Pharmacokinetic Characteristics of Antimicrobials and Optimal Treatment of Urosepsis

Clin Pharmacokinet 2007; 46 (4): 291-305REVIEW ARTICLE 0312-5963/07/0004-0291/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Pharmacokinetic Characteristics ofAntimicrobials and OptimalTreatment of UrosepsisFlorian M.E. Wagenlehner,1 Wolfgang Weidner1 and Kurt G. Naber2

1 Urologic Clinic, Justus-Liebig-University, Giessen, Germany2 Technical University of Munich, Munich, Germany

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2911. Epidemiology of Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2922. Definition and Clinical Manifestation of Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2933. Pathophysiology of Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

3.1 Cytokines as Markers of the Septic Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2943.2 Procalcitonin is a Potential Marker of Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

4. Pathophysiological Conditions Altering Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2945. Treatment of Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

5.1 Adjunctive Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2965.2 Control of the Complicating Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2965.3 Antibacterial Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

5.3.1 General Principles of Antibacterial Therapy in Patients with Urosepsis . . . . . . . . . . . . . . . . 2965.3.2 Parameters for Antibacterial Treatment in Urosepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

5.4 Fluoroquinolone Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2986. Relationship between Renal Excretion and Bactericidal Titres of Different Fluoroquinolones . . . . . . 3007. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3028. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

Urosepsis accounts for approximately 25% of all sepsis cases and may developAbstractfrom a community-acquired or nosocomial urinary tract infection (UTI). Never-theless, the underlying UTI is almost exclusively a complicated one with involve-ment of the parenchymatous urogenital organs (e.g. kidneys, prostate) and mostlyassociated with any kind of obstructive uropathy. If urosepsis originates from anosocomial infection, a broad spectrum of Gram-negative and Gram-positivepathogens have to be expected, which are often multiresistant.

In urosepsis, as in other types of sepsis, the severity of sepsis depends mostlyupon the host response. The treatment of urosepsis follows the generally acceptedrules of the ‘Surviving Sepsis’ campaign guidelines. Early normalisation of bloodpressure and early adequate empirical antibacterial therapy with optimised dosingare equally important to meet the requirements of early goal-directed therapy. Inmost cases of urosepsis, early control of the infectious focus is possible and asimportant. Optimal supportive measures need to follow the early phase of resusci-tation. To lower mortality from urosepsis, an optimal interdisciplinary approachbetween intensive care, anti-infective therapy and urology is essential, assisted byeasy access to the necessary laboratory and imaging diagnostic procedures.

292 Wagenlehner et al.

Although most antibacterials achieve high urinary concentrations, there areseveral unique features of complicated UTI, and thus urosepsis, that influence theactivity of antibacterial substances: (i) renal pharmacokinetics differ in unilateraland 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 mayincrease the minimal inhibitory concentrations (MIC) of the antibacterials at thesite of infection by several hundred folds. Assessment of antibacterial pharmaco-dynamic properties in such situations should take into account not only the MIC asdetermined in vitro and the plasma concentrations of the free (unbound) drug,which are the guiding principles for many infections, but also the actual renalexcretion and urinary bactericidal activity of the antibacterial substance. In thetreatment of urosepsis, it is important to achieve optimal exposure to antibacterialsboth in plasma and in the urinary tract. The role of drugs with low renal excretionrates is therefore limited.

Since urosepsis quite often originates from catheter-associated UTI and uro-logical interventions, optimal catheter care and optimal strategies to preventnosocomial UTI may be able to reduce the frequency of urosepsis.

1. Epidemiology of Urosepsis lations[7] or in patients with inadequate manage-ment. The bacterial spectrum in urosepsis may con-sist of 50% Escherichia coli, 15% Proteus spp., 15%Urinary tract infections (UTIs) can manifest asEnterobacter and Klebsiella spp., 5% Pseudomonasbacteriuria with limited clinical symptoms, sepsis oraeruginosa and 15% Gram-positive organisms, ac-severe sepsis, depending on localised or systemiccording to different surveillance studies.[8] If hostextension.defence is impaired, less virulent organisms such asIn 20–30% of all patients with sepsis, the infec-

tious focus is localised in the urogenital tract.[1,2] enterococci or P. aeruginosa may also cause urosep-Frequent causes of urosepsis are obstructive diseas- sis.es of the urinary tract, such as ureteral stones, anom- Unfortunately, the published resistance ratesalies, stenosis or tumour. Urosepsis may occur after

have not been determined specifically in patientsoperations in the urogenital tract or after infections

with urosepsis, but instead have been determinedof the parenchymatous organs.mainly in patients with complicated/nosocomialSevere sepsis has a reported mortality rate rang-UTIs. However, there is no reason to believe thating from 20% to 42%.[3] Most severe sepsis reportedisolates causing urosepsis would be less resistant.in the literature is related to pulmonary (50%) orThe resistance patterns found in adults with compli-abdominal infections (24%), with UTIs accountingcated/nosocomial UTIs also encompass an increas-for approximately 5%.[4] Sepsis is more common ining number of resistant and multiresistant patho-men than in women.[3] In recent years, the incidencegens. Resistance against the quinolones in E. coli,of sepsis has increased[3,5] but the associated mortal-for example, is rapidly rising to alarming levelsity rate has decreased, suggesting improved man-worldwide, making this class of drugs increasinglyagement of patients.[3,5] In an evaluation of patientsinappropriate for empirical treatment of severe sep-with sepsis, it was shown that those with a designat-sis with a suspected source in the urinary tract.[9,10]ed urinary source of sepsis had a significantly lowerTo guide adequate empirical antibacterial therapy inbaseline risk of death (30%) than patients with otherurosepsis, the local susceptibility profile of compli-causes of sepsis (54%).[6] Urosepsis may, however,

result in high mortality rates in special patient popu- cated UTIs must constantly be evaluated.

