A woman in her 80s, who had a history of treatment with pembrolizumab for biliary tract cancer and was taking low-dose corticosteroids for immune-related adverse events (irAEs) involving nephritis and hepatitis, was admitted to the hospital complaining of a cough and increased sputum production that had begun two weeks prior. Computed tomography (CT) revealed patchy infiltrates predominantly in the lower lobes of both lungs. Since one of the Nocardia species was detected in the sputum collected at admission, we diagnosed her with pulmonary nocardiosis. In addition to this case, other cases of nocardiosis that developed following the use of immune checkpoint inhibitors (ICIs) have been reported. These cases include instances in which nocardiosis developed despite the absence of immunosuppressive therapy. Here, we review nocardiosis following ICI use.
BACKGROUND:Ceftriaxone is a widely used third-generation cephalosporin that can cause rare central nervous system (CNS) toxicity. High levels of unbound ceftriaxone because of hypoalbuminemia or hyperbilirubinemia might contribute to this adverse event. This study evaluated the association between the baseline albumin-bilirubin (ALBI) score and ceftriaxone-associated CNS toxicity in hospitalized adult patients. METHODS:We conducted a single-center, retrospective matched case-control study of adult inpatients treated with ceftriaxone between January 2019 and December 2024. Patients aged <18 years, with baseline Japan Coma Scale score ≥10, or missing laboratory data were excluded. Ceftriaxone-associated CNS toxicity was identified by record review, alternative-cause exclusion, and Naranjo Adverse Drug Reaction assessment. Probable or definite cases were analyzed. Controls were selected using 1:5 Mahalanobis distance matching for age, sex, Charlson Comorbidity Index, estimated glomerular filtration rate, hemodialysis status, mean daily and cumulative ceftriaxone dose. Robustness analyses included alternative matching ratios, exploratory specificity analyses, and bootstrap resampling. RESULTS:Of the 3,014 patients treated with ceftriaxone, 1,730 met the eligibility criteria and 6 had probable or definite ceftriaxone-related CNS toxicity. The median ALBI scores were significantly higher in cases than in controls (-1.47 versus -2.17; P < 0.001). The findings with 1:3 and 1:10 matching were similar. Negative-control analyses using the Fibrosis-4 index and rash showed no significant association. Bootstrap validation yielded significant results in 973 of 1,000 resamples. CONCLUSIONS:Ceftriaxone-associated CNS toxicity was associated with a higher baseline ALBI score. The ALBI score may aid in identifying patients at risk of CNS toxicity.
INTRODUCTION:There is limited information on the prevalence of Helicobacter pylori seropositivity in pediatric patients with type 1 diabetes mellitus (T1DM), despite the fact that both conditions constitute significant healthcare issues. However, in these children, H. pylori seropositivity may worsen both glycemic control and diabetes management. MATERIALS AND METHODS:This study sought to determine the prevalence of CagA IgG and H. pylori IgG antibodies in Bulgarian children with T1DM. RESULTS:Of the 334 children assessed, 20.4% were H. pylori seropositive and 15.0% were CagA seropositive. Fewer children aged 1 to 6 years tested positive for H. pylori (12.2%) and CagA (8.7%) than those aged 7 to 17 years (24.7% and 18.3%, respectively). Among the 145 diabetic children, 28.3% were H. pylori positive versus only 14.3% of the 189 control participants. In addition, significantly more (23.4%) diabetic children were CagA positive, compared to 8.5% among the controls. CONCLUSION:H. pylori seropositivity was twice as common in children with T1DM compared to the control group. Likewise, pediatric patients were approximately three times more frequently seropositive for more virulent strains (CagA-positive status) than other children. If confirmed as an active infection, early diagnosis of H. pylori- and CagA-seropositive children may lower the lifetime risk of gastric cancer and peptic ulcers in adulthood. The current study's findings support additional prospective research before screening recommendations are issued.
