Kana Matsumoto

Correlation between serum linezolid concentration and the development of thrombocytopenia

Abstract We evaluated the possible association between trough linezolid (LZD) concentrations and platelet counts using a dose–response curve with a logit model equation. We demonstrated that trough LZD concentrations correlated with platelet counts. A significant decrease in platelet count was observed in patients with trough LZD concentrations higher than 22.1 μg/ml.

Evaluation of the pharmacokinetics of linezolid in an obese Japanese patient

Abstract We evaluated the pharmacokinetics of linezolid in the case of an obese Japanese patient (body weight 116 kg; body mass index 37 kg/m2). Linezolid was administered at a dose of 600 mg by intravenous drip infusion for 60–90 min at 12-h intervals. The results showed increased clearance of linezolid and a reduced serum concentration compared to population pharmacokinetic parameters, with trough levels below the 90% minimum inhibitory concentration. However, linezolid was effective for improving lung infection and inflammation in our patient, which may be due to its particularly effective transfer into lung tissues. Linezolid undergoes slow non-enzymatic oxidation in vivo that may be increased in obese patients, and this may account for the greater clearance. Our findings are useful for the planning of linezolid therapy in obese patients.

Population Pharmacokinetic Analysis of Linezolid in Low Body Weight Patients with Renal Dysfunction

Linezolid has antibacterial activity against aerobic Gram‐positive cocci, including methicillin‐resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high‐performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h) = 0.00327 × TBW × eGFR0.428 × HB0.502 × 0.283 (ALT ≥ 100 IU/L) and CL (L/h) = 0.00327 × TBW × eGFR0.428 × HB0.502 (ALT < 100 IU/L), Vd (L) = 1.310 × TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics.

Comparison between concentrations of amphotericin B in infected lung lesion and in uninfected lung tissue in a patient treated with liposomal amphotericin B (AmBisome)

Generally, the primary lesion of a mold infection is in the airway, an extravascular site. Therefore, the antifungal drug concentration at the actual tissue lesion of a mold infection is as important as in the blood compartment. Although our antifungal armamentarium has expanded recently, polyenes are still often needed in clinical practice because of their potent fungicidal activity and the rarity of resistance. Nevertheless, the distribution of amphotericin B (AmB) in infected lung tissue has not yet been evaluated. Using high-performance liquid chromatography analysis, we determined the concentrations of AmB in plasma and infected and uninfected tissues of resected lung simultaneously, in a patient with pulmonary aspergillosis treated with liposomal amphotericin B (L-AmB). The AmB concentration in the infected lesion of the lung was approximately 5.2 times higher than that in plasma and 3.7 times higher than in uninfected lung tissue. L-AmB accumulated in the infected lesion of the lung at a higher concentration. Although our data are from only one patient, they may be useful in helping to develop better strategies for the use of L-AmB against pulmonary fungal infections.

Influence of Linezolid Clearance on the Induction of Thrombocytopenia and Reduction of Hemoglobin

Introduction:Although linezolid (LZD) has proven effective for the treatment of infections caused by multidrug-resistant Gram-positive cocci, thrombocytopenia and anemia associated with reduced hemoglobin (Hb) levels are common side effects. To study the association between the development of these adverse effects and blood LZD levels, the authors evaluated the correlation between LZD clearance (LZD-CL), platelet (PLT) counts and Hb levels. Methods:Sixteen patients with methicillin-resistant Staphylococcus aureus infection were administered LZD over a period of 4 to 41 days, and blood was collected at variable time points beginning on day 4 (n = 31). Blood LZD levels were measured by high-performance liquid chromatography, and LZD-CL was estimated by the population pharmacokinetics mean parameter and Bayesian methods. The relationship between the estimated LZD-CL and reductions in PLT counts and Hb levels was then evaluated by regression analysis. Results:During the LZD treatment period, a weak correlation was identified between the LZD-CL rate and PLT counts (r2 = 0.31, n = 31). Significantly, the regression analysis between LZD-CL and Hb levels showed a stronger correlation (r2 = 0.54, n = 31), with Hb levels clearly decreasing with reductions in the LZD-CL rate. Conclusions:In patients undergoing treatment with LZD, low LZD-CL rates correlated with reductions of both PLT counts and Hb levels, suggesting that increase of blood LZD levels influences hematopoietic function. Because a strong correlation was noted between LZD-CL and Hb levels, closely monitoring changes in Hb levels during treatment with LZD may detect the development of adverse effects such as thrombocytopenia and anemia.

