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1.
Anal Chim Acta ; 1177: 338760, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34482897

RESUMO

Beta-lactam antibiotics are of vital importance for the treatment of infections in a broad range of patients. Although most systemically administered antibiotics will be excreted renally, a fraction will reach the gastro-intestinal tract, affecting the intestinal microbiome by eradicating a wide range of bacterial species while facilitating the growth of antimicrobial-resistant species. A better understanding of the kinetics of beta-lactam antibiotics in the gastro-intestinal tract is essential to study their role in the development of antibiotic resistance in bacteria and to help develop future therapies to prevent damage to, or restore, the intestinal microbiome. Analysis of beta-lactam antibiotics in faeces is particularly challenging due to the heterogeneous nature of the matrix, rapid degradation of some beta-lactam antibiotics in faeces and very strong ion suppression when using mass spectrometry. Sample preparation was optimized using a sequential strategy of experimental designs. It resulted in lyophilization, a MOPS buffer system and the addition of the beta-lactamase inhibitor avibactam to minimize degradation of antibiotics allowing sensitive quantification. The developed liquid chromatography method with high-resolution mass spectrometric detection was successfully validated according to bioanalytical EMA guidelines and had a linear range of 1-200 µg g-1 lyophilized faeces for amoxicillin, piperacillin and meropenem; and 0.5-100 µg g-1 lyophilized faeces for tazobactam. Despite the highly complex and heterogeneous composition of faeces, the accuracy (0.1-15%) and precision (1.7-12.1%) were in line with those obtained for quantification methods of beta-lactam antibiotics in plasma, the golden standard matrix for therapeutic drug monitoring. The applicability of the method was illustrated by successful quantification of piperacillin and tazobactam in faeces from an intensive care unit patient receiving piperacillin/tazobactam in a continuous intravenous infusion. Both piperacillin and tazobactam were still present six days after discontinuation of the therapy.


Assuntos
Amoxicilina , Piperacilina , Antibacterianos , Cromatografia Líquida , Fezes , Humanos , Espectrometria de Massas , Meropeném , Projetos de Pesquisa , Tazobactam
2.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361749

RESUMO

Cefquinome and ceftiofur are ß-lactam antibiotics used for the treatment of bacterial infections in swine. Although these antimicrobials are administered intramuscularly, the exposure of the gut microbiota to these cephalosporins is not well described. This exposure can contribute to the emergence and spread of antimicrobials in the environment and to the possible spread of antimicrobial resistance genes. To assess the impact of drug administration on the intestinal excretion of these antimicrobials it is essential to measure the amounts of native compound and metabolites in feces. Two (ultra)-high-performance liquid chromatography-tandem mass spectrometry ((U)HPLC-MS/MS) methods were developed and validated, one for the determination of cefquinome and ceftiofur and the other for the determination of ceftiofur residues, measured as desfuroylceftiofuracetamide, in porcine feces. The matrix-based calibration curve was linear from 5 ng g-1 to 1000 ng g-1 for cefquinome (correlation coefficient (r) = 0.9990 ± 0.0007; goodness of fit (gof) = 3.70 ± 1.43) and ceftiofur (r = 0.9979 ± 0.0009; gof = 5.51 ± 1.14) and quadratic from 30 ng g-1 to 2000 ng g-1 for desfuroylceftiofuracetamide (r = 0.9960 ± 0.0020; gof = 7.31 ± 1.76). The within-day and between-day precision and accuracy fell within the specified ranges. Since ß-lactam antibiotics are known to be unstable in feces, additional experiments were conducted to adjust the sampling protocol in order to minimize the impact of the matrix constituents on the stability of the analytes. Immediately after sampling, 500 µL of an 8 µg mL-1 tazobactam solution in water was added to 0.5 g feces, to reduce the degradation in matrix.