INTRODUCTION:There are no available data from Türkiye-a country known for high antimicrobial resistance rates-regarding the etiological distribution and resistance profiles of urinary tract infections (UTIs) developing after radical cystectomy. This lack of evidence constitutes an important gap in global microbiological epidemiology. In this study, we aimed to evaluate the etiological distribution and antimicrobial resistance patterns of UTIs developing after radical cystectomy and urinary diversion. METHODS:Patients who underwent radical cystectomy at our center between January 2006 and December 2025 were retrospectively reviewed. A positive urine culture (≥105 CFU/mL) accompanied by concurrent clinical signs and symptoms was accepted as the diagnostic criterion for UTI. Clinical and microbiological data from the first postoperative UTI episode were analyzed. RESULTS:A total of 56 patients (median age: 65 years) were included in the study. Sixty-two microorganisms were isolated from urine cultures; 77.4% were Gram-negative bacteria, 21.0% were Gram-positive bacteria, and 1.6% were fungi. The most frequently isolated microorganism was Escherichia coli (46.8%), followed by Enterococcus faecium (16.1%). Extended-spectrum beta-lactamase (ESBL) production was detected in 35.4% of Gram-negative isolates. Among enterococci, ampicillin resistance was 76.9% and gentamicin resistance was 53.8%. CONCLUSIONS:Although Gram-negative bacteria predominated in UTIs developing after radical cystectomy, the high ESBL rate and notable frequency of E. faecium indicate that this patient population exhibits a complex resistance profile. Our findings demonstrate that UTIs following radical cystectomy possess a microbiological profile distinct from standard community-acquired infections and that empirical therapy should be planned by taking these specific resistance patterns into consideration.
BACKGROUND:Community-onset isolation of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBLEC) from clinical specimens is an increasing public health concern. We aimed to identify healthcare- and community-associated factors associated with community-onset ESBLEC isolation in Japanese adults. METHODS:We conducted a case-control study at two tertiary care hospitals in Japan, combining chart review with a structured questionnaire. Adults with community-onset ESBLEC isolated in an outpatient setting or within 3 days after admission were enrolled as cases, and adults with community-onset third-generation cephalosporin-susceptible E. coli served as controls. Multivariable logistic regression was used to identify the independent factors associated with ESBLEC isolation. RESULTS:In total, 124 patients, comprising 57 cases and 67 controls, were included. Chart-derived antibiotic exposure within one year (adjusted odds ratio [aOR], 2.68; 95% CI, 1.07-6.72) and self-reported history of antimicrobial-resistant organism detection within one year (aOR, 5.13; 95% CI, 1.24-21.25) were independently associated with ESBLEC isolation. An exploratory inverse association was observed for handwashing before toilet use (aOR, 0.24; 95% CI, 0.06-0.90), but this association was not statistically significant in the sensitivity analysis restricted to soap or alcohol use. Readmission within 30 days was more frequent among cases (5/41 [12.2%] vs. 0/48 [0.0%]); none of the five readmissions was attributed to ESBLEC-related infection. CONCLUSIONS:Prior antibiotic exposure and a history of antimicrobial-resistant organism detection were the principal independent correlates of community-onset ESBLEC isolation. The inverse association with pre-toilet handwashing should be considered exploratory and hypothesis-generating and warrants confirmation in larger prospective studies.
INTRODUCTION:Therapeutic drug monitoring (TDM) of vancomycin is recommended based on the area under the concentration-time curve (AUC). The Practical Antimicrobial TDM (PAT) software incorporates two population pharmacokinetic (popPK) models developed by Oda et al. and Yasuhara et al.; however, no objective criteria for model selection have been established. This study aimed to develop and validate a machine learning (ML) model to optimize popPK model selection for initial vancomycin dosing. METHODS:The primary outcome was comparison of the two models to identify which yielded a lower absolute relative prediction error for AUC in each patient. Thirty-three clinical variables were screened using Lasso regression to select predictors. Six ML algorithms were compared using nested cross-validation. Performance was evaluated using the area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, specificity, calibration plots, and decision curve analysis (DCA). RESULTS:Among 531 patients, Oda et al.'s model was more accurate in 60.1% of cases. Lasso selected 22 predictors. Among the algorithms, logistic regression showed the highest mean AUROC (0.720 ± 0.084), whereas the support vector machine demonstrated favorable calibration performance (intercept = 0.01, slope = 0.97). The multi-layer perceptron achieved the lowest Brier score (0.307). Longer hospitalization, lower C-reactive protein (CRP), and female sex were associated with a high predictive probability of accuracy for Oda et al.'s model. DCA suggested the clinical utility of ML-based model selection. CONCLUSION:We developed an ML model for selecting between two popPK models for planning vancomycin dosing regimens in PAT. Considering length of hospital stay, CRP levels, and sex may aid accurate popPK model selection.
