RESUMEN
We assessed 160 patients who received imipenem/cilastatin/relebactam for ≥2 days. At treatment initiation, the median Charlson Comorbidity Index was 5, 45% were in the intensive care unit, and 19% required vasopressor support. The in-hospital mortality rate was 24%. These data advance our understanding of real-world indications and outcomes of imipenem/cilastatin/relebactam use.
Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , Cilastatina , Imipenem , Humanos , Masculino , Antibacterianos/farmacología , Femenino , Imipenem/farmacología , Persona de Mediana Edad , Anciano , Cilastatina/farmacología , Cilastatina/administración & dosificación , Cilastatina/uso terapéutico , Estados Unidos , Compuestos de Azabiciclo/farmacología , Combinación Cilastatina e Imipenem/administración & dosificación , Mortalidad Hospitalaria , Estudios Retrospectivos , Unidades de Cuidados Intensivos , Anciano de 80 o más Años , Resultado del Tratamiento , AdultoRESUMEN
OBJECTIVE: By creating nephrotoxicity models with cisplatin, vancomycin, and gentamicin in HK-2 (human renal proximal tubule cell) and HEK293T (human embryonic kidney epithelial cells) cell lines, we aimed to evaluate the effect of cilastatin on recovery of cell damage after toxicity had occurred. MATERIALS AND METHODS: In the first phase of the study, the doses of cisplatin, vancomycin, and gentamicin (50% inhibitive concentration; IC50) were determined. In the second phase, the effective dose of cilastatin against these drugs was determined, and IC50 doses of nephrotoxic agents were administered simultaneously. In the third phase of our study, to evaluate the possible therapeutic effect of cilastatin after toxicity had occurred, the analyses of cell viability, apoptosis, oxidative stress, expression of kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) were performed. RESULTS: In the second phase of the study, it was observed that cilastatin increased cell viability when treated simultaneously with a nephrotoxic agent. In the third phase, cilastatin provided a significant increase in cell viability. After treatment with each agent for 24 hours, we determined that adding cilastatin to the medium had an effect on the recovery of cell damage by increasing cell viability and reducing apoptosis and oxidative stress. The expression of KIM-1 and NGAL increased when nephrotoxicity occurred and decreased with the addition of cilastatin to the medium. CONCLUSIONS: The findings of the study suggest that cilastatin may have a healing effect after the development of nephrotoxicity.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Cilastatina/farmacología , Enfermedades Renales/prevención & control , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular , Cilastatina/administración & dosificación , Cisplatino/administración & dosificación , Cisplatino/toxicidad , Relación Dosis-Respuesta a Droga , Gentamicinas/administración & dosificación , Gentamicinas/toxicidad , Células HEK293 , Receptor Celular 1 del Virus de la Hepatitis A/genética , Humanos , Concentración 50 Inhibidora , Enfermedades Renales/inducido químicamente , Lipocalina 2/genética , Vancomicina/administración & dosificación , Vancomicina/toxicidadRESUMEN
Imipenem/cilastatin/relebactam (Recarbrio™) is an intravenously administered combination of the carbapenem imipenem, the renal dehydropeptidase-I inhibitor cilastatin, and the novel ß-lactamase inhibitor relebactam. Relebactam is a potent inhibitor of class A and class C ß-lactamases, conferring imipenem activity against many imipenem-nonsusceptible strains. Imipenem/cilastatin/relebactam is approved in the USA and EU for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) in adults and other gram-negative infections, including complicated urinary tract infections (cUTIs) [including pyelonephritis] and complicated intra-abdominal infections (cIAIs), in adults with limited or no alternative treatment options. In pivotal phase II and III trials, imipenem/cilastatin/relebactam was noninferior to piperacillin/tazobactam in patients with HABP/VABP and to imipenem/cilastatin in patients with cUTIs and cIAIs. It was also effective in imipenem-nonsusceptible infections. Imipenem/cilastatin/relebactam was generally well tolerated, with a safety profile consistent with that of imipenem/cilastatin. Available evidence indicates that imipenem/cilastatin/relebactam is an effective and generally well tolerated option for gram-negative infections in adults, including critically ill and/or high-risk patients, and a potential therapy for infections caused by carbapenem-resistant pathogens.
