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REVIEW

Levofl oxacin in the treatment of complicated urinary tract infections and acute pyelonephritis

Jessina C McGregor Abstract: Levofl oxacin is a widely used fl uoroquinolone approved for the treatment of George P Allen complicated urinary tract infections and acute pyelonephritis. A comprehensive review of the David T Bearden medical literature identifi ed fi ve publications evaluating levofl oxacin for the treatment of either complicated urinary tract infections or acute pyelonephritis. All trials, although variable in Oregon State University College of Pharmacy, Portland, OR, USA their inclusion criteria and levofl oxacin dosing strategies, reported microbiologic, clinical, and safety-related outcomes. High microbiologic eradication rates, ranging from 79.8% to 95.3%, were observed in all studies. Escherichia coli was the most commonly isolated uropathogen. Data on levofl oxacin resistance, both at baseline and after therapy, were limited. Clinical success was observed to range from 82.6% to 93% when measured after the completion of therapy. These clinical and microbiologic results were comparable to the fl uoroquinolone comparators in all trials. Insuffi cient data are available to evaluate the outcomes in any meaningful patient subgroups, including catheterized patients, and those with other specifi c complicating factors. Levofl oxacin was well tolerated in these studies, with headache, gastrointenstinal effects, and dizziness being the most commonly reported adverse events. The published data support the use of levofl oxacin in complicated urinary tract infections and acute pyelonephritis. Further trials are necessary to evaluate levofl oxacin within specifi c patient sub-populations. Keywords: urinary tract infection, pyelonephritis, levofl oxacin

Introduction Urinary tract infections are one of the most frequently occurring bacterial infections. In the United States alone, they account for over 7 million offi ce visits and approximately 15% of community-prescribed antibiotics (Mazzulli 2001; Foxman 2002). While the majority of these infections are uncomplicated, patients with complicated urinary tract infections (cUTI) are, by defi nition, at greater risk for adverse outcomes. Levofl oxacin, a widely-used fl uoroquinolone, was approved in the US for the treatment of cUTI and acute pyelonephritis (AP) in 1996 and, more recently, in 2008 a higher dose, short-course regimen was also approved for this indication. This review will examine the clinical data available to evaluate the effi cacy and safety of this antimicrobial for cUTI and AP.

Complicated urinary tract infections and pyelonephritis Generally, a cUTI is considered to be an infection that occurs in the setting of any factor that predisposes to treatment failure or recurrence (McCue 1999). However, no true consensus has been reached within the medical community as to what specifi cally Correspondence: Jessina C McGregor Oregon State University/Oregon defi nes a cUTI. Traditionally, urinary tract infections in patient populations such as those Health & Science University College with diabetes mellitus, pregnant females, and males have been considered to be com- of Pharmacy, Portland Campus at OHSU, 3303 SW Bond Ave., Mail Code: CH12C, plicated infections (Anderson 1996). Other descriptions of a cUTI have also included Portland, OR 97239, USA patients who are elderly, have experienced recent instrumentation or antimicrobial + Tel 1 503 494 4722 treatment, or possess functional or anatomic abnormalities of the genitourinary tract Fax +1 503 494 8797 Email [email protected] (Hooton and Stamm 1991). Ronald et al proposed an alternate classifi cation scheme,

