RESUMEN

BACKGROUND AND OBJECTIVE: Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF). METHODS: Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cleff) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days. RESULTS: HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem (ß = - 8.90 (95% CI - 12.9 to - 4.87), p < 0.001) and tazobactam (ß = - 8.29 (95% CI - 13.5 to - 3.08), p = 0.002) and Cleff for each antibiotic (meropenem ß = - 10,206 (95% CI - 14,787 to - 5787), p = 0.001); tazobactam (ß = - 4551 (95% CI - 7781 to - 1322), p = 0.012); piperacillin (ß = - 3913 (95% CI - 6388 to - 1437), p = 0.002), even if the carryover effect influenced the Cleff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin (ß = - 38.1 (95% CI - 47.9 to - 28.3), p < 0.001) and tazobactam (ß = - 4.45 (95% CI - 6.17 to - 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type. CONCLUSION: MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.

Asunto(s)

Antibacterianos , Terapia de Reemplazo Renal Continuo , Estudios Cruzados , Meropenem , Diálisis Renal , Choque Séptico , Humanos , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Antibacterianos/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Choque Séptico/terapia , Choque Séptico/tratamiento farmacológico , Choque Séptico/sangre , Proyectos Piloto , Terapia de Reemplazo Renal Continuo/métodos , Diálisis Renal/métodos , Meropenem/uso terapéutico , Meropenem/administración & dosificación , Meropenem/farmacocinética , Tazobactam/uso terapéutico , Tazobactam/farmacocinética , Piperacilina/farmacocinética , Piperacilina/uso terapéutico , Piperacilina/administración & dosificación , Hemodiafiltración/métodos

RESUMEN

We evaluated the activity of piperacillin in relation to INCREASING TAZOBACTAM CONCENTRATION against ESBL-producing Enterobacterales collected from patients with bacteraemia. Increasing tazobactam concentration (4, 12 or 24 mg/L) exerted a reduction of piperacillin MICs under the clinical breakpoint in a concentration-dependent manner (0%, 60% and 90% of clinical isolates). Also, activity of piperacillin/tazobactam based at higher achievable serum concentrations (123/14 mg/L) is needed to reduce the bacterial growth in 92% of ESBL-producers. CHANGES IN THE PIPERACILLIN MIC IN RELATION TO INCREASING TAZOBACTAM SUGGEST THAT REALTIME TDM COULD BE USED FOR DRIVEN ANTIMICROBIAL THERAPY WITH PIPERACILLIN/TAZOBACTAM IN BSI DUE TO ESBL STRAINS.

Asunto(s)

Antibacterianos , Bacteriemia , Infecciones por Enterobacteriaceae , Enterobacteriaceae , Pruebas de Sensibilidad Microbiana , Piperacilina , Tazobactam , beta-Lactamasas , Humanos , Antibacterianos/farmacología , Bacteriemia/microbiología , beta-Lactamasas/metabolismo , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/aislamiento & purificación , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Piperacilina/farmacología , Combinación Piperacilina y Tazobactam/farmacología , Tazobactam/farmacología

