definitions for sepsis and
organ failure. Crit Care Med 1992; 20 (6): 724-6
Clin Pharmacokinet 2007; 46 (4)
Optimisation of Urosepsis Treatment
14. Astiz ME, Rackow EC. Septic shock. Lancet 1998; 351 (9114):
1501-5
15. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in
C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
Science 1998; 282 (5396): 2085-8
16. Opal SM, Huber CE. Bench-to-bedside review: Toll-like recep-
tors and their role in septic shock. Crit Care 2002; 6 (2): 125-36
17. Means TK, Golenbock DT, Fenton MJ. Structure and function
of Toll-like receptor proteins. Life Sci 2000; 68 (3): 241-58
18. Harbarth S, Holeckova K, Froidevaux C, et al. Diagnostic value
of procalcitonin, interleukin-6, and interleukin-8 in critically
ill patients admitted with suspected sepsis. Am J Respir Crit
Care Med 2001; 164 (3): 396-402
19. Naber KG, Madsen PO. Renal function during acute total ureter-
al occlusion and the role of the lymphatics: an experimental
study in dogs. J Urol 1973; 109 (3): 330-8
20. Naber KG, Madsen PO, Maroske D, et al. Antibiotics and
chemotherapeutics in renal lymph: an experimental study in
dogs. Invest Urol 1976; 14 (1): 23-7
21. Naber K, Madsen PO, Bichler KH, et al. Determination of renal
tissue levels of antibiotics [in German]. Infection 1973; 1:
208-13
22. Jaenike JR. The renal response to ureteral obstruction: a model
for the study of factors which influence glomerular filtration
pressure. J Lab Clin Med 1970; 76 (3): 373-82
23. Gulmi FA FD, Vaughan Jr ED. Pathophysiology of urinary tract
obstruction. In: Walsh PC, Retik AB, Vaughan ED, et al.,
editors. Campbell’s urology. 8th ed. Philadelphia: Saunders,
2002: 411-62
24. Naber KG, Kuni H. Renale Pharmakokinetik. Hahnenklee-Sym-
posium ‘Pyelonephritis’; 1976 May 20-21; Roche, Basel,
271-85
25. Bricker NS, Morrin PA, Kime Jr SW. The pathologic physiolo-
gy of chronic Bright’s disease: an exposition of the ‘intact
nephron hypothesis’. Am J Med 1960; 28: 77-98
26. Naber KG, Bishop MC, Bjerklund-Johansen TE, et al. Guide-
lines on the management of urinary and male genital tract
infections. EAU Working Group on Urinary and Male Genital
Tract Infections. Arnhem: European Association of Urology,
2006 [online]. Available from URL: http://www.uroweb.nl/
files/uploaded_files/guidelines/15%20Male%20UTI.pdf [Ac-
cessed 2007 Feb 26]
27. Wheeler AP, Bernard GR. Treating patients with severe sepsis.
N Engl J Med 1999; 340 (3): 207-14
28. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed
therapy in the treatment of severe sepsis and septic shock. N
Engl J Med 2001; 345 (19): 1368-77
29. Gluck T, Opal SM. Advances in sepsis therapy. Drugs 2004; 64
(8): 837-59
30. Annane D, Sebille V, Charpentier C, et al. Effect of treatment
with low doses of hydrocortisone and fludrocortisone on mor-
tality in patients with septic shock. JAMA 2002; 288 (7):
862-71
31. van den Berghe G, Wouters P, Weekers F, et al. Intensive
insulin therapy in the critically ill patients. N Engl J Med 2001;
345 (19): 1359-67
32. Bernard GR, Ely EW, Wright TJ, et al. Safety and dose relation-
ship of recombinant human activated protein C for
coagulopathy in severe sepsis. Crit Care Med 2001; 29 (11):
2051-9
33. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis
campaign guidelines for management of severe sepsis and
septic shock. Crit Care Med 2004; 32 (3): 858-73
34. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis
campaign guidelines for management of severe sepsis and
septic shock. Intensive Care Med 2004; 30 (4): 536-55
© 2007 Adis Data Information BV. All rights reserved.
