Pharmacokinetics and Adverse Effects of Clofazimine in the Treatment of Pulmonary Non-Tuberculous Mycobacterial Infection.

Clofazimine (CFZ) is used to treat pulmonary non-tuberculous mycobacterial (NTM) infection; however, its pharmacokinetics remain unexplored in patients with pulmonary NTM, and the relationship between CFZ serum concentration and adverse effects has not been investigated. The objectives of this study were to characterize the pharmacokinetics of CFZ in pulmonary NTM disease treatment and to investigate the relationship between the steady-state CFZ serum concentration and adverse effects. A prospective observational study was conducted on 45 patients with pulmonary NTM treated with CFZ (UMIN000041053). A maximum of five serum samples per patient were taken at the CFZ trough, and serum concentration was measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The pharmacokinetics of CFZ were analyzed using a nonlinear mixed effect model. The relationships among steady-state CFZ serum concentration and adverse effects, pigmentation, and heart rate-corrected QT (QTc) interval were investigated. Twenty-six patients had M. avium or M. intracellulare infection and nineteen had M. abscessus infection. The primary CFZ dosage was 50 mg/day. The estimated apparent CFZ clearance, apparent volume of distribution, and half-life were 2.4 L/h, 2,960 L, and 36 days, respectively. The combined use of rifampicin and CFZ significantly reduced CFZ exposure by 22%. Although there was no relationship between CFZ serum concentration and pigmentation intensity, the QTc interval was significantly correlated with CFZ serum concentration. The estimation of accurate pharmacokinetics for CFZ required approximately 5 months of monitoring. The relationship between the serum concentration and specific adverse effects of CFZ confirmed that CFZ serum concentration was not associated with pigmentation but did affect the QTc interval.

Low-dosage ethambutol, less than 12.5 mg/kg/day, does not worsen the clinical outcomes of pulmonary Mycobacterium avium and Mycobacterium intracellulare disease: a retrospective cohort study.

OBJECTIVES: Multidrug chemotherapy is recommended for treating pulmonary Mycobacterium avium and Mycobacterium intracellulare disease. Although ethambutol has been demonstrated to inhibit macrolide resistance, the ethambutol dosage is sometimes decreased due to concerns about optic neuropathy. We aimed to assess whether lower ethambutol doses impact treatment outcomes. METHODS: Patients treated over 12 months between 2016 and 2020 were collected retrospectively. Clinical outcomes, including negative culture conversion, microbiological cure, adverse events, resistance to macrolides, and recurrence, were compared according to daily ethambutol dosage. RESULTS: Among 146 patients, 42 were treated with ethambutol dosages over 12.5 mg/kg/day, and 104 were treated with lower dosages. Negative culture conversion was achieved for 125 patients, and 90 patients achieved microbiological cure. Recurrence was identified in 16 patients who achieved microbiological cure. No macrolide resistance was observed, and no significant difference was observed in the percentage of negative culture conversion (P = 1.00) or microbiological cure (P = 0.67) between the high- and low-dosage ethambutol groups. Sputum smear positivity was associated with a lower adjusted odds ratio (aOR) of negative culture conversion (aOR: 0.48, 95% CI: 0.29-0.80). A lower aOR of microbiological cure was independently associated with sputum smear positivity (aOR: 0.52, 95% CI: 0.37-0.74) and with the use of an intermittent regimen (aOR: 0.60, 95% CI: 0.41-0.87). Daily ethambutol dosage was not identified as a prognostic factor for any of the outcomes. Optic neuropathy was observed in 7.1% of the high-dose ethambutol group and 1.0% of the low-dosage ethambutol group (P = 0.07). CONCLUSION: An ethambutol dosage of 12.5 mg/kg/day or less in guideline-based chemotherapy may reduce optic neuropathy without worsening clinical outcomes.

Enhancing the antibacterial efficacy of aluminum foil by nanostructuring its surface using hot water treatment.

