Treatment Of Complicated Urinary Tract Infections Research Articles

Real-world evidence: Telemedicine for complicated cases of urinary tract infection.

Telemedicine programs for the treatment of urinary tract infections (UTIs) offer an opportunity to reduce burdens on patients and providers. However, these programs are typically restricted to patients with uncomplicated UTIs. This real-world analysis evaluated treatment and resolution rates in a large-scale, national UTI telemedicine program inclusive of patients with uncomplicated and complicated UTIs. We conducted a retrospective analysis of data obtained from a commercially available telemedicine program for the treatment of UTIs among adult women in the US between 2017 and 2021 (n = 51,474). The primary outcomes were the number of women who presented with symptoms of uncomplicated UTI, complicated UTI, and vaginal infection; prescription use and antibiotic type; symptom resolution within seven days after appointment; and treatment failure or relapse. Most patients reported frequent urination (94.4%), urgency (94.5%), and dysuria (97.6%). Those with uncomplicated UTI symptoms represented the majority of patients (61.6%); however, a substantial number of patients (36.5%) also reported at least one symptom associated with a complicated UTI. One-fifth of patients (19.2%) reported at least one co-occurring symptom of vaginal infection or sexually transmitted infection. Across all treated patients, 94.0% received recommended antibiotics according to the clinical protocol. Of the treated patients who provided follow-up data (n = 3,521), 89.7% reported seven-day symptom resolution. Symptom resolution rates were similar between patients with uncomplicated UTI symptoms (90.8%) and complicated UTI symptoms (87.9%), and symptom resolution among all treated patients (89.7%) was similar to reports for in-person standard of care. These findings suggest that large-scale telemedicine programs for the treatment of UTIs can be effective in the treatment of complicated UTIs.

Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis

Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections. To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis. A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens. Eligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline). The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified. Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events. Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis. ClinicalTrials.gov Identifier: NCT03687255.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

1043. Activity of Mecillinam Against Enterobacterales Isolates Collected From Patients With Urinary Tract Infections (UTIs) in the USA During 2019

BackgroundMecillinam is a β-lactam antibiotic that exerts its antibacterial activity by binding to penicillin-binding protein 2. In the USA, intravenous (IV) mecillinam is in development for the treatment of complicated UTIs in the hospital setting and as step-down therapy transitioning from IV mecillinam to oral pivmecillinam so that patients can continue treatment at home. To support the clinical development of mecillinam in the USA for the treatment of both complicated and uncomplicated UTI, this observational study investigated the activity of mecillinam against Enterobacterales isolates from patients with UTI in the USA, collected during 2019. MethodsThis study evaluated the activity of mecillinam and other antimicrobial agents against 1075 selected Enterobacterales clinical isolates collected from patients with UTI in the USA during 2019. Antibiotic activity (minimum inhibitory concentration [MIC]) was determined by Clinical & Laboratory Standards Institute (CLSI) agar dilution methodology, and susceptibility was interpreted according to CLSI guidelines. ResultsAmong the selected 1075 isolates, producers of extended-spectrum beta-lactamase (ESBL) represented 9.6% of Escherichia coli and 50% of Klebsiella pneumoniae. Ninety-five percent of the isolates tested were susceptible to mecillinam (Table 1). The MIC50 and MIC90 values for mecillinam were 0.25 and 2 µg/mL, respectively. Fosfomycin MIC50 and MIC90 were 1 and 32 µg/mL, respectively (97.6% of isolates were susceptible). Mecillinam showed the lowest MIC90 value of all single antibiotics tested. The highest MIC90 was 128 µg/mL for both nitrofurantoin and cefotaxime. The lowest percentage of resistance was obtained with fosfomycin (1.7%), followed by mecillinam (4%).Table 1: Summary MIC and susceptibility data for all isolates tested (n=1075) ConclusionOverall, mecillinam showed excellent activity and a comparable resistance profile to fosfomycin. Resistance rates to ceftazidime, cefotaxime, ciprofloxacin and trimethoprim/sulfamethoxazole of greater than 20% are concerning due to the frequent use of these antibiotics in clinical practice to treat UTIs. Taken together, these data demonstrate that mecillinam has promising activity, with low resistance observed in Enterobacterales species causing UTIs in the USA. Clinical development of mecillinam in the USA is ongoing. Disclosures Stephen Hawser, PhD, Utility Therapeutics (Grant/Research Support) Ian Morrissey, Utility Therapeutics (Grant/Research Support) Anne Santerre Henriksen, MS, Advanz (Consultant)Shionogi BV (Consultant)UTILITY Therapeutics (Consultant)

