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1.
Ann Clin Microbiol Antimicrob ; 23(1): 61, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965586

RESUMO

OBJECTIVES: The emergence of multidrug-resistant (MDR) Salmonella strains, especially resistant ones toward critically important antimicrobial classes such as fluoroquinolones and third- and fourth-generation cephalosporins, is a growing public health concern. The current study, therefore, aimed to determine the prevalence, and existence of virulence genes (invA, stn, and spvC genes), antimicrobial resistance profiles, and the presence of ß-lactamase resistance genes (blaOXA, blaCTX-M1, blaSHV, and blaTEM) in Salmonella strains isolated from native chicken carcasses in Egypt marketed in Mansoura, Egypt, as well as spotlight the risk of isolated MDR, colistin-, cefepime-, and levofloxacin-resistant Salmonella enterica serovars to public health. METHODS: One hundred fifty freshly dressed native chicken carcasses were collected from different poultry shops in Mansoura City, Egypt between July 2022 and November 2022. Salmonella isolation was performed using standard bacteriological techniques, including pre-enrichment in buffered peptone water (BPW), selective enrichment in Rappaport Vassiliadis broth (RVS), and cultivating on the surface of xylose-lysine-desoxycholate (XLD) agar. All suspected Salmonella colonies were subjected to biochemical tests, serological identification using slide agglutination test, and Polymerase Chain Reaction (PCR) targeting the invasion A gene (invA; Salmonella marker gene). Afterward, all molecularly verified isolates were screened for the presence of virulence genes (stn and spvC). The antimicrobial susceptibility testing for isolated Salmonella strains towards the 16 antimicrobial agents tested was analyzed by Kirby-Bauer disc diffusion method, except for colistin, in which the minimum inhibition concentration (MIC) was determined by broth microdilution technique. Furthermore, 82 cefotaxime-resistant Salmonella isolates were tested using multiplex PCR targeting the ß-lactamase resistance genes, including blaOXA, blaCTX-M1, blaSHV, and blaTEM genes. RESULTS: Salmonella enterica species were molecularly confirmed via the invA Salmonella marker gene in 18% (27/150) of the freshly dressed native chicken carcasses. Twelve Salmonella serotypes were identified among 129 confirmed Salmonella isolates with the most predominant serotypes were S. Kentucky, S. Enteritidis, S. Typhimurium, and S. Molade with an incidence of 19.4% (25/129), 17.1% (22/129), 17.1% (22/129), and 10.9% (14/129), respectively. All the identified Salmonella isolates (n = 129) were positive for both invA and stn genes, while only 31.8% (41/129) of isolates were positive for the spvC gene. One hundred twenty-one (93.8%) of the 129 Salmonella-verified isolates were resistant to at least three antibiotics. Interestingly, 3.9%, 14.7%, and 75.2% of isolates were categorized into pan-drug-resistant, extensively drug-resistant, and multidrug-resistant, respectively. The average MAR index for the 129 isolates tested was 0.505. Exactly, 82.2%, 82.2%, 63.6%, 51.9%, 50.4%, 48.8%, 11.6%, and 10.1% of isolated Salmonella strains were resistant to cefepime, colistin, cefotaxime, ceftazidime/clavulanic acid, levofloxacin, ciprofloxacin, azithromycin, and meropenem, respectively. Thirty-one out (37.8%) of the 82 cefotaxime-resistant Salmonella isolates were ß-lactamase producers with the blaTEM as the most predominant ß-lactamase resistance gene, followed by blaCTX-M1 and blaOXA genes, which were detected in 21, 16, and 14 isolates respectively). CONCLUSION: The high prevalence of MDR-, colistin-, cefepime-, and levofloxacin-resistant Salmonella serovars among Salmonella isolates from native chicken is alarming as these antimicrobials are critically important in treating severe salmonellosis cases and boost the urgent need for controlling antibiotic usage in veterinary and human medicine to protect public health.


