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878Wag2015MS Urosepsis Overview
878Wag2015MS Urosepsis Overview
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ASMscience.org/MicrobiolSpectrum 1
Wagenlehner et al.
TABLE 1 Definitions
Infection: Presence of organisms in a normally sterile site that is usually, but not necessarily, accompanied by an inflammatory host response
Bacteremia: Bacteria present in blood as confirmed by culture. May be transient
Systemic inflammatory response syndrome (SIRS): Response to a wide variety of clinical insults, which can be infectious, as in sepsis, but may be
non-infectious in etiology (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 <32 mmHg (<4.3k Pa)
- WBC >12,000 cells/mm3 or <4,000 cells/mm3 or ≥10% immature (band) forms
Sepsis: Activation of the inflammatory process due to infection
Hypotension: A systolic blood pressure of <90 mmHg or a reduction of >40 mmHg 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 an 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 an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may
not be hypotensive at the time that perfusion abnormalities are measured
Refractory septic shock: Septic shock that lasts for more than 1 hour and does not respond to fluid administration or pharmacological
intervention
symptoms must be considered (Table 2). The classifica- c. refractory septic shock is defined by an absence of
tions of sepsis differentiate severity levels: response to therapy.
a. severe sepsis is defined as sepsis associated with For therapeutic purposes, the diagnostic criteria
organ dysfunction; of sepsis should identify patients at an early stage of
b. septic shock is persistence of hypoperfusion or the syndrome, prompting urologists and intensive-
hypotension despite fluid resuscitation, and care specialists to search for and treat infection, apply
Criterion I: Presence of bacteremia (positive blood culture) or clinical suspicion of sepsis. Bacteremia can be of low inoculum
(<10 bacteria/ml) or of short duration. Multiple blood cultures are recommended.
Criterion II: Systemic inflammatory response syndrome [SIRS]
Body temperature ≥38°C or ≤36°C
Tachycardia ≥90 beats/min
Tachypnea ≥20 breaths/min
Respiratory alkalosis PaCO2 ≤32 mmHg
Leukocytes ≥12,000/μl or ≤4,000/μl
Segmented neutrophils >10%
Criterion III: Multiple organ dysfunction syndrome [MODS]
Circulation: Arterial systolic blood pressure ≤90 mmHg or mean arterial blood pressure ≤70 mmHg during
≥1 hour despite adequate fluid resuscitation and adequate intravascular volume or use of
vasopressors, in order to maintain systolic blood pressure ≥90 mmHg.
Kidney: Urine production <0.5 ml/kg body weight/hour during 1 hour despite adequate fluid resuscitation.
Lung: PaO2 ≤75 mmHg (at ambient air) or PaO2/FiO2 ≤300 (acute lung injury), or PaO2/FiO2
≤200 (acute respiratory distress syndrome) at assisted ventilation [PaO2, arterial O2-partial
pressure; FiO2, inspiratory O2 concentration].
Thrombocytopenia: Platelets <80,000/μl or decrease of platelets ≥50% within 3 days.
Metabolic acidosis: Blood pH ≤7,30 or base excess ≥5 mmol/l; plasma lactate ≥1.5 fold of normal.
Encephalopathy: Somnolence, agitation, coma, confusion.
Following these criteria sepsis can be classified in three grades:
Simple sepsis Criterion I + ≥2 Criterion II Lethality
-2 Criterion II 7%
-3 Criterion II 10%
-4 Criterion II 17%
Severe Sepsis Criterion I + ≥2 Criteria II + ≥1 Criterion III per affected organ (kidney, lung, liver) lethality increases + 15% to + 20%
Septic Shock Criterion I + ≥2 Criteria II + therapy-refractory arterial hypotension ≤90 mmHg
Lethality 50% to 80%
2 ASMscience.org/MicrobiolSpectrum
Urosepsis
appropriate therapy, and monitor for organ failure and PATHOPHYSIOLOGY OF UROSEPSIS
other complications (4). Microorganisms reach the urinary tract mostly by way
of the intraluminal-ascending route, more rarely by he-
matogenous or lymphatic routes. Inflammation is the
EPIDEMIOLOGY OF UROSEPSIS physiologic response of the body to infection and is
Urinary tract infections (UTIs) can manifest in a wide mediated by the release of soluble substances by cells of
clinical range from bacteriuria with no or limited clinical the immune system. For urosepsis to be established from
symptoms, to sepsis, severe sepsis, or septic shock. In the urinary tract, the pathogens or pathogenic factors
approximately 30% of all septic patients, the infectious have to reach the bloodstream (15). The risk of bacter-
focus is localized in the urogenital tract and arises from emia is increased in severe urogenital infections, such
infections of the parenchymatous urogenital organs, as pyelonephritis and acute bacterial prostatitis (ABP),
e.g., kidneys, prostate, or testicles. This may comprise and is facilitated by obstruction of the urinary tract.