Therapeutics and Clinical Risk Management 2008:4(5) 843–853 843 © 2008 Dove Medical Press Limited. All rights reserved McGregor et al in which a cUTI is characterized by the presence of structural preferred empiric therapy, with trimethoprim/sulfamethoxazole abnormalities (urinary obstructions, neurogenic bladder, etc.), (TMP/SMX) offered as an alternative. In patients that are to be metabolic and/or hormonal abnormalities (diabetes mellitus, hospitalized, the guidelines recommend the use of intravenous pregnancy, renal impairment, etc.), impaired host responses therapy with a fl uoroquinolone, an aminoglycoside with or (transplant recipients, neutropenic patients, etc.), or infec- without ampicillin, or an extended-spectrum penicillin with tion with an unusual pathogen (including yeasts, fungi, and or without an aminoglycoside. After such patients are stabi- antimicrobial-resistant bacteria) (Ronald and Harding 1997). lized, the IDSA recommends that the course of treatment be Mandell’s Principles and Practice of Infectious Diseases completed with an oral fl uoroquinolone or oral TMP/SMX. defi nes cUTIs as urinary tract infections in men, pregnant Alternatives are recommended for each of the above patient women, children, hospitalized patients, and patients with populations if the infecting organism is known to be a Gram- functional or structural abnormalities of the urinary tract positive coccus. Recommended fi rst-line agents for the treat- (Sobel and Kaye 2005). ment of uncomplicated cystitis include a fl uoroquinolone AP is commonly described as an infection of the upper or TMP/SMX, depending on the local rate of TMP/SMX urinary tract that encompasses fever and fl ank pain and/or resistance in E. coli. IDSA is currently working towards assem- tenderness that are accompanied by dysuria and urinary bling guidelines for the treatment of cUTI, and publication is urgency and frequency, although it is more accurately anticipated in late 2008. The European Association of Urology diagnosed based on the presence of these symptoms along (EAU) has published guidelines that include recommenda- with bacteriuria and acute renal infection (Sobel and Kaye tions for cUTI, which advise the use of fl uoroquinolones with 2005). AP was formerly treated largely on an inpatient basis, mainly renal excretion when empiric therapy is necessary. The but a recent trend towards outpatient management of this EAU recommends avoiding TMP/SMX as fi rst-line treatment condition has been noted (Czaja et al 2007). As seen in cUTI, because of the increasingly high prevalence of resistance to the most common pathogen causing AP is Escherichia coli that antimicrobial agent (Grabe et al 2008). (Nicolle 1997; Czaja et al 2007). Fluoroquinolone resistance Fluoroquinolones have been extensively used in the The role of fl uoroquinolones management of genitourinary infections, especially acute in the management of genitourinary uncomplicated cystitis. While fl uoroquinolone resistance in infections uropathogens was once rare, resistance in E. coli has emerged Currently available fl uoroquinolones that are approved by the and continues to increase. Fluoroquinolone resistance occurs US Food and Drug Administration (FDA) for the treatment through multiple mechanisms including chromosomal of cUTI and/or AP include ciprofl oxacin, levofl oxacin, nor- point mutations in the genes encoding DNA gyrase and/or fl oxacin, and ofl oxacin. The fl uoroquinolones gemifl oxacin topoisomerase iv, mutations that cause decreased expression and moxifl oxacin are not approved for either condition. of outer membrane proteins (OMPs), alterations in the Gatifl oxacin was awarded FDA approval for the manage- lipopolysaccharide (LPS) component of the cell envelope, ment of cUTI and AP, but this agent was withdrawn from and enhanced fl uoroquinolone effl ux by effl ux pumps such as the US market in 2006. Levofl oxacin, approved by the US AcrAB (Chenia et al 2006; Chang et al 2007). Plasmid-borne FDA in 1996, is the S enantiomer of the racemate ofl oxacin. resistance has also recently been discovered, and is caused by The S enantiomer of ofl oxacin displays antibacterial activity protection of DNA gyrase and topoisomerase IV by Qnr-like that is approximately 2 orders of magnitude greater than that proteins, including QnrA (Chenia et al 2006). Surveillance of the R enantiomer; this enhanced activity is due to greater of urinary isolates collected between 1989 and 1997 found binding to and saturation of the binding site on the DNA that fl uoroquinolone resistance in E. coli was essentially gyrase enzyme (Morrissey et al 1996). Studies of ofl oxacin nonexistent during this time frame (Gupta et al 1999a; Gupta were not included in the present analysis. et al 1999b). More recently, results of the North American The Infectious Diseases Society of America (IDSA) has Urinary Tract Infection Collaborative Alliance (NAUTICA) published guidelines for the management of acute uncompli- study, a multicenter surveillance study performed between cated cystitis and AP (Warren et al 1999). For cases of AP that 2003 and 2004 in the US and Canada, reported that overall are manageable on an outpatient basis using oral antimicrobial resistance rates to ciprofl oxacin and levofl oxacin were 5.5% therapy, the IDSA recommends a fl uoroquinolone as the and 5.1%, respectively (Zhanel et al 2006). Similar increases

