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1.
Clin Infect Dis ; 78(2): 248-258, 2024 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-37738153

RESUMO

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAb) is 1 of the most problematic antimicrobial-resistant bacteria. We sought to elucidate the international epidemiology and clinical impact of CRAb. METHODS: In a prospective observational cohort study, 842 hospitalized patients with a clinical CRAb culture were enrolled at 46 hospitals in five global regions between 2017 and 2019. The primary outcome was all-cause mortality at 30 days from the index culture. The strains underwent whole-genome analysis. RESULTS: Of 842 cases, 536 (64%) represented infection. By 30 days, 128 (24%) of the infected patients died, ranging from 1 (6%) of 18 in Australia-Singapore to 54 (25%) of 216 in the United States and 24 (49%) of 49 in South-Central America, whereas 42 (14%) of non-infected patients died. Bacteremia was associated with a higher risk of death compared with other types of infection (40 [42%] of 96 vs 88 [20%] of 440). In a multivariable logistic regression analysis, bloodstream infection and higher age-adjusted Charlson comorbidity index were independently associated with 30-day mortality. Clonal group 2 (CG2) strains predominated except in South-Central America, ranging from 216 (59%) of 369 in the United States to 282 (97%) of 291 in China. Acquired carbapenemase genes were carried by 769 (91%) of the 842 isolates. CG2 strains were significantly associated with higher levels of meropenem resistance, yet non-CG2 cases were over-represented among the deaths compared with CG2 cases. CONCLUSIONS: CRAb infection types and clinical outcomes differed significantly across regions. Although CG2 strains remained predominant, non-CG2 strains were associated with higher mortality. Clinical Trials Registration. NCT03646227.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Humanos , Acinetobacter baumannii/genética , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Estudos Prospectivos , Testes de Sensibilidade Microbiana , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/epidemiologia , Infecções por Acinetobacter/microbiologia , beta-Lactamases/genética , Proteínas de Bactérias/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico
2.
Antimicrob Agents Chemother ; 68(5): e0017424, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38557171

RESUMO

Mycobacterium abscessus (MAB) infections pose a growing public health threat. Here, we assessed the in vitro activity of the boronic acid-based ß-lactamase inhibitor, vaborbactam, with different ß-lactams against 100 clinical MAB isolates. Enhanced activity was observed with meropenem and ceftaroline with vaborbactam (1- and >4-fold MIC50/90 reduction). CRISPRi-mediated blaMAB gene knockdown showed a fourfold MIC reduction to ceftaroline but not the other ß-lactams. Our findings demonstrate vaborbactam's potential in combination therapy against MAB infections.


Assuntos
Antibacterianos , Ácidos Borônicos , Cefoxitina , Ceftarolina , Cefalosporinas , Imipenem , Meropeném , Testes de Sensibilidade Microbiana , Mycobacterium abscessus , Mycobacterium abscessus/efeitos dos fármacos , Meropeném/farmacologia , Ácidos Borônicos/farmacologia , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Imipenem/farmacologia , Cefoxitina/farmacologia , Humanos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Inibidores de beta-Lactamases/farmacologia
3.
Antimicrob Agents Chemother ; 68(4): e0134623, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38426743

RESUMO

We evaluated the in vitro activity of meropenem-vaborbactam plus aztreonam (MEV-ATM) against 140 metallo-ß-lactamase (MBL)-producing Klebsiella pneumoniae isolates. Among them, 25 isolates (17.9%) displayed minimum inhibitory concentrations (MIC) ≥ 8 µg/mL, while 112 (80.0%) had MIC ≤ 2 µg/mL. Genomic analysis and subsequent gene cloning experiments revealed OmpK36 134-135GD-insertion and increased carbapenemase gene (blaNDM-1 and blaOXA-48-like) copy numbers are the main factors responsible for MEV-ATM non-susceptibility. Notably, MEV-ATM is actively against aztreonam-avibactam-resistant mutants due to CMY-16 mutations.


