strains have not been fully characterized. Recent evidence suggests that the dominant penicillin-binding protein of ORSA strains (PBP 2a) shows good affinity for ampicillin and that these strains commonly produce 13-lactamase. Therefore, we compared the in vivo efficacy of the combination of ampicillin plus sulbactam with that of vancomycin against ORSA strains. Also, the moderate resistance of BORSA strains appears to be attributable mainly to the hyperproduction of ,-lactamase. Therefore, we also studied the in vivo efficacy of ampicillin plus sulbactam against such organisms. Experimental aortic endocarditis was induced in rabbits by the following three strains: j3-lactamase-producing BORSA strain VP-986, I3-lactamase-producing ORSA strain 67-0, and its ,3-lactamase-negative clone. In animals with BORSA endocarditis, ampicillin plus sulbactam and oxacillin were highly effective in reducing mean intravegetation bacterial densities, with each being significantly better than either ampicillin alone or no therapy. In animals with endocarditis caused by the ,-lactamase-producing ORSA strain, ampicillin plus sulbactam was significantly better at reducing mean vegetation bacterial densities than the other regimens. For endocarditis caused by the 3-lactamase-negative ORSA clone, ampicillin was better than vancomycin in reducing mean intravegetation bacterial densities. These data show that infections caused by P-lactamaseproducing BORSA strains respond therapeutically in a manner similar to that of infections caused by oxacillinsusceptible strains, with both oxacillin and ampicillin plus sulbactam being highly efficacious. Moreover, high-dose ampicillin treatment strategies were effective in the therapy of ORSA endocarditis; this efficacy is presumably related to the relatively high affinity profile of this compound (compared with that of oxacillin) for the functionally dominant ORSA PBP 2a.

The in vivo efficacies of pefloxacin, a new fluoroquinolone, and amikacin-ceftazidime were compared in 50 rabbits with experimental aortic endocarditis caused by Pseudomonas aeruginosa. Animals were randomly chosen to receive 4 or 10 days of no therapy (controls) Pefloxacin and both amikacin regimens significantly reduced vegetation bacterial densities compared with controls at days 4 and 10 of treatment (P < 0.0005). By day 10 of therapy, between 33 and 40% of vegetations from amikacin-ceftazidime recipients contained ceftazidime-resistant bacteria (MICs, >25 ,ug/ml); nitrocefin agar overlay confirmed that these ceftazidime-resistant variants were constitutive overproducers of 0-lactamase. At therapy days 4 and 10, -30% of vegetations sampled from pefloxacin recipients contained bacteria for which pefloxacin MICs were four-to eightfold higher than the MIC for the parental strain used to initially induce endocarditis (MIC, 0.19 ,ig/ml). These variants also exhibited increases in ciprofloxacin and ticarcillin MICs, as well as pleotropic resistance to chloramphenicol (but not to amikacin, ceftazidime, or tetracycline). Amikacin-ceftazidime, as well as pefloxacin, was effective in this model of aortic pseudomonal endocarditis. However, in vivo development of ceftazidime resistance and step-ups in pefloxacin MICs among intravegetation isolates were associated with inability to completely eradicate P. aeruginosa from aortic vegetations.,Infective endocarditis caused by Pseudomonas aeruginosa has been prevalent among parenteral drug abusers in major metropolitan centers (e.g., Detroit and Chicago [25]). Although clinical outcomes have improved for patients with right-sided valvular infection, the medical cure rates for those with aortic or mitral valve involvement continue to be disappointing (25). In vivo development of antibiotic resistances to the P-lactams and aminoglycosides commonly used to treat these infections has been an important factor in the suboptimal outcome of left-sided pseudomonal endocarditis in both humans and experimental models (6,19,23,25). The new fluoroquinolones, possessing potent in vitro bactericidal activity against P. aeruginosa strains (2, 9, 13), are important potential agents for evaluation in invasive pseudomonal infections such as endocarditis.The current study was designed to (i) evaluate pefloxacin, a new quinolone with a prolonged half-life, in experimental aortic valve P. aeruginosa endocarditis; (ii) compare this regimen to high-dose aminoglycoside-p-lactam (amikacinceftazidime) therapy, which exhibits in vitro bactericidal synergy against the infecting strain; and (iii) examine these two therapeutic regimens for in vivo development of antimicrobial resistances.(Part of this research was presented at the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, N.Y., 4 to 7 October 1987.) MATERIALS AND METHODS Organism. The P. aeruginosa strain used to infect catheterized rabbits in this study (PA-96) was a clinical isolate that has been used in our earlie...

