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 specifically defines a cUTI. Traditionally, urinary tract infections in patient populations such as those with diabetes mellitus, pregnant females, and males have been considered to be complicated infections (Anderson 1996). Other descriptions of a cUTI have also included patients who are elderly, have experienced recent instrumentation or antimicrobial treatment, or possess functional or anatomic abnormalities of the genitourinary tract (Hooton and Stamm 1991). Ronald et al proposed an alternate classification scheme, in which a cUTI is characterized by the presence of structural abnormalitiesa (urinary obstructions, neurogenic bladder, etc.), metabolic and/or hormonal abnormalities (diabetes mellitus, pregnancy, renal impairment, etc.), impaired host responses (transplant recipients, neutropenic patients, etc.), or infection with an unusual pathogen (including yeasts, fungi, and antimicrobial-resistant bacteria) (Ronald and Harding 1997). Mandell’s Principles and Practice of Infectious Diseasesdefines cUTIs as urinary tract infections in men, pregnant women, children, hospitalized patients, and patients with functional or structural abnormalities of the urinary tract (Sobel and Kaye 2005).

AP is commonly described as an infection of the upper urinary tract that encompasses fever and flank pain and/or tenderness that are accompanied by dysuria and urinary urgency and frequency, although it is more accurately diagnosed based on the presence of these symptoms along with bacteriuria and acute renal infection (Sobel and Kaye 2005). AP was formerly treated largely on an inpatient basis, but a recent trend towards outpatient management of this condition has been noted (Czaja et al 2007). As seen in cUTI, the most common pathogen causing AP is Escherichia coli (Nicolle 1997; Czaja et al 2007).Comparing Levofloxacin And Ofloxacin Health Essay.

The role of fluoroquinolones in the management of genitourinary infections

Currently available fluoroquinolones that are approved by the US Food and Drug Administration (FDA) for the treatment of cUTI and/or AP include ciprofloxacin, levofloxacin, norfloxacin, and ofloxacin. The fluoroquinolones gemifloxacin and moxifloxacin are not approved for either condition. Gatifloxacin was awarded FDA approval for the management of cUTI and AP, but this agent was withdrawn from the US market in 2006. Levofloxacin, approved by the US FDA in 1996, is the Senantiomer of the racemate ofloxacin. The S enantiomer of ofloxacin displays antibacterial activity that is approximately 2 orders of magnitude greater than that of the R enantiomer; this enhanced activity is due to greater binding to and saturation of the binding site on the DNA gyrase enzyme (Morrissey et al 1996). Studies of ofloxacin were not included in the present analysis.

The Infectious Diseases Society of America (IDSA) has published guidelines for the management of acute uncomplicated cystitis and AP (Warren et al 1999). For cases of AP that are manageable on an outpatient basis using oral antimicrobial therapy, the IDSA recommends a fluoroquinolone as the preferred empiric therapy, with trimethoprim/sulfamethoxazole (TMP/SMX) offered as an alternative. In patients that are to be hospitalized, the guidelines recommend the use of intravenous therapy with a fluoroquinolone, an aminoglycoside with or without ampicillin, or an extended-spectrum penicillin with or without an aminoglycoside. After such patients are stabilized, the IDSA recommends that the course of treatment be completed with an oral fluoroquinolone or oral TMP/SMX. Alternatives are recommended for each of the above patient populations if the infecting organism is known to be a Gram-positive coccus. Recommended first-line agents for the treatment of uncomplicated cystitis include a fluoroquinolone or TMP/SMX, depending on the local rate of TMP/SMX resistance in E. coli. IDSA is currently working towards assembling guidelines for the treatment of cUTI, and publication is anticipated in late 2008. The European Association of Urology (EAU) has published guidelines that include recommendations for cUTI, which advise the use of fluoroquinolones with mainly renal excretion when empiric therapy is necessary. The EAU recommends avoiding TMP/SMX as first-line treatment because of the increasingly high prevalence of resistance to that antimicrobial agent (Grabe et al 2008).

Fluoroquinolone resistance

Fluoroquinolones have been extensively used in the management of genitourinary infections, especially acute uncomplicated cystitis. While fluoroquinolone resistance in uropathogens was once rare, resistance in E. coli has emerged and continues to increase. Fluoroquinolone resistance occurs through multiple mechanisms including chromosomal point mutations in the genes encoding DNA gyrase and/or topoisomerase iv, mutations that cause decreased expression of outer membrane proteins (OMPs), alterations in the lipopolysaccharide (LPS) component of the cell envelope, and enhanced fluoroquinolone efflux by efflux pumps such as AcrAB (Chenia et al 2006; Chang et al 2007). Plasmid-borne resistance has also recently been discovered, and is caused by protection of DNA gyrase and topoisomerase IV by Qnr-like proteins, including QnrA (Chenia et al 2006). Surveillance of urinary isolates collected between 1989 and 1997 found that fluoroquinolone resistance in E. coli was essentially nonexistent during this time frame (Gupta et al 1999a; Gupta et al 1999b). More recently, results of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, a multicenter surveillance study performed between 2003 and 2004 in the US and Canada, reported that overall resistance rates to ciprofloxacin and levofloxacin were 5.5% and 5.1%, respectively (Zhanel et al 2006). Comparing Levofloxacin And Ofloxacin Health Essay.Similar increases in fluoroquinolone resistance have been noted in the setting of AP (Czaja et al 2007). Also, among the emerging extended-spectrum beta-lactamase (ESBL)-producing E. coli, higher rates of fluoroquinolone resistance have been reported. In China, levofloxacin resistance among ESBL-producing E. coli was reported in 86% of isolates (Xiong et al 2002). In the US, one healthcare system reported that 56% of ESBL-producing E. coli and Klebsiella pneumoniae were resistant to fluoroquinolones (Lautenbach et al 2001).