Bacterial biofilm has become one of the most frequent health problems as it contributes to persistent chronic infections. Therefore, it is vital to find alternatives to currently used bactericidal agents to prevent bacterial contamination on surfaces effectively and prevent the biofilms formation. Several metallic materials are well known for their antimicrobial activity; this includes copper, copper alloys, silver, gold, titanium, and zinc. On the other hand, some metals, such as aluminum, do not have noteworthy antimicrobial properties. In this study, we demonstrate that the antibacterial activity of household aluminum foil can be enhanced by nanostructuring the foil's surface by a simple hot water treatment (HWT) process. Cultures ofEscherichia coliandStaphylococcus aureuswere grown on nutrient agar while exposed to the samples of treated and untreated Al foils and left for 24 h. Our results indicate that treated Al foil can more effectively inhibit the bacteria growth compared to the regular untreated Al foil. This enhancement in antibacterial property might be due to a combination of chemical and morphological changes that the cell undergoes once it encounters nanofeatures of HWT-Al foil surface.

Dendritic cell biocompatibility of ether-based urethane films.

The use of synthetic materials for biomedical applications is ever expanding. One of the major requirements for these materials is biocompatibility, which includes prevention of immune system responses. Due to the inherent complexity of their structural composition, the polyurethane (PU) family of polymers is being used in a variety of medical applications, from soft and hard tissue scaffolds to intricate coatings on implantable devices. Herein, we investigated whether two polymer materials, D3 and D7, induced an immune response, measured by their effects on a dendritic cell (DC) line, JAWS II. Using a lactate dehydrogenase cytotoxicity assay and Annexin V/PI staining, we found that the PU materials did not induce cytotoxicity in DC cells. Using confocal microscopy, we also showed that the materials did not induce activation or maturation, as compared to positive controls. This was confirmed by looking at various markers, CD80, CD86, MHC class I, and MHC class II, via flow cytometry. Overall, the results indicated that the investigated PU films are biocompatible in terms of immunotoxicology and immunogenicity and show great promise for use in regenerative medicine.

Upregulation of IFN-ß induced by Sema4D-dependent partial Erk1/2 inhibition promotes NO production in microglia.

Interactions between Sema4D and its receptors, PlexinB1 and CD72, induce various functions, including axon guidance, angiogenesis, and immune activation. Our previous study revealed that Sema4D is involved in the upregulation of nitric oxide production in microglia after cerebral ischemia. In this study, we investigated the underlying mechanisms of the enhancement of microglial nitric oxide production by Sema4D. Primary microglia expressed PlexinB1 and CD72, and cortical microglia expressed CD72. Sema4D promoted nitric oxide production and slightly inhibited Erk1/2 phosphorylation in microglia. Partial Erk1/2 inhibition enhanced microglial nitric oxide production. Inhibition of Erk1/2 phosphorylation induced the expression of Ifn-ß mRNA, and IFN-ß promoted nitric oxide production in microglia. In the ischemic cortex, the expression of Ifn-ß mRNA was downregulated by Sema4D deficiency. These findings indicated that the enhancement of nitric oxide production by Sema4D is involved in partial Erk1/2 inhibition and upregulation of IFN-ß.

Plasmonic gap-enhanced Raman tag nanorods for imaging 3D pancreatic spheroids using surface-enhanced Raman spectroscopy and darkfield microscopy.

Plasmonic gap-enhanced Raman tags (GERTs) are new emerging nanoprobes that, based on their unique surface-enhanced Raman spectroscopy (SERS) signal, can play a major role in complex imaging and detection of biological systems. GERTs are generated from a metal core nanostructure and layered with one or more metal nanosized layers, encasing a Raman active molecule. The advantages of GERTs are enhanced surface plasmon and electromagnetic resonance, as well as inherent protection of the Raman active molecule from environmental deterioration that could reduce their spectroscopic signatures over time. In this study, we used in vitro three-dimensional (3D) spheroid cultures to demonstrate these advantages. 3D spheroids mimic the in vivo tumor microenvironment better than 2D culture, with abundant extracellular matrix and hypoxia inducing variability of pH and enzymatic reactions. Here, we report the use of GERTs in large pancreatic 3D spheroids (>500 µm in apparent diameter) for complex penetration visualization. Our combined imaging technique of enhanced darkfield microscopy and SERS was able to identify the presence and distribution of the GERTs within the 3D spheroid structure. The distribution of GERTs 2 hours after the nanorods' incubation indicated accumulation, generally in the outermost layer of the spheroids but also, more randomly, in non-uniform patterns in deep layers of the 3D spheroids. These observations bring into question the mechanism of uptake and flow of the nanoparticles in function of their incubation time while demonstrating the promising potential of our approach. Additionally, the SERS signal was still detectable after 24 hours of incubation of GERTs with the 3D culture, indicating the stability of the Raman signal.

