Experimental Endocarditis

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Philippe Moreillon - One of the best experts on this subject based on the ideXlab platform.

  • Vancomycin-intermediate Staphylococcus aureus selected during vancomycin therapy of Experimental Endocarditis are not detected by culture-based diagnostic procedures and persist after treatment arrest
    The Journal of antimicrobial chemotherapy, 2011
    Co-Authors: Philippe Moreillon, Jacques Vouillamoz, Marlyse Giddey, Alain Bizzini, José M. Entenza
    Abstract:

    Results: Vancomycin cured 14 of 26 animals (54%; P,0.05 versus controls) after 2 days of treatment. When vegetation homogenates were plated directly on vancomycin-containing plates, 6 of 13 rats killed 8 h after treatment arrest had positive cultures, 1 of which harboured hVISA. Likewise, 6 of 13 rats killed 3 days thereafter had positive valve cultures, 5 of which harboured hVISA. However, one subculture of vegetations in drug-free broth was enough to revert all the hVISA phenotypes to the susceptible pattern of the parent. Thus, vancomycin selected for hVISA during therapy of Experimental Endocarditis due to vancomycin-susceptible S. aureus. These hVISA were associated with vancomycin failure. The hVISA phenotype persisted in vivo, even after vancomycin arrest, but was missed in vitro after a single passage of the vegetation homogenate on drug-free medium. Conclusions: hVISA might escape detection in clinical samples if they are subcultured before susceptibility tests.

  • Continuous Infusion May Improve the Efficacy of Vancomycin in Treatment of Experimental Endocarditis Due to Heterogeneous Vancomycin-Intermediate Staphylococcus aureus
    Antimicrobial Agents and Chemotherapy, 2011
    Co-Authors: Federico Pea, Jacques Vouillamoz, José M. Entenza, Tiago Rafael Veloso, Marlyse Giddey, Piergiorgio Cojutti, Nicola Petrosillo, Mario Furlanut, Philippe Moreillon
    Abstract:

    We read with interest the paper of Entenza and coworkers suggesting failure of continuous vancomycin infusion against Experimental Endocarditis due to heterogeneous vancomycinintermediate Staphylococcus aureus (hVISA) and VISA (1). In that study, it was stated that continuous vancomycin infusion for 5 days was unsuccessful, as 20 mg/liter was barely active against hVISA PC1 (6 of 13 sterile vegetations) and 40 mg/liter failed against VISA PC3 (2 of 9 sterile vegetations). Generally speaking, we agree that in this Experimental model vancomycin led to suboptimal treatment of VISA infection; however, we believe that some findings related to the role that continuous infusion may have in improving the outcome of vancomycin treatment of hVISA infections deserve attention. Indeed, in the hVISA PC1 model (vancomycin MIC, 2 mg/ liter), there was a misinterpretation of the results, since it appears from Fig. 1 in that paper that the number of sterile vegetations obtained by continuous infusion was higher than stated (7/13 and not 6/13). More importantly, compared with intermittent vancomycin administration (peak and trough levels of at least 50 and 10 mg/liter, respectively), continuous infusion with a constant serum drug concentration of 20 mg/ liter was significantly more effective in sterilizing hVISA PC1 vegetations (54% versus 18%, P 0.05). Although fewer than 100% of the vegetations were sterilized, it must be highlighted that continuous infusion was the only bactericidal regimen, since it led to a more-than-4-log reduction of the mean bacterial burden in the vegetations at day 5 compared to that in the controls (3.57 2.1 versus 7.64 0.4 log 10 CFU/g [P 0.001]), which is different from what occurred with intermittent infusion (6.82 3.1 log 10 versus 7.64 0.4 log10 CFU/g [no statistically significant difference]). These data suggest that continuous infusion of vancomycin may significantly improve the treatment outcome of Experimental Endocarditis due to hVISA. Indeed, the incomplete sterilization seen even after 5 days of continuous vancomycin infusion may be in line with the time-dependent activity of this glycopeptide, which may take a much longer time for complete healing to occur, especially if the bacteria are embedded in biofilm (2). However, it is worth noting that by ensuring that the concentration persistently exceeds a value of at least four to five times the MIC, this strategy may also reduce the selective pressure due to very low trough levels (3) and may avert the development of frank vancomycin resistance, even in cases of long-term treatment (4). Considering that a recent systematic review and meta-analysis of the clinical significance of hVISA isolates (5) showed that hVISA infections were associated with a glycopeptide failure rate 2.37-fold greater than that obtained with vancomycinsusceptible S. aureus infections, we do believe that these Experimental data may support the idea that continuous infusion may be worthwhile with the intent to decrease the failure rate of vancomycin treatment of humans with hVISA infections.

  • In Vivo Synergism of Ceftobiprole and Vancomycin against Experimental Endocarditis Due to Vancomycin-Intermediate Staphylococcus aureus
    Antimicrobial agents and chemotherapy, 2011
    Co-Authors: José M. Entenza, Jacques Vouillamoz, Tiago Rafael Veloso, Marlyse Giddey, Paul Majcherczyk, Philippe Moreillon
    Abstract:

