7-oxo-DHEA enhances impaired M. tuberculosis-specific T cell responses during HIV-TB coinfection.

BACKGROUND: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), affecting approximately one third of the world's population. Development of an adequate immune response will determine disease progression or progress to chronic infection. Risk of developing TB among human immunodeficiency virus (HIV)-coinfected patients (HIV-TB) is 20-30 times higher than those without HIV infection, and a synergistic interplay between these two pathogens accelerates the decline in immunological functions. TB treatment in HIV-TB coinfected persons is challenging and it has a prolonged duration, mainly due to the immune system failure to provide an adequate support for the therapy. Therefore, we aimed to study the role of the hormone 7-oxo-dehydroepiandrosterone (7-OD) as a modulator of anti-tuberculosis immune responses in the context of HIV-TB coinfection. METHODS: A cross-sectional study was conducted among HIV-TB patients and healthy donors (HD). We characterized the ex vivo phenotype of CD4 + T cells and also evaluated in vitro antigen-specific responses by Mtb stimulation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of 7-OD. We assessed lymphoproliferative activity, cytokine production and master transcription factor profiles. RESULTS: Our results show that HIV-TB patients were not able to generate successful anti-tubercular responses in vitro compared to HD, as reduced IFN-γ/IL-10 and IFN-γ/IL-17A ratios were observed. Interestingly, treatment with 7-OD enhanced Th1 responses by increasing Mtb-induced proliferation and the production of IFN-γ and TNF-α over IL-10 levels. Additionally, in vitro Mtb stimulation augmented the frequency of cells with a regulatory phenotype, while 7-OD reduced the proportion of these subsets and induced an increase in CD4 + T-bet+ (Th1) subpopulation, which is associated with clinical data linked to an improved disease outcome. CONCLUSIONS: We conclude that 7-OD modifies the cytokine balance and the phenotype of CD4 + T cells towards a more favorable profile for mycobacteria control. These results provide new data to delineate novel treatment approaches as co-adjuvant for the treatment of TB.

The Yin and Yang of Streptococcus Lung Infections in Cystic Fibrosis: a Model for Studying Polymicrobial Interactions.

The streptococci are increasingly recognized as a core component of the cystic fibrosis (CF) lung microbiome, yet the role that they play in CF lung disease is unclear. The presence of the Streptococcus milleri group (SMG; also known as the anginosus group streptococci [AGS]) correlates with exacerbation when these microbes are the predominant species in the lung. In contrast, microbiome studies have indicated that an increased relative abundance of streptococci in the lung, including members of the oral microflora, correlates with impacts on lung disease less severe than those caused by other CF-associated microflora, indicating a complex role for this genus in the context of CF. Recent findings suggest that streptococci in the CF lung microenvironment may influence the growth and/or virulence of other CF pathogens, as evidenced by increased virulence factor production by Pseudomonas aeruginosa when grown in coculture with oral streptococci. Conversely, the presence of P. aeruginosa can enhance the growth of streptococci, including members of the SMG, a phenomenon that could be exacerbated by the fact that streptococci are not susceptible to some of the frontline antibiotics used to treat P. aeruginosa infections. Collectively, these studies indicate the necessity for further investigation into the role of streptococci in the CF airway to determine how these microbes, alone or via interactions with other CF-associated pathogens, might influence CF lung disease, for better or for worse. We also propose that the interactions of streptococci with other CF pathogens is an ideal model to study clinically relevant microbial interactions.

Polymicrobial Bacteremia Involving Klebsiella pneumoniae in Patients with Complicated Intra-Abdominal Infections: Frequency, Co-Pathogens, Risk Factors, and Clinical Outcomes.

Background: Klebsiella pneumoniae has gained notoriety because of its high antibiotic resistance and mortality. We compared the clinical features and outcomes of polymicrobial bacteremia involving K. pneumoniae (PBKP). Patients and Methods: A retrospective observational study of patients with polymicrobial and monomicrobial bacteremia involving K. pneumoniae from January 2012 to December 2016 was performed. The expression of resistance and virulence genes of 27 strains was also compared by polymerase chain reaction (PCR). Results: Among the polymicrobial group, the most common accompanying micro-organism was Escherichia coli. No differences in the expression of resistance and virulence genes was found among the 27 strains collected from the group. The analysis of the outcomes revealed that the patients with PBKP were more likely to have recurrent blood stream infections (p = 0.038), longer intensive care unit (ICU) lengths of stay (p = 0.043), and a higher total hospitalization cost (p = 0.045). However, no substantial differences in mortality were found between the two groups. The multivariable analysis revealed that a longer hospital stay prior to the onset of bacteremia (>20 days) was an independent risk factor for PBKP (p = 0.034), and the Sequential Organ Failure Assessment (SOFA) score upon onset of infection (p = 0.013), the adequacy of source control (p < 0.001), and iron supplementation (p = 0.003) were identified as independent predictors of mortality in patients with KP bacteremia. Conclusions: The development of septic shock and the concomitant use of iron supplementation are associated with higher mortality in patients with KP bacteremia, and PBKP did not increase the mortality of these patients, possibly because of the ability of K. pneumoniae to obscure the effects of other bacteria. Thus, adequate source control is more important than high-dose antibiotic therapy and is linked to higher survival.