844 Therapeutics and Clinical Risk Management 2008:4(5) Levofl oxacin for complicated UTI and pyelonephritis in fl uoroquinolone resistance have been noted in the setting of terms: “fluoroquinolone,” “levofloxacin,” “complicated AP (Czaja et al 2007). Also, among the emerging extended- urinary tract infection,” “complicated UTI,” “cystitis,” spectrum beta-lactamase (ESBL)-producing E. coli, higher “pyelonephritis,” “urinary tract infection,” and “UTI.” This rates of fl uoroquinolone resistance have been reported. In query was also limited to English-language publications. China, levofloxacin resistance among ESBL-producing The search criteria were chosen to maximize the sensitivity E. coli was reported in 86% of isolates (Xiong et al 2002). of the search. The same search criteria were used to query In the US, one healthcare system reported that 56% of the Cochrane Database of Clinical Trials and the Clinical ESBL-producing E. coli and Klebsiella pneumoniae were Trials.gov database. We included all English-language pub- resistant to fl uoroquinolones (Lautenbach et al 2001). lications of either randomized controlled trials or analytical observational studies of the effi cacy of levofl oxacin in treat- Levofl oxacin pharmacology ing cUTI and/or AP that were published before February 1, Levofloxacin possesses activity against a variety of 2008. We excluded studies performed in pediatric patients uropathogens, including E. coli (Davis and Bryson 1994). or that included no comparator group. For each publication, The pharmacokinetics of levofl oxacin have been reviewed the authors’ defi nition of cUTI and AP were used. The cita- elsewhere, and a comprehensive evaluation of levofl oxacin’s tions of all included publications were also considered for pharmacokinetics is beyond the scope of this review (Fish inclusion in this review. All publications were assessed for and Chow 1997). The bioavailability of levofl oxacin is 100%, potential duplication of reported data. although absorption is delayed in the presence of food; the For each of the included publications, two authors degree of protein binding ranges from 24 to 38%. Levofl oxacin extracted data on the study design and methods, the defi ni- displays linear pharmacokinetics, and an elimination half-life tions of key variables (cUTI, AP, microbiologic eradication, of 7.6 hours after multiple doses of 500 mg. The primary route and clinical cure), timing of outcome assessments, effi cacy of elimination is renal, with approximately 71% of a dose elim- and safety results, infecting pathogens, and the presence inated as unchanged drug within 24 hours. Tissue distribution and/or development of antibiotic resistance. Data extraction is extensive; urinary levofl oxacin concentrations have been was conducted in this manner so as to evaluate not only the reported to be as high as 128–343 mg/L (the corresponding safety and effi cacy but also the generalizability of the studies plasma maximum concentration (Cmax) after a single 500 mg to general practice. dose ranges from 4.5 to 5.2 mg/L) (Langtry and Lamb 1998). Levofl oxacin also attains adequate penetration into the prostate, Results with a mean 2.96:1 prostate: plasma concentration ratio, and Study selection this agent has demonstrated success in the management of The PubMed query yielded 385 publications. Of these, chronic bacterial prostatitis, including equivalent effi cacy to fi ve publications met the inclusion and exclusion criteria. ciprofl oxacin (Drusano et al 2000; Bundrick et al 2003; Naber However, one of these publications reported the fi ndings et al 2008). The urinary excretion of levofl oxacin (84%) is of a subset of patients (those with AP) and these data were higher than that of ciprofl oxacin (43%), gatifl oxacin (80%), also subsequently published with the results of the full trial gemifl oxacin (28%), and moxifl oxacin (20%) (Naber 2001). (Klausner et al 2007; Peterson et al 2008). Thus, only the

Renal clearance of levofl oxacin (but not the plasma Cmax) is latter publication was included in this review (Peterson reduced in the presence of renal impairment. et al 2008). Of the publications that were excluded, 86% Few current guidelines describing the optimal treatment were excluded because they were not human subjects-based of cUTI and AP are available, and the role of levofl oxacin research (including, for example, systematic reviews), did not in comparison to alternate antimicrobials (including other include levofl oxacin as a study drug, or were not evaluating fl uoroquinolones) in the management of these conditions therapies for cUTI or AP. must be further defi ned. The objective of this review is to The query of the Cochrane Database of Clinical Trials provide a summary of the clinical effi cacy and safety of yielded 55 publications. Of these, eight studies were not levofl oxacin in the treatment of cUTI and AP. included because levofl oxacin was not evaluated, seven were excluded because they were not studies of cUTI or Methods AP, 13 were non-English publications, and the remaining The PubMed search engine was used to query the National 27 studies had already been identifi ed for consideration in Library of Medicine database using the following search the PubMed query. Similarly, the ClinicalTrials.gov query

