RESUMO
Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.
Assuntos
Aminoglicosídeos/farmacologia , Antibacterianos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Infecções por Enterobacteriaceae/microbiologia , Enterobacteriaceae/efeitos dos fármacos , Sisomicina/análogos & derivados , Farmacorresistência Bacteriana/genética , Enterobacteriaceae/genética , Hospitais , Humanos , Testes de Sensibilidade Microbiana , RNA Ribossômico 16S/genética , Sisomicina/farmacologia , Estados UnidosRESUMO
The polymyxins are important agents for carbapenem-resistant Gram-negative bacilli. The United States Committee on Antimicrobial Susceptibility Testing breakpoint recommendations for colistin and polymyxin B are that isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae are considered susceptible at MIC values of ≤2 mg/liter. These recommendations are contingent upon dosing and testing strategies that are described in this commentary. Importantly, these recommendations are not applicable to lower respiratory tract infections, for which we recommend no breakpoints. Furthermore, there is no breakpoint recommendation for polymyxin B for lower urinary tract infections.
Assuntos
Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana/normas , Polimixinas/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Colistina/farmacologia , Guias como Assunto , Humanos , Polimixina B/farmacologia , Polimixinas/administração & dosagem , Polimixinas/uso terapêutico , Infecções Respiratórias/microbiologia , Estados Unidos , Infecções Urinárias/microbiologiaRESUMO
BACKGROUND: Infections caused by antibiotic-resistant bacteria, including carbapenem-resistant Enterobacteriaceae, have increased in frequency, resulting in signiï¬cant patient morbidity and mortality. The Infectious Diseases Society of America continues to propose legislative, regulatory, and funding solutions to address this escalating crisis. This report updates the status of development and approval of systemic antibiotics in the United States as of late 2018. METHODS: We performed a review of the published literature and on-line clinical trials registry at www.clinicaltrials.gov to identify new systemically acting orally and/or intravenously administered antibiotic drug candidates in the development pipeline, as well as agents approved by the US Food and Drug Administration since 2012. RESULTS: Since our 2013 pipeline status report, the number of new antibiotics annually approved for marketing in the United States has reversed its previous decline, likely influenced by new financial incentives and increased regulatory flexibility. Although our survey demonstrates progress in development of new antibacterial drugs that target infections caused by resistant bacterial pathogens, the majority of recently approved agents have been modifications of existing chemical classes of antibiotics, rather than new chemical classes. Furthermore, larger pharmaceutical companies continue to abandon the field, and smaller companies face financial difficulties as a consequence. CONCLUSIONS: Unfortunately, if 20 × '20 is achieved due to efforts embarked upon in decades past, it could mark the apex of antibiotic drug development for years to come. Without increased regulatory, governmental, industry, and scientific support and collaboration, durable solutions to the clinical, regulatory, and economic problems posed by bacterial multidrug resistance will not be found.
Assuntos
Antibacterianos/uso terapêutico , Aprovação de Drogas/estatística & dados numéricos , United States Food and Drug Administration , Aprovação de Drogas/organização & administração , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla , Sociedades Médicas , Estados UnidosRESUMO
Bloodstream infection (BSI) organisms were consecutively collected from >200 medical centers in 45 nations between 1997 and 2016. Species identification and susceptibility testing followed Clinical and Laboratory Standards Institute broth microdilution methods at a central laboratory. Clinical data and isolates from 264,901 BSI episodes were collected. The most common pathogen overall was Staphylococcus aureus (20.7%), followed by Escherichia coli (20.5%), Klebsiella pneumoniae (7.7%), Pseudomonas aeruginosa (5.3%), and Enterococcus faecalis (5.2%). S. aureus was the most frequently isolated pathogen overall in the 1997-to-2004 period, but E. coli was the most common after 2005. Pathogen frequency varied by geographic region, hospital-onset or community-onset status, and patient age. The prevalence of S. aureus isolates resistant to oxacillin (ORSA) increased until 2005 to 2008 and then declined among hospital-onset and community-acquired BSI in all regions. The prevalence of vancomycin-resistant enterococci (VRE) was stable after 2012 (16.4% overall). Daptomycin resistance among S. aureus and enterococci (DRE) remained rare (<0.1%). In contrast, the prevalence of multidrug-resistant (MDR) Enterobacteriaceae increased from 6.2% in 1997 to 2000 to 15.8% in 2013 to 2016. MDR rates were highest among nonfermentative Gram-negative bacilli (GNB), and colistin was the only agent with predictable activity against Acinetobacter baumannii-Acinetobacter calcoaceticus complex (97% susceptible). In conclusion, S. aureus and E. coli were the predominant causes of BSI worldwide during this 20-year surveillance period. Important resistant phenotypes among Gram-positive pathogens (MRSA, VRE, or DRE) were stable or declining, whereas the prevalence of MDR-GNB increased continuously during the monitored period. MDR-GNB represent the greatest therapeutic challenge among common bacterial BSI pathogens.
