Hu-Zhang Qing-Mai Formulation anti-oxidative stress alleviates diabetic retinopathy: Network pharmacology analysis and in vitro experiment.

BACKGROUND: In this study, the potential mechanism of the Hu-Zhang Qing-Mai Formulation (HZQMF) on diabetic retinopathy (DR) in inhibiting oxidative stress was explored through network pharmacology analysis and in vitro experiments. METHODS: The Traditional Chinese Medicine Systematic Pharmacology Analysis Platform was used to retrieve the active pharmaceutical ingredients and targets of HZQMF. DR-related genes and oxidative stress-related genes were obtained from PharmGKB, TTD, OMIM, GeneCards, and Drugbank. STRING was used to construct a protein-protein interaction network to screen core targets. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were performed using R 4.0.3. Network topology analysis was carried out using Cytoscape 3.8.2. Finally, we looked into how well the main API protected human retinal pigment epithelial cells from damage brought on by hydrogen peroxide (H2O2). RESULTS: Quercetin (Que) was identified as the primary API of HZQMF through network pharmacology analysis, while JUN, MAPK1, and STAT3 were identified as the primary hub genes. Kyoto encyclopedia of genes and genomes enrichment analysis showed that the AGE-RAGE signaling pathway may be crucial to the therapeutic process. In vitro experiments confirmed that Que increased cell vitality and inhibited apoptosis. CONCLUSION: Que might significantly reduce H2O2-induced ARPE-19 cell injury by inhibiting apoptosis-related genes of the AGE-RAGE pathway (JUN, MAPK1, STAT3). This study lays the foundation for further research on HZQMF in treating DR.

Importance of asking a social history: atypical pulmonary infections and occupational hazards.

Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment, but NTM infection is limited to individuals with risk factors. We present a case of a 62-year-old man who presented with a 1 year history of cough and shortness of breath. History was notable for significant tobacco use and work as a sandblaster without the use of personal protective equipment. His chest X-ray showed bilateral upper lobe cavitary lesions, which were redemonstrated on chest CT. A sputum Gram stain was positive for acid-fast bacilli, but his tuberculosis QuantiFERON was negative. He was started on empiric tuberculosis treatment. Sputum cultures ultimately returned for Mycobacterium avium intracellulare complex, and treatment was narrowed to azithromycin, rifampin and ethambutol. The case highlights risk factors for NTM infection, notably for this patient, occupational exposures that likely lead to the development of pneumoconiosis. Healthcare providers should ask about occupational history and counsel patients about protection from occupational hazards.

Immunoadjunctive Therapy against Bacterial Infections Using Herbal Medicines Based on Th17 Cell-mediated Protective Immunity.

One of the major health concerns in the world is the global increase in intractable bacterial infectious diseases due to the emergence of multi- and extensively drug-resistant bacterial pathogens as well as increase in compromised hosts around the world. Particularly, in the case of mycobacteriosis, the high incidence of tuberculosis in developing countries, resurgence of tuberculosis in industrialized countries, and increase in the prevalence of Mycobacterium avium complex infections are important worldwide health concerns. However, the development of novel antimycobacterial drugs is currently making slow progress. Therefore, it is considered that devising improved administration protocols for clinical treatment against refractory mycobacteriosis using existing chemotherapeutics is more practical than awaiting the development of new antimycobacterial drugs. The regulation of host immune responses using immunoadjunctive agents may increase the efficacy of antimicrobial treatment against mycobacteriosis. The same situations also exist in cases of intractable infectious diseases due to common bacteria other than mycobacteria. The mild and long-term up-regulation of host immune reactions in hosts with intractable chronic bacterial infections, using herbal medicines and medicinal plants, may be beneficial for such immunoadjunctive therapy. This review describes the current status regarding basic and clinical studies on therapeutic regimens using herbal medicines, useful for the clinical treatment of patients with intractable bacterial infections. In particular, we focus on immunoadjunctive effects of herbal medicines on the establishment and manifestation of host antibacterial immunity related to the immunological roles of Th17 cell lineages.