RESUMEN

BACKGROUND AND OBJECTIVES: Piperacillin/tazobactam is extensively used off-label to treat late-onset neonatal sepsis, but safety and pharmacokinetic data in this population are limited. Additionally, the organic immaturity of the newborns contributes to a high piperacillin pharmacokinetic variability. This affects the clinical efficacy of the antibiotic treatment and increases the probability of developing drug resistance. This study aimed to evaluate the predictive performance of reported piperacillin population pharmacokinetic models for their application in a model-informed precision dosing strategy in preterm and term Mexican neonatal intensive care patients. METHODS: Published population pharmacokinetic models for piperacillin which included neonates in their study population were identified. From the reference models, structured models, population pharmacokinetic parameters, and interindividual and residual variability data were extracted to be replicated in pharmacokinetic software (NONMEM® version 7.4). For the clinical study, a sampling schedule was designed, and 2-3 blood samples of 250 µL were taken from neonates who met the inclusion criteria. Piperacillin plasma concentrations were determined by liquid chromatography/tandem mass spectrometry. The clinical treatment data were collected, and piperacillin plasma concentrations were estimated using reference pharmacokinetic models for an a priori or Bayesian approach. Statistical methods were used in terms of bias and precision to evaluate the differences between observed and estimated neonatal piperacillin plasma concentrations with the different approaches and to identify the pharmacokinetic model that best fits the neonatal data. RESULTS: A total of 70 plasma samples were collected from 25 neonatal patients, of which 15 were preterm neonates. The overall median value (range) postnatal age, gestational age, body weight, and serum creatinine at the sampling collecting day were 12 (3-26) days, 34.2 (26-41.1) weeks, 1.78 (0.08-3.90) Kg, 0.47 (0.20-0.90) mg/dL, respectively. Three population pharmacokinetic models for piperacillin in infants up to 2 months were identified, and their predictive performance in neonatal data was evaluated. No pharmacokinetic model was suitable for our population using an a priori approach. The model published by Cohen-Wolkowiez et al. in 2014 with a Bayesian approach showed the best performance of the pharmacokinetic models evaluated in our neonatal data. The procedure requires two blood samples (predose and postdose), and, when applied, it predicted 66.6% of the observations with a relative median absolute predicted error of less than 30%. CONCLUSIONS: The population pharmacokinetic model developed by Cohen-Wolkowiez et al. in 2014 demonstrated superior performance in predicting the plasma concentration of piperacillin in preterm and term Mexican neonatal intensive care patients. The Bayesian approach, including two different piperacillin plasma concentrations, was clinically acceptable regarding bias and precision. Its application for model-informed precision dosing can be an option to optimize the piperacillin dosage in our population.

Asunto(s)

Antibacterianos , Teorema de Bayes , Recien Nacido Prematuro , Modelos Biológicos , Piperacilina , Humanos , Recién Nacido , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Piperacilina/farmacocinética , Piperacilina/administración & dosificación , Masculino , Femenino , Cuidado Intensivo Neonatal/métodos , Combinación Piperacilina y Tazobactam/farmacocinética , Combinación Piperacilina y Tazobactam/administración & dosificación , México , Edad Gestacional

RESUMEN

BACKGROUND: Pancreatoduodenectomy is associated with an increased incidence of surgical-site infections, often leading to a significant rise in morbidity and mortality. This trend underlines the inadequacy of traditional antibiotic prophylaxis strategies. Hence, the aim of this meta-analysis was to assess the outcomes of antimicrobial prophylaxis, comparing piperacillin/tazobactam with traditional antibiotics. METHODS: Upon registering in PROSPERO, the international prospective register of systematic reviews (CRD42023479100), a systematic search of various databases was conducted over the interval 2000-2023. This inclusive search encompassed a wide range of study types, including prospective and retrospective cohorts and RCTs. The subsequent data analysis was carried out utilizing RevMan 5.4. RESULTS: A total of eight studies involving 2382 patients who underwent pancreatoduodenectomy and received either piperacillin/tazobactam (1196 patients) or traditional antibiotics (1186 patients) as antibiotic prophylaxis during surgery were included in the meta-analysis. Patients in the piperacillin/tazobactam group had significantly reduced incidences of surgical-site infections (OR 0.43 (95% c.i. 0.30 to 0.62); P < 0.00001) and major surgical complications (Clavien-Dindo grade greater than or equal to III) (OR 0.61 (95% c.i. 0.45 to 0.81); P = 0.0008). Subgroup analysis of surgical-site infections highlighted significantly reduced incidences of superficial surgical-site infections (OR 0.34 (95% c.i. 0.14 to 0.84); P = 0.02) and organ/space surgical-site infections (OR 0.47 (95% c.i. 0.28 to 0.78); P = 0.004) in the piperacillin/tazobactam group. Further, the analysis demonstrated significantly lower incidences of clinically relevant postoperative pancreatic fistulas (grades B and C) (OR 0.67 (95% c.i. 0.53 to 0.83); P = 0.0003) and mortality (OR 0.51 (95% c.i. 0.28 to 0.91); P = 0.02) in the piperacillin/tazobactam group. CONCLUSION: Piperacillin/tazobactam as antimicrobial prophylaxis significantly lowers the risk of postoperative surgical-site infections, major surgical complications (complications classified as Clavien-Dindo grade greater than or equal to III), clinically relevant postoperative pancreatic fistulas (grades B and C), and mortality, hence supporting the implementation of piperacillin/tazobactam for surgical prophylaxis in current practice.

