Compound 511 ameliorates MRSA-induced lung injury by attenuating morphine-induced immunosuppression in mice via PI3K/AKT/mTOR pathway.

BACKGROUND: Opioids are widely used in clinical practice. However, their long-term administration causes respiratory depression, addiction, tolerance, and severe immunosuppression. Traditional Chinese medicine (TCM) can alleviate opioid-induced adverse effects. Compound 511 is particularly developed for treating opioid addiction, based on Jiumi Liangfang, an ancient Chinese drug treatment and rehabilitation monograph completed in 1833 A.D. It is an herbal formula containing eight plants, each of them contributing to the overall pharmacological effect of the product: Panax ginseng C. A. Meyer (8.8%), Astragalus membranaceus (Fisch.) (18.2%), Datura metel Linn. (10.95%), Corydalis yanhusuo W. T. Wang (14.6%), Acanthopanar gracilistµlus W. W. Smith (10.95%), Ophiopogon japonicus (Linn. f.) Ker-Gawl. (10.95%), Gynostemma pentaphyllum (Thunb.) Makino (10.95%), Polygala arvensis Willd. (14.6%). This formula effectively ameliorates opioid-induced immunosuppression. However, the underlying mechanism remains unclear. PURPOSE: To reveal the effects of Compound 511 on the immune response of morphine-induced immunosuppressive mice and their potential underlying molecular mechanism. This study provides information for a better clinical approach and scientific use of opioids. METHODS: Immunosuppression was induced in mice by repeated morphine administration. Th1/Th2/Th17/Treg cell levels were measured using flow cytometry. Splenic transcription factors of Th1/Th2/Th17/Treg and outputs of the regulatory PI3K/AKT/mTOR signaling pathway were determined. Subsequently, methicillin-resistant Staphylococcus aureus (MRSA) was administered intranasally to morphine-induced immunosuppressive mice pretreated with Compound 511. Their lung inflammatory status was assessed using micro-computer tomography (CT), hematoxylin and eosin (H&E) staining, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to morphine, Compound 511 significantly decreased the immune organ indexes of mice, corrected the Th1/Th2 and Treg/Th17 imbalance in the immune organs and peripheral blood, reduced the mRNA levels of FOXP3 and GATA3, and increased those of STAT3 and T-bet in the spleen. It improved immune function and reduced MRSA-induced lung inflammation. CONCLUSION: Compound 511 ameliorates opioid-induced immunosuppression by regulating the balance of Th1/Th2 and Th17/Treg via PI3K/AKT/mTOR signaling pathway. Thus, it effectively reduces susceptibility of morphine-induced immunosuppressive mice to MRSA infection.

Omadacycline Pharmacokinetics/Pharmacodynamics in the Hollow Fiber System Model and Potential Combination Regimen for Short Course Treatment of Mycobacterium kansasii Pulmonary Disease.

The 12-month therapy duration for the treatment of Mycobacterium kansasii pulmonary disease calls for more efficacious drugs for better treatment outcomes and to shorten the therapy duration. We performed (i) omadacycline MIC with M. kansasii ATCC 12478 strain and 21 clinical isolates, (ii) dose-response study in the hollow fiber system model of M. kansasii (HFS-Mkn) with six human equivalent omadacycline daily doses to determine the optimal drug exposure for the maximal kill, and (iii) a second HFS-Mkn study to determine the efficacy of omadacycline (300 mg/day) plus moxifloxacin (600 mg/day) plus tedizolid (200 mg/day) combination regimen with standard regimen as comparator. GraphPad Prism was used for data analysis and graphing. MIC of the reference strain was 4 mg/L but ranged from 8 to 32 mg/L among the 21 clinical isolates. In the HFS-Mkn, the exposure required for 50% of the maximal effect (EC50) was an omadacycline area under the concentration-time curve to MIC (AUC0-24/MIC) ratio of 1.95. The optimal exposure was an AUC0-24/MIC of 3.05, which could be achieved with 300 mg/day clinical dose. The omadacycline-moxifloxacin-tedizolid combination sterilized the HFS-Mkn in 14 days with a linear-regression based kill rate of -0.309 ± 0.044 log10 CFU/mL/day compared to the kill rate of -0.084 ± 0.036log10 CFU/mL/day with the standard regimen or 3.7-times faster. Omadacycline has efficacy against M. kansasii and could be used at 300 mg/day in combination with moxifloxacin and tedizolid for the treatment of M. kansasii pulmonary diseases with the potential to shorten the currently recommended 12-month therapy duration.

