Importance of penicillinase production for activity of penicillin alone or in combination with sulbactam in experimental endocarditis due to methicillin-resistant Staphylococcus aureus

Abstract

The activity of penicillin, alone and in combination with sulbactam, against a heterogeneously methicillin-resistant, penicillinase-producing clinical isolate of Staphylococcus aureus and its penicillinase-negative derivative was investigated in vitro and in a rabbit experimental endocarditis model. Penicillin was significantly more effective than vancomycin against the penicillinase-negative derivative in vivo (P < 0.001), and it sterilized 25% of the vegetations. The combination of penicillin and sulbactam exhibited an in vivo synergistic effect on the penicillinase-producing strain (P < 0.01) but did not produce any advantage over treatment with vancomycin, even when a high dose of sulbactam was used (100 mg/kg of body weight every 6 h). This combination was significantly less effective against the penicillinase-producing strain than was penicillin alone against the penicillinase-negative derivative (P < 0.03). In addition, the most resistant subpopulation of the surviving bacteria, which grew on agar containing 16 micrograms of methicillin per ml, was detected in 5 of 6 animals treated with penicillin and a high dose of sulbactam against the penicillinase-producing strain compared with only 1 of 12 animals treated with penicillin alone against the penicillinase-negative derivative (P < 0.01). We conclude that penicillin is highly effective against penicillinase-negative methicillin-resistant S. aureus and that penicillinase production, rather than methicillin resistance, appears to be the limiting factor for the activity of the penicillin-sulbactam combination against penicillinase-producing, methicillin-resistant S. aureus.

Lysostaphin Treatment of Experimental Methicillin-Resistant Staphylococcus aureus Aortic Valve Endocarditis

“…Although vancomycin is considered the best agent in this model, it is relatively ineffective at sterilizing aortic valve vegetations, results that mirror the lack of efficacy reported for vancomycin therapy of human S. aureus endocarditis. Of 15 studies of experimental MRSA aortic valve endocarditis with vancomycin doses and treatment durations similar to those used in our study, 6 reported no sterilization of aortic valve vegetations (5,7,13,16,18,19), while 4 described sterilization of fewer than half of the vegetations (1,6,10,32). Five remaining studies (11,14,(26)(27)(28) reported aortic valve sterilization rates of 55 to 87%, although three of those studies used an MRSA strain that appears to have been more easily eradicated by a variety of antimicrobial agents in this model (26)(27)(28).…”

In Vivo Efficacies of Combinations of β-Lactams, β-Lactamase Inhibitors, and Rifampin against Acinetobacter baumannii in a Mouse Pneumonia Model

“…Limits of quantification were 0.1 mg/liter and 0.1 mg/kg for plasma and lung samples, respectively. The method for dosing sulbactam was adapted from the technique reported by Fantin et al (8). Plasma and lung sulbactam levels were determined by RP-HPLC with UV detection at 313 nm.…”

Rapid isolation and identification of staphylococcal exoproteins by reverse phase capillary high performance liquid chromatography–electrospray ionization mass spectrometry

“…These toxins include cytotoxins such as the 33-kDa K-toxin [6,7] and leukocytolytic toxins [8], exfoliative toxins including epidermolytic toxins A and B [9], pyrogenic superantigens such as enterotoxins [4,10] and toxic shock syndrome toxin (TSST-1) [10,11], and protein A [7,12]. Extracellular enzymes include lipase [13], hyaluronidase [14,15], coagulase [16], acid and alkaline phosphatases [17], penicillinase [18], nu-clease [19], staphylokinase [20] and various other proteases [3,21]. Most other staphylococcal exoproteins have not been well characterized yet.…”