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1.
J Glob Antimicrob Resist ; 36: 252-259, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38272210

RESUMO

OBJECTIVES: To investigate the factors influencing imipenem/cilastatin (IMI) and meropenem (MEM) concentrations in critically ill adult patients and the role of these concentrations in the clinical outcome. METHODS: Plasma trough concentrations of IMI and MEM were detected by high-performance liquid chromatography. A target value of 100%-time above MIC was used for the drugs. RESULTS: A total of 186 patients were included, with 87 receiving IMI and 99 receiving MEM. The percentages of patients reaching the target IMI and MEM concentrations were 44.8% and 38.4%, respectively. The proportions of patients infected with drug-resistant bacteria were 57.5% and 69.7% in the IMI group and MEM group, respectively. In the multivariate analysis, the risk factors for an IMI concentration that did not reach the target were infection with drug-resistant bacteria, and those for MEM were infection with drug-resistant bacteria, estimated glomerular filtration rate, and diabetes mellitus. A total of 47.1% of patients had good outcomes in the IMI cohort, and 38.1% of patients had good outcomes in the MEM cohort. The duration of mechanical ventilation and IMI concentration were associated with ICU stay in patients in the IMI cohort, while MEM concentration and severe pneumonia affected the clinical outcome of patients in the MEM cohort. CONCLUSION: Infection with drug-resistant bacteria is an important factor influencing whether IMI and MEM concentrations reach the target. Furthermore, IMI and MEM concentrations are associated with the clinical outcome, and elevated doses of IMI and MEM should be given to patients who are infected with drug-resistant bacteria.


Assuntos
Cilastatina , Imipenem , Adulto , Humanos , Meropeném/uso terapêutico , Imipenem/uso terapêutico , Cilastatina/uso terapêutico , Estado Terminal , Monitoramento de Medicamentos , Combinação de Medicamentos , Combinação Imipenem e Cilastatina
2.
Mil Med ; 188(Suppl 6): 346-353, 2023 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-37948276

RESUMO

INTRODUCTION: Rhabdomyolysis-induced acute kidney injury (RIAKI) can interrupt physical training and increase mortality in injured warfighters. The legal performance-enhancing drugs caffeine and ibuprofen, which can cause renal injury, are widely used by service members. Whether caffeine or ibuprofen affects RIAKI is unknown. Cilastatin treatment was recently identified as an experimental treatment to prevent RIAKI at injury. To determine potential interacting factors in RIAKI treatment, we test the hypothesis that caffeine and ibuprofen worsen RIAKI and interfere with treatment. MATERIALS AND METHODS: In mice, RIAKI was induced by glycerol intramuscular injection. Simultaneously, mice received caffeine (3 mg/kg), ibuprofen (10 mg/kg), or vehicle. A second cohort received volume resuscitation (PlasmaLyte, 20 mL/kg) in addition to caffeine or ibuprofen. In a third cohort, cilastatin (200 mg/kg) was administered concurrently with drug and glycerol administration. Glomerular filtration rate (GFR), blood urea nitrogen (BUN), urine output (UOP), renal pathology, and renal immunofluorescence for kidney injury molecule 1 were quantified after 24 hours. RESULTS: Caffeine did not worsen RIAKI; although BUN was modestly increased by caffeine administration, 24-hour GFR, UOP, and renal histopathology were similar between vehicle-treated, caffeine-treated, and caffeine + PlasmaLyte-treated mice. Ibuprofen administration greatly worsened RIAKI (GFR 14.3 ± 19.5 vs. 577.4 ± 454.6 µL/min/100 g in control, UOP 0.5 ± 0.4 in ibuprofen-treated mice vs. 2.7 ± 1.7 mL/24 h in control, and BUN 264 ± 201 in ibuprofen-treated mice vs. 66 ± 21 mg/dL in control, P < .05 for all); PlasmaLyte treatment did not reverse this effect. Cilastatin with or without PlasmaLyte did not reverse the deleterious effect of ibuprofen in RIAKI. CONCLUSIONS: Caffeine does not worsen RIAKI. The widely used performance-enhancing drug ibuprofen greatly worsens RIAKI in mice. Standard or experimental treatment of RIAKI including the addition of cilastatin to standard resuscitation is ineffective in mice with RIAKI exacerbated by ibuprofen. These findings may have clinical implications for the current therapy of RIAKI and for translational studies of novel treatment.


