RESUMO
The present study evaluated the rational prescription of linezolid, the prevalence of thrombocytopenia, and major drug interactions in patients with cardiovascular diseases. We conducted a retrospective cross-sectional study on linezolid-treated patients at Shahid Chamran Heart Hospital in Isfahan from March 21, 2021, to March 20, 2022. Our research involved 132 patients who received linezolid. We reported 43.18% of linezolid prescriptions as irrational. Linezolid-induced thrombocytopenia is more common than previous studies, with a prevalence of 47.9%. We found a significant relationship between thrombocytopenia and the concomitant use of aspirin. The duration of treatment was identified as predicting factor for linezolid-induced thrombocytopenia. Moreover, the prevalence of interactions in the X and D categories was determined. Serotonergic and catecholamine medications were associated with 56.1% and 47.7% medication interactions, respectively. Our study found a high prevalence of linezolid-induced thrombocytopenia among patients with cardiovascular diseases. Based on this study, physicians should focus more closely on prescribing linezolid to patients with cardiovascular diseases. In addition to following rational antibiotic use, this susceptible group is also at an elevated risk of side effects (thrombocytopenia) and medication interactions.
Assuntos
Antibacterianos , Doenças Cardiovasculares , Interações Medicamentosas , Linezolida , Trombocitopenia , Humanos , Linezolida/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia , Doenças Cardiovasculares/tratamento farmacológico , Masculino , Feminino , Estudos Retrospectivos , Estudos Transversais , Pessoa de Meia-Idade , Idoso , Prevalência , Antibacterianos/efeitos adversos , AdultoRESUMO
INTRODUCTION: This single-center, observational cohort study aimed to investigate the risk factors associated with linezolid-induced hematological toxicity by analyzing the linezolid trough concentration (Cmin) obtained from patients undergoing treatment between January 2020 and December 2021. METHODOLOGY: A total of 111 eligible individuals were included in the study, of which 47 were diagnosed with linezolid-induced thrombocytopenia and 18 were diagnosed with linezolid-induced hemoglobin decrease. RESULTS: Binary logistic regression analysis revealed that creatinine clearance level (Ccr) < 50 mL/min/1.73 m2 (OR, 5.463; 95% CI, 1.249-23.888, p = 0.024) and Cmin > 7 mg/L (OR, 62.660; 95% CI, 14.293-274.708, p = 0.001) were risk factors associated with linezolid-induced thrombocytopenia. Area under the ROC curve for Cmin was 0.955, with a maximum Youden index of 0.837. The corresponding critical value was 6.94 mg/L (sensitivity 91.5%; specificity 92.2%). Ccr < 50 mL/min/1.73 m2 (OR, 7.282; 95% CI, 1.765-30.048, p = 0.006) and Cmin > 7mg/L (OR, 6.364; 95% CI, 1.937-20.910, p = 0.020) were found to be associated with linezolid-induced hemoglobin reduction. The area under the ROC curve for Cmin was 0.755, Youden index was 0.477 at the maximum, and the corresponding critical value was 7.53 mg/L (sensitivity 77.8%; specificity 69.9%). CONCLUSIONS: Renal insufficiency is a related risk factor for linezolid-induced hematological toxicity. Patients receiving linezolid treatment should be closely monitored with blood routine and plasma concentration, particularly in patients with moderate or severe renal insufficiency. The plasma trough concentration of linezolid could be a suitable predictor for linezolid-induced thrombocytopenia and anemia.