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (4)

Optimisation of Urosepsis Treatment 293

2. Definition and Clinical Manifestation and radiological features, and laboratory data suchof Urosepsis as bacteriuria and leukocyturia. The following defi-

nitions apply (table I):• Sepsis is a systemic response to infection. TheIn urosepsis, as in other types of sepsis, the

symptoms of systemic inflammatory responseseverity of sepsis depends mostly upon the hostsyndrome (SIRS), which were initially consid-response. Urosepsis predominantly depends on localered to be ‘mandatory’ for the diagnosis of sep-factors, such as urinary tract calculi, obstruction atsis,[11,13] are now considered to be alerting symp-any level in the urinary tract, congenital uropathies,toms.[12] Many other clinical or biological symp-neurogenic bladder disorders or endoscopic ma-toms must be considered.noeuvres. Patients who are more likely to develop

• Severe sepsis is sepsis associated with organurosepsis include elderly patients, diabetics, immu-dysfunction.nosuppressed patients such as transplant recipients,

• Septic shock is persistence of hypoperfusion orpatients receiving cancer chemotherapy or corticos-hypotension despite fluid resuscitation.teroids, and patients with acquired immunodeficien-

• Refractory septic shock is defined by absence ofcy syndrome. However, all patients can be affecteda response to therapy.by bacterial species capable of inducing inflamma-

tion within the urinary tract.3. Pathophysiology of UrosepsisFor therapeutic purposes, the diagnostic criteria

of sepsis should identify patients at an early stage ofthe syndrome, prompting urologists and intensive Microorganisms reach the urinary tract by way ofcare specialists to search for and treat infection, the ascending, haematogenous or lymphatic routes.apply appropriate therapy, and monitor for organ For urosepsis to be established, the pathogens havefailure and other complications. In the case of to reach the bloodstream. The risk of bacteraemia isurosepsis, the clinical evidence of UTI is based on increased in severe UTIs, such as pyelonephritis andthe symptoms, physical examination, sonographic acute bacterial prostatitis, and is facilitated by ob-

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

Disorder Definition

Infection Presence of organisms in a normally sterile site that is usually, but not necessarily, accompaniedby an inflammatory host response

Bacteraemia Bacteria present in the blood as confirmed by culture. May be transient

Systemic inflammatory response Response to a wide variety of clinical insults, which can be infectious, as in sepsis, but may besyndrome non-infectious in aetiology (e.g. burns, pancreatitis). This systemic response is manifested by two

or more of the following conditions:temperature >38°C or <36°Cheart rate >90 beats/minrespiratory rate >20 breaths/min or PaCO2 <32mm Hg (<4.3 kPa)white blood count >12 000 cells/mm3 or <4000 cells/mm3 or ≥10% immature (band) forms

Sepsis Activation of the inflammatory process due to infection

Hypotension Systolic blood pressure <90mm Hg or reduction of >40mm Hg from baseline in the absence ofother causes of hypotension

Severe sepsis Sepsis associated with organ dysfunction, hypoperfusion or hypotension. Hypoperfusion andperfusion abnormalities may include but are not limited to lactic acidosis, oliguria or acutealteration of mental status

Septic shock Sepsis with hypotension despite adequate fluid resuscitation along with the presence of perfusionabnormalities that may include but are not limited to lactic acidosis, oliguria, or acute alteration inmental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensiveat the time when perfusion abnormalities are measured

Refractory septic shock Septic shock that lasts >1h and does not respond to fluid administration or pharmacologicalintervention

PaCO2 = partial pressure of carbon dioxide in arterial blood.



struction. SIRS is then triggered: an initially pro- 3.2 Procalcitonin is a Potential Markerof Sepsisinflammatory reaction, activated by mediators such

as bacterial toxins, is accompanied by a counter-Procalcitonin is the propeptide of calcitonin butregulatory anti-inflammatory response syndrome

is devoid of hormonal activity. Normally, pro-(CARS). Pro-inflammatory cytokines from stimu-calcitonin levels are undetectable in healthylated macrophages (e.g. tumour necrosis factorhumans. During severe generalised infections (bac-[TNF]-α, interleukin [IL]-1 and IL-6) damage organterial, parasitic and fungal) with systemic manifesta-function, directly or indirectly, via secondarytions, procalcitonin levels may rise to >100 ng/mL.mediators. Inducible nitric oxide synthetase causesIn contrast, during severe viral infections or inflam-loss of vessel tone in arterioles and venules of thematory reactions of non-infectious origin, pro-systemic circulation and thus leads to low systemiccalcitonin levels show only a moderate increase orvascular resistance and venous pooling of the in-no increase. The exact site of procalcitonin produc-travasal volume. The mean arterial blood pressuretion during sepsis is not known. Procalcitonin moni-

falls. In the pulmonary circulation, pulmonary vas-toring may be useful in patients who are likely to

cular resistance may rise because of lowered left develop SIRS of infectious origin. High pro-ventricular compliance and consecutive dilatation. calcitonin levels, or an abrupt increase in pro-Besides increased capillary permeability, rheologic calcitonin levels in these patients, should prompt adisturbances and arteriovenous shunts, which di- search for the source of infection. Procalcitonin mayminish organ perfusion, inflammatory mediators be useful in differentiating between infectious andsuch as TNFα, nitric oxide, endotoxin or IL-1 can non-infectious causes of a severe inflammatory sta-damage cells directly by interfering with oxidative tus.[18]

cellular metabolism.[14]