Therapeutics and Clinical Risk Management 2008:4(5) 845 McGregor et al yielded 60 registered trials (some on-going). Of these trials, renal tumor or fi brosis, distorted urethral structure; and/or 47 were not studies of cUTI or AP, four were conducted in intermittent catheterization (Peng 1999; Peterson et al 2008). pediatric patients, fi ve were studies not including levofl oxacin, The studies of cUTI published by Klimberg et al and Richard and one was an uncontrolled study. Only three trials were et al required that all subjects possess an anatomic or func- identifi ed as having met inclusion and exclusion criteria. The tional abnormality of the urinary tract and at least one of the fi ndings of these trials were published, either in whole or in following symptoms: urgency frequency, dysuria, hematuria, part, in the publications identifi ed through PubMed. Thus, or fever or history of fever (Klimberg et al 1998; Richard the summary data available through ClinicalTrials.gov were et al 1998a). Klimberg et al also required that patients present not included in this review. Review of the cited publications with a baseline urinary sample with more than fi ve urinary yielded one additional, previously unidentifi ed publication white blood cells/high-power fi eld (Klimberg et al 1998). that met inclusion and exclusion criteria. Three trials also required that study participants present with Five publications met all inclusion and exclusion criteria 105 or more colony-forming units (cfu)/mL of at least one and are included in this review (Klimberg et al 1998; Richard species of uropathogen (Klimberg et al 1998; Richard et al et al 1998a, b; Peng 1999; Peterson et al 2008). Table 1 1998a; Peterson et al 2008), although Peterson et al excluded summarizes the design of the trials reported in these publica- patients with more than two species of uropathogen present tions. All fi ve publications reported the fi ndings of random- at baseline (Peterson et al 2008). ized controlled trials. One reported the results of two such Four trials included AP patients. In three of the trials, trials (Richard et al 1998b); thus six trials were described the defi nitions of AP were similar and required that patients among the fi ve publications. We should also note that three present with 105 or more cfu/mL of at least one species of of the publications included in this review arise from two uropathogen and two or more of the following symptoms: trials. More specifi cally, data from two trials for the subset fever, fl ank pain or costovertebral angle tenderness, periph- of AP patients were published in one publication (Richard eral white blood cell count (WBC) more than 12,500/mm3 or et al 1998b) and the data pertaining to the cUTI patients from 10% or greater bands, and/or WBC casts in the urine, or, in each of these trials were published separately (Klimberg et al the case of Peterson et al a positive antibody-coated bacteria 1998; Richard et al 1998a). From this point forward, we will test (Richard et al 2002; Peterson et al 2008). Similar to the consider these three publications as presenting the results of defi nition of cUTI, Peterson et al required that subjects with four distinct trials. AP have at least one of the following symptoms: urgency frequency, dysuria, hematuria, or fever or history of fever Overview of study designs (Peterson et al 2008). In contrast, Peng required only a Three trials were conducted in the US (Klimberg et al 1998; diagnosis of AP (Peng 1999). All trials assessed the outcomes Richard et al 1998b; Peterson et al 2008), two trials in the of microbiologic eradication and clinical success. These US and Canada (Richard et al 1998b), and one trial was defi nitions were similar across all trials (Table 1). conducted in Taiwan (Peng 1999). The latter was also the In each of the six trials, another fl uoroquinolone was only single-center trial. Only two publications specifi cally selected as the comparator treatment (ciprofl oxacin in three stated that the targeted sample size was selected to show trials, lomefl oxacin in two trials, and ofl oxacin in one trial). equivalence within a margin of 15% (Richard et al 1998a; One trial allowed patients to be administered either oral or Peterson et al 2008). One of these publications did not intravenous formulations. The effi cacy and safety results achieve the sample size targeted by their power calculation of this trial were not stratifi ed by formulation, although (Richard et al 1998a). The remaining trials, which were all 97% of the intention to treat group were started on an oral of smaller sample sizes, did not specifi cally describe the formulation of either levofl oxacin or the comparator (Peter- statistical power, sample size, or margin of equivalence that son et al 2008). The fi ve remaining trials evaluated oral the trial was designed to target. administration of levofl oxacin. Of these, four trials were The defi nition of cUTI varied across the four trials includ- specifi cally limited to outpatients and/or patients deemed ing these patients. The trials performed by Peng and Peterson appropriate candidates for oral therapy (Klimberg et al 1998; et al stated only that a diagnosis of cUTI was required, Richard et al 1998a, b). Five trials specifi cally included although females in the latter trial were also required to in their defi nitions of cUTI and AP that patients’ urine have at least one of the following complicating factors: cultures at the time of enrollment must contain at least 105 neurogenic bladder or urinary retention; partial obstruction, cfu/mL of a uropathogen (Klimberg et al 1998; Richard et al

846 Therapeutics and Clinical Risk Management 2008:4(5) Levofl oxacin for complicated UTI and pyelonephritis 1 ± Post-therapy: 5–9 days 5–9 days Post-therapy: after completion of therapy 4–6 Long-term follow-up: after completion of weeks therapy End of blinded therapy: 11 study day study days Post-therapy: 15–19 study days Post-study: 38–45 5–9 days Post-therapy: after completion of therapy 4–6 Long-term follow-up: after therapy weeks 3–5 of therapy Days 5–9 days Post-therapy: after completion of therapy 4–6 Long-term follow-up: after therapy weeks Endpoint evaluation: study Endpoint evaluation: 5 day Endpoints nition fi Cured (complete resolution (complete resolution Cured of the signs and symptoms associated with cUTI) (incomplete Improved of symptoms resolution for and no requirement further antibiotic therapy) Complete resolution of signs and symptoms associated with active infection Cured (resolution of signs (resolution Cured and symptoms associated disease) with active Improved (incomplete Improved of signs and resolution symptoms but no need for antibiotic therapy) additional Cured (resolution of (resolution Cured clinical signs pretreatment and symptoms without addi- tional antibacterial therapy) Improved (incomplete reso- Improved lution of signs and symptoms for and no requirement further antibiotic therapy)