Treatment outcome of continuation of intravenous amikacin for Mycobacterium abscessus pulmonary disease with a persistent culture positivity after the treatment initiation.

INTRODUCTION: Whether prolonged intravenous amikacin treatment would lead to better treatment results in patients with Mycobacterium abscessus subspecies abscessus (M. abscessus) pulmonary disease (PD) is unknown. We investigated the efficacy of continued amikacin treatment for the microbiological outcome of M. abscessus PD patients with persistent culture positivity after treatment initiation. METHODS: We retrospectively evaluated 62 patients with M. abscessus PD who were treated with intravenous amikacin and beta-lactams along with a macrolide-based regimen at 3 tertiary referral centers in South Korea. The intravenous antibiotic treatment duration was determined by the attending physician. RESULTS: The median treatment durations with amikacin and beta-lactam in the 62 patients were 25.1 and 8.2 weeks, respectively. The overall microbiological cure rate was 29.0%. Among the 62 patients, 44 showed persistent culture positivity at 8 weeks after treatment with an amikacin-containing multidrug regimen. The median parenteral amikacin treatment duration after 8 weeks in these patients was 18.0 weeks. The conditional probability of microbiological cure with continuation of the amikacin-containing regimen in these patients was 18.2% (95% confidence interval 8.2-32.7). Additionally, the conditional probability of microbiological cure in the 34 patients with persistent culture positivity at 12 weeks was 8.8% (95% confidence interval 1.9-23.7). After 16 weeks, the conditional probability of microbiological cure decreased further, reaching 0% at 28 weeks after treatment initiation. CONCLUSION: The continuation of intravenous amikacin therapy was usually not followed by culture conversion in M. abscessus PD patients with persistent sputum culture positivity after treatment initiation.

An overview of drugs for the treatment of Mycobacterium kansasii pulmonary disease.

OBJECTIVES: The aim of this study was to determine and compare the efficacy of drugs to treat Mycobacterium kansasii (Mkn) pulmonary disease by performing minimum inhibitory concentration (MIC) determination and time-kill studies. METHODS: We determined the MICs to 13 drugs against the Mkn standard laboratory strain ATCC 12478 and 20 clinical isolates and performed time-kill studies with 18 drugs from different classes using the standard laboratory strain of Mkn. The ß-lactam antibiotics were tested with or without the combination of the ß-lactamase inhibitor avibactam. An inhibitory sigmoid Emax model was used to describe the relationship between drug concentrations and bacterial burden. RESULTS: Among the 13 tested drugs in the MIC experiments, the lowest MIC was recorded for bedaquiline. Among the 18 drugs used in the time-kill studies, maximum kill with cefdinir, tebipenem, clarithromycin, azithromycin, moxifloxacin, levofloxacin, tedizolid, bedaquiline, pretomanid and telacebac was greater than that for some of the drugs (isoniazid, rifampicin and ethambutol) used in standard combination therapy. CONCLUSION: We report preclinical data on the efficacy and potency of drugs that can potentially be repurposed to create a safe, effective and likely shorter-duration regimen for the treatment of Mkn pulmonary disease.

Minimum Inhibitory Concentrations before and after Antibacterial Treatment in Patients with Mycobacterium abscessus Pulmonary Disease.