Assuntos
Injúria Renal Aguda , Substâncias para Melhoria do Desempenho , Rabdomiólise , Humanos , Camundongos , Animais , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Substâncias para Melhoria do Desempenho/uso terapêutico , Cafeína/farmacologia , Cafeína/uso terapêutico , Glicerol/uso terapêutico , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Cilastatina/farmacologia , Cilastatina/uso terapêutico , Rabdomiólise/complicações , Rabdomiólise/tratamento farmacológico
3.
J Clin Pharmacol ; 63(12): 1387-1397, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37562063

RESUMO

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.


Assuntos
Infecções Bacterianas , Infecções por Bactérias Gram-Negativas , Adulto , Criança , Humanos , Imipenem/farmacocinética , Cilastatina/efeitos adversos , Cilastatina/farmacocinética , Antibacterianos , Compostos Azabicíclicos/efeitos adversos , Combinação de Medicamentos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Testes de Sensibilidade Microbiana , Infecções Bacterianas/tratamento farmacológico
4.
J Vasc Interv Radiol ; 34(9): 1485-1492.e1, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37295555

RESUMO

PURPOSE: To evaluate the effectiveness and safety of intra-arterial imipenem/cilastatin sodium (IPM/CS) infusion for painful interphalangeal joint osteoarthritis (OA). MATERIALS AND METHODS: Fifty-eight patients with interphalangeal joint OA who underwent intra-arterial IPM/CS infusion were retrospectively evaluated. Intra-arterial infusions were performed via percutaneous wrist arterial access. The Numerical Rating Scale (NRS), Functional Index for Hand Osteoarthritis (FIHOA), and Patient Global Impression of Change (PGIC) scale scores were assessed at intervals of 1, 3, 6, 12, and 18 months. Clinical success was evaluated based on PGIC. RESULTS: All patients were followed up for at least 6 months after treatment. Of them, 30 and 6 patients were followed up for 12 and 18 months, respectively. No severe or life-threatening adverse events were encountered. The mean NRS score was 6.0 ± 1.4 at baseline, which significantly decreased to 2.8 ± 1.4, 2.2 ± 1.9, and 2.4 ± 1.9 at 1, 3, and 6 months after treatment, respectively (all P < .001). The mean NRS scores were 2.8 ± 1.7 and 2.9 ± 1.9 at 12 and 18 months, respectively, in the remaining patients. The mean FIHOA score significantly decreased from 9.8 ± 5.0 at the baseline to 4.1 ± 3.5 at 3 months (P < .001). The mean FIHOA score was 4.5 ± 3.3 at 12 months in the remaining 30 patients. The clinical success rates based on PGIC at 1, 3, 6, 12, and 18 months were 62.1%, 77.6%, 70.7%, 63.4%, and 50.0%, respectively. CONCLUSIONS: Intra-arterial IPM/CS infusion is a potential treatment option for interphalangeal joint OA refractory to medical management.


Assuntos
Infecções Bacterianas , Osteoartrite , Humanos , Combinação Imipenem e Cilastatina/uso terapêutico , Imipenem/efeitos adversos , Cilastatina/efeitos adversos , Infusões Intra-Arteriais , Estudos Retrospectivos , Osteoartrite/diagnóstico , Osteoartrite/tratamento farmacológico , Osteoartrite/induzido quimicamente , Artralgia/diagnóstico , Artralgia/tratamento farmacológico , Artralgia/etiologia
6.
J Ethnopharmacol ; 312: 116449, 2023 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-37023835

