RESUMO
PURPOSE: The current study evaluated the in vitro activities of ceftolozane/tazobactam (C/T), imipenem/relebactam (IMI/REL), and comparators against recent (2017-2021) clinical isolates of gram-negative bacilli from two countries in southern Europe. METHODS: Nine clinical laboratories (two in Greece; seven in Italy) each collected up to 250 consecutive gram-negative isolates per year from lower respiratory tract, intraabdominal, urinary tract, and bloodstream infection samples. MICs were determined by the CLSI broth microdilution method and interpreted using 2022 EUCAST breakpoints. ß-lactamase genes were identified in select ß-lactam-nonsusceptible isolate subsets. RESULTS: C/T inhibited the growth of 85-87% of Enterobacterales and 94-96% of ESBL-positive non-CRE NME (non-Morganellaceae Enterobacterales) isolates from both countries. IMI/REL inhibited 95-98% of NME, 100% of ESBL-positive non-CRE NME, and 98-99% of KPC-positive NME isolates from both countries. Country-specific differences in percent susceptible values for C/T, IMI/REL, meropenem, piperacillin/tazobactam, levofloxacin, and amikacin were more pronounced for Pseudomonas aeruginosa than Enterobacterales. C/T and IMI/REL both inhibited 84% of P. aeruginosa isolates from Greece and 91-92% of isolates from Italy. MBL rates were estimated as 4% of Enterobacterales and 10% of P. aeruginosa isolates from Greece compared to 1% of Enterobacterales and 3% of P. aeruginosa isolates from Italy. KPC rates among Enterobacterales isolates were similar in both countries (7-8%). OXA-48-like enzymes were only identified in Enterobacterales isolates from Italy (1%) while GES carbapenemase genes were only identified in P. aeruginosa isolates from Italy (2%). CONCLUSION: We conclude that C/T and IMI/REL may provide viable treatment options for many patients from Greece and Italy.
Assuntos
Antibacterianos , Cefalosporinas , Enterobacteriaceae , Imipenem , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa , Tazobactam , Humanos , Itália , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/genética , Antibacterianos/farmacologia , Tazobactam/farmacologia , Grécia , Imipenem/farmacologia , Cefalosporinas/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Enterobacteriaceae/genética , Compostos Azabicíclicos/farmacologia , beta-Lactamases/genética , beta-Lactamases/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Infecções por Pseudomonas/microbiologiaRESUMO
Antimicrobial susceptibility was determined for clinical gram-negative isolates from Czech Republic, Hungary, and Poland, where published data for ceftolozane/tazobactam (C/T) and imipenem/relebactam (IMI/REL) is scarce. C/T was active against 94.3% of Enterobacterales, 10-18% higher than the tested cephalosporins and piperacillin/tazobactam. IMI/REL was the most active tested agent against non-Morganellaceae Enterobacterales (99.7% susceptible). C/T was the most active among all studied agents except colistin against Pseudomonas aeruginosa (96.0% susceptible); susceptibility to IMI/REL was 90.7%. C/T maintained activity against 73.7-85.3% of ß-lactam-resistant or multidrug-resistant P. aeruginosa subsets. C/T and IMI/REL could represent important treatment options for patients from these countries.
Assuntos
Infecções por Pseudomonas , Humanos , República Tcheca , Polônia , Hungria , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Tazobactam/farmacologia , Tazobactam/uso terapêutico , Pseudomonas aeruginosa , Imipenem/farmacologia , Imipenem/uso terapêutico , Testes de Sensibilidade MicrobianaRESUMO
Ceftolozane-tazobactam (C/T), imipenem-relebactam (IMR), and ceftazidime-avibactam (CZA) were tested against 2,531 P. aeruginosa strains isolated from patients in the United States from 2018 to 2020 as part of the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance program. MICs were determined by CLSI broth microdilution and interpreted using CLSI M100 (2021) breakpoints. Imipenem-, IMR-, or C/T-nonsusceptible isolates were screened for ß-lactamase genes: 96.4% of all isolates and ≥70% of multidrug-resistant (MDR), pan-ß-lactam-nonsusceptible, and difficult-to-treat resistance (DTR) isolates were C/T-susceptible; 52.2% of C/T-nonsusceptible isolates remained susceptible to IMR compared to 38.9% for CZA; and 1.7% of isolates tested were nonsusceptible to both C/T and IMR versus 2.2% of isolates with a C/T-nonsusceptible and CZA-resistant phenotype (a difference of 12 isolates). C/T and IMR modal MICs for pan-ß-lactam-nonsusceptible isolates remained at or below their respective susceptible MIC breakpoints from 2018 to 2020, while the modal MIC for CZA increased 2-fold from 2018 to 2019 and exceeded the CZA-susceptible MIC breakpoint in both 2019 and 2020. Only six of 802 molecularly characterized isolates carried a metallo-ß-lactamase, and two isolates carried a GES carbapenemase. Most P. aeruginosa isolates were C/T-susceptible, including many with MDR, pan-ß-lactam-nonsusceptible, DTR, CZA-resistant, and IMR-nonsusceptible phenotypes. While C/T was the most active antipseudomonal agent, IMR demonstrated greater activity than CZA against isolates nonsusceptible to C/T.
