Antipseudomonal Beta-lactam Antibiotics Research Articles

Combinations of antibiotics against Pseudomonas aeruginosa

Pseudomonas aeruginosa continues to cause serious infections, especially bacteremias, in hospitalized and immunocompromised patients. During the past 10 years, bacteremia due to this organism has Increased in frequency in many institutions, and mortality rates in patients with rapidly fatal disease remain as high as 85 percent despite antibiotic therapy. Available data do not allow firm conclusions regarding the in vivo predictive value of in vitro synergy testing for P. aeruglnosa, but in vitro demonstration of synergy appears Important in selecting therapy for patients with P. aeruglnosa infections. Combinations of aminoglycosides (amikacin or tobramycin) with highly active antipseudomonal beta-lactam antibiotics are most likely to be associated with in vitro synergy. Experimental studies in animal models support the use of combination therapy for local and bacteremic infections. Similarly, the retrospective and prospective studies in humans suggest better survival with combinations of antimicrobials, usually including aminoglycosides and beta-lactams, in immunocompromised hosts. At present, the use of newer penicillins, piperacillin, azlocillin, or selected antipseudomonal cephalosporins, in combination with amikacin or tobramycin, appears to be the preferable antimicrobial therapy for serious P. aeruginosa infections.

Relevance of in vitro antibacterial activities and pharmacokinetic properties of antipseudomonal .BETA.-lactam antibiotics to their therapeutic effects on urinary tract infection caused by Pseudomonas aeruginosa P 9 in mice.

The therapeutic effects of seven antipseudomonal beta-lactam antibiotics on experimental urinary tract infection caused by Pseudomonas aeruginosa P 9 in mice were compared, and the results were analyzed in relation to their in vitro antibacterial activities and pharmacokinetic properties. The CD50 values were (mg/kg): cefsulodin, 6.19; cefoperazone, 162; sulbenicillin, 167; ticarcillin, 184; azlocillin, 121; mezlocillin, 390; and piperacillin, 227. Cefsulodin was more active than the other antibiotics not only in therapeutic effects but also in in vitro antibacterial effects evaluated according to growth inhibitory, bactericidal, and bacteriolytic activities. It also penetrated and persisted well in the kidney of mice. The therapeutic effects of cefoperazone, azlocillin, and piperacillin were much less than expected from their in vitro antibacterial activities; the CD50 values were more than 18-fold as large as that of cefsulodin, whereas the differences of their MIC values were less than four-fold.

Synergistic activity of astromicin and beta-lactam antibiotics against Pseudomonas aeruginosa in vitro and in vivo.

Synergistic activity of astromicin and an antipseudomonal beta-lactam antibiotic such as piperacillin, cefsulodin or carbenicillin against Pseudomonas aeruginosa was demonstrated in vitro and in vivo. Synergy in vitro was observed more often when astromicin was combined with piperacillin or cefsulodin than when it was combined with carbenicillin. The combination of astromicin with piperacillin showed a bactericidal activity against Pseudomonas aeruginosa at a bacteriostatic concentration of each antibiotic alone. The synergy observed in vitro was reproduced against experimental mouse infections, and the astromicin-piperacillin or cefsulodin combination produced significantly greater protective effects than the single use of individual antibiotics.

Beta-Lactam-resistant Pseudomonas aeruginosa with modified penicillin-binding proteins emerging during cystic fibrosis treatment.

The emergence of beta-lactam-resistant strains of Pseudomonas aeruginosa in a cystic fibrosis patient treated with high-dose tobramycin and piperacillin was studied. Two serotypes, M and K, were present before treatment and persisted, with changes in their beta-lactam resistance spectra, during treatment. The resistance was correlated with changes in the penicillin-binding proteins (PBPs) in both serotypes. In the low-level-resistant serotype K organism, PBP-3 either was absent or had lost the ability to bind [14C]penicillin G. Tow serotypes M strains, one with low- and one with high-level resistance to several antipseudomonal beta-lactam antibiotics, were isolated at progressively later stages of therapy. Several differences were noted between the PBP patterns of the resistant M and the susceptible M strains. The affinity for [14C]penicillin G was reduced in both resistant strains. PBP bands, with the exception of PBP-6 in the most resistant M type, were barely or not detectable at a [14C]penicillin G concentration of 39 microgram/ml. The graduated decrease in affinity for [14c]penicillin G was correlated with increasing beta-lactam resistance and with an increase in the quantity of the protein corresponding to PBP-6. The emergence of the low-level-resistant strains midway through, and of the highly resistant strain in the final stages of, the reported treatment strongly suggested that the resistance resulted from mutation in those strains present before treatment selected for by the high-dose piperacillin treatment.