Assuntos
Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Infecções por Acinetobacter/epidemiologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/isolamento & purificação , Antibacterianos/farmacologia , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/isolamento & purificação , Europa (Continente)/epidemiologia , Infecções por Bactérias Gram-Positivas/epidemiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/isolamento & purificação , América Latina/epidemiologia , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificaçãoRESUMO
Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log10(CFU/ml) [IQR, 5.43 to 6.46 log10(CFU/ml)]. In a subset of patients, repeat BAL on day 5 showed a good stability of the dilution factor. We previously showed that large bacterial burdens reduce or stop bacterial killing by granulocytes. (This study has been registered at ClinicalTrials.gov under registration no. NCT01570192.).
Assuntos
Técnicas Bacteriológicas/métodos , Líquido da Lavagem Broncoalveolar/microbiologia , Pneumonia Bacteriana/microbiologia , Pneumonia Associada à Ventilação Mecânica/microbiologia , Ureia/análise , Carga Bacteriana , Humanos , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Ureia/sangueRESUMO
We evaluated the correlation between MIC and disk diffusion inhibition zones when testing ceftazidime-avibactam, using the 30/20-µg disk and the disk diffusion and MIC breakpoints established by the U.S. FDA and the Clinical and Laboratory Standards Institute (CLSI). Organisms used included 2 groups of Enterobacteriaceae isolates and 2 groups of Pseudomonas aeruginosa isolates; 1 group of each consisted of randomly selected isolates and the second group consisted of a challenge group from thousands of surveillance isolates with an increased proportion of organisms displaying ceftazidime-avibactam MIC values close to the breakpoints. Broth microdilution, disk diffusion tests, and data analysis were performed according to reference standardized methods. Ceftazidime-avibactam breakpoints of ≤8/4 (susceptible) and ≥16/4 µg/ml (resistant) for MIC and ≥21/≤20 mm for disk diffusion, as established by the U.S. FDA and the CLSI, were applied for Enterobacteriaceae and P. aeruginosa Ceftazidime-avibactam MIC and disk zone (30/20-µg disk) correlation were acceptable when testing Enterobacteriaceae (overall, very major [VM] and major [Ma] error rates of 0.4% and 0.0%, respectively) and nearly so when testing P. aeruginosa (2.3% VM and 2.9% Ma errors). In summary, disk diffusion and broth microdilution testing results demonstrated good categorical agreement for ceftazidime-avibactam against Enterobacteriaceae and P. aeruginosa, using 30/20-µg disks.
Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão/métodos , Enterobacteriaceae/efeitos dos fármacos , Testes de Sensibilidade Microbiana/métodos , Pseudomonas aeruginosa/efeitos dos fármacos , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão/normas , Combinação de Medicamentos , Humanos , Testes de Sensibilidade Microbiana/normas , Estados Unidos , United States Food and Drug AdministrationRESUMO
WCK 5222 consists of cefepime combined with zidebactam, a bicyclo-acyl hydrazide ß-lactam enhancer antibiotic with a dual action involving binding to Gram-negative bacterial PBP2 and ß-lactamase inhibition. We evaluated the in vitro activity of cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (n = 5,946), Pseudomonas aeruginosa (n = 1,291), and Acinetobacter spp. (n = 639) from the United States (n = 2,919), Europe (n = 3,004), the Asia-Pacific (n = 1,370), and Latin America (n = 583). The isolates were tested by a reference broth microdilution method for susceptibility against cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC50/90, ≤0.03/0.12 µg/ml [1:1] and 0.06/0.25 µg/ml [2:1]; 99.9% of isolates were inhibited at ≤4 [1:1] and ≤8 µg/ml [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC50/90, ≤0.03 to 0.06/≤0.03 to 0.5 µg/ml [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC50/90, 1/4 µg/ml; 99.3% of isolates were inhibited at ≤8 µg/ml [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 µg/ml (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC50/90 values of 1/4 µg/ml, and 99.5% of isolates were inhibited at ≤8 µg/ml (1:1). The MIC values for cefepime-zidebactam at the 1:1 ratio were generally 2-fold lower than those for cefepime-zidebactam at the 2:1 ratio (MIC50/90, 2/8 µg/ml) and zidebactam alone (MIC50/90, 4/8 µg/ml). Against Acinetobacter spp., cefepime-zidebactam at 1:1 and 2:1 ratios (MIC50/90, 16/32 µg/ml for both) was 4-fold more active than cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support the clinical development of WCK 5222 for the treatment of Gram-negative bacterial infections, including those caused by multidrug-resistant isolates.
Assuntos
Acinetobacter/efeitos dos fármacos , Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Cefalosporinas/farmacologia , Ciclo-Octanos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Piperidinas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Acinetobacter/isolamento & purificação , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Cefepima , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Enterobacteriaceae/isolamento & purificação , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/isolamento & purificação , beta-Lactamases/genéticaRESUMO
Cefepime-tazobactam (WCK 4282) is currently under clinical development for use at a dosage of 2 g/2 g every 8 h. A total of 7,981 isolates were collected from 146 medical centers (39 countries) in 2014 as a part of the SENTRY Antimicrobial Surveillance Program, and their susceptibilities to cefepime-tazobactam (with tazobactam at fixed concentrations of 4 and 8 µg/ml) were tested by a reference broth microdilution method. Isolates were mainly from patients with pneumonia (29.5%) and bloodstream infections (26.9%). Cefepime-tazobactam (with tazobactam at a fixed concentration of 8 µg/ml) and cefepime inhibited 96.9 and 87.9% of Enterobacteriaceae strains at ≤8 µg/ml. The activity of cefepime-tazobactam against Enterobacteriaceae strains was comparable to that of meropenem (96.7% of isolates were susceptible) and greater than that of piperacillin-tazobactam (87.7% susceptible). All Enterobacteriaceae species from the United States except Klebsiella pneumoniae had >99.0% of isolates inhibited by cefepime-tazobactam at ≤8/8 µg/ml. The prevalence of the extended-spectrum ß-lactamase (ESBL)-screening-positive phenotype was the highest among Escherichia coli isolates in China (66.3%) and among K. pneumoniae isolates (58.0%) in Latin America. Cefepime-tazobactam at ≤8/8 µg/ml inhibited 98.7 and 71.3% of ESBL-screening-positive phenotype E. coli strains and K. pneumoniae strains, respectively. Meropenem showed limited activity against ESBL-screening-positive phenotype K. pneumoniae strains (69.6% susceptible). Cefepime-tazobactam was active against Enterobacter spp. (MIC50 and MIC90, 0.06 and 0.5 µg/ml, respectively), including ceftazidime-nonsusceptible isolates (96.1% of isolates were inhibited by cefepime-tazobactam at ≤8/8 µg/ml). The activity of cefepime-tazobactam against Pseudomonas aeruginosa (82.4 and 91.6% of isolates were inhibited by cefepime-tazobactam at ≤8/8 and ≤16/8 µg/ml, respectively) was comparable to that of meropenem and piperacillin-tazobactam (79.2% susceptible). In summary, cefepime-tazobactam was highly active against P. aeruginosa and Enterobacteriaceae strains, including ESBL-screening-positive phenotype E. coli strains and ceftazidime-nonsusceptible Enterobacter spp. These results support the further clinical development of the cefepime-tazobactam combination.