The emergence of multi-4-lactam resistance is a limiting factor in treating invasive Pseudomonas infections with newer cephalosporins. The in vivo efficacy of ciprofloxacin, a new carboxy-quinolone, was evaluated in experimental aortic valve endocarditis caused by a strain of Pseudomonas aeruginosa which is stably derepressed for ,l-lactamase production and is resistant to ceftazidime and multiple other P-lactam agents. A total of 51 catheterized rabbits with aortic catheters in place were infected with this strain and then received no therapy (controls), ceftazidime (75 mg/kg per day), or ciprofloxacin (80 mg/kg per day). Ciprofloxacin sterilized all blood cultures and significantly lowered vegetation densities of P. aeruginosa by day 2 of treatment versus controls (P < 0.0005) and animals receiving ceftazidime (P < 0.0005). This beneficial effect of ciprofloxacin was also noted on therapy days 6 and 11. Ciprofloxacin rendered most vegetations (85%) culture negative over the 11-day treatment period and achieved bacteriologic cure in 73% of animals (P < 0.0005 versus other therapy groups). Ciprofloxacin prevented bacteriologic relapse at 6 days posttherapy. No ciprofloxacin resistance was detected among Pseudomonas isolates from cardiac vegetations. Ciprofloxacin warrants further evaluation in vivo versus multi-drug-resistant gram-negative bacillary infections.Recent experiences in the treatment of Pseudomonas aeruginosa endocarditis in humans and experimental animals have emphasized the difficulties in achieving cures with antibiotics alone, especially in left-sided valve involvement (13-15; K. Rajashekarasah, L. Bhatia, T. Price, J. Kowalski, D. McCulley, and C. Kallick, Program Abstr. 22nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 367, 1982). This has been related to either primary drug failures or development of resistance in vivo, resulting in recrudescent bacteremia and endocarditis (13)(14)(15).One limiting factor in the therapy of endocarditis and other invasive pseudomonal infections has been in vivo development of antibiotic resistance that may cross class lines (e.g., P-lactams --aminoglycosides) (11,19

We investigated the in vitro and in vivo effects of a combination of a 1-lactam (ceftazidime) and a P-lactamase inhibitor (dicloxacillin) The medical therapy in human cases of Pseudomonas aeraginosa endocarditis has been disappointing, particularly in aortic and mitral valve involvements (25,26). One of the limiting factors in this regard, as exemplified in human as well as experimental Pseudomonas endocarditis, has been in vivo development of antibiotic resistahce. Such resistances have been variably directed towards the aminoglycoside or P-lactam components of the combination therapy regimens generally used to treat Pseudomonas endocarditis (1,19,23,26). The mechanism of P-lactam resistance in these situations has usually been associated with either inducible or constitutive P-lactamase overproduction (3,19,26).One possible strategy to circumvent the above P-lactamase-related resistances is to interfere with the function of the enzyme by using P-lactamase inhibitors. The present study was designed to (i) evaluate several P-lactamase inhibitors in vitro for their ability, when combined with a P-lactam agent (ceftazidime), to synergistically kill a ceftazidime-resistant strain of P. aeruginosa which constitutively overproduces ,-lactamase; (ii) define the ability of P-lactamase inhibitors to specifically abrogate enzyme activity in vitro; and (iii) determine the in vivo effect of combinations of P-lactam plus P-lactamase inhibitors in experimental endocarditis caused by the variant, P. aeruginosa PA-48, which conistitutively overproduces type Id 1B-lactamase.