Assuntos
Antibacterianos , Linezolida , Trombocitopenia , Humanos , Linezolida/efeitos adversos , Masculino , Estudos Retrospectivos , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Trombocitopenia/induzido quimicamente , Antibacterianos/efeitos adversos , Idoso , Adulto , Idoso de 80 Anos ou maisRESUMO
OBJECTIVES: Linezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB). METHODS: We conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992-2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0). RESULTS: Of all participants (nâ¯=â¯132), 43.2% were female and the median age 28 y. The median linezolid treatment was 6.5 months (IQR 3.0-12.7) with a median daily dose of 9.6 mg/kg/d. Any ADR was seen in 58.3% (nâ¯=â¯77) of participants, with 35.6% having peripheral neuropathy (nâ¯=â¯47), 27.3% anaemia (nâ¯=â¯36), 22.0% leukopenia (nâ¯=â¯36) while 6.1% (nâ¯=â¯8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1-5.9) and 8.3 months (6.2-10.7) for optic neuritis. A >2.0 mg/L trough concentration (nâ¯=â¯40) was associated with anaemia (Pâ¯=â¯0.0038) and thrombocytopenia (Pâ¯=â¯0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/d was associated with time to peripheral neuropathy (HR 2.89, 95% CI 1.08-7.74, Pâ¯=â¯0.035), anaemia (HR 6.62, 95% CI 2.22-19.8, Pâ¯=â¯0.001) and leukopenia (HR 5.23, 95% CI 1.48-18.5, Pâ¯=â¯0.010). CONCLUSIONS: Linezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.
Assuntos
Antituberculosos , Linezolida , Doenças do Sistema Nervoso Periférico , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Linezolida/efeitos adversos , Linezolida/administração & dosagem , Feminino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Masculino , Estudos Retrospectivos , Adulto , Antituberculosos/efeitos adversos , Antituberculosos/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Suécia/epidemiologia , Fatores de Risco , Adulto Jovem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Pessoa de Meia-Idade , Anemia/induzido quimicamente , Leucopenia/induzido quimicamenteRESUMO
World Health Organization (WHO) issued the latest recommendations regarding the management of drug-resistant Tuberculosis (TB) in 2022, allowing the replacement of ethambutol (6 months) with linezolid (2 months). This recommendation also introduced a new regimen, namely bedaquiline, pretomanide, linezolid, moxifloxacin (BPaLM) for fluoroquinolone-sensitive patients and bedaquiline, pretomanide, linezolid, (BPaL) for patients insensitive to fluoroquinolone (6-9 months). The latest TB regimen introduced by WHO provides a shorter-course treatment, however not much has been discussed about the impact of this new regimen on chronic kidney disease (CKD) patients, particularly on hemodialysis (HD). The condition of CKD can interfere with the pharmacokinetics of TB medication, thus could reduce effectiveness and increase toxicity. The drugs used on this new regimen are mostly safe for renal impairment patients due to the dominant metabolism in the liver. Particular precaution is given to the administration of linezolid due to increased hematology side effects and bedaquiline with the side effect of QTC interval lengthening and increased risk of arrhythmias. Although this regimen research has not been in many studies in renal failure patients, no significant side effects nor kidney damage evidence was found. This remains to be proven by more research on the patient population with renal failure.
Assuntos
Antituberculosos , Diálise Renal , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Linezolida/uso terapêutico , Linezolida/efeitos adversos , Diarilquinolinas/uso terapêuticoRESUMO
BACKGROUND: Monitoring and managing adverse drug reactions (ADR) are critical for treating drug-resistant tuberculosis (TB). OBJECTIVE: To study symptomatic, linezolid-attributable ADRs in TB patients initiated on all oral longer bedaquiline-based treatment regime for multidrug-resistant/rifampicin-resistant (MDR/RR)-TB under programmatic conditions. METHODS: It was a multicenter, retrospective study of people with MDR/RR-TB in nine TB units in Nagpur, India, from March 2020 to April 2022. RESULTS: The study consisted of a sample size of 106 individuals with multidrug-resistant and rifampicin-resistant tuberculosis out of a total of 110 individuals with the disease. Of these, 45 (42.45%) experienced linezolid ADRs, with an incidence of 11.37 cases per 1000 person-weeks. These patients were significantly younger (31.24 ± 11.13 years) and more likely to be female (27, 50%) than those without ADRs. ADR severity was mild in 20 (44.45%), moderate in 15 (33.33%), and severe in 10 (22.22%) patients. The most common ADR was peripheral neuropathy (42, 93.33%), followed by lactic acidosis (3, 6.67%), anemia (2, 4.44%), and optic neuritis (2, 4.44%). Dosing was reduced in 17 (37.78%) patients, and linezolid was withdrawn entirely in 19 (42.22%) patients. Only 9 (20%) patients continued linezolid unmodified. For mild to moderate linezolid-associated symptomatic peripheral neuropathy, symptom management with or without dose reduction is an effective strategy; however, immediate linezolid withdrawal is necessary in severe or life-threatening peripheral neuropathy cases. After a mean follow-up of 41 ± 21.33 weeks, ADR symptoms resolved completely in 4 (6.67%) patients and decreased in 42 (93.33%) patients. CONCLUSION: Linezolid ADRs, often neuropathy, frequently occur in patients on an all-oral bedaquiline-based treatment regime for MDR/RR-TB. Women and younger patients are more likely to experience these ADRs, usually mild to moderate in severity. Management of symptomatic linezolid-associated peripheral neuropathy should be based on ADR severity. These ADRs often affect linezolid dosing, so it is important to identify and manage them early.