    The efficacy of ceftobiprole combined with vancomycin was tested against two vancomycin-intermediate Staphylococcus aureus (VISA) strains, PC3 and Mu50, in rats with Experimental Endocarditis. Animals with infected aortic vegetations were treated for 3 days with doses simulating the kinetics after intravenous administration in humans of (i) the standard dose of ceftobiprole of 500 mg every 12 h (b.i.d.) (SD-ceftobiprole), (ii) a low dose of ceftobiprole of 250 mg b.i.d. (LD-ceftobiprole), (iii) a very low dose of ceftobiprole of 125 mg b.i.d. (VLD-ceftobiprole), (iv) SD-vancomycin of 1 g b.i.d., or (v) LD- or VLD-ceftobiprole combined with SD-vancomycin. Low dosages of ceftobiprole were purposely used to highlight positive drug interactions. Treatment with SD-ceftobiprole sterilized 12 of 14 (86%) and 10 of 13 (77%) vegetations infected with PC3 and Mu50, respectively (P 0.05 versus controls). VLD-ceftobiprole and SD-vancomycin alone were ineffective against both strains (≤8% sterile vegetations). In contrast, the combination of VLD-ceftobiprole and SD-vancomycin sterilized 7 of 9 (78%) and 6 of 14 (43%) vegetations infected with PC3 and Mu50, respectively, and the combination of LD-ceftobiprole and SD-vancomycin sterilized 5 of 6 (83%) vegetations infected with Mu50 (P < 0.05 versus controls and monotherapy). Thus, ceftobiprole monotherapy simulating standard therapeutic doses was active against VISA Experimental Endocarditis. Moreover, subtherapeutic LD- and VLD-ceftobiprole synergized with ineffective vancomycin to restore efficacy. Hence, combining ceftobiprole with vancomycin broadens the therapeutic margin of these two compounds against VISA infections.

  • Induction of Experimental Endocarditis by Continuous Low-Grade Bacteremia Mimicking Spontaneous Bacteremia in Humans
    Infection and immunity, 2011
    Co-Authors: Tiago Rafael Veloso, Jacques Vouillamoz, Philippe Moreillon, Marlyse Giddey, M. Amiguet, Valentin Rousson, José M. Entenza
    Abstract:

    Transient high-grade bacteremia following invasive procedures carries a risk of infective Endocarditis (IE). This is supported by Experimental Endocarditis. On the other hand, case-control studies showed that IE could be caused by cumulative exposure to low-grade bacteremia occurring during daily activities. However, no Experimental demonstration of this latter possibility exists. This study investigated the infectivity in animals of continuous low-grade bacteremia compared to that of brief high-grade bacteremia. Rats with aortic vegetations were inoculated with Streptococcus intermedius, Streptococcus gordonii or Staphylococcus aureus (strains Newman and P8). Animals were challenged with 10(3) to 10(6) CFU. Identical bacterial numbers were given by bolus (1 ml in 1 min) or continuous infusion (0.0017 ml/min over 10 h). Bacteremia was 50 to 1,000 times greater after bolus than during continuous inoculation. Streptococcal bolus inoculation of 10(5) CFU infected 63 to 100% vegetations compared to 30 to 71% infection after continuous infusion (P > 0.05). When increasing the inoculum to 10(6) CFU, bolus inoculation infected 100% vegetations and continuous infusion 70 to 100% (P > 0.05). S. aureus bolus injection of 10(3) CFU infected 46 to 57% valves. This was similar to the 53 to 57% infection rates produced by continuous infusion (P > 0.05). Inoculation of 10(4) CFU of S. aureus infected 80 to 100% vegetations after bolus and 60 to 75% after continuous infusion (P > 0.05). These results show that high-level bacteremia is not required to induce Experimental Endocarditis and support the hypothesis that cumulative exposure to low-grade bacteremia represents a genuine risk of IE in humans.

  • Failure of vancomycin continuous infusion against Experimental Endocarditis due to vancomycin-intermediate Staphylococcus aureus.
    Antimicrobial agents and chemotherapy, 2010
    Co-Authors: José M. Entenza, Jacques Vouillamoz, Tiago Rafael Veloso, Marlyse Giddey, Philippe Moreillon
    Abstract:

    Continuous infusion of vancomycin was evaluated against Experimental Endocarditis due to heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and VISA. Animals were infected with hVISA PC1 (vancomycin MIC, 2 mg/liter) or VISA PC3 (vancomycin MIC, 8 mg/liter) and treated for 5 days with constant serum levels of 20 or 40 mg/liter. Vancomycin continuous infusion was unsuccessful, as 20 mg/liter was barely active against PC1 (6 of 13 sterile vegetations) and 40 mg/liter failed against PC3 (2 of 9 sterile vegetations).

José M. Entenza - One of the best experts on this subject based on the ideXlab platform.

  • Vancomycin-intermediate Staphylococcus aureus selected during vancomycin therapy of Experimental Endocarditis are not detected by culture-based diagnostic procedures and persist after treatment arrest
    The Journal of antimicrobial chemotherapy, 2011
    Co-Authors: Philippe Moreillon, Jacques Vouillamoz, Marlyse Giddey, Alain Bizzini, José M. Entenza
    Abstract:

    Results: Vancomycin cured 14 of 26 animals (54%; P,0.05 versus controls) after 2 days of treatment. When vegetation homogenates were plated directly on vancomycin-containing plates, 6 of 13 rats killed 8 h after treatment arrest had positive cultures, 1 of which harboured hVISA. Likewise, 6 of 13 rats killed 3 days thereafter had positive valve cultures, 5 of which harboured hVISA. However, one subculture of vegetations in drug-free broth was enough to revert all the hVISA phenotypes to the susceptible pattern of the parent. Thus, vancomycin selected for hVISA during therapy of Experimental Endocarditis due to vancomycin-susceptible S. aureus. These hVISA were associated with vancomycin failure. The hVISA phenotype persisted in vivo, even after vancomycin arrest, but was missed in vitro after a single passage of the vegetation homogenate on drug-free medium. Conclusions: hVISA might escape detection in clinical samples if they are subcultured before susceptibility tests.

