A retrospective cohort study to screen linezolid-induced thrombocytopenia in adult patients hospitalized in the Midwestern Region of Brazil

ABSTRACT Background: Thrombocytopenia (TP) is the major event associated with linezolid (LZD) therapy. We investigated the incidence and risk factors for thrombocytopenia in hospitalized adults who received LZD (1200 mg/day) between 2015 and 2017. HIV-positive, death during follow-up and those with a baseline platelet count ≤100 × 103/mm3 were excluded. Method: TP was defined as a decrease in platelet count of ≥20% from the baseline level at the initiation of linezolid therapy and a final count of <100 × 103/mm3. The odds ratios (OR) for thrombocytopenia were obtained using multivariate stepwise logistic regression analysis. Main results: A total of 66 patients were included (mean age [SD] 62 [18], male gender [%], 37 [56]). LZD-associated TP was identified in 12 patients (18.2%). For TP, the adjusted OR [95% CI] of the platelet count ≤200 × 103/mm3, serum creatinine and renal impairment at baseline were 5.66 [1.15-27.9], 4.57 [1.26-16.5] and 9.41 [1.09-80.54], respectively. Male gender and dosage per weight per day (DPWD) >20 mg/kg/day were not risk factors. Conclusion: The results showed that the incidence of linezolid-induced thrombocytopenia was lower in patients with normal renal function and higher in those with platelet counts ≤200 × 103/mm3 or serum creatinine >1.5 mg/dL at the start of the treatment.

Mielosupresión inducida por linezolid: un caso pediátrico / Myelosupression induced by linezolid: a pediatric case

El linezolid es un antibiótico de la familia de las oxazolidinonas, que actúa inhibiendo la síntesis proteica. Se emplea en infecciones graves por cocos Gram-positivos multirresistentes. Sus principales efectos secundarios son los gastrointestinales y, con menor frecuencia, la neuropatía periférica, la acidosis láctica y la mielosupresión. Se presenta el caso clínico de un niño de 12 años con diagnóstico de osteoartritis séptica de cadera derecha con osteomielitis femoral en tratamiento con linezolid, que presentó un cuadro de intolerancia digestiva, asociado a astenia y pérdida de peso. Presentaba, además, anemia normocítica, junto con leucopenia y trombopenia leves, con datos sugestivos de alteración de la hematopoyesis en el frotis sanguíneo, sugerente de toxicidad por fármacos. El cuadro se resolvió con la interrupción de la administración del fármaco. La mielosupresión reversible asociada a linezolid se relaciona con tratamientos prolongados (> 28 días), por lo que son necesarios los controles hematológicos periódicos durante ellos.

Linezolid is an antibiotic of oxazolidinones family that inhibits proteical synthesis. It is used in several Gram-positive multirresistent infections. Its more frequent side effects are gastrointestinal, followed by peripheral neuropathy and myelosuppression. We report the case of a 12-year-old boy diagnosed with septic osteoarthritis of the hip and femoral osteomyelitis, following treatment with linezolid, who complained about digestive intolerance and weight loss. He showed severe normocytic anemia and mild leukopenia and thrombocytopenia with data of hematopoiesis disorder in the blood smear that suggested drug toxicity. These findings reverted when the treatment was discontinued. Reversible myelosuppression associated with linezolid is related to long treatments (more than 28 days). So it is necessary to check the blood count during long treatments.

Efectos adversos relacionados con la linezolida en la práctica clínica pediátrica / Linezolid-related adverse effects in clinical practice in children

Introducción. La linezolida puede causar efectos adversos, como trombocitopenia, que, según lo observado, se relacionan con la administración de linezolida durante más de 2 semanas. Se ha realizado una cantidad limitada de estudios sobre la seguridad y el momento de aparición de los efectos adversos relacionados con la linezolida en los niños. El objetivo de este estudio fue evaluar la incidencia de los efectos adversos asociados con la linezolida, especialmente en relación con el momento de su aparición. Población y métodos. Se incluyeron a todos los niños (< 18 años de edad) que recibieron tratamiento con linezolida durante > 3 días. Se evaluaron los efectos adversos atribuidos a la linezolida y el momento de aparición de los efectos secundarios. Resultados. En total, se incluyeron 179 niños. La mediana de edad de los pacientes fue 4 años (entre 6 días y 17 años). Durante el tratamiento con linezolida, 36 (20,1%) pacientes tuvieron efectos adversos. El efecto adverso más frecuente fue la trombocitopenia, detectada en 26 (14,5%) pacientes. Los demás efectos adversos fueron: elevación de las enzimas hepáticas en 4 pacientes, leucopenia y anemia en 2 pacientes, disfunción renal en 1 y reacciones cutáneas graves en 3 pacientes. Los efectos adversos se detectaron dentro de una mediana de 7,5 días de tratamiento (intervalo: de 4 a 18 días). Entre los 36 pacientes, 26 (72,2%) presentaron un efecto adverso en los primeros 10 días de tratamiento. Conclusiones. Se detectaron efectos adversos transitorios en el 20,1% de los pacientes durante el tratamiento con linezolida. Estos efectos adversos podrían detectarse antes de los 10 días de tratamiento. La linezolida debe recetarse de manera segura a los niños siempre que se vigilen los efectos adversos, en especial el recuento de trombocitos y el nivel de enzimas hepáticas.