An In Vitro Perspective on What Individual Antimicrobials Add to Mycobacterium avium Complex Therapies.

For Mycobacterium avium complex pulmonary disease (MAC-PD), current treatment regimens yield low cure rates. To obtain an evidence-based combination therapy, we assessed the in vitro activity of six drugs, namely, clarithromycin (CLR), rifampin (RIF), ethambutol (EMB), amikacin (AMK), clofazimine (CLO), and minocycline (MIN), alone and in combination, against Mycobacterium avium and studied the contributions of individual antibiotics to efficacy. The MICs of all antibiotics against M. avium ATCC 700898 were determined by broth microdilution. We performed kinetic time-kill assays of all single drugs and clinically relevant two-, three-, four-, and five-drug combinations against M. avium. Pharmacodynamic interactions of these combinations were assessed using area under the time-kill curve-derived effect size and Bliss independence. Adding a second drug yielded an average increase of the effect size (E) of 18.7% ± 32.9%, although antagonism was seen in some combinations. Adding a third drug showed a smaller increase in effect size (+12.2% ± 11.5%). The RIF-CLO-CLR (E of 102 log10 CFU/ml · day), RIF-AMK-CLR (E of 101 log10 CFU/ml · day), and AMK-MIN-EMB (E of 97.8 log10 CFU/ml · day) regimens proved more active than the recommended RIF-EMB-CLR regimen (E of 89.1 log10 CFU/ml · day). The addition of a fourth drug had little impact on effect size (+4.54% ± 3.08%). In vitro, several two- and three-drug regimens are as effective as the currently recommended regimen for MAC-PD. Adding a fourth drug to any regimen had little additional effect. In vitro, the most promising regimen would be RIF-AMK-macrolide or RIF-CLO-macrolide.

Managing Mycobacterium avium Complex Lung Disease With a Little Help From My Friend.

Management of Mycobacterium avium complex (MAC) lung disease is complicated, frequently unsuccessful, and frustrating to patients and clinicians. The initial treatment effort may not be directed solely at MAC infection, rather it is often initiating airway clearance measures for bronchiectasis. The next important steps are deciding who to treat and when to initiate therapy. Definitive or unambiguous guidance for these decisions is often elusive. The evidence supporting the current macrolide-based regimen for treating MAC lung disease is compelling. This regimen has been recommended in consensus nontuberculous mycobacterial treatment guidelines from 1997, 2007, and 2020, although clinician compliance with these recommendations is inconsistent. Understanding the idiosyncrasies of MAC antibiotic resistance is crucial for optimal antibiotic management. As a corollary, the importance of avoiding development of macrolide resistance due to inadequate therapy cannot be overstated. An inhaled liposome amikacin preparation is now approved for treating refractory MAC lung disease and holds promise for an even broader role in MAC therapy. Surgery is also an important therapeutic adjunct for selected patients. Microbiologic recurrences due either to new infection or treatment relapse/failure are common and require the same level of rigorous assessment and clinical judgment for determining their significance as initial MAC isolates. In summary, treatment of patients with MAC lung disease is rarely straight forward and requires familiarity with multiple factors directly and indirectly related to MAC lung disease. The many nuances of MAC lung disease therapy defy simple treatment algorithms; however, with patience, attention to detail, and perseverance, the outcome for most patients is favorable.

Development of an in vivo-mimic silkworm infection model with Mycobacterium avium complex.