Asunto(s)

Antibacterianos , Profilaxis Antibiótica , Pancreaticoduodenectomía , Combinación Piperacilina y Tazobactam , Infección de la Herida Quirúrgica , Humanos , Pancreaticoduodenectomía/efectos adversos , Combinación Piperacilina y Tazobactam/uso terapéutico , Infección de la Herida Quirúrgica/prevención & control , Antibacterianos/uso terapéutico , Piperacilina/uso terapéutico

RESUMEN

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

Asunto(s)

Antibacterianos , Cefepima , Infecciones Comunitarias Adquiridas , Enfermedad Crítica , Unidades de Cuidados Intensivos , Combinación Piperacilina y Tazobactam , Humanos , Cefepima/uso terapéutico , Cefepima/administración & dosificación , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/mortalidad , Combinación Piperacilina y Tazobactam/uso terapéutico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Antibacterianos/uso terapéutico , Funciones de Verosimilitud , Neumonía/tratamiento farmacológico , Neumonía/mortalidad , Piperacilina/uso terapéutico

RESUMEN

Amikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the family Enterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37 have been "harvested" by insertion sequence IS26 as a transposon that is widely disseminated among the Enterobacterales. This transposon encodes the enzymes AAC(6')-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from three hospitals serving a population of 1.2 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, increased transposon copy number is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance.

Asunto(s)

Antibacterianos , Elementos Transponibles de ADN , Humanos , Antibacterianos/farmacología , Elementos Transponibles de ADN/genética , Farmacorresistencia Bacteriana Múltiple/genética , Piperacilina/farmacología , Amicacina/farmacología , Pruebas de Sensibilidad Microbiana , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Infecciones por Enterobacteriaceae/genética , Enterobacteriaceae/genética , Enterobacteriaceae/efectos de los fármacos , Integrones/genética , Bacteriemia/microbiología , Bacteriemia/tratamiento farmacológico , Bacteriemia/genética

RESUMEN

The standard treatment for an infected pressure ulcer (PU) with osteomyelitis is debridement, wound coverage and antibiotic administration. However, systemic administration of antibiotics in patients with osteomyelitis is controversial, and the optimal treatment duration for chronic osteomyelitis has not been standardised. We report a case of sudden severe thrombocytopenia induced by piperacillin/tazobactam (PIPC/TAZ) in a patient with PU-related osteomyelitis. A 57-year-old male patient with paraplegia, using a wheelchair full-time, presented to our plastic surgery department with infection of a stage IV hard-to-heal ischial PU. We surgically debrided the necrotising tissue and raised an ipsilateral biceps femoris musculocutaneous propeller flap for wound coverage. Polymicrobial infections, including Pseudomonas aeruginosa, were detected in the bone biopsy sample; therefore, systemic PIPC/TAZ was administered for the osteomyelitis. Unexpectedly, during the next 12 days of antibiotic administration, the patient's platelet count acutely dropped to 1×103/µl over three days. Based on a series of examinations, PIPC/TAZ was suspected to be the most likely cause of the severe thrombocytopenia. After drug discontinuation, the thrombocytopenia gradually improved. PIPC/TAZ is one of the most widely used antibiotic combinations in the plastic surgery field; it is conventionally administered for hard-to-heal wounds such as PUs and diabetic foot. The present case suggests that surgeons must take special precautions for patients undergoing PIPC/TAZ treatment. In this report, PIPC/TAZ-induced thrombocytopenia and the efficacy of antibiotic treatment for PU-related osteomyelitis are discussed in light of the available literature.

