Behavior of antibiotics during human necrotizing pancreatitis

Abstract

The aim of the study was to verify whether antibiotics excreted by the normal pancreas are also excreted in human necrotizing pancreatitis, reaching the tissue sites of the infection. Twelve patients suffering from acute necrotizing pancreatitis were treated with imipenem-cilastatin (0.5 g), mezlocillin (2 g), gentamicin (0.08 g), amikacin (0.5 g), pefloxacin (0.4 g), and metronidazole (0.5 g). Serum and necrotic samples were collected simultaneously at diferent time intervals after parenteral drug administration by computed tomographyguided needle aspiration, intraoperatively, and from surgical drainages placed during surgery. Drug concentrations were determined by microbiological and high-performance liquid chromatography assays. All antibiotics reached the necrotic tissues, but with varying degrees of penetration, this being low for aminoglycosides (13%) and high in the case of pefloxacin (89%o) and metronidazole (990%). The concentrations of pefloxacin (13.0 to 23 ,Lg/g) and metronidazole (8.4 ,ug/g) in the necrotic samples were distinctly higher than the MICs for the organisms most commonly isolated in this disease; the concentrations in tissue of imipenem (3.35 ,ug/g) and mezlocillin (8.0 and 15.0 ,ug/g) did not always exceed the MICs for 90% of strains tested, whereas the aminoglycoside concentrations in necrotic tissue (0.5 p.g/g) were inadequate. Repeated administration of drugs (for 3, 7, 17, and 20 days) seems to enhance penetration of pefloxacin, imipenem, and metronidazole into necrotic pancreatic tissue. The choice of antibiotics in preventing infected necrosis during necrotizing pancreatitis should be based on their antimicrobial activity, penetration rate, persistence, and therapeutic concentrations in the necrotic pancreatic area. These requisites are provided by pefloxacin and metronidazole and to a variable extent by imipenem and mezlocillin.Superinfection of necrotic tissue in the course of acute necrotizing pancreatitis is a decisive prognostic factor with regard to morbidity and mortality (2,3,5,7,20,25,33,34,40).This has prompted attempts to identify the patients at septic risk (3,5,20), the microorganisms responsible for the superinfection (1), the times of infection in the natural history of the disease (3,20), the therapeutic measures to be adopted (1-3, 5, 20, 34), and possible effective prophylaxis (7,9,10,19,23,25,33).The ideal antibiotic for therapy and/or prophylaxis should be targeted at the microorganisms responsible for the septic complications and should reach the infection site in therapeutic concentrations.To date, several studies have been conducted to evaluate the penetration of various different antibiotics into healthy pancreatic tissue and juice (4, 7-11, 28, 35-38). None of these studies has been conducted with humans in the course of disease, and to the best of our knowledge, the effective ability of antibiotics to penetrate the infection risk areas has never been assessed. Such areas of the retroperitoneum are characterized by the presence of necrotic fragments of pa...

Modern Phase-Specific Management of Acute Pancreatitis

“…However, the advantage was limited to patients with severe pancreatitis who received broad-spectrum antibiotics that achieved therapeutic pancreatic tissue levels. Büchler [75][76][77] and others have identified imipenem as the antibiotic agent of first choice because it reached higher pancreatic tissue levels and provided higher bactericidal activity against most of the bacteria present in pancreatic infection compared to other types of antibiotics. An alternative antibiotic regimen is either ciprofloxacin or ofloxacin in combination with metronidazole, although a previous trial has not shown any benefit with this regimen [78].…”

Piperacillin-Tazobactam Penetration into Human Pancreatic Juice

“…Few broad-spectrum antibiotics present appropriate characteristics for the treatment of pancreatic tissue infections (2,6,20,22,25). ␤-Lactam drugs exhibit time-dependent bactericidal activity, extravascular distribution, and tissue extracellular fluid concentration: the therapeutic goal is to optimize the duration of antimicrobial exposure (10,18).…”

“…This is a critical point for infections caused by gram-negative bacilli (9, 23) and for particular infection sites, such as the pancreas (2-4, 6). ␤-Lactam agents are useful for treatment of infected acute necrotizing pancreatitis (1,2,6,8,11,25), a disease associated with a high mortality rate (7,24).…”

“…Pharmacokinetic parameters were determined by the model-independent approach (noncompartmental analysis) The concentrations of PIP and TZ alone and in combination were determined in serum and PJ by an agar well diffusion method (2,4,27) according to CLSI (formerly NCCLS) guidelines (19) utilizing Pseudomonas aeruginosa NCTC 10701 (0.02% final concentration) as the test microorganism and Difco antibiotic medium 1. All samples were assayed in duplicate or triplicate.…”

Activity of Moxifloxacin, Imipenem, and Ertapenem against Escherichia coli, Enterobacter cloacae, Enterococcus faecalis, and Bacteroides fragilis in Monocultures and Mixed Cultures in an In Vitro Pharmacokinetic/Pharmacodynamic Model Simulating Concentrations in the Human Pancreas

“…Drug concentrations were deduced by log-linear regression from published data following infusions of 400 mg moxifloxacin (22) and 1,000 mg each of imipenem (3,18) and ertapenem (24). The following maximal total drug concentrations (C max ), time to C max (T max ), and elimination half-life (t 1/2 ) in human pancreatic tissue were deduced from these published data: for moxifloxacin, C max ϭ 4.6 mg/liter, T max ϭ 5 h, and t 1/2 ϭ 8; for imipenem, C max ϭ 16 mg/liter, T max ϭ 0.25 h, and t 1/2 ϭ 1.3 h; for ertapenem, C max ϭ 1.3 mg/liter, T max ϭ 0.5 h, and t 1/2 ϭ 4 h. For calculation of free drug concentrations, the following was considered.…”