Assuntos
Antibacterianos , Aztreonam , Ácidos Borônicos , Meropeném/farmacologia , Aztreonam/farmacologia , Antibacterianos/farmacologia , Klebsiella pneumoniae/genética , beta-Lactamases/genética , Combinação de Medicamentos , Testes de Sensibilidade Microbiana , Compostos Azabicíclicos/farmacologia
4.
Antimicrob Agents Chemother ; 68(10): e0077024, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39287402

RESUMO

Gram-negatives harboring metallo-ß-lactamases (MBLs) and extended-spectrum ß-lactamases (ESBLs) pose a substantial risk to the public health landscape. In ongoing efforts to combat these "superbugs," we explored the clinical combination of aztreonam and ceftazidime/avibactam together with varying dosages of polymyxin B and imipenem against Klebsiella pneumoniae (Kp CDC Nevada) in a 9-day hollow fiber infection model (HFIM). As previously reported by our group, although the base of aztreonam and ceftazidime/avibactam alone leads to 3.34 log10 fold reductions within 72 hours, addition of polymyxin B or imipenem to the base regimen caused maximal killing of 7.55 log10 and 7.4 log10 fold reduction, respectively, by the 72-hour time point. Although low-dose polymyxin B and imipenem enhanced the bactericidal activity as an adjuvant to aztreonam +ceftazidime/avibactam, regrowth to ~9 log10CFU/mL by 216 hours rendered these combinations ineffective. When aztreonam +ceftazidime/avibactam was supplemented with high-dose polymyxin B and or low-dose polymyxin B + imipenem, it resulted in effective long-term clearance of the bacterial population. Time lapse microscopy profiled the emergence of long filamentous cells in response to PBP3 binding due to aztreonam and ceftazidime. The emergence of spheroplasts via imipenem and damage to the outer membrane via polymyxin B was visualized as a mechanism of persister killing. Despite intrinsic mgrB and blaNDM-1 resistance, polymyxin B and ß-lactam combinations represent a promising strategy. Future studies using an integrated molecularly precise pharmacodynamic approach are warranted to unravel the mechanistic details to propose optimal antibiotic combinations to combat untreatable, pan-drug-resistant Gram-negatives.


Assuntos
Antibacterianos , Compostos Azabicíclicos , Aztreonam , Ceftazidima , Combinação de Medicamentos , Imipenem , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Polimixina B , beta-Lactamases , Klebsiella pneumoniae/efeitos dos fármacos , beta-Lactamases/metabolismo , beta-Lactamases/genética , Compostos Azabicíclicos/farmacologia , Antibacterianos/farmacologia , Ceftazidima/farmacologia , Aztreonam/farmacologia , Polimixina B/farmacologia , Imipenem/farmacologia , Humanos , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Farmacorresistência Bacteriana Múltipla/genética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Quimioterapia Combinada
5.
Antimicrob Agents Chemother ; 68(10): e0020824, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39162528

RESUMO

We characterized the molecular determinants of meropenem-vaborbactam (MV) non-susceptibility among non-metallo-ß-lactamase-producing KPC-Klebsiella pneumoniae (KPC-KP). Whole-genome sequencing was performed to identify mutations associated with MV non-susceptibility. Isolates with elevated MV MICs were found to have mutations encoding truncated or altered OmpK36 porins and increased blaKPC copy numbers. KPC-KP isolates with decreased susceptibility to MV were detected among a collection of isolates predating the availability of MV.


Assuntos
Antibacterianos , Proteínas de Bactérias , Ácidos Borônicos , Klebsiella pneumoniae , Meropeném , Testes de Sensibilidade Microbiana , Sequenciamento Completo do Genoma , beta-Lactamases , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Meropeném/farmacologia , beta-Lactamases/genética , beta-Lactamases/metabolismo , Antibacterianos/farmacologia , Ácidos Borônicos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Porinas/genética , Porinas/metabolismo , Humanos , Mutação , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/tratamento farmacológico , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/genética , Compostos Heterocíclicos com 1 Anel
6.
Eur J Clin Microbiol Infect Dis ; 43(2): 389-393, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38062176

RESUMO

The OXA-48-producing hypervirulent Klebsiella pneumoniae (hvKP) strains were rarely reported. In this study, we characterized three carbapenem-resistant hvKP strains (KP2185, NCRE61, and KP2683-1) isolated from renal abscess, scrotal abscess, and blood samples in a Taiwan hospital. The three strains belonged to two different clones: ST23 K1 (KP2683-1) and ST11 KL64 (KP2185 and NCRE61). KP2683-1 exhibited the highest virulence in an in vivo model. Whole-genome sequencing analysis showed that KP2185 and NCRE61 acquired IncFIB type plasmids containing a set of virulence genes (iroBCDN, iucABCD, rmpA, rmpA2, and iutA), while KP2683-1 acquired an IncL type plasmid harboring blaOXA-48.