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Jinhongtang as a traditional Chinese medicine (TCM) formula, has been widely used as a clinical adjuvant in the treatment of acute abdominal diseases and sepsis. Clinical benefits of the concurrent use of Jinhongtang and antibiotics have been observed, however, the mechanism has not been fully understood. AIM OF THE STUDY: The present study aimed to explore the effect of Jinhongtang on the antibacterial activity of Imipenem/Cilastatin and to clarify the underlying mechanism of herb-drug interaction (HDI). MATERIALS AND METHODS: A mouse model of sepsis induced by Staphylococcus aureus (S. aureus) was used to evaluate the pharmacodynamic interaction in vivo. In vitro antibacterial activity of Imipenem/Cilastatin was studied by determining minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Pharmacokinetic interaction was investigated by pharmacokinetic studies in rats and uptake assays using OAT1/3-HEK293 cells. The main constituents ingested into blood of rats were qualitatively identified by UHPLC-Q-TOF-MS. RESULTS: Mice treated by Imipenem/Cilastatin and Jinhongtang exhibited higher survival rate, lower bacteria load and less inflammation in blood and lung tissues, compared with those treated by Imipenem/Cilastatin alone after injection of S. aureus. However, MIC and MBC of Imipenem/Cilastatin against S. aureus in vitro were not significantly changed in the presence of Jinhongtang. On the contrary, Jinhongtang increased the plasma concentration of Imipenem and decreased its urinary excretion in rats. CLr of Imipenem was reduced by 58.5%, while its half-life (t1/2) was prolonged for approximate 1.2 times after coadministered Jinhongtang. Furthermore, the extracts of Jinhongtang, single herb in the prescription, and main absorbable constituents inhibited cellular uptake of probe substrates and Imipenem by OAT1/3-HEK293 cells to different extents. Among them, rhein exhibited the strongest inhibition capacity with IC50 values of 0.08 ± 0.01 µM (OAT1) and 2.86 ± 0.28 µM (OAT3). Moreover, coadministration of rhein also significantly enhanced the antibacterial activity of Imipenem/Cilastatin in sepsis mice. CONCLUSION: Concomitant administration of Jinhongtang enhanced antibacterial activity of Imipenem/Cilastatin in sepsis mice induced by S. aureus through reducing renal elimination of Imipenem via inhibition of OATs. Our investigation provided the insight of Jinhongtang as an effective supplement to enhance the antibacterial activity of Imipenem/Cilastatin and can be useful for future clinical studies.


Assuntos
Transportadores de Ânions Orgânicos , Sepse , Humanos , Ratos , Animais , Camundongos , Interações Ervas-Drogas , Cilastatina/farmacocinética , Cilastatina/uso terapêutico , Staphylococcus aureus , Células HEK293 , Combinação Imipenem e Cilastatina/uso terapêutico , Imipenem/farmacocinética , Imipenem/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Sepse/tratamento farmacológico , Combinação de Medicamentos
8.
Cardiovasc Intervent Radiol ; 46(6): 748-757, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36826491

RESUMO

PURPOSE: To compare the efficacy of embolization with imipenem/cilastatin and microspheres in chronic shoulder pain. METHODS: This retrospective study included 29 patients who underwent embolization for chronic shoulder pain between June 2017 and March 2022 with calibrated MSs from 100 to 250 µm or IMP/CS. The main objective was the clinical success evaluated by the Minimum Clinically Important Difference (MCID) at 3 months after the procedure, validated if the patient responded yes to 2 questions: (1) Is the pain less severe than before the procedure? (2) Are you satisfied with the procedure? The decrease in visual analogue pain scale scores and the safety of the procedure were evaluated. RESULTS: Embolization was achieved in all patients. In the MS group, 4/15 patients (26.7%) experienced clinical success at 3 months according to MCID versus 10/14 patients (71.4%) in the IMP/CS group (p = 0.02). The mean VAS decreases were respectively - 28.6% ± 34.6 in the MS group and - 36.8% ± 27.8 in the IMP/CS group at 1 month (p = 0.50), - 29.9% ± 29.0 and - 39.6% ± 23.0 at 3 months (p = 0.33) and - 30.6% ± 32.8 and - 46.6% ± 28.4 at 6 months after the procedure (p = 0.26). Eleven patients (73.3%) in the MS group and 3 patients (21.4%) in the IMP/CS group had complications (p = 0.01). Among them, 2/15 patients (13.3%) had transient skin ischaemia in the MS group. CONCLUSION: Embolization with IMP/CS may be more effective and safer than MSs in the management of chronic shoulder pain.