Assuntos
Antibacterianos , Cefepima , Galinhas , Colistina , Farmacorresistência Bacteriana Múltipla , Levofloxacino , Testes de Sensibilidade Microbiana , Salmonella enterica , Sorogrupo , Animais , Egito , Salmonella enterica/efeitos dos fármacos , Salmonella enterica/genética , Salmonella enterica/isolamento & purificação , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Colistina/farmacologia , Levofloxacino/farmacologia , Cefepima/farmacologia , beta-Lactamases/genética , Fatores de Virulência/genética , Proteínas de Bactérias/genética , Salmonelose Animal/microbiologia , Humanos
2.
Microbiol Spectr ; 12(7): e0070424, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38860818

RESUMO

The impact of chromosomally encoded wild-type or extended-spectrum (ESAC) AmpC ß-lactamases of Escherichia coli on susceptibility to ceftazidime, cefepime, and cefiderocol was evaluated in different genetic backgrounds, including wild-type, PBP3-modified, and porin-deficient E. coli strains. Recombinant E. coli strains possessing the different backgrounds and producing variable ESACs were evaluated. Although ESAC enzymes conferred resistance to ceftazidime and decreased susceptibility to cefepime as expected, we showed here that cefiderocol was also a substrate of ESAC enzymes. IMPORTANCE: We showed here that chromosomally encoded intrinsic extended-spectrum cephalosporinases of Escherichia coli may impact susceptibility not only to ceftazidime and cefepime but also to cefiderocol.


Assuntos
Antibacterianos , Proteínas de Bactérias , Cefiderocol , Cefalosporinas , Escherichia coli , Testes de Sensibilidade Microbiana , beta-Lactamases , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , beta-Lactamases/genética , beta-Lactamases/metabolismo , Cefalosporinas/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Ceftazidima/farmacologia , Cromossomos Bacterianos/genética , Cefepima/farmacologia
3.
Ann Intern Med ; 177(6): JC67, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38830218

RESUMO

SOURCE CITATION: Wagenlehner FM, Gasink LB, McGovern PC, et al; CERTAIN-1 Study Team. Cefepime-taniborbactam in complicated urinary tract infection. N Engl J Med. 2024;390:611-622. 38354140.


Assuntos
Antibacterianos , Cefepima , Meropeném , Infecções Urinárias , Cefepima/uso terapêutico , Humanos , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Infecções Urinárias/tratamento farmacológico , Meropeném/uso terapêutico , Resultado do Tratamento , Feminino , Masculino , Pessoa de Meia-Idade , Combinação de Medicamentos
4.
Sci Rep ; 14(1): 13392, 2024 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862579

RESUMO

Cefepime and piperacillin/tazobactam are antimicrobials recommended by IDSA/ATS guidelines for the empirical management of patients admitted to the intensive care unit (ICU) with community-acquired pneumonia (CAP). Concerns have been raised about which should be used in clinical practice. This study aims to compare the effect of cefepime and piperacillin/tazobactam in critically ill CAP patients through a targeted maximum likelihood estimation (TMLE). A total of 2026 ICU-admitted patients with CAP were included. Among them, (47%) presented respiratory failure, and (27%) developed septic shock. A total of (68%) received cefepime and (32%) piperacillin/tazobactam-based treatment. After running the TMLE, we found that cefepime and piperacillin/tazobactam-based treatments have comparable 28-day, hospital, and ICU mortality. Additionally, age, PTT, serum potassium and temperature were associated with preferring cefepime over piperacillin/tazobactam (OR 1.14 95% CI [1.01-1.27], p = 0.03), (OR 1.14 95% CI [1.03-1.26], p = 0.009), (OR 1.1 95% CI [1.01-1.22], p = 0.039) and (OR 1.13 95% CI [1.03-1.24], p = 0.014)]. Our study found a similar mortality rate among ICU-admitted CAP patients treated with cefepime and piperacillin/tazobactam. Clinicians may consider factors such as availability and safety profiles when making treatment decisions.


Assuntos
Antibacterianos , Cefepima , Infecções Comunitárias Adquiridas , Estado Terminal , Unidades de Terapia Intensiva , Combinação Piperacilina e Tazobactam , Humanos , Cefepima/uso terapêutico , Cefepima/administração & dosagem , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/mortalidade , Combinação Piperacilina e Tazobactam/uso terapêutico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Funções Verossimilhança , Pneumonia/tratamento farmacológico , Pneumonia/mortalidade , Piperacilina/uso terapêutico
5.
Med ; 5(5): 380-382, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38733970

RESUMO

Wagenlehner and colleagues1 demonstrated non-inferiority and superiority with respect to a primary endpoint of composite success (microbiological plus clinical) of cefepime/taniborbactam vs. meropenem in treating complicated urinary tract infections and acute pyelonephritis caused by carbapenem-susceptible gram-negative bacteria in adults. A major area of interest in real-world application of cefepime/taniborbactam is its potential role in treating carbapenem-resistant infections, which deserves further investigation.