Omega-3 decreases IL-6 levels in HIV and human herpesvirus-8 coinfected patients in Uganda.

OBJECTIVE: Kaposi sarcoma is a HIV-associated malignancy caused by human herpesvirus-8 (HHV-8) that occurs at highest incidence in sub-Saharan Africa. Kaposi sarcoma patients often present with inflammatory symptoms associated with higher mortality. DESIGN: We conducted a double-blind, randomized, placebo-controlled study in Uganda to test whether omega-3 supplementation could reduce inflammation in HIV and HHV-8 coinfected adults. Patients with acute illness, AIDS, or advanced Kaposi sarcoma were ineligible, as were pregnant women. Participant IDs were pre-randomized, blocked by Kaposi sarcoma status, to either the omega-3 or placebo arm. METHODS: Omega-3 participants received a 3-g pill dose daily for 12 weeks (1.8-g eicosapentaenoic acid, 1.2-mg docosapentaenoic acid); placebo participants received 44.8 mg of high oleic safflower oil that appeared indistinguishable from the active supplement. Intervention effects were evaluated as the baseline-adjusted mean difference after 12 weeks between omega-3 and placebo participants in concentrations of fatty acids, inflammatory cytokines, and immune cells. RESULTS: The final study population included 56 Kaposi sarcoma patients and 11 Kaposi sarcoma-negative, HIV and HHV-8-positive participants randomized to receive either omega-3 (N = 33) or placebo (N = 34). Inflammatory cytokine IL-6 concentrations decreased in omega-3 participants (-0.78 pg/ml) but increased in placebo participants (+3.2 pg/ml; P = 0.04). We observed a trend toward decreased IL-6 after omega-3 supplementation specific to Kaposi sarcoma patients (P = 0.08). CD8 T-cell counts tended to increase in the omega-3 arm Kaposi sarcoma patients (+60 cells/µl), in contrast to decreases (-47 cells/µl) among placebo (P = 0.11). CONCLUSION: Omega-3 supplementation decreased IL-6 concentrations among HIV and HHV-8 coinfected Ugandans, which may have clinical benefit for Kaposi sarcoma patients.

Isolation of bacteria from diabetic foot ulcers with special reference to anaerobe isolation by simple two-step combustion technique in candle jar.

BACKGROUND & OBJECTIVES: Although polymicrobial infections involving both aerobic and anaerobic bacteria are very common in diabetic foot ulcers, in many centres of developing countries, anaerobes are rarely isolated due to technical difficulties. This can be overcome by using a new simple, innovative technique of a combination of candle combustion and use of acidified copper-coated steel wool, as reported here. METHODS: In-house developed method was used in a prospective clinico-microbiological study for anaerobes from randomly selected 43 patients with diabetic foot ulcers along with conventional method of anaerobic culture in GasPak system and aerobic culture by standard laboratory procedures. For primary isolation of anaerobes, Brucella blood agar supplemented with hemin (5 µg/ml) and menadione (1 µg/ml) was used. Antibiotic sensitivity tests were performed by the standard disc diffusion method for aerobes and E-test method for anaerobes. RESULTS: All the 43 samples were culture positive, of which aerobic Gram-negative bacteria (GNB) predominated, followed by Staphylococcus aureus, Enterococcus and diphtheroids. Anaerobes isolated from 21 samples were Peptostreptococcus, Bacteroides, Porphyromonas, Veillonella spp. and Clostridium perfringens by both GasPak and in-house developed and modified candle jar techniques. Imipenem and metronidazole were most sensitive while clindamycin, penicillin and cefoxitin were least sensitive drugs for anaerobes. Aerobic GNB were found to be multidrug resistant, especially to penicillin and cephalosporins. The most sensitive drug was piperacillin-tazobactam. INTERPRETATION & CONCLUSIONS: For isolation of anaerobes from clinical specimens such as diabetic foot ulcers, modified candle jar technique was found to be as reliable as GasPak system. This modified technique needs to be tested for many other clinical materials which are not yet evaluated.

