RESUMEN
JNJ-Q2 is a broad-spectrum fluoroquinolone with bactericidal activity against Gram-positive and Gram-negative pathogens and is currently in clinical development for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin-structure infections. This study determined the activity of JNJ-Q2 against a worldwide year 2010 collection (89 centres in 27 countries) of three common respiratory pathogens (3757 isolates) from patients with CABP. Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were tested by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, and susceptibility rates for comparators were assessed using CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint criteria. JNJ-Q2 had activity against all three species, with 96.9% of strains inhibited at ≤0.015 mg/L. JNJ-Q2 [minimum inhibitory concentration for 50% and 90% of the organisms, respectively (MIC(50/90))=0.008/0.015 mg/L] demonstrated a 16-fold greater potency compared with moxifloxacin (MIC(50/90)=0.12/0.25 mg/L) and at least 128-fold greater activity compared with levofloxacin (MIC(50/90)=1/ 1 mg/L) and ciprofloxacin (MIC(50/90)=1/2 mg/L) against S. pneumoniae. Haemophilus influenzae isolates were 21.9-23.3% resistant to ampicillin, but JNJ-Q2 (MIC(50/90)≤0.004/0.015 mg/L) was at least two-fold more active than moxifloxacin (MIC(50/90)=0.015/0.03 mg/L) as well as being potent against M. catarrhalis (MIC(90)=0.015/0.015 mg/L). In conclusion, JNJ-Q2 demonstrated increased potency compared with other marketed fluoroquinolones that have been used to treat CABP pathogens, thus favouring further clinical development.
Asunto(s)
Infecciones Comunitarias Adquiridas/microbiología , Fluoroquinolonas/farmacología , Haemophilus influenzae/efectos de los fármacos , Moraxella catarrhalis/efectos de los fármacos , Neumonía Bacteriana/microbiología , Streptococcus pneumoniae/efectos de los fármacos , Antibacterianos/farmacología , Compuestos Aza/farmacología , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Geografía , Haemophilus influenzae/aislamiento & purificación , Humanos , Concentración 50 Inhibidora , Levofloxacino , Pruebas de Sensibilidad Microbiana , Moraxella catarrhalis/aislamiento & purificación , Moxifloxacino , Ofloxacino/farmacología , Quinolinas/farmacología , Streptococcus pneumoniae/aislamiento & purificaciónRESUMEN
JNJ-Q2 is a novel broad-spectrum bactericidal fluorinated 4-quinolone with potent activity against Gram-positive and -negative pathogens with a balanced potency against both DNA gyrase and topoisomerase IV targets. JNJ-Q2 is in clinical development for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) and community-acquired bacterial pneumonia. With the use of reference broth microdilution methods in a central reference laboratory design, MIC values were obtained for 3650 pathogens (44.4% were from patients diagnosed with ABSSSI) obtained during the 2010 SENTRY antimicrobial surveillance program. Isolates were collected from patients in 96 medical centers in 26 countries in North America, Europe, Latin America, and Asia Pacific. JNJ-Q2 demonstrated good activity overall (MIC(50/90), 0.015/0.5 µg/mL) and against 3081 Staphylococcus aureus with >95% of the isolates inhibited at a MIC of ≤0.5 µg/mL; against 1410 levofloxacin-resistant Staphylococcus aureus isolates, >90% were inhibited by MIC ≤0.5 µg/mL. All isolates were inhibited at a MIC of ≤2 µg/mL. In addition, JNJ-Q2 demonstrated excellent activity (MIC(90), 0.015 µg/mL) against 569 isolates of beta-hemolytic streptococci (including 278 Streptococcus pyogenes and 161 Streptococcus agalactiae). JNJ-Q2 was the most potent fluoroquinolone tested overall and against all pathogens when compared directly to moxifloxacin, levofloxacin, and ciprofloxacin.