Assuntos
Infecções por Klebsiella , beta-Lactamases , Humanos , beta-Lactamases/genética , Klebsiella pneumoniae , Taiwan/epidemiologia , Abscesso , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/microbiologia , Plasmídeos/genética , Antibacterianos/farmacologia
7.
Nucleic Acids Res ; 50(10): 5739-5756, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35639764

RESUMO

The spread of drug-resistant bacteria represents one of the most significant medical problems of our time. Bacterial fitness loss associated with drug resistance can be counteracted by acquisition of secondary mutations, thereby enhancing the virulence of such bacteria. Antibiotic rifampicin (Rif) targets cellular RNA polymerase (RNAP). It is potent broad spectrum drug used for treatment of bacterial infections. We have investigated the compensatory mechanism of the secondary mutations alleviating Rif resistance (Rifr) on biochemical, structural and fitness indices. We find that substitutions in RNAP genes compensating for the growth defect caused by ßQ513P and ßT563P Rifr mutations significantly enhanced bacterial relative growth rate. By assaying RNAP purified from these strains, we show that compensatory mutations directly stimulated basal transcriptional machinery (2-9-fold) significantly improving promoter clearance step of the transcription pathway as well as elongation rate. Molecular modeling suggests that compensatory mutations affect transcript retention, substrate loading, and nucleotidyl transfer catalysis. Strikingly, one of the identified compensatory substitutions represents mutation conferring rifampicin resistance on its own. This finding reveals an evolutionary process that creates more virulent species by simultaneously improving the fitness and augmenting bacterial drug resistance.


Assuntos
Escherichia coli , Rifampina , Antibacterianos/farmacologia , Catálise , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/metabolismo , Farmacorresistência Bacteriana/genética , Escherichia coli/metabolismo , Mutação , Rifampina/farmacologia
8.
Clin Infect Dis ; 77(4): 499-509, 2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37154071

RESUMO

BACKGROUND: Carbapenemase-producing (CP) Escherichia coli (CP-Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from several countries with CP-Ec isolates obtained from a prospective cohort. METHODS: Patients with CP-Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-ß-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture. RESULTS: Of the 114 CP-Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly blaNDM-5 (38/49, 78%). Strong regional variations were noted with MBL-Ec predominantly found among patients in China (23/49). Clinically, MBL-Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P = .04), and had lower acuity of illness when compared with non-MBL-Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL-Ec as compared with non-MBL-Ec was 62% (95% CI: 48.2-74.3%). Among infected patients, non-MBL-Ec had increased 30-day (26% vs 0%; P = .02) and 90-day (39% vs 0%; P = .001) mortality compared with MBL-Ec. CONCLUSIONS: Emergence of CP-Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL-Ec and non-MBL-Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , beta-Lactamases , Humanos , Estudos Prospectivos , beta-Lactamases/genética , Escherichia coli/genética , Proteínas de Bactérias/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana
9.
Clin Infect Dis ; 76(2): 229-237, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36173830