Assuntos
Acetamidas/isolamento & purificação , Antibacterianos/isolamento & purificação , Cefalosporinas/isolamento & purificação , Cromatografia Líquida de Alta Pressão/normas , Furanos/isolamento & purificação , Espectrometria de Massas em Tandem/normas , Acetamidas/administração & dosagem , Animais , Antibacterianos/administração & dosagem , Calibragem , Cefalosporinas/administração & dosagem , Cromatografia Líquida de Alta Pressão/métodos , Fezes/química , Feminino , Furanos/administração & dosagem , Injeções Intramusculares , Masculino , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Suínos , Espectrometria de Massas em Tandem/métodos , Tazobactam/química
4.
J Glob Antimicrob Resist ; 25: 282-286, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33933698

RESUMO

OBJECTIVES: Ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) are two novel antibacterials with known efficacy against Gram-negative bacteria (GNB). We aimed to describe the efficacy and safety of surgical management combined with C/A or C/T treatment for bone and joint infections (BJIs). METHODS: We conducted an observational, bicentric study of patients treated with C/A or C/T for a BJI between May 2016 and June 2019. Failure was defined as the need for unplanned additional antibiotic treatment or orthopaedic surgery, or death due to the BJI up to the patient's latest visit. RESULTS: Overall, 15 patients were included. Nine patients were treated with C/A, mainly for polymicrobial BJI due to multidrug-resistant (MDR) bacteria (Enterobacteriaceae, n = 7). Six patients were male, the median age was 66 years and the median Charlson comorbidity index (CCI) was 5. It was the first septic episode at the site in 3/9 patients. The cure rate was 7/9 (median follow-up, 272 days). Two patients showed C/A-related confusion. Five patients were treated with C/T for BJI involving MDR Pseudomonas aeruginosa. Four patients were male, the median age was 53 years and the median CCI was 2. All patients had previous septic episodes at the infection site. The cure rate was 3/5 (median follow-up, 350 days). One patient was successfully treated by C/T then C/A for multistage spondylodiscitis. CONCLUSION: In our experience, C/A and C/T are two effective and safe options, even as salvage treatment for BJI due to MDR-GNB despite the absence of label, however more data are warranted.


Assuntos
Ceftazidima , Idoso , Compostos Azabicíclicos , Ceftazidima/uso terapêutico , Cefalosporinas , Estudos de Coortes , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tazobactam/uso terapêutico
5.
J Int Med Res ; 49(5): 3000605211019661, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34057835

RESUMO

OBJECTIVE: To compare the occurrence and prognosis of antibiotic-associated diarrhea (AAD) between patients treated with cefoperazone/sulbactam and piperacillin/tazobactam in the neurosurgery department. METHODS: This study retrospectively analyzed patients who received cefoperazone/sulbactam or piperacillin/tazobactam to prevent or treat hospital-acquired infections in the Department of Neurosurgery of The First Medical Center of Chinese PLA General Hospital between October 2019 and October 2020. For patients with AAD, clinical data, antibiotic usage, the incidence of diarrhea, treatment, and prognosis were collected and analyzed. RESULTS: In total, 356 patients were enrolled, and 65 (18.6%) experienced AAD, 38 patients in the cefoperazone/sulbactam group and 27 patients in the piperacillin/tazobactam group. The AAD rate did not differ between the treatment arms. Conversely, the dosage, intensity, and duration of antibiotic therapy differed between the groups, whereas no differences were noted in the time to the appearance of diarrhea and prognosis. According to regression analysis, the incidence of AAD did not differ between the groups (odds ratio [OR] = 0.85, 95% confidence interval [CI] = 0.46-1.48). CONCLUSION: Cefoperazone/sulbactam or piperacillin/tazobactam can lead to a similar incidence rate of AAD. The combined application of antibiotics and empiric therapy often occurs. The rational use of antibiotics should be improved.


Assuntos
Cefoperazona , Neurocirurgia , Antibacterianos/efeitos adversos , Cefoperazona/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Ácido Penicilânico/efeitos adversos , Piperacilina/efeitos adversos , Estudos Retrospectivos , Sulbactam/efeitos adversos , Tazobactam
7.
J Glob Antimicrob Resist ; 25: 346-350, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33984530