The sequential occurrence of two or more types of lymphomas is rare, particularly when they involve different cell lineages. We herein report a rare case of the sequential development of T-cell lymphoproliferative disorder (LPD) after treatment with rituximab for follicular lymphoma (FL). Although the efficacy and safety of rituximab have been established, the immunosuppressive effects of rituximab-containing therapy and the development of iatrogenic LPD/lymphoma, which is typically related to Epstein-Barr virus (EBV), need to be considered. EBV may infect T lymphocytes and manifest as hemophagocytic lymphohistiocytosis (HLH). Disease progression from HLH to clonal T-cell LPD has been reported in a high percentage of HLH patients. We herein report the clinical effects of HLH-2004 and CHOP in an elderly patient who developed EBV-positive T-cell LPD with HLH after treatment with rituximab for FL. An awareness of its clinical symptoms, bone marrow examination, and monitoring of the EBV load may help to discriminate EBV-positive T-cell LPD from the recurrence of FL or histologic transformation, and facilitate the timely initiation of life-saving therapies.
Objective To report a case of severe Plasmodium falciparum malaria with marked ADAMTS13 reduction and secondary microangiopathic manifestations resembling TTP, highlighting the diagnostic challenge of distinguishing malaria-associated microangiopathic changes from primary TTP-spectrum disorders. Methods The patient’s clinical features, laboratory data, peripheral blood smear findings, ADAMTS13 activity, treatment, outcomes,and relevant literature were retrospectively analyzed. Results A 46-year-old man returning from Nigeria presented with severe P. falciparum malaria after 11 days of intermittent fever and fatigue, followed by jaundice and dark urine. Laboratory testing showed severe anemia, thrombocytopenia, hyperbilirubinemia, acute kidney injury, and elevated lactate dehydrogenase. Peripheral blood smear revealed intraerythrocytic P. falciparum with high parasitemia (approximately 17%) and a low proportion of schistocytes (approximately 1%).The patient subsequently developed impaired consciousness and multi-organ dysfunction. ADAMTS13 activity was 7.6%. Given the coexistence of thrombocytopenia, microangiopathic hemolysis, neurological impairment, renal dysfunction, and marked ADAMTS13 reduction, a TMA phenotype raising concern for TTP-spectrum disease was suspected. However, because severe falciparum malaria itself can cause endothelial injury, secondary TMA, and reduced ADAMTS13 activity, immune-mediated TTP could not be confirmed. After combined treatment with intravenous artesunate, therapeutic plasma exchange, continuous renal replacement therapy, and intensive supportive care, the patient showed improvement in platelet count, hemolysis markers, renal function, and neurologic status, with ADAMTS13 activity increasing to 42%. Conclusion Severe falciparum malaria may be accompanied by marked ADAMTS13 reduction and secondary microangiopathic features resembling TTP-spectrum manifestations. Early recognition of microangiopathic features and evaluation of ADAMTS13 activity when available may support timely diagnostic evaluation and individualized management in selected patients.
An 83-year-old man was admitted to the hospital with a fever 10 days after undergoing transarterial chemoembolization (TACE) for recurrent hepatocellular carcinoma. The computed tomography (CT) scan showed a fluid collection in the liver near the lesion after TACE, and he was diagnosed with a liver abscess. Despite initial treatment with piperacillin-tazobactam, initiated on the day of admission, the abscess enlarged with persistent fever. Puncture drainage of the abscess was performed, and Gram stain revealed numerous Gram-positive rods. Cutibacterium avidum was detected in the drainage specimen. Post-drainage, his fever improved. His symptoms improved after drainage, and he remained free of recurrence as of this writing. Pyogenic liver abscesses caused by usual indigenous skin bacteria, such as staphylococci, can occur after TACE, but the one caused by C. avidum has never been reported. Transcutaneous interventions such as TACE could lead to liver abscesses caused by this rare organism.