303
35. Yoshimura K, Utsunomiya N, Ichioka K, et al. Emergency
drainage for urosepsis associated with upper urinary tract
calculi. J Urol 2005; 173 (2): 458-62
36. Paterson DL. Restrictive antibiotic policies are appropriate in
intensive care units. Crit Care Med 2003; 31 (1 Suppl.): S25-8
37. Eggimann P, Pittet D. Infection control in the ICU. Chest 2001;
120 (6): 2059-93
38. Wagenlehner FM, Krcmery S, Held C, et al. Epidemiological
analysis of the spread of pathogens from a urological ward
using genotypic, phenotypic and clinical parameters. Int J
Antimicrob Agents 2002; 19 (6): 583-91
39. Kreger BE, Craven DE, McCabe WR. Gram-negative bacter-
emia: IV. Re-evaluation of clinical features and treatment in
612 patients. Am J Med 1980; 68 (3): 344-55
40. Kreger BE, Craven DE, Carling PC, et al. Gram-negative
bacteremia: III. Reassessment of etiology, epidemiology and
ecology in 612 patients. Am J Med 1980; 68 (3): 332-43
41. Elhanan G, Sarhat M, Raz R. Empiric antibiotic treatment and
the misuse of culture results and antibiotic sensitivities in
patients with community-acquired bacteraemia due to urinary
tract infection. J Infect 1997; 35 (3): 283-8
42. Kollef MH, Ward S. The influence of mini-BAL cultures on
patient outcomes: implications for the antibiotic management
of ventilator-associated pneumonia. Chest 1998; 113 (2):
412-20
43. Luna CM, Vujacich P, Niederman MS, et al. Impact of BAL
data on the therapy and outcome of ventilator-associated pneu-
monia. Chest 1997; 111 (3): 676-85
44. Singh N, Yu VL. Rational empiric antibiotic prescription in the
ICU. Chest 2000; 117 (5): 1496-9
45. Mutlu GM, Wunderink RG. Severe pseudomonal infections.
Curr Opin Crit Care 2006; 12 (5): 458-63
46. Frimodt-Møller N. How predictive is PK/PD for antibacterial
agents? Int J Antimicrob Agents 2002; 19 (4): 333-9
47. Frimodt-Møller N. Correlation between pharmacokinetic/phar-
macodynamic parameters and efficacy for antibiotics in the
treatment of urinary tract infection. Int J Antimicrob Agents
2002; 19 (6): 546-53
48. Hvidberg H, Struve C, Krogfelt KA, et al. Development of a
long-term ascending urinary tract infection mouse model for
antibiotic treatment studies. Antimicrob Agents Chemother
2000; 44 (1): 156-63
49. Naber KG. Which fluoroquinolones are suitable for the treat-
ment of urinary tract infections? Int J Antimicrob Agents 2001;
17 (4): 331-41
50. Mulvey MA, Schilling JD, Hultgren SJ. Establishment of a
persistent Escherichia coli reservoir during the acute phase of
a bladder infection. Infect Immun 2001; 69 (7): 4572-9
51. Ivanyi B, Rumpelt HJ, Thoenes W. Acute human pyelonephri-
tis: leukocytic infiltration of tubules and localization of bacte-
ria. Virchows Arch A Pathol Anat Histopathol 1988; 414 (1):
29-37
52. Deguchi T, Kuriyama M, Maeda S, et al. Electron microscopic
study of acute retrograde pyelonephritis in mice. Urology
1990; 35 (5): 423-7
53. Chippendale GR, Warren JW, Trifillis AL, et al. Internalization
of Proteus mirabilis by human renal epithelial cells. Infect
Immun 1994; 62 (8): 3115-21
54. Anderson GG, Martin SM, Hultgren SJ. Host subversion by
formation of intracellular bacterial communities in the urinary
tract. Microbes Infect 2004; 6 (12): 1094-101
55. Justice SS, Hung C, Theriot JA, et al. Differentiation and
developmental pathways of uropathogenic Escherichia coli in
urinary tract pathogenesis. Proc Natl Acad Sci U S A 2004;
101 (5): 1333-8
56. Kumon H. Management of biofilm infections in the urinary
tract. World J Surg 2000; 24 (10): 1193-6
Clin Pharmacokinet 2007; 46 (4)
304
57. Nickel JC, Olson ME, Costerton JW. Rat model of experimental
bacterial prostatitis. Infection 1991; 19 Suppl. 3: S126-30
58. Zogaj X, Bokranz W, Nimtz M, et al. Production of cellulose
