Development of beta-lactam resistance and increased quinolone MICs during therapy of experimental Pseudomonas aeruginosa endocarditis

Abstract

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...

Infective Endocarditis

“…161 Although valve replacement often is necessary for curing left-sided IE caused by P aeruginosa, 162 results in a series of 10 patients (7 with left-sided involvement alone or in combination with tricuspid disease) suggest that medical therapy alone is occasionally curative. 149 Studies in animals with experimental Pseudomonas endocarditis 163 offer a potential explanation for these disparate results: The penetration into vegetations and the time during which antibiotic concentrations exceeded the MBC were both significantly greater with tricuspid than with aortic vegetations for both ceftazidime and tobramycin.…”

“…The toxicity associated with this regimen is surprisingly low; combination treatment should be given for a minimum of 6 weeks. The use of quinolones (in combination with an aminoglycoside) for the treatment of Pseudomonas endocarditis appears promising, based on favorable results in animal models 163 and humans, 168 but the development of stepwise resistance during therapy may limit the efficacy of this class of drugs in the future. On the basis of limited experimental data, 169 ceftazidime-tobramycin is preferred over aztreonamtobramycin for this disease.…”

“…Problems have emerged with all potential regimens in animal models of P aeruginosa IE, including failure of ␤-lactam (eg, ceftazadime) therapy as a result of constitutive hyperproduction of type Id ␤-lactamase by isolates within valve vegetations in animal models 163 and clinically 164 ; isolates demonstrating aminoglycoside resistance caused by permeability defects that emerge during therapy 165 ; absence of a postantibiotic effect of ␤-lactams against P aeruginosa in vivo, 166 thus necessitating frequent (or continuous) drug administration; and reduced hostmediated clearance of mucoid strains from the valvular vegetation resulting from alginate exopolysaccharide. 167 On the basis of clinical experience, 154,156,157 however, the preferred regimen for IE caused by P aeruginosa is high-dose tobramycin (8 mg/kg per day IV or intramuscularly in once-daily doses) with maintenance of peak and trough concentrations of 15 to 20 g/mL and Յ2 g/mL, respectively, in combination with either an extended-spectrum penicillin (eg, ticarcillin, piperacillin, azlocillin) or ceftazidime or cefepime in full doses (Class IIa, Level of Evidence: B).…”

Quinolones: a class of antimicrobial agents

“…When the fluoroquinolones are used, data support that intensive therapy, such as maximum concentrations achieved at the site of infection 4-8 times higher than the MIC or areas under the curve (AUC) to MIC doses of higher than 125, is associated with the minimization of resistance development (Felmingham et al, 1988;Forrest at al., 1993). Conversely, therapy over prolonged periods of time (4-10 days) in human beings is associated with the emergence of resistant strains of bacteria (Bayer et al, 1988). Clearly, intermittent dosing regardless of the route of administration is one of the methods of minimizing the development of bacterial resistance.…”

Development of multiple-antibiotic-resistant (Mar) mutants of Pseudomonas aeruginosa after serial exposure to fluoroquinolones

“…Genetic characterization by DNA sequencing of gyrA from E. coli reveals that mutations leading to fluoroquinolone resistance are clustered within a narrow region between nucleotides 199 (Ala-67) and 318 (Gln-106) (21). It has been suggested that mutants possessing a single nucleotide change (point mutation) produce single changes in amino acid sequence which result in an altered DNA gyrase which either reduces the affinity of the fluoroquinolone for the enzyme or blocks the access of the antibiotic to the DNA-DNA gyrase complex (21,39).In addition to DNA gyrase changes, fluoroquinolone resistance in P. aeruginosa can occur as a result of alterations in the outer membrane (2,3,12,14,20,27,31,38,45,46). Resistance selection with fluoroquinolones results in many instances in changes in outer membrane proteins and is manifested as not only resistance to fluoroquinolones but multiple antibiotic resistance (Mar) including beta-lactams, tetracyclines, and chloramphenicol (2,3,12,27,37,38).…”