  • Continuous Infusion May Improve the Efficacy of Vancomycin in Treatment of Experimental Endocarditis Due to Heterogeneous Vancomycin-Intermediate Staphylococcus aureus
    Antimicrobial Agents and Chemotherapy, 2011
    Co-Authors: Federico Pea, Jacques Vouillamoz, José M. Entenza, Tiago Rafael Veloso, Marlyse Giddey, Piergiorgio Cojutti, Nicola Petrosillo, Mario Furlanut, Philippe Moreillon
    Abstract:

    We read with interest the paper of Entenza and coworkers suggesting failure of continuous vancomycin infusion against Experimental Endocarditis due to heterogeneous vancomycinintermediate Staphylococcus aureus (hVISA) and VISA (1). In that study, it was stated that continuous vancomycin infusion for 5 days was unsuccessful, as 20 mg/liter was barely active against hVISA PC1 (6 of 13 sterile vegetations) and 40 mg/liter failed against VISA PC3 (2 of 9 sterile vegetations). Generally speaking, we agree that in this Experimental model vancomycin led to suboptimal treatment of VISA infection; however, we believe that some findings related to the role that continuous infusion may have in improving the outcome of vancomycin treatment of hVISA infections deserve attention. Indeed, in the hVISA PC1 model (vancomycin MIC, 2 mg/ liter), there was a misinterpretation of the results, since it appears from Fig. 1 in that paper that the number of sterile vegetations obtained by continuous infusion was higher than stated (7/13 and not 6/13). More importantly, compared with intermittent vancomycin administration (peak and trough levels of at least 50 and 10 mg/liter, respectively), continuous infusion with a constant serum drug concentration of 20 mg/ liter was significantly more effective in sterilizing hVISA PC1 vegetations (54% versus 18%, P 0.05). Although fewer than 100% of the vegetations were sterilized, it must be highlighted that continuous infusion was the only bactericidal regimen, since it led to a more-than-4-log reduction of the mean bacterial burden in the vegetations at day 5 compared to that in the controls (3.57 2.1 versus 7.64 0.4 log 10 CFU/g [P 0.001]), which is different from what occurred with intermittent infusion (6.82 3.1 log 10 versus 7.64 0.4 log10 CFU/g [no statistically significant difference]). These data suggest that continuous infusion of vancomycin may significantly improve the treatment outcome of Experimental Endocarditis due to hVISA. Indeed, the incomplete sterilization seen even after 5 days of continuous vancomycin infusion may be in line with the time-dependent activity of this glycopeptide, which may take a much longer time for complete healing to occur, especially if the bacteria are embedded in biofilm (2). However, it is worth noting that by ensuring that the concentration persistently exceeds a value of at least four to five times the MIC, this strategy may also reduce the selective pressure due to very low trough levels (3) and may avert the development of frank vancomycin resistance, even in cases of long-term treatment (4). Considering that a recent systematic review and meta-analysis of the clinical significance of hVISA isolates (5) showed that hVISA infections were associated with a glycopeptide failure rate 2.37-fold greater than that obtained with vancomycinsusceptible S. aureus infections, we do believe that these Experimental data may support the idea that continuous infusion may be worthwhile with the intent to decrease the failure rate of vancomycin treatment of humans with hVISA infections.

  • In Vivo Synergism of Ceftobiprole and Vancomycin against Experimental Endocarditis Due to Vancomycin-Intermediate Staphylococcus aureus
    Antimicrobial agents and chemotherapy, 2011
    Co-Authors: José M. Entenza, Jacques Vouillamoz, Tiago Rafael Veloso, Marlyse Giddey, Paul Majcherczyk, Philippe Moreillon
    Abstract:

    The efficacy of ceftobiprole combined with vancomycin was tested against two vancomycin-intermediate Staphylococcus aureus (VISA) strains, PC3 and Mu50, in rats with Experimental Endocarditis. Animals with infected aortic vegetations were treated for 3 days with doses simulating the kinetics after intravenous administration in humans of (i) the standard dose of ceftobiprole of 500 mg every 12 h (b.i.d.) (SD-ceftobiprole), (ii) a low dose of ceftobiprole of 250 mg b.i.d. (LD-ceftobiprole), (iii) a very low dose of ceftobiprole of 125 mg b.i.d. (VLD-ceftobiprole), (iv) SD-vancomycin of 1 g b.i.d., or (v) LD- or VLD-ceftobiprole combined with SD-vancomycin. Low dosages of ceftobiprole were purposely used to highlight positive drug interactions. Treatment with SD-ceftobiprole sterilized 12 of 14 (86%) and 10 of 13 (77%) vegetations infected with PC3 and Mu50, respectively (P 0.05 versus controls). VLD-ceftobiprole and SD-vancomycin alone were ineffective against both strains (≤8% sterile vegetations). In contrast, the combination of VLD-ceftobiprole and SD-vancomycin sterilized 7 of 9 (78%) and 6 of 14 (43%) vegetations infected with PC3 and Mu50, respectively, and the combination of LD-ceftobiprole and SD-vancomycin sterilized 5 of 6 (83%) vegetations infected with Mu50 (P < 0.05 versus controls and monotherapy). Thus, ceftobiprole monotherapy simulating standard therapeutic doses was active against VISA Experimental Endocarditis. Moreover, subtherapeutic LD- and VLD-ceftobiprole synergized with ineffective vancomycin to restore efficacy. Hence, combining ceftobiprole with vancomycin broadens the therapeutic margin of these two compounds against VISA infections.

  • Induction of Experimental Endocarditis by Continuous Low-Grade Bacteremia Mimicking Spontaneous Bacteremia in Humans
    Infection and immunity, 2011
    Co-Authors: Tiago Rafael Veloso, Jacques Vouillamoz, Philippe Moreillon, Marlyse Giddey, M. Amiguet, Valentin Rousson, José M. Entenza
    Abstract:

    Transient high-grade bacteremia following invasive procedures carries a risk of infective Endocarditis (IE). This is supported by Experimental Endocarditis. On the other hand, case-control studies showed that IE could be caused by cumulative exposure to low-grade bacteremia occurring during daily activities. However, no Experimental demonstration of this latter possibility exists. This study investigated the infectivity in animals of continuous low-grade bacteremia compared to that of brief high-grade bacteremia. Rats with aortic vegetations were inoculated with Streptococcus intermedius, Streptococcus gordonii or Staphylococcus aureus (strains Newman and P8). Animals were challenged with 10(3) to 10(6) CFU. Identical bacterial numbers were given by bolus (1 ml in 1 min) or continuous infusion (0.0017 ml/min over 10 h). Bacteremia was 50 to 1,000 times greater after bolus than during continuous inoculation. Streptococcal bolus inoculation of 10(5) CFU infected 63 to 100% vegetations compared to 30 to 71% infection after continuous infusion (P > 0.05). When increasing the inoculum to 10(6) CFU, bolus inoculation infected 100% vegetations and continuous infusion 70 to 100% (P > 0.05). S. aureus bolus injection of 10(3) CFU infected 46 to 57% valves. This was similar to the 53 to 57% infection rates produced by continuous infusion (P > 0.05). Inoculation of 10(4) CFU of S. aureus infected 80 to 100% vegetations after bolus and 60 to 75% after continuous infusion (P > 0.05). These results show that high-level bacteremia is not required to induce Experimental Endocarditis and support the hypothesis that cumulative exposure to low-grade bacteremia represents a genuine risk of IE in humans.

