In Vitro and In Vivo Properties of BAL30376, a β-Lactam and Dual β-Lactamase Inhibitor Combination with Enhanced Activity against Gram-Negative Bacilli That Express Multiple β-Lactamases

Abstract

BAL30376 is a triple combination comprising a siderophore monobactam, BAL19764; a novel bridged monobactam, BAL29880, which specifically inhibits class C ␤-lactamases; and clavulanic acid, which inhibits many class A and some class D ␤-lactamases. The MIC 90 was <4 g/ml (expressed as the concentration of BAL19764) for most species of the Enterobacteriaceae family, including strains that produced metallo-␤-lactamases and were resistant to all of the other ␤-lactams tested. The MIC 90 for Stenotrophomonas maltophilia was 2 g/ml, for multidrug-resistant (MDR) Pseudomonas aeruginosa it was 8 g/ml, and for MDR Acinetobacter and Burkholderia spp. it was 16 g/ml. The presence of the class C ␤-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 ␤-lactamases. The activity of BAL30376 against strains with metallo-␤-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.

Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen

“…BAL30376 is a triple-␤-lactamase inhibitor combination composed of a siderophore monobactam, a specific inhibitor of class C ␤-lactamases, and clavulanic acid, an inhibitor of most class A and some class D ␤-lactamases (255). BAL30376 demonstrated an MIC 90 of 2 g/ml against S. maltophilia (255).…”

Comparative Study of Different Methods of Detection of β-lactamase Production in Gram Negative Bacterial Isolates and Studying Induction of Resistance to Cefipime

“…If the test strains did not produce β-lactamase no clover leaf pattern was produced. (Rand et al, 2011) Induction of cefepime resistance among selected cefepime sensitive isolates Induction of cefepime resistance was done according to Page et al, with some modifications (Page et al, 2011). Selected isolates sensitive to cefepime were inoculated in 2 ml nutrient broth containing ¼ MIC of cefepime at 37 ºC for 24 hrs.…”

“…This passage was repeated consecutively for five days. MIC of the subcultured isolates was determined after five passages to assure the stability of the acquired resistance of the isolates (Page et al, 2011).…”

“…They found that Strains with >4-fold elevated MICs toward cefepime appeared within 4 passages suggesting that they had higher levels of expression of β-lactamase (Page et al, 2011).…”

Urinary Concentrations and Antibacterial Activity of BAL30072, a Novel Siderophore Monosulfactam, against Uropathogens after Intravenous Administration in Healthy Subjects

“…Using a transcriptome approach, the FecIRA Fe 3ϩ -dicitrate transporter was identified as a regulatory cascade, and the PiuA iron receptor was identified as a putative uptake system affecting susceptibility to BAL30072 (3). The molecule has potent in vitro activity against many species of MDR isolates of the Enterobacteriaceae family, including isolates harboring a class A carbapenemase or a metallo-␤-lactamase (4,5). BAL30072 also exhibits potent activity against MDR Pseudomonas aeruginosa and Acinetobacter sp.…”