Asunto(s)

Antibacterianos , Osteomielitis , Combinación Piperacilina y Tazobactam , Úlcera por Presión , Trombocitopenia , Humanos , Masculino , Persona de Mediana Edad , Úlcera por Presión/tratamiento farmacológico , Combinación Piperacilina y Tazobactam/efectos adversos , Combinación Piperacilina y Tazobactam/uso terapéutico , Osteomielitis/tratamiento farmacológico , Trombocitopenia/inducido químicamente , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Piperacilina/efectos adversos , Piperacilina/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , Ácido Penicilánico/análogos & derivados , Ácido Penicilánico/efectos adversos , Ácido Penicilánico/uso terapéutico , Desbridamiento

RESUMEN

BACKGROUND: The investigation of drug disposition in tissues is critical to improving dosing strategy and maximizing treatment effectiveness, yet developing a multi-tissue bioanalytical method could be challenging due to the differences among various matrices. Herein, we developed an LC-MS/MS method tailored for the quantitation of piperacillin (PIP), cefazolin (CFZ), and cefoxitin (CFX) in rat plasma and 12 tissues, accompanied by validation data for each matrix according to the FDA and EMA guidelines. RESULTS: The method required only a small sample volume (5 µL plasma or 50-100 µL tissue homogenates) and a relatively simple protocol for simultaneous quantitation of PIP, CFZ, and CFX within different biological matrices. Mobile phase A was composed of 5 mM ammonium formate and 0.1 % formic acid in water, while mobile phase B contained 0.1 % formic acid in acetonitrile. The mobile phase was pumped through a Synergi Fusion-RP column equipped with a guard column with a gradient elution program at a 0.3 mL/min flow rate. The mass spectrometer was operated in positive ionization mode (ESI+) using multiple reaction monitoring. SIGNIFICANCE: The validated method has been successfully applied to quantify PIP, CFZ, and CFX from the plasma and tissue samples collected in a pilot rat study and will further be used in a large pharmacokinetic study. To our knowledge, this is also the first report presenting long-term, freeze-thaw, and autosampler stability data for PIP, CFZ, and CFX in rat plasma and multiple tissues.

Asunto(s)

Cefazolina , Cefoxitina , Piperacilina , Espectrometría de Masas en Tándem , Animales , Espectrometría de Masas en Tándem/métodos , Ratas , Cefazolina/sangre , Cefazolina/farmacocinética , Cefazolina/análisis , Piperacilina/sangre , Piperacilina/farmacocinética , Piperacilina/análisis , Cefoxitina/farmacocinética , Cefoxitina/sangre , Cefoxitina/química , Cefoxitina/análisis , Cromatografía Liquida/métodos , Reproducibilidad de los Resultados , Distribución Tisular , Ratas Sprague-Dawley , Antibacterianos/sangre , Antibacterianos/farmacocinética , Antibacterianos/análisis , Masculino , Cromatografía Líquida con Espectrometría de Masas

Asunto(s)

Antibacterianos , Hipersensibilidad a las Drogas , Combinación Piperacilina y Tazobactam , beta-Lactamas , Humanos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/inmunología , Hipersensibilidad a las Drogas/etiología , Combinación Piperacilina y Tazobactam/efectos adversos , beta-Lactamas/efectos adversos , beta-Lactamas/inmunología , Masculino , Femenino , Antibacterianos/efectos adversos , Antibacterianos/inmunología , Persona de Mediana Edad , Anciano , Etiquetado de Medicamentos , Adulto , Piperacilina/efectos adversos , Piperacilina/inmunología

Asunto(s)

Antibacterianos , Fiebre , Absceso Hepático Amebiano , Combinación Piperacilina y Tazobactam , Humanos , Masculino , Combinación Piperacilina y Tazobactam/uso terapéutico , Combinación Piperacilina y Tazobactam/efectos adversos , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Absceso Hepático Amebiano/tratamiento farmacológico , Adulto , Piperacilina/efectos adversos , Piperacilina/uso terapéutico

Asunto(s)