Assuntos
Cefalosporinas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Ácido Penicilânico/análogos & derivados , Antibacterianos/farmacologia , Cefepima , Enterobacteriaceae/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném , Testes de Sensibilidade Microbiana , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Tazobactam , Tienamicinas/farmacologia , beta-Lactamases/metabolismoRESUMO
High-dose cefepime-tazobactam (1:1; WCK 4282), a novel antibacterial combination consisting of the ß-lactamase inhibitor tazobactam and a fourth-generation cephalosporin, is under clinical development for the treatment of serious Gram-negative infections. A quality control (QC) study was performed to establish disk diffusion and MIC ranges for cefepime-tazobactam for multiple QC reference strains. The cefepime-tazobactam QC ranges for a fixed tazobactam MIC of 8 µg/ml and disk diffusion (30/20-µg disk) test methods were approved by the CLSI Subcommittee on Antimicrobial Susceptibility Testing in January 2015 and January 2016. These QC ranges will be important for accurate in vitro activity evaluations of cefepime-tazobactam when tested against clinical Gram-negative bacteria during clinical studies and routine patient care.
Assuntos
Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão/métodos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Ácido Penicilânico/análogos & derivados , Inibidores de beta-Lactamases/uso terapêutico , Cefepima , Combinação de Medicamentos , Infecções por Bactérias Gram-Negativas/microbiologia , Guias como Assunto , Humanos , Ácido Penicilânico/uso terapêutico , Controle de Qualidade , Tazobactam , beta-Lactamases/metabolismoRESUMO
Background: Zidebactam is a ß-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and ß-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections. Objectives: To evaluate the in vitro activities of cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant ß-lactamase types. Methods: ß-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against cefepime/zidebactam, cefepime and zidebactam. Results: Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC 50/90 0.25/1 mg/L), SHV (20; MIC 50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC 50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC 50/90 ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC 50/90 0.12/0.5 mg/L), KPC (35; MIC 50/90 0.25/1 mg/L) and metallo-ß-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC 50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC 50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC 50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa , including ß-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many ß-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC 50/90 32 mg/L (1:1)]. Conclusions: Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant ß-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available.
Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Cefalosporinas/farmacologia , Ciclo-Octanos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/enzimologia , Antibacterianos/química , Antibacterianos/metabolismo , Cefepima , Sinergismo Farmacológico , Enterobacteriaceae/enzimologia , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Piperidinas/farmacologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/enzimologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismoRESUMO
Resistance to the novel ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-ß-lactamase in diverse Enterobacteriaceae species.
Assuntos
Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Bacteriemia , Ceftazidima/uso terapêutico , Infecções por Enterobacteriaceae , Enterobacteriaceae , Adulto , Idoso , Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Institutos de Câncer , Ceftazidima/farmacologia , Pré-Escolar , Combinação de Medicamentos , Farmacorresistência Bacteriana , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/enzimologia , Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/epidemiologia , Infecções por Enterobacteriaceae/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , beta-LactamasesRESUMO
Dalbavancin, a novel lipoglycopeptide, was approved for use in 2014 by regulatory agencies in the United States and Europe for the treatment of skin and skin structure infections. The activity of dalbavancin was also widely assessed by determination of its activity against Streptococcus pneumoniae clinical isolates collected from patients on six continents monitored during two time intervals (2011 to 2013 and 2014). A total of 18,186 pneumococcal isolates were obtained from 49 nations and submitted to a monitoring laboratory as part of the SENTRY Antimicrobial Surveillance Program for reference susceptibility testing. The potency of dalbavancin against S. pneumoniae was consistent across the years that it was monitored, with the MIC50 and MIC90 being 0.015 and 0.03 µg/ml, respectively, and all isolates were inhibited by ≤0.12 µg/ml. The activity of dalbavancin was not adversely influenced by nonsusceptibility to ß-lactams (ceftriaxone or penicillin), macrolides, clindamycin, fluoroquinolones, or tetracyclines or multidrug resistance (MDR). Regional variations in dalbavancin activity were not detected, but S. pneumoniae strains isolated in the Asia-Pacific region were more likely to be nonsusceptible to penicillin and ceftriaxone as well as to be MDR than strains isolated in North or South America and Europe. Direct comparisons of potency illustrated that dalbavancin (MIC50 and MIC90, 0.015 and 0.03 µg/ml, respectively) was 16-fold or more active than vancomycin (MIC50, 0.25 µg/ml), linezolid (MIC50, 1 µg/ml), levofloxacin (MIC50, 1 µg/ml), ceftriaxone (MIC90, 1 µg/ml), and penicillin (MIC90, 2 µg/ml). In conclusion, dalbavancin had potent and consistent activity against this contemporary (2011 to 2014) collection of S. pneumoniae isolates.