4. Pathophysiological ConditionsAltering Renal Function3.1 Cytokines as Markers of the

Septic ResponseImpairment of renal function can be acute or

chronic, or unilateral or bilateral. Postrenal obstruc-Cytokines are heavily involved in the pathogene- tion is one of the most frequent causes of urosepsis

sis of sepsis syndrome. They are peptides that regu- in urological cases. In this instance, the obstructionlate the amplitude and duration of the host inflam- is the cause of the sepsis on one side and severelymatory response. They are released from various influences the pharmacokinetics of drugs such ascells, including monocytes, macrophages and endo- antibacterials in the urinary tract on the other side. Inthelial cells, in response to various infectious stimuli this context, the pharmacokinetics of drugs at thesuch as peptidoglycans or lipopolysaccharides bind- affected site are also significantly influenced bying to Toll-like receptors 2 or 4.[15-17] When they total renal function and thus by the function of thebecome bound to specific receptors on other cells, contralateral kidney. Furthermore, the pharmacoki-cytokines change their behaviour in the inflammato- netics of a drug in the kidney are influenced by thery response. The complex balance between pro- and arterial plasma concentration, the renal plasma con-anti-inflammatory responses is modified in severe centration, the renal tissue concentration and thesepsis. An immunodepressive phase follows the ini- urine concentration. The renal tissue concentrationtial pro-inflammatory mechanism. Other cytokines, is complex and is a function of renal blood flow,such as interleukins, are involved. TNF-9 pt, IL-1, glomerular filtration, tubular secretion and reabsorp-IL-6 and IL-8 are cytokines that are associated with tion, pyelovenous- and lymphous backflow, and thesepsis. A genetic predisposition probably explains number of intact nephrons. The renal tissue concen-the unfavourable outcome of sepsis in certain pa- tration of a drug is therefore difficult to assess;tients. The mechanisms of organ failure and death in representative concentrations have been investigat-patients with sepsis remain only partially under- ed, and one of those could be the concentrations instood.[4] the renal lymph which might resemble interstitial



concentrations.[19] Renal lymph concentrations in phase is not seen in bilateral ureteral obstruction,unobstructed normal kidneys and unobstructed but which leads to a progressive rise in ureteral pressureinfected kidneys have been determined for a variety despite a decrease in renal blood flow. The singleof β-lactam antibacterials, aminoglycosides and ni- nephron glomerular filtration rate declines in unilat-trofurantoin. Concentrations in the renal lymph were eral and bilateral ureteral occlusion, which is secon-generally lower than the corresponding arterial plas- dary to an increase in afferent arteriolar resistance inma concentrations, which suggests that there is no unilateral occlusion and secondary to a rise in in-concentration effect in the renal interstitial space.[20] tratubular pressure in bilateral occlusion.[23] These

differences between unilateral and bilateral obstruc-In acute total unilateral ureteral obstruction, how-tion are most probably due to substances that accu-ever, there is still some glomerular filtration andmulate in bilateral obstruction or unilateral obstruc-renal plasma flow present. In an experimental studytion of a solitary kidney but do not accumulate inin dogs,[19] it was shown that the glomerular filtra-unilateral obstruction with a functioning contralater-tion rate and the effective renal plasma flow in theal kidney. One important factor of these changes isobstructed kidney in the first hours decreased to anthe atrial natriuretic peptide that plays an importantaverage of 14% and 12%, respectively, comparedrole in renal homeostasis.[23]

with the unobstructed kidney. The persisting turno-The urinary concentrations of most antibacterialsver of urine is due primarily to pyelovenous back-

are usually much higher than the plasma concentra-flow and also, but less importantly, due to drainagetions. Most aminoglycosides, tetracyclines and sul-into the hilar lymph. The concentrations of a clear-fonamides are excreted exclusively by glomerularance substance such as certain antibacterials in thefiltration; most β-lactams and quinolones addition-renal hilar lymph are higher than the correspondingally undergo tubular secretion and reabsorption.arterial plasma concentrations in the acute phase ofApart from renal clearance, protein binding, ex-unilateral obstruction (from the first hours to thetrarenal excretion and metabolism are also impor-first week) and become equal to the arterial plasmatant for urinary concentration.concentrations in chronic obstructive disease (long-

er than 1 week).[21] Mathematical models were calculated for an an-tibacterial substance with glomerular filtration andThe glomerular filtration rate is influenced by theextrarenal elimination (trimethoprim) and one withbalance of inward and outward pressures at theexclusive renal elimination (cephalexin) in the caseglomerular arterioles and Bowman’s capsule. In-of unilateral and bilateral renal impairment and inward forces are significantly increased with pos-the case of acute and chronic unilateral obstructiontrenal obstruction and are the cause of a reducedin conjunction with normal and differently impairedfiltration rate.[19,22] An increasing number of neph-contralateral renal function.[24] The following resultsrons will cease filtering if the ureteral pressure ex-can be summarised:ceeds one-third of the mean blood pressure. Acute1. In the case of severe unilateral renal insufficiencyunilateral occlusion of a ureter results in a character-(glomerular filtration 1 mL/minute) but normal con-istic triphasic relationship between renal blood flowtralateral renal function (glomerular filtrationand ureteral pressure. The first phase, lasting ap-60 mL/minute), the urinary antibacterial concentra-proximately 1.5 hours, shows a rise in both ureteraltions of both kidneys are high, whereby the impairedpressure and renal blood flow, followed by a secondkidney achieves half the urinary concentration of thephase with a decline in renal blood flow and aintact kidney.continued increase in ureteral pressure lasting from