The clinical importance of Mycobacterium abscessus (MABS) pulmonary disease has been increasing. However, there is still a lack of information about MIC distribution patterns and changes in clinical practice settings. The MIC results of rapidly growing mycobacteria isolated from 92 patients with nontuberculous mycobacterial pulmonary disease diagnosed from May 2019 to March 2021 were retrospectively analyzed. Most of the patients (86 patients; 93.5%) were infected with MABS; 46 with Mycobacterium abscessus subsp. abscessus (Mab), and 40 with Mycobacterium abscessus subsp. massiliense (Mma). Significant differences in susceptibility to clarithromycin (15.2% versus 80.0%, P < 0.001) and azithromycin (8.7% versus 62.5%, P < 0.001) were observed between Mab and Mma. Most isolates were susceptible to amikacin (80; 93.0%), and over half were susceptible to linezolid (48; 55.8%). Only one-quarter of isolates (22, 25.6%) were susceptible to imipenem, while more than half (56; 65.1%) had intermediate susceptibility. Fifty-one isolates (59.3%) had MIC values of less than 1 µg/mL for sitafloxacin, which were significantly higher than isolates for moxifloxacin (5; 5.8%), especially in Mab. Sixty-five (75.6%) isolates had MICs of less than 0.5 µg/mL to clofazimine. Two patients showed obvious MIC result changes: from susceptible to resistant to clarithromycin and from resistant to susceptible to amikacin and imipenem. In conclusion, MABS isolates were relatively susceptible to amikacin and linezolid, and clarithromycin and azithromycin were especially effective against Mma. In addition, sitafloxacin and clofazimine had low MICs and might be effective treatment agents. IMPORTANCE The MICs of isolates from 86 patients with Mycobacterium abscessus (MABS); 46 with Mycobacterium abscessus subsp. abscessus (Mab), and 40 with Mycobacterium abscessus subsp. massiliense (Mma) were retrospectively analyzed. The main findings are as follows: (i) Mma were significantly more susceptible to clarithromycin and azithromycin than Mab, and both subspecies tended to be more susceptible to clarithromycin than azithromycin. (ii) Most isolates were susceptible to amikacin (93.0%), and over half to linezolid (55.8%). (iii) Fifty-one isolates (59.3%) had MIC values of less than 1 µg/mL for sitafloxacin, and 65 (75.6%) had less than 0.5 µg/mL for clofazimine, which seems worth clinical investigating. (iv) Among nine cases analyzed chronological changes, only two patients showed obvious MIC result changes even after the long-term multidrug treatment. The present study revealed MICs of MABS clinical isolates before and after treatment in clinical settings, which could help develop future MABS treatments strategies.