Assuntos
Cilastatina , Imipenem , Humanos , Estudos Retrospectivos , Imipenem/uso terapêutico , Cilastatina/uso terapêutico , Microesferas , Dor de Ombro/terapia , Combinação de Medicamentos , Combinação Imipenem e Cilastatina , Resultado do Tratamento
9.
J Comp Eff Res ; 12(3): e220113, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36688591

RESUMO

Aim: This study evaluates the cost-effectiveness of imipenem/cilastatin/relebactam (IMI/REL) for treating hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in an 'early adjustment prescribing scenario'. Methods: An economic model was constructed to compare two strategies: continuation of empiric piperacillin/tazobactam (PIP/TAZ) versus early adjustment to IMI/REL. A decision tree was used to depict the hospitalization period, and a Markov model used to capture long-term outcomes. Results: IMI/REL generated more quality-adjusted life years than PIP/TAZ, at an increased cost per patient. The incremental cost-effectiveness ratio of $17,529 per QALY is below the typical US willingness-to-pay threshold. Conclusion: IMI/REL may represent a cost-effective treatment for payers and a valuable option for clinicians, when considered alongside patient risk factors, local epidemiology, and susceptibility data.


Assuntos
Imipenem , Pneumonia Bacteriana , Humanos , Análise Custo-Benefício , Imipenem/uso terapêutico , Cilastatina/uso terapêutico , Combinação de Medicamentos , Combinação Piperacilina e Tazobactam/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Ventiladores Mecânicos , Hospitais , Antibacterianos/uso terapêutico
10.
Ren Fail ; 45(2): 2259230, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38376456

RESUMO

Wasp venom can trigger local and systemic reactions, with the kidneys being commonly affected, potentially causing acute kidney injury (AKI). Despite of the recent advances, our knowledge on the underlying mechanisms of toxicity and targeted therapies remain poor. AKI can result from direct nephrotoxic effects of the wasp venom or secondary rhabdomyolysis and intravascular hemolysis, which will release myoglobin and free hemoglobin. Inflammatory responses play a central role in these pathological mechanisms. Noteworthily, the successful establishment of a suitable experimental model can assist in basic research and clinical advancements related to wasp venom-induced AKI. The combination of therapeutic plasma exchange and continuous renal replacement therapy appears to be the preferred treatment for wasp venom-induced AKI. In addition, studies on cilastatin and varespladib for wasp venom-induced AKI treatment have shown their potential as therapeutic agents. This review summarizes the available evidence on the mechanisms and treatment of wasp venom-induced AKI, with a particular focus on the role of inflammatory responses and potential targets for therapeutic drugs, and, therefore, aiming to support the development of clinical treatment against wasp venom-induced AKI.


Assuntos
Injúria Renal Aguda , Venenos de Vespas , Humanos , Venenos de Vespas/toxicidade , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/terapia , Rim , Plasmaferese , Cilastatina
11.
Toxicon ; 220: 106960, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36341900

RESUMO

Cilastatin has been shown to prevent various drug-induced nephrotoxicities and confer renoprotection in a mouse model of glycerol-mediated rhabdomyolysis-induced acute kidney injury (AKI). The present study aimed to investigate whether cilastatin attenuates wasp sting-induced AKI in rats. Male Wistar rats were divided into the control, cilastatin, AKI, and AKI + cilastatin groups. Nephrotoxicity was assessed using renal function, rhabdomyolysis (creatine kinase, CK) and intravascular hemolysis (lactate dehydrogenase, LDH) markers, and histological changes. In addition, tubular injury biomarkers, apoptosis, oxidative stress markers, complement C3 expression, and urine and blood myoglobin levels were examined. Compared with the control or cilastatin group, the AKI group showed significant histological damage, increased levels of CK, LDH, and creatinine, and increased mRNA expression of tubular injury biomarkers. Cilastatin ameliorated wasp venom-induced kidney injury by attenuating oxidative stress and apoptosis. Cilastatin also reduced C3 expression in the renal tubular cells. In addition, cilastatin reduced serum myoglobin levels and increased urine myoglobin concentrations. Therefore, megalin blockade with cilastatin attenuates wasp venom-induced AKI owing to its antioxidative and antiapoptotic properties.