1417. Fosfomycin Use in the Treatment of Complicated Urinary Tract Infections at a Veterans Affairs Medical Center

BackgroundThe prevalence of multidrug resistant gram-negative urinary tract infections (UTIs) is increasing, often requiring intravenous antimicrobial therapy. Oral fosfomycin is a recommended alternative agent for the treatment of cystitis caused by extended spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli). The primary objective of this study is to evaluate the efficacy of fosfomycin in the treatment of UTIs at the Veterans Affairs Long Beach Healthcare System. The secondary objective is to assess the incidence of adverse drug reactions associated with fosfomycin. MethodsThis is a retrospective, single-center, cohort study. Patients who received fosfomycin between June 1st, 2015 – June 30th, 2020 were included. Data collection was completed by chart review through the Computerized Patient Record System (CPRS). Descriptive analysis was used to evaluate data. Treatment outcomes were analyzed using a composite of clinical and microbiological cure. Clinical cure was defined as resolution of UTI symptoms. Microbiological cure was defined as urine sterilization within 1 month after completing treatment course with fosfomycin.ResultsA total of 62 unique patients were evaluated in this study. The mean age was 71.9 years. 56 patients (90.3%) were male, 31 patients (50.0%) had an indwelling catheter present at the time of treatment, and 48 patients (77.4%) had the presence of genitourinary tract pathology that may increase the risk of developing UTIs. Majority of patients (50%) had a urine culture result positive for E. coli prior to treatment, of which 43.5% were ESBL-producing. 60 patients (96.8%) received more than 1 dose of Fosfomycin. Out of 29 patients who were eligible to be evaluated for clinical outcomes, 20 patients (68.9%) met a positive composite outcome of either microbiological cure, clinical cure, or both. 4 patients (6.5%) experienced an adverse drug reaction of diarrhea that was self-limited. ConclusionFosfomycin is an effective and well-tolerated antimicrobial agent that may be considered for treatment of complicated UTIs without evidence of pyelonephritis or bacteremia caused by multi-drug resistant organisms in the veteran population.Disclosures All Authors: No reported disclosures

What place does ceftolozane/tazobactam have in the treatment of complicated urinary-tract infections?

Complicated urinary infections (cUTI) are among the most frequent health-care associated diseases and a large part of them are caused by multidrug-resistant microorganisms. Infections due to multid...

Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)

Treatment of complicated urinary-tract infections is challenging due to rising antimicrobial resistance. We assessed the efficacy and safety of ceftolozane-tazobactam, a novel antibacterial with Gram-negative activity, in the treatment of patients with complicated lower-urinary-tract infections or pyelonephritis. ASPECT-cUTI was a randomised, double-blind, double-dummy, non-inferiority trial done in 209 centres in 25 countries. Between July, 2011, and September, 2013, hospital inpatients aged 18 years or older who had pyuria and a diagnosis of a complicated lower-urinary-tract infection or pyelonephritis were randomly assigned in a 1:1 ratio to receive intravenous 1·5 g ceftolozane-tazobactam every 8 h or intravenous high-dose (750 mg) levofloxacin once daily for 7 days. The randomisation schedule was computer generated in blocks of four and stratified by study site. The next allocation was obtained by the study site pharmacist via an interactive voice-response system. The primary endpoint was a composite of microbiological eradication and clinical cure 5-9 days after treatment in the microbiological modified intention-to-treat (MITT) population, with a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, numbers NCT01345929 and NCT01345955. Of 1083 patients enrolled, 800 (73·9%), of whom 656 (82·0%) had pyelonephritis, were included in the microbiological MITT population. Ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (306 [76·9%] of 398 vs 275 [68·4%] of 402, 95% CI 2·3-14·6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious. Treatment with ceftolozane-tazobactam led to better responses than high-dose levofloxacin in patients with complicated lower-urinary-tract infections or pyelonephritis. Cubist Pharmaceuticals.