obstructive diseases of the urinary tract, such as ureteral The systemic inflammatory response syndrome (SIRS)
stones, stenosis of the collecting system, tumor for- is than triggered: an initially overwhelming proinflam-
mations, or anomalies of the urinary system. Urosepsis matory reaction, activated by mediators such as bac-
may also occur after operations in the urogenital tract. terial toxins, is accompanied by a counter-regulatory
In patients with nosocomial UTI treated in urology, the anti-inflammatory response syndrome (CARS) (16).
prevalence of urosepsis was, on average, about 12% in a Complete bacteria and components of the bacterial
multinational surveillance study (5). cell wall act as exogenous pyrogens on eukaryotic target
Severe sepsis is a critical situation with a reported cells of patients. These include lipopolysaccharides
mortality rate ranging from 20% to 50% (6–8). Severe (LPS), especially the lipid A component (endotoxin)
sepsis and septic shock are also the major causes of ad- of the outer membrane of Gram-negative bacteria; the
mission and death in intensive-care units (ICUs) (7). In peptidoglycan, teichon- or lipoteichoic acids of Gram-
the U.S., there is a steady increase of 71% in the number positive bacteria; and toxins like toxic-shock syndrome
of cases of severe sepsis, from 415,280 cases in 2003 to toxin 1 and Staphylococcus aureus toxin A (17). Many
711,736 in 2007. The total hospital costs for all patients of these factors bind to cellular receptors and co-
with severe sepsis also increased by 57%, from $15.4 receptors of the innate immune system (e.g., CD 14,
billion in 2003 to $24.3 billion in 2007 (9). Sepsis is “Toll-like receptors” TLR2 and TLR4, CD 18, and
more common in men than in women (6). In recent years, selectin) on the surface of macrophages, neutrophils,
the incidence of sepsis has increased (6, 10), but the as- endothelial cells, and others. Intracellular messenger
sociated mortality has decreased, suggesting improved molecules, such as nuclear factor kappa-light-chain-
management of patients (6, 10). Most severe sepsis cases enhancer of activated B cells (NF-κB) or protein-kinase
reported in the literature are related to pulmonary (50%) C, are activated, which induce transcription of mediator
or abdominal infections (24%), with the urogenital tract genes and thus the synthesis of numerous endogenous
accounting for only 5% (11) to 7% (12). Urosepsis, mediators, such as cytokines.
however, may still show high mortality rates of 25% to
60% in special patient groups (13). Hofmann (14) ana- Cytokines as Markers of the Septic Response
lyzed 59 patients (54% females) treated for uroseptic Cytokines are produced with different kinetics and are
shock and hospitalized over a 10-year period: 78% of classified into pro-inflammatory and anti-inflammatory
patients showed urinary obstruction as predisposing cytokines. Tumor necrosis factor (TNF)-α and interleu-
factors, mainly due to nephrolithiasis, and the remain- kin (IL)-1 are the most important pro-inflammatory
ing 22% patients also had uropathies with significant cytokines and exhibit similar biologic properties. They
impact on urodynamics. Seventeen percent of patients influence the temperature-regulatory centers in the hy-
developed urosepsis after urological interventions. pothalamus, which results in fever. They also have an
Ninety-two percent of patients needed operative inter- effect on the formatio reticularis in the brain stem that
vention and at that time 24% underwent nephrectomy. renders the patient somnolent and comatose. Release of
Of the 12% patients who died due to the critical illness, adrenocorticotrophic hormone (ACTH) in the pituitary
no intervention was performed. A consistent finding, gland is increased, which stimulates the adrenal gland.
however, is that the mortality associated with sepsis from These factors also stimulate hematopoietic growth fac-
a urinary source is substantially lower than all other tors leading to the formation of new neutrophils and the
sources. release of stored ones. The neutrophils are additionally
ASMscience.org/MicrobiolSpectrum 3
Wagenlehner et al.
activated and produce bactericidal substances, such as vasopressin in the hypothalamus and ACTH in the
proteases and oxygen radicals. B and T lymphocytes pituitary gland. The consecutive release of cortisol
are stimulated for synthesis of antibodies and cellular from the adrenal gland leads to an anti-inflammatory
immune reaction. response by suppressing NF-κB and increasing anti-
In the continuing septic process, however, apoptosis inflammatories IL-4 and IL-10 (25). The parasympa-
of B cells, CD4-helper cells, and follicular-dendritic thetic system acts via the vagal-nerve system sensing
cells cause an anti-inflammatory immune suppression, inflammation and informing specific centers in the brain.
called transient-immune paralysis (18). In the liver, the Release of acetyl-choline reduces pro-inflammatory
production of acute-phase proteins (C-reactive protein, cytokines as well as releasing high-mobility-group-box 1
α1-antitrypsin, and complement factors) is triggered. (HMGB1), a critical pro-inflammatory mediator (26,
The muscular protein is degraded and the released 27).