RESUMO

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated CRKp clustering in patients in US hospitals. METHODS: From April 2016 to August 2017, 350 patients with clonal group 258 CRKp were enrolled in the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae, a prospective, multicenter, cohort study. A maximum likelihood tree was constructed using RAxML. Static clusters shared ≤21 single-nucleotide polymorphisms (SNP) and a most recent common ancestor. Dynamic clusters incorporated SNP distance, culture timing, and rates of SNP accumulation and transmission using the R program TransCluster. RESULTS: Most patients were admitted from home (n = 150, 43%) or long-term care facilities (n = 115, 33%). Urine (n = 149, 43%) was the most common isolation site. Overall, 55 static and 47 dynamics clusters were identified involving 210 of 350 (60%) and 194 of 350 (55%) patients, respectively. Approximately half of static clusters were identical to dynamic clusters. Static clusters consisted of 33 (60%) intrasystem and 22 (40%) intersystem clusters. Dynamic clusters consisted of 32 (68%) intrasystem and 15 (32%) intersystem clusters and had fewer SNP differences than static clusters (8 vs 9; P = .045; 95% confidence interval [CI]: -4 to 0). Dynamic intersystem clusters contained more patients than dynamic intrasystem clusters (median [interquartile range], 4 [2, 7] vs 2 [2, 2]; P = .007; 95% CI: -3 to 0). CONCLUSIONS: Widespread intrasystem and intersystem transmission of CRKp was identified in hospitalized US patients. Use of different methods for assessing genetic similarity resulted in only minor differences in interpretation.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Infecções por Klebsiella , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Klebsiella pneumoniae/genética , Estudos de Coortes , Estudos Prospectivos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/tratamento farmacológico , Carbapenêmicos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Hospitais , Farmacorresistência Bacteriana
10.
Eur J Clin Microbiol Infect Dis ; 42(10): 1173-1181, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37597051

RESUMO

PURPOSE: To identify the predictors of morbidity and mortality in matched COVID-19 positive and negative patients who were septic with Gram positive or Gram negative infections. METHODS: We conducted a retrospective review, from March to October 2020, of matched septic patients at five Hackensack Meridian Health hospitals who had bacteremia with Staphylococcus aureus, Klebsiella pneumoniae or Escherichia coli with and without COVID-19. We extracted patient demographics, comorbidities and clinical outcomes data using ICD-10 codes. Bacterial isolates were compared by whole genome sequencing analysis. Multivariate logistic regression was used to analyze independent predictors of morbidity and mortality. RESULTS: A total of 208 patients were grouped by positive bloodstream infection (BSI) with COVID-19 (n = 104) and without COVID-19 (n = 104). Most patients were over age 50 (90% vs. 89%) and Caucasian (78% vs. 86%). Inpatient mortality was higher in patients with COVID-19 for both GP (35% vs. 8%, p < 0.05) and GN (28% vs. 10%, p < 0.05) BSIs. Patients with Gram positive (GP) BSIs had a significant increase in mortality risk (OR 4.5, CI 1.4-14.5, p < 0.05) in contrast to those with Gram negative (GN) infections (OR 0.4, CI 0.4-4.0, p = 0.4). CONCLUSION: Concurrent COVID-19 infection is associated with a significant increase in morbidity and mortality in patients with GP and GN BSIs. Patients with S. aureus BSIs with COVID-19 are more likely to develop shock and respiratory failure and have higher rates and odds of mortality than those without COVID-19. These findings provide an essential insight into the care of these patients, especially those co-infected with Staphylococcus aureus.


Assuntos
Bacteriemia , COVID-19 , Sepse , Infecções Estafilocócicas , Humanos , Pessoa de Meia-Idade , Staphylococcus aureus , COVID-19/complicações , Sepse/complicações , Sepse/epidemiologia , Bacteriemia/complicações , Bacteriemia/epidemiologia , Pacientes Internados , Escherichia coli
11.
BMC Infect Dis ; 23(1): 399, 2023 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-37308817

RESUMO

Staphylococcus aureus is among the top three causative agents of nosocomial infection in Ethiopia. The majority of studies in Ethiopia have focused on the epidemiology of S. aureus in hospital settings, with limited molecular genotyping results. Molecular characterization of S. aureus is essential for identification of strains, and contributes to the control and prevention of S. aureus infection. The aim of the current study was to determine the molecular epidemiology of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) isolates recovered from clinical specimens in Ethiopia. A total of 161 MSSA and 9 MRSA isolates were characterized using pulsed-field gel electrophoresis (PFGE) and staphylococcal protein A (spa) typing. Based on the PFGE analysis, MSSA isolates were grouped into eight pulso-types groups (from A to I), while MRSA isolates clustered into three (A, B and C) pulso-types with more than 80% similarity. The spa typing analysis showed diversity of S. aureus with 56 distinct spa types. Spa type t355 was most prevalent (56/170, 32.9%), while eleven new spa types were detected including t20038, t20039, and t20042. The identified spa types were clustered into 15 spa-clonal complexes (spa-CCs) using BURP analysis; novel/unknown spa types were further subjected to MLST analysis. The majority of isolates belonged to spa-CC 152 (62/170, 36.4%), followed by spa-CC 121 (19/170, 11.2%), and spa-CC 005 (18 /170, 10.6%). Of the nine MRSA isolates, 2 (22.2%) were spa-CC 239 with staphylococcal cassette chromosome (SCC)mec III. These findings highlight the diversity of S. aureus strains in Ethiopia, as well as the presence of potentially epidemic strains circulating in the country necessitating further characterization of S. aureus for antimicrobial resistance detection and infection prevention purposes.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Etiópia , Tipagem de Sequências Multilocus , Instalações de Saúde
12.
Clin Infect Dis ; 74(3): 395-406, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33970222