Assuntos
Antituberculosos , Linezolida , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Feminino , Masculino , Adulto , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Estudos Retrospectivos , Índia/epidemiologia , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Adulto Jovem , Pessoa de Meia-Idade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Adolescente , IncidênciaRESUMO
In developing countries like India, Linezolid is widely used for the treatment of Multi drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB). Long-term administration of Linezolid is reported to cause toxic optic neuropathy causing bilateral, progressive visual loss in patients. We report case details of three patients on anti-tubercular therapy presented to us with sudden, progressive, painless blurring of vision of both eyes the cause of which was confirmed to be toxic optic neuropathy due to linezolid. Subsequently, cessation of the drug resulted in complete visual recovery in two patients whereas one patient had minimal visual improvement due to secondary optic atrophy. Clinicians and health care workers need to be aware of sight threatening complications of Linezolid.
Assuntos
Antituberculosos , Linezolida , Neuropatia Óptica Tóxica , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Masculino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Neuropatia Óptica Tóxica/tratamento farmacológico , Feminino , Pessoa de Meia-IdadeRESUMO
Detailed data on safety associated with drug-drug interactions (DDIs) between Linezolid (LZD) and other antibiotics are limited. The aim of this study was to investigate the safety signals related to these DDIs and to provide a reference for clinically related adverse drug event monitoring. Adverse event (AE) information from 1 January 2004 to 16 June 2022 of the target antibiotics including LZD using alone or in combination with LZD was extracted from the OpenVigil FDA data platform for safety signal analysis. The combined risk ratio model, reporting ratio method, Ω shrinkage measure model, and chi-square statistics model were used to analyze the safety signals related to DDIs. Meanwhile, we evaluated the correlation and the influence of sex and age between the drug(s) and the target AE detected. There were 18991 AEs related to LZD. There were 2293, 1726, 4449, 821, 2431, 1053, and 463 AE reports when LZD was combined with amikacin, voriconazole, meropenem, clarithromycin, levofloxacin, piperacillin-tazobactam, and azithromycin, respectively. Except for azithromycin, there were positive safety signals related to DDIs between LZD and these antibiotics. These DDIs might influence the incidence of 13, 16, 7, 7, 6, and 15 types of AEs, respectively, and is associated with higher reporting rates of AEs compared with use alone. Moreover, sex and age might influence the occurrence of AEs. We found that the combinations of LZD and other antibiotics are related to multiple AEs, such as hepatotoxicity, drug resistance and electrocardiogram QT prolonged, but further research is still required to investigate their underlying mechanisms. This study can provide a new reference for the safety monitoring of LZD combined with other antibiotics in clinical practice.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Antibacterianos , Interações Medicamentosas , Linezolida , Humanos , Linezolida/efeitos adversos , Masculino , Antibacterianos/efeitos adversos , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Adolescente , Adulto Jovem , Criança , Pré-Escolar , Lactente , Idoso de 80 Anos ou mais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Monitoramento de Medicamentos/métodos , Fatores Etários , Recém-Nascido , Fatores SexuaisRESUMO