Assuntos
Injúria Renal Aguda , Cilastatina , Mordeduras e Picadas de Insetos , Rabdomiólise , Venenos de Vespas , Animais , Masculino , Camundongos , Ratos , Injúria Renal Aguda/induzido quimicamente , Biomarcadores , Cilastatina/uso terapêutico , Creatina Quinase , Rim , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Mioglobina/metabolismo , Ratos Wistar , Venenos de Vespas/toxicidade , Vespas
12.
Microbiol Spectr ; 10(4): e0093822, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-35852323

RESUMO

In the absence of a molecule that would collectively inhibit both metallo-ß-lactamases and serine-reactive carbapenemases, containment of their genes is the main weapon currently available for confronting carbapenem resistance in hospitals. Cost-effective methodologies rapidly detecting carbapenemase-producing enterobacteria (CPE) would facilitate such measures. Herein, a low-cost CPE detection method was developed that was based on the direct colorimetry of the yellow shift caused by the accumulation of diketopiperazines-products of the acid-catalyzed imipenem oligomerization-induced by carbapenemase action on dense solutions of imipenem/cilastatin. The reactions were studied by spectrophotometry in the visible spectrum using preparations of ß-lactamases from the four molecular classes. The effects of various buffers on reaction mixtures containing the potent carbapenemases NDM-1 and NMC-A were monitored at 405 nm. Optimal conditions were used for the analysis of cell suspensions, and the assay was evaluated using 66 selected enterobacteria, including 50 CPE as well as 16 carbapenemase-negative strains overexpressing other ß-lactamases. The development of the yellow color was specific for carbapenemase-containing enzyme preparations, and the maximum intensity was achieved in acidic or unbuffered conditions in the presence of zinc. When applied on bacterial cell suspensions, the assay could detect CPE with 98% sensitivity and 100% specificity, with results being comparable to those obtained with the Carba NP technique. Direct colorimetry of carbapenemase-induced imipenem decomposition required minimum reagents while exhibiting high accuracy in detecting CPE. Therefore, it should be considered for screening purposes after further clinical evaluation. IMPORTANCE Currently, the spread of multidrug-resistant (MDR) carbapenemase-producing enterobacteria (CPE), mostly in the clinical setting, is among the most pressing public health problems worldwide. In order to effectively control CPE, use of reliable and affordable methods detecting carbapenemase genes or the respective ß-lactamases is of vital importance. Herein, we developed a novel method, based on a previously undescribed phenomenon, that can detect CPE with few reagents by direct colorimetry of bacterial suspensions and imipenem/cilastatin mixtures.


Assuntos
Enterobacteriaceae , Imipenem , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Cilastatina/farmacologia , Colorimetria , Análise Custo-Benefício , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Suspensões , beta-Lactamases/genética
13.
J Antimicrob Chemother ; 77(11): 2992-2999, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-35906810

RESUMO

BACKGROUND: Imipenem and relebactam are predominantly excreted via glomerular filtration. Augmented renal clearance (ARC) is a common syndrome in critically-ill patients with sepsis, and sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the pharmacokinetics of imipenem/relebactam in critically-ill patients with ARC. METHODS: Infected patients in the ICU with ARC (CLCR ≥ 130 mL/min) received a single dose of imipenem/cilastatin/relebactam 1.25 g as a 30 min infusion. Blood samples were collected over 6 h for concentration determination. Protein binding was assessed by ultrafiltration. An 8 h urine creatinine collection confirmed ARC. Population pharmacokinetic models with and without covariates were fit using the non-parametric adaptive grid algorithm in Pmetrics. A 5000 patient Monte Carlo simulation assessed joint PTA using relebactam fAUC/MIC ≥8 and imipenem ≥40% fT>MIC. RESULTS: Eight patients with ARC completed the study. A base population pharmacokinetic model with two-compartments fitted the data best. The mean ±â€ŠSD parameters were: CL, 17.31 ±â€Š5.76 L/h; Vc, 16.15 ±â€Š7.75 L; k12, 1.62 ±â€Š0.99 h-1; and k21, 3.53 ±â€Š3.31 h-1 for imipenem, and 11.51 ±â€Š4.79 L/h, 16.54 ±â€Š7.43 L, 1.59 ±â€Š1.12 h-1, and 2.83 ±â€Š2.91 h-1 for relebactam. Imipenem/cilastatin/relebactam 1.25 g as a 30 min infusion every 6 h achieved 100% and 93% PTA at MICs of 1 and 2 mg/L, respectively. CONCLUSIONS: Despite enhanced clearance of both imipenem and relebactam, the currently approved dosing regimen for normal renal function was predicted to achieve optimal exposure in critically-ill patients with ARC sufficient to treat most susceptible pathogens.