RESUMO

BACKGROUND: Multidrug-resistant Enterobacterales (MDR-E), including carbapenem-resistant and third-generation cephalosporin-resistant Enterobacterales (CRE, CefR-E), are major pathogens following solid organ transplantation (SOT). METHODS: We prospectively studied patients who underwent lung, liver, and small bowel transplant from February 2015 through March 2017. Weekly perirectal swabs (up to 100 days post-transplant) were cultured for MDR-E. Whole-genome sequencing (WGS) was performed on gastrointestinal (GI) tract-colonizing and disease-causing isolates. RESULTS: Twenty-five percent (40 of 162) of patients were MDR-E GI-colonized. Klebsiella pneumoniae was the most common CRE and CefR-E. Klebsiella pneumoniae carbapenemases and CTX-M were leading causes of CR and CefR, respectively. Thirty-five percent of GI colonizers developed MDR-E infection vs 2% of noncolonizers (P < .0001). The attack rate was higher among CRE colonizers than CefR-E colonizers (53% vs 21%, P = .049). GI colonization and high body mass index were independent risk factors for MDR-E infection (P ≤ .004). Thirty-day mortality among infected patients was 6%. However, 44% of survivors developed recurrent infections; 43% of recurrences were late (285 days to 3.9 years after the initial infection). Long-term survival (median, 4.3 years post-transplant) did not differ significantly between MDR-E-infected and MDR-E-noninfected patients (71% vs 77%, P = .56). WGS phylogenetic analyses revealed that infections were caused by GI-colonizing strains and suggested unrecognized transmission of novel clonal group-258 sublineage CR-K. pneumoniae and horizontal transfer of resistance genes. CONCLUSIONS: MDR-E GI colonization was common following SOT and predisposed patients to infections by colonizing strains. MDR-E infections were associated with low short- and long-term mortality, but recurrences were frequent and often occurred years after initial infections. Findings provide support for MDR-E surveillance in our SOT program.


Assuntos
Transplante de Órgãos , Transplantados , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos , Humanos , Klebsiella pneumoniae/genética , Epidemiologia Molecular , Transplante de Órgãos/efeitos adversos , Filogenia
13.
Clin Infect Dis ; 75(5): 768-776, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34984435

RESUMO

BACKGROUND: Evidence describing the impact of diabetes mellitus (DM) on the recurrence and mutation rate of Mycobacterium tuberculosis (Mtb) is limited. METHODS: This study was nested in 3 cohort studies of tuberculosis (TB) patients with and without DM in India. Paired Mtb isolates recovered at baseline and treatment failure/recurrence underwent whole genome sequencing. We compared acquisition of single-nucleotide polymorphisms (SNPs), TB drug resistance mutations, and type of recurrence (endogenous reactivation [<8 SNPs] or exogenous reinfection [≥8 SNPs]) by DM status. RESULTS: Of 1633 enrolled in the 3 parent cohorts, 236 (14.5%) had microbiologically confirmed TB treatment failure/recurrence; 76 Mtb isolate pairs were available for sequencing (22 in TB-DM and 54 in TB-only). The SNP acquisition rate was overall was 0.43 (95% confidence interval [CI], .25-.64) per 1 person-year (PY); 0.77 (95% CI, .40-1.35) per 1 PY, and 0.44 (95% CI, .19-.86) per 1 PY at treatment failure and recurrence, respectively. Significant difference in SNP rates by DM status was seen at recurrence (0.21 [95% CI, .04-.61]) per 1 PY for TB-only vs 1.28 (95% CI, .41-2.98) per 1 PY for TB-DM; P = .02). No significant difference in SNP rates by DM status was observed at treatment failure. Acquired TB drug resistance was seen in 4 of 18 (22%) in TB-DM vs 4 of 45 (9%) in TB-only (P = .21). Thirteen (17%) participants had exogenous reinfection; the reinfection rate at recurrence was 25% (3/12) for TB-DM vs 17% (4/24) in TB-only (P = .66). CONCLUSIONS: Considerable intrahost Mtb mutation rates were present at recurrence among patients with DM in India. One-fourth of patients with DM had exogenous reinfection at recurrence.