SP17-1 How to use PK–sPD for our best practice – From the standpoint of the physician

Urinary tract infections (UTIs) are among the most prevalent infectious diseases in the general population. They cause a substantial financial burden in the community and are associated with significant morbidity and mortality, particularly in hospitals. With increased rates of antimicrobial resistance, especially in the Asia-Pacific region, treatment of complicated UTIs (cUTIs) can be challenging for clinicians. Consideration of an optimal antimicrobial agent should be based on local resistance patterns, patient-specific factors, pharmacokinetic and pharmacodynamic principles, and cost. In the Asia-Pacific region, nearly half of Escherichia coli urinary isolates were resistant (including intermediate and resistant) to levofloxacin or ciprofloxacin and ≥30% were resistant to third-generation cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) and cefepime. Overall, 33% of urinary E. coli isolates exhibited extended-spectrum β-lactamase (ESBL)-producing phenotypes. Prevalence of ESBL-producing urinary E. coli was highest in India (60%), followed by Hong Kong (48%) and Singapore (33%). All urinary isolates of E. coli were susceptible to both ertapenem and imipenem. All urinary isolates of Klebsiella pneumoniae were susceptible to imipenem and 4% of them were resistant to ertapenem. Care should be exercised when using trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones, and cephalosporins for the empirical treatment of UTIs, particularly cUTI among moderately to severely ill patients. Empiric antimicrobial treatment for serious cUTIs in which risk factors for resistant organisms exist should include broad-spectrum antibiotics such as carbapenems (ertapenem, imipenem, meropenem, and doripenem) and piperacillin–tazobactam. Aminoglycosides, tigecycline, and polymyxins (colistin or polymyxin B) can be used for the treatment of multidrug-resistant organisms or serious cUTIs when first-line options are deemed inappropriate or patients fail therapy. Because of considerable variability in different countries, local epidemiological data is critical in the effective management of UTIs in the Asia-Pacific region.

Consensus review of the epidemiology and appropriate antimicrobial therapy of complicated urinary tract infections in Asia-Pacific region

Urinary tract infections (UTIs) are among the most prevalent infectious diseases in the general population. They cause a substantial financial burden in the community and are associated with significant morbidity and mortality, particularly in hospitals. With increased rates of antimicrobial resistance, especially in the Asia-Pacific region, treatment of complicated UTIs (cUTIs) can be challenging for clinicians. Consideration of an optimal antimicrobial agent should be based on local resistance patterns, patient-specific factors, pharmacokinetic and pharmacodynamic principles, and cost. In the Asia-Pacific region, nearly half of Escherichia coli urinary isolates were resistant (including intermediate and resistant) to levofloxacin or ciprofloxacin and ≥30% were resistant to third-generation cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) and cefepime. Overall, 33% of urinary E. coli isolates exhibited extended-spectrum β-lactamase (ESBL)-producing phenotypes. Prevalence of ESBL-producing urinary E. coli was highest in India (60%), followed by Hong Kong (48%) and Singapore (33%). All urinary isolates of E. coli were susceptible to both ertapenem and imipenem. All urinary isolates of Klebsiella pneumoniae were susceptible to imipenem and 4% of them were resistant to ertapenem. Care should be exercised when using trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones, and cephalosporins for the empirical treatment of UTIs, particularly cUTI among moderately to severely ill patients. Empiric antimicrobial treatment for serious cUTIs in which risk factors for resistant organisms exist should include broad-spectrum antibiotics such as carbapenems (ertapenem, imipenem, meropenem, and doripenem) and piperacillin-tazobactam. Aminoglycosides, tigecycline, and polymyxins (colistin or polymyxin B) can be used for the treatment of multidrug-resistant organisms or serious cUTIs when first-line options are deemed inappropriate or patients fail therapy. Because of considerable variability in different countries, local epidemiological data is critical in the effective management of UTIs in the Asia-Pacific region.