and curli fimbriae by members of the family Enterobacter-
iaceae isolated from the human gastrointestinal tract. Infect
Immun 2003; 71 (7): 4151-8
59. Sabbuba NA, Mahenthiralingam E, Stickler DJ. Molecular epi-
demiology of Proteus mirabilis infections of the catheterized
urinary tract. J Clin Microbiol 2003; 41 (11): 4961-5
60. Jansen AM, Lockatell V, Johnson DE, et al. Mannose-resistant
Proteus-like fimbriae are produced by most Proteus mirabilis
strains infecting the urinary tract, dictate the in vivo localiza-
tion of bacteria, and contribute to biofilm formation. Infect
Immun 2004; 72 (12): 7294-305
61. Ando E, Monden K, Mitsuhata R, et al. Biofilm formation
among methicillin-resistant Staphylococcus aureus isolates
from patients with urinary tract infection. Acta Med Okayama
2004; 58 (4): 207-14
62. Debbia EA, Dolcino M, Marchese A, et al. Enhanced biofilm-
production in pathogens isolated from patients with rare meta-
bolic disorders. New Microbiol 2004; 27 (4): 361-7
63. Seno Y, Kariyama R, Mitsuhata R, et al. Clinical implications of
biofilm formation by Enterococcus faecalis in the urinary
tract. Acta Med Okayama 2005; 59 (3): 79-87
64. Bokranz W, Wang X, Tschape H, et al. Expression of cellulose
and curli fimbriae by Escherichia coli isolated from the gastro-
intestinal tract. J Med Microbiol 2005; 54 (Pt 12): 1171-82
65. Goto T, Nakame Y, Nishida M, et al. In vitro bactericidal
activities of beta-lactamases, amikacin, and fluoroquinolones
against Pseudomonas aeruginosa biofilm in artificial urine.
Urology 1999; 53 (5): 1058-62
66. Goto T, Nakame Y, Nishida M, et al. Bacterial biofilms and
catheters in experimental urinary tract infection. Int J An-
timicrob Agents 1999; 11 (3-4): 227-31, discussion 237-9
67. Scheld WM. Maintaining fluoroquinolone class efficacy: re-
view of influencing factors. Emerg Infect Dis 2003; 9 (1): 1-9
68. Pea F, Pavan F, Di Qual E, et al. Urinary pharmacokinetics and
theoretical pharmacodynamics of intravenous levofloxacin in
intensive care unit patients treated with 500mg b.i.d. for venti-
lator-associated pneumonia. J Chemother 2003; 15 (6): 563-7
69. Hansen GT, Blondeau JM. Comparison of the minimum inhibi-
tory, mutant prevention and minimum bactericidal concentra-
tions of ciprofloxacin, levofloxacin and garenoxacin against
enteric Gram-negative urinary tract infection pathogens. J
Chemother 2005; 17 (5): 484-92
70. Hansen GT, Zhao X, Drlica K, et al. Mutant prevention concen-
tration for ciprofloxacin and levofloxacin with Pseudomonas
aeruginosa. Int J Antimicrob Agents 2006; 27 (2): 120-4
71. Fang GD, Brennen C, Wagener M, et al. Use of ciprofloxacin
versus use of aminoglycosides for therapy of complicated
urinary tract infection: prospective, randomized clinical and
pharmacokinetic study. Antimicrob Agents Chemother 1991;
35 (9): 1849-55
72. Peters HJ. Comparison of intravenous ciprofloxacin and
mezlocillin in treatment of complicated urinary tract infection.
Eur J Clin Microbiol 1986; 5 (2): 253-5
73. Peters HJ. Sequential therapy with ofloxacin in complicated
urinary tract infections: a randomized comparative study with
ciprofloxacin. Infection 1992; 20 (3): 172-3
74. Naber KG, di Silverio F, Geddes A, et al. Comparative efficacy
of sparfloxacin versus ciprofloxacin in the treatment of com-
plicated urinary tract infection. J Antimicrob Chemother 1996;
37 Suppl. A: 135-44
75. Mombelli G, Pezzoli R, Pinoja-Lutz G, et al. Oral vs intrave-
nous ciprofloxacin in the initial empirical management of
severe pyelonephritis or complicated urinary tract infections: a
prospective randomized clinical trial. Arch Intern Med 1999;
159 (1): 53-8
© 2007 Adis Data Information BV. All rights reserved.
Wagenlehner et al.