Dasatinib maintenance therapy after allogeneic hematopoietic stem cell transplantation for an isolated central nervous system blast crisis in chronic myelogenous leukemia.

A 22-year-old male with Ph-positive chronic myelogenous leukemia (CML) was started on treatment with imatinib. After 12 months of therapy, he achieved a complete cytogenetic response (CCyR). Although the CCyR persisted in his bone marrow, he developed an isolated CML blast crisis in his central nervous system (CNS) after 29 months of therapy. He underwent allogeneic hematopoietic stem cell transplantation (HSCT) following combination therapy with dasatinib, intrathecal chemotherapy and cranial irradiation. Subsequently, 168 days after allogeneic HSCT, he was started on dasatinib maintenance therapy to prevent a CNS relapse. Thirty-eight months after allogeneic HSCT, he has sustained a complete molecular response in both bone marrow and CNS. We believe dasatinib has the potential to prevent CNS relapse if used for maintenance therapy after allogeneic HSCT.

Pharmacokinetics and protein binding of linezolid in cerebrospinal fluid and serum in a case of post-neurosurgical bacterial meningitis

Abstract We describe a case of bacterial meningitis in a patient administered linezolid (LZD). The ratio of free to total LZD concentrations in cerebrospinal fluid (CSF) was 1 for all measurements, and the LZD concentration in CSF measured at the trough level was almost the same as the free serum concentration.

Philadelphia chromosome-positive acute lymphoblastic leukemia with extramedullary and meningeal relapse after allogeneic hematopoietic stem cell transplantation that was successfully treated with dasatinib

Central nervous system (CNS) relapse is a critical issue while treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). A 58-year-old woman with Ph-positive ALL who relapsed after bone marrow transplantation for meningeal leukemia was treated with high-dose methotrexate, which resulted in remission. She underwent allogeneic cord blood transplantation followed by reduced intensity conditioning chemotherapy with imatinib; however, she experienced CNS relapse and developed an extramedullary mass on the right side of the temporal region. We treated 40 mg of dasatinib once daily, which had to be temporarily discontinued because she developed grade 2 pleural effusion and grade 2 hematemesis. After reinitiation of dasatinib, the extramedullary mass disappeared and meningeal leukemia ameliorated almost immediately. With 40 mg dasatinib administered once daily, its trough level and cerebrospinal fluid (CSF) concentration were 32 ng/mL and below the sensitivity threshold of 1 ng/mL, respectively. Treatment was continued, and the patient remained in complete remission until she died of pneumonia 7 years after the initial diagnosis of ALL. Dasatinib can be an effective treatment for Ph-positive ALL with CNS relapse. Although the concentration in the CSF seems low, it may be sufficient to exert anti-leukemic effects in the human CNS.

Chronic invasive sinus and intracerebral aspergillosis controlled by combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution

Chronic invasive aspergillosis of the sinus is frequently fatal in the absence of early surgical and chemotherapeutic intervention because of its invasion of vascular tissue. We attempted to control a case of inoperable invasive aspergillosis of the sinus with micafungin and itraconazole oral solution. We prescribed a daily oral dose of 400 mg of itraconazole, which is twice the usual dose, and monitored the serum concentration of the drug. Finally, we were able to control the spread of the lesion. This case indicates that combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution is an alternative treatment strategy for inoperable invasive aspergillosis of the sinus.

Pharmacokinetics and Elimination Efficiency of Linezolid during Dialysis

Linezolid (LZD) is an option for treating infections caused by multi-resistant Gram-positive bacteria. The protein-binding rate of LZD markedly influences its elimination by dialysis, with limited data suggesting that LZD is cleared by intermittent hemodialysis. Here, we investigated the protein-binding rate and elimination efficiency of LZD in a sepsis patient receiving dialysis. The oral administration of LZD at 600 mg/day resulted in protein-binding and free rates of the drug of 20.4% and 79.6%, respectively, 24 h after administration. By comparing the LZD concentration before and after dialysis, the elimination efficiency of free LZD as a result of dialysis was found to be 40.6%. Our sepsis patient showed higher plasma concentrations of LZD at trough after hemodialysis than the reported concentrations in normal renal function patients. However, it is not clear from our present findings if a relationship exists between myelosuppression and plasma LZD concentration.