  • Failure of vancomycin continuous infusion against Experimental Endocarditis due to vancomycin-intermediate Staphylococcus aureus.
    Antimicrobial agents and chemotherapy, 2010
    Co-Authors: José M. Entenza, Jacques Vouillamoz, Tiago Rafael Veloso, Marlyse Giddey, Philippe Moreillon
    Abstract:

    Continuous infusion of vancomycin was evaluated against Experimental Endocarditis due to heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and VISA. Animals were infected with hVISA PC1 (vancomycin MIC, 2 mg/liter) or VISA PC3 (vancomycin MIC, 8 mg/liter) and treated for 5 days with constant serum levels of 20 or 40 mg/liter. Vancomycin continuous infusion was unsuccessful, as 20 mg/liter was barely active against PC1 (6 of 13 sterile vegetations) and 40 mg/liter failed against PC3 (2 of 9 sterile vegetations).

James M. Steckelberg - One of the best experts on this subject based on the ideXlab platform.

  • garenoxacin treatment of Experimental Endocarditis caused by viridans group streptococci
    Antimicrobial Agents and Chemotherapy, 2006
    Co-Authors: Paloma Anguitaalonso, Mark S. Rouse, James M. Steckelberg, Kerryl E. Piper, Robin Patel
    Abstract:

    Viridans group streptococci are commensal bacterial flora that are common causes of native valve Endocarditis. Viridans group streptococcal Endocarditis is a severe infection associated with high morbidity and mortality. Its treatment includes administration of a prolonged course of a bactericidal antimicrobial regimen, typically administered intravenously (1). The long-term care and costs associated with such therapy and the emergence of viridans group streptococci relatively resistant to beta-lactams (8, 25) have led to a search for new antimicrobials for the treatment (and prophylaxis) of viridans group streptococcal Endocarditis. Combination therapy including an aminoglycoside has been advocated by the American Heart Association to treat penicillin-intermediate and -resistant viridans group streptococcal strains causing infective Endocarditis (1) and to shorten therapy for Endocarditis caused by penicillin-susceptible viridans group streptococcal strains (26). However, aminoglycoside side effects limit the use of such approaches (16). Quinolones are generally considered bactericidal antimicrobial agents with high oral bioavailability and good penetration into valvular vegetations (12), making them theoretically suitable for treatment of infective Endocarditis. Quinolones in combination with rifampin have been used to treat right-sided Staphylococcus aureus Endocarditis (10). However, in the case of viridans group streptococci, quinolones have, in some cases, failed as treatments for Experimental Endocarditis (4, 22), and emergence of quinolone-resistant viridans group streptococci in bone marrow transplant patients receiving prophylaxis with levofloxacin has been reported (24). Garenoxacin is a new quinolone with enhanced potency against gram-positive bacteria, including penicillin-resistant Streptococcus spp. and Staphylococcus spp. (3, 17), that could potentially address the above-mentioned limitations of quinolones. Experimental infective Endocarditis is a rigorous test of bactericidal activity of antimicrobial agents (9). We designed a rabbit model of infective Endocarditis to determine the in vivo activity of garenoxacin in the treatment of viridans group streptococcal Endocarditis in comparison to penicillin and levofloxacin. (This work was presented in part at the 43rd [14 to 17 September 2003, Chicago, Ill.] and 44th [30 October to 2 November 2004, Washington, D.C.] Interscience Conference on Antimicrobial Agents and Chemotherapy.)

  • Garenoxacin Treatment of Experimental Endocarditis Caused by Viridans Group Streptococci
    Antimicrobial agents and chemotherapy, 2006
    Co-Authors: Paloma Anguita-alonso, Mark S. Rouse, James M. Steckelberg, Kerryl E. Piper, Robin Patel
    Abstract:

    The activity of garenoxacin was compared to that of levofloxacin or penicillin in a rabbit model of Streptococcus mitis group (penicillin MIC, 0.125 microg/ml) and Streptococcus sanguinis group (penicillin MIC, 0.25 microg/ml) Endocarditis. Garenoxacin and levofloxacin had MICs of 0.125 and 0.5 microg/ml, respectively, for both study isolates. Rabbits with catheter-induced aortic valve Endocarditis were given no treatment, penicillin at 1.2x10(6) IU/8 h intramuscularly, garenoxacin at 20 mg/kg of body weight/12 h intravenously, or levofloxacin at 40 mg/kg/12 h intravenously. For both isolates tested, garenoxacin area under the curve (AUC)/MIC and maximum concentration of drug in serum (Cmax)/MIC ratios were 368 and 91, respectively. Rabbits were sacrificed after 3 days of treatment; cardiac valve vegetations were aseptically removed and quantitatively cultured. For S. mitis group Experimental Endocarditis, all studied antimicrobial agents were more active than no treatment (P

  • Linezolid Therapy of Vancomycin-Resistant Enterococcus faecium Experimental Endocarditis
    Antimicrobial agents and chemotherapy, 2001
    Co-Authors: Robin Patel, Mark S. Rouse, Kerryl E. Piper, James M. Steckelberg
    Abstract:

    We compared the activities of linezolid (25 mg/kg of body weight, administered intraperitoneally every 8 h) and of vancomycin (25 mg/kg of body weight, administered intraperitoneally every 8 h) in a rat model of vanA vancomycin-resistant Enterococcus faecium Experimental Endocarditis. Results were expressed as median log10 CFU per gram of vegetation after 3 days of treatment. The median log10 CFU per gram of vegetation was 10.1 among 7 untreated control animals, 10.2 among 9 vancomycin-treated animals, and 7.9 among 10 linezolid-treated animals. Linezolid treatment was more active (P < 0.05) than vancomycin treatment or no treatment.