Asunto(s)
Antibacterianos/farmacología , Compuestos de Azabiciclo/farmacología , Cilastatina/farmacología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Imipenem/farmacología , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , Antibacterianos/administración & dosificación , Compuestos de Azabiciclo/administración & dosificación , Cilastatina/administración & dosificación , Combinación de Medicamentos , Infecciones por Bacterias Gramnegativas/metabolismo , Humanos , Imipenem/administración & dosificación , Inyecciones Intravenosas , Inhibidores de beta-Lactamasas/administración & dosificaciónRESUMEN
Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias del Colon/tratamiento farmacológico , Insuficiencia Renal/prevención & control , Animales , Apoptosis , Proliferación Celular , Cilastatina/administración & dosificación , Cisplatino/administración & dosificación , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Tasa de Filtración Glomerular , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.
Asunto(s)
Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Cilastatina/uso terapéutico , Imipenem/uso terapéutico , Infecciones Urinarias/tratamiento farmacológico , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Compuestos de Azabiciclo/administración & dosificación , Compuestos de Azabiciclo/farmacocinética , Cilastatina/administración & dosificación , Cilastatina/farmacocinética , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Quimioterapia Combinada , Bacterias Gramnegativas/efectos de los fármacos , Humanos , Imipenem/administración & dosificación , Imipenem/farmacocinética , Masculino , Pruebas de Sensibilidad Microbiana , Infecciones Urinarias/microbiologíaRESUMEN
INTRODUCTION: Cilastatin, a dehydropeptidase I inhibitor, has been used alongside imipenem, a broad spectrum antibiotic, in order to reduce its renal metabolism, consequently increasing its urinary recovery and effectiveness for many years. However, this measure could be useful in preventing imipenem-induced renal damage and decreasing the number of nephrotoxicity reports with imipenem. In this review, the authors gathered all available studies focusing on cilastatin use as a nephroprotective agent, beside well-known nephrotoxic medications like vancomycin, cisplatin, cyclosporine, or tacrolimus. AREAS COVERED: PubMed, Scopus, Google Scholar, and Medline databases were searched using key words like 'cilastatin,' 'nephroprotective,' 'nephroprotection,' 'vancomycin,' 'nephrotoxicity,' 'cisplatin,' 'cyclosporine,' 'tacrolimus,' and 'prevention' with varying combinations. All relevant animal and human studies up to the date of publication were included. EXPERT OPINION: It seems that cilastatin could potentially be effective against drug-induced nephrotoxicity via mechanisms such as reducing reactive oxygen species (ROS) production, apoptosis, P-glycoprotein suppression, and morphological changes of renal cells. Nearly all the in vitro, in vivo and human studies have supported this hypothesis. Though since cilastatin protective effect has not extensively been researched in humans, its efficacy and widespread use with other nephrotoxic agents is yet to be defined in large well-designed human studies.
Asunto(s)
Cilastatina/administración & dosificación , Enfermedades Renales/prevención & control , Inhibidores de Proteasas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Cilastatina/farmacología , Humanos , Enfermedades Renales/inducido químicamente , Inhibidores de Proteasas/farmacología , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Imipenem-cilastatin-relebactam (IMI-REL) is a novel ß-lactam-ß-lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a ß-lactamase inhibitor with the ability to inhibit a broad spectrum of ß-lactamases such as class A and class C ß-lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem-resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI-REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem-resistant bacteria. In a phase III trial comparing IMI-REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30-minute infusion of imipenem 500 mg-cilastatin 500 mg-relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI-REL represents another important step in the ongoing fight against multidrug-resistant gram-negative pathogens.
