Pharmacokinetic and pharmacodynamic requirements for antibiotic therapy of experimental endocarditis

The bactericidal activity and emergence of resistance to RP 59500 (quinupristin/dalfopristin) when it was administered alone and in combination with vancomycin against fibrin clots that have been infected with methicillin-susceptible Staphylococcus aureus ATCC 25923 or methicillin-resistant S. aureus (MRSA) 67 were evaluated in an in vitro pharmacodynamic infected fibrin clot model. Fibrin clots were infected with S. aureus to achieve an inoculum of approximately 10 9 CFU/g. Antibiotics were administered to simulate pharmacokinetics in humans: RP 59500 (7.5 mg/kg of body weight) every 8 h and vancomycin (15 mg/kg) every 12 h over 72 h. Preliminary test tube time-kill experiments with an inoculum of ϳ10 5 CFU/ml suggested that RP 59500 was more rapid in achieving a 99.9% reduction in the number of CFU per milliliter than vancomycin against ATCC 25923 (6.94 versus 24 h; P ‫؍‬ 0.0003) and MRSA 67 (6.77 versus 17.03 h; P ‫؍‬ 0.004). At a higher inoculum (ϳ10 8 CFU/ml), 99.9% kill was achieved only with the combination regimen against ATCC 25923 and MRSA 67 (10.9 and 10.5 h, respectively), with total reductions of 6.35 and 6.33 log 10 CFU/ml over 24 h, respectively. In the fibrin clot model, RP 59500 was more effective than vancomycin in reducing organism titers over 72 h. However, the combination regimen was the most effective therapy, with a total reduction of colony count against ATCC 25923 (total reduction of 1.24 log 10 CFU/g for RP 59500, 0.56 log 10 CFU/g for vancomycin, and 3.3 log 10 CFU/g for the combination; P < 0.002) and MRSA 67 (total reduction of 1.66 log 10 CFU/g for RP 59500, 0.50 log 10 CFU/g for vancomycin, and 2.48 log 10 CFU/g for the combination; P < 0.04). Resistance of both strains of S. aureus was noted in the model only after exposure to RP 59500 (32-fold increase in the MIC), as was a simultaneous increase in the erythromycin MIC (32-fold) for ATCC 25923, but no changes in the lincomycin MIC were noted. Overall, RP 59500 demonstrated more potent bactericidal activity than vancomycin against S. aureus over 72 h. In the fibrin clot model, the most optimal therapy was the combination regimen.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model

Kang

Rybak

1995

“…VOL. 38,1994 on April 27, 2019 by guest http://aac.asm.org/ Downloaded from vegetation, decreased antibiotic activity under anaerobic and acidic conditions, impaired host defenses at the site of infection, the high degree of virulence of some infecting pathogens, and the development of resistance (4,14,28). These problems have been highlighted with the recent failure of teicoplanin for the treatment of endocarditis caused by susceptible strains of S. aureus (10,22).…”

Section: In Vitro Model Of Endocarditis a One-compartment In Vitromentioning

confidence: 99%

“…Infective endocarditis continues to be a difficult therapeutic problem because of the poor penetration of antibiotics, large inoculum size, the development of resistance, and the lack of host defense at the infection site (4,10,14,22,28,33). In the case of endocarditis caused by Staphylococcus aureus, the treatment choices remain extremely limited.…”

mentioning

confidence: 99%

Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis

McGrath

Kang

Kaatz

et al. 1994

We adapted an in vitro pharmacodynamic model of infection to incorporate simulated endocardial vegetations. The bactericidal activities of teicoplanin, vancomycin, gentamicin, and various combinations of these drugs were studied against a strain of methicillin-susceptible Staphylococcus aureus obtained from a patient being treated for endocarditis at Detroit Receiving Hospital. Bacteria were grown overnight, concentrated, and added to a mixture of cryoprecipitate (80%o)

“…For the time-kill studies, series of flasks containing fresh prewarmed medium were inoculated with ca. 10 6 CFU/ml (final concentration) from an overnight culture of bacteria, and the bacteria were further incubated at 35°C. Immediately after inoculation, the antibiotics were added to the flasks at final concentrations that approximated the peak and trough levels of antibiotics produced in the serum of humans with therapeutic doses of the drugs (see Results).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Garenoxacin in Treatment of Experimental Endocarditis Due to Staphylococcus aureus or Viridans Group Streptococci

Entenza

Vouillamoz

Glauser³

et al. 2004

The activity of garenoxacin was investigated in rats with experimental endocarditis due to staphylococci and viridans group streptococci (VGS). The staphylococci tested comprised one ciprofloxacin-susceptible and methicillin-susceptible Staphylococcus aureus (MSSA) isolate (isolate 1112), one ciprofloxacin-susceptible but methicillin-resistant S. aureus (MRSA) isolate (isolate P8), and one ciprofloxacin-resistant mutant (grlA) of P8 (isolate P8-4). The VGS tested comprised one penicillin-susceptible isolate and one penicillin-resistant isolate (Streptococcus oralis 226 and Streptococcus mitis 531, respectively). To simulate the kinetics of drugs in humans, rats were infused intravenously with garenoxacin every 24 h (peak and trough levels in serum, 6.1 and Gram-positive bacteria are major causes of both communityand hospital-acquired severe infections. Over the years, grampositive pathogens have progressively developed resistance against almost all of the available antibacterial agents. For instance, therapeutic options for methicillin-resistant Staphylococcus aureus (MRSA) are often limited to glycopeptides such as vancomycin or, alternatively, to the novel agents quinupristin-dalfopristin and linezolid (3). However, vancomycinintermediate and highly resistant clinical MRSA isolates have recently been described in several countries (5, 6, 23), jeopardizing the use of glycopeptides. In parallel, viridans group streptococci (VGS), which are the leading cause of infectious endocarditis, are becoming resistant to beta-lactams and numerous other drugs (13). The emergence of bacterial resistance to most classes of antibiotics has stimulated the search for new antimicrobial drugs.Garenoxacin (BMS-284756) is a novel des-fluoro(6)-quinolone that appears to be very active against multiresistant S. aureus strains and penicillin-resistant streptococci (20). Therefore, garenoxacin may be particularly well suited as an agent that targets both Staphylococcus spp. and Streptococcus spp. Furthermore, garenoxacin seems to be active against many quinolone-resistant gram-positive cocci (24).The aims of the experiments described below were to determine both the activity of garenoxacin and the risk of the emergence of resistance in vitro and in a rat model of experimental endocarditis. Rats with catheter-induced aortic vegetations were infected with either ciprofloxacin-susceptible or ciprofloxacin-resistant S. aureus or penicillin-susceptible or penicillin-resistant VGS. Infected rats were treated with (i) garenoxacin; (ii) the control quinolone levofloxacin, a new quinolone recently introduced in the clinical setting; (iii) flucloxacillin or vancomycin, the reference drugs for the treatment of endocarditis due to methicillin-susceptible S. aureus (MSSA) and MRSA, respectively, in humans (31); or (iv) ceftriaxone, a recommended alternative for the treatment of endocarditis due to VGS in humans (31). The rats were treated with the drugs so that the kinetics in the serum of rats simulated those in the serum of humans.