Microbiological efficacy and pharmacokinetics of prophylactic antibiotics in liver transplant patients

Abstract

The pharmacokinetics of perioperative systemic antibiotics and the microbiological effectiveness of oral nonabsorbable antibiotics started immediately prior to surgery were studied in 18 adult patients undergoing liver transplantation. All patients received cefotaxime, 2 g intravenously, at 6-h intervals during surgery and then at 8-h intervals thereafter for 48 h; eight patients also received ampicillin at the same dose and schedule. This regimen produced levels of antibiotics in blood that appeared appropriate for prophylaxis. The first dose peak (68 ± 18 ,ig/ml) and trough (6.9 + 4.7 ,g/ml) levels of cefotaxime in serum and the first dose peak (73 ± 22 ,ug/ml) and trough (4.1 + 2.3 ,ug/ml) levels of ampicillin in serum, which were assayed by high-performance liquid chromatography, were similar to levels reported in normal volunteers, despite mean intraoperative blood loss of 3.3 liters and fluid replacement of 21 liters. On postoperative days 1 and 2, the levels of cefotaxime and ampicillin were maintained at or above 0.9 and 1.3 pg/ml, respectively, with little accumulation. By random assignment, 8 patients received systemic antibiotics alone and 10 patients received systemic antibiotics plus a 3-week regimen of oral nonabsorbable antibiotics (gentamicin, polymyxin E, and nystatin) beginning when a donor liver was procured. Pre-and postoperative cultures of rectum, throat, and gastric aspirate samples showed persistence of aerobic gram-negative bacilli for the first 2 postoperative weeks in about half of the patients in each group. Failure of the regimen of oral nonabsorbable antibiotics to supplement cefotaxime in eradicating aerobic gram-negative bacilli from stools probably results from impaired peristalsis during and after surgery and warrants earlier initiation of the regimen.Bacterial and fungal infections frequently complicate orthotopic liver transplantation (OLT), despite routine perioperative prophylaxis with broad-spectrum antibiotics and sometimes antifungal agents. Most liver transplant patients experience at least one serious bacterial infection (11, 16), and the incidence of fungal infection has ranged from 16 to 42% (4,6,17,38). The characteristics of posttransplant bacterial and fungal infections are that most occur during the first few weeks after transplantation; the predominant pathogens in each category are aerobic gram-negative bacilli (AGNB) and Candida albicans; and the most common sites of infection are the abdomen, lower respiratory tract, and bloodstream (4,6,11,16,17,38). These features suggest that posttransplant infections usually result from perioperative inoculation or translocation of potentially pathogenic bowel flora into the abdomen and bloodstream or from aspiration of oropharyngeal AGNB.In an effort to reduce the incidence of posttransplant infection beyond that achieved with systemic antibiotic prophylaxis, several centers have supplemented systemic antibiotics with regimens of topical oropharyngeal and oral nonabsorbable antimicrobial agents to selectively eliminate AG...

Clinical practice guidelines for antimicrobial prophylaxis in surgery

“…No studies have assessed the optimal duration of antimicrobial prophylaxis in liver transplantation. Although antimicrobials have been administered in studies for five days 937,944,946,949,[957][958][959] and seven days, 964 the majority of recent studies have limited the duration of prophylaxis to 72 hours, 981 48 hours, 936,943,945,952,955,956,960,961,967,970,979,980,991 36 hours, 981 24 hours, 935,948,962,970 and a single dose, 963 with no apparent differences in early infection rates. A prospective, nonrandomized, controlled study found no difference in bacterial infections within the first three months after liver transplantation in patients receiving cefotaxime and ampicillin as short-term antimicrobial prophylaxis for two to three days, compared with long-term prophylaxis for five to seven days.…”

“…936,943,949,955,956,967,968,980,990,991 These studies used combinations of nonabsorbable antibacterials (aminoglycosides, polymyxin B or E), antifungals (nystatin, amphotericin B), and other antimicrobials (cefuroxime in suspension) administered orally and applied to the oropharyngeal cavity in combination with systemically administered antimicrobials. Results are conflicting, with no differences in patient outcomes (e.g., infection rates, mortality) or cost and concerns of increasing gram-positive infections with potential resistance in several studies 939,955,956,980,991 and others with positive results.…”

“…The pathogens most commonly associated with early SSIs and intraabdominal infections are those derived from the normal flora of the intestinal lumen and the skin. Aerobic gram-negative bacilli, including E. coli, 935,937,939,940,942,945,[947][948][949]951,967,968 Klebsiella species, 933,936,937,939,940,945,[947][948][949][967][968][969] Enterobacter species, 936,939,940,942,945,947,952,959,964,967,968 Acinetobacter baumannii, [935][936][937]942,951 and Citrobacter species, 939,940,945,947,952,959,967,968 are common...…”

“…Traditional prophylactic regimens have therefore consisted of a thirdgeneration cephalosporin (usually cefotaxime, because of its antistaphylococcal activity) plus ampicillin. 936,937,943,944,[946][947][948]951,952,954,962,965,967,979 The use of cefoxitin and ampicillinsulbactam, cefotaxime and ampicillin-sulbactam and gentamicin, [957][958][959] cefuroxime and metronidazole, 971 ceftriaxone and metronidazole, 980 cefotaxime and metronidazole, 953 ceftriaxone and ampicillin, 949 ceftizoxime alone, 955 cefotaxime and tobramycin, 956 cefoxitin alone, 960,961 cefazolin alone, 951 amoxicillinclavulanate and gentamicin, 970 amoxicillin-clavulanate alone, 951 glycopeptides and antipseudomonal penicillin, 951 quinolone and amoxicillin-clavulanate or glycopeptide, 951 vancomycin and aztreonam, 951,981 and piperacillintazobactam 964,970 has also been reported. Alternative prophylaxis regimens for b-lactam-allergic patients have included cefuroxime and metronidazole, 970 clindamycin and gentamicin or aztreonam, 948,960-962 ciprofloxacin and metronidazole, 970 and vancomycin or ciprofloxacin.…”

Prevention of infections in solid organ transplant recipients

“…The rationale for the use of OSBD is based on the fact that Gram‐negative bacteremias carry a higher mortality rate than those caused by Gram‐positive organisms. To achieve optimal elimination of aerobic Gram‐negative bacilli from the gastrointestinal tract with OSBD, the regimen has to be started at least 3 days prior to transplant ( 20–23). This can present a problem with compliance in patients that have to wait prolonged periods for a donor (up to one year) and in cases of fulminant hepatic failure that require transplantation in less than 3 days.…”