Efficacy and Safety of Ciprofloxacin XR 1000 mg Once Daily Versus Ciprofloxacin 500 mg Twice Daily in the Treatment of Complicated Urinary Tract infections

The aim of this trial was to compare the efficacy and safety of extended-release ciprofloxacin (CIPRO XR) versus the immediate-release formulation (CIPRO IR) in the treatment of complicated urinary tract infections (UTIs). 212 patients were randomized to CIPRO XR 1,000 mg tablet once daily or CIPROXIN IR 500 mg tablet twice daily. Treatment efficacy was evaluated by bacteriological outcome. Safety was measured by recording adverse events. The rate of bacteriological eradication was 83% in the CIPRO XR group and 75% in the CIPRO IR. The overall incidence of adverse events reported was higher in the CIPRO IR group. The authors conclude that CIPRO XR is a safe and effective treatment for complicated UTIs. Although the limited data available do not consent to support a statistically superior efficacy or safety compared to CIPRO IR, a trend in favor of CIPRO XR is clearly evident in all efficacy and safety variables. CIPRO XR is associated with reduced frequencies of drug-related adverse events compared to CIPRO IR.

Urinary Bactericidal Activity and Pharmacokinetics of Enoxacin Versus Norfloxacin and Ciprofloxacin in Healthy Volunteers After a Single Oral Dose

In an open, randomised monocentric crossover study in six male and six female healthy volunteers, the urinary antibacterial activity and pharmacokinetics of enoxacin, norfloxacin and ciprofloxacin were assessed. Urine was collected up to 6 days, and venous blood samples up to 12 h, after a single oral dose of 400 mg enoxacin, 400 mg norfloxacin and 500 mg ciprofloxacin. Enoxacin (250 mg:l) demonstrated the highest peak concentration (median) in the urine (0‐6 h), followed by ciprofloxacin (237 mg:l) and norfloxacin (157 mg:l) as determined by the HPLC assay. The total amount (mean) excreted by the kidneys as parent drugs were as follows: enoxacin 54% of dose, ciprofloxacin 33% of dose, and norfloxacin 22% of dose. The mean plasma concentrations decreased from 1 to 4 h after administration for enoxacin from 1.9 to 1.4 mg:l, for ciprofloxacin from 2.0 to 0.8 mg:l and for norfloxacin from 1.3 to 0.5 mg:l. The antibacterial activity in urine was determined as urinary bactericidal titers (UBT), i.e. the highest 2-fold dilution of urine still bactericidal for the reference organism (E. coli ATCC 25922) and for five uropathogens with minimal inhibitory (MIC) and bactericidal (MBC) concentrations ranging from highly susceptible to resistant cultured from the urine of patients with complicated urinary tract infections (UTI). For the E. coli ATCC 25922, the organism with the lowest MIC, median UBTs of ciprofloxacin were present for 4 days, decreasing from 1:512 to 1:2, that of enoxacin for 2 days, decreasing from 1:256 to 1:4, and that of norfloxacin for 2 days, decreasing from 1:128 to 1:2. For the five uropathogens (with increasing MICs: K. pneumoniae, P. mirabilis, E. coli (resistant to nalidixic acid), P. aeruginosa and E. faecalis), the UBTs decreased in general, according to MICs, demonstrating the same relations of UBTs for ciprofloxacin (highest) versus enoxacin (medium) versus norfloxacin (lowest) with one exception (P. mirabilis) for which norfloxacin showed higher UBTs than enoxacin. The minimal urinary bactericidal concentrations (MUBC), as derived from urinary concentrations, and UBTs showed a fairly wide inter- and intraindividual range and were generally higher than the corresponding MBCs as determined in Mueller Hinton broth. In conclusion, according to antibacterial activity in urine determined as UBTs, a single oral dose of ciprofloxacin (500 mg) generally resulted in the highest and longest-lasting UBTs followed by that of enoxacin (400 mg) and norfloxacin (400 mg). A dose of 400 mg enoxacin can be expected to be at least equivalent if not superior to that of 400 mg norfloxacin. Only enoxacin and ciprofloxacin exhibited urinary bactericidal activity against all test organisms up to 12 h in all individuals. Therefore, clinical comparison of enoxacin versus ciprofloxacin in the treatment of complicated UTI could be worth testing. © 1998 Elsevier Science B.V.:International Society of Chemotherapy. All rights reserved.

