RESUMEN
Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against Enterococcus faecalis, Enterococcus faecium (resistant to vancomycin and ampicillin), and Staphylococcus aureus As a monotherapy, TZD for 5 days was not effective in a comparison with no-treatment controls, while DAP for 5 days was significantly effective against these bacteria. Step-down therapy (DAP for 3 days followed by TZD for 2 days) was as effective as DAP for 5 days and was comparable to 3 days of DAP plus ceftriaxone against all bacteria and to 3 days of DAP plus gentamicin against E. faecalis OG1RF.
Asunto(s)
Antibacterianos/uso terapéutico , Daptomicina/uso terapéutico , Endocarditis Bacteriana/tratamiento farmacológico , Enterococcus , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Staphylococcus aureus Resistente a Meticilina , Oxazolidinonas/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Tetrazoles/uso terapéutico , Resistencia a la Vancomicina , Staphylococcus aureus Resistente a Vancomicina , Animales , Antibacterianos/farmacología , Recuento de Colonia Microbiana , Daptomicina/farmacología , Endocarditis Bacteriana/microbiología , Enterococcus/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecium/efectos de los fármacos , Infecciones por Bacterias Grampositivas/microbiología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/farmacología , Ratas , Infecciones Estafilocócicas/microbiología , Tetrazoles/farmacologíaRESUMEN
Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A ß-lactamase (ßla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its ßla-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to ≥128 µg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P = 0.001; CPT versus NAF, P = 0.9830). Both CFZ and CPT were efficacious against the ßla-cured derivative, TX0117c, compared to time zero (t0) (P = <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for high-inoculum infections caused by MSSA exhibiting the CFZ InE.
Asunto(s)
Antibacterianos/farmacología , Cefazolina/uso terapéutico , Cefalosporinas/uso terapéutico , Endocarditis/tratamiento farmacológico , Endocarditis/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidad , Animales , Peso Corporal/efectos de los fármacos , Masculino , Meticilina/uso terapéutico , Pruebas de Sensibilidad Microbiana , Nafcilina/uso terapéutico , Ratas , Ratas Sprague-Dawley , beta-Lactamasas/metabolismo , CeftarolinaRESUMEN
We first assessed telavancin (TLV) pharmacokinetics in rats after a single subcutaneous dose of 35 mg/kg of body weight. The pharmacokinetic data were used to predict a TLV dose that simulates human exposure, and the efficacy of TLV was then evaluated using a TLV dose of 21 mg/kg every 12 h against Enterococcus faecalis OG1RF (TLV MIC of 0.06 µg/ml) in a rat endocarditis model with an indwelling catheter. Therapy was given for 3 days with TLV, daptomycin (DAP), or ampicillin (AMP) monotherapy and with combinations of TLV plus AMP, AMP plus gentamicin (GEN), and AMP plus ceftriaxone (CRO); rats were sacrificed 24 h after the last dose. Antibiotics were given to simulate clinically relevant concentrations or as used in other studies. TLV treatment resulted in a significant decrease in bacterial burden (CFU per gram) in vegetations from 6.0 log10 at time 0 to 3.1 log10 after 3 days of therapy. Bacterial burdens in vegetations were also significantly lower in the TLV-treated rats than in the AMP (P = 0.0009)- and AMP-plus-GEN (P = 0.035)-treated rats but were not significantly different from that of the AMP-plus-CRO-treated rats. Bacterial burdens from vegetations in TLV monotherapy and TLV-plus-AMP-and-DAP groups were similar to each other (P ≥ 0.05). Our data suggest that further study of TLV as a therapeutic alternative for deep-seated infections caused by vancomycin-susceptible E. faecalis is warranted.
Asunto(s)
Aminoglicósidos/uso terapéutico , Ampicilina , Animales , Antibacterianos/uso terapéutico , Ceftriaxona/uso terapéutico , Cefalosporinas/uso terapéutico , Daptomicina/uso terapéutico , Quimioterapia Combinada , Endocarditis Bacteriana , Enterococcus faecalis , Gentamicinas/uso terapéutico , Lipoglucopéptidos , Masculino , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Sprague-Dawley , Vancomicina/uso terapéuticoRESUMEN
Methicillin (meticillin)-susceptible Staphylococcus aureus (MSSA) strains producing large amounts of type A beta-lactamase (Bla) have been associated with cefazolin failures, but the frequency and impact of these strains have not been well studied. Here we examined 98 MSSA clinical isolates and found that 26% produced type A Bla, 15% type B, 46% type C, and none type D and that 13% lacked blaZ. The cefazolin MIC(90) was 2 microg/ml for a standard inoculum and 32 microg/ml for a high inoculum, with 19% of isolates displaying a pronounced inoculum effect (MICs of >or=16 microg/ml with 10(7) CFU/ml) (9 type A and 10 type C Bla producers). At the high inoculum, type A producers displayed higher cefazolin MICs than type B or C producers, while type B and C producers displayed higher cefamandole MICs. Among isolates from hemodialysis patients with MSSA bacteremia, three from the six patients who experienced cefazolin failure showed a cefazolin inoculum effect, while none from the six patients successfully treated with cefazolin showed an inoculum effect, suggesting an association between these strains and cefazolin failure (P = 0.09 by Fisher's exact test). In summary, 19% of MSSA clinical isolates showed a pronounced inoculum effect with cefazolin, a phenomenon that could explain the cases of cefazolin failure previously reported for hemodialysis patients with MSSA bacteremia. These results suggest that for serious MSSA infections, the presence of a significant inoculum effect with cefazolin could be associated with clinical failure in patients treated with this cephalosporin, particularly when it is used at low doses.