In vivo-mimic silkworm infection models with Mycobacterium avium and Mycobacterium intracellulare were newly established to evaluate the therapeutic effects of anti-M. avium complex (MAC) antibiotics. Silkworms raised at 37°C died within 72 hours of an injection of M. avium or M.intracellulare (2.5 × 107 colony-forming unit (CFU)/larva·g) into the hemolymph. Clinical anti-mycobacterial (tuberculosis) antibiotics were evaluated under these conditions. Clarithromycin, kanamycin, streptomycin, amikacin, and ciprofloxacin exerted therapeutic effects in a dose-dependent manner, which was consistent with those in the mouse model. Furthermore, three effective actinomycete culture broths were selected in the screening program of our microbial broth library using the silkworm model, and four active metabolites, ohmyungsamycins A and B (1 and 2), chartreusin (3), and griseoviridin (4), were identified. Among these compounds, 1 showed the lowest 50% effective dose (ED50) value (8.5 µg/larva·g), while 3 had the best ED50/minimum inhibitory concentration (MIC) ratio (7.4). These results indicate that silkworm models are a useful tool for identifying anti-MAC antibiotics candidates with veritable therapeutic effects.

Efficacy and safety of fluoroquinolone-containing regimens in treating pulmonary Mycobacterium avium complex disease: A propensity score analysis.

BACKGROUND: Although combination therapy using clarithromycin, rifampicin, and ethambutol is recommended for patients with pulmonary Mycobacterium avium complex (MAC) disease, some patients do not tolerate it because of adverse effects or underlying diseases. The efficacy and safety of fluoroquinolone-containing combination regimens as an alternative remain uncertain. This study aimed to compare the efficacy and safety of fluoroquinolone-containing regimens with those of the standard regimens for treating pulmonary MAC disease. METHODS: We retrospectively included consecutive MAC patients who were treated in our hospital between January 2011 and May 2019. Patients treated with fluoroquinolone-containing regimens who had relapsed after treatment with standard regimens were excluded. A propensity score analysis was conducted to reduce selection bias, and the proportions of clinical improvement, defined by chest imaging findings and sputum conversion, were compared between the fluoroquinolone-containing regimen and standard regimen groups. RESULTS: We analyzed 28 patients who received fluoroquinolone-containing regimens and 46 who received the standard regimen. Fluoroquinolone-containing regimens were more likely selected for patients with cavitary lesions, diabetes mellitus, culture negativity, a low daily physical activity level, a decreased lymphocyte count and an increased CRP level. The propensity score was calculated using these variables (C-statistic of the area under the receiver operating characteristic curve of the propensity score: 0.807, p < 0.0001). The fluoroquinolone-containing regimens were significantly inferior to the standard regimen in clinical improvements (p = 0.002, Log-rank test) in the univariate analysis, but the significance was lost after adjusting for the propensity score (HR 0.553, 95% CI 0.285-1.074, p = 0.080). Six (21%) patients in the fluoroquinolone-containing regimen group and ten (22%) patients in the standard regimen group experienced low-grade adverse effects. CONCLUSIONS: There was no significant difference in clinical improvement between these regimens after propensity score adjustment. A large-scale prospective study is required to validate these results.

Impact of prognostic nutritional index on outcomes in patients with Mycobacterium avium complex pulmonary disease.

Onodera's prognostic nutritional index (PNI) is useful in predicting prognosis of various diseases. But the usefulness of PNI in non-surgical patients has not been sufficiently proven yet. In patients with mycobacterium avium complex pulmonary disease (MAC-PD), malnutrition is an important factor that affects the quality of life and morbidity. Here, we aimed to evaluate whether PNI is related with clinical outcomes in MAC-PD patients. We examined 663 patients diagnosed with MAC-PD between May 2005 and November 2017. PNI score was calculated at the time of diagnosis and treatment initiation, and patients were divided into malnutrition and non-malnutrition groups according to a cut-off PNI score of 45. As the recommended duration of treatment for MAC-PD is 12 months following sputum conversion, treatment duration less than 12 months was defined as treatment intolerance. Survivals were compared with the log-rank test. Multivariate logistic regression and multivariate Cox proportional hazards models were used to estimate the odds ratio (OR) and hazards ratio (HR) for treatment intolerance and mortality, respectively. Of the 306 patients that received treatment, 193 received treatment longer than 12 months. In the multivariable logistic regression model, malnutrition at the time of treatment initiation was related with treatment intolerance (OR: 2.559, 95% confidence interval [CI]: 1.414-4.634, P = 0.002). Patients in the malnutrition group at the time of diagnosis exhibited lower survival (P<0.001) and malnutrition at the time of diagnosis was a significant risk for all-cause mortality (HR: 2.755, 95% CI: 1.610-4.475, P<0.001). Malnutrition, as defined by PNI, is an independent predictor for treatment intolerance and all-cause mortality in patients with MAC-PD.