RESUMO

OBJECTIVES: Ceftolozane/tazobactam is a cephalosporin/ß-lactamase inhibitor combination with activity against Gram-negative bacilli. Here we report the use of ceftolozane/tazobactam in Canada using a national registry. METHODS: The CLEAR registry uses a REDCapTM online survey to capture details associated with clinical use of ceftolozane/tazobactam. RESULTS: Data from 51 patients treated in 2020 with ceftolozane/tazobactam are available. Infections treated included hospital-acquired bacterial pneumonia (37.3% of patients), ventilator-associated bacterial pneumonia (15.7%), bone and joint infection (11.8%), complicated intra-abdominal infection (7.8%) and complicated skin and skin-structure infection (7.8%). Moreover, 17.6% of patients had bacteraemia and 47.1% were in intensive care. Ceftolozane/tazobactam was primarily used as directed therapy for Pseudomonas aeruginosa infections (92.2% of patients). Ceftolozane/tazobactam was used because of resistance to (86.3%), failure of (11.8%) or adverse effects from (2.0%) previously prescribed antimicrobials. Ceftolozane/tazobactam susceptibility testing was performed on isolates from 88.2% of patients. Ceftolozane/tazobactam was used in combination with another antimicrobial active against Gram-negative bacilli in 39.2% of patients [aminoglycosides (15.7%), fluoroquinolones (9.8%) and colistin/polymyxin B (7.8%)]. The dosage regimen was customised in all patients based on creatinine clearance. The treatment duration was primarily >10 days (60.8% of patients), with microbiological success in 60.5% and clinical success in 64.4% of patients. Moreover, 7.8% of patients had adverse effects not requiring drug discontinuation. CONCLUSION: In Canada, ceftolozane/tazobactam is used as directed therapy to treat a variety of severe infections caused by multidrug-resistant P. aeruginosa. It is commonly used in combination with other antimicrobials with relatively high microbiological/clinical cure rates and an excellent safety profile.


Assuntos
Cefalosporinas , Liderança , Antibacterianos/uso terapêutico , Canadá , Cefalosporinas/uso terapêutico , Humanos , Sistema de Registros , Tazobactam
8.
Int J Antimicrob Agents ; 57(6): 106335, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33838223

RESUMO

OBJECTIVES: To evaluate ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) use in haematological patients with febrile neutropenia receiving high-dose chemotherapy and haematopoietic stem cell transplantation (HSCT). METHODS: A retrospective study was conducted to assess C/A and C/T efficacy through infection-related mortality (IRM) and bacteraemia clearance for carbapenem-resistant Gram-negative bacteria (CR-GNB) pre-engraftment blood-stream infections (PE-BSIs) between January-December 2018. RESULTS: Seventy patients underwent allogeneic HSCT: C/A and C/T were dispensed in 13% and 3%, respectively. C/A was administered as definite therapy for carbapenem-resistant Klebsiella pneumoniae (CR-Kp) PE-BSI in four carriers (bacteraemia clearance in 5 days), empirical therapy for a clinically documented infection in two patients (one carrier with pneumonia and one non-carrier with shock) and empirical therapy for fever of unknown origin in three CR-Kp carriers. C/T was administered as definite therapy for carbapenem-resistant Pseudomonas aeruginosa (CR-Pa) intra-abdominal infection in one carrier and empirical therapy for a clinically documented infection (pneumonia) in one non-carrier. Among patients without PE-BSIs and with Gram-positive bacteria PE-BSIs, IRM was 0% at +30 days; conversely, it was 30% in GNB PE-BSIs (two CR-Kp and one CR-Pa C/T-resistant). Thirty-nine patients underwent autologous HSCT: C/A and C/T were administered, respectively, as definite therapy for CR-Kp PE-BSI in one carrier (bacteraemia clearance in 3 days) and for Pa PE-BSI (three strains, one CR-Pa) in one non-carrier (bacteraemia clearance in 2 days). Overall, IRM at +30 days was 0%. CONCLUSIONS: Monitoring multidrug-resistant GNB colonisation enabled selection of carriers who benefit from prompt administration of new antibiotics, improving HSCT outcomes in a high-risk population. C/A and C/T were effective in bacteraemia clearance; unfortunately, multidrug-resistant GNB PE-BSIs were still a burden to IRM.