OBJECTIVES:Febrile urinary tract infection (fUTI) is common in young children, but associated symptoms may suggest alternative febrile illnesses. This study clarified the prevalence of associated symptoms in children younger than 2 years with first-episode fUTI and evaluated their association with delayed antimicrobial treatment. METHODS:We conducted a single-center retrospective cohort study of children younger than 2 years with first-episode fUTI between January 2010 and December 2024. Associated symptoms documented at the initial medical evaluation were categorized as cough/rhinorrhea, vomiting, diarrhea, seizure, other symptoms, or multiple symptoms. The primary outcome was the prevalence of associated symptoms. Secondary outcomes were days from fever onset to antimicrobial treatment and delayed antimicrobial treatment, defined as treatment initiation on or after the fourth calendar day of fever. RESULTS:Among 420 children, fever alone was the most common presentation in 292 (69.5%). Associated symptoms were documented in 128 (30.5%), including cough/rhinorrhea in 56 (13.3%), vomiting in 19 (4.5%), diarrhea in 13 (3.1%), seizure in 15 (3.6%), other isolated symptoms in 4 (1.0%), and multiple symptoms in 21 (5.0%). Associated symptoms were more frequent in children aged 2-23 months than in infants younger than 2 months (33.9% vs. 13.0%; p < 0.001). Among 395 patients included in isolated symptom-specific analyses, older age and cough/rhinorrhea were associated with delayed treatment in the age-adjusted model. The association with cough/rhinorrhea remained significant after adjustment for sex but was attenuated after additional adjustment for previous medical visit before treatment. CONCLUSIONS:Approximately 30% of children younger than 2 years with fUTI had associated symptoms. Respiratory symptoms were the most common associated symptoms and were associated with delayed antimicrobial treatment in age- and sex-adjusted analyses, although the association was attenuated after additional adjustment for previous medical visit before treatment.
BACKGROUND:Nursing- and healthcare-associated pneumonia (NHCAP) refers to pneumonia occurring in nursing-home residents or individuals with frequent healthcare exposure. Although the Age, Dehydration, Respiratory Status, Orientation Disturbance, Low Blood Pressure (A-DROP) score is widely used to assess community-acquired pneumonia severity in Japan, it does not account for frailty or functional status, potentially limiting its predictive accuracy for NHCAP. This study aimed to develop an improved mortality prediction model for NHCAP. METHODS:We developed and validated a penalized logistic regression model to predict 30-day in-hospital mortality in patients with NHCAP using a nationwide Japanese inpatient database. Patients hospitalised for NHCAP between April 2018 and March 2020 were enrolled. Candidate predictors were selected based on clinical relevance. Logistic least absolute shrinkage and selection operator (LASSO) regression was employed to identify influential variables, from which the most important predictors were used to construct a risk score model (N-DROP) based on the A-DROP framework. RESULTS:The 30-day in-hospital mortality in 116,185 eligible patients was 11.7%. LASSO regression identified five variables, and three key predictors-A-DROP score, impaired oral intake, and diminished activities of daily living (ADL)-were retained for N-DROP. N-DROP assigned one point per A-DROP score increment, one point for impaired oral intake, and one or two points based on ADL dependence. N-DROP demonstrated improved discriminatory performance compared with A-DROP [C-statistic: 0.746 (95% CI 0.734-0.757) vs. 0.708 (95% CI 0.695-0.720); P < 0.001]. CONCLUSION:The novel N-DROP model improves prediction of in-hospital mortality compared with A-DROP in patients with NHCAP.
