A case of mediastinal abscess and infected aortic aneurysm caused by dissemination of Mycobacterium abscessus subsp. massiliense pulmonary disease

An 81-year-old man was admitted to our hospital because of fever and malaise that had persisted for 3 months. The patient had undergone two aortic valve replacements, 10 and 5 years previously, because of aortic valve regurgitation and infectious endocarditis. He also had had asymptomatic Mycobacterium abscessus complex (MABC) pulmonary disease for the two previous years. Contrast-enhanced computed tomography showed a mediastinal abscess and an ascending aortic aneurysm. Mycobacterium abscessus subsp. massiliense was cultured from his blood, suggesting the aortic aneurysm was secondary to infection of an implanted device. After enlargement over only a few days, a leakage of contrast medium to the mediastinal abscess was found on computed tomography. The patient was diagnosed with rupture of an infectious aortic aneurysm, and emergency aortic replacement and drainage of the mediastinal abscess were successful. The patient was treated with several antibiotics, including meropenem, amikacin, and clarithromycin, and his general condition improved. Cultures from both the mediastinal abscess and a pericardial patch that was placed at the time of surgery 5 years previously revealed MABC. In our case, the infected aortic aneurysm most likely resulted from MABC pulmonary disease rather than from previous intraoperative contamination. This route of infection is rare. Physicians should be aware of the possibility of dissemination and subsequent infection of implants related to MABC pulmonary disease.     

Redevelopment after spontaneous sputum conversion in noncavitary nodular bronchiectatic Mycobacterium avium complex lung disease

BackgroundAlthough spontaneous sputum conversion can occur in noncavitary nodular bronchiectatic (NC-NB) Mycobacterium avium complex lung disease (MAC-LD), little is known about redevelopment after spontaneous conversion. We investigated the redevelopment phenomenon after spontaneous sputum conversion in patients with NC-NB MAC-LD.Material and methodsAmong patients diagnosed with NC-NB MAC-LD between 2000 and 2013, 140 patients who experienced spontaneous sputum conversion, and whose follow-up duration after conversion was ≥6 months, were enrolled at a tertiary referral center in South Korea. Their medical records were retrospectively reviewed.ResultsOf the 140 patients, 34 (24.3%) underwent redevelopment during the median follow-up period of 71.0 months (interquartile range [IQR], 58.8–87.5). Redevelopment occurred at a median interval of 25.0 months (IQR, 11.5–41.8) after spontaneous sputum conversion. The mean age of the 34 patients with redevelopment was 63.6 years, and 73.5% were women. No statistically significant differences in clinical characteristics were noted between the 34 patients with redevelopment and those with persistent conversion. Among the 34 patients with redevelopment, 6 received treatment at a median interval of 8 months (IQR, 1.5–16.8) after redevelopment. No significant differences in clinical characteristics were noted between the six treated and 28 untreated patients.ConclusionAt least approximately 24% of patients with spontaneous sputum conversion in NC-NB MAC-LD had redevelopment, and a portion of them required treatment. These findings suggest that long-term follow-up is necessary for patients with NC-NB MAC-LD, even those who experience spontaneous sputum conversion.     

Disseminated Mycobacterium abscessus subspecies massiliense infection and subsequent prosthetic joint infection in a hemodialysis patient: A case report