Clinical success or improvement) (cure • • or Clinical success (cure improvement) • • Clinical cure • or Clinical Success (cured improved) • • Clinical cure based on Clinical cure on effect combined results and bacteriuria, on pyuria, symptoms. subjective Clinical outcome de cfu/mL) cfu/mL) cfu/mL) cfu/mL) cfu/mL) 4 4 4 4 4 nition 10 10 10 10 fi 10 < < < < < ed at study entry ed at study entry ed at study entry fi fi fi ts. ed at study entry bacteriuria ( Eradication ( Eradication ( Eradication ( Microbiologic Microbiologic outcome de of uropathogen(s) identi- of uropathogen(s) fi of uropathogen(s) identi of uropathogen(s) identi of uropathogen(s) identi Eradication ( 46 or decreased Cleared 380 461 185 1093 randomized oxacin oxacin oxacin oxacin oxacin oxacin oxacin oxacin oxacin oxacin fl fl fl fl fl oxacin 200 mg oxacin fl po three times po three 10 days for daily 500 mg po twice 10 days for daily 400 mg iv/500 for po twice daily 10 days 400 mg po once 14 days for daily Cipro 500 mg po twice 10 days for daily Lome 400 mg po once 14 days for daily vs O vs Cipro vs Cipro vs Lome vs vs oxacin 100 mg oxacin 250 mg oxacin oxacin 750 mg oxacin oxacin 250 mg oxacin oxacin 250 mg oxacin 250 mg oxacin fl fl fl fl fl fl Levo for po 3 times daily 10 days Levo for po once a day 10 days Levo for iv/po once daily 5 days Levo for po once daily 7–10 days po once a day for for po once a day 10 days Levo for po once daily 7–10 days Levo Double-blind, Double-blind, multi-center RCT Open-label, multi-center RCT Double-blind, Double-blind, single-center RCT Double-blind, RCT multi-center Double-blind, Double-blind, RCT multi-center Open-label, Open-label, RCT multi-center 1. 2. ndings of two trials. ndings of two fi AP, acute pyelonephritis; cUTI, complicated urinary tract infection; RCT, randomized controlled trial; cfu, colony-forming uni colony-forming cfu, trial; randomized controlled RCT, complicated urinary tract infection; cUTI, acute pyelonephritis; AP, and older with AP cUTI and Adult (18 yrs or older ) outpatients with cUTI Adults (18 yrs or AP older) with or cUTI Population Study design Treatment Comparator subjects No. Adults (18 yrs or AP older) with Adult (18 yrs or older) outpatients with cUTI a Overview of the study design of reviewed publications of the study design reviewed Overview Publications reports the Peng 1999Peng age 16 Persons Richard et al 1998a Richard et al 1998b Peterson Peterson et al 2008 Table 1 Table a Klimberg et al 1998 Abbreviations:

Therapeutics and Clinical Risk Management 2008:4(5) 847 McGregor et al

1998a, b; Peterson et al 2008). Four of these trials excluded spp., and Enterococcus spp. While not all studies reported subjects with previous infections with organisms known to the frequency with which these organisms were isolated, be resistant to any study medication (Klimberg et al 1998; among those that did, K. pneumoniae was isolated on average Richard et al 1998a, b). The fi fth excluded subjects if the UTI in 16% of subjects, while the remaining uropathogens were was caused by a pathogen resistant to either study medication all isolated in 10% or less of subjects. Among the studies (Peterson et al 2008). that reported species-specifi c microbiologic eradication Four trials also excluded patients with decreased renal rates, eradication failed on average in 7% of cases caused by function. Peng excluded patients with renal failure (and other E. coli within levofl oxacin-treated subjects (Klimberg et al extremely severe underlying diseases) (Peng 1999). Of the 1998; Richard et al 1998a; Peterson et al 2008). Peterson two trials described in Richard et al, one excluded all patients et al reported that levofl oxacin non-susceptible bacteria with a creatinine clearance less than 50 mL/min and the were isolated from 6% of levofl oxacin-treated subjects, and second excluded those with a creatinine clearance less than that no acquired resistance was observed (Peterson et al 20 mL/min (Richard et al 1998b). In the latter trial, dosing 2008). In their cUTI trial, Richard et al (1998a) reported that was altered for those with a creatinine clearance between 9.8% of isolates tested were not susceptible to levofl oxacin 20 and 50 mL/min. This same exclusion criteria (creatinine (Richard et al 1998a). These were the only publications to clearance of less than 20 mL/min) and altered dosing scheme provide these data. was also applied in the study by Klimberg et al (Klimberg As may be expected, the usage of urinary catheters was et al 1998). In both publications, no data were provided as observed in a number of patients in the included trials. All to the number of patients receiving altered dosing, nor were of the included studies allowed the inclusion of catheter- the effi cacy and safety results reported within this subset of ized patients, but only 2 of the studies reported the total subjects. Richard et al’s cUTI trial also excluded patients number of these patients, which constituted approximately with creatinine clearance less than 50 mL/min (Richard 5% of the subjects enrolled in these trials (Klimberg et al et al 1998a). 1998; Peterson et al 2008). Only one of the trials reported outcomes based on catheter usage. Peterson et al reported Microbiologic response a signifi cantly worse microbiologic eradication in the 68 Microbiologic eradication rates for levofloxacin were catheterized patients compared to those without catheters high in all trials. When assessed after the completion of (74.1% vs 89.0%; 95% CI: −26.6% to −3.3%). therapy, eradication rates ranging from 79.8% to 95.3% were observed (Table 2). These rates were not statistically Clinical response signifi cantly different from that of the comparator treatments. Clinical success was observed to range from 82.6% to 93% Peng evaluated microbiologic effi cacy only on day 5 of a when measured after the completion of therapy (Table 2). 10-day course of levofl oxacin and observed an eradication Again, Peng (1999) measured clinical effi cacy mid-treatment rate of 90%, which was also not signifi cantly different and observed a clinical success rate of 90%. Statistical testing from that of the comparator (Peng 1999). Richard et al of the differences in clinical effi cacy was only reported in reported relapse rates from the two trials described in that three publications, and none of these reported any signifi cant publication; at 4–6 weeks post-therapy, microbiologic relapse difference between the levofl oxacin and comparator groups was observed in 13% of levofl oxacin-treated subjects and in (Richard et al 1998a; Peng 1999; Peterson et al 2008). In 6.5% of comparator-treated (ciprofl oxacin or lomefl oxacin) the remaining two publications, reported clinical effi cacy study subjects. The difference was not statistically signifi - rates were higher for levofl oxacin than for the comparator cant (Richard et al 1998b). In their cUTI trial, Richard et al (Klimberg et al 1998; Richard et al 1998b). (1998a) reported a relapse rates of 9% in the levofl oxacin- treated group at 4–6 weeks post-therapy, though 38% of the Adverse events relapse cases were asymptomatic. Only Peterson et al (2008) reported the occurrence of serious All publications provided information regarding the adverse events (17 events in levofl oxacin-treated study uropathogens that were most frequently isolated, and in all subjects). While not all events were detailed in the publication, E. coli was the most commonly isolated (average = 61%). one allergic reaction and one death were reported. The Other commonly isolated pathogens included K. pneumoniae, death was not found to be treatment-related. Adverse event Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter rates were similar for levofl oxacin and comparators in all