Assuntos
Estado Terminal , Imipenem , Humanos , Cilastatina , Antibacterianos/uso terapêutico
14.
Int J Clin Pharmacol Ther ; 60(8): 358-363, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35652550

RESUMO

Imipenem cilastatin sodium, as a member of a new generation of ß-lactam antibiotics, has a broad spectrum of antibacterial activity and a very wide range of application. Thrombocytopenia has been reported as a rare adverse event in several studies of patients treated with imipenem cilastatin sodium. In this study, we present a case of thrombocytopenia associated with imipenem cilastatin sodium in an older patient. The 78-year-old male patient with pulmonary infection was initiated on anti-infection therapy with imipenem cilastatin sodium. On the 9th day after imipenem cilastatin sodium administration, the patient experienced a sudden and dramatic decrease in platelet count. Similarly, on the 4th day after the re-administration of imipenem cilastatin sodium for anti-infection therapy, the patient's platelet count showed a remarkable downward trend again. A time correlation between the drug therapy and the occurrence of platelet reaction was found. The patient's platelet count gradually returned to the normal level on the 6th day after the first drug withdrawal and the 13th day after the second drug withdrawal, respectively. Considering the widespread use of imipenem cilastatin sodium, healthcare providers should improve the notification of thrombocytopenia associated with imipenem cilastatin sodium.


Assuntos
Infecções Bacterianas , Trombocitopenia , Idoso , Antibacterianos/efeitos adversos , Infecções Bacterianas/tratamento farmacológico , Cilastatina/efeitos adversos , Combinação Imipenem e Cilastatina/uso terapêutico , Combinação de Medicamentos , Humanos , Imipenem/efeitos adversos , Masculino , Tienamicinas/uso terapêutico , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombocitopenia/tratamento farmacológico
15.
Cells ; 11(9)2022 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-35563891

RESUMO

The immunophilin FKBP51, the angiomotin AmotL2, and the scaffoldin IQGAP1 are overexpressed in many types of cancer, with the highest increase in leucocytes from patients undergoing oxaliplatin chemotherapy. Inflammation is involved in the pathogenesis of nephrotoxicity induced by platinum analogs. Cilastatin prevents renal damage caused by cisplatin. This functional and confocal microscopy study shows the renal focal-segmental expression of TNFα after cisplatin administration in rats, predominantly of tubular localization and mostly prevented by co-administration of cilastatin. FKBP51, AmotL2 and IQGAP1 protein expression increases slightly with cilastatin administration and to a much higher extent with cisplatin, in a cellular- and subcellular-specific manner. Kidney tubule cells expressing FKBP51 show either very low or no expression of TNFα, while cells expressing TNFα have low levels of FKBP51. AmotL2 and TNFα seem to colocalize and their expression is increased in tubular cells. IQGAP1 fluorescence increases with cilastatin, cisplatin and joint cilastatin-cisplatin treatment, and does not correlate with TNFα expression or localization. These data suggest a role for FKBP51, AmotL2 and IQGAP1 in cisplatin toxicity in kidney tubules and in the protective effect of cilastatin through inhibition of dehydropeptidase-I.