Assuntos
Diabetes Mellitus , Mycobacterium tuberculosis , Tuberculose , Humanos , Diabetes Mellitus/epidemiologia , Índia/epidemiologia , Mutação , Mycobacterium tuberculosis/genética , Recidiva , Reinfecção , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose/microbiologia , Sequenciamento Completo do Genoma
14.
Clin Infect Dis ; 75(12): 2066-2075, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-35522019

RESUMO

BACKGROUND: Patients with bacteremia due to carbapenem-resistant Enterobacterales (CRE) experience delays until appropriate therapy and high mortality rates. Rapid molecular diagnostics for carbapenemases and new ß-lactam/ß-lactamase inhibitors may improve outcomes. METHODS: We conducted an observational study of patients with CRE bacteremia from 2016 to 2018 at 8 New York and New Jersey medical centers and assessed center-specific clinical microbiology practices. We compared time to receipt of active antimicrobial therapy and mortality between patients whose positive blood cultures underwent rapid molecular testing for the Klebsiella pneumoniae carbapenemase (KPC) gene (blaKPC) and patients whose cultures did not undergo this test. CRE isolates underwent antimicrobial susceptibility testing by broth microdilution and carbapenemase profiling by whole-genome sequencing. We also assessed outcomes when ceftazidime-avibactam and polymyxins were used as targeted therapies. RESULTS: Of 137 patients with CRE bacteremia, 89 (65%) had a KPC-producing organism. Patients whose blood cultures underwent blaKPC PCR testing (n = 51) had shorter time until receipt of active therapy (median: 24 vs 50 hours; P = .009) compared with other patients (n = 86) and decreased 14-day (16% vs 37%; P = .007) and 30-day (24% vs 47%; P = .007) mortality. blaKPC PCR testing was associated with decreased 30-day mortality (adjusted odds ratio: .37; 95% CI: .16-.84) in an adjusted model. The 30-day mortality rate was 10% with ceftazidime-avibactam monotherapy and 31% with polymyxin monotherapy (P = .08). CONCLUSIONS: In a KPC-endemic area, blaKPC PCR testing of positive blood cultures was associated with decreased time until appropriate therapy and decreased mortality for CRE bacteremia, and ceftazidime-avibactam is a reasonable first-line therapy for these infections.


Assuntos
Bacteriemia , Infecções por Klebsiella , Humanos , Klebsiella pneumoniae , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Infecções por Klebsiella/tratamento farmacológico , Ceftazidima/uso terapêutico , beta-Lactamases/genética , Proteínas de Bactérias/genética , Compostos Azabicíclicos/uso terapêutico , Combinação de Medicamentos , Inibidores de beta-Lactamases/uso terapêutico , Bacteriemia/tratamento farmacológico , Testes de Sensibilidade Microbiana
15.
Emerg Infect Dis ; 28(5)2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35451367

