REVIEW ARTICLE

Clin Pharmacokinet 2007; 46 (4): 291-305 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 2 Urologic Clinic, Justus-Liebig-University, Giessen, Germany 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). Nevertheless, the underlying UTI is almost exclusively a complicated one with involvement 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 resuscitation. 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.

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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 pharmacodynamic 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 urological interventions, optimal catheter care and optimal strategies to prevent nosocomial UTI may be able to reduce the frequency of urosepsis.

1. Epidemiology of Urosepsis Urinary tract infections (UTIs) can manifest as bacteriuria with limited clinical symptoms, sepsis or severe sepsis, depending on localised or systemic extension. In 2030% of all patients with sepsis, the infectious focus is localised in the urogenital tract.[1,2] Frequent causes of urosepsis are obstructive diseases of the urinary tract, such as ureteral stones, anomalies, 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 ranging 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 mortality rate has decreased, suggesting improved management of patients.[3,5] In an evaluation of patients with sepsis, it was shown that those with a designated 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 2007 Adis Data Information BV. All rights reserved.

lations[7] or in patients with inadequate management. The bacterial spectrum in urosepsis may consist of 50% Escherichia coli, 15% Proteus spp., 15% Enterobacter and Klebsiella spp., 5% Pseudomonas aeruginosa and 15% Gram-positive organisms, according to different surveillance studies.[8] If host defence is impaired, less virulent organisms such as enterococci or P. aeruginosa may also cause urosepsis. 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 complicated/nosocomial UTIs also encompass an increasing number of resistant and multiresistant pathogens. 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 sepsis with a suspected source in the urinary tract.[9,10] To guide adequate empirical antibacterial therapy in urosepsis, the local susceptibility profile of complicated UTIs must constantly be evaluated.
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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 manoeuvres. Patients who are more likely to develop urosepsis include elderly patients, diabetics, immunosuppressed patients such as transplant recipients, patients receiving cancer chemotherapy or corticosteroids, and patients with acquired immunodeficiency syndrome. However, all patients can be affected by bacterial species capable of inducing inflammation 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
Table I. Clinical diagnostic criteria of sepsis and septic shock[11,12] Disorder Infection Bacteraemia Systemic inflammatory response syndrome Definition

and radiological features, and laboratory data such as bacteriuria and leukocyturia. The following definitions apply (table I): Sepsis is a systemic response to infection. The symptoms of systemic inflammatory response syndrome (SIRS), which were initially considered to be mandatory for the diagnosis of sepsis,[11,13] are now considered to be alerting symptoms.[12] Many other clinical or biological symptoms 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-

Presence of organisms in a normally sterile site that is usually, but not necessarily, accompanied by an inflammatory host response Bacteria present in the blood as confirmed by culture. May be transient Response to a wide variety of clinical insults, which can be infectious, as in sepsis, but may be non-infectious in aetiology (e.g. burns, pancreatitis). This systemic response is manifested by two or more of the following conditions: temperature >38C or <36C 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 Activation of the inflammatory process due to infection Systolic blood pressure <90mm Hg or reduction of >40mm Hg from baseline in the absence of other causes of hypotension 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 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

Sepsis Hypotension Severe sepsis

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.

Refractory septic shock

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struction. SIRS is then triggered: an initially proinflammatory reaction, activated by mediators such as bacterial toxins, is accompanied by a counterregulatory anti-inflammatory response syndrome (CARS). Pro-inflammatory cytokines from stimulated macrophages (e.g. tumour necrosis factor [TNF]-, 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 intravasal volume. The mean arterial blood pressure falls. In the pulmonary circulation, pulmonary vascular resistance may rise because of lowered left ventricular compliance and consecutive dilatation. Besides increased capillary permeability, rheologic disturbances and arteriovenous shunts, which diminish organ perfusion, inflammatory mediators such as TNF, 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

