In vitro and in vivo properties of BAL30376, a β-lactam and dual beta-lactamase inhibitor combination with enhanced activity against Gram-negative Bacilli that express multiple β-lactamases.
BAL30376 is a triple combination comprising a siderophore monobactam, BAL19764; a novel bridged monobactam, BAL29880, which specifically inhibits class C β-lactamases; and clavulanic acid, which inhibits many class A and some class D β-lactamases. The MIC(90) was ≤ 4 μg/ml (expressed as the concentration of BAL19764) for most species of the Enterobacteriaceae family, including strains that produced metallo-β-lactamases and were resistant to all of the other β-lactams tested. The MIC(90) for Stenotrophomonas maltophilia was 2 μg/ml, for multidrug-resistant (MDR) Pseudomonas aeruginosa it was 8 μg/ml, and for MDR Acinetobacter and Burkholderia spp. it was 16 μg/ml. The presence of the class C β-lactamase inhibitor BAL29880 contributed significantly to the activity of BAL30376 against strains of Citrobacter freundii, Enterobacter species, Serratia marcescens, and P. aeruginosa. The presence of clavulanic acid contributed significantly to the activity against many strains of Escherichia coli and Klebsiella pneumoniae that produced class A extended-spectrum β-lactamases. The activity of BAL30376 against strains with metallo-β-lactamases was largely attributable to the intrinsic stability of the monobactam BAL19764 toward these enzymes. Considering its three components, BAL30376 was unexpectedly refractory toward the development of stable resistance.
Basilea Pharmaceutica International Ltd., PO Box 3255, CH-4005 Basel, Switzerland. Malcolm.page@basilea.com
Malcolm G P
MG
Page
Clothilde
C
Dantier
Eric
E
Desarbre
Bérangère
B
Gaucher
Klaus
K
Gebhardt
Anne
A
Schmitt-Hoffmann
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016971:Citrobacter freundii / Q000187:drug effects; D019818:Clavulanic Acid / Q000494:pharmacology*; D004754:Enterobacter / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008297:Male; D051379:Mice; D008997:Monobactams / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D012706:Serratia marcescens / Q000187:drug effects; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; C000612851:BAL29880; D008997:Monobactams; D010671:Phenylurea Compounds; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid
Drug Resist Updat. 2000 Apr;3(2):109-125
11498375
Curr Med Chem. 2002 Jun;9(12):1145-65
12052169
Biometals. 2009 Aug;22(4):615-24
19214755
Antimicrob Agents Chemother. 1982 Nov;22(5):832-8
6891198
Biochem Pharmacol. 2006 Mar 30;71(7):930-40
16359643
Clin Infect Dis. 2009 Jan 1;48(1):1-12
19035777
Int J Antimicrob Agents. 1996 Apr;6 Suppl:S31-4
18611717
Trends Microbiol. 2006 Sep;14(9):413-20
16876996
Antimicrob Agents Chemother. 2010 Jun;54(6):2291-302
20308379
Antimicrob Agents Chemother. 1993 Apr;37(4):851-8
8388201
J Med Chem. 1998 Oct 8;41(21):3961-71
9767633
J Antimicrob Chemother. 2005 May;55(5):810-1
15772141
J Bacteriol. 1981 Jan;145(1):156-63
7007312
Clin Microbiol Rev. 2010 Jan;23(1):160-201
20065329
Curr Opin Microbiol. 2005 Oct;8(5):518-24
16126451
Clin Infect Dis. 2006 Mar 1;42(5):657-68
16447111
Clin Infect Dis. 2007 Nov 1;45(9):1179-81
17918079
Pharmacotherapy. 2008 Feb;28(2):235-49
18225969
Biochem J. 1993 Oct 1;295 ( Pt 1):295-304
8216231
Chem Pharm Bull (Tokyo). 1981 Nov;29(11):3342-9
7337933