Asunto(s)
Antibacterianos/farmacología , Cefazolina/farmacología , Staphylococcus aureus/efectos de los fármacos , Bacteriemia/tratamiento farmacológico , Cefamandol/farmacología , Cefazolina/uso terapéutico , Humanos , Meticilina/farmacología , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas/tratamiento farmacológico , Insuficiencia del Tratamiento , beta-Lactamasas/metabolismoRESUMEN
A patient with native valve endocarditis caused by a vancomycin "heteroresistant" strain of Enterococcus faecium experienced failure of daptomycin monotherapy without evidence of daptomycin resistance. The infecting organism exhibited in vivo emergence of a vancomycin-susceptible subpopulation lacking vanA. Treatment with a combination of high-dose daptomycin, gentamicin, and high-dose ampicillin cleared the infection.
Asunto(s)
Daptomicina/uso terapéutico , Endocarditis Bacteriana/tratamiento farmacológico , Endocarditis Bacteriana/microbiología , Enterococcus faecium/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Resistencia a la Vancomicina/genética , Ampicilina/uso terapéutico , Antibacterianos/uso terapéutico , Proteínas Bacterianas/genética , Ligasas de Carbono-Oxígeno/genética , ADN Bacteriano/genética , Quimioterapia Combinada , Enterococcus faecium/genética , Enterococcus faecium/aislamiento & purificación , Gentamicinas/uso terapéutico , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Familia de Multigenes , Insuficiencia del TratamientoRESUMEN
OBJECTIVES: Ceftobiprole is a novel broad-spectrum cephalosporin with good in vitro activity against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. The objective of this study was to assess the in vivo activity of ceftobiprole against four strains of E. faecalis, including beta-lactamase- producing (Bla+) and vancomycin-resistant strains. METHODS: Mice were infected intraperitoneally with strains of E. faecalis: (i) the Bla+ strain HH22; (ii) two vancomycin-resistant strains (TX2484 and V583); and (iii) OG1RF (a laboratory strain), using 10 x the LD50 for each strain. Ceftobiprole doses of 25, 12.5 and 6.25 mg/kg (single doses) and ampicillin 50, 25, 12.5 and 6.25 mg/kg (single and double doses) were administered subcutaneously immediately after bacterial challenge and mice were monitored for 96 h. RESULTS: All four E. faecalis had ceftobiprole MICs
Asunto(s)
Antibacterianos/uso terapéutico , Cefalosporinas/uso terapéutico , Enterococcus faecalis , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Peritonitis/tratamiento farmacológico , Resistencia a la Ampicilina , Animales , Relación Dosis-Respuesta a Droga , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/enzimología , Infecciones por Bacterias Grampositivas/enzimología , Infecciones por Bacterias Grampositivas/microbiología , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Peritonitis/microbiología , Resistencia a la Vancomicina , beta-Lactamasas/metabolismoRESUMEN
Our experience with a patient with methicillin-susceptible Staphylococcus aureus aortic native valve endocarditis, who had a relapse involving fever and positive blood culture results while receiving cefazolin, led us to evaluate this organism's ability to hydrolyze cefazolin at high inocula, a previously well-documented phenomenon. Analysis of the infecting strain disclosed a high minimum inhibitory concentration of cefazolin when a large inoculum was used, as well as rapid and complete cefazolin degradation, which was associated with regrowth in a time-kill experiment. DNA sequencing of the beta-lactamase gene showed that it was identical to that of the S. aureus type A beta-lactamase, known to efficiently inactivate cefazolin. A word of caution is given regarding the use of this antibiotic for treatment of endocarditis caused by this type of S. aureus isolate.
Asunto(s)
Antibacterianos/uso terapéutico , Cefazolina/uso terapéutico , Endocarditis Bacteriana/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/enzimología , beta-Lactamasas/metabolismo , Endocarditis Bacteriana/microbiología , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Recurrencia , Staphylococcus aureus/efectos de los fármacos , beta-Lactamasas/clasificaciónRESUMEN
Using six Enterococcus faecalis and five Enterococcus faecium strains, the ketolide ABT-773 (ABT), now known as cethromycin, was found to have in vivo efficacy against both erythromycin (ERY)-susceptible (Ery(s)) and -intermediate (Ery(i)) enterococci (ABT 50% protective doses [PD(50)s], 0.5 to 4.1 and 10.3 to 16.2 mg/kg of body weight, respectively). Against four highly Ery-resistant (Ery(r)) strains for which ABT MICs were low, ABT showed much greater activity (PD(50), 6.3 to 32.5 mg/kg) than ERY (PD(50), >200 mg/kg) but was not protective for strains for which ABT MICs were high. In conclusion, ABT-773 showed in vivo efficacy and considerably greater activity than ERY in a mouse peritonitis model.