approximately 1.5 to 5 hours, followed by a third 2. In the case of bilateral renal insufficiency, thephase resulting in a further decline in renal blood urinary concentrations significantly decrease downflow accompanied by a progressive decrease in ure- to plasma concentrations in the case of severe im-teral pressure. Phase I is characterised by initial pairment (glomerular filtration 2 mL/minute). Thisafferent arteriole vasodilatation followed by efferent difference in unilateral and bilateral renal insuffi-arteriole vasoconstriction in phase II and afferent ciency can be explained by the intact-nephron theo-arteriole vasoconstriction in phase III. This third ry. The single nephrons (e.g. the concentration abili-



ty) remain intact in the case of physiological prer- Recombinant activated protein C (drotrecogin α)enal conditions. In bilateral renal insufficiency, is a new drug that has been approved for therapy ofthere is an increased offer of solutes per nephron, severe sepsis. This expensive treatment has beenwhich results in diuresis with impaired powers of proven to be more effective in patients with moreconcentration.[25] severe disease, as assessed by Acute Physiology and

Chronic Health Evaluation (APACHE) II scores of3. In acute unilateral obstruction, the urinary con-≥25 or the presence of ≥2 organ dysfunctions.[32]centrations of the obstructed kidney are almost as

high as those of the normal unobstructed kidney, The best strategy has been summarised and grad-which is also due to the maximal urinary concentra- ed according to a careful evidence-based methodol-tion in acute obstruction. ogy in the recently published ‘Surviving Sepsis’

campaign guidelines.[33,34]4. Even in chronic unilateral obstruction, rather highurinary concentrations are achieved depending on

5.2 Control of the Complicating Factorthe function of the contralateral kidney.

Drainage of any obstruction in the urinary tract5. Treatment of Urosepsis and removal of foreign bodies, such as urinary cath-

eters or stones, may themselves cause resolution ofEffective treatment improves organ perfusion symptoms and lead to recovery. These are key com-

and eliminates the infectious focus. Treatment of ponents of the strategy. This condition is an absoluteurosepsis comprises three basic strategies: adjunc- emergency.[35]

tive measures, control or elimination of the compli-cating factor and antimicrobial therapy.[26-28] All 5.3 Antibacterial Therapythree strategies need to be started as early as possible(e.g. within the first hour). 5.3.1 General Principles of Antibacterial Therapy in

Patients with Urosepsis5.1 Adjunctive Measures Antibacterials are among the most important and

commonly prescribed drugs in the management ofManagement of the fluid and electrolyte balance patients with severe infections.[36] Inappropriate use

is a crucial aspect of patient care in sepsis syndrome, of antibacterials may cause therapeutic failure in theparticularly when the clinical course is complicated individual patient and additionally may contributeby shock. An early goal-directed therapy has been towards promoting the emergence of resistantshown to reduce mortality.[28,29] Volaemic expan- pathogens, which might also readily spread in thesion and vasopressor therapy have a considerable hospital setting.[37] It has been shown that cross-impact on the outcome. Early intervention with ap- contamination and cross-infection are also frequentpropriate measures to maintain adequate tissue per- with UTIs.[38] Adequate initial antibacterial therapyfusion and oxygen delivery by prompt institution of ensures an improved outcome in septic shock[39,40]

fluid therapy, stabilization of arterial pressure and and is also critical in severe UTI. Inappropriateproviding sufficient oxygen transport capacity are antibacterial therapy in community-acquired bacter-highly effective and can be surveilled by the central aemia due to UTI in adults has been linked to avenous oxygen saturation. higher mortality rate,[41] as has also been shown with

Hydrocortisone is useful in patients with relative other infections.[42,43] Empirical antibacterial ther-insufficiency in the pituitary gland-adrenal cortex apy therefore needs to follow certain rules,[44] whichaxis.[30] As yet, however, there has been no well may be based upon the expected bacterial spectrum,designed, large study confirming the benefit of hy- the institutional specific resistance rates and thedrocortisone in severe sepsis. individual patient’s requirements. Initial empirical

Tight blood glucose control by administration of treatment should provide broad antibacterial cover-insulin doses of up to 50 units/hour has been shown age and should later be adapted on the basis ofto be beneficial in critically ill patients after sur- culture results. To cover a broad spectrum, combina-gery.[31] tion therapy may be applied.[45] If enterobacteria are



expected, a third-generation cephalosporin (e.g. cef- pyelonephritis and uncomplicated cystitis, theretriaxone or cefotaxime) can be used in combination is interstitial and intracellular invasion of thewith an aminoglycoside. In the case of Pseu- uropathogens.[50-53] The antibacterial concentrationsdomonas spp., acylaminopenicillins (e.g. azlocillin), in tissue are dependent on the plasma concentra-piperacillin in combination with a β-lactamase-in- tions, the specific tissue architecture, the pharma-hibitor, a Pseudomonas-active cephalosporin (e.g. cokinetic parameters of the antibacterial drug (theceftazidime) or a carbapenem should be chosen.[26] charge and size of the molecule, protein binding, pHIn any case, microbiological sampling (urine, blood, in the infectious focus) and the distribution of thetissue culture) prior to initiation of treatment is infection in the tissue (stroma, epithelium).compulsory in order to tailor the initial empirical Moreover, biofilm infection plays a considerabletherapy according to laboratory results. Additional- role in urosepsis, not only in association with urina-ly, the correct dosing and duration of therapy are ry catheters but also in scar tissue, stones, prostatitisequally important. and the obstructed urinary tract.[54-57] For most