OBJECTIVE:To evaluate the association between colchicine administration and 28-day mortality in septic patients while assessing its real-world safety profile. METHODS:This retrospective study utilized the MIMIC-IV (v3.1) database to identify adults meeting Sepsis-3.0 criteria. We employed 1:2 propensity score matching (PSM) and a time-dependent Cox proportional hazards model to mitigate immortal time bias. Exposure was stratified into new users (therapy initiated >24 h after ICU admission) and pre-ICU users (maintenance therapy). RESULTS:Among 25,119 patients, 434 received colchicine. After PSM (423 users, 835 controls), colchicine was associated with a significantly lower risk of 28-day mortality (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.26 - 0.87; P = 0.016). This observed survival association was concentrated among new users (HR, 0.26; 95% CI, 0.13 - 0.51; P < 0.001), whereas no significant advantage was observed for pre-ICU users (P = 0.168). While risks for acute kidney injury and hepatotoxicity were comparable, colchicine recipients had a higher incidence of thrombocytopenia (17.3% vs. 12.9%; P = 0.016). Hospital length of stay was significantly longer in the colchicine group compared to controls (median, 10.75 vs. 8.43 days; P < 0.001). CONCLUSIONS:Colchicine administration exhibits a significant survival association in patients with sepsis, with lower 28-day mortality risks observed primarily when initiated during the acute phase. However, these retrospective findings are purely hypothesis-generating, and prospective randomized controlled trials are essential to validate these clinical implications.
Non-typhoidal Salmonella (NTS) infections cause severe disease in immunocompromised individuals and represent a significant clinical problem in the modern era as the number of patients receiving chemotherapy continues to increase. However, as chemotherapeutic regimens have become increasingly diverse in terms of intensity and immunosuppressive effects, applying uniform dietary guidance across all patient populations is challenging, and adequate individualized dietary counseling is not always provided in routine clinical practice. We report a case of disseminated Salmonella infection that occurred during outpatient chemotherapy for a gynecological malignancy. In this case, the infection was presumed to have been acquired through the consumption of fresh confectionery, followed by secondary seeding of an indwelling central venous (CV) port. This subsequently resulted in vertebral osteomyelitis and septic pulmonary embolism. Dietary counseling for patients undergoing chemotherapy should be individualized according to the patient's lifestyle and intensity of chemotherapy. In addition, the CV port should be recognized as an intravascular foreign body that may serve as a potential site for secondary Salmonella infection.
INTRODUCTION:BICSTaR (BICtegravir Single Tablet Regimen) is a multinational observational study assessing the virologic effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with human immunodeficiency virus (HIV). Previously, the 12-month analysis of the Japan cohort of BICSTaR showed high levels of virologic effectiveness and tolerability with B/F/TAF. METHODS:Data for 84 treatment-experienced (TE) or 116 treatment-naïve (TN) participants aged ≥20 years receiving B/F/TAF as part of routine clinical care in Japan were collected retrospectively and prospectively. Outcomes analyzed at 24 months included HIV-1 RNA <50 copies/mL, treatment persistence, drug-related adverse events (DRAEs), and patient-reported outcomes (prospective cohort only). RESULTS:At 24 months, 97% of TN and TE participants had HIV-1 RNA <50 copies/mL (missing-equals-excluded analysis), and 96% of participants remained in the study and were receiving B/F/TAF. DRAEs were reported by 14% of participants (TN: 16%; TE: 10%), with diarrhea (TN: 3%; TE: 2%) and weight gain (TN: 4%; TE: 0%) being the most common; the majority of DRAEs occurred in the first 12 months. Participants enrolled prospectively reported stable or improved quality of life through 24 months. CONCLUSION:Treatment with B/F/TAF in routine HIV clinical care in Japan was associated with high persistence, virologic effectiveness, and was well tolerated through 24 months.
La Crosse virus (LACV) is a mosquito-borne orthobunyavirus within the California serogroup that primarily causes neuroinvasive disease in pediatric populations in the upper Midwestern, mid-Atlantic, and southeastern states of USA. Despite its substantial impact on public health, no vaccine or effective antiviral treatment has been developed so far. In this study, we investigated the role of the cell-surface heparan sulfate proteoglycan (HSPG) in LACV cell attachment and assessed the in vitro antiviral potential of bovine lactoferrin (bLf), which interacts with both the cell surface molecules and HSPG. Our results demonstrated that HSPG facilitates LACV infection and that bLf inhibits this process in a dose-dependent manner. These observations suggest that the antiviral mechanism of bLf may involve competitive inhibition at HSPG receptor sites, thereby preventing viral attachment to the host cell membrane. This provides further insights into the antiviral activity of bLf against LACV.