Assuntos
Cilastatina , Cisplatino , Angiomotinas , Animais , Proteínas de Transporte/metabolismo , Cilastatina/metabolismo , Cilastatina/farmacologia , Cilastatina/uso terapêutico , Cisplatino/metabolismo , Cisplatino/toxicidade , Humanos , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo
16.
Rev Esp Quimioter ; 35 Suppl 1: 46-49, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35488826

RESUMO

Imipenem combined with beta-lactamase inhibitor relebactam (IMI/REL) has an extensive bactericidal activity against Gram-negative pathogens producing class A or class C beta-lactamases, not active against class B and class D. The phase 3 clinical trial (RESTORE-IMI-2), double-blind, randomized, evaluated IMI/REL vs. piperacillin-tazobactam (PIP/TAZ) for treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), demonstrated non-inferiority at all-cause mortality at 28 days (15.9% vs 21.3%), favorable clinical response at 7-14 days end of treatment (61% vs 59.8%) and with minor serious adverse effects (26.7% vs 32%). IMI/REL is a therapeutic option in HAP and VAP at approved dosage imipenem 500 mg, cilastatin 500 mg and relebactam 250 mg once every 6h, by an IV infusion over 30 min.


Assuntos
Antibacterianos , Quimioterapia Combinada , Pneumonia Associada à Ventilação Mecânica , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Cilastatina/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Quimioterapia Combinada/efeitos adversos , Humanos , Imipenem/uso terapêutico , Gravidade do Paciente , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
J Antimicrob Chemother ; 77(6): 1570-1577, 2022 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-35373297

RESUMO

OBJECTIVES: The novel carbapenem/ß-lactamase inhibitor combination imipenem/cilastatin/relebactam has been developed for the treatment of infections due to carbapenemase-producing Enterobacteriaceae (CPE). Herein, we describe the in vivo evolution of imipenem/cilastatin/relebactam resistance in longitudinal intra-patient Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) strains isolated from a patient following ceftazidime/avibactam-based treatments. METHODS: WGS analysis was performed on KPC-Kp strains isolated at different times and during antimicrobial treatments from the same patient. Genome assemblies were performed using a hybrid approach using Illumina iSeq 100 and Minion Oxford Nanopore platforms. Subpopulation analysis and allele frequency determination was performed by mapping Illumina reads to blaKPC. RESULTS: During antimicrobial treatment, resistance to ceftazidime/avibactam was observed following 16 days of antimicrobial therapy. WGS results showed that all KPC-Kp exhibited a low SNP rate of divergence, belonged to ST512 and shared similar antimicrobial resistance and porin gene patterns. Genetic analysis demonstrated that the first ceftazidime/avibactam-resistant KPC-Kp strain harboured a blaKPC-53 gene in a Tn4401 transposon moved from IncFII(K) to a 43 kb IncX3 plasmid, while a imipenem/cilastatin/relebactam-resistant strain exhibited two copies of the Tn4401 transposon in IncFII(K) and IncX3 plasmids, resulting in an increased blaKPC copy number. Of note, frequency analysis demonstrated that imipenem/cilastatin/relebactam-resistant KPC-Kp consisted of mixed subpopulations harbouring blaKPC-40 and blaKPC-53 alleles. CONCLUSIONS: Our results show the in vivo evolution of genetic rearrangement conferring resistance to imipenem/relebactam in a patient with KPC-Kp infection and treated with different ceftazidime/avibactam-based treatments. The rapid development of mutations and the high adaptability of its genome highlight the potential threat of KPC-Kp.