amino acids are used for antibody synthesis. In endo- Thus, the neuro-endocrine axis appears to be a criti-
thelial cells, the production of platelet-activating factor cal regulator of systemic inflammation important for
(PAF) and nitric oxide (NO) is triggered, leading to a fine tuning of the inflammatory response, which might
decreased vessel tone. The endothelial cells are damaged also become an important target for pharmacological
and increased permeability results. Surface receptors intervention.
of endothelial cells and neutrophils are upregulated,
increasing the mutual adhesiveness. Additionally, the
endothelial procoagulatory activity and the synthesis PATHOPHYSIOLOGICAL CONDITIONS
of a plasminogen activator-inhibitor substance is in- ALTERING RENAL FUNCTION
creased, which activates the blood-coagulation system Pyelonephritis is the most frequent cause for urosepsis.
(11, 17, 19–22). The cytokines IL-4 and IL-10, among The renal function is therefore most important in the
others, act as anti-inflammatories and inhibit the for- consideration of urosepsis (28). Impairment of renal
mation of IL-1 and TNF (11, 21). function can be acute or chronic and unilateral or bi-
All of these factors may act on target organs and are lateral. Post-renal obstruction is one of the most frequent
responsible for the local and systemic effects within the causes of urosepsis in urological cases. The obstruction
target organs (11, 19, 21, 22). Sepsis may indicate an causes sepsis on the one side and severely influences
immune system that is severely compromised and unable the pharmacokinetics of drugs, such as antibiotics, in
to eradicate pathogens or a nonregulated and excessive the urinary tract on the other side. In this context the
activation of inflammation, or both. A genetic predis- pharmacokinetics of drugs at the affected site is also
position likely explains different outcomes in septic significantly influenced by the total renal function and
patients. Mechanisms of organ failure and death in thus by the function of the contralateral kidney. Fur-
patients with sepsis remain only partially understood thermore, pharmacokinetics and the concentration of
(11). an antibiotic in the kidney is influenced by its arterial
and venous plasma concentration, the various renal
The Importance of the Neuro-Endocrine Axis (proximal and distal) tubular concentrations, the renal
The immune system and central nervous system com- concentration in tissue, and the final urine concentra-
municate and regulate each other via the autonomic tion. The renal concentration of an antibiotic in tissue
nervous system and the hypothalamo-pituitary-adreno- is complex and is a function of renal blood flow, glo-
cortical axis (23). The sympathetic system innervates merular filtration, tubular secretion and reabsorption,
all lymphoid organs and thereby modulates the immune pyelovenous- and lymphous backflow, and the number
system. Under pathological circumstances noradrena- of intact nephrons. The renal-tissue concentration of a
lin can stimulate α2-receptors on the surface of mac- drug is therefore difficult to assess; representative con-
rophages and thus stimulate release of TNF-α (24). centrations have been investigated and one of these
Stimulation of β-receptors inhibits release of pro- could be the concentrations in the renal lymph that
inflammatory cytokines. might resemble interstitial concentrations (29). Renal-
Release of pro-inflammatory cytokines in response lymph concentrations in unobstructed, normal, and
to infection stimulates hypothalamic centers activating unobstructed, but infected kidneys, have been deter-
the sympathetic-nerve system and the hypothalamo- mined for a variety of ß-lactam antibiotics, aminogly-
pituitary-adrenocortical axis, inducing the expression cosides, and nitrofurantoin. Concentrations in the renal
of corticotropin-releasing hormone (CRH) or arginine- lymph were generally lower than the corresponding
4 ASMscience.org/MicrobiolSpectrum
Urosepsis
arterial-plasma concentrations, which suggests that there obstruction with a functioning contralateral kidney.
is no concentration effect in the renal-interstitial space. One important factor of these changes is the atrial-
In acute, complete, unilateral ureteral obstruction natriuretic peptide (32).
there is still some residual glomerular filtration and tu- Using different antibiotic pharmacological models,
bular secretion present. An experimental study in dogs mainly with β-lactam agents, the following findings
(29) showed that within the first hours of obstruction, in the different settings of renal functions and renal
glomerular-filtration rate, as well as the effective renal- obstructions can be summarized (33):
plasma flow, decreased significantly to an average of
1. In the case of a severe unilateral renal insufficiency
14% in the obstructed kidney, compared to the unob-
(glomerular filtration rate 1 ml/min) but normal
structed kidney. The persisting turnover of urine is pri-
contralateral renal function (glomerular filtration
marily due to pyelovenous backflow and also, but less
rate 60 ml/min) the urine antibiotic concentrations
importantly, due to drainage into the renal lymphatics.
of both kidneys are high, whereby the impaired
Then the concentration of a substance, such as certain
kidney achieves half the urine concentration of the
antibiotics, in the renal lymph are higher than the cor-
intact kidney.
responding arterial-plasma concentrations in the acute
phase of an unilateral obstruction (first hours to first 2. In the case of a bilateral renal insufficiency, the
week) and become equal to the arterial-plasma con- urinary antibiotic concentrations significantly de-
centrations in chronic-obstructive disease (longer than 1 crease down to plasma levels in the case of severe
week) (30). impairment (glomerular filtration rate 2 ml/min).