Liu Shen Wan inhibits influenza virus-induced secondary Staphylococcus aureus infection in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Liu Shen Wan (LSW) is a traditional Chinese medicine (TCM) with detoxification and antiphlogistic activity; it is composed of bezoar, toad venom, musk, pearl powder, borneol and realgar. In recent years, LSW has been widely used in traditional medicine for the treatment of influenza, tonsillitis, pharyngitis, mumps, cancer and leukaemia. AIM OF STUDY: The anti-influenza virus properties of LSW and its inhibition of the inflammatory response was demonstrated in our previous research; however, the effect and potential mechanism of LSW against influenza induced secondary bacteria have remained obscure. Therefore, in the present study, a model of influenza virus PR8 with secondary infection by Staphylococcus aureus (S. aureus) in vitro and in mice was established to examine the effect and potential mechanism by which LSW inhibits bacterial adhesion and subsequent severe pneumonia after viral infection. MATERIALS AND METHODS: We investigated the effect of LSW on the PR8-induced adhesion of live S. aureus in A549 cells. RT-qPCR was used to detect the expression of adhesion molecules. Western blotting was used to determine the expression of CEACAM1, RIG-1, MDA5, p-NF-κB, and NF-κB in A549 cells. Inflammatory cytokines were detected using a Bio-Plex Pro Human Cytokine Screening Panel (R&D) in A549 cells and Mouse Magnetic Luminex Assays (R&D) in mice infected with PR8 virus and secondarily with S. aureus, respectively. Moreover, the survival rate, lung index, viral titre, bacterial loads and pathological changes in the lung tissue of mice infected with PR8 and S. aureus were investigated to estimate the effect of LSW in inhibiting severe pneumonia. RESULTS: LSW significantly decreased S. aureus adhesion following influenza virus infection in A549 cells, which may have occurred by suppressing expression of the adhesion molecule CEACAM1. In addition, treatment with LSW dramatically suppressed the induction of proinflammatory cytokines (CCL2/MCP-1 and CXCL-9/MIG) and chemokines (IL-6 and TNF-α) by PR8 infection following secondary LPS stimulation in A549 cells. Upregulation of related signalling proteins (RIG-I, MDA5 and NF-κB) induced by viruses and bacteria was suppressed by LSW in A549 cells. LSW significantly decreased the viral titres and bacterial load, prolonged survival time, and ameliorated lung inflammation and injury in mice with S. aureus infection secondary to PR8 infection. CONCLUSIONS: We demonstrated that LSW prevents S. aureus adherence to influenza virus-infected A549 cells, perhaps by inhibiting the expression of the adhesion molecule CEACAM1. The upregulation of proinflammatory cytokines and related signalling proteins induced by viruses and bacteria was suppressed by LSW in A549 cells. LSW significantly ameliorated lung injury caused by viral and secondary bacterial infection. These findings provide a further evaluation of LSW and suggest a beneficial effect of LSW for the prevention of secondary bacterial infection and related complications.

A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.

Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide-lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising D-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.

Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis.

BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. This leads to lung destruction and eventually death through respiratory failure. There are no antibiotics in development that exert a new mode of action and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Antibiotic adjuvants - therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering it less virulent or killing it by other means, would be a significant therapeutic advance. This is an update of a previously published review. OBJECTIVES: To determine if antibiotic adjuvants improve clinical and microbiological outcome of pulmonary infection in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Trials Register which is compiled from database searches, hand searches of appropriate journals and conference proceedings. Date of most recent search: 16 January 2020. We also searched MEDLINE (all years) on 14 February 2019 and ongoing trials registers on 06 April 2020. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials of a therapy exerting an antibiotic adjuvant mechanism of action compared to placebo or no therapy for people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two of the authors independently assessed and extracted data from identified trials. MAIN RESULTS: We identified 42 trials of which eight (350 participants) that examined antibiotic adjuvant therapies are included. Two further trials are ongoing and five are awaiting classification. The included trials assessed ß-carotene (one trial, 24 participants), garlic (one trial, 34 participants), KB001-A (a monoclonal antibody) (two trials, 196 participants), nitric oxide (two trials, 30 participants) and zinc supplementation (two trials, 66 participants). The zinc trials recruited children only, whereas the remaining trials recruited both adults and children. Three trials were located in Europe, one in Asia and four in the USA. Three of the interventions measured our primary outcome of pulmonary exacerbations (ß-carotene, mean difference (MD) -8.00 (95% confidence interval (CI) -18.78 to 2.78); KB001-A, risk ratio (RR) 0.25 (95% CI 0.03 to 2.40); zinc supplementation, RR 1.85 (95% CI 0.65 to 5.26). ß-carotene and KB001-A may make little or no difference to the number of exacerbations experienced (low-quality evidence); whereas, given the moderate-quality evidence we found that zinc probably makes no difference to this outcome. Respiratory function was measured in all of the included trials. ß-carotene and nitric oxide may make little or no difference to forced expiratory volume in one second (FEV1) (low-quality evidence), whilst garlic probably makes little or no difference to FEV1 (moderate-quality evidence). It is uncertain whether zinc or KB001-A improve FEV1 as the certainty of this evidence is very low. Few adverse events were seen across all of the different interventions and the adverse events that were reported were mild or not treatment-related (quality of the evidence ranged from very low to moderate). One of the trials (169 participants) comparing KB001-A and placebo, reported on the time to the next course of antibiotics; results showed there is probably no difference between groups, HR 1.00 (95% CI 0.69 to 1.45) (moderate-quality evidence). Quality of life was only reported in the two KB001-A trials, which demonstrated that there may be little or no difference between KB001-A and placebo (low-quality evidence). Sputum microbiology was measured and reported for the trials of KB001-A and nitric oxide (four trials). There was very low-quality evidence of a numerical reduction in Pseudomonas aeruginosa density with KB001-A, but it was not significant. The two trials looking at the effects of nitric oxide reported significant reductions in Staphylococcus aureus and near-significant reductions in Pseudomonas aeruginosa, but the quality of this evidence is again very low. AUTHORS' CONCLUSIONS: We could not identify an antibiotic adjuvant therapy that we could recommend for treating of lung infection in people with cystic fibrosis. The emergence of increasingly resistant bacteria makes the reliance on antibiotics alone challenging for cystic fibrosis teams. There is a need to explore alternative strategies, such as the use of adjuvant therapies. Further research is required to provide future therapeutic options.