Lesión Renal Aguda , Antibacterianos , Modelos Animales de Enfermedad , Combinación Piperacilina y Tazobactam , Vancomicina , Vancomicina/efectos adversos , Vancomicina/administración & dosificación , Vancomicina/toxicidad , Animales , Lesión Renal Aguda/inducido químicamente , Combinación Piperacilina y Tazobactam/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Ratones , Sinergismo Farmacológico , Riñón/efectos de los fármacos , Riñón/patología , Piperacilina/efectos adversos , Piperacilina/administración & dosificación , Quimioterapia Combinada

RESUMEN

We subjected seven P. aeruginosa isolates to a 10-day serial passaging against five antipseudomonal agents to evaluate resistance levels post-exposure and putative resistance mechanisms in terminal mutants were analyzed by whole-genome sequencing analysis. Meropenem (mean, 38-fold increase), cefepime (14.4-fold), and piperacillin-tazobactam (52.9-fold) terminal mutants displayed high minimum inhibitory concentration (MIC) values compared to those obtained after exposure to ceftolozane-tazobactam (11.4-fold) and ceftazidime-avibactam (5.7-fold). Fewer isolates developed elevated MIC values for other ß-lactams and agents belonging to other classes when exposed to meropenem in comparison to other agents. Alterations in nalC and nalD, involved in the upregulation of the efflux pump system MexAB-OprM, were common and observed more frequently in isolates exposed to ceftazidime-avibactam and meropenem. These alterations, along with ones in mexR and amrR, provided resistance to most ß-lactams and levofloxacin but not imipenem. The second most common gene altered was mpl, which is involved in the recycling of the cell wall peptidoglycan. These alterations were mainly noted in isolates exposed to ceftolozane-tazobactam and piperacillin-tazobactam but also in one cefepime-exposed isolate. Alterations in other genes known to be involved in ß-lactam resistance (ftsI, oprD, phoP, pepA, and cplA) and multiple genes involved in lipopolysaccharide biosynthesis were also present. The data generated here suggest that there is a difference in the mechanisms selected for high-level resistance between newer ß-lactam/ß-lactamase inhibitor combinations and older agents. Nevertheless, the isolates exposed to all agents displayed elevated MIC values for other ß-lactams (except imipenem) and quinolones tested mainly due to alterations in the MexAB-OprM regulators that extrude these agents.

Asunto(s)

Antibacterianos , Compuestos de Azabiciclo , Ceftazidima , Meropenem , Pruebas de Sensibilidad Microbiana , Combinación Piperacilina y Tazobactam , Pseudomonas aeruginosa , Tazobactam , Inhibidores de beta-Lactamasas , beta-Lactamas , Antibacterianos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Inhibidores de beta-Lactamasas/farmacología , Compuestos de Azabiciclo/farmacología , Meropenem/farmacología , Tazobactam/farmacología , Ceftazidima/farmacología , beta-Lactamas/farmacología , Combinación Piperacilina y Tazobactam/farmacología , Combinación de Medicamentos , Cefalosporinas/farmacología , Cefepima/farmacología , Humanos , Piperacilina/farmacología , Secuenciación Completa del Genoma , Farmacorresistencia Bacteriana Múltiple/genética

RESUMEN

We evaluated the performance of automated susceptibility testing for piperacillin/tazobactam (PTZ) MICs against the reference microbroth dilution method. The Minimum Inhibitory Concentration of PTZ against a clinical isolate of Klebsiella pneumoniae was determined by reference broth micro-dilution method in 10 replicates which yielded a modal MIC of 16 mg/L (susceptible dose-dependent). Out of 434 laboratories who obtained MIC of 16 mg/L correctly, only 301 interpreted the result as susceptible dose dependent as per 2022 revised CLSI criteria. Educating the clinical laboratories in validating AST methods as per latest CLSI guidelines is of utmost important.