Overview of study designs

Three trials were conducted in the US (Klimberg et al 1998; Richard et al 1998b; Peterson et al 2008), two trials in the US and Canada (Richard et al 1998b), and one trial was conducted in Taiwan (Peng 1999). The latter was also the only single-center trial. Only two publications specifically stated that the targeted sample size was selected to show equivalence within a margin of 15% (Richard et al 1998a; Peterson et al 2008). One of these publications did not achieve the sample size targeted by their power calculation (Richard et al 1998a).Comparing Levofloxacin And Ofloxacin Health Essay.  The remaining trials, which were all of smaller sample sizes, did not specifically describe the statistical power, sample size, or margin of equivalence that the trial was designed to target.

The definition of cUTI varied across the four trials including these patients. The trials performed by Peng and Peterson et al stated only that a diagnosis of cUTI was required, although females in the latter trial were also required to have at least one of the following complicating factors: neurogenic bladder or urinary retention; partial obstruction, renal tumor or fibrosis, distorted urethral structure; and/or intermittent catheterization (Peng 1999; Peterson et al 2008). The studies of cUTI published by Klimberg et al and Richard et al required that all subjects possess an anatomic or functional abnormality of the urinary tract and at least one of the following symptoms: urgency frequency, dysuria, hematuria, or fever or history of fever (Klimberg et al 1998; Richard et al 1998a). Klimberg et al also required that patients present with a baseline urinary sample with more than five urinary white blood cells/high-power field (Klimberg et al 1998). Three trials also required that study participants present with 10⁵ or more colony-forming units (cfu)/mL of at least one species of uropathogen (Klimberg et al 1998; Richard et al 1998a; Peterson et al 2008), although Peterson et al excluded patients with more than two species of uropathogen present at baseline (Peterson et al 2008).

Four trials included AP patients. In three of the trials, the definitions of AP were similar and required that patients present with 10⁵ or more cfu/mL of at least one species of uropathogen and two or more of the following symptoms: fever, flank pain or costovertebral angle tenderness, peripheral white blood cell count (WBC) more than 12,500/mm³ or 10% or greater bands, and/or WBC casts in the urine, or, in the case of Peterson et al a positive antibody-coated bacteria test (Richard et al 2002; Peterson et al 2008). Similar to the definition of cUTI, Peterson et al required that subjects with AP have at least one of the following symptoms: urgency frequency, dysuria, hematuria, or fever or history of fever (Peterson et al 2008). In contrast, Peng required only a diagnosis of AP (Peng 1999). All trials assessed the outcomes of microbiologic eradication and clinical success. These definitions were similar across all trials (Table 1).

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In each of the six trials, another fluoroquinolone was selected as the comparator treatment (ciprofloxacin in three trials, lomefloxacin in two trials, and ofloxacin in one trial). One trial allowed patients to be administered either oral or intravenous formulations. The efficacy and safety results of this trial were not stratified by formulation, although 97% of the intention to treat group were started on an oral formulation of either levofloxacin or the comparator (Peterson et al 2008). The five remaining trials evaluated oral administration of levofloxacin. Of these, four trials were specifically limited to outpatients and/or patients deemed appropriate candidates for oral therapy (Klimberg et al 1998; Richard et al 1998a, b). Five trials specifically included in their definitions of cUTI and AP that patients’ urine cultures at the time of enrollment must contain at least 10⁵ cfu/mL of a uropathogen (Klimberg et al 1998; Richard et al 1998a, b; Peterson et al 2008).Comparing Levofloxacin And Ofloxacin Health Essay.  Four of these trials excluded subjects with previous infections with organisms known to be resistant to any study medication (Klimberg et al 1998; Richard et al 1998a, b). The fifth excluded subjects if the UTI was caused by a pathogen resistant to either study medication (Peterson et al 2008).

Four trials also excluded patients with decreased renal function. Peng excluded patients with renal failure (and other extremely severe underlying diseases) (Peng 1999). Of the two trials described in Richard et al, one excluded all patients with a creatinine clearance less than 50 mL/min and the second excluded those with a creatinine clearance less than 20 mL/min (Richard et al 1998b). In the latter trial, dosing was altered for those with a creatinine clearance between 20 and 50 mL/min. This same exclusion criteria (creatinine clearance of less than 20 mL/min) and altered dosing scheme was also applied in the study by Klimberg et al (Klimberg et al 1998). In both publications, no data were provided as to the number of patients receiving altered dosing, nor were the efficacy and safety results reported within this subset of subjects. Richard et al’s cUTI trial also excluded .Comparing Levofloxacin And Ofloxacin Health Essay.