CuO/Cu core/shell nanostructured photoconductive devices by hot water treatment and high pressure sputtering techniques.

This work demonstrates the fabrication of simple photoconductive devices based on CuO/Cu core/shell nanostructured heterojunction that performs notable photocurrent response. Copper oxide (CuO) nanoleaf structures (NLs) have been successfully grown on ITO-coated glass substrate via a simple hot water treatment (HWT) method. A conformal Cu shell was fabricated by high pressure sputtered (HIPS) deposition technique on the CuO nanoleaves to produce NLs-core/metal shell photoconductive devices. For comparison, CuO thin film (TF) was prepared by the thermal oxidation method to manufacture the conventional planar thin film devices. Results showed that the HWT method resulted in the formation of dense 3D CuO nanoleaves on ITO/glass substrate with a high surface area. CuO NLs showed higher optical absorption than CuO TF in the ultraviolet and visible spectrum. Further, the optical band gaps of CuO NLs and TF samples have been estimated from Touc's plot to be 1.45 ± 0.10 eV and 1.63 ± 0.20 eV, respectively. Current density-voltage measurements' result revealed that core/shell devices have superior photocurrent response compared to TF devices. The average photocurrent density at zero-bias for the NLs devices was 23.5 ± 2.0 µA cm-2 and for TF devices was 6.7 ± 1.0 µA cm-2. Besides, NLs core/shell photoconductive devices exhibit a remarkable increase in photocurrent response values with increasing bias voltage compared to the increased values in TF devices. The results demonstrate that the devices based on HWT-NLs-core/HIPS-shell design showed a significant enhancement on the photoconductivity response compared with the conventional TF design. The performance enhancement can be attributed to improving light trapping, photocarriers generation-recombination times and carrier collection by introducing an alternative radial interface in core/shell design. Also, HWT CuO NLs geometry feature with the high surface area has worked to enhance light absorption that enables the design of high efficiency, functional and commercial photoconductive detectors.

Innate Biomineralization.

In vertebrates, biomineralization is a feature considered unique to mature osteoblasts and odontoblasts by which they synthesize hydroxyapatite (HAP), which is deposited in the collagen matrix to construct endoskeleton. For many decades, the mechanisms that modulate differentiation and maturation of these specialized cells have been sought as a key to understanding bone-remodeling defects. Here, we report that biomineralization is an innate ability of all mammalian cells, irrespective of cell type or maturation stage. This innate biomineralization is triggered by the concomitant exposure of living cells to three indispensable elements: calcium ion, phosphoester salt, and alkaline phosphatase. Any given somatic cell, including undifferentiated mononuclear cells, can undergo a biomineralization process to produce calcium-phosphate agglomerates. The biologically generated minerals under such conditions are composed of genuine HAP crystallites of Ca10(PO4)6(OH)2 and 5-10 nanometer (nm) in size. This discovery will profoundly improve our understanding of bone metabolism and ectopic calcifications.

High temperature, transparent, superhydrophobic Teflon AF-2400/Indium tin oxide nanocomposite thin films.

