Penetration of beta-lactamase inhibitors tazobactam and sulbactam in severe acute pancreatitis

Abstract number: 1134_02_112

Förster S., Eckleben E., Werner U., Adam U., Wacke R., Klar E., Drewelow B.

Objectives:

Despite of high standard intensive care and surgical management, acute necrotising pancreatitis is still related with an extremely high mortality rate. This is determined by local infectious complications, especially in necrotising areas. Limited penetration of antimicrobial drugs in these areas is considered to be a major cause for failure of therapy of severe infections. Combinations of beta-lactamase inhibitors (BLI) and beta-lactam antibiotics like broad-spectrum penicillines (BSP) have antibacterial activity against most of the common pathogens in severe necrotising pancreatitis. Co-administration leads to an increase of antibacterial activity due to an inhibition of beta-lactamases compared to those of beta-lactam antibiotics alone. Some BSP has been shown to penetrate rapidly and efficiently into pancreatic tissue. The penetration of BLI into inflamed pancreatic tissue has not been investigated yet.

Methods:

Addressing the penetration capability of BLI, a clinical trial was designed to investigate the penetration of Tazobactam (Taz, n = 8) and Sulbactam (Sul, n = 5) in patients with severe necrotising pancreatitis undergoing pancreas surgery. Samples were taken from blood, necrotic areas of pancreatic tissue (PN), peripancreatic fatty tissue (PFT) and bursa secretion (BS) following intravenous administration of 0.5 g Taz or 1.0 g Sul. Concentrations of BLI were determined by HPLC/UV. The aimed concentration for full enzymatic effect of BLI should be 4 mg/mg (Taz) and 8 mg/mg (Sul), respectively.

Results:

Mean plasma concentrations at 1.0 h after application were 20.6 ± 9.58 mg/ml (Taz) and 48.6 ± 18.8 mg/ml (Sul). Corresponding mean concentrations were in PN 2.95 ± 0.25 mg/mg (Taz) and 8.48 ± 0.68 mg/mg (Sul), in PFT 1.72 ± 1.09 mg/mg (Taz) and 4.70 ± 0.88 mg/mg (Sul), in BS 8.22 ± 2.12 mg/mg (Taz) and 14.3 ± 5.59 mg/mg (Sul). The penetration rate into PN was 14.5% (Taz) and 18.8% (Sul), into BS 44.4% (Taz) and 31.7% (Sul). The aimed concentration for both BLI was reached or exceeded in plasma, PN and BS but not in PFT.

Conclusion:

Both BLI has been demonstrated to reach rapidly effective inhibitory concentrations into relevant areas and compartments of pancreatic and parapancreatic tissue. In combination with BSP Taz and Sul either may have a potential clinical benefit in prevention and treatment of local infectious complications of severe necrotising pancreatitis.