Efficacy of ciprofloxacin in experimental aortic valve endocarditis caused by a multiply beta-lactam-resistant variant of Pseudomonas aeruginosa stably derepressed for beta-lactamase production

Abstract

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

Fluoroquinolone antimicrobial agents.

“…Data on treatment of bacterial endocarditis with quinolones comes almost entirely from rabbit models with infection caused by Staphylococcus aureus (87, 277, 398, 575, 747), enterococci (219), Enterobacter aerogenes (67, 68), or P. aeruginosa (37,38,741). For Staphylococcus aureus infections as assessed by colony counts of aortic valve vegetations after several days of therapy, ciprofloxacin given in doses which produced serum levels approximating those achievable in humans was comparable to nafcillin alone or cloxacillin plus gentamicin (87,575) or, for methicillinresistant strains, comparable to vancomycin (87,398), the only currently available agent effective for these infections when used alone.…”

Efficacy of Amikacin, Ofloxacin, Pefloxacin, Ciprofloxacin, Enoxacin and Fleroxacin in Experimental Left-Sided <i>Pseudomonas aeruginosa</i> Endocarditis

“…The drug has been proven effective, exerting a rapid bactericidal effect in vivo by significantly reducing the mean vegetation counts of the organism [17,20,30,31]. No emergence of resistance to the drug during treatment has been reported in several studies [17,20,30].…”

Discovery and development of new antimicrobial agents

“…Furthermore, with the increased incidence of immunosuppressed patients seen in hospitals today, there is a major need for new antimicrobial agents that provide adequate therapy in patients lacking an intact immune system (57,98,134). Therefore, new infection models have been developed in immunosuppressed animals that measure the efficacy of antimicrobial agents against bacterial and fungal pathogens found in immunosuppressed patients (6,91,132). Usually, the animals are chemically immunosuppressed with repeated doses of agents such as dexamethasone or cyclophosphamide before challenge with a lethal inoculum of test organism (91,132).…”

“…Such fermentation discovery efforts initially rely on testing large numbers of soil samples by rapid, automated techniques. One early study, for instance, estimated that, of 21,830 fermentation cultures tested, 6,464 produced antibiotics, 490 of which possessed activities of interest; 6 were eventually submitted for structural determinations, from which two novel structures were isolated (178). Reports of new antimi- (120).…”

“…6) marked the beginning of the modern antibiotic era and served as a model for the development of future agents in at least two ways. First, the isolation in 1957 of the active nucleus of penicillin G, 6-aminopenicillanic acid (6-APA) (Fig. 6), provided a key intermediate for production of a large number of new semisynthetic derivatives.…”