The outstanding properties of Teflon AF-2400-chemical, optical, etc-inspired us to make modifications to enhance its hydrophobicity. We prepared an AF-2400/indium tin oxide (ITO) nanocomposite by a spin coating technique at room temperature, using the AF-2400 polymer as the matrix and ITO nanoparticles as the filler. Different ITON concentrations ranging from 3 to 30 mg ml-1 were prepared to study the effect of nanoparticle loading on the films' properties and superhydrophobicity. The effect of spin speed and annealing temperature was also studied. Atomic force microscopy, x-ray photoelectron spectroscopy, and UV-vis analysis were employed to characterize the prepared films. The results indicated that the film's low surface energy and nano/micro-features made it superhydrophobic. Increasing the ITON concentration to 15 mg ml-1 improved the superhydrophobicity of the composite film by increasing the surface roughness. The coating showed superhydrophobic behavior with a static contact angle (SCA) around 152° and contact angle hysteresis less than 2°. The nanocomposite films also exhibited excellent thermal stability, sustaining temperatures as high as 240 °C without losing their superhydrophobic behavior. Three models, Wenzel, Cassie-Baxter, and Shuttleworth-Bailey, were used to predict the SCA. The results confirmed that the latter model gave the best prediction. In addition to superhydrophobicity, the AF-2400/ITON films coated on a glass substrate showed very high transparency-around 95% in the visible and infrared ranges. An effective medium theory, the Bergman representation, was used to simulate the transmittance of the AF-2400/ITON nanocomposites. The measured and simulated transmittance values were in good agreement in the visible range. Based on our results, this coating may be highly useful for many practical applications, including solar cell coatings, chemical resistance protective coatings, and more.

Plasmonic nano surface for neuronal differentiation and manipulation.

Neurodegenerative diseases and traumatic brain injuries can destroy neurons, resulting in sensory and motor function loss. Transplantation of differentiated neurons from stem cells could help restore such lost functions. Plasmonic gold nanorods (AuNR) were integrated in growth surfaces to stimulate and modulate neural cells in order to tune cell physiology. An AuNR nanocomposite system was fabricated, characterized, and then utilized to study the differentiation of embryonic rat neural stem cells (NSCs). Results demonstrated that this plasmonic surface 1) accelerated differentiation, yielding almost twice as many differentiated neural cells as a traditional NSC culture surface coated with poly-D-lysine and laminin for the same time period; and 2) promoted differentiation of NSCs into neurons and astrocytes in a 2:1 ratio, as evidenced by the expression of relevant marker proteins. These results indicate that the design and properties of this AuNR plasmonic surface would be advantageous for tissue engineering to address neural degeneration.

X-ray photoelectron spectroscopy and transmission electron microscopy analysis of silver-coated gold nanorods designed for bionanotechnology applications.

Multicomponent nano-agents were designed and built via a core-shell approach to enhance their surface enhanced Raman scattering (SERS) signals. These nano-agents had 36 nm × 12 nm gold nanorod cores coated by 4 nm thick silver shell films and a subsequent thin bifunctional thiolated polyethylene glycol (HS-PEG-COOH) layer. Ambient time-lapsed SERS signal measurements of these functionalized nanorods taken over a two-week period indicated no signal degradation, suggesting that large portions of the silver shells remained in pure metallic form. The morphology of the nanorods was characterized by transmission electron microscopy (TEM) and ultra-high resolution scanning TEM. X-ray photoelectron spectroscopy (XPS) and Auger electron spectroscopy (AES) were utilized to assess the oxidation states of the silver shells covered by HS-PEG-COOH. The binding energies of Ag 3d XPS spectra yielded very small chemical shifts with oxidation; however, the AES peak shapes gave meaningful information about the extent of oxidation undergone by the nano-agent. While the silver shells without HS-PEG-COOH coatings oxidized significantly, the silver shells with HS-PEG-COOH remained predominantly metallic. In fact, six month-old samples still retained mostly metallic silver shells. These findings further demonstrate the stability and longevity of the nanostructures, indicating their significant potential as plasmonically active agents for highly sensitive detection in various biological systems, including cancer cells, tissues, or even organisms.

The role of surface chemistry in the cytotoxicity profile of graphene.