The glomerular filtration rate is influenced by the This difference in unilateral and bilateral renal in-
balance of inward and outward pressures at the glo- sufficiency can be explained by the intact-nephron
merular arterioles and Bowman’s capsule. Inward forces theory: the single nephrons, e.g., the concentration
are significantly increased with postrenal obstruction ability, remain intact in the case of physiologic
and are the cause of reduced filtration rate (29, 31). prerenal conditions. In bilateral renal insufficiency
An increasing number of nephrons will cease filtering there is an increased offer of solutes per nephron
if the ureteral pressure exceeds one-third of the mean that results in diuresis with impaired ability for
blood pressure. The acute unilateral occlusion of a ureter concentration (34).
results in a characteristic triphasic relationship between 3. In acute obstruction, urinary concentrations of
renal blood flow and ureteral pressure. The first phase, filtered and secreted substances will at first reach a
lasting approximately 1.5 hours, shows a rise in both high plateau. If the ureteral pressure rises and
ureteral pressure and renal blood flow, followed by a exceeds one-third of the mean blood pressure, an
second phase with decline in renal blood flow and a increasing number of nephrons will cease filtering,
continued increase in ureteral pressure, lasting from resulting in decrease of glomerular filtration and
approximately 1.5 to 5 hours, followed by a third also in decrease of urinary concentrations. This
phase resulting in a further decline of renal blood flow process is very much enhanced by infection of an
accompanied by a progressive decrease in ureteral obstructed kidney with the result that, in urosepsis
pressure. Phase I is characterized by an initial afferent- due to obstruction, high doses of antimicrobials
arteriole vasodilatation followed by an efferent-arteriole mainly excreted by the kidneys are necessary.
vasoconstriction in phase II and afferent-arteriole vaso- 4. In acute unilateral obstruction the urinary antibi-
constriction in phase III. This third phase is not seen in otic concentrations of the obstructed kidney are
bilateral ureteral obstruction, which leads to a progres- almost as high as those of the normal unobstructed
sive rise in ureteral pressure despite a decrease in renal kidney, which is also due to the maximal urinary
blood flow. Single-nephron glomerular-filtration rate concentration in acute obstruction.
declines in unilateral and bilateral ureteral occlusion, 5. Even in chronic unilateral obstruction rather high
which is secondary to an increase in afferent-arteriolar urinary antibiotic concentrations are achieved, de-
resistance in unilateral occlusion, and secondary to a rise pending on the function of the contralateral kidney.
in intratubular pressure in bilateral occlusion (32). These
differences between unilateral and bilateral obstruction Although antibiotic concentration is an important
are most probably due to substances that accumulate pharmacological parameter, it does not necessarily re-
in bilateral obstruction or unilateral obstruction of a flect antibacterial activity of an antimicrobial substance
solitary kidney, but do not accumulate in unilateral at the site of infection. (see below)
ASMscience.org/MicrobiolSpectrum 5
Wagenlehner et al.
6 ASMscience.org/MicrobiolSpectrum
Urosepsis
the time the antimicrobial concentration remains above correlated directly with standard MIC. By determining
the minimum inhibitory concentration (MIC; T>MIC). the urinary-bactericidal titer (UBT), i.e., the highest
There was a significant correlation between the cumu- urinary dilution still bactericidal, pharmacokinetic and
lative T>MIC in serum and bacteriological cure, wherein pharmacodynamic parameters of an antibiotic in urine
a cumulative T>MIC of 30 hours provided a maximal are linked together. The reciprocal value of an UBT cor-
cure rate of 80% to 90% (52). responds to the ratio of urinary concentration/minimal
bactericidal concentrationurine.
Fluoroquinolones and Aminoglycosides In a study of complicated UTI and pyelonephritis, the
For drugs with concentration-dependent time-kill ac- UBTs were measured for levofloxacin and doripenem.
tivity, such as the aminoglycosides and the fluoroquino- The results showed that microbiological failures in
lones, a positive outcome appears to be more dependent patients treated with levofloxacin correlated well with
on the Cmax/MIC or AUC/MIC ratio. While it remains low urinary-bactericidal activity, whereas there was no
unclear which ratio is a better predictor of outcome, such correlation for doripenem (59). Such data evalu-
in either case a high ratio is desirable. In pharmacody- ating antibiotic activity in patients with urosepsis are
namic UTI studies of ciprofloxacin in mice infected with missing.