Asunto(s)

Antibacterianos , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Combinación Piperacilina y Tazobactam , Pruebas de Sensibilidad Microbiana/normas , Pruebas de Sensibilidad Microbiana/métodos , Humanos , Combinación Piperacilina y Tazobactam/farmacología , Antibacterianos/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Piperacilina/farmacología , Infecciones por Klebsiella/microbiología , Garantía de la Calidad de Atención de Salud , Ácido Penicilánico/análogos & derivados , Ácido Penicilánico/farmacología

RESUMEN

Effective treatment of gonorrhea is threatened by the increasing prevalence of Neisseria gonorrhoeae strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we demonstrated the promise of the third-generation cephalosporin cefoperazone as an antigonococcal agent due to its rapid second-order rate of acylation against penicillin-binding protein 2 (PBP2) from the ESC-resistant strain H041 and robust antimicrobial activity against H041. Noting the presence of a ureido moiety in cefoperazone, we evaluated a subset of structurally similar ureido ß-lactams, including piperacillin, azlocillin, and mezlocillin, for activity against PBP2 from H041 using biochemical and structural analyses. We found that the ureidopenicillin piperacillin has a second-order rate of acylation against PBP2 that is 12-fold higher than cefoperazone and 85-fold higher than ceftriaxone and a lower MIC against H041 than ceftriaxone. Surprisingly, the affinity of ureidopenicillins for PBP2 is minimal, indicating that their inhibitory potency is due to a higher rate of the acylation step of the reaction compared to cephalosporins. Enhanced acylation results from the combination of a penam scaffold with a 2,3-dioxopiperazine-containing R1 group. Crystal structures show that the ureido ß-lactams overcome the effects of resistance mutations present in PBP2 from H041 by eliciting conformational changes that are hindered when PBP2 interacts with the weaker inhibitor ceftriaxone. Overall, our results support the potential of piperacillin as a treatment for gonorrhea and provide a framework for the future design of ß-lactams with improved activity against ESC-resistant N. gonorrhoeae.

Asunto(s)

Ceftriaxona , Gonorrea , Humanos , Ceftriaxona/metabolismo , Ceftriaxona/farmacología , Neisseria gonorrhoeae/genética , Gonorrea/tratamiento farmacológico , Proteínas de Unión a las Penicilinas/genética , Proteínas de Unión a las Penicilinas/metabolismo , Cefoperazona/farmacología , Cefalosporinas/farmacología , Cefalosporinas/metabolismo , Piperacilina/metabolismo , Piperacilina/farmacología , beta-Lactamas/farmacología

RESUMEN

OBJECTIVES: WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam. METHODS: We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination. RESULTS: We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30-59, 15-29 and 8-14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180 mL/min), a prolonged 4 h infusion of standard dose is required. CONCLUSIONS: The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L.

Asunto(s)

Antibacterianos , Cefepima , Cefalosporinas , Pruebas de Sensibilidad Microbiana , Combinación Piperacilina y Tazobactam , Diálisis Renal , Humanos , Cefepima/administración & dosificación , Cefepima/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Combinación Piperacilina y Tazobactam/administración & dosificación , Combinación Piperacilina y Tazobactam/farmacocinética , Cefalosporinas/administración & dosificación , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapéutico , Masculino , Femenino , Tazobactam/administración & dosificación , Tazobactam/uso terapéutico , Persona de Mediana Edad , beta-Lactamasas , Adulto , Ácido Penicilánico/análogos & derivados , Ácido Penicilánico/administración & dosificación , Ácido Penicilánico/farmacocinética , Voluntarios Sanos , Adulto Joven , Piperacilina/administración & dosificación , Piperacilina/farmacocinética , Piperacilina/farmacología , Animales

RESUMEN

BACKGROUND: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. METHODS: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. RESULTS: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04). CONCLUSIONS: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.

Asunto(s)

Antibacterianos , Infecciones por Klebsiella , Klebsiella pneumoniae , Meropenem , Combinación Piperacilina y Tazobactam , Piperacilina , Humanos , Meropenem/uso terapéutico , Meropenem/farmacología , Combinación Piperacilina y Tazobactam/uso terapéutico , Combinación Piperacilina y Tazobactam/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Piperacilina/uso terapéutico , Piperacilina/farmacología , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/mortalidad , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Bacteriemia/mortalidad , Escherichia coli/efectos de los fármacos , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/mortalidad , Ácido Penicilánico/análogos & derivados , Ácido Penicilánico/uso terapéutico , Ácido Penicilánico/farmacología , Ceftriaxona/uso terapéutico , Ceftriaxona/farmacología , Masculino , Femenino , Persona de Mediana Edad , Tienamicinas/uso terapéutico , Tienamicinas/farmacología , Anciano , Resultado del Tratamiento