Assuntos
Antibacterianos , Carbapenêmicos , Cefepima , Infecções Urinárias , Cefepima/uso terapêutico , Cefepima/farmacologia , Humanos , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Carbapenêmicos/uso terapêutico , Carbapenêmicos/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Cefalosporinas/uso terapêutico , Cefalosporinas/farmacologia , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Combinação de Medicamentos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Meropeném/uso terapêutico , Meropeném/farmacologia , Ácidos Borínicos , Ácidos Carboxílicos
6.
Allergy Asthma Proc ; 45(3): 207-210, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38755784

RESUMO

Background: ß-Lactam antibiotics are widely used with increased utilization in hospitalized patients. Of this population, as high as 10-20% report an allergy to ß-lactam antibiotics but <5% are at risk of developing clinically significant immunoglobulin E- or T-lymphocyte-mediated reactions. Most of the time, these reported allergies are present during an illness with no previous inquiry of their validity, which makes investigation and possible removal of this allergy label a challenge. Methods: We report a 16-year-old boy who presented with 1 week of night sweats, chills, headaches, and fatigue, followed by 1 day of fever and right knee swelling and who was diagnosed with septic bursitis. Due to concern of a penicillin allergy label, the patient was started on a cefepime infusion. Five minutes into the infusion, the patient reported puffy eyes and itchy throat, followed by a witnessed cascading flat nonpruritic erythematous rash from head to shoulders. This rash went away in 3 minutes after stopping the infusion and the patient being given 50 mg of intravenous diphenhydramine and 10 mg of oral dexamethasone. He was subsequently diagnosed with a cefepime allergy. Results: Allergy/immunology was the speciality consulted, and, by using a screening questionnaire, the patient's reported penicillin allergy was determined to be low risk. Subsequent 1-step oral challenge was the key to providing the patient with the necessary antibiotic course to resolve his infection. Conclusion: Multiple reported antibiotic allergies lead to poor antibiotic stewardship that causes impactful health and financial burden on the patient and health-care system. It is thus important to have an evidence-based systematic approach to de-label penicillin antibiotic allergy labels to reduce these potential harms.


Assuntos
Antibacterianos , Cefalosporinas , Hipersensibilidade a Drogas , Penicilinas , Humanos , Masculino , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologia , Adolescente , Penicilinas/efeitos adversos , Antibacterianos/efeitos adversos , Cefalosporinas/efeitos adversos , Rotulagem de Medicamentos , Alérgenos/imunologia , Hospitalização , Cefepima/efeitos adversos
7.
JAMA Intern Med ; 184(7): 769-777, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38739397

RESUMO

Importance: Experimental and observational studies have suggested that empirical treatment for bacterial sepsis with antianaerobic antibiotics (eg, piperacillin-tazobactam) is associated with adverse outcomes compared with anaerobe-sparing antibiotics (eg, cefepime). However, a recent pragmatic clinical trial of piperacillin-tazobactam and cefepime showed no difference in short-term outcomes at 14 days. Further studies are needed to help clarify the empirical use of these agents. Objective: To examine the use of piperacillin-tazobactam compared with cefepime in 90-day mortality in patients treated empirically for sepsis, using instrumental variable analysis of a 15-month piperacillin-tazobactam shortage. Design, Setting, and Participants: In a retrospective cohort study, hospital admissions at the University of Michigan from July 1, 2014, to December 31, 2018, including a piperacillin-tazobactam shortage period from June 12, 2015, to September 18, 2016, were examined. Adult patients with suspected sepsis treated with vancomycin and either piperacillin-tazobactam or cefepime for conditions with presumed equipoise between piperacillin-tazobactam and cefepime were included in the study. Data analysis was conducted from December 17, 2022, to April 11, 2023. Main Outcomes and Measures: The primary outcome was 90-day mortality. Secondary outcomes included organ failure-free, ventilator-free, and vasopressor-free days. The 15-month piperacillin-tazobactam shortage period was used as an instrumental variable for unmeasured confounding in antibiotic selection. Results: Among 7569 patients (4174 men [55%]; median age, 63 [IQR 52-73] years) with sepsis meeting study eligibility, 4523 were treated with vancomycin and piperacillin-tazobactam and 3046 were treated with vancomycin and cefepime. Of patients who received piperacillin-tazobactam, only 152 (3%) received it during the shortage. Treatment groups did not differ significantly in age, Charlson Comorbidity Index score, Sequential Organ Failure Assessment score, or time to antibiotic administration. In an instrumental variable analysis, piperacillin-tazobactam was associated with an absolute mortality increase of 5.0% at 90 days (95% CI, 1.9%-8.1%) and 2.1 (95% CI, 1.4-2.7) fewer organ failure-free days, 1.1 (95% CI, 0.57-1.62) fewer ventilator-free days, and 1.5 (95% CI, 1.01-2.01) fewer vasopressor-free days. Conclusions and Relevance: Among patients with suspected sepsis and no clear indication for antianaerobic coverage, administration of piperacillin-tazobactam was associated with higher mortality and increased duration of organ dysfunction compared with cefepime. These findings suggest that the widespread use of empirical antianaerobic antibiotics in sepsis may be harmful.


