Comparative Efficacies of Liposomal Amikacin (MiKasome) plus Oxacillin versus Conventional Amikacin plus Oxacillin in Experimental Endocarditis Induced by Staphylococcus aureus: Microbiological and Echocardiographic Analyses

ABSTRACT Optimal treatment strategies for serious infections caused byStaphylococcus aureus have not been fully characterized. The combination of a β-lactam plus an aminoglycoside can act synergistically against S. aureus in vitro and in vivo. MiKasome, a new liposome-encapsulated formulation of conventional amikacin, significantly prolongs serum half-life (t 1/2) and increases the area under the concentration-time curve (AUC) compared to free amikacin. Microbiologic efficacy and left ventricular function, as assessed by echocardiography, were compared in animals administered either oxacillin alone or oxacillin in combination with conventional amikacin or MiKasome in a rabbit model of experimental endocarditis due toS. aureus. In vitro, oxacillin, combined with either free amikacin or MiKasome, prevented the bacterial regrowth observed with aminoglycosides alone at 24 h of incubation. Rabbits with S. aureus endocarditis were treated with either oxacillin alone (50 mg/kg, given intramuscularly three times daily), oxacillin plus daily amikacin (27 mg/kg, given intravenously twice daily), or oxacillin plus intermittent MiKasome (160 mg/kg, given intravenously, a single dose on days 1 and 4). The oxacillin-alone dosage represents a subtherapeutic regimen against the infecting strain in the endocarditis model (L. Hirano and A. S. Bayer, Antimicrob. Agents Chemother. 35:685–690, 1991), thus allowing recognition of any enhanced bactericidal effects between oxacillin and either aminoglycoside formulation. Treatment was administered for either 3 or 6 days, and animals were sacrificed after each of these time points or at 5 days after a 6-day treatment course (to evaluate for posttherapy relapse). Left ventricular function was analyzed by utilizing serial transthoracic echocardiography during treatment and posttherapy by measurement of left ventricular fractional shortening. At all sacrifice times, both combination regimens significantly reduced S. aureus vegetation counts versus control counts (P < 0.05). In contrast, oxacillin alone did not significantly reduce S. aureus vegetation counts after 3 days of therapy. Furthermore, at this time point, the two combinations were significantly more effective than oxacillin alone (P < 0.05). All three regimens were effective in significantly decreasing bacterial counts in the myocardium during and after therapy compared to controls (P < 0.05). In kidney and spleen abscesses, all regimens significantly reduced bacterial counts during therapy (P < 0.0001); however, only the combination regimens prevented bacteriologic relapse in these organs posttherapy. By echocardiographic analysis, both combination regimens yielded a significant physiological benefit by maintaining normal left ventricular function during treatment and posttherapy compared with oxacillin alone (P < 0.001). These results suggest that the use of intermittent MiKasome (similar to daily conventional amikacin) enhances the in vivo bactericidal effects of oxacillin in a severe S. aureusinfection model and preserves selected physiological functions in target end organs.

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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”)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00487-10 ◽

2010 ◽

Vol 54 (8) ◽

pp. 3161-3169 ◽

Cited By ~ 86

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.

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Transverse aortic banding leads to depressed in vivo left ventricular function in phospholamban ablated mice

Journal of Cardiac Failure ◽

10.1016/s1071-9164(98)90020-3 ◽

1998 ◽

Vol 4 (3) ◽

pp. 6

Author(s):

Helen Kiriazis ◽

Vivek J. Kadambi ◽

Damodhar P. Suresh ◽

Robert G. Johnson ◽

Evangelia G. Kranias ◽

...

Keyword(s):

Left Ventricular Function ◽

Ventricular Function ◽

Left Ventricular ◽

Aortic Banding

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In Vitro and In Vivo Activities of Novel Fluoroquinolones Alone and in Combination with Clarithromycin against Clinically Isolated Mycobacterium avium Complex Strains in Japan

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00410-07 ◽

2007 ◽

Vol 51 (11) ◽

pp. 4071-4076 ◽

Cited By ~ 31

Author(s):

Yoshihisa Kohno ◽

Hideaki Ohno ◽

Yoshitsugu Miyazaki ◽

Yasuhito Higashiyama ◽

Katsunori Yanagihara ◽

...