A 74-year-old man with diabetic nephropathy undergoing dialysis after total knee arthroplasty presented to our hospital with dyspnea and abnormal behavior such as wearing his pants on his head. The patient was in shock with ventricular tachycardia. Urine and blood cultures showed MAM with sterile pyuria. We administered amikacin and imipenem cilastatin, but repeated cultures were persistently positive. Although we initially chose not to administer azithromycin because of a higher risk of fatal arrhythmia, we had no choice but to administer azithromycin because of treatment failure. Upon close monitoring, we observed no arrhythmia, and the blood cultures became negative. The patient was discharged on day 106 without any symptoms. However, 2 months after discontinuation of antibiotics, he was readmitted and diagnosed with prosthetic joint infection due to MAM. He could not undergo total knee arthroplasty resection because of his low tolerance to surgery. We re-administered same antibiotics, and repeated draining and cleaning of his left knee for several weeks. The inflammation in the knee joint gradually improved, and the patient was discharged while treatment with azithromycin and amikacin was continued. After being discharged, the patient did not experience recurrent disease for at least 6 months.Our case suggests that MAM can cause sterile pyuria and infection in a patient with diabetic nephropathy. The macrolide agent is a key drug for MAM infection, and repeated joint lavage in addition to administering antibiotics may be an alternative treatment for prosthetic joint infection in patients with intolerance to surgery.     

Effective treatment for clarithromycin-resistant Mycobacterium avium complex lung disease

Clinical management of macrolide-resistant Mycobacterium avium complex (MR-MAC) lung disease is difficult. To date, there only exist a limited number of reports on the treatment of clarithromycin-resistant MAC (CR-MAC) lung disease. This study aimed to evaluate prognostic factors and identify effective treatments in CR-MAC lung disease. We retrospectively collected clinical data of patients newly diagnosed with CR-MAC lung disease at the Kinki-Chuo Chest Medical Center between August 2010 and June 2018. Altogether, 37 patients with CR-MAC lung disease were enrolled. The median age was 69 years; 30, 22, and 21 patients received clarithromycin, ethambutol, and rifampicin, respectively, on their own or in drug combination. The observed sputum culture conversion rate was 29.7% (11/37 patients). In univariate analysis, ethambutol significantly increased the rate of sputum culture conversion (p = 0.027, odds ratio (OR) 10; 95% confidence interval (CI) 1.11–89.77). Multivariate analysis confirmed that ethambutol increased sputum culture conversion rate (p = 0.026; OR 21.8; 95% CI 1.45–329) while the existence of lung cavities decreased it (p = 0.04; OR 0.088; 95% CI 0.009–0.887). The combined use of ethambutol with other drugs may improve sputum culture conversion rate in CR-MAC lung disease.     

Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection

IntroductionClarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hydroxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy.MethodsCAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated.ResultsMedian area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4–1.8) μg·h/mL vs. 21.5 (IQR, 17.7–32.3) μg·h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9–10.9) μg·h/mL] and CAM monotherapy [8.2 (IQR, 6.3–9.3) μg·h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy.ConclusionsWhen RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.     

A meta-analysis of the target trough concentration of gentamicin and amikacin for reducing the risk of nephrotoxicity

IntroductionAntimicrobial resistance is one of the biggest threats to public health systems worldwide, and aminoglycosides are key drugs for treating drug-resistant infections. Because of the nephrotoxicity of aminoglycosides, therapeutic drug monitoring is recommended, but few studies of the target trough concentration (Cmin) have been reported. To address the problem, we performed a meta-analysis to confirm the target Cmin of aminoglycosides for minimizing the risk of nephrotoxicity.MethodsWe conducted a literature search using MEDLINE, the Cochrane Library, and Ichushi-Web. In the meta-analysis, nephrotoxicity was compared between the Cmin ≥2 mg/L and Cmin <2 mg/L groups for gentamicin and between the Cmin ≥10 mg/L and Cmin <10 mg/L groups for amikacin.ResultsNo randomized controlled trials were reported for any of the drugs. Five observational studies involving 615 patients were reported for gentamicin, and two observational studies involving 159 patients were identified for amikacin. For gentamicin, Cmin <2 mg/L was linked to a significantly lower rate of nephrotoxicity than Cmin ≥2 mg/L (odds ratio [OR] = 0.22, 95% confidence interval [CI] = 0.12–0.40). For amikacin, Cmin <10 mg/L was associated with a significantly lower rate of nephrotoxicity than Cmin ≥10 mg/L (OR = 0.05, 95% CI = 0.01–0.21).ConclusionsAlthough further well-controlled studies with a low risk of bias are needed, the current meta-analysis demonstrated that Cmin <2 mg/L and Cmin <10 mg/L may reduce the risk of nephrotoxicity linked to gentamicin and amikacin, respectively.     