Assuntos
Antibacterianos , Cefepima , Combinação Piperacilina e Tazobactam , Sepse , Humanos , Cefepima/administração & dosagem , Cefepima/uso terapêutico , Combinação Piperacilina e Tazobactam/administração & dosagem , Combinação Piperacilina e Tazobactam/uso terapêutico , Masculino , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Feminino , Sepse/tratamento farmacológico , Sepse/mortalidade , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade
8.
J Int Med Res ; 52(5): 3000605241244743, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38713455

RESUMO

The world population is rapidly aging. Societal aging poses many challenges for individuals, families, nations, and the global healthcare system. Therefore, geriatric care is a crucial issue that demands our attention. In this case report, we describe a woman in her early 70s with multiple comorbidities, polypharmacy, and renal insufficiency who developed cefepime-induced encephalopathy with moderate to severe cerebral dysfunction during treatment of a urinary tract infection. The patient's consciousness level gradually improved, and no further seizures were observed following the discontinuation of cefepime for several days. This case report underscores the fact that polypharmacy and medication safety are significant concerns that are often overlooked when caring for older patients. The report also highlights the increased susceptibility of older individuals to antibiotic-associated adverse reactions during the management of infectious diseases. Therefore, optimization of antibiotic therapy for older patients is a critical issue that requires thorough investigation and consideration in geriatric care.


Assuntos
Antibacterianos , Encefalopatias , Cefepima , Polimedicação , Insuficiência Renal , Infecções Urinárias , Humanos , Cefepima/efeitos adversos , Cefepima/uso terapêutico , Feminino , Idoso , Encefalopatias/induzido quimicamente , Infecções Urinárias/tratamento farmacológico , Insuficiência Renal/induzido quimicamente , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico
9.
Drug Dev Ind Pharm ; 50(6): 511-523, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38718267

RESUMO

OBJECTIVES: This research aimed to overcome challenges posed by cefepime excessive elimination rate and poor patient compliance by developing transdermal delivery system using nano-transfersomes based chitosan gel. METHODS: Rotary evaporation-sonication method and the Box-Behnken model were used to prepare cefepime loaded nano-transfersomes (CPE-NTFs). The physiochemical characterization of CPE-NTFs were analyzed including DLS, deformability index, DSC and antimicrobial study. Optimized CPE-NTFs loaded into chitosan gel and appropriately characterized. In vitro release, ex vivo and in vivo studies were performed. RESULTS: The CPE-NTFs were physically stable with particle size 222.6 ± 1.8 nm, polydispersity index 0.163 ± 0.02, zeta potential -20.8 ± 0.1 mv, entrapment efficiency 81.4 ± 1.1% and deformability index 71 ± 0.2. DSC analysis confirmed successful drug loading and thermal stability. FTIR analysis showed no chemical interaction among the excipients of CPE-NTFs gel. The antibacterial activity demonstrated a remarkable reduction in the minimum inhibitory concentration of cefepime when incorporated into nano-transfersomes. CPE-NTFs based chitosan gel (CPE-NTFs gel) showed significant physicochemical properties. In vitro release studies exhibited sustained release behavior over 24 h, and ex vivo studies indicated enhanced permeation and retention compared to conventional cefepime gel. In vivo skin irritation studies confirmed CPE-NTFs gel was nonirritating and biocompatible for transdermal delivery. CONCLUSION: This research showed nano-transfersomes based chitosan gel is a promising approach for cefepime transdermal delivery and provides sustained release of cefepime.