uropathogens, the ability to form biofilms has been5.3.2 Parameters for Antibacterial Treatmentdemonstrated.[58-64] Goto et al.[65,66] investigated kill-in Urosepsiscurves of P. aeruginosa in a biofilm-catheter infec-Adequate treatment of UTI depends on the an-tion model. β-lactam antibacterials (piperacillin,tibacterial being able to inhibit the growth or killceftazidime) were not able to eradicate the biofilmbacteria that are present in the urinary tract. In anycells, even when concentrations 128 times the mini-infection of the kidney or bladder, a significant partmal bactericidal concentrations were administered.of the bacteria (sometimes more than 106/mL) isWith fluoroquinolones (ciprofloxacin, levoflox-also found free in the bladder lumen. Therefore,acin), eradication was possible, but only in concen-high urinary excretion of the antibacterial is alsotrations that reached 32- to 64-fold the minimalneeded.[46-48] Accordingly, antibacterials that arebactericidal concentrations.[65,66] Therefore, in gen-primarily eliminated via renal excretion and achieveeral, high dosages of antibacterials need to be ap-high urinary concentrations (100- to 1000-fold con-plied in conjunction with the attempt to eliminatecomitant serum concentrations) [e.g. ampicillin/the biofilm and the biofilm-causing complicatingsulbactam, cefuroxime, gatifloxacin, levofloxacin]factor. If there is a chance to remove the biofilm, thistheoretically represent optimal choices for the treat-should be done, e.g. by removing infected stones orment of UTIs. But besides favourable pharmacoki-catheters.netics, an agent suitable for the treatment of severe

While pharmacodynamic studies in UTI are rela-complicated UTI should also provide optimal phar-tively scarce, at least one recent study has docu-macodynamic properties at the site of infection,mented that therapeutic success following β-lactami.e. urinary bactericidal activity. Thus, even fortherapy depends on the time during which the anti-agents that are modestly eliminated by renal mecha-microbial concentration remains above the MICnisms, high intrinsic potency (minimum inhibitory(T>MIC). A recent data analysis by Frimodt-Møl-concentration [MIC]) against the most commonler[47] reported that there was a significant correla-uropathogens (e.g. ciprofloxacin), is also an impor-tion between the cumulative T>MIC in serum andtant consideration in antibacterial selection.[49]

bacteriological cure, wherein a cumulative T>MICAgents whose antibacterial activity is compro-of 30 hours provided a maximal cure rate ofmised by changes in the urinary pH, such as fluoro-80–90%. The investigators postulated that the rea-quinolones, should be administered in doses highson why β-lactams have often not provided success-enough to compensate for the possible negative in-ful outcomes in the treatment of UTIs comparedfluence on activity by the urinary pH.with other antibacterial classes is most likely im-If the infection involves renal tissues or the pa-proper dosing (i.e. dose too low and infrequenttient has urosepsis, adequate serum concentrationsdosage interval).are necessary to produce high tissue concentrations,

thereby necessitating administration of high-dose For drugs with concentration-dependent time-killintravenous antibacterials. Even in uncomplicated activity, such as the aminoglycosides and the fluoro-



quinolones, a positive outcome appears to be more Blondeau,[69] compared the MPC results fordependent on the maximum concentration (Cmax)/ ciprofloxacin, levofloxacin and garenoxacin againstMIC or the area under the concentration-time curve clinical isolates of urinary tract pathogens (E. coli,(AUC)/MIC ratio. While it remains unclear which Citrobacter freundii, E. cloacae, K. pneumoniae andratio is a better predictor of outcome, a high ratio is P. aeruginosa). The ciprofloxacin, levofloxacin anddesirable in either case. The pharmacodynamics of garenoxacin MPC results in this study for E. coli,ciprofloxacin were investigated in one animal model C. freundii, E. cloacae, K. pneumoniae andUTI study in mice infected with E. coli.[47] While the P. aeruginosa, respectively, were 0.5, 1, 1, 1 anddata were limited to three points, there was an 4 mg/L; 1, 2, 4, 2 and 16 mg/L; and 1, 8, >8, 4 andobvious correlation between reduced bacterial ≥32 mg/L. By comparison, the MIC required tocounts and the AUC/MIC ratio. Despite the paucity inhibit the growth of 90% of organisms (MIC90)of pharmacodynamic data to guide therapy in UTIs, results ranged from ≤0.06 to 4 mg/L for the Enter-it has been noted that among the available qui- obacteriaceae organisms and from 1 to 4 mg/L fornolones, the Cmax/MIC in serum and AUC/MIC in P. aeruginosa. Therefore, MPC testing may provideserum ratios are highest for ciprofloxacin against remarkably different results in some substances andP. aeruginosa.[67] For other Gram-negative infec- bacterial strains that are tested. Incorporation oftions, the pharmacodynamic properties of the availa- MPC strategies into current fluoroquinolone dosingble quinolone agents are more similar. This model in UTI represents a realistic approach for preventingwas unable to evaluate the aminoglycosides using the further selection of resistant organisms associat-pharmacodynamic principles because these agents ed with UTIs.[69]

are characterised by high binding to the renal cor-5.4 Fluoroquinolone Clinical Trialstex.[47]