Keyword(s):

Infectious Disease ◽

Mycobacterium Avium ◽

Antimicrobial Agents ◽

Histopathological Examination ◽

Bacterial Counts ◽

Viable Bacteria ◽

The Individual ◽

Combination Regimens

ABSTRACT The recommended treatments for Mycobacterium avium complex (MAC) infectious disease are combination regimens of clarithromycin (CLR) or azithromycin with ethambutol and rifamycin. However, these chemotherapy regimens are sometimes unsuccessful. Recently developed antimicrobial agents, such as newer fluoroquinolones (FQs) containing C-8 methoxy quinolone (moxifloxacin [MXF] and gatifloxacin [GAT]), are expected to be novel antimycobacterial agents. Here, we evaluated the in vitro and in vivo antimycobacterial activities of three FQs (MXF, GAT, and levofloxacin) and CLR against clinically isolated MAC strains. Subsequently, the in vitro and in vivo synergic activities of FQ-CLR combinations against MAC strains were investigated. CLR and the individual FQs alone showed promising activity against MAC strains in vitro, and the bacterial counts in organs (lungs, liver, and spleen) of MAC-infected mice treated with single agents were significantly reduced compared to control mice. CLR showed the best anti-MAC effect in vivo. When the three FQs were individually combined with CLR in vitro, mild antagonism was observed for 53 to 57% of the tested isolates. Moreover, mice were infected with MAC strains showing mild antagonism for FQ-CLR combinations in vitro, and the anti-MAC effects of the FQ-CLR combinations were evaluated by counting the viable bacteria in their organs and by histopathological examination after 28 days of treatment. Several FQ-CLR combinations exhibited bacterial counts in organs significantly higher than those in mice treated with CLR alone. Our results indicate that the activity of CLR is occasionally attenuated by combination with an FQ both in vitro and in vivo and that this effect seems to be MAC strain dependent. Careful combination chemotherapy using these agents against MAC infectious disease may be required.

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Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00458-08 ◽

2008 ◽

Vol 52 (10) ◽

pp. 3681-3686 ◽

Cited By ~ 27

Author(s):

O. Murillo ◽

M. E. Pachón ◽

G. Euba ◽

R. Verdaguer ◽

F. Tubau ◽

...

Keyword(s):

Foreign Body ◽

Combined Therapy ◽

Antagonistic Effect ◽

Control Treatment ◽

High Dose ◽

Bacterial Counts ◽

Days Of Therapy ◽

Resistant Strains

ABSTRACT Since levofloxacin at high doses was more active than levofloxacin at conventional doses and was the best therapy alone in a rat model of staphylococcal foreign-body infection, in this study we tested how these differences affect the activities of their respective combinations with rifampin in vitro and in vivo. In vitro studies were performed in the log and stationary phases. By using this model, rifampin at 25 mg/kg of body weight/12 h, levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, levofloxacin at 50 mg/kg/day, levofloxacin at 50 mg/kg/day plus rifampin, or a control treatment was administered for 7 days; and therapy with for levofloxacin at 100 mg/kg/day alone and rifampin alone was prolonged to 14 days. We screened for the appearance of resistant strains. Killing curves in the log phase showed a clear antagonism with levofloxacin at concentrations ≥2× MIC and rifampin and tended to occur in the stationary phase. At the end of 7 days of therapy, levofloxacin at 100 mg/kg/day was the best treatment and decreased the bacterial counts from tissue cage fluid (P < 0.05 compared with the results for groups except those receiving rifampin alone). At the end of 14 days of therapy with levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, and the control treatment, the bacterial counts on the coverslips were 2.24 (P < 0.05 compared with the results with the combined therapy), 3.36, and 5.4 log CFU/ml, respectively. No rifampin or levofloxacin resistance was detected in any group except that receiving rifampin alone. In conclusion, high-dose levofloxacin was the best treatment and no resistant strains appeared; the addition of rifampin showed an antagonistic effect. The efficacy of the rifampin-levofloxacin combination is not significantly improved by the dosage of levofloxacin.

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Effects of dietary omega–3 fatty acids on ventricular function in dogs with healed myocardial infarctions: in vivo and in vitro studies

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01065.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. H1219-H1228 ◽

Cited By ~ 23

Author(s):

George E. Billman ◽

Yoshinori Nishijima ◽

Andriy E. Belevych ◽

Dmitry Terentyev ◽

Ying Xu ◽

...

