Review of the literature and individual patients’ data meta-analysis on efficacy and tolerance of nitroxoline in the treatment of uncomplicated urinary tract infections

Abstract

BackgroundNitroxoline, a hydroxychinoline derivate, has been used for many years to treat urinary tract infections (UTI). Many uncontrolled, but only few controlled clinical studies have been published. Four so far unpublished, controlled clinical studies were meta-analysed.MethodsA narrative literature review was performed. In addition the individual patient data (IPD) of 466 females with uncomplicated UTI of four prospective, single blind, randomized, clinical studies with similar protocols using nitroxoline (250 mg tid) versus cotrimoxazole (960 mg bid) or norfloxacin (400 mg bid) as controls for 5 days (sporadic UTI) or 10 days (recurrent UTI) were meta-analysed. The primary aim was eradication of bacteriuria 7–13 days after end of therapy (test of cure). Clinical efficacy was determined by elimination of symptoms and safety by adverse events and laboratory tests.ResultsReviewing a total of 26 uncontrolled, 2 controlled and one postmarketing studies including more than 11,000 patients, good efficacy and safety of nitroxoline could be confirmed. In the four unpublished controlled studies a total of 234 patients were treated orally with nitroxoline and 232 with controls. The safety of nitroxoline was very good and comparable to the controls (adverse events 9.4% vs 7.8%; p = 0.360). In the mMITT set (at least one outcome result), in the PP set (test of cure outcome) and in the modified PP set (missing test of cure rated failure) more than 90% of the patients showed eradication of bacteriuria with nitroxoline, which also met statistical non-inferiority compared to the controls (10% non-inferiority margin) in all three evaluation sets. The clinical efficacy was similar between the two treatment groups.ConclusionThe IPD meta-analysis using objective parameters (elimination of bacteriuria) demonstrated equivalent efficacy (non-inferiority) of nitroxoline with the controls tested (cotrimoxazole, norfloxacin) in the treatment of uncomplicated UTI. Considering the good safety and efficacy of nitroxoline as also shown in many uncontrolled and observational studies and the world wide increase of resistance of uropathogens against cotrimoxazole and fluoroquinolones, but not against nitroxoline within the last 20 years, nitroxoline should be reconsidered as one of the first line antibiotics for the treatment of uncomplicated UTI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0628-7) contains supplementary material, which is available to authorized users.

Nitroxoline: repurposing its antimicrobial to antitumor application

“…As a result, the bacterial surface becomes more hydrophobic, decreasing adherence to the catheter surface. The reduced antibacterial activity of nitroxoline in the presence of Mn 2+ and Mg 2+ , but not of Ca 2+ , Na + or K + , also confirms this mode of action (Pelletier et al, 1995;Oviedo et al, 2000;Naber et al, 2014). By chelating bivalent cations essential for RNA synthesis, nitroxoline selectively and rapidly inhibits RNA synthesis in yeast during cell division (Fraser & Creanor, 1974;Naber et al, 2014).…”

“…Despite long time of its clinical use still no increase of resistance of uropathogens against nitroxoline has been observed. For example, nitroxoline showed no decrease of activity against E. coli, regardless of their broad resistance profiles towards other antimicrobial agents used in clinical practice for treatment of urinary tract infections (Kresken & Körber-Irrgang, 2014;Naber et al, 2014).…”

Discovery of novel halogenated 8‐hydroxyquinoline‐based anti‐MRSA agents: In vitro and QSAR studies

“…According to the on‐going trend of drug repositioning, our finding disclosed that the existing simple small molecule, cloxyquin ( 2 ), exerted high bactericidal effect against the MRSA isolated from various clinical specimens. The other 8HQ derivatives such as clioquinol ( 4 ) and nitroxoline ( 6 ) have been used as the antimicrobial drugs (Bareggi & Umberto, ; Naber, Niggemann, Stein, & Stein, ). In addition, the cloxyquin ( 2 ) displayed high safety index (SI = 14.68) compared with the other 8HQ derivatives.…”

Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoebaBalamuthia mandrillaris

“…The pharmacokinetic properties of nitroxoline suggest further promise for its therapeutic value as an inhibitor of B. mandrilliaris. Nitroxoline has been safely used for over 50 years in the treatment of urinary tract infections with minimal adverse effects reported (72). Nitroxoline is available in oral and intravenous administration and is typically dosed at 600-800 mg/day for adults, resulting in maximal plasma concentrations (C max ) up to approximately 30 µM (5.6 mg/L) (62)(63)(64), which is 10-fold higher than the IC 50 for B. mandrillaris trophozoites in vitro (Fig.…”

“…Laurie and White et al, Inhibition of Balamuthia mandrillaris by nitroxoline 26 The data presented in this study strongly indicate that nitroxoline warrants further investigation as a potential treatment for B. mandrillaris infections. As an approved compound with an established safety profile (72), nitroxoline may be rapidly deployed as an experimental treatment in dire cases of GAE. In particular, since the current standard of care generally consists of experimental combinations of several antimicrobial agents, adding nitroxoline to these regimens may be a reasonable step in the effort to improve patient prognosis.…”