Assuntos
Antibacterianos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Teicoplanina/análogos & derivados , Ceftriaxona/farmacologia , Cefalosporinas/farmacologia , Levofloxacino/farmacologia , Linezolida/farmacologia , Testes de Sensibilidade Microbiana , Penicilinas/farmacologia , Teicoplanina/farmacologia , Vancomicina/farmacologiaRESUMO
Solithromycin, a fourth-generation macrolide (a fluoroketolide with enhanced activity against macrolide-resistant bacteria due to interaction with three ribosomal sites) and the first fluoroketolide, was tested against a 2014 collection of 6,115 isolates, including Streptococcus pneumoniae (1,713 isolates), Haemophilus influenzae (1,308), Moraxella catarrhalis (577), Staphylococcus aureus (1,024), and beta-hemolytic streptococci (1,493), by reference broth microdilution methods. The geographic samples included 2,748 isolates from the United States, 2,536 from Europe, 386 from Latin America, and 445 from the Asia-Pacific region. Solithromycin was observed to be very active against S. pneumoniae (MIC50/90, 0.008/0.12 µg/ml), demonstrating 2-fold greater activity than telithromycin (MIC50/90, 0.015/0.25 µg/ml) and 16- to >256-fold greater activity than azithromycin (MIC50/90, 0.12/>32 µg/ml), with all strains being inhibited at a solithromycin MIC of ≤1 µg/ml. Against H. influenzae, solithromycin showed potency identical to that of telithromycin (MIC50/90, 1/2 µg/ml), and both of these compounds were 2-fold less active than azithromycin (MIC50/90, 0.5/1 µg/ml). All but one of the M. catarrhalis isolates were inhibited by solithromycin at ≤0.25 µg/ml. Solithromycin inhibited 85.3% of S. aureus isolates at ≤1 µg/ml, and its activity was lower against methicillin-resistant (MIC50/90, 0.06/>32 µg/ml) than against methicillin-susceptible (MIC50/90, 0.06/0.06 µg/ml) isolates. Little variation in solithromycin activity was observed by geographic region for the species tested. Solithromycin was very active against beta-hemolytic streptococci (MIC50/90, 0.015/0.03 µg/ml), and all isolates were inhibited at MIC values of ≤0.5 µg/ml. In conclusion, solithromycin demonstrated potent activity against global and contemporary (2014) pathogens that represent the major causes of community-acquired bacterial pneumonia. These data support the continued clinical development of solithromycin for the treatment of this important indication.
Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/epidemiologia , Infecções Comunitárias Adquiridas/epidemiologia , Monitoramento Epidemiológico , Macrolídeos/farmacologia , Triazóis/farmacologia , Ásia/epidemiologia , Azitromicina/farmacologia , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Europa (Continente)/epidemiologia , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/crescimento & desenvolvimento , Haemophilus influenzae/isolamento & purificação , Humanos , Cooperação Internacional , Cetolídeos/farmacologia , América Latina/epidemiologia , Testes de Sensibilidade Microbiana , Moraxella catarrhalis/efeitos dos fármacos , Moraxella catarrhalis/crescimento & desenvolvimento , Moraxella catarrhalis/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/isolamento & purificação , Streptococcus/efeitos dos fármacos , Streptococcus/crescimento & desenvolvimento , Streptococcus/isolamento & purificação , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimento , Streptococcus pneumoniae/isolamento & purificação , Estados Unidos/epidemiologiaRESUMO
A total of 7,272 unique patient clinical isolates were collected from 71 U.S. medical centers from patients with urinary tract infections in 2012 to 2014 and tested for susceptibility to ceftazidime-avibactam and comparators by broth microdilution methods. Ceftazidime-avibactam inhibited >99.9% of all Enterobacteriaceae at the susceptible breakpoint of ≤8 µg/ml (there were only three nonsusceptible strains). Ceftazidime-avibactam was also active against Pseudomonas aeruginosa isolates (MIC50, 2 µg/ml; MIC90, 4 µg/ml; 97.7% susceptible), including many isolates not susceptible to meropenem, ceftazidime, and/or piperacillin-tazobactam.