Clinical features and treatment outcomes of Mycobacterium chimaera lung disease and antimicrobial susceptibility of the mycobacterial isolates.

BACKGROUND: Mycobacterium chimaera, one of the Mycobacterium avium complex (MAC) members, was recently identified using modern gene sequencing analysis. Unlike M. avium and M. intracellulare, little is known about the clinical features, antimicrobial susceptibilities, and treatment outcomes of M. chimaera lung disease. METHODS: This study was conducted in a medical center from December 2012 to July 2015. Patients who fulfilled the 2007 ATS/IDSA diagnostic criteria for nontuberculous mycobacterial lung disease were enrolled. M. chimaera isolates were identified based on the findings of sequencing of rpoB gene, the internal transcribed spacer (ITS) region of the 16S-23S rRNA gene, and the heat-shock protein 65 gene (hsp65). Minimum inhibitory concentrations (MICs) of 13 antimicrobial agents were determined. RESULTS: During the study period, 247 patients with MAC lung disease were identified, and 11.3% (28/247) of the patients had lung disease caused by M. chimaera. Among these patients, 17 (60.7%) were female, and their median age was 72.5 (40-100) years. All M. chimaera isolates were susceptible to clarithromycin and rifabutin. All the isolates were resistant to moxifloxacin and only 10 (35.7%) and 2 (7.1%) were susceptible to amikacin and linezolid, respectively. Of the nine patients who received macrolide-based regimens, more achieved radiographic resolution than those treated with non-macrolide-based regimens (66.7% vs. 15.8%, P = 0.013), and they tended to have better survival (P = 0.10). CONCLUSIONS: A substantial portion (11.3%) of MAC lung disease cases were caused by M. chimaera, and treatment with macrolide-based regimens resulted in better clinical outcomes for patients with M. chimaera lung disease.

Raman spectroscopy reveals distinct differences between two closely related bacterial strains, Mycobacterium indicus pranii and Mycobacterium intracellulare.

A common technique used to differentiate bacterial species and to determine evolutionary relationships is sequencing their 16S ribosomal RNA genes. However, this method fails when organisms exhibit high similarity in these sequences. Two such strains that have identical 16S rRNA sequences are Mycobacterium indicus pranii (MIP) and Mycobacterium intracellulare. MIP is of significance as it is used as an adjuvant for protection against tuberculosis and leprosy; in addition, it shows potent anti-cancer activity. On the other hand, M. intracellulare is an opportunistic pathogen and causes severe respiratory infections in AIDS patients. It is important to differentiate these two bacterial species as they co-exist in immuno-compromised individuals. To unambiguously distinguish these two closely related bacterial strains, we employed Raman and resonance Raman spectroscopy in conjunction with multivariate statistical tools. Phenotypic profiling for these bacterial species was performed in a kinetic manner. Differences were observed in the mycolic acid profile and carotenoid pigments to show that MIP is biochemically distinct from M. intracellulare. Resonance Raman studies confirmed that carotenoids were produced by both MIP as well as M. intracellulare, though the latter produced higher amounts. Overall, this study demonstrates the potential of Raman spectroscopy in differentiating two closely related mycobacterial strains. Graphical abstract.

Moxifloxacin resistance and genotyping of Mycobacterium avium and Mycobacterium intracellulare isolates in Japan.