Graphene and its derivative, because of their unique physical, electrical and chemical properties, are an important class of nanomaterials being proposed as foundational materials in nanomedicine as well as for a variety of industrial applications. A major limitation for graphene, when used in biomedical applications, is its poor solubility due to its rather hydrophobic nature. Therefore, chemical functionalities are commonly introduced to alter both its surface chemistry and biochemical activity. Here, we show that surface chemistry plays a major role in the toxicological profile of the graphene structures. To demonstrate this, we chemically increased the oxidation level of the pristine graphene and compared the corresponding toxicological effects along with those for the graphene oxide. X-ray photoelectron spectroscopy revealed that pristine graphene had the lowest amount of surface oxygen, while graphene oxide had the highest at 2.5% and 31%, respectively. Low and high oxygen functionalized graphene samples were found to have 6.6% and 24% surface oxygen, respectively. Our results showed a dose-dependent trend in the cytotoxicity profile, where pristine graphene was the most cytotoxic, with decreasing toxicity observed with increasing oxygen content. Increased surface oxygen also played a role in nanomaterial dispersion in water or cell culture medium over longer periods. It is likely that higher dispersity might result in graphene entering into cells as individual flakes ~1 nm thick rather than as more cytotoxic aggregates. In conclusion, changes in graphene's surface chemistry resulted in altered solubility and toxicity, suggesting that a generalized toxicity profile would be rather misleading. Copyright © 2016 John Wiley & Sons, Ltd.

p53-competent cells and p53-deficient cells display different susceptibility to oxygen functionalized graphene cytotoxicity and genotoxicity.

Due to the distinctive physical, electrical, and chemical properties of graphene nanomaterials, numerous efforts pursuing graphene-based biomedical and industrial applications are underway. Oxidation of pristine graphene surfaces mitigates its otherwise hydrophobic characteristic thereby improving its biocompatibility and functionality. Yet, the potential widespread use of oxidized graphene derivatives raises concern about adverse impacts on human health. The p53 tumor suppressor protein maintains cellular and genetic stability after toxic exposures. Here, we show that p53 functional status correlates with oxygen functionalized graphene (f-G) cytotoxicity and genotoxicity in vitro. The f-G exposed p53-competent cells, but not p53-deficient cells, initiated G0 /G1 phase cell cycle arrest, suppressed reactive oxygen species, and entered apoptosis. There was p53-dependent f-G genotoxicity evident as increased structural chromosome damage, but not increased gene mutation or chromatin loss. In conclusion, the cytotoxic and genotoxic potential for f-G in exposed cells was dependent on the p53 functional status. These findings have broad implications for the safe and effective implementation of oxidized graphene derivatives into biomedical and industrial applications. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Graphene nanoparticles as osteoinductive and osteoconductive platform for stem cell and bone regeneration.

The potential of graphene-based nanoparticles (GNPs) has recently gained significant attention in biomedicine, especially in tissue engineering. In this study, we investigated the osteoinductive and osteoconductive effects of low oxygen content graphene (LOG) nanoparticles on adult mesenchymal stem cells (MSCs) in vitro and in vivo. We showed that adult goat MSCs were viable in the presence of 0.1 mg/mL LOG and retained their stem cell properties. A 3D scaffold made from agarose was used to encapsulate MSCs and LOG nanoparticles. Scanning electron microscopy demonstrated the cell morphology and adherence of MSCs to LOG in the 3D form. The LOG and MSCs in the 3D scaffold were xenogenically implanted into a rat unicortical tibial bone defect. The combination of MSCs and LOG nanoparticles resulted in improved active bone formation and increased mineralization. These results strengthen the applicability of LOG nanoparticles as an adjunct treatment for bone tissue engineering.

Effect of Sema4D on microglial function in middle cerebral artery occlusion mice.