BACKGROUND: The concentrations of linezolid, its optimal regimen and the associated side effects in elderly patients remain unclear. METHODS: In this multicentre, prospective study, elderly patients receiving linezolid at four tertiary hospitals in Beijing between May 2021 and December 2022 were included. Linezolid concentrations and haematological toxicity were monitored dynamically. Risk factors for linezolid overexposure and moderate-to-severe linezolid-induced thrombocytopenia (M/S LIT) were analysed, and a predictive model of M/S LIT was developed. RESULTS: A total of 860 linezolid concentrations were measured in 313 patients. The median trough concentrations of linezolid were 24.4 (15.3, 35.8) mg/L at 36-72â h and 26.1 (17.0, 38.1) mg/L at 5-10â days (Pâ=â0.132). Severe linezolid exposure was independently associated with age, estimated glomerular filtration rate (eGFR) and the worst SOFA score (SOFA1), and we further recommended dose regimens for elderly patients based on these findings. The incidences of linezolid-induced thrombocytopenia(LIT) and M/S LIT were 73.5% and 47.6%, respectively. M/S LIT was independently correlated with treatment duration, average trough concentration (TDMa), baseline platelet count, eGFR and baseline SOFA score (SOFA0). The developed nomogram predicted M/S LIT with an area under the curve of 0.767 (95% CI 0.715-0.820), a sensitivity of 71.1% and a specificity of 73.2%. CONCLUSIONS: Linezolid trough concentrations increased dramatically in the elderly, by about 10â mg/L in patients aged 65-80â years, followed by a further increase of 10â mg/L for every 10â years of age. Therapeutic drug monitoring is recommended in elderly patients receiving linezolid. The developed nomogram may predict M/S LIT and guide dosage adjustments of linezolid. Clinical trial registration number: ChiCTR2100045707.
Assuntos
Antibacterianos , Monitoramento de Medicamentos , Linezolida , Nomogramas , Trombocitopenia , Humanos , Linezolida/efeitos adversos , Linezolida/farmacocinética , Linezolida/administração & dosagem , Idoso , Masculino , Feminino , Estudos Prospectivos , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Trombocitopenia/induzido quimicamente , Idoso de 80 Anos ou mais , Fatores de Risco , Pessoa de Meia-IdadeRESUMO
Patients treated with ECMO are at great risk of nosocomial infections, and around 10% of isolates are gram-positive pathogens. Linezolid (LZD) is effective in the treatment of these infections but appropriate dosing is challenging. The aim was to evaluate the occurrence of thrombocytopenia during ECMO when treated with LZD. An LZD trough concentration of 8 mg/L was set as the cutoff value for thrombocytopenia occurrence among critically ill patients who received parenteral LZD therapy at a dose of 600 mg every 8 h during ECMO. Eleven patients were included in this prospective observational study. Median LZD trough concentrations were 7.85 (interquartile range (IQR), 1.95-11) mg/L. Thrombocytopenia was found in 81.8% of patients. Based on the median LZD trough concentrations cutoff value, patients were divided into two groups, 1.95 (IQR, 0.91-3.6) and 10.3 (IQR, 9.7-11.7) mg/L, respectively. Median platelet values differed significantly between groups on admission, ECMO day 0, ECMO day 1, and LZD sampling day [194 and 152.5, (p < 0.05)], [113 and 214, (p < 0.05)], [76 and 147.5, (p < 0.01)], and [26 and 96.5, (p < 0.01)], respectively. Duration of LZD therapy was similar between the groups. Significant platelet reduction was observed in both groups, emphasizing the need for closer monitoring to prevent LZD-associated thrombocytopenia.