BACKGROUND: Although fluoroquinolones are considered as alternative therapies of pulmonary Mycobacterium avium complex (MAC) disease, the association between fluoroquinolone resistance and MAC genotypes in clinical isolates from individuals not previously treated for MAC infection is not fully clear. METHODS: Totals of 154 M. avium isolates and 35 Mycobacterium intracellulare isolates were obtained from treatment-naïve patients with pulmonary MAC disease at the diagnosis of MAC infection at 8 hospitals in Japan. Their susceptibilities of moxifloxacin were determined by broth microdilution methods. Moxifloxacin-resistant isolates were examined for mutations of gyrA and gyrB. Variable numbers of tandem repeats (VNTR) assay was performed using 15 M. avium VNTR loci and 16 M. intracellulare VNTR loci. RESULTS: Moxifloxacin susceptibility was categorized as resistant and intermediate for 6.5% and 16.9%, respectively, of M. avium isolates and 8.6% and 17.1% of M. intracellulare isolates. Although the isolates of both species had amino acid substitutions of Thr 96 and Thr 522 at the sites corresponding to Ser 95 in the M. tuberculosis GyrA and Gly 520 in the M. tuberculosis GyrB, respectively, these substitutions were observed irrespective of susceptibility and did not confer resistance. The VNTR assays showed revealed three clusters among M. avium isolates and two clusters among M. intracellulare isolates. No significant differences in moxifloxacin resistance were observed among these clusters. CONCLUSIONS: Although resistance or intermediate resistance to moxifloxacin was observed in approximately one-fourth of M. avium and M. intracellulare isolates, this resistance was not associated with mutations in gyrA and gyrB or with VNTR genotypes.

Minocycline treatment for pulmonary Mycobacterium avium complex disease based on pharmacokinetics/pharmacodynamics and Bayesian framework mathematical models.

OBJECTIVES: Our aim was to identify the pharmacokinetic/pharmacodynamic parameters of minocycline in the hollow-fibre system (HFS) model of pulmonary Mycobacterium avium complex (MAC) and to identify the optimal clinical dose. METHODS: Minocycline MICs for 55 MAC clinical isolates from the Netherlands were determined. We also co-incubated primary isolated macrophages infected with MAC with minocycline. Next, we performed a 28 day HFS-MAC model dose-response study in which we mimicked pulmonary concentration-time profiles achieved in patients. The HFS-MAC model was sampled at intervals to determine the minocycline pharmacokinetics and MAC burden. We identified the AUC0-24/MIC ratios associated with 1.0 log10 cfu/mL kill below day 0 (stasis), defined as a bactericidal effect. We then performed 10000 Monte Carlo experiments to identify the optimal dose for a bactericidal effect in patients. RESULTS: The MIC for 50% and 90% of cumulative clinical isolates was 8 and 64 mg/L, respectively. Minocycline decreased MAC bacterial burden below stasis in primary isolated macrophages. In the HFS-MAC model, minocycline achieved a microbial kill of 3.6 log10 cfu/mL below stasis. The AUC0-24/MIC exposure associated with a bactericidal effect was 59. Monte Carlo experiments identified a minocycline susceptibility MIC breakpoint of 16 mg/L. At this proposed breakpoint, the clinical dose of 200 mg/day achieved the bactericidal effect exposure target in ∼50% of patients, while 400 mg/day achieved this in 73.6% of patients, in Monte Carlo experiments. CONCLUSIONS: Minocycline at a dose of 400 mg/day is expected to be bactericidal. We propose a clinical trial for validation.

A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria.