Assuntos
Infecções por Pseudomonas , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Combinação de Medicamentos , Hospitais , Humanos , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/genética , Tazobactam/farmacologia , Estados Unidos , beta-Lactamases/genéticaRESUMO
BACKGROUND: Multidrug-resistant (MDR) bacteria are frequently defined using the criteria established by Magiorakos et al [Clin Microbiol Infect 2012;18:268-81]. Difficult-to-treat resistance (DTR) [Kadri et al, Clin Infect Dis 2018;67:1803-14] is a novel approach to defining resistance in gram-negative bacilli focusing on treatment-limiting resistance to first-line agents (all ß-lactams and fluoroquinolones). METHODS: Clinical and Laboratory Standards Institute-defined broth microdilution minimum inhibitory concentrations (MICs) were determined for imipenem/relebactam, ceftolozane/tazobactam, and comparators against respiratory, intraabdominal, and urinary isolates of Enterobacterales (nâ =â 10â 516) and Pseudomonas aeruginosa (nâ =â 2732) collected in 26 US hospitals in 2015-2017. RESULTS: Among all Enterobacterales, 1.0% of isolates were DTR and 15.6% were MDR; 8.4% of P. aeruginosa isolates were DTR and 32.4% were MDR. MDR rates for Enterobacterales and DTR and MDR rates for P. aeruginosa were significantly higher (Pâ <â .05) in isolates collected in intensive care units (ICUs) than in non-ICUs and in respiratory tract isolates than in intraabdominal or urinary tract isolates. In addition, 82.4% of DTR and 92.1% of MDR Enterobacterales and 62.2% of DTR and 82.2% of MDR P. aeruginosa were imipenem/relebactam-susceptible, and 1.5% of DTR and 65.8% of MDR Enterobacterales and 67.5% of DTR and 84.0% of MDR P. aeruginosa were ceftolozane/tazobactam-susceptible. CONCLUSIONS: MDR phenotypes defined using the Magiorakos criteria may overcall treatment-limiting resistance in gram-negative bacilli. In the US, DTR Enterobacterales were infrequent, while MDR Enterobacterales isolates and DTR and MDR P. aeruginosa were common. Imipenem/relebactam (Enterobacterales, P. aeruginosa) and ceftolozane/tazobactam (P. aeruginosa) retained in vitro activity against most DTR and MDR isolates.
Assuntos
Antibacterianos , Infecções por Pseudomonas , Antibacterianos/farmacologia , Compostos Azabicíclicos , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana , Farmacorresistência Bacteriana Múltipla , Humanos , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Fenótipo , Pseudomonas aeruginosa , Tazobactam/farmacologia , Estados UnidosRESUMO
BACKGROUND: Ceftolozane/tazobactam (C/T) is approved in 70 countries, including the United States, for the treatment of patients with hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible Gram-negative pathogens. C/T is of particular importance as an agent for the treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa infections. The current study summarizes 2018-2019 data from the United States on lower respiratory tract isolates of Gram-negative bacilli from the SMART global surveillance program. The CLSI reference broth microdilution method was used to determine in vitro susceptibility of C/T and comparators against isolates of P. aeruginosa and Enterobacterales. RESULTS: C/T inhibited 96.0% of P. aeruginosa (n = 1237) at its susceptible MIC breakpoint (≤4 µg/ml), including > 85% of meropenem-nonsusceptible and piperacillin/tazobactam (P/T)-nonsusceptible isolates and 76.2% of MDR isolates. Comparator agents demonstrated lower activity than C/T against P. aeruginosa: meropenem (74.8% susceptible), cefepime (79.2%), ceftazidime (78.5%), P/T (74.4%), and levofloxacin (63.1%). C/T was equally active against ICU (96.0% susceptible) and non-ICU (96.7%) isolates of P. aeruginosa. C/T inhibited 91.8% of Enterobacterales (n = 1938) at its susceptible MIC breakpoint (≤2 µg/ml); 89.5% of isolates were susceptible to cefepime and 88.0% susceptible to P/T. 67.1 and 86.5% of extended-spectrum ß-lactamase (ESBL) screen-positive isolates of Klebsiella pneumoniae (n = 85) and Escherichia coli (n = 74) and 49.6% of MDR Enterobacterales were susceptible to C/T. C/T was equally active against ICU (91.3% susceptible) and non-ICU (92.6%) Enterobacterales isolates. CONCLUSION: Data from the current study support the use of C/T as an important treatment option for lower respiratory tract infections including those caused by MDR P. aeruginosa.