Keyword(s):

Myocardial Infarction ◽

Fatty Acids ◽

Ventricular Function ◽

Contractile Function ◽

Left Ventricular ◽

Calcium Currents ◽

Calcium Handling ◽

Omega 3

Since omega–3 polyunsaturated fatty acids (n-3 PUFAs) can alter ventricular myocyte calcium handling, these fatty acids could adversely affect cardiac contractile function, particularly following myocardial infarction. Therefore, 4 wk after myocardial infarction, dogs were randomly assigned to either placebo (corn oil, 1 g/day, n = 16) or n-3 PUFAs supplement [docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) ethyl esters; 1, 2, or 4 g/day; n = 7, 8, and 12, respectively] groups. In vivo, ventricular function was evaluated by echocardiography before and after 3 mo of treatment. At the end of the 3-mo period, hearts were removed and in vitro function was evaluated using right ventricular trabeculae and isolated left ventricular myocytes. The treatment elicited significant ( P < 0.0001) dose-dependent increases (16.4-fold increase with 4 g/day) in left ventricular tissue and red blood cell n-3 PUFA levels (EPA + DHA, placebo, 0.42 ± 0.04; 1 g/day, 3.02 ± 0.23; 2 g/day, 3.63 ± 0.17; and 4 g/day, 6.97 ± 0.33%). Regardless of the dose, n-3 PUFA treatment did not alter ventricular function in the intact animal (e.g., 4 g/day, fractional shortening: pre, 42.9 ± 1.6 vs. post, 40.1 ± 1.7%; placebo: pre, 39.2 ± 1.3 vs. post, 38.4 ± 1.6%). The developed force per cross-sectional area, changes in length- and frequency-dependent behavior in contractile force, and the inotropic response to β-adrenoceptor activation were also similar for trabeculae obtained from placebo- or n-3 PUFA-treated dogs. Finally, calcium currents and calcium transients were the same in myocytes from n-3 PUFA- and placebo-treated dogs. Thus dietary n-3 PUFAs did not adversely alter either in vitro or in vivo ventricular contractile function in dogs with healed infarctions.

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In Vivo Left Ventricular Function and Collagen Expression in Aldosterone/Salt-Induced Hypertension

Journal of Cardiovascular Pharmacology ◽

10.1097/00005344-199812000-00009 ◽

1998 ◽

Vol 32 (6) ◽

pp. 927-934 ◽

Cited By ~ 11

Author(s):

Juan Fernando Ramirez-Gil ◽

Claude Delcayre ◽

Valerie Robert ◽

Michel Wassef ◽

Pascal Trouve ◽

...

Keyword(s):

Left Ventricular Function ◽

Ventricular Function ◽

Left Ventricular ◽

Collagen Expression ◽

Induced Hypertension

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Y-688, a New Quinolone Active against Quinolone-Resistant Staphylococcus aureus: Lack of In Vivo Efficacy in Experimental Endocarditis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.8.1889 ◽

1998 ◽

Vol 42 (8) ◽

pp. 1889-1894 ◽

Cited By ~ 7

Author(s):

J. M. Entenza ◽

O. Marchetti ◽

M. P. Glauser ◽

P. Moreillon

Keyword(s):

Staphylococcus Aureus ◽

In Vivo Efficacy ◽

Methicillin Resistant ◽

Bacterial Counts ◽

Resistance Selection ◽

New Quinolones ◽

Increased Activity ◽

Trough Levels

ABSTRACT Y-688 is a new fluoroquinolone with increased activity against ciprofloxacin-resistant staphylococci. The MICs of Y-688 and other quinolones were determined for 58 isolates of ciprofloxacin-resistant and methicillin-resistant Staphylococcus aureus (MRSA). The MICs at which 50% and 90% of bacteria were inhibited were ≥128 and ≥128 mg/liter, respectively, for ciprofloxacin, 16 and 32 mg/liter, respectively, for sparfloxacin, and 0.25 and 1 mg/liter, respectively, for Y-688. This new quinolone was further tested in rats with experimental endocarditis due to either of two isolates of ciprofloxacin-resistant MRSA (namely, P8/128 and CR1). Infected animals were treated for 3 days with ciprofloxacin, vancomycin, or Y-688. Antibiotics were administered through a computerized pump to simulate human-like pharmacokinetics in the serum of rats. The anticipated peak and trough levels of Y-688 were 4 and 1 mg/liter at 0.5 and 12 h, respectively. Treatment with ciprofloxacin was ineffective. Vancomycin significantly decreased vegetation bacterial counts for both organisms (P ≲ 0.05). In contrast, Y-688 only marginally decreased vegetation bacterial counts (P ≳ 0.05). Moreover, several vegetation that failed Y-688 treatment grew staphylococci for which the MICs of the test antibiotic were increased two to eight times. Y-688 also selected for resistance in vitro, and isolates for which the MICs were increased eight times emerged at a frequency of ca. 10−8. Thus, in spite of its low MIC for ciprofloxacin-resistant MRSA, Y-688 failed in vivo and its use carried the risk of resistance selection. The fact that ciprofloxacin-resistant staphylococci became rapidly resistant to this potent new drug suggests that the treatment of ciprofloxacin-resistant MRSA with new quinolones might be more problematic than expected.

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