Assuntos
Oxigenação por Membrana Extracorpórea , Linezolida , Síndrome do Desconforto Respiratório , Trombocitopenia , Humanos , Linezolida/efeitos adversos , Linezolida/administração & dosagem , Linezolida/uso terapêutico , Trombocitopenia/induzido quimicamente , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/diagnóstico , Oxigenação por Membrana Extracorpórea/efeitos adversos , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , COVID-19/complicações , COVID-19/sangue , COVID-19/diagnóstico , Tratamento Farmacológico da COVID-19 , AdultoRESUMO
Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25-2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38⯵M. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.
Assuntos
Linezolida , Trombocitopenia , Linezolida/efeitos adversos , Linezolida/farmacocinética , Humanos , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Células HEK293 , Animais , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Ratos , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacologia , Lansoprazol/farmacologia , Transporte Biológico , Ratos Sprague-Dawley , Fatores de Risco , Adulto , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismoRESUMO
OBJECTIVES: This study conducted a network meta-analysis comparing linezolid, teicoplanin, daptomycin, tigecycline, and ceftaroline fosamil with vancomycin for treating MRSA-related diseases, addressing the lack of comprehensive evaluations in existing research on antibiotic therapy for MRSA infections. METHODS: We systematically searched databases including PubMed, Embase, Web of Science, the Cochrane Librar up to August 22, 2023. All eligible randomized controlled trials of the six antibiotics were included in the NMA, and their effectiveness and safety were compared across various MRSA-related diseases. Categorical data were used for the odds ratio (OR), and continuous data were used for mean difference (SMD). The surface under the cumulative ranking (SUCRA) was employed to evaluate the incidence rate. RESULTS: According to SUCRA results, daptomycin was the most effective treatment (73.0%) in bloodstream infections. In pulmonary infections and skin and soft tissue infections, linezolid out-performed other antibiotics in effectiveness rate (90.6% and 86.3%), microbial killing rate (93.3% and 93.1%). Vancomycin showed lower adverse reactions than teicoplanin, with less hepatotoxicity compared to linezolid and tigecycline. Linezolid had higher thrombocytopenia risk but lower nephrotoxicity risk than others. Vancomycin was less effective in microbial killing rates than linezolid across various infections. CONCLUSION: The present research suggests that in pulmonary infections and skin and soft tissue infections, linezolid may be a better option for treating MRSA-related diseases. However, caution is warranted due to the association of linezolid with thrombocytopenia. TRIAL REGISTRATION: Our study protocol was registered with the International Prospective Register of SystematicReviews (PROSPERO); Registration number: CRD42024535142.
Assuntos
Antibacterianos , Linezolida , Staphylococcus aureus Resistente à Meticilina , Metanálise em Rede , Infecções Estafilocócicas , Tigeciclina , Vancomicina , Humanos , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Vancomicina/uso terapêutico , Vancomicina/efeitos adversos , Linezolida/uso terapêutico , Linezolida/efeitos adversos , Tigeciclina/uso terapêutico , Tigeciclina/efeitos adversos , Teicoplanina/análogos & derivados , Teicoplanina/uso terapêutico , Teicoplanina/efeitos adversos , Daptomicina/uso terapêutico , Daptomicina/efeitos adversos , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/microbiologiaRESUMO
PURPOSE: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. METHODS: Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. RESULTS: A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. CONCLUSION: In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.
Assuntos
Antibacterianos , Área Sob a Curva , Linezolida , Aprendizado de Máquina , Modelos Biológicos , Trombocitopenia , Humanos , Linezolida/farmacocinética , Linezolida/administração & dosagem , Linezolida/efeitos adversos , Linezolida/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Trombocitopenia/induzido quimicamente , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Hepatopatias/metabolismo , Método de Monte Carlo , Adulto , Fatores de RiscoRESUMO
Mycetoma is a chronic granulomatous infectious disease with a triad of subcutaneous swelling, discharging sinuses and the presence of granules. The infection may occur following minor trauma or penetrating thorn injury. We report a case of a man in his 40s with a history of thorn prick 9 years ago, followed by the formation of painless discharging sinuses on the right foot for the past 2 years. Clinical, local epidemiological, histopathological examination and Gram stain confirmed the diagnosis of actinomycetoma. Prior to initiating the Welsh regimen, a pretreatment assessment of the patient's auditory function was conducted through pure tone audiometry, indicating the existence of pre-existing high-frequency bilateral sensorineural hearing loss. The patient was treated with linezolid as an alternative to amikacin, at a dosage of 600 mg two times per day, leading to complete resolution within 3 weeks. This underscores linezolid's efficacy as a safe and cost-effective alternative for actinomycetoma, without causing ototoxic side effects.