Assuntos
Cefalosporinas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Tazobactam/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Enterobacteriaceae/efeitos dos fármacos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Infecções Respiratórias/microbiologia , Estados UnidosRESUMO
Eravacycline is a novel, fully synthetic fluorocycline antibiotic being developed for the treatment of serious infections, including those caused by resistant Gram-positive pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a recent global collection of frequently encountered clinical isolates of Gram-positive bacteria. The CLSI broth microdilution method was used to determine in vitro MIC data for isolates of Enterococcus spp. (n = 2,807), Staphylococcus spp. (n = 4,331), and Streptococcus spp. (n = 3,373) isolated primarily from respiratory, intra-abdominal, urinary, and skin specimens by clinical laboratories in 37 countries on three continents from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. There were no substantive differences (a >1-doubling-dilution increase or decrease) in eravacycline MIC90 values for different species/organism groups over time or by region. Eravacycline showed MIC50 and MIC90 results of 0.06 and 0.12 µg/ml, respectively, when tested against Staphylococcus aureus, regardless of methicillin susceptibility. The MIC90 values of eravacycline for Staphylococcus epidermidis and Staphylococcus haemolyticus were equal (0.5 µg/ml). The eravacycline MIC90s for Enterococcus faecalis and Enterococcus faecium were 0.06 µg/ml and were within 1 doubling dilution regardless of the vancomycin susceptibility profile. Eravacycline exhibited MIC90 results of ≤0.06 µg/ml when tested against Streptococcus pneumoniae and beta-hemolytic and viridans group streptococcal isolates. In this surveillance study, eravacycline demonstrated potent in vitro activity against frequently isolated clinical isolates of Gram-positive bacteria (Enterococcus, Staphylococcus, and Streptococcus spp.), including isolates collected over a 5-year period (2013 to 2017), underscoring its potential benefit in the treatment of infections caused by common Gram-positive pathogens.
Assuntos
Bactérias Gram-Positivas/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Tetraciclinas/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Vancomicina/farmacologiaRESUMO
Eravacycline is a novel, fully synthetic fluorocycline antibiotic developed for the treatment of serious infections, including those caused by multidrug-resistant (MDR) pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a global collection of frequently encountered clinical isolates of Gram-negative bacilli. The CLSI broth microdilution method was used to determine MIC data for isolates of Enterobacterales (n = 13,983), Acinetobacter baumannii (n = 2,097), Pseudomonas aeruginosa (n = 1,647), and Stenotrophomonas maltophilia (n = 1,210) isolated primarily from respiratory, intra-abdominal, and urinary specimens by clinical laboratories in 36 countries from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. Multidrug-resistant (MDR) isolates were defined by resistance to agents from ≥3 different antimicrobial classes. The MIC90s ranged from 0.25 to 1 µg/ml for Enterobacteriaceae and were 1 µg/ml for A. baumannii and 2 µg/ml for S. maltophilia, Proteus mirabilis, and Serratia marcescens Eravacycline's potency was up to 4-fold greater than that of tigecycline against genera/species of Enterobacterales, A. baumannii, and S. maltophilia The MIC90s for five of six individual genera/species of Enterobacterales and A. baumannii were within 2-fold of the MIC90s for their respective subsets of MDR isolates, while the MDR subpopulation of Klebsiella spp. demonstrated 4-fold higher MIC90s. Eravacycline demonstrated potent in vitro activity against the majority of clinical isolates of Gram-negative bacilli, including MDR isolates, collected over a 5-year period. This study further underscores the potential benefit of eravacycline in the treatment of infections caused by MDR Gram-negative pathogens.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Tetraciclinas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Tigeciclina/farmacologiaRESUMO
OBJECTIVES: Relebactam is a diazabicyclooctane non-ß-lactam inhibitor of Ambler class A and C ß-lactamases that is in clinical development in combination with imipenem/cilastatin. The current study evaluated the in vitro activity of imipenem/relebactam against 5447 isolates of Pseudomonas aeruginosa submitted to the SMART global surveillance programme in 2015-17 by 67 clinical laboratories in 22 European countries. METHODS: MICs were determined using the CLSI broth microdilution reference method (Eleventh Edition: M07, 2018). Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. MICs were interpreted using EUCAST clinical breakpoints (version 8.1); imipenem breakpoints were applied to imipenem/relebactam. RESULTS: Rates of susceptibility to imipenem and imipenem/relebactam (MIC ≤4 mg/L) were 69.4% and 92.4%, respectively, for all isolates of P. aeruginosa. Over one-third of all isolates (34.9%, 1902/5447) were MDR; lower respiratory tract isolates (38.3%, 1327/3461) were more frequently MDR than were intraabdominal (28.5%, 355/1245) or urinary tract (29.7%, 212/714) isolates. Of all MDR isolates, 78.2% were susceptible to imipenem/relebactam, a rate that was 50-77 percentage points higher than the rate of susceptibility to imipenem or any other ß-lactam tested; rates of susceptibility to imipenem/relebactam were similar for MDR isolates from lower respiratory tract (77.8% susceptible), intraabdominal (80.3%) and urinary tract (76.4%) infections. Overall, relebactam restored imipenem susceptibility to 75.2% (1254/1668) of imipenem-non-susceptible isolates of P. aeruginosa and to 69.6% (947/1361) of imipenem-non-susceptible isolates with an MDR phenotype. CONCLUSIONS: Relebactam restored in vitro susceptibility to imipenem for most imipenem-non-susceptible and MDR clinical isolates of P. aeruginosa from European patients.
Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Farmacorresistência Bacteriana Múltipla , Imipenem/farmacologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Pseudomonas aeruginosa/isolamento & purificação , Adulto JovemRESUMO
Relebactam is a non-ß-lactam, bicyclic diazabicyclooctane ß-lactamase inhibitor of class A and class C ß-lactamases, including Klebsiella pneumoniae carbapenemases (KPCs). It is in phase 3 clinical development in combination with imipenem/cilastatin. The in vitro activities of imipenem-relebactam, imipenem, and comparators were determined using the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method for isolates of Enterobacteriaceae (n = 3,419) and Pseudomonas aeruginosa (n = 896) collected in 2016 by 21 U.S. hospital laboratories participating in the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 µg/ml. Imipenem-relebactam MICs were interpreted using CLSI breakpoints for imipenem. Rates of susceptibility to imipenem-relebactam and imipenem for non-ProteeaeEnterobacteriaceae (n = 3,143) and P. aeruginosa were 99.1% (3,115/3,143) and 95.9% (3,013/3,143) and were 94.4% (846/896) and 74.7% (669/896), respectively. Relebactam restored imipenem susceptibility to 78.5% (102/130) of imipenem-nonsusceptible non-ProteeaeEnterobacteriaceae and to 78.0% (177/227) of imipenem-nonsusceptible P. aeruginosa isolates. Susceptibility to imipenem-relebactam was 98.2% (444/452) and 82.2% (217/264) for multidrug-resistant (MDR) non-ProteeaeEnterobacteriaceae and MDR P. aeruginosa, respectively. Given the ability of relebactam to restore susceptibility to imipenem in nonsusceptible isolates of both non-ProteeaeEnterobacteriaceae and P. aeruginosa and to demonstrate potent activity against current MDR isolates of both non-ProteeaeEnterobacteriaceae and P. aeruginosa, further development of imipenem-relebactam appears warranted.
Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Imipenem/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/crescimento & desenvolvimento , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Farmacorresistência Bacteriana Múltipla/fisiologia , Humanos , Laboratórios Hospitalares , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/isolamento & purificação , Estados UnidosRESUMO
Objectives: Relebactam is an inhibitor of class A ß-lactamases, including KPC ß-lactamases, and class C ß-lactamases, and is currently under clinical development in combination with imipenem. The objective of the current study was to evaluate the in vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) submitted by clinical laboratories in 17 European countries to the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance programme in 2015. Methods: MICs were determined using the CLSI standard broth microdilution method and interpreted using EUCAST clinical breakpoints. Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. Imipenem/relebactam MICs were interpreted using breakpoints for imipenem. Results: Rates of susceptibility to imipenem and imipenem/relebactam for isolates of P. aeruginosa (n = 1705), K. pneumoniae (n = 1591) and Enterobacter spp. (n = 772) were 72.0/94.7%, 88.7/94.8% and 95.6/96.8%, respectively. Relebactam restored imipenem susceptibility to 81.1%, 54.2% and 26.5% of imipenem-non-susceptible isolates of P. aeruginosa (n = 477), K. pneumoniae (n = 179) and Enterobacter spp. (n = 34). Most imipenem/relebactam-non-susceptible isolates carried MBLs, OXA-48 or GES carbapenemases. Relebactam did not increase the number of isolates of A. baumannii (n = 486) susceptible to imipenem. Conclusions: Relebactam restored susceptibility to imipenem for the majority of imipenem-non-susceptible isolates of P. aeruginosa and K. pneumoniae tested as well as some isolates of imipenem-non-susceptible Enterobacter spp. Based on our results, imipenem/relebactam appears to be a promising therapeutic option for treating patients with infections caused by antimicrobial-resistant Gram-negative bacilli.
Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Imipenem/farmacologia , Vigilância de Evento Sentinela , Acinetobacter baumannii/efeitos dos fármacos , Proteínas de Bactérias , Enterobacter/efeitos dos fármacos , Europa (Continente) , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Negativas/isolamento & purificação , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia , beta-LactamasesRESUMO
Antimicrobial resistance among Enterobacteriaceae has been increasing globally especially due to extended-spectrum-ß-lactamases (ESBLs), which typically necessitate the use of carbapenems for treatment of serious infections. Emerging carbapenem-resistant Enterobacteriaceae further complicate therapy. As part of the Study for Monitoring Antimicrobial Resistance Trends (SMART), this analysis examined the recent activity of a key carbapenem (ertapenem) and other important therapeutic options against Enterobacteriaceae. From 2012 to 2016, 224 hospitals in 57 countries collected up to 100 consecutive gram-negative bacilli from intra-abdominal (IAI) and 50 from urinary tract infections (UTI) per year, totaling 106,300 Enterobacteriaceae isolates. Susceptibility was determined using CLSI broth microdilution and breakpoints. Although statistically significant decreasing trends in ertapenem activity against Enterobacteriaceae were found in all regions except Middle East, the actual size of the decreases was < 3 percentage points, and susceptibility in 2015-2016 remained ca. 90% or higher, ranging from 89.5% in Asia to 97.3% in US/Canada. Of the comparators, only amikacin exceeded these results. Ertapenem was active against > 90% of isolates with ESBL phenotype from Latin America, Middle East, South Pacific, and US/Canada, and against > 80% of MDR isolates in all regions except Africa (72.9%), Asia (75.1%), and Europe (78.0%). Only imipenem, amikacin, and colistin exceeded these rates. Ertapenem, which is popular among clinicians due to its convenient once-daily dosing schedule and favorable safety and tolerability profile, remains highly active against Enterobacteriaceae from IAI and UTI, even as ESBLs and other resistance mechanisms limit therapeutic options, but continued susceptibility testing for surveillance and individual patients is important.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Infecções por Enterobacteriaceae/microbiologia , Enterobacteriaceae/efeitos dos fármacos , Saúde Global , beta-Lactamas/farmacologia , Infecções por Enterobacteriaceae/epidemiologia , Ertapenem , HumanosRESUMO
Relebactam (formerly MK-7655) is an inhibitor of class A and C ß-lactamases, including Klebsiella pneumoniae carbapenemase (KPC), and is currently in clinical development in combination with imipenem-cilastatin. Using Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution methodology, we evaluated the in vitro activities of imipenem-relebactam, imipenem, and seven routinely tested parenteral antimicrobial agents against Gram-negative ESKAPE pathogens (including Klebsiella pneumoniae, n = 689; Acinetobacter baumannii, n = 72; Pseudomonas aeruginosa, n = 845; and Enterobacter spp., n = 399) submitted by 21 clinical laboratories in the United States in 2015 as part of the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 µg/ml in combination with doubling dilutions of imipenem. Imipenem-relebactam MICs were interpreted using CLSI imipenem breakpoints. The respective rates of susceptibility to imipenem-relebactam and imipenem were 94.2% (796/845) and 70.3% (594/845) for P. aeruginosa, 99.0% (682/689) and 96.1% (662/689) for K. pneumoniae, and 100% (399/399) and 98.0% (391/399) for Enterobacter spp. Relebactam restored imipenem susceptibility to 80.5% (202/251), 74.1% (20/27), and 100% (8/8) of isolates of imipenem-nonsusceptible P. aeruginosa, K. pneumoniae, and Enterobacter spp. Relebactam did not increase the number of isolates of Acinetobacter spp. susceptible to imipenem, and the rates of resistance to all of the agents tested against this pathogen were >30%. Further development of imipenem-relebactam is warranted given the demonstrated ability of relebactam to restore the activity of imipenem against current clinical isolates of Enterobacteriaceae and P. aeruginosa that are nonsusceptible to carbapenems and its potential as a therapy for treating patients with antimicrobial-resistant Gram-negative infections.
Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Imipenem/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Enterobacteriaceae/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
The Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program collected 103,960 isolates of Enterobacteriaceae from 2008 to 2014. From this isolate collection, all ertapenem-nonsusceptible isolates (MIC, ≥1 µg/ml; n = 3,428) and 9,371 isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis with an ertapenem-susceptible extended-spectrum-ß-lactamase (ESBL)-positive phenotype were assessed for the presence of common carbapenemase genes using a Check-MDR CT101 microarray (Check-Points, Wageningen, the Netherlands) and published multiplex PCR assays. Testing identified 1,493 isolates that harbored a carbapenemase gene (1,485 ertapenem-nonsusceptible isolates and 8 ertapenem-susceptible ESBL-positive isolates) and accounted for 1.4% (1,493/103,960) of all isolates of Enterobacteriaceae The most frequently identified carbapenemase genes were the KPC (n = 794), OXA-48-like (n = 300), and NDM (n = 290) genes. Carbapenemase genes were most frequently identified in Klebsiella pneumoniae (n = 1,127), Escherichia coli (n = 149), and Enterobacter cloacae (n = 110). Among the carbapenemase-positive isolates, 66.7% (2/3), 37.0% (111/300), 20.0% (8/40), 3.3% (3/92), 2.3% (18/794), and 0% (0/290) of the isolates with genes for GES, OXA-48-like, IMP, VIM, KPC, and NDM, respectively, were susceptible to imipenem (MIC, ≤1 µg/ml). Isolates that tested as susceptible to imipenem were not uncommon among carbapenemase-positive isolates (9.4%, 141/1,493) and most frequently carried OXA-48-like enzymes (78.7%; 111/141); however, overall, these isolates remained rare (0.1%, 141/103,960). The practice of screening clinical isolates of Enterobacteriaceae that test as susceptible to carbapenems in vitro for the presence of carbapenemase genes remains controversial and requires further study.