  • Trovafloxacin Treatment of Viridans Group Streptococcus Experimental Endocarditis
    Antimicrobial agents and chemotherapy, 2000
    Co-Authors: Kerryl E. Piper, Mark S. Rouse, James M. Steckelberg, Walter R. Wilson, Karen L. Ronningen, Robin Patel
    Abstract:

    The activity of trovafloxacin was compared with those of vancomycin and penicillin in a model of Streptococcus sanguis species group (trovafloxacin MIC, 0.125 mg/ml) and Streptococcus mitis species group (trovafloxacin MIC, 0.125 mg/ml) Experimental Endocarditis. Rabbits with catheter-induced aortic valve vegetations were given no treatment, trovafloxacin at 15 mg/kg of body weight three times a day (t.i.d.), vancomycin at 15 mg/kg twice a day, or penicillin at 1.2 3 10 6 IU t.i.d. After 3 days of treatment, the animals were sacrificed; cardiac valve vegetations were aseptically removed and cultured quantitatively. Penicillin was as active as vancomycin as measured by in vivo clearance of bacteria. Trovafloxacin was less active (P < 0.05) than vancomycin or penicillin against S. sanguis species group infection but had similar efficacy against S. mitis species group infection. Quinolones, despite MICs in the susceptible range, may not be active for serious infections caused by some viridans group streptococci. Trovafloxacin, a fluoroquinolone antimicrobial agent, has activity in vitro against many gram-positive cocci which is superior to that of several other quinolone antimicrobial agents (2). This activity includes activity against viridans group streptococci (2). Viridans group streptococci are the etiological agents in 30 to 40% of cases of native valve Endocarditis (7). Patients with viridans group streptococcal Endocarditis receive parenteral therapy with either penicillin G or ceftriaxone with or without an aminoglycoside, or with vancomycin administered alone (8). The potential role of trovafloxacin and of other new orally administered fluoroquinolones for the treatment of viridans group streptococcal Endocarditis or other serious viridans group streptococcal infection is unknown. An oral antimicrobial regimen for the treatment of such infections in compliant patients would be convenient, would eliminate potential complications related to the use of intravenous therapy, and would likely be cost-effective. The purpose of our study was to investigate whether the activity in vitro of trovafloxacin against viridans group streptococci is predictive of activity in vivo in a rabbit model of Experimental Endocarditis. (This study was reported in part at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 28 September to 1 October 1997.) Trovafloxacin was obtained from Pfizer (Groton, Conn.), vancomycin hydrochloride was obtained from Lederle (Wayne, N.J.), and penicillin was obtained from Wyeth-Ayerst (Philadelphia, Pa.). MICs for 50 viridans group streptococcal isolates obtained from patients with infection, including 30 from patients with infective Endocarditis, were determined by a standard microtube dilution assay, and minimum bactericidal concentrations (MBCs) were determined with a 0.1-ml subculture onto blood agar plates (6). The trovafloxacin MIC at which 90% of the isolates were inhibited (MIC90) was 0.25 mg/ml (range, #0.125 to 0.6 mg/ml), and the trovafloxacin MBC at which 90% of the isolates were killed (MBC90) was 1 mg/ml (range, #0.125 to 4 mg/ml). The vancomycin MIC90 was 1 mg/ml (range, 0.25 to 4 mg/ml), and

  • Efficacy of azithromycin or clarithromycin for prophylaxis of viridans group streptococcus Experimental Endocarditis.
    Antimicrobial agents and chemotherapy, 1997
    Co-Authors: Mark S. Rouse, James M. Steckelberg, Robin Patel, C M Brandt, J M Miro, Walter R. Wilson
    Abstract:

    The efficacy of azithromycin or clarithromycin was compared to that of amoxicillin, clindamycin, or erythromycin for the prevention of viridans group streptococcus Experimental Endocarditis. Rabbits with catheter-induced aortic valve vegetations were given no antibiotics or two doses of amoxicillin at 25 mg/kg of body weight, azithromycin at 10 mg/kg, clarithromycin at 10 mg/kg, clindamycin at 40 mg/kg followed by clindamycin at 20 mg/kg, or erythromycin at 10 mg/kg. Antibiotics were administered 0.5 h before and 5.5 h after intravenous infusion of 5 x 10(5) CFU of Streptococcus milleri. Forty-eight hours after bacterial inoculation, the rabbits were killed and aortic valve vegetations were aseptically removed and cultured for bacteria. Infective Endocarditis occurred in 88% of untreated animals, 1% of animals receiving amoxicillin, 9% of animals receiving erythromycin, 0% of animals receiving clindamycin, 2.5% of animals receiving clarithromycin, and 1% of animals receiving azithromycin. All five regimens were more effective (P < 0.001) than no prophylaxis. Erythromycin was less effective (P < 0.05) than amoxicillin or clindamycin. Azithromycin or clarithromycin was as effective as amoxicillin, clindamycin, or erythromycin for the prevention of viridans group streptococcus Experimental Endocarditis in this model.

Bruno Fantin - One of the best experts on this subject based on the ideXlab platform.