Purified ß-glucans from the Shiitake mushroom ameliorates antibiotic-resistant Klebsiella pneumoniae-induced pulmonary sepsis.

Bacterial infection remains the main cause of acute respiratory distress syndrome and is a leading cause of death and disability in critically ill patients. Here we report on the use of purified ß-glucan (lentinan) extracts from Lentinus edodes (Shiitake) mushroom that can reduce infection by a multidrug-resistant clinical isolate of Klebsiella pneumoniae in a rodent pneumonia model, likely through immunomodulation. Adult male Sprague-Dawley rats were subjected to intra-tracheal administration of K. pneumoniae to induce pulmonary sepsis and randomized to three groups; vehicle control (Vehicle, n = 12), commercial lentinan (CL, n = 8) or in-house extracted lentinan (IHL, n = 8) were administered intravenously 1 h postinfection. Physiological parameters and blood gas analysis were measured, bacterial counts from bronchoalveolar-lavage (BAL) were determined, along with differential staining of white cells and measurement of protein concentration in BAL 48 h after pneumonia induction. Use of IHL extract significantly decreased BAL CFU counts. Both CL and IHL extractions reduced protein concentration in BAL. Use of IHL resulted in an improvement in physiological parameters compared to controls and CL. In conclusion, administration of lentinan to treat sepsis-induced lung injury appears safe and effective and may exert its effects in an immunomodulatory manner.

Spectrum of pulmonary fungal pathogens, associated risk factors, and anti-fungal susceptibility pattern among persons with presumptive tuberculosis at Gombe, Nigeria.

Background: Pulmonary mycosis (PM) poses a great diagnostic challenge due to the lack of pathognomonic and radiological features, especially in the absence of mycology laboratory tests. This study was aimed to isolate, phenotypically identify, determine the prevalence of pulmonary fungal pathogens and antifungal susceptibility pattern of isolates of presumptive tuberculosis (PTB) patients attending Federal Teaching Hospital (FTH) Gombe, Nigeria. Methods: After ethical approval, three consecutive early morning sputa were collected from 216 participants with presumptive of PTB attending FTH Gombe, between May 2, 2017 and May 30, 2018. Samples were processed using standard mycological staining, microscopy, sugar biochemistry, and antifungal susceptibility test protocols. Sociodemographic variables and risk factors of pulmonary fungal infection were assessed through structured questionnaires. Pulmonary fungal infection was defined by the positive culture in at least two sputa. PTB was defined by Genexpert® nested polymerase chain reaction. Results: Of the 216 participants, 19.9% had PTB and 73.6% had pulmonary fungal pathogens. Among the isolated pulmonary fungal pathogens, Aspergillus fumigatus made the highest occurrence, while 6.5% had PTB-fungal co-infection. No significant association existed between the prevalence of PM with age and sex of participants (P < 0.05). Cigarette smoking (adjusted odds ratio [aOR] = 15.9 [95% confidence interval (CI): 0.9-268.8]), prolong antibiotic use (aOR = 77.9 [95% CI: 4.7-1283]) and possession of domestic pet (aOR = 77.9 [95% CI: 4.7-1283]) were significant risk factors of PM (P < 0.05). Penicillium citrinum, Mucor spp. and Aspergillus flavus are more susceptible to voriconazole, and Candida albicans was found to be more susceptible to Nystatin. Of the 159 fungal isolates, 92.5% were resistant to fluconazole. Conclusion: Findings from this study revealed high level pulmonary fungal pathogens, especially among PTB patients. A majority of fungal isolates were resistant to fluconazole. It's recommended that persons should do away with or minimize risk factors for pulmonary fungal pathogens identified in this study.