Assuntos
Compostos Azabicíclicos/uso terapêutico , Ceftazidima/uso terapêutico , Cefalosporinas/uso terapêutico , Neutropenia Febril/complicações , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Tazobactam/uso terapêutico , Adulto , Idoso , Aloenxertos , Antibacterianos/uso terapêutico , Autoenxertos , Bacteriemia/complicações , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Carbapenêmicos/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Neutropenia Febril/terapia , Feminino , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
Antimicrob Agents Chemother ; 65(7): e0231820, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33875428

RESUMO

Ceftolozane-tazobactam (C/T) is a new fifth-generation cephalosporin/beta-lactamase inhibitor combination approved by the Food and Drug Administration and the European Medicines Agency for treatment of complicated intraabdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia in adult patients. This review will briefly describe the pharmacology of C/T and focus on the emerging clinical trial and real-world data supporting its current utilization. Additionally, our synthesis of these data over time has set our current usage of C/T at Barnes-Jewish Hospital (BJH). C/T is primarily employed as directed monotherapy at BJH when Pseudomonas aeruginosa isolates are identified with resistance to other beta-lactams. C/T can also be used empirically in specific clinical situations at BJH prior to microbiological detection of an antibiotic-resistant P. aeruginosa isolate. These situations include critically ill patients in the intensive care unit (ICU) setting, where there is a high likelihood of infection with multidrug-resistant (MDR) P. aeruginosa; patients failing therapy with a carbapenem; specific patient populations known to be at high risk for infection with MDR P. aeruginosa (e.g., lung transplant and cystic fibrosis patients); and patients know to have previous infection or colonization with MDR P. aeruginosa.


Assuntos
Infecções por Pseudomonas , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Tazobactam/farmacologia
11.
Trials ; 22(1): 301, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888139

RESUMO

BACKGROUND: Extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales are common causes of bloodstream infection. ESBL-producing bacteria are typically resistant to third-generation cephalosporins and result in a sizeable economic and public health burden. AmpC-producing Enterobacterales may develop third-generation cephalosporin resistance through enzyme hyper-expression. In no observational study has the outcome of treatment of these infections been surpassed by carbapenems. Widespread use of carbapenems may drive the development of carbapenem-resistant Gram-negative bacilli. METHODS: This study will use a multicentre, parallel group open-label non-inferiority trial design comparing ceftolozane-tazobactam and meropenem in adult patients with bloodstream infection caused by ESBL or AmpC-producing Enterobacterales. Trial recruitment will occur in up to 40 sites in six countries (Australia, Singapore, Italy, Spain, Saudi Arabia and Lebanon). The sample size is determined by a predefined quantity of ceftolozane-tazobactam to be supplied by Merck, Sharpe and Dohme (MSD). We anticipate that a trial with 600 patients contributing to the primary outcome analysis would have 80% power to declare non-inferiority with a 5% non-inferiority margin, assuming a 30-day mortality of 5% in both randomised groups. Once randomised, definitive treatment will be for a minimum of 5 days and a maximum of 14 days with the total duration determined by treating clinicians. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. DISCUSSION: Participants will have bloodstream infection due to third-generation cephalosporin non-susceptible E. coli and Klebsiella spp. or Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens. They will be randomised 1:1 to ceftolozane-tazobactam 3 g versus meropenem 1 g, both every 8 h. Secondary outcomes will be a comparison of 14-day all-cause mortality, clinical and microbiological success at day 5, functional bacteraemia score, microbiological relapse, new bloodstream infection, length of hospital stay, serious adverse events, C. difficile infection, multidrug-resistant organism colonisation. The estimated trial completion date is December 2024. TRIAL REGISTRATION: The MERINO-3 trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number: NCT04238390 . Registered on 23 January 2020.


Assuntos
Clostridioides difficile , Sepse , Adulto , Antibacterianos/efeitos adversos , Austrália , Cefalosporinas/efeitos adversos , Escherichia coli , Humanos , Itália , Líbano , Meropeném/efeitos adversos , Testes de Sensibilidade Microbiana , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Arábia Saudita , Sepse/tratamento farmacológico , Singapura , Espanha , Tazobactam , beta-Lactamases
12.
Artigo em Inglês | MEDLINE | ID: mdl-33820773

RESUMO

We compared the in vitro susceptibility of multidrug-resistant Pseudomonas aeruginosa isolates collected before and after treatment-emergent resistance to ceftolozane-tazobactam. Median baseline and postexposure ceftolozane-tazobactam MICs were 2 and 64 µg/ml, respectively. Whole-genome sequencing identified treatment-emergent mutations in ampC among 79% (11/14) of paired isolates. AmpC mutations were associated with cross-resistance to ceftazidime-avibactam but increased susceptibility to piperacillin-tazobactam and imipenem. A total of 81% (12/16) of ceftolozane-tazobactam-resistant isolates with ampC mutations were susceptible to imipenem-relebactam.