Asunto(s)
Antibacterianos/farmacología , Fluoroquinolonas/farmacología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/efectos de los fármacos , Asia , Europa (Continente) , Humanos , América Latina , Pruebas de Sensibilidad Microbiana , América del Norte , Staphylococcus aureus/aislamiento & purificación , Streptococcus agalactiae , Streptococcus pyogenes/aislamiento & purificaciónRESUMEN
JNJ-Q2 is a fluoroquinolone with broad coverage including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind, multicenter, phase II noninferiority study treated 161 patients for 7 to 14 days, testing the efficacy of JNJ-Q2 (250 mg, twice a day [BID]) versus linezolid (600 mg, BID) in patients with acute bacterial skin and skin structure infections (ABSSSI). The prespecified criterion for noninferiority was 15%. Primary intent-to-treat analysis was unable to declare noninferiority, as the risk difference lower bound of the 95% confidence interval between treatments was 19% at 36 to 84 h postrandomization for the composite end point of lesion assessment and temperature. Prespecified clinical cure rates 2 to 14 days after completion of therapy were similar (83.1% for JNJ-Q2 versus 82.1% for linezolid). Post hoc analyses revealed that JNJ-Q2 was statistically noninferior to linezolid (61.4% versus 57.7%, respectively; P = 0.024) based on the 2010 FDA guidance, which defines treatment success as lack of lesion spread and afebrile status within 48 to 72 h postrandomization. Despite evidence of systemic disease, <5% of patients presented with fever, suggesting fever is not a compelling surrogate measure of systemic disease resolution for this indication. Nausea and vomiting were the most common adverse events. Of the patients, 86% (104/121) had S. aureus isolated from the infection site; 63% of these were MRSA. The results suggest JNJ-Q2 shows promise as an effective treatment for ABSSSI, demonstrating (i) efficacy for early clinical response (i.e., lack of spread of lesions and absence of fever at 48 to 72 h), and (ii) cure rates for ABSSSI pathogens (especially MRSA) consistent with the historical literature.
Asunto(s)
Acetamidas , Fluoroquinolonas , Oxazolidinonas , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Acetamidas/efectos adversos , Acetamidas/uso terapéutico , Adolescente , Adulto , Anciano , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Método Doble Ciego , Femenino , Fluoroquinolonas/efectos adversos , Fluoroquinolonas/uso terapéutico , Humanos , Linezolid , Masculino , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Persona de Mediana Edad , Oxazolidinonas/efectos adversos , Oxazolidinonas/uso terapéutico , Enfermedades Cutáneas Bacterianas/microbiología , Infecciones de los Tejidos Blandos/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
JNJ-Q2 is a novel fluorinated 4-quinolone in development for treatment of acute bacterial skin and skin structure infection and community-acquired bacterial pneumonia. This quality control (QC) study was performed to establish ranges for control strains: Staphylococcus aureus ATCC 29213 (0.004 to 0.015 µg/ml), Enterococcus faecalis ATCC 29212 (0.015 to 0.06 µg/ml), Pseudomonas aeruginosa ATCC 27853 (0.5 to 2 µg/ml and 17 to 23 mm), Escherichia coli ATCC 25922 (0.008 to 0.03 µg/ml and 30 to 36 mm), Haemophilus influenzae ATCC 49247 (0.002 to 0.015 µg/ml and 31 to 39 mm), Streptococcus pneumoniae ATCC 49619 (0.004 to 0.015 µg/ml and 28 to 35 mm), and S. aureus ATCC 25923 (32 to 38 mm). These ranges will be crucial in evaluating JNJ-Q2 potency as it progresses through clinical trial development.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Fluoroquinolonas/farmacología , Humanos , Pruebas de Sensibilidad Microbiana/normas , Control de CalidadRESUMEN
JNJ-Q2 is a broad-spectrum bactericidal fluoroquinolone with potent activity against Gram-positive and -negative pathogens. In this study, the in vitro activity of JNJ-Q2 was evaluated against 511 selected Staphylococcus aureus samples isolated in 2008-2009 from patients with acute bacterial skin and skin structure infections in the United States by using reference methodology. JNJ-Q2 was the most potent fluoroquinolone tested overall (MIC(50) and MIC(90), 0.12 and 0.5 µg/ml, respectively) and against methicillin- and fluoroquinolone-resistant subgroups in direct comparisons to moxifloxacin, levofloxacin, and ciprofloxacin (each being ≥ 16-fold less potent than JNJ-Q2).