848 Therapeutics and Clinical Risk Management 2008:4(5) Levofl oxacin for complicated UTI and pyelonephritis

Table 2 Summary of reported microbiologic and clinical effi cacy data Condition Effi cacy after completion No. subjects Days post-therapy Signifi cantly of therapy evaluated different from a Microbiologic Clinical comparator(s)? Klimberg et al 1998c cUTI 95.3% 93.0% 171 5–9 Nof Peng 1999d AP and cUTI 90.0% 90.0% 20 −5 No Peterson et al 2008b AP and cUTI 79.8% 82.6% 317 5–7 No Richard et al 1998ac,e AP 94.0% 92.0% 89 5–9 Nog Richard et al 1998b cUTI 91.0% 92.0% 126 5–9 No aalpha = 0.05. bData are presented from the modifi ed intention to treat analysis. cData are presented from the microbiologically evaluable study subjects; effi cacy not reported for intention to treat or modifi ed intention to treat groups. dNo end of therapy endpoint assessed. Data presented was collected on day 5 of therapy. ePublication reports the fi ndings of two trials; average effi cacy presented here. fStatistical comparison performed only for microbiologic effi cacy outcome. gNo statistical comparisons reported; however, microbiologic and clinical effi cacy rates for levofl oxacin were higher than for the comparators. Abbreviations: AP, acute pyelonephritis; cUTI, complicated urinary tract infection. publications. Only one publication specifi cally reported that be equivalent to the comparator (ciprofl oxacin) in both safety no statistically signifi cant differences in individual adverse and effi cacy (Klausner et al 2007). The average levofl oxacin event rates were found between treatment groups (Peterson effi cacy rates for this publication and Richard et al’s report of et al 2008). The most commonly observed adverse events two AP trials were 88.3% for microbiologic eradication and across all of the trials include: headache, diarrhea, dyspepsia, 88.5% for clinical success. Also noteworthy is that Peterson nausea, dyspnea, vaginitis, fl atulence, and dizziness. Labora- et al (2008) is the only trial of high-dose, short duration tory test abnormalities were infrequently reported. Klimberg levofl oxacin therapy. This trial observed effi cacy rates that et al (1998) reported that changes in clinical laboratory results were 12.8% lower on average for microbiologic eradication occurred infrequently and were comparable across groups. and 9.2% lower on average for clinical success than reported Peng (1999) described patients receiving levofl oxacin who by the other publications. As described above, this was also experienced elevated alanine aminotransferase, potassium, the only trial to report the occurrence of serious adverse blood urea nitrogen, and hemoglobin, but these laboratory events among levofl oxacin-treated study subjects. changes were not attributed to levofl oxacin therapy. No other studies described laboratory value alterations. Discussion The objective of this review was to provide a summary of Acute pyelonephritis versus the existing effi cacy and safety data pertaining to the use complicated UTI of levofl oxacin for the treatment of cUTI and AP. While Four of the trials included in this review included patients our search of the literature revealed only fi ve publications with cUTI. However, two of these trials included patients meeting the criteria for inclusion, all reported generally with AP, and did not provide results stratifi ed by infection. Of high microbiologic and clinical effi cacy rates with minimal these two studies, that of Peng (1999) consisted primarily of occurrences of serious adverse events. Despite this, the AP patients (16/20 in the levofl oxacin arm and 19/26 in the paucity of data in this area leaves several questions as to the ofl oxacin arm), while Peterson et al (2008) enrolled primarily generalizability of these trials. cUTI patients (391/537 in the levofl oxacin arm and 391/556 The US FDA approves medications for the indication of in the ciprofl oxacin arm). The average levofl oxacin effi cacy urinary tract infections, including pyelonephritis, under two rates for the two publications reporting effi cacy for cUTI categories: (1) uncomplicated urinary tract infections and alone was 93.5% for microbiologic eradication and 92.6% for (2) complicated urinary tract infections and pyelonephritis. clinical success (Klimberg et al 1998; Richard et al 1998a). The trials included in this review used defi nitions generally While Peterson et al did not report stratifi ed effi cacy results, consistent with this classifi cation. In contrast to this, the a second publication by the authors (that was not included IDSA has utilized a relatively more complex categorization in this review due to duplicity) reports the results for AP scheme that recommends the use of the following categories patients alone. This publication also found levofl oxacin to in the evaluation of anti-infectives for urinary tract