Assuntos
Infecções por Pseudomonas , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/genética , Tazobactam/farmacologia
13.
Diagn Microbiol Infect Dis ; 100(2): 115343, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33652305

RESUMO

Minimal inhibitory concentrations (MICs) of ticarcillin/clavulanic acid (TLc), ceftolozane/tazobactam (C/T), and aztreonam (AT) were determined for 6 SPM-1-producing Pseudomonas aeruginosa (PSA) using Etest® strips and the synergistic effect of such antimicrobials against was evaluated by gradient diffusion strip crossing (GDSC) test. The fraction inhibitory concentration indexes (FICI) were calculated and showed a synergistic (n = 3) and additive (n = 2) effects of TLc + AT against SPM-1 producers, while TLc + C/T combination caused no effect. Average MIC reduction of TLc and AT by GDSC was 3-fold and 2-fold dilutions, respectively. Thus, TLc + AT might be a candidate as a combination therapy to treat SPM-1-producing PSA infections.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , beta-Lactamases/metabolismo , Aztreonam/administração & dosagem , Aztreonam/farmacologia , Cefalosporinas/farmacologia , Ácidos Clavulânicos/administração & dosagem , Ácidos Clavulânicos/farmacologia , Sinergismo Farmacológico , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Tazobactam/farmacologia , Ticarcilina/administração & dosagem , Ticarcilina/farmacologia , beta-Lactamases/genética
14.
Int J Antimicrob Agents ; 57(4): 106299, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33567333

RESUMO

OBJECTIVE: To determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection. METHODS: ARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 µg/mL for ceftolozane and time that the unbound concentration exceeded the 1 µg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated. RESULTS: Mean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (Vss) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and Vss were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate. CONCLUSIONS: In patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam. CLINICALTRIALS. GOV IDENTIFIER: NCT02387372.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Insuficiência Renal/patologia , Tazobactam/farmacocinética , Tazobactam/uso terapêutico , Adulto , Antibacterianos/efeitos adversos , Cefalosporinas/efeitos adversos , Estado Terminal , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , Pseudomonas aeruginosa/efeitos dos fármacos , Tazobactam/efeitos adversos , Adulto Jovem
15.
Ann Palliat Med ; 10(1): 810-817, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33545803

RESUMO

Pseudomonas aeruginosa (PA) is a common gram-negative bacterium. Imipenem (IMP) is considered to be the most effective clinical drug for the treatment of PA infection. IMP-resistant ceftazidime-susceptible PA is relatively rare in clinical practice; so far, there have been no clinical reports regarding the treatment of IMP-resistant PA with piperacillin/tazobactam alone. This paper will report the case of a severe pneumonia patient with IMP-resistant ceftazidime-susceptible PA infection that was successfully treated with piperacillin/tazobactam monotherapy after initial therapy with biapenem (BIP) according to the drug sensitivity test. The patient was a 75-year-old female, her main symptom was drowsiness. She was admitted to hospital due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and pulmonary encephalopathy. After admission, endotracheal intubation was performed immediately, and the lavage fluid was sent to the laboratory for sputum culturing for several times. BIP was selected for the initial anti-infection regimen, and other symptomatic treatments were performed at the same time. On the day 8, the sputum culture drug sensitivity test results showed PA (sensitive to: piperacillin/tazobactam sodium, ceftazidime, aminoglycoside, and fluoroquinolones; resistant to IMP; and intermediate sensitivity to: cefoperazone-sulbactam and meropenem), so we adjusted the anti-infection regimen as piperacillin/tazobactam sodium. After that, the infection index of the patient declined steadily, and the patient was discharged from hospital after continuous treatment with piperacillin tazobactam until the 24th day. For severe pneumonia patients with IMP-resistant ceftazidime-susceptible PA infection, piperacillin/tazobactam is still an option specially when the MIC of piperacillin/tazobactam is very low.