Asunto(s)
Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Compuestos de Azabiciclo/administración & dosificación , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Cilastatina/administración & dosificación , Cilastatina/farmacología , Cilastatina/uso terapéutico , Quimioterapia Combinada , Bacterias Gramnegativas/efectos de los fármacos , Humanos , Imipenem/administración & dosificación , Imipenem/farmacología , Imipenem/uso terapéutico , Pruebas de Sensibilidad MicrobianaRESUMEN
OBJECTIVES: Relebactam is a small molecule ß-lactamase inhibitor under clinical investigation for use as a fixed-dose combination with imipenem/cilastatin. Here we present a translational pharmacokinetic/pharmacodynamic mathematical model to support optimal dose selection of relebactam. METHODS: Data derived from in vitro checkerboard and hollow fiber infection studies of imipenem-resistant strains of Pseudomonas aeruginosa were incorporated into the model. The model integrates the effect of relebactam concentration on imipenem susceptibility in a semi-mechanistic manner using the checkerboard data and characterizes the bacterial time-kill profiles from the hollow fiber infection model data. RESULTS: Simulations demonstrated that the ratio of the area under the concentration-time curve for free drug to the minimum inhibitory concentration (fAUC/MIC) was the pharmacokinetic driver for relebactam, with a target fAUC/MIC=7.5 associated with 2-log kill. At a clinical dose of 250mg relebactam, greater than 2-log reductions in bacterial load are projected for imipenem-resistant strains with an imipenem/relebactam MIC≤4µg/mL. CONCLUSIONS: The study confirms that the pharmacokinetic/pharmacodynamic driver for relebactam is fAUC/MIC, that an fAUC/MIC ratio of 7.5 is associated with 2-log kill in vitro, and that a 250mg clinical dose of relebactam achieves this target value when delivered in combination with imipenem/cilastatin.
Asunto(s)
Antibacterianos/farmacocinética , Compuestos de Azabiciclo/farmacocinética , Imipenem/farmacocinética , Modelos Teóricos , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Inhibidores de beta-Lactamasas/farmacocinética , Antibacterianos/administración & dosificación , Compuestos de Azabiciclo/administración & dosificación , Cilastatina/administración & dosificación , Cilastatina/farmacocinética , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana , Humanos , Imipenem/administración & dosificación , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/microbiología , Inhibidores de beta-Lactamasas/administración & dosificaciónRESUMEN
RATIONALE: A 27-year-old woman with a history of systemic lupus erythaematosus (SLE) developed hemophagocytic syndrome (HPS) secondary due to an unrecognized infection that led to severe SLE with a prolonged recovery. PATIENT CONCERNS: The patient showed a high spiking fever and myalgia. Laboratory data revealed pancytopenia and immunological abnormalities. Pulse methylprednisone plus intravenous immunoglobulin (IVIG) failed to improve the clinical symptoms and laboratory data. DIAGNOSES: As activated macrophages with hemophagocytosis were confirmed in bone marrow histology, the patient was diagnosed as having reactive HPS. INTERVENTIONS AND OUTCOMES: Her reactive HPS was successfully treated with intravenous antibiotics and was followed by oral prednisolone and hydroxychloroquine maintenance therapy. LESSONS: In severe SLE, patients with persistent high fever, cytopenia, and elevated levels of serum ferritin and liver enzymes should be strongly suspected of reactive HPS, and aggressive examination, such as bone marrow biopsy, needs to be considered for early diagnosis and proper treatment.