Assuntos
Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções Urinárias/microbiologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Enterobacteriaceae/patogenicidade , Bactérias Gram-Negativas/genética , Bactérias Gram-Negativas/patogenicidade , Humanos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/patogenicidadeRESUMO
Among 15,588 Enterobacteriaceae isolates collected in 63 U.S. hospitals from 2012 to 2014, 2,129 (13.7%) displayed an extended-spectrum ß-lactamase (ESBL) phenotype. These rates were similar over time (13.2 to 13.9%); however, differences among Escherichia coli (12.7 and 15.1% in 2012 and 2014; P = 0.007) and Klebsiella pneumoniae (18.9 and 15.5% in 2012 and 2014; P = 0.006) were noted when comparing 2014 and 2012. Carbapenem-resistant Enterobacteriaceae (CRE) (2.3 and 1.8%) and carbapenem-resistant K. pneumoniae (6.8 and 5.1%; P = 0.003) rates were lower in 2014 than in 2012. Isolates carrying blaCTX-M-15-like genes were stable (42.1 to 42.4%), but a decrease among E. coli isolates (59.1 and 49.7%; P = 0.008) and an increase among K. pneumoniae isolates (32.7 and 41.2%; P = 0.022) in 2014 were observed. Isolates carrying blaKPC (304) decreased over the years (16.5 and 10.9%; P = 0.008), mainly due to the decrease in K. pneumoniae isolates harboring blaKPC (n = 285; 35.6 and 28.4%; P = 0.041) in hospitals in the Mid-Atlantic and South Atlantic regions, where these isolates were highly prevalent during 2012 and 2013. Isolates carrying blaCMY-2-like and blaCTX-M-14-like genes increased (8.2 and 11.9% and 9.1 and 12.9%, respectively; P = 0.04 for both), and those producing blaSHV ESBL decreased (24.9 and 12.7%; P < 0.001) over the studied years, due to a decreased occurrence of the enzymes among K. pneumoniae isolates. Other enzymes were detected in smaller numbers of isolates, including four K. pneumoniae isolates carrying blaNDM-1 metallo-ß-lactamase (two in 2012 and two in 2014). Ceftazidime-avibactam, a recently approved ß-lactamase inhibitor combination, was very active against the ESBL phenotype isolates (MIC50/90, 0.12 and 1 µg/ml; 99.7% susceptible) and CRE strains (MIC50/90, 0.5 and 2 µg/ml; 98.5% susceptible) that displayed elevated MIC values for many comparator agents. In conclusion, significant changes were noted in the frequencies of isolates harboring various ß-lactamases among U.S. hospitals between 2012 and 2014 that will require continued monitoring.
Assuntos
Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/uso terapêutico , Infecções por Enterobacteriaceae/tratamento farmacológico , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , beta-Lactamases/genética , Carbapenêmicos/uso terapêutico , Combinação de Medicamentos , Hospitais , Humanos , Testes de Sensibilidade Microbiana/métodos , Inibidores de beta-Lactamases/uso terapêuticoRESUMO
Fusidic acid (FA) activity was evaluated against 2,002 clinical staphylococcal isolates collected in U.S. hospitals during 2014. FA (MIC50/90, 0.12/0.12 µg/ml) inhibited 99.8% of Staphylococcus aureus isolates at ≤1 µg/ml. Only four S. aureus isolates displayed FA values of >2 µg/ml (three strains with fusC and one with an L461K substitution in fusA), and they were isolated from patients in four states. In conclusion, FA demonstrated sustained, potent activity against this recent collection of U.S. staphylococci.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana/genética , Ácido Fusídico/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Monitoramento Epidemiológico , Expressão Gênica , Hospitais , Humanos , Testes de Sensibilidade Microbiana , Mutação , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/isolamento & purificação , Estados Unidos/epidemiologiaRESUMO