Assuntos
Pneumonia , Pseudomonas aeruginosa , Idoso , Feminino , Humanos , Imipenem/uso terapêutico , Testes de Sensibilidade Microbiana , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam/uso terapêutico , Tazobactam/uso terapêutico
16.
BMJ Case Rep ; 14(2)2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547106

RESUMO

The management of infections caused by carbapenem-resistant organisms has been a challenge. We report a rare emergence of resistance to the novel beta-lactam/ beta-lactamase combination ceftolozane/tazobactam by Klebsiella pneumoniae, causing urinary tract infection. The K. pneumoniae, in this case, was reported to be sensitive to the other novel beta-lactam/ beta-lactamase combination of ceftazidime/avibactam. The timely administration of ceftazidime/avibactam resulted in prompt clinical resolution of the urinary tract infection caused by an extensively drug-resistant K. pneumoniae.


Assuntos
Anti-Infecciosos Urinários/uso terapêutico , Cefalosporinas/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Infecções por Klebsiella/tratamento farmacológico , Tazobactam/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Idoso , Humanos , Klebsiella pneumoniae , Masculino , Testes de Sensibilidade Microbiana
17.
Artigo em Inglês | MEDLINE | ID: mdl-33431414

RESUMO

WCK 4282 (cefepime 2 g-tazobactam 2 g) maximizes systemic exposure of tazobactam and restores cefepime activity against various extended-spectrum ß-lactamase (ESBL)- and cephalosporinase-producing strains in vitro We describe clinical WCK 4282 exposure efficacies against various serine ß-lactamase-producing Enterobacterales and Pseudomonas aeruginosa isolates in a murine pneumonia model. Clinical cefepime-resistant isolates (17 Enterobacterales and 2 P. aeruginosa) were utilized. Isolates expressed ESBLs, cephalosporinases, and/or serine carbapenemases (KPC and OXA-48-like). WCK 4282 MICs were 4 to 32 µg/ml. For in vivo experiments, lungs of neutropenic mice were inoculated using standard inoculum (107 log10 CFU/ml). Serine carbapenemase-producing isolates were also assessed using a low inoculum (1:5 dilution). Treatment mice received a human-simulated regimen (HSR) of cefepime, meropenem (control for serine carbapenemase expression with low inoculum experiments), or WCK 4282 human-simulated regimens. Efficacy was assessed as change in log10 CFU/lungs at 24 h compared with 0-h controls. At standard inoculum, the mean 0-h bacterial burden was 6.65 ± 0.23 log10 CFU/lungs, and it increased at 24 h by 2.48 ± 0.60 log10 CFU/lungs among untreated controls. Initial bacterial burdens of lower inocula ranged from 5.81 ± 0.12 to 6.39 ± 0.13 log10 CFU/lungs. At standard and/or low inocula, cefepime and meropenem provided minimal activity. WCK 4282 produced a >1 log10 reduction against 9/9 ESBL-/cephalosporinase-producing strains. WCK 4282 provided variable activity among mice infected with standard or lower inocula of OXA-48-like-producers. WCK 4282 exposures provided 0.53 ± 1.07 log10 CFU/lungs growth against KPC producers at a standard inoculum versus bacteriostasis (-0.15 ± 0.54 change in log10 CFU/lungs) at a low inoculum. WCK 4282 produced potent in vivo activity against ESBL- and cephalosporinase-producing Enterobacterales and P. aeruginosa isolates and potential activity against OXA-48-like-producing Enterobacterales isolates in a neutropenic pneumonia model.