3.2 Procalcitonin is a Potential Marker of Sepsis

Procalcitonin is the propeptide of calcitonin but is devoid of hormonal activity. Normally, procalcitonin levels are undetectable in healthy humans. During severe generalised infections (bacterial, parasitic and fungal) with systemic manifestations, procalcitonin levels may rise to >100 ng/mL. In contrast, during severe viral infections or inflammatory reactions of non-infectious origin, procalcitonin levels show only a moderate increase or no increase. The exact site of procalcitonin production during sepsis is not known. Procalcitonin monitoring may be useful in patients who are likely to develop SIRS of infectious origin. High procalcitonin levels, or an abrupt increase in procalcitonin 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 status.[18] 4. Pathophysiological Conditions Altering Renal Function Impairment of renal function can be acute or chronic, or unilateral or bilateral. Postrenal obstruction 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 pharmacokinetics of a drug in the kidney are influenced by the arterial plasma concentration, the renal plasma concentration, 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 reabsorption, pyelovenous- and lymphous backflow, and the number of intact nephrons. The renal tissue concentration of a drug is therefore difficult to assess; representative concentrations have been investigated, and one of those could be the concentrations in the renal lymph which might resemble interstitial
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Cytokines are heavily involved in the pathogenesis of sepsis syndrome. They are peptides that regulate the amplitude and duration of the host inflammatory response. They are released from various cells, including monocytes, macrophages and endothelial cells, in response to various infectious stimuli such as peptidoglycans or lipopolysaccharides binding 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 inflammatory response. The complex balance between pro- and anti-inflammatory responses is modified in severe sepsis. An immunodepressive phase follows the initial 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 patients. The mechanisms of organ failure and death in patients with sepsis remain only partially understood.[4]
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concentrations.[19] Renal lymph concentrations in unobstructed normal kidneys and unobstructed but infected kidneys have been determined for a variety of -lactam antibacterials, aminoglycosides and nitrofurantoin. Concentrations in the renal lymph were generally lower than the corresponding arterial plasma concentrations, which suggests that there is no concentration effect in the renal interstitial space.[20] In acute total unilateral ureteral obstruction, however, there is still some glomerular filtration and renal plasma flow present. In an experimental study in dogs,[19] it was shown that the glomerular filtration 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 turnover of urine is due primarily to pyelovenous backflow and also, but less importantly, due to drainage into the hilar lymph. The concentrations of a clearance 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 (longer than 1 week).[21] The glomerular filtration rate is influenced by the balance of inward and outward pressures at the glomerular arterioles and Bowmans capsule. Inward forces are significantly increased with postrenal obstruction and are the cause of a reduced filtration rate.[19,22] An increasing number of nephrons will cease filtering if the ureteral pressure exceeds one-third of the mean blood pressure. Acute unilateral occlusion of a ureter results in a characteristic triphasic relationship between renal blood flow and ureteral pressure. The first phase, lasting approximately 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 ureteral 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
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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 unilateral and bilateral ureteral occlusion, which is secondary to an increase in afferent arteriolar resistance in unilateral occlusion and secondary to a rise in intratubular pressure in bilateral occlusion.[23] These differences between unilateral and bilateral obstruction are most probably due to substances that accumulate in bilateral obstruction or unilateral obstruction of a solitary kidney but do not accumulate in unilateral obstruction with a functioning contralateral 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 concentrations. Most aminoglycosides, tetracyclines and sulfonamides are excreted exclusively by glomerular filtration; most -lactams and quinolones additionally undergo tubular secretion and reabsorption. Apart from renal clearance, protein binding, extrarenal excretion and metabolism are also important for urinary concentration. Mathematical models were calculated for an antibacterial 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 contralateral renal function (glomerular filtration 60 mL/minute), the urinary antibacterial concentrations 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 impairment (glomerular filtration 2 mL/minute). This difference in unilateral and bilateral renal insufficiency can be explained by the intact-nephron theory. The single nephrons (e.g. the concentration abiliClin Pharmacokinet 2007; 46 (4)

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ty) remain intact in the case of physiological prerenal 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 concentrations of the obstructed kidney are almost as high as those of the normal unobstructed kidney, which is also due to the maximal urinary concentration 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: adjunctive measures, control or elimination of the complicating 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

Recombinant activated protein C (drotrecogin ) 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 graded according to a careful evidence-based methodology 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 catheters or stones, may themselves cause resolution of symptoms and lead to recovery. These are key components 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

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 expansion and vasopressor therapy have a considerable impact on the outcome. Early intervention with appropriate measures to maintain adequate tissue perfusion 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 hydrocortisone 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 surgery.[31]
2007 Adis Data Information BV. All rights reserved.