Mycobacterium kansasii arthritis of the elbow in an immunocompetent patient with a suspected soft-tissue tumor

Mycobacterium kansasii is one of the major non-tuberculous mycobacteria species that typically cause pulmonary diseases. M. kansasii is known to cause septic arthritis as an extrapulmonary disease in immunosuppressed patients or chronic skin disease. Herein, we present a case of M. kansasii arthritis involving the elbow of an immunocompetent patient, which was initially suspected to be a soft-tissue tumor. A 70-year-old man presented with a swollen left elbow that had progressed for 18 months with deteriorating arthralgia and limited range of motion. Magnetic resonance imaging revealed filling of the intra-articular space of the elbow and surrounding of the radial head with a soft tissue mass with mixed signal intensity. Initial incisional biopsy was performed via the lateral approach to the elbow joint, and pathological examination of the mass did not reveal any evidence of malignancy. One year after the first operation, arthroscopic surgery was performed to excise the mass following the recurrence of swelling and limited function of the elbow. Pathological examination of the resected synovium revealed epithelioid granulomas containing a multinucleated giant cell and inflammatory cell infiltration, characteristic of mycobacterial infection. M. kansasii was cultured after 2 weeks of incubation of the synovial sample. He experienced full resolution of the swelling and limited function following a combination of synovectomy and multidrug antimycobacterial treatment (rifampin 600 mg/day, clarithromycin 800 mg/day, and ethambutol 750 mg/day). This case highlights the need to consider this rare infection in the differential diagnosis of intra-articular soft tissue tumor-like lesions even in immunocompetent patients.     

Disseminated tuberculosis with paradoxical reactions caused by a Mycobacterium tuberculosis strain belonging to the Indo-Oceanic lineage: An imported case in Japan

Tuberculosis remains a major public health concern. Millions of tuberculosis cases and associated deaths have been reported worldwide. The Indo-Oceanic lineage Mycobacterium tuberculosis is common in Southeast Asia and causes extrapulmonary lesions. Only a few case studies on this lineage with genetic analysis using whole-genome sequencing have been reported in the literature. We present a case of disseminated tuberculosis, characterized by a variety of extrapulmonary lesions and paradoxical reactions, caused by the Indo-Oceanic lineage M. tuberculosis in a woman in Myanmar. A 22-year-old Burmese woman had arthritis in the right knee, with unknown aetiology, and was referred to our hospital. Computed tomography of the trunk revealed multiple nodular shadows in both lungs; swollen mediastinal lymph nodes; and small, low-density areas in the spleen. M. tuberculosis was detected in the sputum sample, joint aspirate, subcutaneous tumor, and exudate. She experienced a variety of paradoxical reactions together with aggressive tuberculosis dissemination in all areas of the body. Whole-genome sequencing of the DNA of MTB obtained from sputum and the right cervical subcutaneous abscess confirmed the Indo-Oceanic lineage of M. tuberculosis, the predominant strain in Myanmar. The Indo-Oceanic lineage M. tuberculosis causes disseminated tuberculosis all over the body including the periungual region. When patients show unusual symptoms, physicians should consider the introduction of new strains from foreign countries. Genetic analyses of the strains are recommended to define and confirm the lineages.     