RESUMO

We describe the global molecular epidemiology of 229 carbapenemase-producing Escherichia coli in 36 countries during 2015-2017. Common carbapenemases were oxacillinase (OXA) 181 (23%), New Delhi metallo-ß-lactamase (NDM) 5 (20%), OXA-48 (17%), Klebsiella pneumoniae carbapenemase 2 (15%), and NDM-1 (10%). We identified 5 dominant sequence types (STs); 4 were global (ST410, ST131, ST167, and ST405), and 1 (ST1284) was limited to Turkey. OXA-181 was frequent in Jordan (because of the ST410-B4/H24RxC subclade) and Turkey (because of ST1284). We found nearly identical IncX3-blaOXA-181 plasmids among 11 STs from 12 countries. NDM-5 was frequent in Egypt, Thailand (linked with ST410-B4/H24RxC and ST167-B subclades), and Vietnam (because of ST448). OXA-48 was common in Turkey (linked with ST11260). Global K. pneumoniae carbapenemases were linked with ST131 C1/H30 subclade and NDM-1 with various STs. The global carbapenemase E. coli population is dominated by diverse STs with different characteristics and varied geographic distributions, requiring ongoing genomic surveillance.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Infecções por Escherichia coli , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Escherichia coli/genética , Infecções por Escherichia coli/epidemiologia , Humanos , Klebsiella pneumoniae/genética , Testes de Sensibilidade Microbiana , beta-Lactamases/genética
16.
Antimicrob Agents Chemother ; 66(4): e0009322, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35311518

RESUMO

We utilized a CRISPR interference (CRISPRi) assay to control the gene expressions of two predicted essential peptidoglycan biosynthesis genes, pbpB and cwIM, in Mycobacterium abscessus and to evaluate their contribution to ß-lactam susceptibility. Our results showed that CRISPR inhibition of each gene led to a significant 3-log10 reduction in CFU in the presence of imipenem but not for cefoxitin. These results demonstrate that CRISPRi provides an experimental approach to study drug/target interactions in M. abscessus.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Antibacterianos/farmacologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium abscessus/genética , Peptidoglicano/genética , beta-Lactamas/farmacologia
17.
Antimicrob Agents Chemother ; 66(9): e0041422, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-35972242

RESUMO

Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, we describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2-oxa-8-azaspiro[4.5]decan-3-yl)methanol], which was developed to target both ATP-binding regions of DNA gyrase (GyrB) and topoisomerase (ParE). JSF-2414 displays potent activity against N. gonorrhoeae, including drug-resistant strains. A phosphate pro-drug, JSF-2659, was developed to facilitate oral dosing. In two different animal models of Neisseria gonorrhoeae vaginal infection, JSF-2659 was highly efficacious in reducing microbial burdens to the limit of detection. The parent molecule also showed potent in vitro activity against high-threat Gram-positive organisms, and JSF-2659 was shown in a deep tissue model of vancomycin-resistant Staphylococcus aureus (VRSA) and a model of Clostridioides difficile-induced colitis to be highly efficacious and protective. JSF-2659 is a novel preclinical drug candidate against high-threat multidrug resistant organisms with low potential to develop new resistance.


Assuntos
Gonorreia , Staphylococcus aureus Resistente à Meticilina , Pró-Fármacos , Trifosfato de Adenosina , Animais , Antibacterianos/química , Antibacterianos/farmacologia , DNA Girase/genética , Farmacorresistência Bacteriana , Feminino , Gonorreia/tratamento farmacológico , Metanol/farmacologia , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae , Fosfatos/farmacologia , Pró-Fármacos/farmacologia , Inibidores da Topoisomerase II/farmacologia
18.
Antimicrob Agents Chemother ; 66(9): e0052722, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-35924913

RESUMO

Metallo-ß-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM). A novel de-escalation approach to polymyxin B dosing was also explored, whereby a standard 0-h loading dose was followed by maintenance doses that were 50% of the typical clinical regimen. In the HFIM, the addition of polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing, leading to eradication, including for the novel de-escalation dosing strategy. Serial samples from the growth control and monotherapies were explored in a Galleria mellonella virulence model to assess virulence changes. Weibull regression showed that low-level ceftazidime resistance and treatment with monotherapy resulted in increased G. mellonella mortality (P < 0.05). A neutropenic rabbit pneumonia model demonstrated that aztreonam plus ceftazidime-avibactam with or without polymyxin B resulted in similar bacterial killing, and these combination therapies were statistically significantly better than monotherapies (P < 0.05). However, only the polymyxin B-containing combination therapy produced a statistically significant decrease in lung weights (P < 0.05), indicating a decreased inflammatory process. Altogether, adding polymyxin B to the combination of aztreonam plus ceftazidime-avibactam for NDM- and CTX-M-producing K. pneumoniae improved bacterial killing effects, reduced lung inflammation, suppressed resistance amplification, and limited virulence changes.