Asunto(s)
Cilastatina/administración & dosificación , Hidroxicloroquina/administración & dosificación , Imipenem/administración & dosificación , Pulmón/diagnóstico por imagen , Lupus Eritematoso Sistémico , Linfohistiocitosis Hemofagocítica , Neumonía , Prednisolona/administración & dosificación , Adulto , Antibacterianos/administración & dosificación , Antirreumáticos/administración & dosificación , Recuento de Células Sanguíneas/métodos , Examen de la Médula Ósea/métodos , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/inmunología , Neumonía/complicaciones , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: The appropriate use of broad-spectrum antibiotics, including appropriate de-escalation, is essential to reduce the emergence of antibiotic resistance. In surgical floors antibiotics are prescribed for prophylaxis (mostly, single dose), empirical treatment (started if infection is suspected till bacteria are identified with its sensitivity to antibiotics), or treatment of well-defined infection of previously isolated bacteria with its sensitivity to antibiotics. In this study, we aimed to evaluate the use of broad-spectrum antibiotics based on requests for cultures and de-escalation based on sensitivity results of culture tests at tertiary care hospital. METHOD: A retrospective cohort study was conducted to evaluate the utilization of broad-spectrum antibiotics on surgical floors at a tertiary care center in Jeddah, Saudi Arabia. Patients who are admitted to surgical floors were included if they received any of three broad-spectrum antibiotics (piperacillin-tazobactam, imipenem-cilastatin or meropenem) from 1 June 2014 to 31 August 2014. Data were collected on whether culture and sensitivity test requests were made within 24h of starting antibiotics, the duration of antibiotic therapy and the number of days to de-escalation after receiving culture and sensitivity results. RESULTS: Of the 163 patients who received broad-spectrum antibiotics, culture tests were requested in 112. Before receiving culture results, one patient was discharged and one died. The results of culture tests justified continuation of broad-spectrum antibiotics in only 22 patients, whereas 24 showed no microbial growth in any culture. De-escalation was delayed >24h after culture results became available in 33 out of 64 eligible patients. On the other hand, 51 patients continued receiving broad spectrum antibiotics without any culture test during the whole treatment course. CONCLUSION: The use of broad-spectrum antibiotics in surgical floors at a tertiary care hospital in Saudi Arabia was largely unjustified by culture-test result. Interventions are needed to enforce culture and sensitivity test requests within 24h of starting the broad spectrum antibiotics therapy with further follow up to ensure appropriate de-escalation and discontinuation whenever indicated.
Asunto(s)
Antibacterianos/administración & dosificación , Cilastatina/administración & dosificación , Utilización de Medicamentos/estadística & datos numéricos , Imipenem/administración & dosificación , Ácido Penicilánico/análogos & derivados , Infección de la Herida Quirúrgica/prevención & control , Centros de Atención Terciaria , Adulto , Anciano , Antibacterianos/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos/métodos , Cilastatina/uso terapéutico , Combinación Cilastatina e Imipenem , Estudios de Cohortes , Recuento de Colonia Microbiana , Combinación de Medicamentos , Femenino , Humanos , Imipenem/uso terapéutico , Masculino , Meropenem , Persona de Mediana Edad , Ácido Penicilánico/administración & dosificación , Ácido Penicilánico/uso terapéutico , Piperacilina/administración & dosificación , Piperacilina/uso terapéutico , Combinación Piperacilina y Tazobactam , Mal Uso de Medicamentos de Venta con Receta/estadística & datos numéricos , Estudios Retrospectivos , Arabia Saudita , Infección de la Herida Quirúrgica/tratamiento farmacológico , Infección de la Herida Quirúrgica/microbiología , Tienamicinas/administración & dosificación , Tienamicinas/uso terapéuticoRESUMEN
BACKGROUND: Burn patients are prone to infections which often necessitate broad antibiotic coverage. Vancomycin is a common antibiotic after burn injury and is administered alone (V), or in combination with imipenem-cilastin (V/IC) or piperacillin-tazobactam (V/PT). Sparse reports indicate that the combination V/PT is associated with increased renal dysfunction. The purpose of this study was to evaluate the short-term impact of the three antibiotic administration types on renal dysfunction. METHODS: All pediatric and adult patients admitted to our centers between 2004 and 2016 with a burn injury were included in this retrospective review if they met the criteria of exposition to either V, V/IC, or V/PT for at least 48 h, had normal baseline creatinine, and no pre-existing renal dysfunction. Creatinine was monitored for 7 days after initial exposure; the absolute and relative increase was calculated, and patient renal outcomes were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria depending on creatinine increases and estimated creatinine clearance. Secondary endpoints (demographic and clinical data, incidences of septicemia, and renal replacement therapy) were analyzed. Antibiotic doses were modeled in logistic and linear multivariable regression models to predict categorical KDIGO events and relative creatinine increase. RESULTS: Out of 1449 patients who were screened, 718 met the inclusion criteria, 246 were adults, and 472 were children. Between the study cohorts V, V/IC, and V/PT, patient characteristics at admission were comparable. V/PT administration was associated with a statistically higher serum creatinine, and lower creatinine clearance compared to patients receiving V alone or V/IC in adults and children after burn injury. The incidence of KDIGO stages 1, 2, and 3 was higher after V/PT treatment. In children, the incidence of KDIGO stage 3 following administration of V/PT was greater than after V/IC. In adults, the incidence of renal replacement therapy was higher after V/PT compared with V or V/IC. Multivariate modeling demonstrated that V/PT is an independent predictor of renal dysfunction. CONCLUSION: Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in pediatric and adult burn patients when compared to vancomycin alone or vancomycin plus imipenem-cilastin. The mechanism of this increased nephrotoxicity remains elusive and warrants further scientific evaluation.