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 crosscontamination 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 bacteraemia 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 therapy therefore needs to follow certain rules,[44] which may be based upon the expected bacterial spectrum, the institutional specific resistance rates and the individual patients requirements. Initial empirical treatment should provide broad antibacterial coverage and should later be adapted on the basis of culture results. To cover a broad spectrum, combination therapy may be applied.[45] If enterobacteria are
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expected, a third-generation cephalosporin (e.g. ceftriaxone or cefotaxime) can be used in combination with an aminoglycoside. In the case of Pseudomonas spp., acylaminopenicillins (e.g. azlocillin), piperacillin in combination with a -lactamase-inhibitor, 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. Additionally, 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 antibacterial 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 concomitant serum concentrations) [e.g. ampicillin/ sulbactam, cefuroxime, gatifloxacin, levofloxacin] theoretically represent optimal choices for the treatment of UTIs. But besides favourable pharmacokinetics, an agent suitable for the treatment of severe complicated UTI should also provide optimal pharmacodynamic properties at the site of infection, i.e. urinary bactericidal activity. Thus, even for agents that are modestly eliminated by renal mechanisms, high intrinsic potency (minimum inhibitory concentration [MIC]) against the most common uropathogens (e.g. ciprofloxacin), is also an important consideration in antibacterial selection.[49] Agents whose antibacterial activity is compromised by changes in the urinary pH, such as fluoroquinolones, should be administered in doses high enough to compensate for the possible negative influence on activity by the urinary pH. If the infection involves renal tissues or the patient has urosepsis, adequate serum concentrations are necessary to produce high tissue concentrations, thereby necessitating administration of high-dose intravenous antibacterials. Even in uncomplicated
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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 concentrations, the specific tissue architecture, the pharmacokinetic 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 urinary 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 killcurves of P. aeruginosa in a biofilm-catheter infection model. -lactam antibacterials (piperacillin, ceftazidime) were not able to eradicate the biofilm cells, even when concentrations 128 times the minimal bactericidal concentrations were administered. With fluoroquinolones (ciprofloxacin, levofloxacin), eradication was possible, but only in concentrations that reached 32- to 64-fold the minimal bactericidal concentrations.[65,66] Therefore, in general, high dosages of antibacterials need to be applied 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 relatively scarce, at least one recent study has documented that therapeutic success following -lactam therapy depends on the time during which the antimicrobial concentration remains above the MIC (T>MIC). A recent data analysis by Frimodt-Mller[47] reported that there was a significant correlation between the cumulative T>MIC in serum and bacteriological cure, wherein a cumulative T>MIC of 30 hours provided a maximal cure rate of 8090%. The investigators postulated that the reason why -lactams have often not provided successful outcomes in the treatment of UTIs compared with other antibacterial classes is most likely improper dosing (i.e. dose too low and infrequent dosage interval). For drugs with concentration-dependent time-kill activity, such as the aminoglycosides and the fluoroClin Pharmacokinet 2007; 46 (4)

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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 quinolones, the Cmax/MIC in serum and AUC/MIC in serum ratios are highest for ciprofloxacin against P. aeruginosa.[67] For other Gram-negative infections, the pharmacodynamic properties of the available 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 cortex.[47] Further pharmacodynamic research is needed in order to determine the optimal dosages of all antibacterials used to treat serious UTIs. Appropriate dosing is especially important to minimise the development of resistance and to maintain antibacterial efficacy. For patients with serious UTIs, higher than approved doses may be needed, especially 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 concentration (MPC) could be a suitable parameter for inclusion in the selection of appropriate agents for difficult-to-treat infections. The MPC is a novel susceptibility parameter designed to minimise the selection of first-step resistant mutants present in large (1010 CFU/mL) or heterogeneous bacterial populations, 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
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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 Enterobacteriaceae 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 associated 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 patients, using current diagnostic criteria. Moreover, the findings of these trials are often difficult to compare or interpret because of differing or incomplete definitions of the complicated condition. Although 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 ciprofloxacin in serious UTI employed the conventional twice-daily tablet,[71,77-83] while one recent preliminary 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 excellent bacteriological (>84%) and clinical cure rates (>90%). As expected, all of these trials demonstratClin Pharmacokinet 2007; 46 (4)

