A multicenter, prospective randomized trial was conducted to determine if the addition of rifampin to a combination therapy of an antipseudomonal beta-lactam agent and aminoglycoside improves the outcome of patients with Pseudomonas aeruginosa bacteremia. The Zelen protocol for randomized-consent design was used. Consent was sought only from patients randomized to the experimental therapy (rifampin+). If the experimental therapy was refused, the patient would then receive the standard combination therapy (control); however, when outcome was evaluated, all patients randomized to the rifampin+ group, including those that declined rifampin, were compared with the control group. One hundred twenty-one consecutive hospitalized patients with positive blood cultures for P. aeruginosa were enrolled. Entry was stratified for prior use of empiric antipseudomonal antibiotics, neutropenia, severity of illness, and presence of pneumonia. Fifty-eight patients were randomized to receive rifampin (600 mg orally every 8 h for the first 72 h and then every 12 h for a total of 10 days) plus a beta-lactam agent plus an aminoglycoside. Sixty-three received the standard therapy of a beta-lactam plus an aminoglycoside agent (control). Bacteriologic cure occurred significantly more frequently in patients randomized to the rifampin+ regimen. Breakthrough or relapsing bacteremias occurred in 2% of the three-drug (rifampin+) group, compared with 14% for the two-drug (standard therapy) group. Despite this favorable trend in bacteriological response, no significant differences in survival were seen for the two treatment groups. Rifamycin derivatives warrant further clinical study as antipseudomonal agents. The Zelen protocol appears well suited for comparative trials of antimicrobial agents.Pseudomonas aernginosa continues to be an important pathogen, especially among debilitated and immunocompromised individuals. Infections caused by P. aeruginosa are difficult to treat because of the organism's intrinsic resistance to many antibiotics and its propensity to develop resistance during therapy (10,(13)(14)(15)(16)(17). These properties have so limited the effectiveness of antibiotic monotherapy that combination antibiotic therapy has been advocated for serious P. aeruginosa infection (1,11,13,19). Nevertheless, the mortality rates for bacteremia due to P. aeruginosa continue to be consistently higher than for other bacterial pathogens (1,3,5,8).In an exploration for more potent antipseudomonal combinations of antibiotics, rifampin was found to be synergistic in vitro with antipseudomonal penicillin and an aminoglycoside against P. aeruginosa (20,22,26). Compared with the double combination of an antipseudomonal beta-lactam agent and an aminoglycoside, a triple combination of rifampin, an antipseudomonal beta-lactam agent, and an aminoglycoside significantly improved survival in neutropenic mice infected with P. aeruginosa (9,21,25). Moreover, selected patients with P. aeruginosa sepsis who failed standard antipseudomonal combination therapy w...

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