Escherichia coli (52), there was an obvious correlation
between reduced bacterial counts and the AUC/MIC Biofilm Infection
ratio. In severely ill patients (mainly patients with pneu- Biofilm infection plays a considerable role in urosepsis,
monia) treated with ciprofloxacin, a significant break- not only in association with urinary catheters, but also
point for probabilities of both clinical and microbiologic in scar tissue, stones, prostatitis, and in any obstructed
cures was an AUC/MIC ratio of 125 and higher, leading urinary tract (60–63). For most uropathogens, the abil-
to a significantly higher cure rate (53). In any infection ity to form biofilms has been shown (64–70). In a study
of the urogenital tract, however, a significant level of investigating virulence factors in E. coli strains causing
the bacteria (sometimes more than 106/ml) is also freely bacteremia, 53% of the strains were able to produce bio-
floating in the urine. Therefore, high urinary concen- film (71). In an in vitro biofilm-catheter infection model,
trations of the antibiotic are needed as well (52, 54, 55). kill-curves for Pseudomonas aeruginosa treated with
Antimicrobials primarily eliminated via renal excretion different antibiotic substances were investigated (72,
achieve high urinary concentrations, sometimes 100 to 73). Beta-lactam antibiotics (piperacillin, ceftazidime)
1,000 times of the concomitant serum concentrations. were not able to eradicate the biofilm-cells, even when
Theoretically, these antimicrobials represent optimal concentrations up to 128-fold the minimal-bactericidal
choices for the treatment of UTIs. Besides favorable concentrations were administered. With fluoroquino-
pharmacokinetics, however, an agent suitable for the lones (ciprofloxacin, levofloxacin), eradication was
treatment of severe UTI and urosepsis should also pro- possible within 24 hours; however, only in concentra-
vide optimal pharmacodynamic properties at the site tions that reached 32-fold the minimal-bactericidal
of infection, i.e., in the urine. Therefore, even agents concentrations (72, 73). Therefore, generally high dos-
modestly eliminated by renal mechanisms but with ages of antimicrobials need to be applied in conjunc-
high intrinsic potency (low MIC) against the causative tion with the attempt to eliminate the biofilm. If there
uropathogens, are also important considerations in is a chance to remove the biofilm, this should be done,
antimicrobial selection (56). Correlation of those con- e.g., by removing infected stones or catheters.
siderations to human data in complicated lower UTI
showed that pharmacodynamic targets representing Bacterial Spectrum in Urosepsis
90%-probability thresholds for bacterial eradication There are not many publications on the specific bacterial
were far below the 125 AUC/MIC breakpoint, suggest- spectrum in urosepsis. Mainly the bacterial spectrum of
ing that, in addition to its plasma concentration, the high complicated and nosocomially acquired UTI are taken
concentration of fluoroquinolones in the urine might as representative for urosepsis as well, which in general
have played a significant role in eradicating bacteria might be correct (74). The German septicemia study
(57). published in 2002 (75) discriminated the bacterial spec-
The antimicrobial activity of many antibiotics is, trum of blood-culture isolates according to their origin
however, reduced in urine as compared to standard and showed that if the urinary tract was the source for
growth medium, depending on pH and urinary contents the septicemia, the bacterial spectrum consisted of about
(58). Therefore, the urinary concentrations cannot be 61% E. coli, 16% other enterobacteria, 8% S. aureus,
ASMscience.org/MicrobiolSpectrum 7
Wagenlehner et al.
and 6% enterococci, underlining the predominant countries that collects routinely generated antimicrobial-
role of E. coli (Fig. 1) (75). If host defense is impaired, susceptibility testing data on invasive infections caused
less-virulent organisms such as enterococci, coagulase- by seven important bacterial pathogens. The 2011 results
negative staphylococci, or P. aeruginosa may also cause showed for E. coli 24% ciprofloxacin resistance, 9% 3rd-
urosepsis. generation cephalosporin resistance, 12% aminogly-
coside resistance, 0% carbapenem resistance, and 13%
multidrug resistance. Klebsiella pneumoniae showed
Selection of Antimicrobials 13% ciprofloxacin resistance, 8% 3rd-generation ceph-
for Empiric Therapy alosporin resistance, 8% aminoglycoside resistance,
Since effective antimicrobial therapy is best initiated 2% carbapenem resistance, and 8% multidrug resis-
during the first hour when sepsis is diagnosed, the em- tance. P. aeruginosa had 13% ciprofloxacin resistance,
piric intravenous therapy should be initiated immedi- 8% ceftazidime resistance, 3% piperacillin/tazobactam
ately after microbiological sampling. For the selection of resistance, 7% gentamicin resistance, 8% carbapenem
appropriate antimicrobials it is important to know the resistance, and 4% multidrug resistance. S. aureus
site-of-origin underlying diseases, and whether the sepsis showed 24% methicillin resistance (MRSA) and 0%
is primary or secondary and community or nosocomially vancomycin resistance (VRSA). Enterococcus faecalis