Asunto(s)
Lesión Renal Aguda/etiología , Quemaduras/tratamiento farmacológico , Ácido Penicilánico/análogos & derivados , Vancomicina/efectos adversos , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/fisiopatología , Adolescente , Adulto , Análisis de Varianza , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Niño , Preescolar , Cilastatina/administración & dosificación , Cilastatina/efectos adversos , Cilastatina/uso terapéutico , Combinación Cilastatina e Imipenem , Estudios de Cohortes , Creatinina/análisis , Creatinina/sangre , Combinación de Medicamentos , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/normas , Femenino , Humanos , Imipenem/administración & dosificación , Imipenem/efectos adversos , Imipenem/uso terapéutico , Incidencia , Infecciones/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Ácido Penicilánico/administración & dosificación , Ácido Penicilánico/efectos adversos , Ácido Penicilánico/uso terapéutico , Piperacilina/administración & dosificación , Piperacilina/efectos adversos , Piperacilina/uso terapéutico , Combinación Piperacilina y Tazobactam , Estudios Retrospectivos , Texas/epidemiología , Vancomicina/administración & dosificación , Vancomicina/uso terapéuticoRESUMEN
Objectives: The ß-lactamase inhibitor relebactam can restore imipenem activity against imipenem non-susceptible pathogens. Methods: To explore relebactam's safety, tolerability and efficacy, we conducted a randomized (1:1:1), controlled, Phase 2 trial comparing imipenem/cilastatin+relebactam 250 mg, imipenem/cilastatin+relebactam 125 mg and imipenem/cilastatin alone in adults with complicated urinary tract infections (cUTI) or acute pyelonephritis, regardless of baseline pathogen susceptibility. Treatment was administered intravenously every 6 h for 4-14 days, with optional step-down to oral ciprofloxacin. The primary endpoint was favourable microbiological response rate (pathogen eradication) at discontinuation of intravenous therapy (DCIV) in the microbiologically evaluable (ME) population. Non-inferiority of imipenem/cilastatin+relebactam over imipenem/cilastatin alone was defined as lower bounds of the 95% CI for treatment differences being above -15%. Results: At DCIV, 71 patients in the imipenem/cilastatinâ¯+â¯250 mg relebactam, 79 in the imipenem/cilastatinâ¯+â¯125 mg relebactam and 80 in the imipenem/cilastatin-only group were ME; 51.7% had cUTI and 48.3% acute pyelonephritis. Microbiological response rates were 95.5%, 98.6% and 98.7%, respectively, confirming non-inferiority of both imipenem/cilastatinâ¯+â¯relebactam doses to imipenem/cilastatin alone. Clinical response rates were 97.1%, 98.7% and 98.8%, respectively. All 23 ME patients with imipenem non-susceptible pathogens had favourable DCIV microbiological responses (100% in each group). Among all 298 patients treated, 28.3%, 29.3% and 30.0% of patients, respectively, had treatment-emergent adverse events. The most common treatment-related adverse events across groups (1.0%-4.0%) were diarrhoea, nausea and headache. Conclusions: Imipenem/cilastatinâ¯+â¯relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI. Both relebactam-containing regimens were well tolerated. (NCT01505634).
