scholarly journals In Vitro and In Vivo Synergistic Activities of Linezolid Combined with Subinhibitory Concentrations of Imipenem against Methicillin-Resistant Staphylococcus aureus

2005 ◽  
Vol 49 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Cédric Jacqueline ◽  
Dominique Navas ◽  
Eric Batard ◽  
Anne-Françoise Miegeville ◽  
Virginie Le Mabecque ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Methicillin Resistant ◽  
In Vivo Experiments ◽  
Low Concentrations ◽  
Mrsa Strains ◽  
Kill Curve ◽  
Time Kill

ABSTRACT Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.

scholarly journals Ceftobiprole EfficacyIn Vitroagainst Panton-Valentine Leukocidin Production andIn Vivoagainst Community-Associated Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rabbits

2012 ◽  
Vol 56 (12) ◽  
pp. 6291-6297 ◽  
Author(s):  
Azzam Saleh-Mghir ◽  
Oana Dumitrescu ◽  
Aurélien Dinh ◽  
Yassine Boutrad ◽  
Laurent Massias ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Content Type ◽  
The Mean ◽  
Mrsa Strains ◽  
Time Kill ◽  
Panton Valentine Leukocidin ◽  
Valentine Leukocidin

ABSTRACTCommunity-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected.In vitrosub-MIC antibiotic effects on growth and PVL production by 11 PVL+MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL+methicillin-susceptibleS. aureus(MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 107CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days.In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log10-CFU-count decrease.In vivo, the mean log10CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P= 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P= 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P= 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.

scholarly journals The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-ResistantStaphylococcus aureusin a Rabbit Model of Experimental Endocarditis

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Cristina García-de-la-Mària ◽  
Oriol Gasch ◽  
Javier García-Gonzalez ◽  
Dolors Soy ◽  
Evelyn Shaw ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Combined Therapy ◽  
Rabbit Model ◽  
Bactericidal Effect ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTWe investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistantStaphylococcus aureus(MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to performin vitrotime-kill studies using standard (106) and high (108) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 μg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%,P= 0.046) and the decrease in the density of bacteria within the vegetations (P= 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%,P= 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%,P= 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.

scholarly journals Activities of the Combination of Quinupristin-Dalfopristin with Rifampin In Vitro and in Experimental Endocarditis Due to Staphylococcus aureus Strains with Various Phenotypes of Resistance to Macrolide-Lincosamide-Streptogramin Antibiotics

2001 ◽  
Vol 45 (4) ◽  
pp. 1244-1248 ◽  
Author(s):  
Virginie Zarrouk ◽  
Bülent Bozdogan ◽  
Roland Leclercq ◽  
Louis Garry ◽  
Celine Feger ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Conjugative Transfer ◽  
Constitutive Resistance ◽  
Combination Studies ◽  
Kill Curve ◽  
Time Kill ◽  
High Mics

ABSTRACT We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains ofStaphylococcus aureus susceptible to rifampin (MIC, 0.06 μg/ml) and to Q-D (MICs, 0.5 to 1 μg/ml) but displaying various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics: S. aureus HM1054 was susceptible to quinupristin and dalfopristin (MICs of 8 and 4 μg/ml, respectively); for S. aureus RP13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 μg/ml, respectively); and S. aureus HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 μg/ml, respectively). In vitro time-kill curve studies showed no difference between Q-D and rifampin, at a concentration of four times the MIC, against the three strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bactericidal and synergistic against strains susceptible to quinupristin (HM1054 and RP13) and sterilized 94% of the animals. In contrast, the combination was neither synergistic nor bactericidal against the quinupristin-resistant strain (HM1054R) and did not prevent the emergence of mutants resistant to rifampin. We conclude that the in vivo synergistic and bactericidal activity of the combination of Q-D and rifampin against S. aureus is predicted by the absence of resistance to quinupristin but not by in vitro combination studies.

scholarly journals Telavancin in Therapy of Experimental Aortic Valve Endocarditis in Rabbits Due to Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus

2012 ◽  
Vol 56 (11) ◽  
pp. 5528-5533 ◽  
Author(s):  
Yan Q. Xiong ◽  
Wessam Abdel Hady ◽  
Arnold S. Bayer ◽  
Liang Chen ◽  
Barry N. Kreiswirth ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Aortic Valve ◽  
Rabbit Model ◽  
Methicillin Resistant ◽  
Content Type ◽  
Bacterial Cell Membrane ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTA number of cases of both methicillin-susceptibleStaphylococcus aureus(MSSA) and methicillin-resistantS. aureus(MRSA) strains that have developed daptomycin resistance (DAP-R) have been reported. Telavancin (TLV) is a lipoglycopeptide agent with a dual mechanism of activity (cell wall synthesis inhibition plus depolarization of the bacterial cell membrane). Five recent daptomycin-susceptible (DAP-S)/DAP-R MRSA isogenic strain pairs were evaluated forin vitroTLV susceptibility. All five DAP-R strains (DAP MICs ranging from 2 to 4 μg/ml) were susceptible to TLV (MICs of ≤0.38 μg/ml).In vitrotime-kill analyses also revealed that several TLV concentrations (1-, 2-, and 4-fold MICs) caused rapid killing against the DAP-R strains. Moreover, for 3 of 5 DAP-R strains (REF2145, A215, and B2.0), supra-MICs of TLV were effective at preventing regrowth at 24 h of incubation. Further, the combination of TLV plus oxacillin (at 0.25× or 0.50× MIC for each agent) increased killing of DAP-R MRSA strains REF2145 and A215 at 24 h (∼2-log and 5-log reductions versus TLV and oxacillin alone, respectively). Finally, using a rabbit model of aortic valve endocarditis caused by DAP-R strain REF2145, TLV therapy produced a mean reduction of >4.5 log10CFU/g in vegetations, kidneys, and spleen compared to untreated or DAP-treated rabbits. Moreover, TLV-treated rabbits had a significantly higher percentage of sterile tissue cultures (87% in vegetations and 100% in kidney and spleen) than all other treatment groups (P< 0.0001). Together, these results demonstrate that TLV has potent bactericidal activityin vitroandin vivoagainst DAP-R MRSA isolates.

scholarly journals Antagonistic Effect of Colistin on Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus in In Vitro and In Vivo Studies

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Sungim Choi ◽  
Song Mi Moon ◽  
Su-Jin Park ◽  
Seung Cheol Lee ◽  
Kyung Hwa Jung ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antagonistic Effect ◽  
Infection Model ◽  
Care Hospital ◽  
Methicillin Resistant ◽  
Vancomycin Mics ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACT As concerns arise that the vancomycin MIC of methicillin-resistant Staphylococcus aureus (MRSA) could be increased by concurrent colistin administration, we evaluated the effect of colistin on vancomycin efficacy against MRSA via in vitro and in vivo studies. Among MRSA blood isolates collected in a tertiary-care hospital, we selected representative strains from community-associated MRSA strains (CA-MRSA; ST72-MRSA-SCCmec IV) and hospital-acquired MRSA strains (HA-MRSA; ST5-MRSA-SCCmec II). USA CA-MRSA (USA300), HA-MRSA (USA100), N315 (New York/Japan clone), and a MRSA standard strain (ATCC 43300) were used for comparison. We performed checkerboard assays to identify changes in the vancomycin MIC of MRSA following colistin exposure and evaluated the effect of a vancomycin-colistin combination using time-kill assays. We also assessed the in vivo antagonistic effect by administering vancomycin, colistin, and a combination of these two in a neutropenic murine thigh infection model. In the checkerboard assays, vancomycin MICs of all MRSA strains except N315 were increased by from 0.25 to 0.75 μg/ml following colistin exposure. However, the time-kill assays indicated antagonism only against ST5-MRSA and USA100, when the vancomycin concentration was twice the MIC. In the murine thigh infection model with ST5-MRSA and USA100, vancomycin monotherapy reduced the number of CFU/muscle >1 log10 compared to a combination treatment after 24 h in ST5-MRSA, indicating an antagonistic effect of colistin on vancomycin treatment. This study suggests that exposure to colistin may reduce the susceptibility to vancomycin of certain MRSA strains. Combination therapy with vancomycin and colistin for multidrug-resistant pathogens might result in treatment failure for concurrent MRSA infection.

scholarly journals Daptomycin-Oxacillin Combinations in Treatment of Experimental Endocarditis Caused by Daptomycin-Nonsusceptible Strains of Methicillin-Resistant Staphylococcus aureus with Evolving Oxacillin Susceptibility (the “Seesaw Effect”)

2010 ◽  
Vol 54 (8) ◽  
pp. 3161-3169 ◽  
Author(s):  
Soo-Jin Yang ◽  
Yan Q. Xiong ◽  
Susan Boyle-Vavra ◽  
Robert Daum ◽  
Tiffanny Jones ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Target Tissue ◽  
Modest Improvement ◽  
Methicillin Resistant ◽  
Bactericidal Effects ◽  
Mrsa Strains ◽  
Time Kill ◽  
Combination Regimens

