James E. Leggett

Randomized Controlled Trial of Prophylactic Rifampin for Peritoneal Dialysis-Related Infections

Staphylococcal infections are a major cause of catheter infections and peritonitis in peritoneal dialysis patients. Since catheter-related infections are associated with nasal carriage of Staphylococcus aureus in this population, we studied the effect of intermittent rifampin, an antibiotic known to decrease S aureus nasal carriage, on catheter-related infections and peritonitis. We randomly assigned 64 patients to receive either rifampin 300 mg twice daily for 5 days every 3 months or no treatment. The rifampin-treated patients had a significant delay in time to first catheter-related infection (P less than 0.015) and significantly fewer catheter-related infections overall (P less than 0.001). The catheter-related infection rate in rifampin-treated patients was .26 per patient-year versus .93 per patient-year in untreated patients. Multivariate analysis defined baseline colonization of nares or catheter exit-site and prior renal transplant as risk factors for catheter-related infections. There was no significant difference in peritonitis rates between groups, although the trend was for a delayed time to first episodes and fewer episodes in rifampin-treated patients. Adverse effects necessitated withdrawal of rifampin in four patients. We conclude that intermittent rifampin administration is effective in decreasing catheter-related infections in a peritoneal dialysis population.

Correlation between in vitro and in vivo activity of antimicrobial agents against gram-negative bacilli in a murine infection model.

We studied the relationship between in vitro susceptibility tests (MICs, MBCs) and in vivo activity of tobramycin, pefloxacin, ceftazidime, and imipenem against 15 gram-negative bacilli from five different species in a murine thigh infection model. Complete dose-response curves were determined for each antimicrobial agent against each strain, and three parameters of in vivo activity were defined: maximal attainable antimicrobial effect (i.e., reduction in log10 CFU per thigh compared with untreated controls) at 24 h (Emax), total dose required to reach 50% of maximal effect (P50), and total dose required to achieve a bacteriostatic effect (static dose). Pefloxacin demonstrated the greatest Emax (P less than 0.05). Tobramycin was the most potent antimicrobial agent, as indicated by its having the lowest static dose/MIC ratio (P less than 0.002). Log10 P50s and static doses correlated significantly with log10 MICs or MBCs for the 15 strains of each antibiotic (P less than 0.01) except imipenem (P greater than 0.50). The greater potency of imipenem against the three Pseudomonas aeruginosa strains than against strains of the family Enterobacteriaceae (P less than 0.01) explained this lack of correlation. A longer duration of postantibiotic effect for imipenem against P. aeruginosa (P = 0.02) contributed to its increased potency against these strains. We conclude that in vitro susceptibility tests correlated well with in vivo activity in this animal model and that variations in potency among the four antimicrobial agents could be explained by differences in pharmacokinetics or pharmacodynamic activity.

Enhancing effect of serum ultrafiltrate on the activity of cephalosporins against gram-negative bacilli.

A few studies have suggested that the inhibitory effect of serum on activity of broad-spectrum cephalosporins is less than that predicted by the degree of protein binding. Microdilution MICs of ceftriaxone, cefoperazone, moxalactam, and ceftizoxime were therefore determined against ATCC and clinical strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus in Mueller-Hinton broth containing either human albumin (as 0, 2.5, or 5% solution) or heat-inactivated human serum (as 0, 25, 50, or 95% solution). Arithmetic linear dilutions were used to improve accuracy. For standard bacterial strains, MICs in the presence of 5% albumin were higher than in broth alone by multiples of 10.9 to 21 for ceftriaxone, 5.5 to 16.4 for cefoperazone, 1.9 to 3.7 for moxalactam, and 1.1 to 1.4 for ceftizoxime, as expected by their protein binding. MICs in the presence of 95% serum were similar to those in 5% albumin for all four drugs against S. aureus and P. aeruginosa but were 2.2- to 4.8-fold lower (P less than 0.001) against E. coli and K. pneumoniae. Similar findings were observed at lower protein concentrations and with clinical isolates, except that for some strains of P. aeruginosa MICs were lower in serum than in albumin. Individual sera from five subjects gave comparable results. The addition of serum ultrafiltrate to albumin-containing solutions reduced MICs of ceftriaxone and cefoperazone 1.6- to 7.4-fold against E. coli and K. pneumoniae (P less than 0.01) but did not alter the MICs for S. aureus. Serum may contain an ultrafiltrable component(s) that enhances the activity of third-generation cephalosporins against many gram-negative bacilli.

Pharmacokinetics and pharmacodynamics of cefoperazone-sulbactam in patients on continuous ambulatory peritoneal dialysis.

This study was conducted to determine the pharmacokinetics of the fixed combination antibiotic cefoperazone-sulbactam in patients receiving continuous ambulatory peritoneal dialysis (CAPD). In addition, the pharmacodynamic profile of this combination was determined by the use of mean bactericidal titers against selected bacterial strains. Six noninfected CAPD patients were given a fixed dose of cefoperazone (2 g) and sulbactam (1 g) either intravenously or intraperitoneally over 10 min in a randomized, two-way crossover fashion. The mean peak cefoperazone concentration in serum after intravenous administration was 280.9 micrograms/ml. The mean peak concentration in serum after intraperitoneal cefoperazone administration was 38.9 micrograms/ml and occurred 2 to 4 h postdose. The mean peak sulbactam concentration in serum after intravenous administration was 82.2 micrograms/ml. The mean peak concentration in serum after intraperitoneal sulbactam administration was 24.4 micrograms/ml and occurred at 6 h. The absolute bioavailability of the intraperitoneal dose was 61% for cefoperazone and 70% for sulbactam. Cefoperazone total body and renal clearances were unaffected by renal failure and dialysis. However, both clearance values for sulbactam were reduced markedly. Only intraperitoneal dosing provided peak inhibitory and bactericidal titers in dialysate for all organisms tested. Intravenous dosing provided satisfactory dialysate titers only for very susceptible bacterial strains. End-stage renal disease and CAPD do not alter cefoperazone pharmacokinetics; however, sulbactam dosing may need to be adjusted.