Assuntos
Administração Cutânea , Antibacterianos , Cefepima , Quitosana , Géis , Tamanho da Partícula , Absorção Cutânea , Pele , Quitosana/química , Cefepima/administração & dosagem , Cefepima/farmacocinética , Cefepima/química , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/química , Antibacterianos/farmacologia , Géis/química , Animais , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Ratos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Testes de Sensibilidade Microbiana , Masculino , Portadores de Fármacos/química , Nanopartículas/química , Ratos Wistar
10.
Antimicrob Agents Chemother ; 68(7): e0023624, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38780262

RESUMO

CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.


Assuntos
Antibacterianos , Cefepima , Cefalosporinas , Meropeném , Testes de Sensibilidade Microbiana , Infecções Urinárias , beta-Lactamases , Humanos , Meropeném/uso terapêutico , Meropeném/farmacologia , Cefepima/uso terapêutico , Cefepima/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Cefalosporinas/uso terapêutico , Cefalosporinas/farmacologia , beta-Lactamases/genética , Adulto , Feminino , Masculino , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pessoa de Meia-Idade , Método Duplo-Cego , Proteínas de Bactérias/genética , Genótipo , Fenótipo , Idoso , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Resultado do Tratamento , Ácidos Borínicos , Ácidos Carboxílicos
11.
J Clin Microbiol ; 62(6): e0152023, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38712928

RESUMO

There are increasing reports of carbapenem-resistant Enterobacterales (CRE) that test as cefepime-susceptible (S) or susceptible-dose dependent (SDD). However, there are no data to compare the cefepime testing performance of BD Phoenix automated susceptibility system (BD Phoenix) and disk diffusion (DD) relative to reference broth microdilution (BMD) against carbapenemase-producing (CPblaKPC-CRE) and non-producing (non-CP CRE) isolates. Cefepime susceptibility results were interpreted according to CLSI M100Ed32. Essential agreement (EA), categorical agreement (CA), minor errors (miEs), major errors (MEs), and very major errors (VMEs) were calculated for BD Phoenix (NMIC-306 Gram-negative panel) and DD relative to BMD. Correlates were also analyzed by the error rate-bounded method. EA and CA for CPblaKPC-CRE isolates (n = 64) were <90% with BD Phoenix while among non-CP CRE isolates (n = 58), EA and CA were 96.6%, and 79.3%, respectively. CA was <90% with DD for both cohorts. No ME or VME was observed for either isolate cohort; however, miEs were >10% for CPblaKPC-CRE and non-CP CRE with BD Phoenix and DD tests. For error rate-bounded method, miEs were <40% for IHigh + 1 to ILow - 1 ranges for CPblaKPC-CRE and non-CP CRE with BD Phoenix. Regarding disk diffusion, miEs were unacceptable for all MIC ranges among CPblaKPC-CRE. For non-CP CRE isolates, only IHigh + 1 to ILow - 1 range was acceptable at 37.2%. Using this challenge set of genotypic-phenotypic discordant CRE, the BD Phoenix MICs and DD susceptibility results trended higher (toward SDD and resistant phenotypes) relative to reference BMD results yielding lower CA. These results were more prominent among CPblaKPC-CRE than non-CP CRE.


Assuntos
Antibacterianos , Enterobacteriáceas Resistentes a Carbapenêmicos , Cefepima , Testes de Sensibilidade Microbiana , Cefepima/farmacologia , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Humanos , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão/métodos , Infecções por Enterobacteriaceae/microbiologia , Cefalosporinas/farmacologia
12.
Drugs ; 84(6): 737-744, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38761353

RESUMO

Cefepime/enmetazobactam (EXBLIFEP®), an intravenous (IV) antibacterial fixed-dose combination of a 4th generation cephalosporin and an extended-spectrum ß-lactamase (ESBL) inhibitor, is being developed by Allecra Therapeutics and ADVANZ PHARMA for the treatment of infections caused by multi-drug-resistant (MDR) Gram-negative bacteria. In February 2024, cefepime/enmetazobactam was approved in the USA for use in adults with complicated urinary tract infections (cUTI) including pyelonephritis, caused by susceptible strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex. In March 2024, cefepime/enmetazobactam was approved in the EU for use in adults for the treatment of cUTI, including pyelonephritis, and hospital-acquired pneumonia, including ventilator associated pneumonia, and the treatment of patients with bacteraemia occurring in association with or suspected to be associated with any of these infections. This article summarizes the milestones in the development of cefepime/enmetazobactam leading to this first approval for the treatment of adults with infections caused by MDR Gram-negative bacteria.