Klebsiella pneumoniae carbapenemase (KPC)-producing isolates have become increasingly prevalent worldwide, and these organisms are often multidrug resistant, limiting the therapeutic options available for treating infections. We evaluated the activity of meropenem combined with the serine ß-lactamase inhibitor vaborbactam (formerly RPX7009) against 315 serine carbapenemase-producing Enterobacteriaceae (CPE) isolates by use of checkerboard-designed panels to assess the optimal inhibitor concentration (range tested, 0.5 to 32 µg/ml). Overall, meropenem alone (MIC50 and MIC90, 16 and >64 µg/ml, respectively) inhibited only 2.2% of the isolates at ≤1 µg/ml (the CLSI susceptibility breakpoint) and 7.3% of the isolates at ≤2 µg/ml (the EUCAST breakpoint). Vaborbactam restored meropenem activity for 72.7 to 98.1% of CPE isolates at ≤2 µg/ml, and maximum potentiation was achieved with fixed concentrations of ≥8 µg/ml of the inhibitor (≥96.5% of isolates were inhibited at ≤2 µg/ml of meropenem-vaborbactam). Meropenem-vaborbactam with a fixed concentration of 8 µg/ml of the inhibitor (MIC50, ≤0.06 µg/ml for all organisms) inhibited 93.7% of the CPE isolates displaying elevated meropenem MICs at ≤1 µg/ml. Meropenem-vaborbactam MICs were elevated for isolates producing metallo-ß-lactamases (MIC, 16 to >64 µg/ml) or displaying decreased expression of OmpK37 and/or elevated expression of the AcrAB-TolC efflux system (MIC, 16 µg/ml). Vaborbactam showed no antibacterial activity alone (all MICs, >64 µg/ml). Meropenem-vaborbactam appears to be a good candidate for further development and it could increase the options for treatment of serious infections caused by carbapenemase-producing pathogens.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Enterobacteriaceae/efeitos dos fármacos , Serina/metabolismo , Tienamicinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Enterobacteriaceae/metabolismo , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/metabolismo , Meropeném , Testes de Sensibilidade Microbiana/métodosRESUMO
Oritavancin (MIC50/90, 0.03/0.06 to 0.12 µg/ml) had potent activity against linezolid-resistant staphylococci, as well as Enterococcus faecalis and Enterococcus faecium (oritavancin MIC50/90, 0.015/0.12 µg/ml against both species). All linezolid-resistant isolates were inhibited by oritavancin at ≤0.12 µg/ml. These results confirmed the absence of cross-resistance between linezolid and oritavancin in staphylococci and enterococci.
Assuntos
Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Glicopeptídeos/farmacologia , Linezolida/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Farmacorresistência Bacteriana , Enterococcus faecalis/crescimento & desenvolvimento , Enterococcus faecalis/isolamento & purificação , Enterococcus faecium/crescimento & desenvolvimento , Enterococcus faecium/isolamento & purificação , Humanos , Lipoglicopeptídeos , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/farmacologia , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/isolamento & purificação , beta-Lactamas/farmacologiaRESUMO
Gepotidacin, a novel triazaacenaphthylene antibacterial agent, is the first in a new class of type IIA topoisomerase inhibitors with activity against many biothreat and conventional pathogens, including Neisseria gonorrhoeae To assist ongoing clinical studies of gepotidacin to treat gonorrhea, a multilaboratory quality assurance investigation determined the reference organism (N. gonorrhoeae ATCC 49226) quality control MIC range to be 0.25 to 1 µg/ml (88.8% of gepotidacin MIC results at the 0.5 µg/ml mode).
Assuntos
Acenaftenos/farmacologia , Antibacterianos/farmacologia , Gonorreia/microbiologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Neisseria gonorrhoeae/efeitos dos fármacos , Inibidores da Topoisomerase/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
Among 69 of 139 (49.6%) carbapenem-nonsusceptible Enterobacteriaceae carrying blaKPC, 1 Klebsiella pneumoniae was also positive for blaVIM. The isolate belonged to sequence type 258 (ST258) and carried blaKPC-2 on a copy of Tn4401a and blaVIM-4 on a class 1 integron. Genes were located on distinct plasmids belonging to Inc types A/C and FII. Elevated expression of the efflux pump AcrAB-TolC (acrA, 15.3 times) and reduced expression of outer membrane protein genes ompK35 and ompK37 (0.16 and 0.081 times, respectively) associated with various amino acid alterations on OmpK37 were observed. The presence of two carbapenemases in ST258 K. pneumoniae is of great concern due to the ability of this organism to widely disseminate.