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.

Nutrients and Microbiota in Lung Diseases of Prematurity: The Placenta-Gut-Lung Triangle.

Cardiorespiratory function is not only the foremost determinant of life after premature birth, but also a major factor of long-term outcomes. However, the path from placental disconnection to nutritional autonomy is enduring and challenging for the preterm infant and, at each step, will have profound influences on respiratory physiology and disease. Fluid and energy intake, specific nutrients such as amino-acids, lipids and vitamins, and their ways of administration -parenteral or enteral-have direct implications on lung tissue composition and cellular functions, thus affect lung development and homeostasis and contributing to acute and chronic respiratory disorders. In addition, metabolomic signatures have recently emerged as biomarkers of bronchopulmonary dysplasia and other neonatal diseases, suggesting a profound implication of specific metabolites such as amino-acids, acylcarnitine and fatty acids in lung injury and repair, inflammation and immune modulation. Recent advances have highlighted the profound influence of the microbiome on many short- and long-term outcomes in the preterm infant. Lung and intestinal microbiomes are deeply intricated, and nutrition plays a prominent role in their establishment and regulation. There is an emerging evidence that human milk prevents bronchopulmonary dysplasia in premature infants, potentially through microbiome composition and/or inflammation modulation. Restoring antibiotic therapy-mediated microbiome disruption is another potentially beneficial action of human milk, which can be in part emulated by pre- and probiotics and supplements. This review will explore the many facets of the gut-lung axis and its pathophysiology in acute and chronic respiratory disorders of the prematurely born infant, and explore established and innovative nutritional approaches for prevention and treatment.

The influence of the microbiome on respiratory health.

The revolution in microbiota research over the past decade has provided invaluable knowledge about the function of the microbial species that inhabit the human body. It has become widely accepted that these microorganisms, collectively called 'the microbiota', engage in networks of interactions with each other and with the host that aim to benefit both the microbial members and the mammalian members of this unique ecosystem. The lungs, previously thought to be sterile, are now known to harbor a unique microbiota and, additionally, to be influenced by microbial signals from distal body sites, such as the intestine. Here we review the role of the lung and gut microbiotas in respiratory health and disease and highlight the main pathways of communication that underlie the gut-lung axis.

Dietary zinc and the control of Streptococcus pneumoniae infection.

Human zinc deficiency increases susceptibility to bacterial infection. Although zinc supplementation therapies can reduce the impact of disease, the molecular basis for protection remains unclear. Streptococcus pneumoniae is a major cause of bacterial pneumonia, which is prevalent in regions of zinc deficiency. We report that dietary zinc levels dictate the outcome of S. pneumoniae infection in a murine model. Dietary zinc restriction impacts murine tissue zinc levels with distribution post-infection altered, and S. pneumoniae virulence and infection enhanced. Although the activation and infiltration of murine phagocytic cells was not affected by zinc restriction, their efficacy of bacterial control was compromised. S. pneumoniae was shown to be highly sensitive to zinc intoxication, with this process impaired in zinc restricted mice and isolated phagocytic cells. Collectively, these data show how dietary zinc deficiency increases sensitivity to S. pneumoniae infection while revealing a role for zinc as a component of host antimicrobial defences.