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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 follow-up visit (59 days post-therapy) with ciprofloxacin 500 mg twice daily compared with the aminoglycoside regimen (p = 0.0005). The response rates were similar between the two treatment groups at the long-term follow-up visit (2830 days post-therapy). In this trial, 75% of P. aeruginosa isolates were eradicated at short-term follow-up by both the ciprofloxacin and aminoglycoside regimens, although 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 biofilms and the fact that catheters could not be removed 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 gatifloxacin (400mg once daily) for 710 days in 288 adult patients with complicated UTI. Approximately onethird of patients had more than one complicating factor (e.g. impaired bladder emptying) at study entry. E. coli and K. pneumoniae were the predominant causative baseline pathogens for almost twothirds of patients. As in many clinical trials, patients whose pretreatment pathogen was resistant to either drug therapy were excluded from the efficacyevaluable population. Bacteriological and clinical outcomes were comparable between the two treatments. At the test of cure visit (59 days posttherapy), 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 persistent 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 quinolone-resistant bacteria (Alcaligenes faecalis and
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P. aeruginosa). All five ciprofloxacin-treated patients 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-ofcure (411 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 efficacy of fluoroquinolones for treatment of serious UTIs, including ciprofloxacins efficacy against P. aeruginosa. Mombelli et al.[75] investigated the efficacy of oral ciprofloxacin (500mg twice daily) versus intravenous ciprofloxacin (200mg twice daily) as empirical therapy for 141 patients with community-acquired and nosocomial complicated UTIs or severe pyelonephritis. Only patients with severe sepsis (defined as the presence of infection-related organ dysfunction) were excluded. Resistance to ciprofloxacin was found for 11 baseline organisms (8%), including five Enterococcus spp. and one each of P. aeruginosa, E. coli, Enterobacter spp., Staphylococcus aureus, coagulase negative staphylococci, and Candida albicans. This study found that empirical oral ciprofloxacin was bacteriologically and clinically as effective as intravenous ciprofloxacin for management of serious UTIs, including bacteraemia, in patients without severe sepsis, obstruction or renal foci of suppuration. The rates of bacteriological failure or unsatisfactory clinical response were extremely low (2% and 3%, respectively, for intravenous administration vs 3% and 4%, respectively, for oral administration). Importantly, no infection-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 availability 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
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Table II. Mean single-dose pharmacokinetic parameters of different fluoroquinolones at relatively high dosages Fluoroquinolone Ciprofloxacin XR Levofloxacin Gatifloxacin Gemifloxacin Moxifloxacin Trovafloxacinb a b AUC. Alatrofloxacin. Dose (mg) 1000 500 400 800 400 200 Route of administration Oral Oral Oral Oral Oral Intravenous Cmax (mg/L) 3.3 6.2 3.4 4.3 4.3 2.3 t1/2 (h) 8.2 6.4 6.5 8.0 9.1 12.3 Mean urinary excretion (%) 41 80 81 39 20 10 AUC36h (g h/mL) 19.5 47.8 33.3 31.4 39.3a 29.2 Reference 99 99 100 103,104 96 105