ABSTRACT In vivo development of daptomycin resistance (DAPr) among Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA) strains, in conjunction with clinical treatment failures, has emerged as a major problem. This has raised the question of DAP-based combination regimens to enhance efficacy against such strains. We studied five recent DAP-susceptible (DAPs)/DAPr clinical MRSA strain pairs obtained from patients who failed DAP monotherapy regimens, as well as one DAPs/DAPr MRSA strain pair in which the resistant strain was generated by in vitro passage in DAP. Of note, we identified a DAP-oxacillin (OX) “seesaw” phenomenon in vitro in which development of DAPr was accompanied by a concomitant fall in OX resistance, as demonstrated by 3- to 4-fold decreases in the OX MIC, a susceptibility shift by population analyses, and enhanced early killing by OX in time-kill assays. In addition, the combination of DAP and OX exerted modest improvement in in vitro bactericidal effects. Using an experimental model of infective endocarditis and two DAPs/DAPr strain pairs, we demonstrated that (i) OX monotherapy was ineffective at clearing DAPr strains from any target tissue in this model (heart valve, kidneys, or spleen) and (ii) DAP-OX combination therapy was highly effective in DAPr strain clearances from these organs. The mechanism(s) of the seesaw effect remains to be defined but does not appear to involve excision of the staphylococcal cassette chromosome mec (SCCmec) that carries mecA.

scholarly journals BAL9141, a Novel Extended-Spectrum Cephalosporin Active against Methicillin-Resistant Staphylococcus aureus in Treatment of Experimental Endocarditis

2002 ◽  
Vol 46 (1) ◽  
pp. 171-177 ◽  
Author(s):  
J. M. Entenza ◽  
P. Hohl ◽  
I. Heinze-Krauss ◽  
M. P. Glauser ◽  
P. Moreillon
Keyword(s):  
Staphylococcus Aureus ◽  
Steady State ◽  
Methicillin Resistant ◽  
Treatment Groups ◽  
Test Organisms ◽  
Amoxicillin Clavulanate ◽  
Kill Curve ◽  
Time Kill

ABSTRACT The therapeutic efficacy of BAL9141 (formerly Ro 63-9141), a novel cephalosporin with broad in vitro activity that also has activity against methicillin-resistant Staphylococcus aureus (MRSA), was investigated in rats with experimental endocarditis. The test organisms were homogeneously methicillin-resistant S. aureus strain COL transformed with the penicillinase-encoding plasmid pI524 (COL Bla+) and homogeneously methicillin-resistant, penicillinase-producing isolate P8-Hom, selected by serial exposure of parent strain P8 to methicillin. The MICs of BAL9141 for these organisms (2 mg/liter) were low, and BAL9141was bactericidal in time-kill curve studies after 24 h of exposure to either two, four, or eight times the MIC. Rats with experimental endocarditis were treated in a three-arm study with a continuous infusion of BAL5788 (formerly Ro 65-5788), a carbamate prodrug of BAL9141, or with amoxicillin-clavulanate or vancomycin. The rats were administered BAL9141 to obtain steady-state target levels of 20, 10, and 5 mg of per liter or were administered either 1.2 g of amoxicillin-clavulanate (ratio 5:1) every 6 h or 1 g of vancomycin every 12 h at changing flow rates to simulate the pharmacokinetics produced in humans by intermittent intravenous treatment. Treatment was started 12 h after bacterial challenge and lasted for 3 days. BAL9141 was successful in the treatment of experimental endocarditis due to either MRSA isolate COL Bla+ or MRSA isolate P8-Hom at the three targeted steady-state concentrations and sterilized >90% of cardiac vegetations (P < 0.005 versus controls; P < 0.05 versus amoxicillin-clavulanate and vancomycin treatment groups). These promising in vivo results with BAL9141 correlated with the high affinity of the drug for PBP 2a and its stability to penicillinase hydrolysis observed in vitro.

scholarly journals 204. Antagonistic Effect of Colistin on Vancomycin Activity Against Methicillin-Resistant Staphylococcus aureus in in vitro and in vivo Studies

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S120-S121
Author(s):  
Sungim Choi ◽  
Taeeun Kim ◽  
Seongman Bae ◽  
Eunmi Yang ◽  
Su-Jin Park ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Antagonistic Effect ◽  
In Vivo Studies ◽  
Infection Model ◽  
Methicillin Resistant ◽  
Checkerboard Assay ◽  
Mrsa Strains ◽  
Time Kill