acquired. In addition, the preceding antimicrobial ther- had 1% ampicillin resistance, 5% vancomycin resis-
apies must be recorded as precisely as possible. tance, and 29% high-level gentamicin resistance, while
Resistance surveillance should always be performed Enterococcus faecium showed 96% ampicillin resis-
locally to determine the best suitable empiric treatment. tance, 37% vancomycin resistance, and 37% high-level
Surveillance studies have been performed using blood gentamicin resistance (80). Thus, comparing the 2011
cultures as the data source. For example, the resistance data to earlier reports, the numbers of MRSA have de-
to ciprofloxacin from the German blood-culture studies creased by 52% since 2004, the numbers of vancomycin-
of 1983–1985, 1991–1992, 2000–2001, and 2006– resistant E. faecalis have increased, the number of
2007 and the Paul Ehrlich resistance-surveillance study vancomycin-resistant E. faecium have remained con-
of 2007 are shown in Fig. 2), and to cefotaxime in Fig. 3) stant at a high level, and the proportion of E. coli iso-
(75–79). E. coli resistance to ciprofloxacin is currently lates that are resistant to 3rd-generation cephalosporins,
about 30% and to cefotaxime approximately 10%. ciprofloxacin, and aminoglycosides and multidrug-
The European Antibiotic Resistance Surveillance Study resistant isolates are the highest annual proportions
comprises a network of over 900 microbiological labo- reported to date (80). Taking into account that E. coli is
ratories serving some 1,500 hospitals in 33 European the most frequent pathogen causing severe UTI, it is
8 ASMscience.org/MicrobiolSpectrum
Urosepsis
FIGURE 2 Ciprofloxacin resistance from the German blood culture studies 1983–1985,
1991–1992, 2000–2001, 2006–2007, and the Paul-Ehrlich resistance surveillance study
2007. doi:10.1128/microbiolspec.UTI-0003-2012.f2
concerning that there is a continuous increase of anti- of administering a susceptible antibiotic initially in sep-
biotic resistance by E. coli. sis, the resistance threshold should therefore be below
There is currently no consensus towards a certain 10%. Depending on the local susceptibility patterns,
resistance threshold for an antibiotic to be recommended a third- or fourth-generation cephalosporin, piperacillin
for empiric treatment. Given the paramount importance in combination with a β-lactamase inhibitor (BLI), or a
FIGURE 3 Cefotaxime resistance from the German blood culture studies 1983–1985,
1991–1992, 2000–2001, 2006–2007, and the Paul-Ehrlich resistance surveillance study
2007. doi:10.1128/microbiolspec.UTI-0003-2012.f3
ASMscience.org/MicrobiolSpectrum 9
Wagenlehner et al.
carbapenem may be appropriate. In case of no or partial associated with far greater release. Whether these dif-
response in secondary urosepsis, i.e., after nosocomial ferences are clinically relevant could, however, not be
UTI (especially after urological interventions or in pa- demonstrated in a clinical study in patients with Gram-
tients with long-term indwelling urinary catheters), negative urosepsis (81).
an antipseudomonal, 3rd-generation cephalosporin or
piperacillin and BLI in combination with an amino-
glycoside or a carbapenem may be necessary to cover a SURVIVING SEPSIS CAMPAIGN GUIDELINES
broader bacterial spectrum, including multirestistant
In 2004, the Surviving Sepsis Campaign (SSC) first in-
pathogens (Tables 3 and 4). If the pretreatment history is
troduced guidelines for the management of severe sepsis
known, the same group of antimicrobials should be
and septic shock, as well as strategies for bedside im-
avoided. All alternatives have to be selected in consid-
plementation (20, 82, 83); these were updated in 2008
eration of the local susceptibility patterns. Correct dos-
(84) and 2012 (85, 86). The treatment recommendations
ing in respect to the altered systemic and, especially,
were organized in so-called sepsis bundles, such as a
renal pathophysiology in patients with urosepsis and
resuscitation bundle (tasks to begin immediately and to
length of therapy, are equally important.
be accomplished within 6 hours) and a management
Evidence from in vitro experiments and animal and
bundle (tasks to be completed within 24 hours).
human studies indicate that antibiotic therapy may in-
Key recommendations were listed by category and
duce the release of endotoxin. Antibiotics that bind to
comprise the following recommendations:
penicillin-binding protein (PBP)-2, e.g., imipenem, are
associated with little release of endotoxin, whereas Early goal-directed resuscitation of the septic patient
antibiotics that bind to PBP-3, e.g., ceftazidime, are during the first 6 hours after recognition. Early
Dosage
Antimycotic group
Azole derivatives Fluconazole 400–800 mg daily 400–800 mg daily
Voriconazole 4–6 mg/kg BWc daily 4–6 mg/kg BW daily
Pyrimidine analog Flucytosine 100–150 mg/kg BW 4 times daily
Echinocandin Caspofungin 50–70 mg daily
aIV, intravenous
bBLI, β-lactamase inhibitor
cBW, body weight
10 ASMscience.org/MicrobiolSpectrum
Urosepsis
TABLE 4 Antibiotics recommended for the treatment Administration of crystalloid-fluid resuscitation and
of urosepsis consideration of adding albumin in certain patient
groups.