76. McCue JD. Complicated, recurrent, and geriatric UTI. Contemp
Urol 1995; Suppl.: 10-7
77. McCue JD, Gaziano P, Orders D. A randomised controlled trial
of ofloxacin 200mg 4 times daily or twice daily vs ciproflox-
acin 500mg twice daily in elderly nursing home patients with
complicated UTI. Drugs 1995; 49 Suppl. 2: 368-73
78. Whitby M, Angus L, Nimmo G, et al. Complicated urinary
infection in spinal injury patients: fleroxacin compared with
ciprofloxacin. Chemotherapy 1996; 42 (6): 468-72
79. Pisani E, Bartoletti R, Trinchieri A, et al. Lomefloxacin versus
ciprofloxacin in the treatment of complicated urinary tract
infections: a multicenter study. J Chemother 1996; 8 (3): 210-3
80. Raz R, Naber KG, Raizenberg C, et al. Ciprofloxacin 250mg
twice daily versus ofloxacin 200mg twice daily in the treat-
ment of complicated urinary tract infections in women. Eur J
Clin Microbiol Infect Dis 2000; 19 (5): 327-31
81. Krcmery S, Naber KG. Ciprofloxacin once versus twice daily in
the treatment of complicated urinary tract infections. German
Ciprofloxacin UTI Study Group. Int J Antimicrob Agents
1999; 11 (2): 133-8
82. Frankenschmidt A, Naber KG, Bischoff W, et al. Once-daily
fleroxacin versus twice-daily ciprofloxacin in the treatment of
complicated urinary tract infections. J Urol 1997; 158 (4):
1494-9
83. Cox CE, Marbury TC, Pittman WG, et al. A randomized,
double-blind, multicenter comparison of gatifloxacin versus
ciprofloxacin in the treatment of complicated urinary tract
infection and pyelonephritis. Clin Ther 2002; 24 (2): 223-36
84. Talan DA, Klimberg IW, Nicolle LE, et al. Once daily, extended
release ciprofloxacin for complicated urinary tract infections
and acute uncomplicated pyelonephritis. J Urol 2004; 171 (2 Pt
1): 734-9
85. Matsumoto T, Kumazawa J, Ueda S, et al. Treatment of compli-
cated urinary tract infections with ofloxacin following an
aminoglycoside. Chemotherapy 1991; 37 Suppl. 1: 60-7
86. Schalkhauser K. Comparison of i.v. ofloxacin and piperacillin in
the treatment of complicated urinary tract infections. J An-
timicrob Chemother 1990; 26 Suppl. D: 93-7
87. Cox CE. Comparison of intravenous fleroxacin with ceftazidime
for treatment of complicated urinary tract infections. Am J
Med 1993; 94 (3A): 118S-25S
88. Pittman W, Moon JO, Hamrick Jr LC, et al. Randomized
double-blind trial of high- and low-dose fleroxacin versus
norfloxacin for complicated urinary tract infection. Am J Med
1993; 94 (3A): 101S-4S
89. Gelfand MS, Simmons BP, Craft RB, et al. A sequential study of
intravenous and oral fleroxacin in the treatment of complicated
urinary tract infection. Am J Med 1993; 94 (3A): 126S-30S
90. Giamarellou H. Fleroxacin in complicated urinary tract infec-
tions. Chemotherapy 1996; 42 Suppl. 1: 17-27
91. Nicolle LE, Louie TJ, Dubois J, et al. Treatment of complicated
urinary tract infections with lomefloxacin compared with that
with trimethoprim-sulfamethoxazole. Antimicrob Agents
Chemother 1994; 38 (6): 1368-73
92. Hoepelman IM, Havinga WH, Benne RA, et al. Safety and
efficacy of lomefloxacin versus norfloxacin in the treatment of
complicated urinary tract infections. Eur J Clin Microbiol
Infect Dis 1993; 12 (5): 343-7
93. Gottlieb PL. Comparison of enoxacin versus trimethoprim-
sulfamethoxazole in the treatment of patients with complicated
urinary tract infection. Clin Ther 1995; 17 (3): 493-502
94. Klimberg IW, Cox CE, 2nd, et al. A controlled trial of levoflox-
acin and lomefloxacin in the treatment of complicated urinary
tract infection. Urology 1998; 51 (4): 610-5
95. Peng MY. Randomized, double-blind, comparative study of
