In vitro studies of investigational beta-lactams as possible therapy for Pseudomonas aeruginosa endocarditis

Abstract

The inadequacy of the present medical therapy of Pseudomonas aeruginosa endocarditis prompted an investigation of the in vitro activities of aztreonam, cefsulodin, and imipenem compared with that of ticarcillin against 37 strains of P. aeruginosa isolated from patients with endocarditis. Inhibitory and bactericidal activities were studied for each I-lactam alone and in combination with tobramycin. All agents showed excellent inhibitory activity. Imipenem was the most inhibitory P-lactam yet lacked inhibitory synergy against 95% of the strains and bactericidal synergy against 62%. Tolerance to imipenem was seen in six strains. Aztreonam alone was bactericidal against 46% of the strains (at 16 ,ug/ml) and showed bactericidal synergy in 70%. Cefsulodin alone was even less active but similar to aztreonam synergistically. Ticarcillin and tobramycin inhibited all strains as single agents and showed universal bactericidal synergy in combination. None of the new I-lactams showed consistent superiority to the presently used agent, ticarcillin.Pseudomonas aeruginosa endocarditis often responds poorly to present medical therapy with an antipseudomonal penicillin and an aminoglycoside (16). Investigational Plactams of the cephalosporin, monobactam, and carbapenem classes have considerable inhibitory activity against P. aeruginosa in vitro. However, there is little information available concerning their bactericidal and synergistic activities in combination with an aminoglycoside. Both of these properties are important in determining whether these agents may offer an advantage over current therapy or at least an equipotent alternative in penicillin-allergic patients with P. aeruginosa endocarditis.We therefore investigated the inhibitory and bactericidal activities of aztreonam, cefsulodin, and imipenem alone and in combination with tobramycin against 37 strains of P. aeruginosa isolated from patients with P. aeruginosa endocarditis to determine whether they compared favorably in vitro with the present therapeutic regimen of ticarcillin and tobramycin. MATERIALS AND METHODSOrganisms and patients. Strains of P. aeruginosa were isolated from blood or excised cardiac valves of patients with a diagnosis of P. aeruginosa endocarditis seen at the University of Illinois Hospitals from 1979 through 1983. Diagnostic criteria for P. aeruginosa endocarditis included persistent P. aeruginosa bacteremia and absence of an obvious source other than the heart (17). All patients were intravenous drug users. Duplicate isolates from the same patient were excluded unless they differed in serotype (three instances). The isolates were identified by standard criteria (8).Serotyping. Serotyping was performed by slide agglutination with live P. aeruginosa organisms picked from blood agar plates with antisera against the 17 0 antigens of the International Antigenic Typing Scheme (3). Antisera were obtained from Difco Laboratories (Detroit, Mich. Susceptibility testing. MICs of the five antibiotics were determined for each organism in microtiter wells...

<i>Pseudomonas aeruginosa</i>: In vitro Susceptibility to Antimicrobial Drugs, Single and Combined, with and without Defibrinated Human Blood

“…All two-drug combina tions involving tobramycin augmented the antibacterial activity of human blood; and 3 P-lactam antibiotics (ceftazidime, cefo perazone, and piperacillin, but not aztreo nam), when combined with imipenem, likewise yielded additive effects in con junction with human blood. Thus, the data generated with the first two series of exper iments essentially agreed with those pub lished by other investigators [1,7,8,12,17,21,29,31,33,41], The third series of experiments served to examine triple-drug combinations, with special emphasis on rifampin [39,40,43], with and without hu man blood, against several multiple-drugresistant strains of P. aeruginosa. All tri ple-drug combinations plus human blood resulted in efficient killing of these latter test strains, data confirming those of Yu et al [39,40] and Zuravleff et al [43].…”

Rapid Conversion of Pseudomonas aeruginosa to a Spherical Cell Morphotype Facilitates Tolerance to Carbapenems and Penicillins but Increases Susceptibility to Antimicrobial Peptides

“…Interestingly, despite inhibiting cell growth, ␤-lactams have been found to have very little bactericidal activity against P. aeruginosa (9)(10)(11)(12)(13). This intrinsic tolerance of ␤-lactams likely accounts for the fact that when P. aeruginosa infections are treated, optimal microbiological outcomes occur when ␤-lactam concentrations are maintained at 4 to 6.6 times the MIC throughout the majority of the dosing period (13).…”