Assuntos
Antibacterianos , Cefepima , Aprovação de Drogas , Infecções Urinárias , Humanos , Cefepima/farmacologia , Cefepima/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Cefalosporinas/uso terapêutico , Cefalosporinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Inibidores de beta-Lactamases/administração & dosagem , Estados Unidos , Combinação de Medicamentos , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia
17.
Antimicrob Agents Chemother ; 68(5): e0108523, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38606975

RESUMO

Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough (Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with the two VAN monitoring strategies when used in combination with TZP or FEP/MEM. Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. A Cox Proportional Hazard Model was used to model AKI as a function of the incidence rate of at-risk days, testing monitoring strategy as a treatment effect modification. Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%), and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and monitoring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI; however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.


Assuntos
Injúria Renal Aguda , Antibacterianos , Cefepima , Meropeném , Combinação Piperacilina e Tazobactam , Vancomicina , Humanos , Vancomicina/efeitos adversos , Vancomicina/administração & dosagem , Vancomicina/uso terapêutico , Meropeném/administração & dosagem , Meropeném/uso terapêutico , Meropeném/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Cefepima/administração & dosagem , Cefepima/uso terapêutico , Cefepima/efeitos adversos , Combinação Piperacilina e Tazobactam/efeitos adversos , Combinação Piperacilina e Tazobactam/administração & dosagem , Combinação Piperacilina e Tazobactam/uso terapêutico , Masculino , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Feminino , Pessoa de Meia-Idade , Idoso , Área Sob a Curva , Quimioterapia Combinada , Estudos Retrospectivos , Sepse/tratamento farmacológico
18.
BMC Infect Dis ; 24(1): 434, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38654148

RESUMO

BACKGROUND: The problem of resistance to beta-lactam antibiotics, which is caused by ESBL and AmpC ß-lactamases, is getting worse globally. Infections caused by bacterial isolates harboring these enzymes are difficult to treat with carbapenems being the sole effective treatment option for such infections. The objective of this study was to determine the frequency of ESBLs and AmpC-producing Gram-negative bacilli isolated from clinical specimens and to evaluate the sensitivity of cefepime-tazobactam combination against them. METHODS: This is an observational cross-sectional study carried out on 100 Gram-negative bacilli at Theodor Bilharz Research Institute Hospital during the period from February 2015 to January 2016. ESBL production was screened by using the disc diffusion test followed by confirmation by the combined disc confirmatory test, the screening for AmpC production was conducted using the cefoxitin disc test, which was subsequently confirmed by the AmpC disc test. Isolates confirmed positive for ESBL and/ or AmpC production were investigated for their susceptibility to antibiotics. RESULTS: Among 100 Gram-negative bacilli, 44 isolates were confirmed as ESBL producers by the combined disc confirmatory test out of 56 isolates that tested positive for ESBL production through the disc diffusion test. The presence of AmpC production was assessed using the cefoxitin disc test, 32 isolates were screened to be AmpC producers, and the AmpC disc test confirmed AmpC production in 9 isolates of them. Using the Mast® D68C set, 32 isolates were ESBL producers, 3 were AmpC producers, and 4 isolates were ESBL/AmpC co-producers. The highest sensitivity was to cefepime-tazobactam (91.48%) followed by the carbapenems. CONCLUSION: Cefepime-tazobactam showed remarkable activity against ESBL and/or AmpC-producing Gram-negative bacilli and may be considered as a therapeutic alternative to carbapenems.