Cerebral ischemia evokes neuroinflammatory response. Inflammatory stimulation induces microglial activation, such as changes of their morphology from ramified to ameboid, expression of iNOS and cytokines, and the elevation of proliferative activity. Activated microglia play important roles in pathogenesis of cerebral ischemia. A previous study indicated that Sema4D promoted iNOS expression in cultured microglia; however, roles of Sema4D on microglial activation in ischemic injury remains unclear. We investigated the effect of Sema4D-deficiency on microglial activation by using permanent middle cerebral artery occlusion (MCAO) in mice. In this study, ischemia-induced activated microglia were classified into activated-ramified microglia and ameboid microglia based on their morphology. We demonstrated that the rate of iNOS expression in activated-ramified microglia was lower than that in ameboid microglia, while the most proliferating microglia were activated-ramified microglia but not ameboid microglia after cerebral ischemia. Sema4D-deficiency decreased the number of ameboid microglia and iNOS-expressing activated-ramified microglia in the peri-ischemic cortex. These changes by Sema4D-deficiency contributed to the reduction of NO production that was estimated by nitrite concentration in ischemic cortex. On the other hand, Sema4D-deficiency promoted proliferation of microglia in the peri-ischemic cortex. Importantly, ischemia-induced apoptosis and postischemic behavioral abnormality were moderated in Sema4D(-/-) mice. These findings suggest that Sema4D promotes cytotoxic activation of microglia and inhibits functional recovery after cerebral ischemia.

Clofazimine serum concentration and safety/efficacy in nontuberculous mycobacterial pulmonary disease treatment.

BACKGROUND: Clofazimine (CFZ) has shown promising effects against Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) and Mycobacterium abscessus species pulmonary disease (MABS-PD). However, the optimal CFZ dose remains unknown. We aimed to explore the relationship between steady-state CFZ concentration and its safety and efficacy in MAC-PD and MABS-PD. METHODS: This prospective observational study focused on patients with MAC-PD and MABS-PD treated with CFZ (UMIN 000041053). To understand the safety and efficacy profile of CFZ and elucidate its optimal concentration, we analyzed CFZ-induced pigmentation grade, QTc interval, and culture conversion outcomes in relation to serum CFZ concentration using Student's t-test, a concentration-QTc model, and multivariable logistic regression analysis, respectively. In total, 64 patients (34 with MAC-PD; 30 with MABS-PD) were included. RESULTS: The steady-state concentration of CFZ was higher in the moderate-to-severe pigmentation group than in the none-to-light pigmentation group (P < 0.001). At a CFZ concentration of 1 mg/L, the QTc interval was prolonged by 17.3 ms (95 % confidence interval [CI], 3.9-25.4) from baseline. Culture conversion was achieved in 33 (51.6 %) patients. The only significant predictor of culture conversion was surgery (adjusted odds ratio, 5.4; 95 % CI, 1.3-38.0). CFZ concentration and MIC of CFZ less than 0.25 mg/L were not associated with culture conversion in this study. CONCLUSION: CFZ-induced pigmentation and QT interval prolongation are associated with serum CFZ concentrations. CFZ dosage may be optimized by monitoring serum CFZ concentration.

Beyond Symptoms: Radiologic identification of asymptomatic Mycobacterium avium complex pulmonary infections.

BACKGROUND: Although international nontuberculous mycobacterial pulmonary disease (NTM-PD) guidelines highlight symptom presence at diagnosis, the clinical characteristics of asymptomatic Mycobacterium avium complex pulmonary infection (MAC-PI) patients remain understudied. We clarified the clinical characteristics and course of asymptomatic MAC-PI patients. METHODS: We retrospectively analyzed 200 consecutive patients with MAC-PIs and adequate available data who newly met the microbiological and radiological criteria for NTM-PD at Fukujuji Hospital from January 2018 to June 2020. We compared the clinical characteristics and course of asymptomatic patients with symptomatic patients and evaluated factors influencing treatment initiation through multivariate analysis. RESULTS: 111 patients were symptomatic and 89 were asymptomatic at diagnosis. While the proportion was significantly lower than that in the symptomatic group (28.8 %), 15.7 % of asymptomatic group patients had cavitary lesions (P = 0.042). In the asymptomatic group, treatments were initiated in 38 (42.7 %) patients, and cavitary lesions, a positive acid-fast bacilli smear, and younger age were independent risk factors for treatment initiation. Among 22 (57.9 %) patients who experienced disease progression necessitating treatment during follow-up, 13 (34.2 %) displayed radiological progression without any worsening of symptoms. Agents used for treatment were consistent across the groups, with no significant differences in culture conversion, microbiological recurrence rates, or spontaneous culture conversion rates. CONCLUSION: Routine health checkups and radiological examinations can detect clinically important MAC-PIs even in the absence of symptoms. Considering that the clinical course of asymptomatic MAC-PI patients is largely similar to that of symptomatic patients, timely and appropriate management and intervention are essential for all MAC-PI patients.