In vivo antibacterial activity of Zataria multiflora Boiss extract and its components, carvacrol, and thymol, against colistin-resistant Acinetobacter baumannii in a pneumonic BALB/c mouse model.

BACKGROUND: Acinetobacter baumannii has emerged as a major cause of nosocomial infections. Various resistance mechanisms of A. baumannii against antibiotics have transformed it into a successful nosocomial pathogen. Because of the limited number of available antibiotics, we used a medicinal plant with an antibacterial effect. Zataria multiflora Boiss (ZMB) extract and its components were used for the treatment of pneumonic mice infected with A. baumannii. The biological effects of this extract and the regulation of the outer membrane protein A (ompA) gene were used in a mouse model. METHODS: A pneumonic mouse model was prepared using clinical and standard strains (1.5 × 108 colony-forming units/mL) of A. baumannii. BALB/c mice groups were treated with a ZMB extract, carvacrol, thymol, and sensitive antibiotics. The lung tissues of the treated mice were cultured for 5 days and each day, bacterial clearance and the ompA gene expression were assessed by quantitative real-time polymerase chain reaction. RESULTS: In the lung tissue culture of pneumonic mice infected with standard or clinical isolate, no colony was detected when treated with the ZMB extract after 2 and 3 days (P < 0.01), respectively. In the carvacrol-treated group, bacterial clearance was seen at day 4 and day 5 (P < 0.05). Bacterial clearance was seen 5 days after treatment with thymol and imipenem and 6 days after ampicillin/sulbactam treatment. The regulation of ompA gene was significantly decreased in this order: ZMB extract, carvacrol, thymol, imipenem, and ampicillin/sulbactam. DISCUSSION: The ZMB extract had a potent bactericidal effect against A. baumannii that could downregulate the ompA gene. ZBM extract and carvacrol could be novel therapeutic agents for antibiotic-resistant A. baumannii.

Degradable antimicrobial polycarbonates with unexpected activity and selectivity for treating multidrug-resistant Klebsiella pneumoniae lung infection in mice.

Multidrug resistant (MDR) Klebsiella pneumoniae is a major cause of healthcare-associated infections around the world, with attendant high rates of morbidity and mortality. Progressive reduction in potency of antibiotics capable of treating MDR K. pneumoniae infections - including lung infection - as a consequence of escalating drug resistance provides the motivation to develop drug candidates targeting MDR K. pneumoniae. We recently reported degradable broad-spectrum antimicrobial guanidinium-functionalized polycarbonates with unique antimicrobial mechanism - membrane translocation followed by precipitation of cytosolic materials. These polymers exhibited high potency against bacteria with negligible toxicity. The polymer with ethyl spacer between the quanidinium group and the polymer backbone (pEt_20) showed excellent in vivo efficacy for treating MDR K. pneumoniae-caused peritonitis in mice. In this study, the structures of the polymers were optimized for the treatment of MDR Klebsiella pneumoniae lung infection. Specifically, in vitro antimicrobial activity and selectivity of guanidinium-functionalized polycarbonates containing the same number of guanidinium groups but of a shorter chain length and a structural analogue containing a thiouronium moiety as the pendent cationic group were evaluated. The polymers with optimal compositions and varying hydrophobicity were assessed against 25 clinically isolated K. pneumonia strains for antimicrobial activity and killing kinetics. The results showed that the polymers killed the bacteria more efficiently than clinically used antibiotics, and repeated use of the polymers did not cause drug resistance in K. pneumonia. Particularly, the polymer with butyl spacer (pBut_20) self-assembled into micelles at high concentrations, where the hydrophobic component was shielded in the micellar core, preventing interacting with mammalian cells. A subtle change in the hydrophobicity increased the antimicrobial activity while reducing in vivo toxicity. The in vivo efficacy studies showed that pBut_20 alleviated K. pneumonia lung infection without inducing damage to major organs. Taken together, pBut_20 is promising for treating MDR Klebsiella pneumoniae lung infection in vivo. STATEMENT OF SIGNIFICANCE: Multidrug resistant (MDR) Klebsiella pneumoniae is a major cause of healthcare-associated infections, with attendant high rates of morbidity and mortality. The progressive reduction in antibiotics capable of treating MDR K. pneumoniae infections - including lung infection - as a consequence of escalating drug resistance rates provides the motivation to develop drug candidates. In this study, we report a degradable guanidinium-functionalized polycarbonate with unexpected antimicrobial activity and selectivity towards MDR Klebsiella pneumoniae. A subtle change in polymer hydrophobicity increases antimicrobial activity while reducing in vivo toxicity due to self-assembly at high concentrations. The polymer with optimal composition alleviates Klebsiella pneumonia lung infection without inducing damage to major organs. The polymer is promising for treating MDR Klebsiella pneumoniae lung infection in vivo.