Further pharmacodynamic research is needed in A limited number of US and international clinicalorder to determine the optimal dosages of all an- trials have been published and provide evidence totibacterials used to treat serious UTIs. Appropriate support the effectiveness of the fluoroquinolones indosing is especially important to minimise the de- the treatment of complicated and hospital-acquiredvelopment of resistance and to maintain antibacteri- UTIs.[71-95] However, no clinical trials have assessedal efficacy. For patients with serious UTIs, high- the fluoroquinolones specifically in urosepsis pa-er than approved doses may be needed, especial- tients, using current diagnostic criteria. Moreover,ly against difficult-to-treat pathogens such as the findings of these trials are often difficult toP. aeruginosa.[49] For example, intravenous or oral compare or interpret because of differing or incom-ciprofloxacin 750mg twice daily or levofloxacin plete definitions of the ‘complicated’ condition. Al-500mg twice daily may be more appropriate than though these trials vary in their study design, manyconventional dosing.[68] support the use of fluoroquinolones in the treatment

of serious/complicated UTIs; the most experienceIn this respect, the mutant-prevention concentra-has been garnered with ciprofloxacin.[71-75,77-84]tion (MPC) could be a suitable parameter for inclu-

sion in the selection of appropriate agents for diffi- The majority of the published trials of ciproflox-cult-to-treat infections. The MPC is a novel suscep- acin in serious UTI employed the conventionaltibility parameter designed to minimise the selection twice-daily tablet,[71,77-83] while one recent prelimi-of first-step resistant mutants present in large nary report demonstrated the effectiveness of a new(≥1010 CFU/mL) or heterogeneous bacterial popu- once-daily extended-release tablet formulation.[84]

lations, and is a measurement distinct from MIC Three of these studies were conducted primarily intesting.[69] Ciprofloxacin and levofloxacin have been Germany and used a relatively low dose oftested by the MPC methodology and compared ciprofloxacin (250mg twice daily) but with goodagainst clinical isolates of P. aeruginosa.[70] outcomes.[80-82] The majority of these publishedCiprofloxacin was substantially less likely to select clinical trials of oral ciprofloxacin revealed excel-for quinolone resistance in P. aeruginosa than was lent bacteriological (>84%) and clinical cure rateslevofloxacin. In a separate report, Hansen and (>90%). As expected, all of these trials demonstrat-



ed that ciprofloxacin was at least equivalent to a P. aeruginosa). All five ciprofloxacin-treated pa-comparator regimen (e.g. ofloxacin, gatifloxacin). tients with a baseline P. aeruginosa infectionIn general, ciprofloxacin was effective for serious achieved bacteriological eradication; no evaluableUTIs due to P. aeruginosa. gatifloxacin-treated patient was infected with a

pseudomonal strain. Clinical success at the test-of-One study[71] demonstrated that ciprofloxacincure (4–11 days post-therapy) exceeded 90% in bothwas significantly bacteriologically superior to atreatment groups for those with complicated UTIs.comparator agent in a population with long-termExcluding indeterminate responses, the clinical curebladder catheterisation. Fang et al.[71] demonstratedrate at long-term follow-up was slightly lower: 83%a superior bacteriological response at the early fol-for ciprofloxacin versus 86% for gatifloxacin. Thislow-up visit (5–9 days post-therapy) with ciproflox-contemporary study demonstrates the continued ef-acin 500 mg twice daily compared with the aminog-ficacy of fluoroquinolones for treatment of seriouslycoside regimen (p = 0.0005). The response ratesUTIs, including ciprofloxacin’s efficacy againstwere similar between the two treatment groups atP. aeruginosa.the long-term follow-up visit (28–30 days post-ther-

apy). In this trial, 75% of P. aeruginosa isolates Mombelli et al.[75] investigated the efficacy ofwere eradicated at short-term follow-up by both the oral ciprofloxacin (500mg twice daily) versus intra-ciprofloxacin and aminoglycoside regimens, al- venous ciprofloxacin (200mg twice daily) as empiri-though there was a high rate of recurrence in both cal therapy for 141 patients with community-ac-treatment groups. While ciprofloxacin provided quired and nosocomial complicated UTIs or severeshort-term superiority, recurrence was high in both pyelonephritis. Only patients with severe sepsis (de-treatment groups, likely due to the presence of bi- fined as the presence of infection-related organ dys-ofilms and the fact that catheters could not be re- function) were excluded. Resistance to ciproflox-moved from these patients. These findings stress the acin was found for 11 baseline organisms (8%),difficulty of treating patients who have permanent including five Enterococcus spp. and one each ofindwelling urinary catheters. P. aeruginosa, E. coli, Enterobacter spp., Staphylo-

Cox et al.[83] recently evaluated the efficacy of coccus aureus, coagulase negative staphylococci,ciprofloxacin (500mg twice daily) versus gatiflox- and Candida albicans. This study found that empiri-acin (400mg once daily) for 7–10 days in 288 adult cal oral ciprofloxacin was bacteriologically andpatients with complicated UTI. Approximately one- clinically as effective as intravenous ciprofloxacinthird of patients had more than one ‘complicating’ for management of serious UTIs, including bacter-factor (e.g. impaired bladder emptying) at study aemia, in patients without severe sepsis, obstructionentry. E. coli and K. pneumoniae were the predomi- or renal foci of suppuration. The rates of bacterio-nant causative baseline pathogens for almost two- logical failure or unsatisfactory clinical responsethirds of patients. As in many clinical trials, patients were extremely low (2% and 3%, respectively, forwhose pretreatment pathogen was resistant to either intravenous administration vs 3% and 4%, respec-drug therapy were excluded from the efficacy- tively, for oral administration). Importantly, no in-evaluable population. Bacteriological and clinical fection-related deaths occurred, and no patient hadoutcomes were comparable between the two treat- to be switched early from empirical to alternativements. At the test of cure visit (5–9 days post- therapy because of clinical worsening. However,therapy), the overall bacteriological eradication of treatment was ultimately altered following the avail-organisms was 90% for ciprofloxacin versus 100% ability of susceptibility findings in 7% of patientsfor gatifloxacin. The lower rate of eradication in the randomised to intravenous ciprofloxacin versusciprofloxacin group was largely due to several per- 14% of oral ciprofloxacin recipients (p = 0.31).sistent Enterococcus faecalis organisms. The rates There are several unique aspects/findings of thisof superinfections were comparable between the trial: (i) the enrolled patients had serious UTIs,two treatments (one with ciprofloxacin vs two including 53 patients with proven bacteraemia; (ii)with gatifloxacin) and were typically due to qui- males constituted >40% of the study population andnolone-resistant bacteria (Alcaligenes faecalis and nosocomial acquisition was reported for 23%; and