Urinary bactericidal activity and pharmacokinetics of enoxacin versus norfloxacin and ciprofloxacin in healthy volunteers after a single oral dose

In an open, randomised monocentric crossover study in six male and six female healthy volunteers, the urinary antibacterial activity and pharmacokinetics of enoxacin, norfloxacin and ciprofloxacin were assessed. Urine was collected up to 6 days, and venous blood samples up to 12 h, after a single oral dose of 400 mg enoxacin, 400 mg norfloxacin and 500 mg ciprofloxacin. Enoxacin (250 mg/l) demonstrated the highest peak concentration (median) in the urine (0–6 h), followed by ciprofloxacin (237 mg/l) and norfloxacin (157 mg/l) as determined by the HPLC assay. The total amount (mean) excreted by the kidneys as parent drugs were as follows: enoxacin 54% of dose, ciprofloxacin 33% of dose, and norfloxacin 22% of dose. The mean plasma concentrations decreased from 1 to 4 h after administration for enoxacin from 1.9 to 1.4 mg/l, for ciprofloxacin from 2.0 to 0.8 mg/l and for norfloxacin from 1.3 to 0.5 mg/l. The antibacterial activity in urine was determined as urinary bactericidal titers (UBT), i.e. the highest 2-fold dilution of urine still bactericidal for the reference organism ( E. coli ATCC 25922) and for five uropathogens with minimal inhibitory (MIC) and bactericidal (MBC) concentrations ranging from highly susceptible to resistant cultured from the urine of patients with complicated urinary tract infections (UTI). For the E. coli ATCC 25922, the organism with the lowest MIC, median UBTs of ciprofloxacin were present for 4 days, decreasing from 1:512 to 1:2, that of enoxacin for 2 days, decreasing from 1:256 to 1:4, and that of norfloxacin for 2 days, decreasing from 1:128 to 1:2. For the five uropathogens (with increasing MICs: K. pneumoniae, P. mirabilis, E. coli (resistant to nalidixic acid), P. aeruginosa and E. faecalis), the UBTs decreased in general, according to MICs, demonstrating the same relations of UBTs for ciprofloxacin (highest) versus enoxacin (medium) versus norfloxacin (lowest) with one exception ( P. mirabilis) for which norfloxacin showed higher UBTs than enoxacin. The minimal urinary bactericidal concentrations (MUBC), as derived from urinary concentrations, and UBTs showed a fairly wide inter- and intraindividual range and were generally higher than the corresponding MBCs as determined in Mueller Hinton broth. In conclusion, according to antibacterial activity in urine determined as UBTs, a single oral dose of ciprofloxacin (500 mg) generally resulted in the highest and longest-lasting UBTs followed by that of enoxacin (400 mg) and norfloxacin (400 mg). A dose of 400 mg enoxacin can be expected to be at least equivalent if not superior to that of 400 mg norfloxacin. Only enoxacin and ciprofloxacin exhibited urinary bactericidal activity against all test organisms up to 12 h in all individuals. Therefore, clinical comparison of enoxacin versus ciprofloxacin in the treatment of complicated UTI could be worth testing.

A Controlled Trial of Levofloxacin and Lomefloxacin in the Treatment of Complicated Urinary Tract Infection

Objectives. The efficacy and safety of levofloxacin and lomefloxacin in complicated urinary tract infections (UTIs) were compared in a randomized, open-label, multicenter study. Methods. Outpatients were randomized to receive levofloxacin (250 mg once daily) for 7 to 10 days or lomefloxacin (400 mg once daily) for 14 days. Three hundred thirty-six patients (171 with levofloxacin, 165 with lomefloxacin) were evaluable for microbiologic efficacy, and 461 patients (232 with levofloxacin, 229 with lomefloxacin) for safety. Results. The overall microbiologic eradication rate of pathogens was 95.5% (168 of 176) for levofloxacin and 91.7% (154 of 168) for lomefloxacin. Eradication rates with respect to patients were 95.3% (163 of 171) and 92.1% (152 of 165) for levofloxacin and lomefloxacin, respectively. At the 5 to 9-day post-therapy visit, symptoms were completely resolved in 84.8% of levofloxacin-treated patients and were decreased in 8.2% (93.0% clinical success). Among the lomefloxacin-treated patients, complete resolution was seen in 82.4%, with decreased symptoms in 6.1% (88.5% clinical success). Drug-related adverse events (AEs) were reported by 10 (2.6%) and 18 (5.2%) levofloxacin- and lomefloxacin-treated patients, respectively. Compared with levofloxacin-treated patients, more lomefloxacin-treated patients experienced photosensitivity reactions (3 [1.3%] versus 0) and dizziness (2 [0.9%] versus 0). Nausea (3 [1.3%] versus 1 [0.4%]) was more frequent in the levofloxacin-treated group. Six patients in each treatment group had a gastrointestinal AE (1.7%); rash was reported more frequently with lomefloxacin (4 patients [0.4%]) than with levofloxacin (1 patient [0.4%]). Discontinuation because of AEs was observed in 8 (3.4%) levofloxacin- and 14 (6.1%) lomefloxacin-treated patients. Conclusions. Once-daily levofloxacin is as effective as and has a superior tolerability profile than lomefloxacin in the treatment of complicated UTIs.