BACKGROUND: Non-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed. OBJECTIVES: Our aim was to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials. METHODS: We determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by broth microdilution for 30 isolates. Synergy testing was performed using the chequerboard method for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time-kill kinetics (TK) assays with resistance monitoring of bedaquiline alone and combined with clofazimine were performed for MAB CIP 104536 and M. avium ATCC 700898; bedaquiline/clarithromycin combinations were evaluated against M. avium ATCC 700898. Interactions were assessed for TK experiments based on Bliss independence. RESULTS: Bedaquiline had modest activity against tested NTM, with MICs between <0.007 and 1 mg/L. Bedaquiline showed no interaction with tested drugs against MAB or MAC. Lowest mean fractional inhibitory concentration index (FICI) values were 0.79 with clofazimine for MAB and 0.97 with clofazimine and 0.82 with clarithromycin for MAC. In TK assays, bedaquiline showed a bacteriostatic effect. Clofazimine extended the bacteriostatic activity of bedaquiline against MAB and yielded a slight bactericidal effect against M. avium. The bedaquiline/clofazimine combination slowed emergence of bedaquiline resistance for M. avium but promoted it for MAB. Relative to Bliss independence, bedaquiline/clofazimine showed synergistic interaction over time for MAB and no interaction for M. avium and bedaquiline/clarithromycin showed antagonistic interaction for M. avium. CONCLUSIONS: Following these in vitro data, a bedaquiline/clofazimine combination might add activity to MAB and MAC treatment. The bedaquiline/clarithromycin combination might have lower activity compared with bedaquiline alone for MAC treatment.

[Two cases of hot tub lung disease: Environmental investigations]. / Deux cas de pneumopathie d'hypersensibilité du jacuzzi : enquête environnementale.

INTRODUCTION: Hot tub lung is a hypersensitivity pneumonitis (HP) due to exposure to inhaled non-tuberculous mycobacteria, the most frequent being Mycobacterium avium complex (MAC). CASE REPORT: A French couple developed typicalHP in the context of a repeated use of hot tubs. The husband had a severe hypoxemic form whereas his wife had a micronodular form with patchy ground glass on the thoracic scan, with less severe functional impairment. MAC was recovered in the hot tub water, but not in broncho-alveolar lavage fluid, and serologies were negative. Samples taken at home showed unusual exposure to Aureobasidium pullulans and Aspergillus flavus, as well as the presence of potentially responsible domestic molds. Blood precipitins for these microorganisms were identified. The evolution was favorable after removal of the hot tub. CONCLUSIONS: These cases represent two of the typical presentations of hot tub lung, with a possible HP to an antigen other than MAC, which may have been enhanced by chronic exposure to multiple microorganisms.

Treatment of Mycobacterium avium Complex (MAC).

Mycobacterium avium complex (MAC) is the most commonly isolated nontuberculous mycobacterial respiratory pathogen worldwide. MAC lung disease is manifested either by fibrocavitary radiographic changes similar to pulmonary tuberculosis or by bronchiectasis with nodular and reticulonodular radiographic changes. This latter form of MAC lung disease, termed "nodular bronchiectatic (NB) MAC lung disease" is the most common form of MAC lung disease in the United States. Treatment at the time of diagnosis is always indicated for fibrocavitary MAC lung disease because it is always progressive and associated with increased morbidity and mortality compared with NB MAC lung disease. In contrast, the NB form of MAC lung disease is more indolent and frequently does not require antimycobacterial therapy. For patients with NB MAC lung disease, the priorities are typically to treat the underlying bronchiectasis and determine the course and impact of the MAC infection over time. Guidelines-based MAC therapy with multidrug regimens including macrolides is usually effective, but far from as predictably effective and durable as therapy for tuberculosis. It is imperative that clinicians are familiar with MAC drug resistance mechanisms and the pitfalls of inappropriate dependence on in vitro drug susceptibility testing which can predispose patients to the development of macrolide resistance with its attendant high mortality. It is now more than 20 years since the emergence of macrolides for MAC therapy with no new comparably effective agents introduced in that time, although one new inhaled amikacin therapy under study offers promise.

In Vitro MIC Values of Rifampin and Ethambutol and Treatment Outcome in Mycobacterium avium Complex Lung Disease.