Therapeutics and Clinical Risk Management 2008:4(5) 849 McGregor et al infections: (1) acute uncomplicated UTI in women, (2) acute effi cacy, but would also provide for direct comparisons in uncomplicated pyelonephritis, (3) complicated UTI and UTI safety profi les, which may vary to a greater extent between in men, (4) asymptomatic bacteriuria, and (5) recurrent UTI antimicrobial classes. (antimicrobial prophylaxis) (Rubin et al 1992). While the Levofl oxacin was generally well-tolerated in all of the FDA acknowledges that AP can be either an uncomplicated reviewed trials; this is consistent with what has been observed or complicated disease, it justifi es the aggregation of all AP in other settings at the currently approved doses (Anderson with cUTI by noting that antibiotic dosing regimens for these and Perry 2008). A pooled analysis of patients with respi- conditions are generally similar (US Department of Health ratory tract infections who were prescribed levofl oxacin and Human Services et al 1998). Nevertheless, clinical 500 mg or 750 mg found that patients receiving both and/or microbiologic responses may vary between patients doses experienced a similar rate of adverse events during with different complicating factors, including such factors treatment, and the specifi c adverse events observed were as physical obstruction of the urinary tract, male gender, similar to those in the trials reviewed here (Khashab et al and immunosuppression. These differences may stem from 2006). Additional adverse events not commonly reported the need for additional interventional therapies to ensure the in the reviewed publications, but that have been reported in resolution of the infection. For example, cUTI patients with association with levofl oxacin, include photosensitivity, QTc anatomical abnormalities may require surgery, and for those prolongation, hypersensitivity, convulsions, Clostridium with neurogenic bladders, catheterization may be necessary diffi cile-associated diarrhea, and tendon rupture; many of to manage urination (Matsumoto et al 2001; Neal 2008). these adverse reactions are rarely reported and have been Studies of cUTI included in this review generally did not associated with other fl uoroquinolones (Anderson and Perry present effi cacy results stratifi ed according to the specifi c 2008). A comprehensive review of adverse events associated complicating factor(s). One exception is the trial performed with fl uoroquinolone use is not included here; the reader by Peterson et al (2008), which reported signifi cantly differ- is referred to a recent review of this topic (Mehlhorn and ent microbiologic eradication rates among the catheterized Brown 2007). and non-catheterized patients. These results suggest that the Two of the trials that we reviewed included patients presence of catheters may infl uence outcomes in these studies, who received altered levofl oxacin doses based upon renal and stratifi cation of results by catheter usage is warranted. function, although results were not stratifi ed according to We agree with others who have recommended that studies the dose received (Klimberg et al 1998; Richard et al 1998b). including patients with cUTI should report results stratifi ed An inherent difference in clinical or microbiologic response according to specifi c patient characteristics, since patients would not be expected in these patient groups, assuming with cUTI present with a heterogeneous collection of factors that dosing according to renal function was performed that make their infection complicated (Naber 1999). appropriately. However, further evidence of the effi cacy All of the clinical studies presented compared levofl oxacin of the various approved dosing regimens of levofl oxacin is with another fl uoroquinolone. All studies reported similar needed. Similarly, the trial by Peterson et al (2008) did not microbiologic and clinical responses for these comparators. report outcomes that were stratifi ed according to whether No data are available regarding a comparison of levofl oxacin patients received oral or intravenous therapy. Based on with other classes of antimicrobials. In general, this may levofl oxacin’s oral bioavailability of 100%, we do not expect be due to a lack of suitable oral alternatives. While direct that patients receiving oral levofl oxacin would experience comparisons are lacking, it has been noted that similar poorer outcomes than those receiving intravenous therapy; microbiologic success rates ranging from 71%–91% have however, receipt of intravenous therapy may be a marker of been reported in trials using beta-lactams and monobactams more severe illness (eg, bacteremic patients) and thus a more (piperacillin/tazobactam, ceftriaxone, aztreonam, thorough analysis of effi cacy that is stratifi ed by the route of ceftazidime), carbapenems (imipenem, meropenem, administration is warranted. ertapenem) and aminoglycosides (amikacin) (Melekos et al The majority of the patients included in the trials 1991; Nowe 1994; Cox et al 1995; Wells et al 2004). It is described in this review presented with infections of moderate not possible to directly compare the results of these studies severity, and most studies included only patients who to the included levofl oxacin studies, but crude effi cacy rates received oral therapy on an outpatient basis. The clinical were similar. Additional research using non-fl uoroquinolone and microbiologic effi cacy of levofl oxacin in patients with comparators would provide not only direct comparisons of more severe illness (including hospitalized patients) requires