Introduction: Linezolid may cause adverse effects such as thrombocytopenia, which were found to be dependent on receiving linezolid for longer than 2 weeks. There are limited studies concerning the safety and timing of linezolid-related adverse effects in children. Objective of this study was to evaluate the incidence of adverse effects associated with linezolid, with especially focusing on the time of occurrence. Population and Methods: All children (<18 years of age) who received >3 days of linezolid therapy were included in this study. Adverse effects attributed to linezolid and time of occurrence of side effects was evaluated. Results: A total of 179 children were enrolled to the study. The patients' median age was 4 years (6 days to 17 years). During linezolid treatment, 36 (20.1%) patients experienced adverse effects. The most common adverse effect was thrombocytopenia that was detected in 26 patients (14.5%). Other adverse effects were as following; elevated liver enzymes in 4 patients, leucopenia and anemia in 2 patients, renal function impairment in one patient, and serious skin reactions in 3 patients. Adverse effects were detected within median 7.5 days of therapy (ranging from 4 to 18 days). Among 36 patients, 26 (72.2%) patients had adverse effect on the first 10 days of therapy. Conclusions: Transient adverse effects were detected in 20.1% of the patients during linezolid therapy. These adverse effects may be detected earlier than ten days of treatment. Linezolid should be prescribed safely in children with monitoring adverse effects especially platelet count and level of liver enzymes.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182) vs linezolid (N = 171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Caracterização molecular dos mecanismos de resistência à linezolida em estafilococos coagulase-negativos e estudo da estabilidade do fenótipo resistente / Linezolid resistance in negative-coagulase staphylococci: characterization and stability of resistant phenotype

Linezolid was the first agent of the oxazolidinone class to be introduced clinically. This oxazolidinone inhibits protein biosynthesis by preventing the formation of the initiation complex that consists of the mRNA, the f-Met tRNA and the 50S subunit of the ribosome. Although linezolid resistance has been mediated by the cfr-encoded product or by ribosomal proteins (L3, L4 and L22), the most common mechanism of resistance involves mutations in the central loop of domain V of the 23S rRNA gene. From March 2008 to December 2011, 38 coagulase-negative staphylococci (CNS) strains (20 S. epidermidis, 14 S. haemolyticus, 3 S. hominis e 1 S. warneri) exhibiting resistance to linezolid were isolated from blood and catheter cultures from patients in two tertiary care hospitals in the State of São Paulo and were included in this study for the ascertainment of the resistance mechanisms to this antimicrobial agent and for the analysis of the stability of this resistance. The strains exhibited high-level resistance to linezolid (MICs 16-128 µg/ml) and all were multidrug resistant, remaining susceptible to vancomycin and teicoplanin. The G2576T mutation in domain V region of 23S rRNA was identified in all isolates, except in a linezolid-resistant S. haemolyticus strain. The cfr gene and mutations in ribosomal proteins L4 and L22 were not detected. Regarding L3 protein analysis, all S. epidermidis strains of hospital A, including the linezolid-susceptible control strain, showed the L3 Leu101Val mutation, suggesting that this alteration is probably not involved in linezolid resistance. The one strain from hospital B (S. epidermidis) was wild-type for this ribosomal protein. Only one S. haemolyticus strain had a mutation in the L3 protein, Val154Leu. Two S. hominis strains showed Gly139Arg/Met156Thr mutations whereas one strain had Phe147Ile in L3 protein. The identification of these mutations in L3 protein of the linezolid-resistant S. haemolyticus and S. hominis strains strengthens the role of these sites in the acquisition of linezolid resistance in Staphylococcus spp. However, the presence of G2576T in the 23S rRNA gene makes difficult to determine exactly the role of L3 mutations in conferring elevated linezolid MIC values showed by these clinical strains. In the absence of antibiotic pressure, after 130 passages, linezolid resistance was stable in the clinical strains of this study, which did not have all copies of the 23S rRNA gene mutated, according to the restriction of the domain V fragment with NheI enzyme. Sequencing of the individual copies of the 23S rRNA gene in the serially passaged strains showed G2576T in all amplified copies by PCR: 4/4 and 5/5 in S. epidermidis and 3/3 in S. haemolyticus strains (MIC of 16-32 µg/ml). The stability of the mutant rRNA copy was also observed in the linezolid-susceptible S. epidermidis strain (MIC of 4 µg/ml). After the passages in antibiotic-free medium, the linezolid MIC of this strain fell to 1 µg/ml and the G2576T mutation persisted in one 23S rRNA gene copy. The clonal relatedness of the strains was determined by PFGE and revealed a clonal dissemination of different CNS species. Regarding MLST analysis, all S. epidermidis strains belonged to the sequence type ST2 (CC2). Most likely, the increased selective pressure has contributed to the selection of endemic linezolid-resistant CNS clones showing the G2576T mutation that have been disseminated in the institution A since 2008. Differently, the restricted use of linezolid in the institution B could explain the occurrence of a single resistant strain since 2005