Comparison of Intravenous Fleroxacin with Ceftazidime for Treatment of Complicated Urinary Tract Infections

Intravenous fleroxacin, 400 mg once daily, was compared with intravenous ceftazidime, 0.5-2 g three times a day or 1-2 g twice a day, administered for 4-21 days for treatment of complicated urinary tract infections (UTIs) due to susceptible organisms. Fleroxacin also was tested in an uncontrolled trial. The trial was a multicenter, randomized, open-label study of adults with pyelonephritis or signs and symptoms of UTI and complicating factors. In the controlled trial, 474 patients were randomly assigned in a 2:1 ratio to receive fleroxacin (n = 320) or ceftazidime (n = 154). The microbiologic criterion for diagnosis of UTI was the isolation of > or = 10(5) colony-forming units (CFU) of pathogenic bacteria/mL of urine. The efficacy analyses included 165 fleroxacin-treated and 82 ceftazidime-treated patients in the controlled trial and 97 patients in the uncontrolled trial. In the controlled trial, 317 fleroxacin-treated and 150 ceftazidime-treated patients were included in the safety analysis. In the controlled trial, the respective rates of bacteriologic cure (< or = 10(4) CFU/mL of urine 48-96 hours after first dose and 2-5 days posttherapy) were 94% (confidence interval [CI], 89-97%) and 95% (CI, 88-99%) in the fleroxacin and ceftazidime groups, and those of clinical cure were 86% (CI, 80-91%) and 89% (CI, 80-95%). Rates of clinical and bacteriologic cure in the uncontrolled study were 95%. In the controlled trial, 9% of the patients in each treatment group experienced one or more adverse events possibly or probably related to the study drug. The percentage of patients terminating therapy prematurely was higher in the fleroxacin than in the ceftazidime group. Once-daily dosing with 400 mg of intravenous fleroxacin was equivalent to a standard multidose regimen with respect to rates of bacteriologic and clinical cure in the treatment of complicated UTI.

Randomized Double-Blind Trial of High- and Low-Dose Fleroxacin Versus Norfloxacin for Complicated Urinary Tract Infection

Patients were entered in a double-blind, placebo-controlled, multicenter study to compare low- and high-dose fleroxacin with norfloxacin for the treatment of complicated urinary tract infection (UTI). A total of 296 patients were enrolled; 102, 97, and 97 patients were randomized to receive 200 mg of fleroxacin (low-dose), 400 mg of fleroxacin (high-dose), both once daily, or 400 mg of norfloxacin twice daily, respectively, for 10 days. Of these patients, 101, 94, and 95 were included in the safety analysis, and 71, 61, and 58 in the efficacy analysis. The main reason for exclusion from the efficacy analysis was failure to isolate a pathogen at baseline. The groups were comparable with respect to demographics. In the low-dose fleroxacin group, 68 (96%) of 71 patients had bacteriologic cures (eight with superinfection), compared with 56 (92%) of 61 in the high-dose fleroxacin group (two with superinfection) and 52 (90%) of 58 in the norfloxacin group (four with superinfection). Escherichia coli was the most frequent isolate in all groups. In the low-dose fleroxacin group, clinical cure was recorded in 61 (86%) of 71, improvement in six, and failure in four. In the high-dose group, clinical cure was noted in 58 (95%) of 61 patients, improvement in two, and failure in one. In the norfloxacin group, 50 (86%) of 58 patients were clinically cured, four were improved, and four failed. Clinical adverse events were reported by 22 (22%) of 101, 36 (38%) of 94, and 19 (20%) of 95 patients in the low-dose fleroxacin, high-dose fleroxacin, and norfloxacin groups, respectively. Insomnia and nausea were reported most frequently in the fleroxacin groups, and nausea and headache were most common in the norfloxacin group. The efficacy and safety of low-dose fleroxacin are comparable to those of norfloxacin for treatment of complicated UTI.

