title: Urinary Concentrations and Antibacterial Activity of BAL30072, a Novel Siderophore Monosulfactam, against Uropathogens after Intravenous Administration in Healthy Subjects.
abstract: This annex study to a phase 1 study aimed to correlate urinary concentrations and bactericidal titers (UBTs) of BAL30072, a novel siderophore monosulfactam, in healthy subjects in order to evaluate which dosage of BAL30072 should be investigated in a clinical study on complicated urinary tract infection (UTI). Three cohorts of a total of 19 healthy male subjects were included in the add-on study and received the following BAL30072 dosages. The 1st cohort received 1 g once a day (q.d.) intravenously (i.v.) (1 h) on day 1 and 1 g thrice daily (t.i.d.) on day 2, the 2nd cohort received 2 g q.d. i.v. (1 h) on day 1 and 2 g t.i.d. on day 2, and the 3rd cohort received 1 g q.d. i.v. (4-h infusion) on day 8. Urine was collected up to 24 h after drug administration. UBTs were determined for seven Escherichia coli isolates (three wild type [WT], CTX-M-15, TEM-3, TEM-5, NDM-1), two Klebsiella pneumoniae isolates (WT, KPC), one Proteus mirabilis isolate (WT), and two Pseudomonas aeruginosa isolates (WT, VIM-1 plus AmpC). Urine drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median urinary excretions of BAL30072 ranged between 38% and 46% (3 cohorts). The median UBTs after i.v. administration of 1 or 2 g q.d. and after 1 or 2 g t.i.d. showed positive UBTs for 24 h after the lowest dosage (1 g q.d.) for 5 of 7 of the Enterobacteriaceae strains and after the higher dosage of 2 g administered i.v. t.i.d. for all strains tested. After i.v. infusion of 1 g over 4 h, positive UBTs were demonstrated for three E. coli strains for up to 12 h, for the K. pneumoniae (KPC) strain for up to 8 h, and for the P. aeruginosa (VIM-1 plus AmpC) strain for up to only 4 h. The minimal bactericidal concentrations (MBCs) of the E. coli (NDM-1) strain and the K. pneumoniae (WT) strain correlated well between broth and urine but did not correlate well for the two P. aeruginosa strains. BAL30072 exhibits positive UBTs for 24 h even after a dosage of 1 g administered i.v. q.d. for 5 of 7 Enterobacteriaceae strains and after 2 g administered i.v. t.i.d. for all strains except one P. aeruginosa strain (50% of the time). In general, the UBTs correlated well with the MICs of the Enterobacteriaceae but were lower for P. aeruginosa The clinical efficacy with a dosage regimen of BAL30072 of 2 g administered i.v. t.i.d. should be evaluated in the treatment of complicated UTI.
authors.affiliation: Prokaryon Institute, Nuremberg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Straubinger
authors.affiliation: Prokaryon Institute, Nuremberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Blenk
authors.affiliation: Technical University, Munich, Germany kurt.naber@nabers.de.
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Naber
authors.affiliation: Department of Urology, Pediatric Urology and Andrology of the Justus Liebig University, Giessen, Germany.
authors.forename: Florian M E
authors.initials: FM
authors.lastname: Wagenlehner
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000652:urine*; D002853:Chromatography, Liquid; D004755:Enterobacteriaceae / Q000187:drug effects / Q000472:pathogenicity; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D064368:Healthy Volunteers; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000472:pathogenicity; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008997:Monobactams / Q000008:administration & dosage / Q000627:therapeutic use* / Q000652:urine*; D011513:Proteus mirabilis / Q000187:drug effects / Q000472:pathogenicity; D053719:Tandem Mass Spectrometry; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use* / Q000652:urine*; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology / Q000652:urine*
chemical_list: D000900:Anti-Bacterial Agents; C552042:BAL 30072; D008997:Monobactams; D013844:Thiazoles