Assuntos
Perda Auditiva Neurossensorial , Linezolida , Micetoma , Humanos , Linezolida/uso terapêutico , Linezolida/efeitos adversos , Linezolida/administração & dosagem , Masculino , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/diagnóstico , Micetoma/tratamento farmacológico , Micetoma/diagnóstico , Adulto , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: Oral linezolid is often used as alternative therapy for intravenous vancomycin. According to the current guidelines, no dose adjustment has to be made in case of renal impairment. Nevertheless, in our hospital we have seen several patients with renal impairment who developed linezolid-induced thrombocytopenia when linezolid was taken in the standard dose. In this case series and review we want to emphasize the necessity of reviewing the Dutch and international guidelines. METHODS: We describe five cases with renal impairment that developed linezolid-induced thrombocytopenia in our hospital. A PubMed literature review was conducted to identify other cases and find the optimal dosing regimen for these patients. RESULTS: Our cases join a long list of cases and available literature about linezolid-induced thrombocytopenia in patients with renal impairment. Less linezolid-induced thrombocytopenia was found, both in our cases and in the literature, after dose reduction of 50%. High linezolid trough concentrations were associated with a higher risk of linezolid-induced thrombocytopenia. Besides renal impairment, other risk factors for developing linezolid-induced thrombocytopenia were also identified, such as low body weight, high daily dose/kg, higher age, longer duration of therapy, low baseline count, malignity, low-dose aspirin and interacting co-medication. CONCLUSION: Re-evaluation of the current dose advice is necessary. We advocate for a standard dose reduction to 50% after 2 days of standard dosing for all patients with an estimated glomerular filtration of <60 mL/min/1.73 m2. Besides this, therapeutic drug monitoring and thrombocytes monitoring may be executed weekly when patients have renal impairment or other risk factors for developing linezolid-induced thrombocytopenia.
Assuntos
Antibacterianos , Linezolida , Insuficiência Renal , Trombocitopenia , Linezolida/efeitos adversos , Linezolida/administração & dosagem , Humanos , Trombocitopenia/induzido quimicamente , Masculino , Idoso , Feminino , Insuficiência Renal/induzido quimicamente , Pessoa de Meia-Idade , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , Idoso de 80 Anos ou mais , Relação Dose-Resposta a DrogaRESUMO
INTRODUCTION: Linezolid (LZD) plays an important role in the treatment of severe infections caused by Gram-positive bacteria. Thrombocytopenia is regarded as one of the most common side effects of linezolid, which results from the destruction of platelets or myelosuppression. The study aimed to identify the risk factors associated with the development of thrombocytopenia in Vietnamese patients. METHODOLOGY: This retrospective, descriptive cross-sectional study was performed on adult patients who received parenteral LZD therapy (1,200 mg/day) in at least 3 days between January 2020 and June 2021 at a tertiary referral hospital in Vietnam. Thrombocytopenia was defined as either a final platelet count of less than 100 G/L or a 25% decrease in platelet count from baseline. Multivariate logistic regression analysis was applied to predict risk factors associated with LZD-induced thrombocytopenia. RESULTS: In the 208 patients included in the study, the average age was 69 and males accounted for 73.1%. LZD-induced thrombocytopenia occurred in 37% of patients. LZD-induced thrombocytopenia was significantly associated with shock (HR = 8.26, 95% CI 3.82 - 17.84, p < 0.001), baseline creatinine clearance (HR = 1.02, 95% CI [1.01 - 1.03], p = 0.002), and duration of LZD treatment of at least 14 days (HR = 4.45, 95% CI [1.83 - 11.05], p = 0.001). CONCLUSIONS: The results showed that thrombocytopenia was fairly common in patients using linezolid. Shock, renal failure, and duration of linezolid therapy of at least 14 days were significant risk factors for the incidence of linezolid-induced thrombocytopenia.
