Unusually isolated Staphylococcus arlettae in intra-oral sutures - Case series.

Introduction: The human oral cavity comprises various niches such as teeth, gingiva, tongue, soft and hard palate, and various dental prostheses, all inhabited by different bacterial species. Although more than 600 taxa belong to the oral cavity, identifying Staphylococcus arlettae , an incompletely understood bacterium, has been rare. Methods: Three patients who underwent periodontal flap surgeries were reported with the incidental finding of S. arlettae associated with the intra-oral sutures placed. Environmental sampling was performed, to establish the exact source of this bacterium. Results: Staphylococcus arlettae was isolated in three patients' intra-oral sutures. All environmental samples were negative for the presence of the bacterium. Conclusion: . To this date, no studies have identified such an occurrence of Staphylococcus arlettae with intra-oral sutures. Its identification in association with foreign materials, such as sutures, can be considered a potential for surgical site infections and requires further investigation.

Age of Antibiotic Resistance in MDR/XDR Clinical Pathogen of Pseudomonas aeruginosa.

Antibiotic resistance in Pseudomonas aeruginosa remains one of the most challenging phenomena of everyday medical science. The universal spread of high-risk clones of multidrug-resistant/extensively drug-resistant (MDR/XDR) clinical P. aeruginosa has become a public health threat. The P. aeruginosa bacteria exhibits remarkable genome plasticity that utilizes highly acquired and intrinsic resistance mechanisms to counter most antibiotic challenges. In addition, the adaptive antibiotic resistance of P. aeruginosa, including biofilm-mediated resistance and the formation of multidrug-tolerant persisted cells, are accountable for recalcitrance and relapse of infections. We highlighted the AMR mechanism considering the most common pathogen P. aeruginosa, its clinical impact, epidemiology, and save our souls (SOS)-mediated resistance. We further discussed the current therapeutic options against MDR/XDR P. aeruginosa infections, and described those treatment options in clinical practice. Finally, other therapeutic strategies, such as bacteriophage-based therapy and antimicrobial peptides, were described with clinical relevance.

Genetic Variations in IL-1ß, TNF-α, and TGF-ß Associated with the Severity of Chronic Cervical Spondylitis in Patients.

Chronic cervical spondylitis (CCS), a degenerative disorder of the spine, is known for causing disability among old and young people. Single-nucleotide polymorphisms (SNPs) in various cytokine genes have demonstrated an impactful association with several inflammatory disorders. In the present study, we have investigated the SNPs and allelic distribution of the three most prevalent cytokines genes, IL-1ß (-511C/T), TNF-α (-308G/A), and TGF-ß (-509C/T), along with serum levels of these cytokines in 252 subjects. SNPs were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and digested fragments were separated and visualized using agarose gel electrophoresis and Native Polyacrylamide gel electrophoresis (PAGE). The serum cytokine levels were analyzed with a flow cytometer using a customized multiplex bead-based assay. It was observed that these SNPs did not reflect the susceptibility to CCS but were associated with susceptibility to CCS. We found a significant association between the C/C and G/G genotypes and the C and G alleles of IL-1ß and TNF-α, respectively, suggesting a lower risk of CCS. The frequency distribution of risk alleles (-511T) and (-308A) were simultaneously higher in CCS compared to the control, reflecting the susceptibility to CCS. TGF-ß showed a significant association with disease susceptibility, along with a significant correlation between age and the chronicity of CCS. The serum cytokine levels were significantly different in CCS and controls.

Immunotherapies in rare cancers.