RESUMEN

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

Asunto(s)

Gammaproteobacteria , Inhibidores de beta-Lactamasas , Adulto , Humanos , Masculino , Anciano , Anciano de 80 o más Años , Femenino , Inhibidores de beta-Lactamasas/farmacocinética , Antibacterianos/farmacocinética , beta-Lactamas , Estudios Retrospectivos , Ácido Penicilánico/uso terapéutico , Ácido Penicilánico/farmacocinética , Combinación Piperacilina y Tazobactam/farmacocinética , Piperacilina/farmacocinética , Tazobactam , beta-Lactamasas , Pruebas de Sensibilidad Microbiana

RESUMEN

OBJECTIVES: An Escherichia coli isolate, WGS1363, showed resistance to piperacillin/tazobactam but susceptibility to cephalosporins and contained a previously unrecognized ß-lactamase, CTX-M-255, as the only acquired ß-lactamase. CTX-M-255 was identical to CTX-M-27 except for a G239S substitution. Here, we characterize the hydrolytic spectrum of CTX-M-255 and a previously reported ß-lactamase, CTX-M-178, also containing a G239S substitution and compare it to their respective parental enzymes, CTX-M-27 and CTX-M-15. METHODS: All ß-lactamase genes were expressed in E. coli TOP10 and MICs to representative ß-lactam-antibiotics were determined. Furthermore, blaCTX-M-15,  blaCTX-M-27, blaCTX-M-178 and blaCTX-M-255 with C-terminal His-tag fusions were affinity purified for enzyme kinetic assays determining Michaelis-Menten kinetic parameters against representative ß-lactam-antibiotics and IC50s of clavulanate, sulbactam, tazobactam and avibactam. RESULTS: TOP10-transformants expressing blaCTX-M-178 and blaCTX-M-255 showed resistance to penicillin/ß-lactamase combinations and susceptibility to cephalothin and cefotaxime in contrast to transformants expressing blaCTX-M-15 and blaCTX-M-27. Determination of enzyme kinetic parameters showed that CTX-M-178 and CTX-M-255 both lacked hydrolytic activity against cephalosporins and showed impaired hydrolytic efficiency against penicillin antibiotics compared to their parental enzymes. Both enzymes appeared more active against piperacillin compared to benzylpenicillin and ampicillin. Compared to their parental enzymes, IC50s of ß-lactamase-inhibitors were increased more than 1000-fold for CTX-M-178 and CTX-M-255. CONCLUSIONS: CTX-M-178 and CTX-M-255, both containing a G239S substitution, conferred resistance to piperacillin/tazobactam and may be characterized as inhibitor-resistant CTX-M ß-lactamases. Inhibitor resistance was accompanied by loss of activity against cephalosporins and monobactams. These findings add to the necessary knowledge base for predicting antibiotic susceptibility from genotypic data.

Asunto(s)

Antibacterianos , Inhibidores de beta-Lactamasas , Inhibidores de beta-Lactamasas/farmacología , Antibacterianos/farmacología , Escherichia coli , beta-Lactamasas/genética , Penicilinas/farmacología , Cefalosporinas/farmacología , Tazobactam/farmacología , Piperacilina/farmacología , Monobactamas , Combinación Piperacilina y Tazobactam , Pruebas de Sensibilidad Microbiana