Assuntos
Anemia , Trombocitopenia , Masculino , Adulto , Humanos , Idoso , Linezolida/efeitos adversos , Estudos Retrospectivos , Estudos Transversais , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia , Contagem de Plaquetas , Antibacterianos/efeitos adversosRESUMO
Linezolid is a commonly prescribed antibiotic in clinical practice. Although thrombocytopenia and peripheral neuropathy are frequently encountered following prolonged administration of linezolid, lactic acidosis is a rare adverse drug reaction. We present the case of a patient on linezolid for disseminated multidrug-resistant tuberculosis who presented with vomiting, dyspnoea, hypotension and high anion gap metabolic acidosis. The initial presentation mimicked sepsis syndrome. Ketoacidosis and renal dysfunction were ruled out. There was no history of ingestion of toxins/toxic alcohols. Sepsis was unlikely because extensive radiological and microbiological testing could not identify an infection. Given the possibility of linezolid-induced lactic acidosis (LILA), linezolid was discontinued on admission. The patient's lactic acidosis resolved, and his overall condition improved. A retrospective diagnosis of LILA was thus established. LILA should be considered when patients on linezolid present with lactic acidosis and other causes for the lactic acidosis have been ruled out.
Assuntos
Acidose Láctica , Acidose , Humanos , Linezolida/efeitos adversos , Acidose Láctica/diagnóstico , Estudos Retrospectivos , Antibacterianos/efeitos adversos , Acidose/induzido quimicamenteRESUMO
Electronic health records (EHRs) provide meaningful knowledge of drug-related adverse events (AEs) that are not captured in standard drug development and postmarketing surveillance. Using variables obtained from EHR data in the University of California San Francisco de-identified Clinical Data Warehouse, we aimed to evaluate the potential of machine learning to predict two hematological AEs, thrombocytopenia and anemia, in a cohort of patients treated with linezolid for 3 or more days. Features for model input were extracted at linezolid initiation (index), and outcomes were characterized from index to 14 days post-treatment. Random forest classification (RFC) was used for AE prediction, and reduced feature models were evaluated using cumulative importance (cImp) for feature selection. Grade 3+ thrombocytopenia and anemia occurred in 31% of 2,171 and 56% of 2,170 evaluable patients, respectively. Of the total 53 features, as few as 7 contributed at least 50% cImp, resulting in prediction accuracies of 70% or higher and area under the receiver operating characteristic curves of 0.886 for grade 3+ thrombocytopenia and 0.759 for grade 3+ anemia. Sensitivity analyses in strictly defined patient subgroups revealed similarly high predictive performance in full and reduced feature models. A logistic regression model with the same 50% cImp features showed similar predictive performance as RFC and good concordance with RFC probability predictions after isotonic calibration, adding interpretability. Collectively, this work demonstrates potential for machine learning prediction of AE risk in real-world patients using few variables regularly available in EHRs, which may aid in clinical decision making and/or monitoring.
Assuntos
Anemia , Trombocitopenia , Humanos , Linezolida/efeitos adversos , Anemia/induzido quimicamente , Anemia/epidemiologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Modelos Logísticos , São FranciscoRESUMO
OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450â ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.
Assuntos
Antituberculosos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Ciclosserina/efeitos adversos , Diarilquinolinas/uso terapêutico , Linezolida/efeitos adversos , Moxifloxacina/uso terapêutico , Estudos Prospectivos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BACKGROUND: Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials. METHODS: A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid. RESULTS: Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200â mg linezolid, 68 of 195 (35%) experienced a grade 3-4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600â mg linezolid. CONCLUSIONS: Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600â mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.