Table II. Mean single-dose pharmacokinetic parameters of different fluoroquinolones at relatively high dosages

Fluoroquinolone Dose Route of Cmax t1/2 (h) Mean urinary AUC36h Reference(mg) administration (mg/L) excretion (%) (μg • h/mL)

Ciprofloxacin XR 1000 Oral 3.3 8.2 41 19.5 99

Levofloxacin 500 Oral 6.2 6.4 80 47.8 99

Gatifloxacin 400 Oral 3.4 6.5 81 33.3 100

Gemifloxacin 800 Oral 4.3 8.0 39 31.4 103,104

Moxifloxacin 400 Oral 4.3 9.1 20 39.3a 96

Trovafloxacinb 200 Intravenous 2.3 12.3 10 29.2 105

a AUC∞.

b Alatrofloxacin.

AUC36h = area under the concentration-time curve from 0 to 36 hours; AUC∞ = AUC from time zero to infinity; Cmax = maximumconcentration; t1/2 = elimination half-life; XR = extended release.

(iii) patients with resistant organisms were not auto- Selected pharmacokinetic studies of fluoroqui-matically excluded. It is also noteworthy that the nolones used at relatively high dosages are shown inmajority of ciprofloxacin resistance was against table II. The UBTs of these fluoroquinolones haveGram-positive organisms and that, despite this, most been investigated.[98-102] Although these studies arepatients had an adequate initial clinical and bacterio- not directly comparable, they emphasise the impor-logical response. In fact, the clinical response to tance of special urinary parameters such as the UBTciprofloxacin was satisfactory in six of seven pa- for the assessment of antibacterial substances suita-tients with ciprofloxacin-resistant pathogens, in- ble for the treatment of UTI.cluding two episodes of bacteraemia. Although this In a randomised cross-over study in 12 volun-study was not large, it provides compelling evidence teers, single oral doses of extended-releasethat both intravenous and oral ciprofloxacin are ef- ciprofloxacin 1000mg versus levofloxacin 500mgfective in the initial treatment of patients with seri- were compared to assess UBTs.[102] UBTs wereous UTIs, including nosocomially acquired infec- determined for eight strains with the followingtions. MICs (mg/L) for ciprofloxacin/levofloxacin: E. coli

ATCC 25922 (0.008/0.03), K. pneumoniae (0.008/6. Relationship between Renal Excretion 0.03), P. mirabilis (0.03/0.06), E. coli [nalidixic acidand Bactericidal Titres of resistant] (0.125/0.25), P. aeruginosa (0.5/2),Different Fluoroquinolones S. saprophyticus (0.25/0.25), S. aureus (0.125/

0.125), E. faecalis (1/1). The areas under the UBT-In many infections, antibacterial susceptibilitytime curve within the first 24 hours showed statisti-levels are often gauged relative to what antibacterialcally significant differences only for P. mirabilis inconcentration is achievable in the blood. In thefavour of extended-release ciprofloxacin, and fortreatment of complicated UTI, however, the urinaryS. aureus and S. saprophyticus in favour of lev-concentrations – or, more precisely, the urinary an-ofloxacin. Because levofloxacin shows double thetibacterial activity – are more important. Fluoroqui-excretion rate of ciprofloxacin (levofloxacin ap-nolones differ in their pharmacokinetic properties[96]

proximately 80%, ciprofloxacin approximatelyand antibacterial activity.[97] The urinary concentra-40%),[99] double the dose of ciprofloxacin is neces-tion has to be considered and correlated with thesary to achieve urinary activity (UBTs) comparablerespective antibacterial activities. This can be done,to that achieved with levofloxacin.for example, in an ex vivo model by determining the

Another randomised cross-over study in 12 vol-urinary bactericidal titres (UBTs). In this model, theunteers compared single oral doses of gatifloxacinpharmacokinetic and pharmacodynamic parameters400mg and ciprofloxacin 500mg.[100] Again, ga-of an antibacterial in urine are linked together. Vari-tifloxacin showed double the excretion rate ofous fluoroquinolones have thus been compared with