levofloxacin and ofloxacin in the treatment of complicated
urinary tract infections. J Microbiol Immunol Infect 1999; 32
(1): 33-9
Clin Pharmacokinet 2007; 46 (4)
Optimisation of Urosepsis Treatment
96. Lubasch A, Keller I, Borner K, et al. Comparative
pharmacokinetics of ciprofloxacin, gatifloxacin, grepaflox-
acin, levofloxacin, trovafloxacin, and moxifloxacin after sin-
gle oral administration in healthy volunteers. Antimicrob
Agents Chemother 2000; 44 (10): 2600-3
97. Naber K. Antibacterial activity of antibacterial agents in urine:
an overview of applied methods. In: Bergan T, editor. Urinary
tract infections. Basel, Freiburg, Paris, London, New York:
Karger, 1997: 74-83
98. Wagenlehner F, Tischmeyer, U, Kinzig-Schippers, M, Sörgel,
F, Wagenlehner, C, Naber, KG. Plasma concentrations, urina-
ry excretion and bactericidal activity of ciproloxacin XR
(1,000mg) versus levofloxacin (500mg) in healthy volunteers
receiving a single oral dose. 24th International Congress of
Chemotherapy; 2005 June 4-6; Manila
99. Wagenlehner FM, Kinzig-Schippers M, Tischmeyer U, et al.
Pharmacokinetics of ciprofloxacin XR (1000mg) versus
levofloxacin (500mg) in plasma and urine of male and female
healthy volunteers receiving a single oral dose. Int J An-
timicrob Agents 2006; 27 (1): 7-14
100. Boy D, Well M, Kinzig-Schippers M, et al. Urinary bactericidal
activity, urinary excretion and plasma concentrations of ga-
tifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy
volunteers after a single oral dose. Int J Antimicrob Agents
2004; 23 Suppl. 1: S6-16
101. Stein GE, Schooley S. Urinary concentrations and bactericidal
activities of newer fluoroquinolones in healthy volunteers. Int
J Antimicrob Agents 2004; 24 (2): 168-72
102. Wagenlehner FM, Kinzig-Schippers M, Tischmeyer U, et al.
Urinary bactericidal activity of extended-release ciprofloxacin
(1,000 milligrams) versus levofloxacin (500 milligrams) in
healthy volunteers receiving a single oral dose. Antimicrob
Agents Chemother 2006; 50 (11): 3947-9
© 2007 Adis Data Information BV. All rights reserved.
305
103. Allen A, Bygate E, Oliver S, et al. Pharmacokinetics and tolera-
bility of gemifloxacin (SB-265805) after administration of
single oral doses to healthy volunteers. Antimicrob Agents
Chemother 2000; 44 (6): 1604-8
104. Aminimanizani A, Beringer P, Jelliffe R. Comparative
pharmacokinetics and pharmacodynamics of the newer fluoro-
quinolone antibacterials. Clin Pharmacokinet 2001; 40 (3):
169-87
105. Vincent J, Venitz J, Teng R, et al. Pharmacokinetics and safety
of trovafloxacin in healthy male volunteers following adminis-
tration of single intravenous doses of the prodrug, alatroflox-
acin. J Antimicrob Chemother 1997; 39 Suppl. B: 75-80
106. Richard GA, Klimberg IN, Fowler CL, et al. Levofloxacin
versus ciprofloxacin versus lomefloxacin in acute pyelonephri-
tis. Urology 1998; 52 (1): 51-5
107. Naber KG, Bartnicki A, Bischoff W, et al. Gatifloxacin 200mg
or 400mg once daily is as effective as ciprofloxacin 500mg
twice daily for the treatment of patients with acute pyelone-
phritis or complicated urinary tract infections. Int J Antimicrob
Agents 2004; 23 Suppl. 1: S41-53
108. Data on file, Bayer Healthcare
109. Data on file, SmithKline Beecham
110. Persky L, Liesen D, Yangco B. Reduced urosepsis in a veterans’
hospital. Urology 1992; 39 (5): 443-5
Correspondence: Dr Florian M.E. Wagenlehner, Department
of Urology, Justus-Liebig-University Giessen, Rudolph-
Buchheim-Str. 7, D-35385 Giessen, Germany.
E-mail: wagenlehner@aol.com
Clin Pharmacokinet 2007; 46 (4)