Abstract Background There is a concern that the vancomycin MIC of methicillin-resistant Staphylococcus aureus (MRSA) could be increased by concomitant colistin administered against multidrug-resistant gram-negative pathogen. Methods We confirmed the molecular genotypes of MRSA blood isolates collected in a tertiary hospital in Seoul, South Korea, and selected representative strains from the community-associated MRSA strains (CA-MRSA, ST72-SCCmec IV) and hospital-acquired MRSA strains (HA-MRSA, ST5-SCCmec II). USA CA-MRSA (USA300, ST8-SCCmec IV) and MRSA standard strain (ATCC 43300, ST39-SCCmec II) were also used for comparison with representative. We identified changes of the vancomycin MIC in MRSA by colistin exposure in a checkerboard assay and performed a time-kill assay to evaluate the combined effect of vancomycin and colistin on MRSA. In addition, we administered vancomycin, colistin, and combination of two antibiotics, respectively, to a neutropenic murine thigh infection model to evaluate the in vivo antagonistic effect of colistin on vancomycin treatment. Results In the checkerboard assay, all 4 MRSA strains showed a tendency for the vancomycin MIC to increase along with increasing concentrations of colistin. However, the time-kill assay showed the antagonism of vancomycin and colistin only against ST5-MRSA, when vancomycin concentration was 2 times the vancomycin MIC (Figure 1). No antagonism was observed in other strains. In the murine thigh infection model of ST5-MRSA, vancomycin monotherapy showed a significant log CFU reduction compared with a combination of vancomycin and colistin at 24 hours, demonstrating the antagonistic effect of vancomycin and colistin combination (Figure 2). Conclusion This study showed that exposure of colistin to certain MRSA strains may reduce the susceptibility to vancomycin. Combination therapy with vancomycin and colistin for MDR pathogens infections might result in treatment failure for concurrent MRSA infection. Disclosures All authors: No reported disclosures.

scholarly journals Synergy of Daptomycin with Oxacillin and Other β-Lactams against Methicillin-Resistant Staphylococcus aureus

2004 ◽  
Vol 48 (8) ◽  
pp. 2871-2875 ◽  
Author(s):  
Kenneth H. Rand ◽  
Herbert J. Houck
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Screening Method ◽  
Methicillin Resistant ◽  
Drug Concentrations ◽  
Mueller Hinton ◽  
Mueller Hinton Agar ◽  
High Level ◽  
Time Kill

ABSTRACT We previously observed marked synergy between daptomycin and both rifampin and ampicillin against vancomycin-resistant enterococci (VRE). Because the synergy between daptomycin and ampicillin was observed for 100% of VRE strains with high-level ampicillin resistance (ampicillin MIC of ≥128 μg/ml), we looked for synergy between daptomycin and other β-lactams against 18 strains of methicillin-resistant Staphylococcus aureus (MRSA) by employing a time-kill method using Mueller-Hinton broth supplemented to 50 mg of Ca2+/liter. All strains were resistant to oxacillin (16 of 18 strains were resistant at drug concentrations of ≥256 μg/ml), and all strains were susceptible to daptomycin (the MIC at which 90% of the tested isolates were inhibited was 1 μg/ml). Daptomycin was tested at concentrations of 2, 1, 0.5, 0.25, 0.125, and 0.0625 μg/ml alone or in combination with oxacillin at a fixed concentration of 32 μg/ml. Synergy was found for all 18 strains with daptomycin at one-half the MIC in combination with 32 μg of oxacillin/ml, and synergy was found for 11 of 18 strains (61%) with daptomycin at one-fourth the MIC or less in combination with oxacillin. At 24 h, the daptomycin-oxacillin combination with daptomycin at one-half the MIC showed bactericidal activity against all 18 strains, and the combination with one-fourth the daptomycin MIC showed bactericidal activity against 9 of 18 strains. We also used a novel screening method to look for synergy between daptomycin and other β-lactams. In this approach, daptomycin was incorporated into Ca2+-supplemented Mueller-Hinton agar at subinhibitory concentrations, and synergy was screened by comparing test antibiotic Kirby-Bauer disks on agar with and without daptomycin. By this method, daptomycin with ampicillin-sulbactam, ticarcillin-clavulanate, or piperacillin-tazobactam showed synergy comparable to or greater than daptomycin with oxacillin. For seven of the eight strains tested, time-kill studies confirmed synergy between daptomycin and ampicillin-sulbactam with ampicillin in the range of 2 to 8 μg/ml. The combination of daptomycin and β-lactams may be useful for the treatment of MRSA infection, but further studies are needed to elucidate the mechanisms and to determine the in vivo efficacy of the combination.

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