Asunto(s)
Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Cilastatina/uso terapéutico , Imipenem/uso terapéutico , Infecciones Urinarias/tratamiento farmacológico , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Compuestos de Azabiciclo/administración & dosificación , Compuestos de Azabiciclo/efectos adversos , Cilastatina/administración & dosificación , Cilastatina/efectos adversos , Combinación Cilastatina e Imipenem , Método Doble Ciego , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Imipenem/administración & dosificación , Imipenem/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pielonefritis/tratamiento farmacológico , Infecciones Urinarias/microbiología , Adulto Joven , Inhibidores de beta-Lactamasas/administración & dosificación , Inhibidores de beta-Lactamasas/efectos adversos , Inhibidores de beta-Lactamasas/uso terapéuticoRESUMEN
The Carba NP test is a simple confirmation method for carbapenemase-producing Enterobacteriaceae (CPE) but reagents have to be freshly prepared as imipenem sodium salt is unstable. We evaluated the Carba NP test performance based on a commercially available 10-fold cheaper drug formulation containing cilastatin against 217 CPE and 78 non-CPE isolates with reduced meropenem susceptibility. Specificity and sensitivity were 100 % and 98.6 %, respectively and 3 false negative results of blaVIM-1-producing Proteus mirabilis were reproducible with the RAPIDEC® Carba NP test. Cilastatin does not disturb test performance provided that the imipenem drug quantity is doubled.
Asunto(s)
Proteínas Bacterianas/metabolismo , Técnicas de Tipificación Bacteriana/métodos , Cilastatina/administración & dosificación , Enterobacteriaceae/enzimología , Enterobacteriaceae/aislamiento & purificación , beta-Lactamasas/metabolismo , Proteínas Bacterianas/análisis , Enterobacteriaceae/efectos de los fármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , beta-Lactamasas/análisisRESUMEN
STUDY OBJECTIVE: High-dose continuous venovenous hemofiltration (CVVH) is a continuous renal replacement therapy (CRRT) used frequently in patients with burns. However, antibiotic dosing is based on inference from studies assessing substantially different methods of CRRT. To address this knowledge gap for imipenem/cilastatin (I/C), we evaluated the systemic and extracorporeal clearances (CLs) of I/C in patients with burns undergoing high-dose CVVH. DESIGN: Prospective clinical pharmacokinetic study. PATIENTS: Ten adult patients with burns receiving I/C for a documented infection and requiring high-dose CVVH were studied. METHODS: Blood and effluent samples for analysis of I/C concentrations were collected for up to 6 hours after the I/C infusion for calculation of I/C total CL (CLTotal ), CL by CVVH (CLHF ), half-life during CVVH, volume of distribution at steady state (Vdss ), and the percentage of drug eliminated by CVVH. RESULTS: In this patient sample, the mean age was 50 ± 17 years, total body surface area burns was 23 ± 27%, and 80% were male. Nine patients were treated with high-dose CVVH for acute kidney injury and one patient for sepsis. The mean delivered CVVH dose was 52 ± 14 ml/kg/hour (range 32-74 ml/kg/hr). The imipenem CLHF was 3.27 ± 0.48 L/hour, which accounted for 23 ± 4% of the CLTotal (14.74 ± 4.75 L/hr). Cilastatin CLHF was 1.98 ± 0.56 L/hour, which accounted for 45 ± 19% of the CLTotal (5.16 + 2.44 L/hr). The imipenem and cilastatin half-lives were 1.77 ± 0.38 hours and 4.21 ± 2.31 hours, respectively. Imipenem and cilastatin Vdss were 35.1 ± 10.3 and 32.8 ± 13.8 L, respectively. CONCLUSION: Efficient removal of I/C by high-dose CVVH, a high overall clearance, and a high volume of distribution in burn intensive care unit patients undergoing this CRRT method warrant aggressive dosing to treat serious infections effectively depending on the infection site and/or pathogen.
Asunto(s)
Antibacterianos/farmacocinética , Quemaduras/tratamiento farmacológico , Cilastatina/farmacocinética , Hemofiltración/métodos , Imipenem/farmacocinética , Lesión Renal Aguda/terapia , Adulto , Anciano , Antibacterianos/administración & dosificación , Infecciones Bacterianas/tratamiento farmacológico , Quemaduras/complicaciones , Quemaduras/patología , Cilastatina/administración & dosificación , Combinación Cilastatina e Imipenem , Combinación de Medicamentos , Femenino , Semivida , Humanos , Imipenem/administración & dosificación , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Distribución Tisular , Adulto JovenRESUMEN
Antimicrobial chitosan-polyethylene oxide (CS-PEO) nanofibrous mats containing ZnO nanoparticles (NPs) and hydrocortisone-imipenem/cilastatin-loaded ZnO NPs were produced by electrospinning technique. The FE-SEM images displayed that the spherical ZnO NPs were â¼70-200nm in size and the CS-PEO nanofibers were very uniform and free of any beads which had average diameters within the range of â¼20-130nm. For all of the nanofibrous mats, the water uptakes were the highest in acidic medium but they were decreased in the buffer and the least swellings were obtained in the alkaline environment. The drug incorporated mat preserved its bactericidal activity even after it was utilized in the release experiment for 8days in the PBS buffer. The hydrocortisone release was increased to 82% within first 12h while the release rate of imipenem/cilastatin was very much slower so that 20% of the drug was released during this period of time suggesting this nanofibrous mat is very suitable to inhibit inflammation (by hydrocortisone) and infection (using imipenem/cilastatin antibiotic and ZnO NPs) principally for the wound dressing purposes.