each other. ciprofloxacin (gatifloxacin approximately 80%,



ciprofloxacin approximately 40%). UBTs were de- In clinical studies, newer fluoroquinolones werecompared with ciprofloxacin 500mg twice daily as atermined for 10 strains with the following MICsstandard treatment in the oral treatment of compli-(mg/L) for gatifloxacin/ciprofloxacin: E. coli ATCCcated UTI. Whereas levofloxacin 250mg once dai-25922 (0.008/0.008), E. coli 523 (0.06/0.06),ly[106] and gatifloxacin 400mg once daily[107] (bothK. pneumoniae (0.03/0.016), P. mirabilis (0.125/of which are excreted into the urine at a rate of about0.016), P. aeruginosa (1/0.125), E. faecalis 60 (0.5/80%) showed clinical and microbiological results1) and E. faecalis 55 (8/32), S. aureus (0.03/0.125)equivalent to those achieved with ciprofloxacin,and S. saprophyticus (0.125/0.25). The areas underequivalence could not be achieved when moxiflox-the UBT-time curve calculated for 120 hoursacin 400mg once daily (urinary excretion 20%)[108]showed generally superior results for gatifloxacinor gemifloxacin 320mg once daily (urinary excre-compared with ciprofloxacin, with the exceptiontion 30%)[109] were compared with ciprofloxacin.of Proteus and Pseudomonas spp. Therefore, theAll four newer fluoroquinolones showed almostinferior urinary excretion rate of ciprofloxacin (halfcomplete bioavailability after oral administration,that of gatifloxacin) is levelled out only in thosewith subsequent good corresponding plasma con-species where the pharmacodynamic advantage ofcentrations. The lower urinary concentrations, andciprofloxacin is 8-fold higher than that of gatiflox-hence lower urinary antibacterial activity, of mox-acin (MIC).ifloxacin and gemifloxacin had the consequence that

A different cross-over study in volunteers com- these two compounds did not achieve approval forpared single oral doses of levofloxacin 250mg, ga- treatment of complicated UTI by the regulatory bod-tifloxacin 400mg, moxifloxacin 400mg and ies.trovafloxacin 200mg.[101] Urinary concentrations

Therefore the ex vivo studies assessing urinarywere highest with gatifloxacin followed bybactericidal activity proved to be relevant to the

levofloxacin, moxifloxacin and trovafloxacin. Uri-prediction of results in clinical studies.

nary bactericidal activity was determined againstIn severe UTI, adequate initial antibacterial ther-levofloxacin-susceptible and moderately-suscepti-

apy is critical,[41] therefore empirical treatmentble strains with the following MICs: E. coli (0.125needs to cover also moderately susceptible bacteria.and 4 mg/L), K. pneumoniae (0.125 and 4 mg/L),Pea et al.[68] assessed the urinary pharmacokineticsP. aeruginosa (0.5 and 4 mg/L) and E. faecalis (0.25and theoretical pharmacodynamics of levofloxacinand 4 mg/L). Gatifloxacin and levofloxacin exhibit-in intensive care unit (ICU) patients treated withed prolonged urinary bactericidal activity (≥6 hours)500mg intravenously twice daily. Using this highagainst all study isolates, whereas moxifloxacindosage, urinary concentrations were maintained atfailed to show prolonged urinary bactericidal activi-least 50-fold higher than the MIC90 of most sensi-ty against both Pseudomonas strains, and trovaflox-tive uropathogens during the overall dosing intervalacin failed to show this activity against all moderate-in ICU patients with normal renal function. The

ly susceptible strains, with the exception of E. fae-investigators concluded that considering the major

calis. pharmacodynamic determinants of the concentra-Therefore those fluoroquinolones with very lim- tion-dependent bactericidal activity of levofloxacin

ited urinary excretion (<40%) [moxifloxacin, as applicable at the urinary level (Cmax/MIC >12.2trovafloxacin] showed inferior results in this ex vivo and/or AUC24/MIC >125 hours), this high dosagepharmacokinetic/pharmacodynamic study design. regimen may ensure optimal exposure for the treat-Fluoroquinolones with intermediate urinary excre- ment of catheter-related and severe lower UTIs nottion rates (ciprofloxacin) showed comparable results only against sensitive microorganisms, but probablyonly in those strains where the MICs are favourable also whenever microorganisms that are usually con-in comparison with highly excreted fluoroqui- sidered as intermediate susceptible or resistant tonolones (levofloxacin, gatifloxacin). Otherwise, the levofloxacin may be involved. The resistance levelsadministered daily dose needs to be increased ac- of fluoroquinolones against uropathogens, however,cordingly. are constantly rising to levels where fluoroqui-



nolones may no longer be considered for empirical The recent ‘Surviving Sepsis’ campaign led to thetreatment of UTIs.[9,10] Therefore, in the treatment of formation of guidelines aimed at reducing mortalitysevere UTIs, high dosages should generally be by 25% in the next few years. Early recognition ofmandatory. the symptoms may decrease mortality through time-

ly treatment of urinary tract disorders, e.g. obstruc-7. Prevention tion, urolithiasis. Adequate life-support measures

and appropriate antibacterial treatment, includingSeptic shock is the most frequent cause of death optimized dosing, provide the best conditions for

in patients hospitalised for both community-ac- improving patients’ survival. Prevention of sepsisquired and nosocomial infection (20–40%). Sepsis syndrome is dependent on good practice to avoidinitiates the cascade that progresses to severe sepsis nosocomial infections and use of antibacterial pro-and then septic shock in a clinical continuum. Pre- phylaxis and therapy in a prudent and well acceptedvention of urosepsis can mainly be achieved by manner.preventing nosocomial UTI.[110] The most effectivemethods to prevent nosocomial urosepsis are basi- Acknowledgementscally the same as those used to prevent othernosocomial infections: No sources of funding were used to assist in the prepara-

tion of this review. The authors have no conflicts of interest• Isolation of all patients infected with multi-resis-that are directly relevant to the content of this review.tant organisms to avoid cross-infection.

• Prudent use of antibacterial agents, both in pro-Referencesphylaxis and in treatment of established infec-

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Pharmacokinetic Characteristics of Antimicrobials and Optimal Treatment of Urosepsis

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