850 Therapeutics and Clinical Risk Management 2008:4(5) Levofl oxacin for complicated UTI and pyelonephritis further study. Furthermore, larger studies are needed so that and ongoing surveillance of antimicrobial resistance in levofl oxacin’s effi cacy can be evaluated among patients uropathogens is of paramount importance. infected with organisms other than E. coli, since the incidence In the case of uncomplicated urinary tract infections, of antimicrobial resistance in urinary tract infections caused significant research has led to reduced durations of by these pathogens is not well-described, and cUTI and antimicrobial therapy in patients with these infections. AP are frequently caused by pathogens other than E. coli Reducing unnecessarily long durations of therapy is one (Nicolle 1997). aim of the judicious antimicrobial movement, which aims Furthermore, few studies provided meaningful informa- to reduce the evolutionary selective pressures that drive the tion regarding the development of fl uoroquinolone resistance. emergence and growing prevalence of antibiotic resistance. Although fl uoroquinolone resistance in such uropathogens In 2007, the US FDA approved a higher dose, shorter duration as E. coli remains somewhat rare in the US, the prevalence levofl oxacin regimen for cUTI and AP. We identifi ed only of such resistance is undoubtedly increasing. Regional one trial, sponsored by Ortho-McNeil Pharmaceuticals, Inc., variations in the prevalence of levofl oxacin resistance have in which this therapy was evaluated. Although both micro- already been identifi ed within the US, where the prevalence biologic and clinical effi cacy results were slightly lower for of resistance varies from 3.7% in New England to 9.1% in the this regimen (750 mg daily for 5 days) than had been reported Mid-South region (David et al 2005). Peterson et al (2008) in other trials using longer durations of lower-dose therapy, was the only publication to report data on resistance that this trade-off may be acceptable in patients with less severe emerged during the course of therapy, though they reported disease and may help to limit the increasing development of zero occurrences of this event. Fluoroquinolone-resistant fl uoroquinolone resistance. E. coli has also been isolated in the rectal fl ora of patients who received ciprofl oxacin for acute uncomplicated cystitis; Conclusions thus, evaluating resistance in urinary isolates alone may be Levofl oxacin has demonstrated high rates of microbiologic and insuffi cient (Gupta et al 2005). With the recent proliferation clinical success, with outcomes similar to those obtained by of TMP/SMX-resistant E. coli, fluoroquinolones have comparator fl uoroquinolones in the included trials. All of the frequently become the recommended empiric therapy of available fl uoroquinolones possess activity against common choice for acute uncomplicated cystitis (Le and Miller 2001; uropathogens, including E. coli, and most of these agents Warren 2001). In fact, a recent study found that fl uoroquino- display favorable pharmacokinetics in the setting of UTI. lones had replaced TMP/SMX nationwide as the preferred Alternatives to the fl uoroquinolones for the treatment of cUTI fi rst-line antimicrobial for uncomplicated cystitis (Kallen and AP include penicillins, cephalosporins, and TMP/SMX; et al 2006). Unfortunately, the long-term viability of this little data regarding the comparative effi cacy of these agents strategy in the face of increasing fl uoroquinolone resistance is available. It is diffi cult to assess the generalizability of stud- is uncertain, and investigations of fl uoroquinolone-sparing ies of cUTI and/or AP because of the lack of a standardized regimens for cUTI and AP, using agents such as TMP/SMX, defi nition of cUTI, a high degree of variability in study design, are needed (Kallen et al 2006; Gupta et al 2007). The future and the level of stratifi cation with which data are reported. An use of fl uoroquinolones in the management of cUTI and important clinical outcome that was not adequately reported AP is also threatened by the ongoing increase in the num- in the majority of these publications was the development of ber of these infections that are caused by ESBL-producing antimicrobial resistance while receiving therapy. This may Enterobacteriaceae, which tend to display cross-resistance be an important distinguishing factor among antimicrobials. to fl uoroquinolones (Muratani and Matsumoto 2006; Baudry Ongoing surveillance for fl uoroquinolone resistance among et al 2008). Furthermore, E. coli isolates may harbor resis- uropathogens is needed so that these data can be applied in the tance-conferring mutations yet appear to be fully-susceptible empiric therapy decision-making process. Furthermore, more according to susceptibility breakpoint standards established research is needed to determine optimal treatment durations by the Clinical and Laboratory Standards Institute (Komp and dosing regimens for antibiotics in the treatment of cUTI Lindgren et al 2003). New trials that examine levofl oxacin in and AP. Rational antibiotic use for high-incidence infections, the setting of cUTI and/or AP should include data regarding such as the UTIs, are critical to the control of increasing anti- the prevalence of resistance (whether it is present in the biotic resistance (David et al 2005). Although levofl oxacin has original infecting isolate or develops during fl uoroquinolone been associated with favorable outcomes in patients with AP therapy), as it is a mitigating factor in treatment failure, and cUTI, further comparative trials are needed to establish the

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