Although it is known that the in vitro MICs of rifampin and ethambutol are poorly correlated with the clinical response in Mycobacterium avium complex (MAC) lung disease (MAC-LD), evidence for this is limited. This study investigated the association between treatment outcome and the in vitro MICs of rifampin and ethambutol in patients with MAC-LD. Among patients diagnosed with macrolide-susceptible MAC-LD between January 2008 and December 2013, 274 patients who were treated with a standard regimen for ≥12 months until August 2017 and whose in vitro MIC results were available were enrolled at a tertiary referral center in South Korea. The MICs of antimicrobial agents were determined using the broth microdilution method. The mean age of the included patients was 60.4 years. The overall treatment success rate was 79.6% (218/274 patients) and tended to decrease with increasing MICs of rifampin and ethambutol, particularly at MICs of ≥8 µg/ml. Treatment success rate was significantly different between MAC isolates with MICs of ≥8 µg/ml for rifampin and ethambutol and those with MICs of <8 µg/ml for rifampin and/or ethambutol (64.9% versus 85.3%, P < 0.001). Multivariate analysis showed that an MIC of ≥8 µg/ml for both drugs and initial sputum acid-fast bacillus (AFB) smear positivity were independent risk factors for an unfavorable response (adjusted odds ratio [OR] = 3.154, 95% confidence interval [CI] = 1.641 to 6.063, and P = 0.001 for an MIC of ≥8 µg/ml; adjusted OR = 2.769, 95% CI = 1.420 to 5.399, and P = 0.003 for initial sputum AFB smear positivity). These findings suggest that the in vitro MICs of rifampin and ethambutol may be related to treatment outcome in MAC-LD.

Mutations in gyrA and gyrB in Moxifloxacin-Resistant Mycobacterium avium Complex and Mycobacterium abscessus Complex Clinical Isolates.

Data on the frequency of gyrA and gyrB mutations in fluoroquinolone-resistant isolates of the Mycobacterium avium complex (MAC) and the Mycobacterium abscessus complex (MABC) are limited. In our analysis, we did not find any resistance-associated mutations in gyrA or gyrB in 105 MAC or MABC clinical isolates, including 72 moxifloxacin-resistant isolates. Our findings suggest that mechanisms other than gyrA and gyrB mutations contribute to moxifloxacin resistance in these organisms.

Pulmonary co-infection with nocardia species and nontuberculous mycobacteria mimicking miliary tuberculosis in a patient with Crohn's disease under combined immunosuppressive therapy.

Nocardiosis is a rare infection caused by ubiquitous soil-born, acid-resistant, Gram-positive bacteria that can be life-threatening in immunocompromised patients. Originally usually diagnosed in HIV-positive patients, only few cases have been reported in patients on immunosuppressive therapy for inflammatory bowel disease or rheumatologic disorders. We present a case of a 32-year-old man who was treated with infliximab, prednisolone, and azathioprine for severe terminal ileitis. Although the clinical status improved under triple immunosuppressive therapy, weight loss, weakness, and fatigue persisted. Laboratory studies revealed iron deficiency anemia, hypalbuminemia and raised inflammatory markers. Chest computed tomography scan showed multiple pulmonary nodules and a large cavity in the left upper lobe (segment 3a). Empiric tuberculostatic therapy was introduced for suspected miliary tuberculosis but stopped for lack of clinical improvement and negative tuberculosis tests (interferon-gamma release assay, microscopy, polymerase chain reaction). Finally, the diagnosis of pulmonary nocardiosis with concomitant pulmonary Mycobacterium avium infection was confirmed microbiologically, and the patient was treated with high-dose co-trimoxazole, clarithromycin, ethambutol, and rifampicin for 12 months.This case report underlines the increased risk of severe and rare infections like nocardiosis with combination immunosuppressive therapy and the necessity for thorough diagnostic screening for opportunistic infection. Although long-term antibiotic treatment for nocardiosis is mandatory, the optimal timing to restart immunosuppressive therapy remains ambiguous.