Assuntos
Pseudomonas aeruginosa , Serina , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefepima , Pulmão , Camundongos , Testes de Sensibilidade Microbiana , Tazobactam , beta-Lactamases
18.
Int J Antimicrob Agents ; 57(3): 106278, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33434676

RESUMO

OBJECTIVES: The emergence of nonsusceptibility to ceftolozane/tazobactam and meropenem was evaluated among Pseudomonas aeruginosa (P. aeruginosa) lower respiratory tract isolates obtained from participants in the ASPECT-NP clinical trial. METHODS: ASPECT-NP was a phase-3, randomised, double-blind, multicentre trial that demonstrated noninferiority of 3 g ceftolozane/tazobactam q8h versus 1 g meropenem q8h for treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia. Molecular resistance mechanisms among postbaseline nonsusceptible P. aeruginosa isolates and clinical outcomes associated with participants with emergence of nonsusceptibility were examined. Baseline susceptible and postbaseline nonsusceptible P. aeruginosa isolate pairs from the same participant underwent molecular typing. RESULTS: Emergence of nonsusceptibility was not observed among the 59 participants with baseline susceptible P. aeruginosa isolates in the ceftolozane/tazobactam arm. Among 58 participants with baseline susceptible P. aeruginosa isolates in the meropenem arm, emergence of nonsusceptibility was observed in 13 (22.4%). Among participants who received ceftolozane/tazobactam and meropenem, 5.1% and 3.4% had a new infection with a nonsusceptible strain, respectively. None of the isolates with emergence of nonsusceptibility to meropenem developed co-resistance to ceftolozane/tazobactam. The molecular mechanisms associated with emergence of nonsusceptibility to meropenem were decreased expression or loss of OprD and overexpression of MexXY. CONCLUSIONS: Among participants with emergence of nonsusceptibility to meropenem, clinical outcomes were similar to overall clinical outcomes in the ASPECT-NP meropenem arm. Ceftolozane/tazobactam was more stable to emergence of nonsusceptibility versus meropenem; emergence of nonsusceptibility was not observed in any participants with baseline susceptible P. aeruginosa who received ceftolozane/tazobactam in ASPECT-NP.


Assuntos
Cefalosporinas/uso terapêutico , Farmacorresistência Bacteriana , Pneumonia Associada a Assistência à Saúde/tratamento farmacológico , Meropeném/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Tazobactam/uso terapêutico , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , DNA Bacteriano , Método Duplo-Cego , Pneumonia Associada a Assistência à Saúde/microbiologia , Humanos , Estudos Multicêntricos como Assunto , Tipagem de Sequências Multilocus , Porinas/genética , Porinas/metabolismo , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Sistema Respiratório/microbiologia , Resultado do Tratamento
19.
Eur J Clin Microbiol Infect Dis ; 40(6): 1169-1176, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33415492

RESUMO

The purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.


Assuntos
Agranulocitose/etiologia , Antibacterianos/efeitos adversos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Lactamas/efeitos adversos , Inibidores de beta-Lactamases/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/efeitos adversos , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/efeitos adversos , Ceftazidima/uso terapêutico , Cefalosporinas/efeitos adversos , Cefalosporinas/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Lactamas/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Pancitopenia/etiologia , Farmacovigilância , Estudos Retrospectivos , Tazobactam/efeitos adversos , Tazobactam/uso terapêutico , Inibidores de beta-Lactamases/uso terapêutico
20.
Diagn Microbiol Infect Dis ; 100(1): 115302, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33516987

RESUMO

Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a ß-lactamase inhibitor. Ceftolozane/tazobactam has been approved in >60 countries for treating complicated urinary tract infections, acute pyelonephritis, complicated intra-abdominal infections (with metronidazole), and hospital-acquired pneumonia, including ventilator-associated pneumonia in adults. We analyzed susceptibilities for 35,882 gram-negative isolates collected from patients in 35 US medical centers from 2012 to 2018. The rate of multi-drug resistant Enterobacterales was stable (9.5%-10.1%), while the P. aeruginosa multi-drug resistance rate increased from 15.5% in 2012 to 22.9% in 2018. The carbapenem-resistant Enterobacterales rates varied from 0.9% to 2.2% and extended-spectrum ß-lactamase phenotypes increased from 10.5% to 16.8%. The most active drugs against P. aeruginosa were ceftolozane/tazobactam (95.8%-97.5% susceptible) and amikacin (93.9%-98.0%); against Enterobacterales, amikacin (97.9%-98.8%), meropenem (97.7%-98.8%), and ceftolozane/tazobactam (93.3%-95.6%) were the most active. These data suggest that ceftolozane/tazobactam has effective in vitro activity against organisms causing serious gram-negative infections.


Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas , Tazobactam/farmacologia , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Vigilância em Saúde Pública , Estados Unidos
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