RESUMEN

OBJECTIVES: Recently, reports on antimicrobial-resistant Bacteroides and Prevotella isolates have increased in the Netherlands. This urged the need for a surveillance study on the antimicrobial susceptibility profile of Bacteroides, Phocaeicola, Parabacteroides and Prevotella isolates consecutively isolated from human clinical specimens at eight different Dutch laboratories. METHODS: Each laboratory collected 20-25 Bacteroides (including Phocaeicola and Parabacteroides) and 10-15 Prevotella isolates for 3 months. At the national reference laboratory, the MICs of amoxicillin, amoxicillin/clavulanic acid, piperacillin/tazobactam, meropenem, imipenem, metronidazole, clindamycin, tetracycline and moxifloxacin were determined using agar dilution. Isolates with a high MIC of metronidazole or a carbapenem, or harbouring cfiA, were subjected to WGS. RESULTS: Bacteroides thetaiotaomicron/faecis isolates had the highest MIC90 values, whereas Bacteroides fragilis had the lowest MIC90 values for amoxicillin/clavulanic acid, piperacillin/tazobactam, meropenem, imipenem and moxifloxacin. The antimicrobial profiles of the different Prevotella species were similar, except for amoxicillin, for which the MIC50 ranged from 0.125 to 16 mg/L for Prevotella bivia and Prevotella buccae, respectively. Three isolates with high metronidazole MICs were sequenced, of which one Bacteroides thetaiotaomicron isolate harboured a plasmid-located nimE gene and a Prevotella melaninogenica isolate harboured a nimA gene chromosomally.Five Bacteroides isolates harboured a cfiA gene and three had an IS element upstream, resulting in high MICs of carbapenems. The other two isolates harboured no IS element upstream of the cfiA gene and had low MICs of carbapenems. CONCLUSIONS: Variations in resistance between species were observed. To combat emerging resistance in anaerobes, monitoring resistance and conducting surveillance are essential.

Asunto(s)

Antiinfecciosos , Metronidazol , Humanos , Meropenem , Moxifloxacino , Países Bajos , Laboratorios , Bacteroides , Antibacterianos/farmacología , Carbapenémicos , Bacteroides fragilis , Imipenem , Pruebas de Sensibilidad Microbiana , Piperacilina , Tazobactam , Prevotella/genética , Amoxicilina , Ácido Clavulánico

RESUMEN

OBJECTIVE: To develop and validate an UPLC-MS/MS assay for simultaneous determination of the total concentration of ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, tazobactam, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim, and the protein-unbound concentration of flucloxacillin, in human plasma to be used for research and clinical practice. METHODS: Sample pretreatment included protein precipitation with methanol. For the measurement of protein-unbound flucloxacillin, ultrafiltration was performed at physiological temperature. For all compounds, a stable isotopically labelled internal standard was used. Reliability of the results was assessed by participation in an international quality control programme. RESULTS: The assay was successfully validated according to the EMA guidelines over a concentration range of 0.5-100 mg/L for ceftazidime, 0.05-10 mg/L for ciprofloxacin, 0.4-125 mg/L for flucloxacillin, 0.2-60 mg/L for piperacillin, 0.15-30 mg/L for tazobactam, 1-200 mg/L for sulfamethoxazole and N-acetyl sulfamethoxazole, 0.05-10 mg/L for trimethoprim and 0.10-50 mg/L for unbound flucloxacillin. For measurement of total concentrations, the within- and between-day accuracy ranged from 90.0% to 109%, and 93.4% to 108%, respectively. Within- and between-day precision (variation coefficients, CVs) ranged from 1.70% to 11.2%, and 0.290% to 5.30%, respectively. For unbound flucloxacillin, within-day accuracy ranged from 103% to 106% and between-day accuracy from 102% to 105%. The within- and between-day CVs ranged from 1.92% to 7.11%. Results of the international quality control programme showed that the assay is reliable. CONCLUSIONS: The method provided reliable, precise and accurate measurement of seven commonly prescribed antibiotics, including the unbound concentration of flucloxacillin. This method is now routinely applied in research and clinical practice.

Asunto(s)

Antibacterianos , Floxacilina , Humanos , Ceftazidima , Cromatografía Liquida/métodos , Monitoreo de Drogas/métodos , Reproducibilidad de los Resultados , Cromatografía Líquida con Espectrometría de Masas , Espectrometría de Masas en Tándem/métodos , Piperacilina , Tazobactam , Ciprofloxacina , Trimetoprim , Sulfametoxazol , Cromatografía Líquida de Alta Presión/métodos