Assuntos
Antibacterianos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Imipenem/farmacologia , Proteínas de Bactérias/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Humanos , Testes de Sensibilidade Microbiana , beta-Lactamases/genéticaRESUMO
Objectives Women with longer, healthier pregnancies have more time to enroll in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), biasing associations between WIC and birth outcomes. We examined the association between WIC and preterm birth (PTB), low birth weight (LBW), and perinatal death (PND) using a fetuses-at-risk approach to address this bias, termed gestational age bias. Methods We linked California Medi-Cal recipients with a singleton live birth or fetal death from the 2010 Birth Cohort to WIC participant data (n = 236,564). We implemented a fetuses-at-risk approach using survival analysis, which compared, in each week of gestation, women whose pregnancies reached the same length and who had the same opportunity to utilize WIC. In each gestational week, we assessed WIC enrollment and the number of food packages redeemed thus far and computed hazard ratios (HR) using survival models with time-varying exposures and effects. Results Adjusting for maternal socio-demographic and health characteristics, WIC enrollment was associated with a lower risk of PTB from week 29-36 (HR29 = 0.71; HR36 = 0.52); LBW from week 26-40 (HR26 = 0.77; HR40 = 0.64); and PND from week 29-43 (HR29 = 0.78; HR43 = 0.69) (p < 0.05). The number of food packages redeemed was associated with a lower risk of PTB from week 27-36 (HR27 = 0.90; HR36 = 0.84); LBW from week 25-42 (HR25 = 0.93; HR42 = 0.88); and PND from week 27-46 (HR27 = 0.94; HR46 = 0.91) (p < 0.05). Conclusions for Practice To our knowledge this is the first study to examine the association between WIC and birth outcomes using this approach. We found that beginning from about 29 weeks, WIC enrollment was associated with a reduced risk of PTB by 29-48 %, LBW by 23-36 %, and PND by 22-31 %.
Assuntos
Desenvolvimento Fetal , Assistência Alimentar/estatística & dados numéricos , Saúde Materna/estatística & dados numéricos , Resultado da Gravidez , Adulto , California , Saúde da Criança , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Nascido Vivo , Gravidez , Nascimento Prematuro , Fatores de Risco , Estados UnidosRESUMO
Antimicrobial resistance in Enterobacteriaceae, including resistance to carbapenems, is increasing worldwide. However, using U.S. Study for Monitoring Antimicrobial Resistance Trends (SMART) data for 2009 to 2013, no statistically significant decreasing susceptibility trends were found overall for Escherichia coli isolates from patients with intra-abdominal infections. In the subset of isolates from community-associated infections, susceptibility to levofloxacin decreased significantly and the increasing rate of multidrug-resistant E. coli approached statistical significance. In 2013, ertapenem, imipenem, and amikacin showed the highest susceptibility rates (≥99%) and fluoroquinolones the lowest (<70%). The 10 non-ertapenem-susceptible isolates (0.3% of all E. coli isolates) encoded one or more carbapenemases, extended-spectrum ß-lactamases (ESBLs), AmpC ß-lactamases, or non-ESBL ß-lactamases.
Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções Intra-Abdominais/microbiologia , beta-Lactamas/farmacologia , Ertapenem , Escherichia coli/enzimologia , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Estados Unidos , beta-Lactamases/genética , beta-Lactamases/metabolismoRESUMO
Objectives: To investigate the activities of ceftolozane/tazobactam and imipenem/relebactam against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa isolated from hospitalized patients in Mexico in 2017-2021. Methods: MICs were determined by CLSI broth microdilution and interpreted using CLSI M100 breakpoints. ß-Lactamase genes were identified in ceftolozane/tazobactam-, imipenem/relebactam-, and/or imipenem-non-susceptible isolates. Results: Ceftolozane/tazobactam and imipenem/relebactam inhibited 89% and 99% of E. coli isolates (nâ=â2337), and 87% and 94% of K. pneumoniae isolates (nâ=â1127). Sixty-four percent of E. coli and 47% of K. pneumoniae had an ESBL non-carbapenem-resistant Enterobacterales (ESBL non-CRE) phenotype. Eighty-six percent and 91% of ESBL non-CRE E. coli and K. pneumoniae were ceftolozane/tazobactam susceptible, and 99.9% and 99.8% were imipenem/relebactam susceptible. Ceftolozane/tazobactam was the most active agent studied against P. aeruginosa (nâ=â1068; 83% susceptible), 9-28 percentage points higher than carbapenems and comparator ß-lactams excluding imipenem/relebactam (78% susceptible). Ceftolozane/tazobactam remained active against 35%-58%, and imipenem/relebactam against 32%-42%, of P. aeruginosa in meropenem-, piperacillin/tazobactam-, and cefepime-non-susceptible subsets. The majority of isolates of ceftolozane/tazobactam-non-susceptible E. coli carried an ESBL, whereas among ceftolozane/tazobactam-non-susceptible K. pneumoniae and P. aeruginosa, the majority carried carbapenemases. The most prevalent carbapenemase observed among E. coli (estimated at 0.7% of all isolates), K. pneumoniae (4.8%) and P. aeruginosa (10.0%) was an MBL. Almost all imipenem/relebactam-non-susceptible E. coli and K. pneumoniae carried MBL or OXA-48-like carbapenemases, whereas among imipenem/relebactam-non-susceptible P. aeruginosa, 56% carried MBL or GES carbapenemases. Conclusions: Ceftolozane/tazobactam and imipenem/relebactam may provide treatment options for patients infected with ß-lactam-non-susceptible Gram-negative bacilli, excluding isolates carrying an MBL- or OXA-48-like carbapenemase.