In vitro activity and concentrations in serum, urine, prostatic secretion and adenoma tissue of ofloxacin in urological patients.

Studies in vitro showed that at concentrations of 1 and 4 mg/L ofloxacin inhibited 94 and 99% of the Gram-negative pathogens in isolates cultured from the urine of patients with complicated urinary tract infections (UTI). Against Gram-positive bacteria, 60 and 100% were inhibited at the corresponding concentrations. Comparisons of the MIC90 values of 8 quinolones showed the decreasing order of in vitro antibacterial activity to be ciprofloxacin, ofloxacin, norfloxacin, pefloxacin, enoxacin, pipemidic acid, nalidixic acid and cinoxacin. After an oral dose of ofloxacin 400mg, the mean peak serum concentration in 10 elderly patients was 5.5 mg/L and mean renal excretion during 24 hours was 41%. In 17 patients undergoing transurethral resection of the prostate, ofloxacin 400mg was given for perioperative prophylaxis. Two to 4.5 hours after administration, the median concentrations in prostatic secretion (5 patients) and prostatic adenoma tissue were 4.0 mg/L and 4.1 mg/kg, respectively. The corresponding serum concentrations of ofloxacin were 3.4 and 3.9 mg/L, respectively. In a group of 10 patients, 14.5 to 19.5 hours after oral administration of ofloxacin 400mg the median serum and prostatic adenoma tissue concentrations of ofloxacin were 1.9 mg/L and 1.2 mg/kg, respectively. The in vitro activity of ofloxacin concentrations attained in serum, urine, prostatic secretion and adenoma tissue show that it appears to be well suited for the treatment of complicated UTI.

In vitro activity, pharmacokinetics, clinical safety and therapeutic efficacy of enoxacin in the treatment of patients with complicated urinary tract infections.

Minimal inhibitory concentrations (MIC) of enoxacin, nalidixic acid, pipemidic acid, norfloxacin, ciprofloxacin, ofloxacin and pefloxacin against isolates from 400 urological in-patients with complicated urinary tract infections (UTI) were determined by means of an agar dilution technique (10(4) cfu, multipointer). 28 patients (21 male, seven female) aged 36 to 84 years with complicated UTI due to sensitive bacteria were treated orally with 200 mg enoxacin b.i.d. for six to 14 days. Plasma and urine samples were collected from 19 patients, at intervals prior to and following a 400 mg dose of enoxacin, and enoxacin concentrations were determined by a high pressure liquid chromatography (HPLC) method. The MICs of enoxacin against all but one of the gram-negative isolates cultured from 265 urological patients were between 0.03 and 4 mg/l. The MICs against 134 gram-positive isolates were between 0.25 and 16 mg/l except two strains of streptococci. At a concentration of 4 mg/l (8 mg/l), 90.3% (98%) of the total spectrum of isolates were inhibited by enoxacin. Of the quinolones tested, ciprofloxacin appeared to be the most active compound in vitro and cinoxacin the least active antimicrobial agent. The in vitro activity of enoxacin was comparable to that of norfloxacin, ofloxacin and pefloxacin. Oral administration of 400 mg enoxacin to elderly patients resulted in peak serum concentrations between 0.7 and 6.3 mg/l (mean 3.6 mg/l) attained between 1.0 and 6.0 h following drug ingestion. The mean urinary recovery of parent drug within 24 h was 31.2% of the administered dose. 25 of 28 patients treated orally with enoxacin could be followed-up for five to 14 days after the end of treatment. Enoxacin therapy in these patients resulted in 18 cures, one failure and six relapses (same species). The drug was well tolerated and there was no evidence of renal, hepatic or haematological toxicity. Enoxacin appears to be well suited for the treatment of complicated UTI.