Silver nanoparticles decrease body weight and locomotor activity in adult male rats.

Silver nanoparticles (Ag-NPs) are widely used in FDA regulated products. The physical-chemical properties of Ag-NPs are characterized using various instruments. The dose-dependent activity and body weight alterations are evaluated after rats were exposed to Ag nanoparticles, suggesting a major human health risk, given the wide application of silver nanomaterials.

Population Pharmacokinetic Analysis of Vancomycin in Patients with Solid or Hematological Malignancy in Relation to the Quick Sequential Organ Failure Assessment Scores.

BACKGROUND AND OBJECTIVE: It remains unclear whether sepsis in patients with malignancy interferes with the predictive performance of the dose-estimation formulas. The quick sequential organ failure assessment (qSOFA) score can help identify patients with poor outcomes because of sepsis-associated organ damage. Vancomycin, an important antibiotic, treats systemic infections (sepsis) caused by methicillin-resistant Staphylococcus aureus. We aimed to clarify whether including the qSOFA score in a standard population pharmacokinetic (PopPK) assessment may improve the predictive performance of vancomycin doses in patients with malignancy. METHODS: This was a retrospective, observational study. Serum vancomycin concentration-time datasets were obtained from the therapeutic drug monitoring records of St. Luke's International Hospital (Tokyo, Japan) from January 2011 to August 2016. Clinical and laboratory data of the relevant patients were retrieved from electronic health records. PopPK analysis was performed using the NONMEM program, which includes creatinine clearance (CLCr), blood neutrophil counts, qSOFA scores, and type of malignancy as covariates. We examined the validity of the final PopPK model using bootstrapping, goodness-of-fit plots, and prediction-corrected visual predictive checks. RESULTS: Six hundred and eight blood samples were obtained from 325 patients. In the final PopPK model, the CLCr and qSOFA scores were selected as covariates of systemic vancomycin clearance (p < 0.05): the population mean value was 2.8 (L/h). Regardless of the CLCr, a qSOFA score of greater than 1 was associated with an approximately 10% reduction in vancomycin clearance. CONCLUSIONS: qSOFA scores might be an additional covariate to CLCr for estimating vancomycin concentrations with a PopPK model in patients with malignancy.

Multiple bacterial culture positivity reflects the severity and prognosis as bronchiectasis in Mycobacterium avium complex pulmonary disease.

BACKGROUND: Bacterial coinfections are observed in 19-66% of patients with Mycobacterium avium complex pulmonary disease (MAC-PD) during the entire duration of the disease. The impact of bacterial coinfection at diagnosis on the clinical course of MAC-PD has not been reported. METHODS: Among 558 patients diagnosed with MAC-PD between January 2016 and December 2020, 218 patients who underwent sputum culture tests twice or more within one year before and after diagnosis were included. We compared the patient characteristics and disease courses between the patients who had the same bacterial species detected twice or more (bacterial culture positive group: BCP group) and those who never had bacteria cultured (bacterial culture negative group: BCN group). RESULTS: We included 70 patients in the BCP group and 74 in the BCN group. The radiological findings showed that BCP at diagnosis correlated with a high modified Reiff score. During the median follow-up period of 42 months, the patients in the BCP group were more likely to accomplish spontaneous sputum conversion of MAC. The treatment initiation rate for MAC-PD in the BCP group was lower than that in the BCN group (41.4% vs. 67.6%, P = 0.003). In contrast, the time to the first bronchiectasis exacerbation in the BCP group was shorter than that in the BCN group, and the frequency of bronchiectasis exacerbations was higher in the BCP group. CONCLUSIONS: Patients with BCP at diagnosis are less likely to initiate treatment for MAC-PD and more likely to develop bronchiectasis exacerbation.