RESUMO
Background: Ongoing national and international surveillance efforts are critical components of antimicrobial stewardship, resistance monitoring, and drug development programs. In this report, we summarize the results of ceftolozane/tazobactam, imipenem/relebactam, ceftazidime/avibactam and comparator agent testing against 10â509 Enterobacterales and 2524 Pseudomonas aeruginosa collected by USA clinical laboratories in 2019-21 as part of the SMART global surveillance programme. Methods: MICs were determined by CLSI broth microdilution and interpreted using 2023 CLSI M100 breakpoints. Results: Most Enterobacterales were ceftazidime/avibactam susceptible (>99%), meropenem susceptible (99%) and ceftolozane/tazobactam susceptible (94%). Non-Morganellaceae Enterobacterales were also highly susceptible to imipenem/relebactam (99%). Ceftolozane/tazobactam inhibited 94% of Escherichia coli and 89% of Klebsiella pneumoniae with ceftriaxone non-susceptible/non-carbapenem-resistant phenotypes. Against P. aeruginosa, ceftolozane/tazobactam (97% susceptible) was more active than ceftazidime/avibactam (95%) and imipenem/relebactam (91%). MDR and difficult-to-treat resistance (DTR) phenotypes were identified in 13% and 7% of P. aeruginosa isolates, respectively. Ceftolozane/tazobactam remained active against 78% of MDR P. aeruginosa (13% and 23% higher than ceftazidime/avibactam and imipenem/relebactam, respectively) and against 74% of DTR P. aeruginosa (24% and 37% higher than ceftazidime/avibactam and imipenem/relebactam, respectively). Length of hospital stay at the time of specimen collection, ward type and infection type resulted in percent susceptible value differences of >5% across isolate demographic strata for some antimicrobial agent/pathogen combinations. Conclusions: We conclude that in the USA, in 2019-21, carbapenem (meropenem) resistance remained uncommon in Enterobacterales and ceftolozane/tazobactam was more active than both ceftazidime/avibactam and imipenem/relebactam against P. aeruginosa.
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Objectives: To describe the in vitro activity of imipenem/relebactam against non-Morganellaceae Enterobacterales (NME) and Pseudomonas aeruginosa recently isolated from lower respiratory tract infection samples by hospital laboratories in Western Europe. Methods: From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 4414 NME and 1995 P. aeruginosa isolates. MICs were determined using the CLSI broth microdilution method and interpreted by EUCAST (2021) breakpoints. ß-Lactamase genes were identified in selected isolate subsets (2018-20) and oprD sequenced in molecularly characterized P. aeruginosa (2020). Results: Imipenem/relebactam (99.1% susceptible), amikacin (97.2%), meropenem (96.1%) and imipenem (95.9%) were the most active agents tested against NME; by country, relebactam increased imipenem susceptibility from <1% (France, Germany, UK) to 11.0% (Italy). A total of 96.0% of piperacillin/tazobactam-resistant (nâ=â990) and 81.1% of meropenem-resistant (nâ=â106) NME were imipenem/relebactam-susceptible. Only 0.5% of NME were MBL positive, 0.9% were OXA-48-like-positive (MBL negative) and 2.8% were KPC positive (MBL negative). Amikacin (91.5% susceptible) and imipenem/relebactam (91.4%) were the most active agents against P. aeruginosa; 72.3% of isolates were imipenem-susceptible. Relebactam increased susceptibility to imipenem by 34.4% (range by country, 39.1%-73.5%) in piperacillin/tazobactam-resistant and by 37.4% (3.1%-40.5%) in meropenem-resistant P. aeruginosa. Only 1.8% of P. aeruginosa isolates were MBL positive. Among molecularly characterized imipenem/relebactam-resistant P. aeruginosa isolates from 2020, 90.9% (30/33) were oprD deficient. Conclusions: Imipenem/relebactam appears to be a potential treatment option for lower respiratory tract infections caused by piperacillin/tazobactam- and meropenem-resistant NME and P. aeruginosa in Western Europe.