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 automatically 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 bacteriological response. In fact, the clinical response to ciprofloxacin was satisfactory in six of seven patients with ciprofloxacin-resistant pathogens, including two episodes of bacteraemia. Although this study was not large, it provides compelling evidence that both intravenous and oral ciprofloxacin are effective in the initial treatment of patients with serious UTIs, including nosocomially acquired infections. 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 antibacterial activity are more important. Fluoroquinolones differ in their pharmacokinetic properties[96] and antibacterial activity.[97] The urinary concentration 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. Various fluoroquinolones have thus been compared with each other.
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Selected pharmacokinetic studies of fluoroquinolones 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 importance of special urinary parameters such as the UBT for the assessment of antibacterial substances suitable for the treatment of UTI. In a randomised cross-over study in 12 volunteers, 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 UBTtime curve within the first 24 hours showed statistically significant differences only for P. mirabilis in favour of extended-release ciprofloxacin, and for S. aureus and S. saprophyticus in favour of levofloxacin. Because levofloxacin shows double the excretion rate of ciprofloxacin (levofloxacin approximately 80%, ciprofloxacin approximately 40%),[99] double the dose of ciprofloxacin is necessary to achieve urinary activity (UBTs) comparable to that achieved with levofloxacin. Another randomised cross-over study in 12 volunteers compared single oral doses of gatifloxacin 400mg and ciprofloxacin 500mg.[100] Again, gatifloxacin showed double the excretion rate of ciprofloxacin (gatifloxacin approximately 80%,
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ciprofloxacin approximately 40%). UBTs were determined 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 gatifloxacin (MIC). A different cross-over study in volunteers compared single oral doses of levofloxacin 250mg, gatifloxacin 400mg, moxifloxacin 400mg and trovafloxacin 200mg.[101] Urinary concentrations were highest with gatifloxacin followed by levofloxacin, moxifloxacin and trovafloxacin. Urinary bactericidal activity was determined against levofloxacin-susceptible and moderately-susceptible 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 exhibited prolonged urinary bactericidal activity (6 hours) against all study isolates, whereas moxifloxacin failed to show prolonged urinary bactericidal activity against both Pseudomonas strains, and trovafloxacin failed to show this activity against all moderately susceptible strains, with the exception of E. faecalis. Therefore those fluoroquinolones with very limited urinary excretion (<40%) [moxifloxacin, trovafloxacin] showed inferior results in this ex vivo pharmacokinetic/pharmacodynamic study design. Fluoroquinolones with intermediate urinary excretion rates (ciprofloxacin) showed comparable results only in those strains where the MICs are favourable in comparison with highly excreted fluoroquinolones (levofloxacin, gatifloxacin). Otherwise, the administered daily dose needs to be increased accordingly.
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In clinical studies, newer fluoroquinolones were compared with ciprofloxacin 500mg twice daily as a standard treatment in the oral treatment of complicated UTI. Whereas levofloxacin 250mg once daily[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 moxifloxacin 400mg once daily (urinary excretion 20%)[108] or gemifloxacin 320mg once daily (urinary excretion 30%)[109] were compared with ciprofloxacin. All four newer fluoroquinolones showed almost complete bioavailability after oral administration, with subsequent good corresponding plasma concentrations. The lower urinary concentrations, and hence lower urinary antibacterial activity, of moxifloxacin and gemifloxacin had the consequence that these two compounds did not achieve approval for treatment of complicated UTI by the regulatory bodies. 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 therapy 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 sensitive uropathogens during the overall dosing interval in ICU patients with normal renal function. The investigators concluded that considering the major pharmacodynamic determinants of the concentration-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 treatment of catheter-related and severe lower UTIs not only against sensitive microorganisms, but probably also whenever microorganisms that are usually considered as intermediate susceptible or resistant to levofloxacin may be involved. The resistance levels of fluoroquinolones against uropathogens, however, are constantly rising to levels where fluoroquiClin Pharmacokinet 2007; 46 (4)

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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-acquired and nosocomial infection (2040%). Sepsis initiates the cascade that progresses to severe sepsis and then septic shock in a clinical continuum. Prevention of urosepsis can mainly be achieved by preventing nosocomial UTI.[110] The most effective methods to prevent nosocomial urosepsis are basically the same as those used to prevent other nosocomial infections: Isolation of all patients infected with multi-resistant organisms to avoid cross-infection. Prudent use of antibacterial agents, both in prophylaxis and in treatment of established infections, to avoid selection of resistant strains. Antibacterial 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 urinary tract obstruction until the patient is stabilised. Attention to simple everyday techniques to assure 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 prophylaxis. 8. Conclusion Sepsis syndrome in urology remains a serious situation with a mortality rate as high as 2040%.
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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 timely treatment of urinary tract disorders, e.g. obstruction, 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 prophylaxis and therapy in a prudent and well accepted manner. Acknowledgements
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Correspondence: Dr Florian M.E. Wagenlehner, Department of Urology, Justus-Liebig-University Giessen, RudolphBuchheim-Str. 7, D-35385 Giessen, Germany. E-mail: wagenlehner@aol.com

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