Vancomycin or vancomycin plus netilmicin for methicillin- and gentamicin-resistant Staphylococcus aureus aortic valve experimental endocarditis

Abstract

Using a rabbit model of aortic valve endocarditis, we studied the efficacy of vancomycin alone or in combination with netilmicin and/or rifampin against a methicillin-and gentamicin-resistant strain of Staphylococcus aureus (MGRSA). Antibiotics were given for 6 or 12 days, as follows: vancomycin (15 mg/kg of body weight every 12 h [BID] intravenously), vancomycin plus netilmicin (2.5 mg/kg BID intramuscularly), vancomycin plus rifampin (10 mg/kg BID intramuscularly), and vancomycin plus netilmicin plus rifampin at the same routes, dosages, and schedules mentioned above. Netilmicin was given to two additional groups at a higher dosage (6 mg/kg every 24 h intramuscularly) alone or in combination with vancomycin (15 mg/kg BID intravenously) for 12 days. All regimens resulted in undetectable bacterial counts in a significant proportion of vegetations (except netilmicin alone) or reduced the bacterial counts in the vegetations compared with the counts in the untreated controls (P < 0.01 to P < 0.001). No resistance to rifampin or netilmicin developed during therapy. It is concluded that in the treatment of experimental aortic valve endocarditis caused by MGRSA (i) vancomycin as monotherapy is as efficacious as the triple combination, (ii) the addition of netilmicin (once daily or BID) to vancomycin does not improve the efficacy of the latter antibiotic, even in the presence of rifampin, and (iii) a 12-day course is more effective than a 6-day one, but not at a statistically significant level.Staphylococcus aureus is the second most common cause of infective endocarditis. It affects either native (25 to 35%) or prosthetic valves and is the most common organism (70%) recovered from intravenous drug addicts with endocarditis (23). Methicillin-resistant S. aureus (MRSA) strains have spread worldwide, and the frequency of their isolation has recently increased steeply (5, 12). MRSA isolates should be considered resistant to all ␤-lactams, and very often these organisms are cross resistant to gentamicin; however, they are uniformly susceptible to vancomycin and are usually susceptible to rifampin (5, 23).Vancomycin is clearly the drug of choice for the treatment of infections caused by MRSA as well as an alternative to betalactam antibiotics for the treatment of methicillin-susceptible S. aureus infections, particularly in patients allergic to ␤-lactams (8, 24). Nevertheless, there have been several reports of therapeutic failures in patients with S. aureus endocarditis treated with vancomycin as monotherapy (18,33,35). Even in animal models, vancomycin has been found to be ''surprisingly unsuccessful'' against MRSA endocarditis (9). On the other hand, the therapeutic role of rifampin in MRSA endocarditis is controversial (4), and today the majority of MRSA endocarditis strains are also gentamicin resistant (23). Because netilmicin (i) has been found to be active in vitro against MRSA strains cross resistant to gentamicin (16a), (ii) it possesses decreased nephrotoxic potential in comparison with that of gentamicin (11,22,...

Therapeutic Efficacy of GAR-936, a Novel Glycylcycline, in a Rat Model of Experimental Endocarditis

“…The degree of response would therefore depend on the activity of the antimicrobial agent, diffusion into the site, pharmacodynamic parameters required for efficacy, and the in vivo postantibiotic effect. Studies have confirmed the activity of GAR-936 against both enterococci and staphylococci, two of the more common causative agents of endocarditis (5,15). Petersen et al (38th ICAAC) observed a long in vitro postantibiotic effect for GAR-936 against both S. aureus (Ͼ3 h) and Escherichia coli (1.8 to 2.9 h) isolates.…”

“…Endocarditis was produced in male Wistar rats by insertion of a sealed polyethylene cannula (PE10) through the right carotid artery into the left ventricle; the cannula was sutured in place as a point of adherence for bacterial infection (5,6,15).…”

In Vitro Synergistic Effects of Double and Triple Combinations of β-Lactams, Vancomycin, and Netilmicin against Methicillin-Resistant Staphylococcus aureus Strains

“…Synergism was shown not to be predictable from the aminoglycoside MIC (22). On the other hand, some studies have reported that gentamicin (14,17) or netilmicin (26) can enhance the bactericidal activity of vancomycin but these results were observed at inhibitory antibiotic concentrations and against only one to three strains.…”

Evidence of Less Severe Aortic Valve Destruction after Treatment of Experimental Staphylococcal Endocarditis with Vancomycin and Dexamethasone

“…After 5 days of treatment, two out of a total of nine (22%) rabbits had sterile vegetations, while the mean bacterial burden in vegetations was 6.46 Ϯ 3.25 log 10 CFU/g (mean Ϯ standard deviation [SD]). Because vancomycin alone, at a lower dose (15 mg/kg every 12 h for 6 days, intravenously), exhibited better results (vegetation sterilization rate, 60%; mean bacterial burden, 5.63 Ϯ 1.61 log 10 CFU/g) in a previous study (17), we speculated that the addition of dexamethasone in high doses in the pilot study could be responsible for the lower efficacy of vancomycin compared to that in the previous study (17). Thus, we decided to use a lower dexamethasone dose in the main study.…”