Successful Treatment of Refractory Majocchi's Granuloma with Voriconazole and Review of Published Literature.

Majocchi's granuloma (MG) is a rare deep skin dermatophyte infection that can occur either in immunocompetent or in immunocompromised individuals. Oral itraconazole or terbinafine is considered to be the first choice of treatment. We report an immunocompetent man with deep nodular form of MG, the form which is generally found in immunosuppressed individuals. Previous treatment with either oral itraconazole or terbinafine yielded no apparent improvement. After a series of examination, the man was diagnosed as having Trichophyton rubrum-induced MG mixed with bacterial infection as evidenced by growth of Klebsiella pneumoniae in tissue bacterial culture. The patient was treated with a combination of cefoselis and levofloxacin for bacterial clearance followed by voriconazole treatment. After approximately 4 months of voriconazole treatment, the lesions completely resolved. Alternative medicine (voriconazole) can be considered in case of refractory infections during MG treatment.

Is intensive multimodality therapy the best treatment for fournier gangrene? Evaluation of clinical outcome and survival rate of 41 patients.

BACKGROUND: To evaluate the effect of surgical wound debridement, antibiotics, and hyperbaric oxygen (HBO) in the treatment of Fournier gangrene (FG). METHODS: Forty-one patients with a mean age of 54.3±14.6 years were referred to our department with a diagnosis of FG. To calculate a Fourier Gangrene Severity Index (FGSI), nine factors were assessed (temperature; heart rate; ventilatory rate; serum sodium, potassium, creatinine, and bicarbonate concentrations; hematocrit; and leukocyte count). After clinical stabilization, extensive debridement of the necrotic tissue was performed, and a surgical vacuum-assisted closure (V.A.C.®) device was applied. Hyperbaric oxygen was administered; medical therapy consisted of intravenous antibiotics, electrolyte replacement, and parenteral nutrition. RESULTS: Intraoperative cultures revealed Escherichia coli in 27 patients (66%), Pseudomonas aeruginosa in 28 (68%), gram-positive cocci in 24 (59%), and mixed flora (aerobic and anaerobic bacteria) in 39 (95%). One month after primary debridement, wound granulation was sufficient for plastic surgical reconstruction in all patients. CONCLUSION: Because of the rapid worsening of FG, early diagnosis and immediate, aggressive multi-modality therapy with surgical debridement and broad-spectrum empiric antibiotics is crucial. The utility of HBO remains unproved.

Porcine circovirus type 2 potentiates morbidity of Salmonella enterica serovar Choleraesuis in Cesarean-derived, colostrum-deprived pigs.

PROBLEM ADDRESSED: Porcine circovirus type 2 (PCV2) and Salmonella enterica subspecies enterica serovar Choleraesuis (S. Choleraesuis) are two leading causes of economic loss in the swine industry. Although S. Choleraesuis infection occurs concurrently with PCV2-associated disease in many swine herds, the pathogenesis of concurrent infection with PCV2 and S. Choleraesuis remains largely undefined. OBJECTIVE: We investigated the interactions between PCV2 and S. Choleraesuis in 20 Cesarean-derived, colostrum-deprived (CDCD) pigs randomly assigned to 4 groups (n=5 per group). METHODS AND APPROACH: Pigs in the dual-infected and PCV2-infected groups were inoculated intranasally with PCV2 at 5 weeks of age, and pigs in the dual-infected and S. Choleraesuis-infected groups were inoculated intranasally with S. Choleraesuis at 7 weeks of age. Pigs in the control group served as uninfected controls. RESULTS: After S. Choleraesuis inoculation, severe clinical signs, reduction of weight gain, and severe microscopic lung lesions were observed in dual-infected pigs compared to those in other groups. In addition, the pigs in the dual-infected group shed significantly (P=0.002) higher quantities of S. Choleraesuis in feces 12 days after S. Choleraesuis inoculation, and S. Choleraesuis was recovered from more tissues in this group 14 days after S. Choleraesuis inoculation. CONCLUSIONS: These results indicate that prior PCV2 infection potentiates the severity of clinical signs, lung lesions, and fecal shedding and tissue dissemination of S. Choleraesuis in infected pigs. Therefore, dual infection of pigs with PCV2 and S. Choleraesuis may increase clinical effects of salmonellosis in the field.