RESUMO
Introduction. Piperacillin/tazobactam and carbapenems are important agents for the treatment of serious Gram-negative infections in hospitalized patients. Resistance to both agents is a significant concern in clinical isolates of Enterobacterales and Pseudomonas aeruginosa; new agents with improved activity are needed.Gap Statement. Publication of current, region-specific data describing the in vitro activity of newer agents such as imipenem/relebactam (IMR) against piperacillin/tazobactam-resistant and carbapenem-resistant Enterobacterales and P. aeruginosa are needed to support their clinical use.Aim. To describe the in vitro activity of IMR against non-Morganellaceae Enterobacterales (NME) and P. aeruginosa isolated from bloodstream, intra-abdominal and urinary tract infection samples by hospital laboratories in Western Europe with a focus on the activity of IMR against piperacillin/tazobactam-resistant and meropenem-resistant isolates.Methodology. From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 9487 NME and 1004 P. aeruginosa isolates. MICs were determined by CLSI broth microdilution testing and interpreted by EUCAST (2021) breakpoints. ß-Lactamase genes were identified in selected isolate subsets (2018-2020) and oprD sequenced in molecularly characterized P. aeruginosa (2020).Results. IMR (99.4â% susceptible), amikacin (98.0â%), meropenem (97.7â%) and imipenem (97.6â%) were the most active agents against NME; 83.1â% of NME were piperacillin/tazobactam-susceptible. Relebactam increased imipenem susceptibility of NME from Italy by 8.3â%, from Portugal by 2.9â%, and from France, Germany, Spain and the UK by <1â%. In total, 96.4â% of piperacillin/tazobactam-resistant (n=1601) and 73.7â% of meropenem-resistant (n=152) NME were IMR-susceptible. Also, 0.4â% of NME were MBL-positive, 0.9â% OXA-48-like-positive (MBL-negative) and 1.5â% KPC-positive (MBL-negative). Amikacin (95.4â% susceptible) and IMR (94.1â%) were the most active agents against P. aeruginosa; 81.7â% of isolates were imipenem-susceptible and 79.6â% were piperacillin/tazobactam-susceptible. Relebactam increased susceptibility to imipenem by 12.5â% overall (range by country, 4.3-17.5â%); and by 30.7â% in piperacillin/tazobactam-resistant and 24.3â% in meropenem-resistant P. aeruginosa. In total, 1.6â% of P. aeruginosa isolates were MBL-positive. Seven of eight molecularly characterized IMR-resistant P. aeruginosa isolates from 2020 were oprD-deficient.Conclusion. IMR may be a potential treatment option for bloodstream, intra-abdominal and urinary tract infections caused by NME and P. aeruginosa in Western Europe, including infections caused by piperacillin/tazobactam-resistant and meropenem-resistant isolates.
Assuntos
Infecções por Pseudomonas , Infecções Urinárias , Humanos , Meropeném/farmacologia , Pseudomonas aeruginosa/genética , Amicacina , Antibacterianos/farmacologia , Imipenem , Infecções Urinárias/epidemiologia , Combinação Piperacilina e Tazobactam , Europa (Continente)/epidemiologia , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/epidemiologia , CefalosporinasRESUMO
Multidrug-resistant (MDR) Pseudomonas aeruginosa infections compromise both empirical and definitive antimicrobial therapies. The Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program identified 943 MDR P. aeruginosa (from a total of 4086 P. aeruginosa isolates [23.1%]) collected at 32 clinical laboratories in six countries in Western Europe from 2017 to 2020. Minimum inhibitory concentrations (MICs) for ceftolozane/tazobactam and 10 comparator agents were determined by broth microdilution and interpreted using 2021 EUCAST breakpoints. ß-lactamase genes were identified in selected isolate subsets. Most isolates of P. aeruginosa in Western Europe (93.3%) were ceftolozane/tazobactam-susceptible. A total of 23.1% of P. aeruginosa isolates were MDR. Of these, 72.0% were ceftolozane/tazobactam-susceptible, which is similar to that for ceftazidime/avibactam (73.6%) but >40% higher than for carbapenems, piperacillin/tazobactam, third- and fourth-generation cephalosporins, and levofloxacin. Metallo-ß-lactamases (MBLs) were carried by 8.8% of molecularly characterized MDR P. aeruginosa, and 7.6% of molecularly characterized MDR isolates carried Guiana Extended Spectrum (GES) carbapenemases. MBLs were identified in isolates from all six countries, ranging from 3.2% of all P. aeruginosa isolates from Italy to 0.4% of all isolates from the United Kingdom. Acquired ß-lactamases were not identified in 80.0% of molecularly characterized MDR P. aeruginosa isolates. Percentages of MDR isolates without detected ß-lactamases were higher in the United Kingdom (97.7%), Spain (88.2%), France (88.1%), and Germany (84.7%) than in Portugal (63.0%) and Italy (61.3%), where carbapenemases were more prevalent. Ceftolozane/tazobactam is an important treatment option for patients infected with MDR P. aeruginosa that are not susceptible to first-line antipseudomonal agents.