  • Influence of Reduced Susceptibility to Glycopeptides on Activities of Vancomycin and Teicoplanin against Staphylococcus aureus in Experimental Endocarditis
    Antimicrobial agents and chemotherapy, 2003
    Co-Authors: Juliette Pavie, Agnès Lefort, Marie-cécile Ploy, Laurent Massias, F. Chau, Louis Garry, François Denis, Bruno Fantin
    Abstract:

    The influence of reduced susceptibilities to glycopeptides on the activities of vancomycin and teicoplanin against an isogenic pair of clinical Staphylococcus aureus strains in Experimental Endocarditis was investigated. While vancomycin was similarly active against both strains, teicoplanin was approximately 100-fold less active against the resistant strain and selected for the emergence of more resistant subpopulations.

  • Consequences of VanE-type resistance on efficacy of glycopeptides in vitro and in Experimental Endocarditis due to Enterococcus faecalis.
    Antimicrobial agents and chemotherapy, 2001
    Co-Authors: Matthieu Lafaurie, Agnès Lefort, Patrice Courvalin, Claude Carbon, Bruno Périchon, Bruno Fantin
    Abstract:

    The consequences on glycopeptide activity of low-level resistance to vancomycin due to VanE-type resistance were evaluated in vitro and in Experimental Endocarditis caused by Enterococcus faecalis BM4405 (MICs of vancomycin and teicoplanin: 16 and 0.5 μg/ml, respectively), its susceptible derivative BM4405-1, and susceptible E. faecalis JH2-2. After 24 h of incubation, vancomycin at 8 μg/ml was not active against E. faecalis BM4405 whereas it was bacteriostatic against strains BM4405-1 and JH2-2. Against all three strains, vancomycin at 30 μg/ml and teicoplanin at 8 or 30 μg/ml were bacteriostatic but bactericidal when combined with gentamicin. In rabbits with aortic Endocarditis due to VanE-type resistant strain BM4405, treatment with a standard dose of vancomycin generated subinhibitory plasma concentrations (i.e., peak of 36.3 ± 2.1 μg/ml and trough of 6.0 ± 2.2 μg/ml) and led to no significant reduction in mean aortic valve vegetation counts compared to no treatment of control animals. In contrast, a higher dosing regimen of vancomycin (i.e., resulting in a peak of 38.3 ± 5.2 μg/ml and a trough of 15.0 ± 8.3 μg/ml), providing plasma concentrations above the MIC for the entire dosing interval, led to significant and similar activities against all three strains, which were enhanced by combination with gentamicin. Treatment with teicoplanin led to results similar to those obtained with vancomycin at a high dose. No subpopulations with increased resistance to glycopeptides were selected in vitro or in vivo. In conclusion, the use of a high dose of vancomycin was necessary for the treatment of Experimental enterococcal Endocarditis due to VanE-type strains.

  • Activity of LY333328 Combined with Gentamicin In Vitro and in Rabbit Experimental Endocarditis Due to Vancomycin-Susceptible or -Resistant Enterococcus faecalis
    Antimicrobial agents and chemotherapy, 2000
    Co-Authors: Agnès Lefort, Louis Garry, Azzam Saleh-mghir, Claude Carbon, Bruno Fantin
    Abstract:

    We investigated the activity of LY333328 alone and combined with gentamicin, both in vitro and in a rabbit model of Experimental Endocarditis, against the susceptible strain Enterococcus faecalis JH2-2 and its two glycopeptide-resistant transconjugants, BM4316 (VanA) and BM4275 (VanB). MICs of LY333328 and gentamicin were 2 and 16 μg/ml, respectively, for the three strains. In vitro, LY333328 alone was bactericidal at 24 h against JH2-2 at a concentration of 2 μg/ml and against BM4316 and BM4275 at a concentration of 30 μg/ml. The combination of LY333328 and gentamicin (4 μg/ml) was synergistic and bactericidal after 24 h of incubation against the three strains at LY333328 concentrations of 2 μg/ml for JH2-2 and 8 μg/ml for BM4275 and BM4316. The combination of LY333328 and gentamicin was the only regimen demonstrating in vitro bactericidal activity against BM4316. In vivo, intravenous treatment with LY333328 alone, providing peak and trough serum levels of 83.3 ± 1.3 and 3.8 ± 0.2 μg/ml, respectively, was inactive against BM4316 and BM4275 and selected mutants resistant to LY333328 in half of the rabbits infected with the VanA-type strain (MICs, 8 to 20 μg/ml). However, the LY333328-gentamicin combination was active against the three strains and prevented the emergence of mutants resistant to both components of the combination. We conclude that the LY333328-gentamicin combination might be of interest for the treatment of enterococcal infections, particularly against VanA-type strains.

  • activity and diffusion of ly333328 in Experimental Endocarditis due to vancomycin resistant enterococcus faecalis
    Antimicrobial Agents and Chemotherapy, 1999
    Co-Authors: Azzam Salehmghir, C Carbon, A Lefort, Y Petegnief, S Dautrey, Jeanmarie Vallois, Dominique Le Guludec, Bruno Fantin
    Abstract:

    The activity of LY333328 against Enterococcus faecalis JH2-2, which is susceptible to glycopeptides, and against its transconjugants E. faecalis BM4281 and BM4316, with VanB and VanA phenotypes, respectively, was investigated. LY333328 was active in vitro against the three strains, for which MICs were 2 μg/ml on agar and 0.25 μg/ml in broth. LY333328 was bactericidal in broth against E. faecalis JH2-2 and BM4281 at a concentration of 8 μg/ml and against BM4316 at a concentration of 30 μg/ml. The protein binding of LY333328 to rabbit serum was >99%, and the bactericidal activity of LY333328 in broth was reduced when it was tested in the presence of 90% rabbit serum. Autoradiographic studies performed in rabbits with enterococcal Endocarditis showed that 14[C]LY333328 was distributed heterogeneously throughout cardiac vegetations. In rabbits with aortic Endocarditis, a regimen of 20 mg of LY333328 per kg of body weight administered intramuscularly twice a day for 5 days after a loading dose of 40 mg/kg was active against the three strains in vivo (P < 0.01), whereas vancomycin was not active against the VanB-type strain and teicoplanin was not active against the VanA-type strain. We conclude that the activity of LY333328 is not significantly modified by acquired resistance to glycopeptides in E. faecalis either in vitro or in Experimental Endocarditis.

  • Influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B-type antibiotics in Enterococcus faecium on activity of quinupristin-dalfopristin in vitro and in rabbits with Experimental Endocarditis.
    Antimicrobial agents and chemotherapy, 1997
    Co-Authors: Bruno Fantin, Louis Garry, Roland Leclercq, Claude Carbon
    Abstract:

    The influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B (MLS(B)) type antibiotics (inducible MLS(B) phenotype) on the activity of quinupristin-dalfopristin was investigated against Enterococcus faecium in vitro and in rabbits with Experimental Endocarditis. In vitro, quinupristin-dalfopristin displayed bacteriostatic and bactericidal activities against a MLS(B)-susceptible strain similar to those against two strains with the inducible MLS(B) phenotype. In addition, induction of the two MLS(B)-resistant strains with quinupristin (0.016 to 1 microg/ml) or quinupristin-dalfopristin (0.08 to 0.25 microg/ml) increased the MICs of quinupristin from 8 microg/ml to 32 to > 128 microg/ml, but did not modify the MIC of dalfopristin (2 microg/ml) or quinupristin-dalfopristin (0.5 microg/ml). In a rabbit Endocarditis model, quinupristin-dalfopristin was as active as amoxicillin against the MLS(B)-susceptible E. faecium strain. In contrast, the activity of quinupristin-dalfopristin was significantly decreased in animals infected with either of the two inducible MLS(B)-resistant strains (P < 0.05), although no mutants resistant to quinupristin-dalfopristin were detected. Against the clinical strain with the inducible MLS(B) phenotype, quinupristin-dalfopristin was not effective and was less active than amoxicillin (P < 0.001); however, the activity of the combination of amoxicillin and dalfopristin-quinupristin was superior to that of amoxicillin (P < 0.01). The different impact of the inducible MLS(B) phenotype in E. faecium on the activity of quinupristin-dalfopristin in vitro and in Experimental Endocarditis may be related to the reduced diffusion of dalfopristin compared with that of quinupristin into cardiac vegetations that we previously reported. This result emphasizes the importance of the constant presence of dalfopristin at the site of infection to ensure synergism with quinupristin.

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  • garenoxacin treatment of Experimental Endocarditis caused by viridans group streptococci
    Antimicrobial Agents and Chemotherapy, 2006
    Co-Authors: Paloma Anguitaalonso, Mark S. Rouse, James M. Steckelberg, Kerryl E. Piper, Robin Patel
    Abstract:

    Viridans group streptococci are commensal bacterial flora that are common causes of native valve Endocarditis. Viridans group streptococcal Endocarditis is a severe infection associated with high morbidity and mortality. Its treatment includes administration of a prolonged course of a bactericidal antimicrobial regimen, typically administered intravenously (1). The long-term care and costs associated with such therapy and the emergence of viridans group streptococci relatively resistant to beta-lactams (8, 25) have led to a search for new antimicrobials for the treatment (and prophylaxis) of viridans group streptococcal Endocarditis. Combination therapy including an aminoglycoside has been advocated by the American Heart Association to treat penicillin-intermediate and -resistant viridans group streptococcal strains causing infective Endocarditis (1) and to shorten therapy for Endocarditis caused by penicillin-susceptible viridans group streptococcal strains (26). However, aminoglycoside side effects limit the use of such approaches (16). Quinolones are generally considered bactericidal antimicrobial agents with high oral bioavailability and good penetration into valvular vegetations (12), making them theoretically suitable for treatment of infective Endocarditis. Quinolones in combination with rifampin have been used to treat right-sided Staphylococcus aureus Endocarditis (10). However, in the case of viridans group streptococci, quinolones have, in some cases, failed as treatments for Experimental Endocarditis (4, 22), and emergence of quinolone-resistant viridans group streptococci in bone marrow transplant patients receiving prophylaxis with levofloxacin has been reported (24). Garenoxacin is a new quinolone with enhanced potency against gram-positive bacteria, including penicillin-resistant Streptococcus spp. and Staphylococcus spp. (3, 17), that could potentially address the above-mentioned limitations of quinolones. Experimental infective Endocarditis is a rigorous test of bactericidal activity of antimicrobial agents (9). We designed a rabbit model of infective Endocarditis to determine the in vivo activity of garenoxacin in the treatment of viridans group streptococcal Endocarditis in comparison to penicillin and levofloxacin. (This work was presented in part at the 43rd [14 to 17 September 2003, Chicago, Ill.] and 44th [30 October to 2 November 2004, Washington, D.C.] Interscience Conference on Antimicrobial Agents and Chemotherapy.)

  • Garenoxacin Treatment of Experimental Endocarditis Caused by Viridans Group Streptococci
    Antimicrobial agents and chemotherapy, 2006
    Co-Authors: Paloma Anguita-alonso, Mark S. Rouse, James M. Steckelberg, Kerryl E. Piper, Robin Patel
    Abstract:

    The activity of garenoxacin was compared to that of levofloxacin or penicillin in a rabbit model of Streptococcus mitis group (penicillin MIC, 0.125 microg/ml) and Streptococcus sanguinis group (penicillin MIC, 0.25 microg/ml) Endocarditis. Garenoxacin and levofloxacin had MICs of 0.125 and 0.5 microg/ml, respectively, for both study isolates. Rabbits with catheter-induced aortic valve Endocarditis were given no treatment, penicillin at 1.2x10(6) IU/8 h intramuscularly, garenoxacin at 20 mg/kg of body weight/12 h intravenously, or levofloxacin at 40 mg/kg/12 h intravenously. For both isolates tested, garenoxacin area under the curve (AUC)/MIC and maximum concentration of drug in serum (Cmax)/MIC ratios were 368 and 91, respectively. Rabbits were sacrificed after 3 days of treatment; cardiac valve vegetations were aseptically removed and quantitatively cultured. For S. mitis group Experimental Endocarditis, all studied antimicrobial agents were more active than no treatment (P