INTRODUCTION:A Mycoplasma pneumoniae (MP) infection outbreak occurred in Japan in 2024. Macrolides (MLs) are first-line antibiotics for MP infections; however, ML resistance rates vary by region and time of year. In recent years, point-of-care Quenching Probe PCR (QP-PCR) assays have enabled the detection of MP and macrolide resistance mutations. We aimed to determine the impact of rapid diagnosis by QP-PCR on clinical outcomes, the ML resistance rate, and the therapeutic efficacy of MLs, minocycline (MINO) and tosufloxacin (TFLX) in pediatric patients with MP infection in 2024. METHODS:This single-center retrospective observational study was conducted from January to December 2024. A total of 206 pediatric patients with MP infection and ML susceptibility determined by QP-PCR were included. The primary outcome was fever duration. RESULTS:MLs susceptible MP (MSMP) was identified in 132 (64%) patients and MLs resistant MP (MRMP) in 74 (36%) patients. In the MSMP, the time to defervescence after the initiation of susceptible antibiotics was shorter with MLs than with TFLX (1 vs. 5 days, p < 0.001). Among patients with MRMP aged ≥8 years, it was shorter in MINO than with TFLX (1 vs. 3 days, p = 0.002). QP-PCR-guided antibiotic initiation group had a shorter total fever duration compared with the empirical antibiotic initiation followed by QP-PCR-guided antibiotic modification group (MSMP; 6 [4-7] vs. 7 [6-9] days, p < 0.001, MRMP; 5 [3-7.75] vs. 8 [5-9] days, p = 0.005). CONCLUSIONS:Early diagnosis using QP-PCR may contribute to shortening the duration of fever.
Introduction Pseudomonas aeruginosa (PA) and other glucose non-fermenting gram-negative rods (nonPA-NFs) are critical nosocomial pathogens. Although PA is a known uropathogen, the entry sites for nonPA-NFs remain poorly defined. The primary objective of this study was to evaluate the clinical characteristics and antimicrobial stewardship (AS) recommendations for PA and nonPA-NFs, specifically to explain their contrasting differences from other bloodstream infections (BSIs) used as a baseline reference. Methods We conducted a retrospective study at two university hospitals, analyzing 332 NF BSI cases (205 PA and 127 nonPA-NF) and 5869 other BSI cases. Multivariate logistic regression was used to compare patients with PA and nonPA-NF with other BSIs. Subsequently, the reference category was changed to nonPA-NF to enable a direct comparison between PA and nonPA-NF. Results PA was significantly associated with urogenital tract infections, whereas nonPA-NF was more prevalent in catheter-related infections and unknown sources. A direct comparison confirmed a significant dissociation in the affinity for the urogenital tract (P = 0.002). Discussion Patients with PA and nonPA-NFs exhibited distinct and often contrasting entry portals compared to the baseline represented by other BSIs. The presence of urogenital tract infection in NF bacteremia may suggest a higher likelihood of PA, whereas nonPA-NF should be considered in catheter-related or occult sources. These findings provide a clinical basis for differentiating between these entities to optimize empirical therapies.