Reduced phagocytic activity of human alveolar macrophages infected with Mycobacterium avium complex

IntroductionCo-infection of nontuberculous mycobacteria (NTM) with other bacteria is associated with increased frequency of hospitalization and reduced quality of life. However, the clinical significance of co-infection with NTM and other bacteria remains unclear. Here, we investigated the distribution of alveolar macrophage populations, characterized their phagocytic function in bronchoalveolar lavage fluid (BALF), and assessed the bactericidal function of macrophages infected with NTM using cell lines.MethodsBALF samples were prospectively obtained from 30 patients with suspected NTM lung disease to evaluate phagocytic activities of macrophages using immunostaining. Bactericidal activities of Staphylococcus aureus (S. aureus) and Mycobacterium intracellulare (M. intracellulare)-infected or -non-infected macrophages were evaluated using macrophage cell lines.ResultsEleven patients with Mycobacterium avium complex (MAC) infection and 19 patients with chronic lower respiratory tract infections except for NTM infection (controls) were enrolled. The percentage of non-polarized (HLA-DR⁺, CD40^?, and CD163^?) macrophages in patients infected with MAC was significantly higher than that in controls; non-polarized macrophages demonstrated an impaired ability to phagocytose S. aureus. In vitro experiments revealed higher intracellular S. aureus colony-forming unit counts and proinflammatory cytokine levels in M. intracellulare-infected macrophages than in non-NTM-infected macrophages. Electron microscopy showed morphologically damaged macrophages and M. intracellulare and S. aureus growing in the same phagosome.ConclusionThe proportion of alveolar macrophages (HLA-DR⁺, CD40^?, and CD163^?) with impaired phagocytosis increased in MAC-infected individuals. M. intracellulare-infected macrophages reduced bactericidal activity in vitro. Dysfunction of alveolar macrophages may contribute to persistent infection by other bacteria, leading to MAC lung disease progression.     

A case of primary multidrug-resistant pulmonary tuberculosis with high minimum inhibitory concentration value for bedaquiline

Bedaquiline is a new ATP synthesis inhibitor developed as an anti-tuberculosis agent. It has resistance-associated variants (RAV), regardless of preceding bedaquiline exposure. Herein, we describe the case of a patient with multidrug-resistant tuberculosis (MDR-TB) who had no history of bedaquiline therapy but presented a relatively high minimum inhibitory concentration (MIC) of bedaquiline (1 μg/mL). Whole genome sequencing revealed a mutation in the resistance-associated gene Rv0678. The patient was first treated with a five-drug regimen (bedaquiline, delamanid, levofloxacin, cycloserine, and amikacin), which induced negative sputum culture conversion. Despite the successful treatment outcome, several questions remain regarding the efficacy of bedaquiline in this patient. Bedaquiline is an indispensable drug for MDR-TB treatment, but its clinical efficiency in the presence of Rv0678 mutations remains unclear. Therefore, evaluating the MIC of bedaquiline even in patients without a history of bedaquiline use is important for therapeutic regimen selection and may emphasize the importance of therapeutic drug monitoring in cases of bedaquiline RAV.     

Reproducibility of the T-SPOT.TB test for screening Mycobacterium tuberculosis infection in Japan

ObjectivesThe interferon-gamma release assay (IGRA) is useful for diagnosing Mycobacterium tuberculosis infections, especially in countries where Bacille Calmette–Guérin vaccinations are performed. However, reproducibility of the IGRA is unclear, as recent data suggest high IGRA conversion and reversion rates in serial tests among healthcare workers. This longitudinal study aimed to evaluate reproducibility of T-SPOT.TB for screening M. tuberculosis infections in Japan.MethodsResults of T-SPOT.TB tests performed between April 2014 and March 2016 at two hospitals in Yokohama, Japan, where the incidence of tuberculosis was 18.0 per 100,000 population in 2014, were analyzed.ResultsIn total, 3890 T-SPOT.TB tests were included. Overall, positive and negative test rates were 8.4% and 87.6%, respectively. Among 373 serial tests within two years, conversion and reversion rates were only 1.1% and 12.5%, respectively. Almost all patients who were initially negative (98.9%) remained so. There was no statistically significant difference between the outcomes observed at the two hospitals.ConclusionsThe conversion rate of T-SPOT.TB in Japan is as low as that recently reported in other countries where the incidence of tuberculosis is low. These data indicate that T-SPOT.TB is a reproducible tuberculosis screening tool at local hospitals in areas with a moderate incidence of tuberculosis.     