Most frequent
pathogens/ Initial, empirical Fluid challenge to restore mean circulating-filling
species antimicrobial therapy Therapy duration pressure.
E. coli Cephalosporin (group 3a/b) 3–5 days after Vasopressor preference for norepinephrine to main-
Other Fluoroquinolone* defervescence or
enterobacteria control/elimination tain an initial target of mean arterial pressure ≥65
After urological of complicating mmHg and epinephrine when an additional vaso-
interventions – factor pressor is needed.
multi-resistant
pathogens Avoiding use of steroid therapy.
Pseudomonas Anti-pseudomonas active In the absence of tissue hypoperfusion, coronary ar-
spp. acylaminopenicillin/BLI tery disease, or acute hemorrhage, the hemoglobin
Proteus spp. Carbapenem
Serratia spp. ± Aminoglycoside target is 7 to 9 g/dL.
Enterobacter A low tidal volume and limitation of inspiratory-
spp.
plateau pressure strategy for acute lung injury
*Only in regions where fluoroquinolone resistance is below 10% (ALI)/acute respiratory distress syndrome (ARDS).
Application of at least a minimal amount of positive
goal-directed therapy (8) is simply a protocol de- end-expiratory pressure in acute lung injury.
rived from components that have long been recom- Head of bed elevation in mechanically ventilated
mended as standard care for the septic patient patients unless contraindicated.
to optimize hemodynamics and oxygen supply Protocols for weaning and sedation/analgesia.
(Table 5). Recently, the early goal-directed therapy
Minimizing use of either intermittent-bolus sedation
approach has been challenged by two multicenter
or continuous-infusion sedation.
studies performed in the U.S. and Australia/New
Zealand showing that protocol-based resuscitation Avoidance of neuromuscular blockers, if at all pos-
of patients in whom septic shock was diagnosed sible.
in the emergency department did not improve A protocoled approach to blood-glucose management.
outcomes (87, 88). Continuous veno-veno hemofiltration or intermittent
Blood cultures before antibiotic therapy. hemodialysis is equivalent.
Imaging studies performed promptly to confirm po- Prophylaxis for deep-vein thrombosis.
tential source of infection. Use of stress-ulcer prophylaxis to prevent upper gas-
Administration of broad-spectrum antibiotic therapy trointestinal bleeding in patients at risk.
within 1 hour of diagnosis of septic shock and se- Oral or enteral feedings.
vere sepsis without septic shock. Consideration of limitation of support where appro-
Reassessment of antibiotic therapy with microbiology priate.
and clinical data to narrow coverage, when ap-
propriate.
A usual 7 to 10 days duration of antibiotic therapy ALGORITHM MANAGEMENT OF UROSEPSIS
guided by clinical response. A rapid diagnosis of urosepsis is critical (8). Effective
Source control with attention to the balance of risks treatment eliminates the infectious focus, and improves
and benefits of the chosen method. organ perfusion. Treatment of urosepsis comprises four
basic strategies:
TABLE 5 Target parameters of early goal-directed therapy (8)
a. supportive therapy (stabilization and maintain-
Parameter Target ing blood pressure),
Central venous pressure (CVP) 8–12 mmHg b. antimicrobial therapy in the first hour,
Mean arterial pressure (MAP) 65–90 mmHg c. control or elimination of the complicating factor,
Central venous oxygen (CVO2) ≥70%
and
Hematocrit (HCT) >30%
Urine output >40 ml/h d. specific sepsis therapy (89).
ASMscience.org/MicrobiolSpectrum 11
Wagenlehner et al.
All four strategies need to be started as early as pos- and sufficient tissue oxygenation is mandatory.
sible. A diagnosis and management algorithm is there- The management of fluid and electrolyte balance
fore helpful (Fig. 4): is a crucial aspect of patient care in sepsis syn-
drome, particularly when the clinical course is
The initial patient aspect is often directive. The clini- complicated by shock. An early (immediate) goal-
cal picture of a septic patient frequently, but not directed therapy has been shown to reduce mor-
always, involves warm skin, bounding pulses, and tality in one study (8), but has been questioned
hyperdynamic circulation. If the patient is hypo- in two other studies (87, 88). Volemic expansion
volemic, has pre-existing myocardial dysfunction, and vasopressor therapy have considerable impact
or is at late stage of the septic process, hypotension, on the outcome. Early (immediate) intervention
vasoconstriction, and peripheral cyanosis may be to maintain adequate tissue perfusion and oxygen
present. The internationally accepted criteria for delivery by prompt institution of fluid therapy,
diagnosis of SIRS and sepsis (Table 1) should stabilization of arterial pressure, and provision
rapidly be checked in order to initiate further of sufficient oxygen-transport capacity are highly
investigations. effective (90) (Table 5).