  • Linezolid Therapy of Vancomycin-Resistant Enterococcus faecium Experimental Endocarditis
    Antimicrobial agents and chemotherapy, 2001
    Co-Authors: Robin Patel, Mark S. Rouse, Kerryl E. Piper, James M. Steckelberg
    Abstract:

    We compared the activities of linezolid (25 mg/kg of body weight, administered intraperitoneally every 8 h) and of vancomycin (25 mg/kg of body weight, administered intraperitoneally every 8 h) in a rat model of vanA vancomycin-resistant Enterococcus faecium Experimental Endocarditis. Results were expressed as median log10 CFU per gram of vegetation after 3 days of treatment. The median log10 CFU per gram of vegetation was 10.1 among 7 untreated control animals, 10.2 among 9 vancomycin-treated animals, and 7.9 among 10 linezolid-treated animals. Linezolid treatment was more active (P < 0.05) than vancomycin treatment or no treatment.

  • Trovafloxacin Treatment of Viridans Group Streptococcus Experimental Endocarditis
    Antimicrobial agents and chemotherapy, 2000
    Co-Authors: Kerryl E. Piper, Mark S. Rouse, James M. Steckelberg, Walter R. Wilson, Karen L. Ronningen, Robin Patel
    Abstract:

    The activity of trovafloxacin was compared with those of vancomycin and penicillin in a model of Streptococcus sanguis species group (trovafloxacin MIC, 0.125 mg/ml) and Streptococcus mitis species group (trovafloxacin MIC, 0.125 mg/ml) Experimental Endocarditis. Rabbits with catheter-induced aortic valve vegetations were given no treatment, trovafloxacin at 15 mg/kg of body weight three times a day (t.i.d.), vancomycin at 15 mg/kg twice a day, or penicillin at 1.2 3 10 6 IU t.i.d. After 3 days of treatment, the animals were sacrificed; cardiac valve vegetations were aseptically removed and cultured quantitatively. Penicillin was as active as vancomycin as measured by in vivo clearance of bacteria. Trovafloxacin was less active (P < 0.05) than vancomycin or penicillin against S. sanguis species group infection but had similar efficacy against S. mitis species group infection. Quinolones, despite MICs in the susceptible range, may not be active for serious infections caused by some viridans group streptococci. Trovafloxacin, a fluoroquinolone antimicrobial agent, has activity in vitro against many gram-positive cocci which is superior to that of several other quinolone antimicrobial agents (2). This activity includes activity against viridans group streptococci (2). Viridans group streptococci are the etiological agents in 30 to 40% of cases of native valve Endocarditis (7). Patients with viridans group streptococcal Endocarditis receive parenteral therapy with either penicillin G or ceftriaxone with or without an aminoglycoside, or with vancomycin administered alone (8). The potential role of trovafloxacin and of other new orally administered fluoroquinolones for the treatment of viridans group streptococcal Endocarditis or other serious viridans group streptococcal infection is unknown. An oral antimicrobial regimen for the treatment of such infections in compliant patients would be convenient, would eliminate potential complications related to the use of intravenous therapy, and would likely be cost-effective. The purpose of our study was to investigate whether the activity in vitro of trovafloxacin against viridans group streptococci is predictive of activity in vivo in a rabbit model of Experimental Endocarditis. (This study was reported in part at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 28 September to 1 October 1997.) Trovafloxacin was obtained from Pfizer (Groton, Conn.), vancomycin hydrochloride was obtained from Lederle (Wayne, N.J.), and penicillin was obtained from Wyeth-Ayerst (Philadelphia, Pa.). MICs for 50 viridans group streptococcal isolates obtained from patients with infection, including 30 from patients with infective Endocarditis, were determined by a standard microtube dilution assay, and minimum bactericidal concentrations (MBCs) were determined with a 0.1-ml subculture onto blood agar plates (6). The trovafloxacin MIC at which 90% of the isolates were inhibited (MIC90) was 0.25 mg/ml (range, #0.125 to 0.6 mg/ml), and the trovafloxacin MBC at which 90% of the isolates were killed (MBC90) was 1 mg/ml (range, #0.125 to 4 mg/ml). The vancomycin MIC90 was 1 mg/ml (range, 0.25 to 4 mg/ml), and

  • Efficacy of azithromycin or clarithromycin for prophylaxis of viridans group streptococcus Experimental Endocarditis.
    Antimicrobial agents and chemotherapy, 1997
    Co-Authors: Mark S. Rouse, James M. Steckelberg, Robin Patel, C M Brandt, J M Miro, Walter R. Wilson
    Abstract:

    The efficacy of azithromycin or clarithromycin was compared to that of amoxicillin, clindamycin, or erythromycin for the prevention of viridans group streptococcus Experimental Endocarditis. Rabbits with catheter-induced aortic valve vegetations were given no antibiotics or two doses of amoxicillin at 25 mg/kg of body weight, azithromycin at 10 mg/kg, clarithromycin at 10 mg/kg, clindamycin at 40 mg/kg followed by clindamycin at 20 mg/kg, or erythromycin at 10 mg/kg. Antibiotics were administered 0.5 h before and 5.5 h after intravenous infusion of 5 x 10(5) CFU of Streptococcus milleri. Forty-eight hours after bacterial inoculation, the rabbits were killed and aortic valve vegetations were aseptically removed and cultured for bacteria. Infective Endocarditis occurred in 88% of untreated animals, 1% of animals receiving amoxicillin, 9% of animals receiving erythromycin, 0% of animals receiving clindamycin, 2.5% of animals receiving clarithromycin, and 1% of animals receiving azithromycin. All five regimens were more effective (P < 0.001) than no prophylaxis. Erythromycin was less effective (P < 0.05) than amoxicillin or clindamycin. Azithromycin or clarithromycin was as effective as amoxicillin, clindamycin, or erythromycin for the prevention of viridans group streptococcus Experimental Endocarditis in this model.

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