Assuntos
Antibacterianos , Proteínas de Bactérias , Cefepima , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Tazobactam , beta-Lactamases , beta-Lactamases/metabolismo , Cefepima/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Negativas/isolamento & purificação , Humanos , Estudos Transversais , Antibacterianos/farmacologia , Tazobactam/farmacologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Cefalosporinas/farmacologia , Masculino , Feminino , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia
19.
Int J Antimicrob Agents ; 64(1): 107186, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38688353

RESUMO

INTRODUCTION: The emergence of multidrug-resistant Gram-negative bacilli and the development of new antibiotics have complicated the selection of optimal regimens. International guidelines are valuable tools, but are limited by the scarcity of high-quality randomized trials in many situations. METHODS: A panel of experts from the French and Italian Societies of Infectious Diseases aimed to address unresolved issues in clinical practice based on their experience, an updated literature review and open discussions. RESULTS: The panel reached consensus for the following 'first choices': (i) cefepime for ventilator-acquired pneumonia due to AmpC ß-lactamase-producing Enterobacterales; (ii) the ß-lactam/ß-lactamase inhibitor combination most active in vitro, or cefiderocol combined with fosfomycin, and aerosolized colistin or aminoglycosides, for severe pneumonia due to Pseudomonas aeruginosa resistant to ceftolozane-tazobactam; (iii) high-dose piperacillin-tazobactam (including loading dose and continuous infusion) for complicated urinary tract infections (cUTIs) caused by extended-spectrum ß-lactamase-producing Enterobacterales with piperacillin-tazobactam minimum inhibitory concentration (MIC) ≤8 mg/L; (iv) high-dose cefepime for cUTIs due to AmpC ß-lactamase-producing Enterobacterales other than Enterobacter spp. if cefepime MIC ≤2 mg/L; (v) ceftolozane-tazobactam or ceftazidime-avibactam plus metronidazole for intra-abdominal infections (IAIs) due to third-generation cephalosporin-resistant Enterobacterales; (vi) ceftazidime-avibactam plus aztreonam plus metronidazole for IAIs due to metallo-ß-lactamase-producing Enterobacterales; (vii) ampicillin-sulbactam plus colistin for bloodstream infections (BSIs) caused by carbapenem-resistant Acinetobacter baumannii; (viii) meropenem-vaborbactam for BSIs caused by Klebsiella pneumoniae carbapenemase-producing Enterobacterales; and (ix) ceftazidime-avibactam plus fosfomycin for neurological infections caused by carbapenem-resistant P. aeruginosa. CONCLUSIONS: These expert choices were based on the necessary balance between antimicrobial stewardship principles and the need to provide optimal treatment for individual patients in each situation.


Assuntos
Antibacterianos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas , Humanos , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Itália , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Combinação de Medicamentos , França , Cefalosporinas/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/microbiologia , Cefepima/uso terapêutico , Cefepima/farmacologia , Fosfomicina/uso terapêutico , Fosfomicina/farmacologia , Colistina/uso terapêutico , Colistina/farmacologia , Tazobactam , Ceftazidima , Compostos Azabicíclicos
20.
Int J Antimicrob Agents ; 63(5): 107150, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38513748

RESUMO

OBJECTIVES: To analyse the impact of the most clinically relevant ß-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains. METHODS: We constructed 82 E. coli laboratory transformants expressing the main ß-lactamases circulating in Enterobacterales (70 expressing single ß-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution. RESULTS: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of ß-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present. CONCLUSIONS: Our findings highlight the promising activity that cefiderocol and new ß-lactam/ß-lactamase inhibitors have against recombinant E. coli strains expressing widespread ß-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.


Assuntos
Antibacterianos , Compostos Azabicíclicos , Ácidos Borínicos , Ácidos Carboxílicos , Cefepima , Cefiderocol , Ceftazidima , Cefalosporinas , Ciclo-Octanos , Combinação de Medicamentos , Escherichia coli , Lactamas , Testes de Sensibilidade Microbiana , Triazóis , Inibidores de beta-Lactamases , beta-Lactamases , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , beta-Lactamases/genética , beta-Lactamases/metabolismo , Cefalosporinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , Compostos Azabicíclicos/farmacologia , Antibacterianos/farmacologia , Ciclo-Octanos/farmacologia , Ceftazidima/farmacologia , Cefepima/farmacologia , Ácidos Borônicos/farmacologia , Meropeném/farmacologia , Aztreonam/farmacologia , Imipenem/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Compostos Heterocíclicos com 1 Anel/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos
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