If sepsis is suspected, early (i.e., first hour) supportive Additional symptoms pointing to the urogenital tract
therapy with stabilization of the blood pressure should be examined: flank pain, costovertebral
12 ASMscience.org/MicrobiolSpectrum
Urosepsis
tenderness, renal colic, pain at micturition, urinary is frequently found after removal of the indwelling
retention, and prostatic or scrotal pain. A digital- catheter, but occurs less frequently in elderly patients.
rectal examination of the prostate is therefore (91)
mandatory to rule out acute prostatitis. Urinary
analysis as well as urine and blood cultures must be Pyelonephritis
included as part of the first routine laboratory tests. The pathophysiological early alterations in pyelone-
In the case of urosepsis, the clinical evidence of phritis have recently been addressed in a uropathogenic
UTI is based on symptoms, physical examination, E. coli-induced pyelonephritis animal model, where it
sonographic and radiological features, and labo- was shown that epithelial signaling produced an in-
ratory data, such as bacteriuria and leukocyturia. crease in cellular oxygen consumption and affected mi-
Immediately after microbiological sampling of urine, crovascular flow by clotting, causing localized ischemia
blood, and suspicious secretion, tissue, and abscess (92). The subsequent ischemic damage led to actin
fluids, empirical broad-spectrum antibiotic therapy re-arrangement and epithelial sloughing, leading to
should be instigated parenterally. paracellular bacterial movement. A denuded tubular-
If urosepsis is the putative diagnosis, sonographic basement membrane was able to hinder immediate dis-
examination of the urogenital organs should be semination of bacteria, giving the host time to isolate
followed, including sonographic examination of the infection by clotting. Interestingly, suppression of
the prostate to rule out prostatic abscess. clotting by heparin treatment caused fatal urosepsis
(92). Clinically, these findings may be relevant in anti-
Further radiographic investigations (CT scan; urogra-
biotic delivery in pyelonephritis patients and to the use
phy) of the urinary tract are generally applied to
of anticoagulants in sepsis and should therefore be
specify the complicating factor.
followed up in clinical studies.
If a complicating factor warranting treatment is Clinical symptoms of pyelonephritis are unilateral
identified, control and/or removal of the compli- or bilateral flank pain, and systemic symptoms such as
cating factor should follow immediately. Drainage fever (>38°C), chills, or malaise. Focal nephritis is lim-
of any obstruction in the urinary tract and removal ited to one or more renal lobules, comparable to lobular
of foreign bodies, such as urinary catheters or pneumonia. Ultrasonographic findings are of a circum-
stones, may themselves cause resolution of symp- scribed lesion with interrupted echoes, which break
toms and lead to recovery. These are key com- through the normal cortex-medulla organization. The
ponents of the strategy. This condition is an CT scan shows typical wedge-shaped, poorly limited
absolute emergency. The way by which the com- areas of diminished sonographic density. As differential
plicating factor is controlled should be as least diagnoses, renal abscess, tumor, and renal infarction
invasive as possible. The definitive elimination must be taken into account. Emphysematous pyelone-
of the complicating factor can be performed after phritis characteristically shows gas formation in the re-
days or weeks, until the general condition of the nal parenchyma and perirenal space. Diabetes mellitus
patient has improved. or obstructive renal disease are predisposing factors. The
In parallel with the urological control of the septic most frequently isolated organisms are E. coli, Klebsiella
focus, further intensive medical treatment encom- pneumoniae, and Enterobacter cloacae. Fermentation
passing specific sepsis therapy should be instigated. of glucose in Enterobacteriaceae occurs via two different
metabolic pathways: mixed-acid fermentation and the
butylene-glycol pathway. Organisms of the Klebsiella-
Enterobacter-Hafnia-Serratia group, and to a lesser
SPECIAL CLINICAL PICTURES OF extent E. coli, use the butylene-glycol pathway and
SEVERE URO-GENITAL INFECTIONS produce copious amounts of CO2, which appears clini-
Cystitis cally as gas formation (93). Aggravated by diminished
Cystitis is frequently limited to the bladder mucosa and tissue perfusion, the contralateral side is often affected
hence shows no systemic signs or symptoms. An as- as well.
cending infection can, however, clinically result. Cystitis
in the intensive-care setting is almost exclusively cath- Renal and Perirenal Abscess
eter associated and can cause hematuria, ascending Clinical symptoms are rigors, fever, back or abdominal
infection, and acute prostatitis. Spontaneous elimination pain, flank tenderness, mass lesion and redness of the
ASMscience.org/MicrobiolSpectrum 13
Wagenlehner et al.
14 ASMscience.org/MicrobiolSpectrum
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ASMscience.org/MicrobiolSpectrum 15
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