Stability of benzylpenicillin for continuous intravenous infusions: An isotonic formulation for therapeutic use and a low-dose formulation for clinical trial

IntroductionThe objectives of this study were to develop a stability-indicating high performance liquid chromatography (HPLC) assay for benzylpenicillin (BPC) in pharmaceutical fluids, and to investigate the stability of (i) isotonic citrate-buffered BPC solutions at the clinically relevant concentration of 30 mg/mL, and (ii) low concentration citrate-buffered BPC intravenous infusions (5–30 μg/mL).MethodsThe stability of isotonic BPC solutions containing 3.4 or 7.2 mg/mL sodium citrate was compared against contemporary hypertonic solutions. The HPLC assay was shown to be stability-indicating following acidic, alkali, oxidative and elevated temperature stress testing.ResultsAfter 7 d storage at 4 °C and 24 h at 35 °C, the concentrations of isotonic BPC 30 mg/mL solutions containing 3.4 and 7.2 mg/mL sodium citrate were 96% and 95% respectively, compared to day 0. After 3 d at 4 °C and 24 h at room temperature (22 °C), the concentrations of isotonic BPC solutions with 3.4 and 7.2 mg/mL sodium citrate were 99% and 96% respectively, compared to day 0. These data were comparable to the hypertonic solutions and meet pharmacopeial stability requirements. Low concentration BPC infusions showed 0.5% and 2.5% degradation after 24 h storage at 22 °C and 35 °C, respectively.ConclusionsThe isotonic BPC 30 mg/mL formulation is simple to prepare and may offer clinical benefits in settings where hypertonic solutions are problematic. This study provides assurance that high- and low-dose isotonic BPC infusions are stable at room temperature and our findings may be applicable to in vitro studies of BPC.     

Cystoisospora belli associated persistent diarrhea in an AIDS patient

Cystoisospora belli infection is regarded as an indicator disease of AIDS in Japan; however, only a few case reports showing this association are present. Our case study involved a 49-year-old Thai woman living in Japan since her marriage to a Japanese man. She was repeatedly hospitalized owing to persistent diarrhea. Considering her native country, she was suggested of having AIDS. Serological examination for HIV-1 tested positive, and C. belli infection was diagnosed on detection of oocysts in her stool samples. She was treated successfully for the parasitic infection with oral trimethoprim-sulphamethoxazole therapy for 10 days. No AIDS-associated opportunistic infections other than cystoisosporiasis were detected. Thus, this study suggests that an immunocompromised individual with persistent and recurrent diarrhea should be examined to confirm for C. belli infection. Moreover, it is possible that a person in a high-latitude region will develop a parasitic infection common in tropical areas because of globalization.     

In multiple sclerosis,a Functional Independence Measure ≥ 107 is the best predictor of outcome after clean intermittent catheterization training

BackgroundAssessment of motor and cognitive functions is recommended before clean intermittent catheterization training. Two validated instruments, the Functional Independence Measure (FIM) and the Pencil and Paper Test (PP-Test), are associated with the ability to learn self-catheterization in people with multiple sclerosis.ObjectivesWe aimed to compare the performance of these tools in predicting the outcome of clean intermittent catheterization training in multiple sclerosis.MethodsAll people with multiple sclerosis attending a tertiary neuro-urology department between 2011 and 2019 and eligible for clean intermittent catheterization were included in this retrospective study. The reference standard was the ability to perform at least 2 trials of self-catheterization at the end of the training session. The 2 index tests, the FIM and PP-Test, were administered before the teaching session. Their diagnostic performance was estimated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). The AUC values were compared by a two-sided DeLong test.ResultsWe included 395 individuals (mean [SD] age 49.8 [12] years; 70% women). At the end of the session, 87% of the patients succeeded in learning self-catheterization. The optimal cut-offs for the FIM (107) and PP-Test (13) were estimated, resulting in sensitivity of 73% (95% confidence interval [68–77) and 73% (67–77) and specificity 73% (59–84) and 63% (49–76), respectively. The AUC values for the FIM and PP-Test were significantly different (0.79 vs 0.73, p = 0.049). The effect size was large for both the FIM (Cohen's d = 1.14) and PP-Test (Cohen's d = 0.87).ConclusionsAn FIM value ≥107 has the best specificity to predict outcome after clean intermittent catheterization training for people with multiple sclerosis. The sensitivity of the FIM and PP-Test is similar, and both have a large effect size for the outcome of self-catheterization training in multiple sclerosis.     