BACKGROUND:At a tertiary hospital in Korea, carbapenem stewardship was suspended in March 2024 during a nationwide medical strike, leading to increased carbapenem use. In December 2024, stewardship activities were re-initiated using prospective audit and feedback (PAF), and in January 2025, an augmented PAF strategy incorporating ward round-based feedback was introduced. METHODS:We conducted a quasi-experimental study at a 2400-bed tertiary care hospital in Seoul, South Korea. An interrupted time-series (ITS) analysis evaluated the effects of resuming carbapenem stewardship using PAF on monthly carbapenem days of therapy (DOT) per 1000 patient-days. Prescriber adherence was compared between standard PAF in December 2024 and augmented PAF from January to August 2025. Adherence was defined as discontinuation or modification of carbapenem therapy within 7 days of the initial "not recommended" feedback. RESULTS:A total of 896,495 patient-days were included. Following resumption of carbapenem stewardship using PAF in December 2024, carbapenem DOT showed an immediate level reduction (-17.7 DOT per 1000 patient-days; 95% CI, -26.2 to -9.25; p < 0.001) and a significant slope change (-2.89 per month; 95% CI, -3.84 to -1.93; p < 0.001), with an overall 35.7% reduction compared with the counterfactual projection. Prescriber adherence was higher during augmented PAF than standard PAF (58.4% [97/166] vs. 25.0% [6/24]; risk ratio, 2.34; 95% CI, 1.16-4.73; p = 0.0036). CONCLUSION:Resumption of carbapenem stewardship using PAF after suspension was associated with a substantial reduction in carbapenem use. Adherence appeared higher during augmented PAF incorporating ward round-based follow-up feedback than during standard PAF, suggesting the potential value of active, follow-up-driven stewardship interventions.
INTRODUCTION:At the time of this study, no approved treatment for mpox was available in Japan, and data on the clinical course and virological changes during tecovirimat treatment were limited. METHODS:We conducted a prospective multicenter observational case series of patients with PCR-confirmed mpox between June 28, 2022, and March 31, 2025, to describe the clinical course and safety of a 14-day course of tecovirimat. Participants could choose treatment or no treatment. RESULTS:All 31 participants received tecovirimat; 24 completed a single 14-day course, and 2 received multiple courses plus vaccinia immune globulin. The median age was 39 years (range, 21-74), and all were men. Nineteen (61.3%) were people living with HIV, with a median CD4 count of 531 cells/μL (range, 50-830), including three with CD4 counts <200 cells/μL. Severe mpox occurred in 23 participants (74.2%), three of whom (9.7%) had risk factors for severe disease, all due to CD4 < 200 cells/μL. Skin lesions were present in 30 participants. At day 14, skin PCR results were available for 23 participants; 16 (69.6%) were negative. No deaths occurred within 14 or 30 days, although one patient with advanced HIV infection died following prolonged hospitalization. Adverse events occurred in 2 participants and were considered unrelated to treatment. DISCUSSION:This prospective multicenter case series describes the clinical course of mpox and temporal dynamics of skin PCR negativity in patients receiving tecovirimat in real-world practice.
INTRODUCTION:Macrolides are key drugs for treating Mycobacterium avium pulmonary disease, and combination chemotherapy is essential to preventing macrolide resistance. However, the concentrations of concomitant agents required to suppress resistance emergence remain undefined. Therefore, we aimed to quantify the concentration-dependent effects of companion drugs on macrolide resistance using an improved time-kill assay and pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. METHODS:Time-kill assays were performed using M. avium ATCC 700898 exposed to azithromycin alone or in combination with ethambutol, rifampicin, amikacin, or clofazimine. Total and resistant bacterial populations were quantified over 28 days. A pharmacodynamic model describing the dynamics of susceptible and resistant subpopulations was linked to a pharmacokinetic model incorporating alveolar macrophage exposure to simulate resistance emergence and bactericidal activity under various dosing regimens. RESULTS:Macrolide resistance most frequently emerged at 2-4× the minimum inhibitory concentration (MIC) of azithromycin, whereas resistance was less frequent at 8-16× MIC or sub-MIC levels. The addition of companion drugs suppressed resistance emergence even at sub-MIC levels. PK/PD simulations (excluding clofazimine) demonstrated that standard-dose ethambutol prevented macrolide resistance regardless of whether the regimen was administered daily or three times weekly. In contrast, the addition of rifampicin or amikacin further reduced bacterial burden compared with the macrolide-plus-ethambutol regimen. CONCLUSION:This study defines the concentration-dependent contributions of concomitant agents to macrolide resistance suppression in M. avium and establishes a quantitative PK/PD framework for evaluating resistance emergence. The findings provide mechanistic insights that may help optimize combination dosing strategies for M. avium pulmonary disease.