Asunto(s)
Antibacterianos , Antiinflamatorios , Cilastatina , Sistemas de Liberación de Medicamentos , Hidrocortisona , Imipenem , Antibacterianos/administración & dosificación , Antibacterianos/química , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Quitosano/administración & dosificación , Quitosano/química , Cilastatina/administración & dosificación , Cilastatina/química , Combinación Cilastatina e Imipenem , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Combinación de Medicamentos , Liberación de Fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Hidrocortisona/administración & dosificación , Hidrocortisona/química , Imipenem/administración & dosificación , Imipenem/química , Nanofibras/administración & dosificación , Nanofibras/química , Nanopartículas/administración & dosificación , Nanopartículas/química , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Óxido de Zinc/administración & dosificación , Óxido de Zinc/químicaRESUMEN
A 23-year-old Japanese woman was admitted to A hospital due to pneumonia. IgM for Mycoplasma pneumoniae was positive, and the patient was treated with imipenem/cilastatin, clindamycin, pazufloxacin and minocycline. However, both the chest radiological findings and the symptoms became exacerbated, and she was therefore transferred to our hospital. The bronchoalveolar lavage fluid was obtained, and a 16S rRNA gene sequencing analysis revealed a monobacterial infection of Mycoplasma pneumoniae. Therefore, corticosteroid treatment in addition to minocycline was administered, and the patients symptoms, laboratory data and chest radiographs improved. Corticosteroid therapy may therefore be considered for patients with refractory M. pneumoniae pneumonia.
Asunto(s)
Corticoesteroides/uso terapéutico , Antibacterianos/uso terapéutico , Líquido del Lavado Bronquioalveolar/microbiología , Mycoplasma pneumoniae/aislamiento & purificación , Neumonía por Mycoplasma/diagnóstico , ARN Ribosómico 16S/aislamiento & purificación , Adulto , Cilastatina/administración & dosificación , Combinación Cilastatina e Imipenem , Clindamicina/administración & dosificación , Progresión de la Enfermedad , Combinación de Medicamentos , Farmacorresistencia Bacteriana , Femenino , Fluoroquinolonas/administración & dosificación , Humanos , Imipenem/administración & dosificación , Minociclina/administración & dosificación , Mycoplasma pneumoniae/genética , Oxazinas/administración & dosificación , Neumonía por Mycoplasma/tratamiento farmacológico , Radiografía Torácica , Resultado del TratamientoRESUMEN
A 78-year-old woman who had been treated for two years with ITCZ for chronic pulmonary aspergillosis associated with prior pulmonary tuberculosis was admitted to our hospital because of general fatigue and hemosputum along with deterioration of her chest radiographic findings. Mycobacterium abscessus had been isolated once from her sputum one year before admission. We performed fiberoptic bronchoscopy (FOB) in order to help establish a final diagnosis. Sputum aspirated from her bronchus on FOB stained positive for acid-fast bacilli and was negative for Tbc and MAC using PCR. From these results, we diagnosed the patient with pulmonary M. abscessus infection. Chemotherapy with AMK, IPM/cs, and CAM was initiated. Because her symptoms rapidly improved, we switched the chemotherapy to long-term oral CAM and LVFX, and she has been in a good condition at 12 months after the initiation of the therapy. Recently, subtypes of M. abscessus complex, such as M. massiliense, have been recognized, which are more sensitive to chemotherapy. Considering the good response to therapy, there is a possibility that is the patient in the current case had a M. massiliense infection.