Assuntos
Ceftazidima , Infecções por Klebsiella , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Proteínas de Bactérias/genética , Ceftazidima/farmacologia , Ceftazidima/uso terapêutico , Cilastatina , Combinação de Medicamentos , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Klebsiella , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , beta-Lactamases/genética
18.
Cardiovasc Intervent Radiol ; 45(7): 903-910, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35304614

RESUMO

Genicular artery embolization (GAE) has emerged as a treatment option to improve quality of life in patients suffering from moderate-to-severe pain refractory to conservative treatment of knee osteoarthritis, with encouraging results. This paper describes the study protocol of a single-center, double-blind, randomized controlled trial designed to evaluate and compare the safety and efficacy of GAE using imipenem/cilastatin vs. microspheres for the treatment of moderate-to-severe pain associated with knee osteoarthritis. We hypothesized that there will be no difference in safety and efficacy outcomes. The study received ethics approval of the institutional review board with number 4.364.391 / CAAE: 37590820.3.0000.5342 and is registered onto the Registro Brasileiro de Ensaios Clinicos (ReBEC), with number RBR-2h5rwgb. Technical success was defined as embolization of at least 1 feeding artery supplying the hyperemic synovium of the knee joint. Primary outcome: clinical success was defined as improvement in symptoms, 50% reduction in Western Ontario and McMaster Universities Osteoarthritis Index pain scores or an increase of at least 10 points in the Knee Injury and Osteoarthritis Outcome Score from baseline to 3 months of follow-up. Secondary outcome: radiological success was defined as significant improvement in the Whole-Organ Magnetic Resonance Imaging Score for knee synovitis considering the embolized areas at 12 months of follow-up after GAE and a reduction in the analgesia or other conservative therapies for knee pain used by the patient at 3 and 12 months of follow-up. Clinical assessments will be performed before GAE, during GAE and at hospital discharge (for Visual Analog Scale of pain), and at 30 days, 3 months, and 12 months after GAE.


Assuntos
Osteoartrite do Joelho , Artérias , Cilastatina , Método Duplo-Cego , Humanos , Imipenem/uso terapêutico , Articulação do Joelho , Microesferas , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/terapia , Dor/complicações , Qualidade de Vida , Resultado do Tratamento
19.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35197290

RESUMO

Aminoglycosides (AGs) are commonly used antibiotics that cause deafness through the irreversible loss of cochlear sensory hair cells (HCs). How AGs enter the cochlea and then target HCs remains unresolved. Here, we performed time-lapse multicellular imaging of cochlea in live adult hearing mice via a chemo-mechanical cochleostomy. The in vivo tracking revealed that systemically administered Texas Red-labeled gentamicin (GTTR) enters the cochlea via the stria vascularis and then HCs selectively. GTTR uptake into HCs was completely abolished in transmembrane channel-like protein 1 (TMC1) knockout mice, indicating mechanotransducer channel-dependent AG uptake. Blockage of megalin, the candidate AG transporter in the stria vascularis, by binding competitor cilastatin prevented GTTR accumulation in HCs. Furthermore, cilastatin treatment markedly reduced AG-induced HC degeneration and hearing loss in vivo. Together, our in vivo real-time tracking of megalin-dependent AG transport across the blood-labyrinth barrier identifies new therapeutic targets for preventing AG-induced ototoxicity.


Assuntos
Antibacterianos/metabolismo , Gentamicinas/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Animais , Antibacterianos/toxicidade , Transporte Biológico , Cilastatina/farmacologia , Endolinfa/metabolismo , Gentamicinas/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Audição/efeitos dos fármacos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores , Camundongos , Estria Vascular/metabolismo
20.
Clin Transl Sci ; 15(2): 396-408, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34704389

RESUMO

In the phase III RESTORE-IMI 2 study (ClinicalTrials.gov: NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all-cause mortality at day 28 and favorable clinical response at the early follow-up visit in adult participants with gram-negative hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE-IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to <150 ml/min), renal impairment (mild, CrCl ≥60 to <90 ml/min; moderate, CrCl ≥30 to <60 ml/min; or severe, CrCl ≥15 to <30 ml/min), and end-stage renal disease (CrCl <15 ml/min). At the recommended IMI/REL dosing regimens across renal categories, greater than 90% of patients in all renal function groups were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at a minimum inhibitory concentration breakpoint of ≤2 µg/ml, regardless of ventilation status. This modeling and simulation analysis supports use of the recommended IMI/REL dosing regimens, adjusted based on renal function, in patients with HABP/VABP.


Assuntos
Imipenem , Pneumonia Bacteriana , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos , Cilastatina/uso terapêutico , Hospitais , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Ventiladores Mecânicos
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