Assuntos
Ceftazidima , Klebsiella pneumoniae , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Aztreonam/farmacologia , Ceftazidima/farmacologia , Ceftazidima/uso terapêutico , Parede Celular/metabolismo , Combinação de Medicamentos , Klebsiella/metabolismo , Testes de Sensibilidade Microbiana , Polimixina B/farmacologia , Coelhos , beta-Lactamases/metabolismo
19.
Antimicrob Agents Chemother ; 66(9): e0068822, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36066237

RESUMO

Patients with burn injuries are at high risk for infectious complications, and infections are the most common cause of death after the first 72 h of hospitalization. Hospital-acquired infections caused by multidrug resistant (MDR) Gram-negative bacteria (GNB) in this population are concerning. Here, we evaluated carriage with MDR GNB in patients in a large tertiary-care burn intensive care unit. Twenty-nine patients in the burn unit were screened for intestinal carriage. Samples were cultured on selective media. Median time from admission to the burn unit to first sample collection was 9 days (IQR 5 - 17 days). In 21 (72%) patients, MDR GNB were recovered; the most common bacterial species isolated was Pseudomonas aeruginosa, which was found in 11/29 (38%) of patients. Two of these patients later developed bloodstream infections with P. aeruginosa. Transmission of KPC-31-producing ST22 Citrobacter freundii was detected. Samples from two patients grew genetically similar C. freundii isolates that were resistant to ceftazidime-avibactam. On analysis of whole-genome sequencing, blaKPC-31 was part of a Tn4401b transposon that was present on two different plasmids in each C. freundii isolate. Plasmid curing experiments showed that removal of both copies of blaKPC-31 was required to restore susceptibility to ceftazidime-avibactam. In summary, MDR GNB colonization is common in burn patients and patient-to-patient transmission of highly resistant GNB occurs. These results emphasize the ongoing need for infection prevention and antimicrobial stewardship efforts in this highly vulnerable population.


Assuntos
Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/uso terapêutico , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/genética , beta-Lactamases/uso terapêutico
20.
J Antimicrob Chemother ; 77(12): 3399-3407, 2022 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-36204996

RESUMO

BACKGROUND: Escherichia coli ST410 is an emerging MDR clone linked to blaCTX-M-15 and blaOXA-181. Limited comprehensive data about the global distribution of ST410 clades and mobile genetic elements associated with different ß-lactamases are available. METHODS: Short- and long-read WGS were performed on a collection of ST410 producing carbapenemases (n = 45) obtained from 11 countries. The evolutionary history of global E. coli ST410 was also investigated. RESULTS: OXA-181 and NDM-5 were the most frequent carbapenemases and used different underlying strategies to ensure their successful association with ST410 clades. Our phylogenetic analysis of publicly available ST410 genomes amended the previously published ST410 B subclades: ST410-B1 is identical to B1/H24, ST410-B2 includes B2/H24R and B3/H24Rx, while ST410-B3 corresponds to B4/H24RxC. Long-read WGS identified the following genomic events that likely shaped the evolution of ST410-B3: (i) gyrA and parC mutations were acquired via homologous recombination events; (ii) chromosomal integration of blaCMY-2 among ST410-B3; (iii) the emergence of ST410-B3 from ST410-B2 was accompanied by the replacement of IncFII plasmids harbouring blaCTX-M-15 (i.e. F36:31:A4:B1 in ST410-B2 with F1:A1:B49 plasmids in ST410-B3); and (iv) the NDM-5 gene was integrated within F1:A1:B49 plasmids over time. CONCLUSIONS: The global ST410 population producing carbapenemases is dominated by the ST410-B2 and B3 subclades with varied geographical distribution that requires ongoing genomic surveillance. We provided an updated timeline of pivotal genomic events that have shaped the success of the ST410-B3 subclade.


Assuntos
Infecções por Escherichia coli , Escherichia coli , Humanos , Escherichia coli/genética , Filogenia , Infecções por Escherichia coli/epidemiologia , beta-Lactamases/genética , Plasmídeos/genética , Genômica , Antibacterianos
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