Study of factors related to recurrence within 30 days after pneumonia treatment for community-onset pneumonia

IntroductionIt is not uncommon for patients hospitalized with pneumonia to experience an early relapse. Here, we investigated the factors related to pneumonia recurrence in Japan.PurposeWe aimed to elucidate the factors related to early recurrence after completion of pneumonia treatment.MethodsWe examined 696 patients with community-acquired pneumonia (CAP) and nursing and healthcare-associated pneumonia (NHCAP) who were admitted to our hospital between October 2010 and February 2018, excluding those who died during hospitalization. Logistic regression analysis was used to assess the endpoint of recurrence within 30 days after the end of antibiotic treatment.ResultsNHCAP, chronic lung disease and duration of antibiotic treatment were significant risk factors for recurrence of pneumonia within 30 days after antibiotic discontinuation. Aspiration pneumonia was not be a significant factor in the early recurrence of pneumonia.ConclusionsLong-term use of antimicrobials may be a risk factor in early recurrence of pneumonia.     

First reported isolation of hemin-requiring Proteus vulgaris small-colony variant from urine culture

A hemin-requiring Proteus vulgaris small-colony variant (SCV) was isolated from a urine culture. This isolate was grown on 5% sheep blood agar but not on modified Drigalski agar. The single nucleotide substitution was found in the SCV of the hemC gene (c.55C > T), and this substitution caused a nonsense mutation (p.Gln19Ter). Porphyrin test results showed that the biosynthesis of δ-aminolevulinic acid stopped up to porphobilinogen and not pre-uroporphyrinogen due to a mutation in the hemC gene. To our knowledge, this is the first report of hemin-requiring P. vulgaris.     

Multisystem inflammatory syndrome in adults after acute coronavirus disease 2019 in a Japanese woman: A case report

Multisystem inflammatory syndrome in adults (MIS-A) is a rare and emerging syndrome after coronavirus disease 2019 (COVID-19). To the best of our knowledge, Japanese cases of MIS-A are rarely reported. Here, we describe a case of MIS-A in a 44-year-old Japanese woman presenting with multiorgan dysfunction (i.e., cardiovascular and mucocutaneous involvement) and markedly elevated inflammatory markers 2 weeks after recovery from COVID-19. Treatment with intravenous immunoglobulins and corticosteroids resolved her symptoms. On the 13th day, she was discharged from the hospital with no recurrences on follow-up. This study highlights the importance of recognizing this emerging syndrome when treating patients with multiorgan dysfunction after COVID-19.     

The presentation,etiologies, pathophysiology,and treatment of pulmonary renal syndrome: A review of the literature

Pulmonary renal syndrome (PRS) is a constellation of different disorders that cause both rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. While antineutrophil cytoplasmic antibody associated vasculitis and anti-glomerular basement membrane disease are the predominant causes of PRS, numerous other mechanisms have been shown to cause this syndrome, including thrombotic microangiopathies, drug exposures, and infections, among others. This syndrome has high morbidity and mortality, and early diagnosis and treatment is imperative to improve outcomes. Treatment generally involves glucocorticoids and immunosuppressive agents, but treatment targeted to the underlying disorder can improve outcomes and mitigate side effects. Familiarity with the wide range of possible causes of PRS can aid the clinician in workup, diagnosis and early initiation of treatment. This review provides a summary of the clinical presentation, etiologies, pathophysiology, and treatment of PRS.