Asunto(s)
Antibacterianos/administración & dosificación , Enfermedades Pulmonares/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Administración Oral , Anciano , Amicacina/administración & dosificación , Antibacterianos/uso terapéutico , Cilastatina/administración & dosificación , Combinación Cilastatina e Imipenem , Claritromicina/administración & dosificación , Combinación de Medicamentos , Femenino , Humanos , Imipenem/administración & dosificación , Levofloxacino/administración & dosificación , Micobacterias no TuberculosasAsunto(s)
Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/efectos de los fármacos , Cilastatina/uso terapéutico , Colistina/uso terapéutico , Imipenem/uso terapéutico , Minociclina/análogos & derivados , Neumonía Asociada al Ventilador/tratamiento farmacológico , Infecciones por Acinetobacter/mortalidad , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Cilastatina/administración & dosificación , Combinación Cilastatina e Imipenem , Colistina/administración & dosificación , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Imipenem/administración & dosificación , Minociclina/administración & dosificación , Minociclina/uso terapéutico , Neumonía Asociada al Ventilador/microbiología , Neumonía Asociada al Ventilador/mortalidad , Pronóstico , Estudios Retrospectivos , Terapia Recuperativa , Análisis de Supervivencia , Tigeciclina , Túnez/epidemiologíaRESUMEN
French guidelines recommend central intravenous (i.v.) infusion for high concentrations of vancomycin, but peripheral intravenous (p.i.v.) infusion is often preferred in intensive care units. Vancomycin infusion has been implicated in cases of phlebitis, with endothelial toxicity depending on the drug concentration and the duration of the infusion. Vancomycin is frequently infused in combination with other i.v. antibiotics through the same administrative Y site, but the local toxicity of such combinations has been poorly evaluated. Such an assessment could improve vancomycin infusion procedures in hospitals. Human umbilical vein endothelial cells (HUVEC) were challenged with clinical doses of vancomycin over 24 h with or without other i.v. antibiotics. Cell death was measured with the alamarBlue test. We observed an excess cellular death rate without any synergistic effect but dependent on the numbers of combined infusions when vancomycin and erythromycin or gentamicin were infused through the same Y site. Incompatibility between vancomycin and piperacillin-tazobactam was not observed in our study, and rinsing the cells between the two antibiotic infusions did not reduce endothelial toxicity. No endothelial toxicity of imipenem-cilastatin was observed when combined with vancomycin. p.i.v. vancomycin infusion in combination with other medications requires new recommendations to prevent phlebitis, including limiting coinfusion on the same line, reducing the infusion rate, and choosing an intermittent infusion method. Further studies need to be carried out to explore other drug combinations in long-term vancomycin p.i.v. therapy so as to gain insight into the mechanisms of drug incompatibility under multidrug infusion conditions.
Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Quimioterapia Combinada/efectos adversos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Vancomicina/administración & dosificación , Vancomicina/efectos adversos , Muerte Celular/efectos de los fármacos , Células Cultivadas , Cilastatina/administración & dosificación , Cilastatina/efectos adversos , Combinación Cilastatina e Imipenem , Combinación de Medicamentos , Eritromicina/administración & dosificación , Eritromicina/efectos adversos , Gentamicinas/administración & dosificación , Gentamicinas/efectos adversos , Humanos , Imipenem/administración & dosificación , Imipenem/efectos adversos , Infusiones Intravenosas/métodosRESUMEN
We herein report the case of 34-year-old woman with acute tricuspid valve infective endocarditis (IE) associated with a ruptured sinus of Valsalva and multiple septic pulmonary emboli. She had no history of medical problems, except for atopic dermatitis (AD). Blood cultures identified methicillin-sensitive Staphylococcus aureus. Despite the administration of two months of antibiotic therapy, the patient experienced recurrent pulmonary emboli and developed heart failure due to a left-to-right shunt, whereas the area of vegetation did not change in size. She subsequently underwent surgery for shunt closure and tricuspid valve replacement. The AD was thought to be the cause of the patient's bacteremia, which consequently resulted in aggressive right-sided IE.