New drugs to treat difficult tuberculous and nontuberculous mycobacterial pulmonary disease.

PURPOSE OF REVIEW: Treatment of drug-sensitive tuberculosis (TB) is effective, whereas that of multidrug-resistant and extensively drug-resistant TB as well as nontuberculous mycobacterial (NTM) disease are less so. Therapy in general requires good adherence to potentially toxic drug regimens over prolonged periods. Poor adherence is associated with resistance development and poor outcome. This review will present promising new treatments, both new drugs and regimens, for difficult mycobacterial pulmonary infections. RECENT FINDINGS: A number of new and repurposed drugs including bedaquiline, delamanid, pretomanid, linezolid and clofazimine, and drug regimens, such as the The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) trial regimens, are currently progressing from basic research through clinical trials.

M ycobacterium abscessus pulmonary disease: individual patient data meta-analysis.

Treatment of Mycobacterium abscessus pulmonary disease (MAB-PD), caused by M. abscessus subsp. abscessus, M. abscessus subsp. massiliense or M. abscessus subsp. bolletii, is challenging.We conducted an individual patient data meta-analysis based on studies reporting treatment outcomes for MAB-PD to clarify treatment outcomes for MAB-PD and the impact of each drug on treatment outcomes. Treatment success was defined as culture conversion for ≥12 months while on treatment or sustained culture conversion without relapse until the end of treatment.Among 14 eligible studies, datasets from eight studies were provided and a total of 303 patients with MAB-PD were included in the analysis. The treatment success rate across all patients with MAB-PD was 45.6%. The specific treatment success rates were 33.0% for M. abscessus subsp. abscessus and 56.7% for M. abscessus subsp. massiliense For MAB-PD overall, the use of imipenem was associated with treatment success (adjusted odds ratio (aOR) 2.65, 95% CI 1.36-5.10). For patients with M. abscessus subsp. abscessus, the use of azithromycin (aOR 3.29, 95% CI 1.26-8.62), parenteral amikacin (aOR 1.44, 95% CI 1.05-1.99) or imipenem (aOR 7.96, 95% CI 1.52-41.6) was related to treatment success. For patients with M. abscessus subsp. massiliense, the choice among these drugs was not associated with treatment outcomes.Treatment outcomes for MAB-PD are unsatisfactory. The use of azithromycin, amikacin or imipenem was associated with better outcomes for patients with M. abscessus subsp. abscessus.

Minocycline Has No Clear Role in the Treatment of Mycobacterium abscessus Disease.

Mycobacterium abscessus causes a difficult-to-treat pulmonary disease (MAb-PD). After initial intravenous treatment, minocycline is recommended in the oral continuation phase of treatment. We determined the MICs, synergy, and time-kill kinetics of minocycline against M. abscessus With MICs of 8 to 512 mg/liter, rapid emergence of tolerance in time-kill assays, and no synergy with other drugs used to treat MAb-PD, minocycline appears ineffective against M. abscessus These in vitro data question its role as a MAb-PD treatment modality.

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.