Cancer remains a leading cause of death worldwide, placing a significant burden on healthcare systems as well as the global economy. Rare cancers comprise a group of about 200 cancers that individually occur at extremely low frequencies. In the United States (US), their frequency is approximately 15 cases per 100,000 people, and it is even lower in Europe with approximately 6 cases per 100,000 people. However, combined their frequency of occurrence is much higher than any singular cancer. Cancer treatment and management has tremendously improved in the last decade, particularly with the administration of immune-based therapies. The four most prevalent immune-based therapies are (1) the use of immune-checkpoint inhibitors, (2) macrophage therapy, (3) Chimeric Antigen Receptor (CAR) T cell therapy, and (4) neoantigen-based therapies. In our review, we discuss these various aproaches and their implementation in the treatment of a variety of rare cancers. Furthermore, we discuss their limitations and potential strategies to overcome them to enhance the therapeutic efficacy of these approaches. Finally, our article presents the future directions and other additional immune therapies that may be incorporated into the treatment of rare cancers.

Small Molecule IITR00693 (2-Aminoperimidine) Synergizes Polymyxin B Activity against Staphylococcus aureus and Pseudomonas aeruginosa.

The rise of antibiotic resistance among skin-infecting pathogens poses an urgent threat to public health and has fueled the search for new therapies. Enhancing the potency of currently used antibiotics is an alternative for the treatment of infections caused by drug-resistant pathogens. In this study, we aimed to identify a small molecule that can potentiate currently used antibiotics. IITR00693 (2-aminoperimidine), a novel antibacterial small molecule, potentiates the antibacterial activity of polymyxin B against Staphylococcus aureus and Pseudomonas aeruginosa. Herein, we investigated in detail the mode of action of this interaction and the molecule's capability to combat soft-tissue infections caused by S. aureus and P. aeruginosa. A microdilution checkerboard assay was performed to determine the synergistic interaction between polymyxin B and IITR00693 in clinical isolates of S. aureus and P. aeruginosa. Time-kill kinetics, post-antibiotic effect, and resistance generation studies were performed to assess the pharmacodynamics of the combination. Assays based on different fluorescent probes were performed to decipher the mechanism of action of this combination. The in vivo efficacy of the IITR00693-polymyxin B combination was determined in a murine acute wound infection model. IITR00693 exhibited broad-spectrum antibacterial activity. IITR00693 potentiated polymyxin B and colistin against polymyxin-resistant S. aureus. IITR00693 prevented the generation of resistant mutants against multiple antibiotics. The IITR00693-polymyxin B combination decreased the S. aureus count by >3 log10 CFU in a murine acute wound infection model. IITR00693 is a potential and promising candidate for the treatment of soft-tissue infections along with polymyxins.

Association of antibiotics and heavy metal arsenic to horizontal gene transfer from multidrug-resistant clinical strains to antibiotic-sensitive environmental strains.

The emergence of multidrug-resistant bacteria is currently posing a significant threat to global public health. By testing for resistance to different antibiotic classes, we discovered that the majority of clinical bacteria are multidrug-resistant. These clinical multidrug-resistant species have antibiotic resistance genes on their plasmids that can be horizontally transferred to various antibiotic susceptible environmental bacterial species, resulting in antibiotic-resistant transconjugates. Furthermore, we discovered that the presence of an optimal concentration of antibiotics or heavy metal (arsenic) facilitates horizontal gene transfer through the formation of transconjugants. Notably, the addition of a conjugation inhibitor (2-hexadecynoic acid, a synthetic fatty acid) completely blocked the formation of antibiotic or arsenic-induced transconjugants. We discovered a high level of arsenic in water from the Shukratal region, Uttarakhand, India, which corresponded to a high serum level of arsenic in clinically infected individuals from the Shukratal region compared to other locations in Uttarakhand. Importantly, bacterial strains isolated from infected people who drink water from the Shukratal region with high arsenic levels were found to be more antibiotic-resistant than strains isolated from other sites. We discovered that bacterial strains isolated from individuals with high serum arsenic levels are significantly more resistant to antibiotics than individuals with low serum arsenic levels within the Shurkratal. This research sheds light on imminent threats to global health in which improper clinical, industrial, and other waste disposal, increased antibiotic concentrations in the environment, and increased human interference can easily transform commensal and pathogenic bacteria found in environmental niches into life-threatening multidrug-resistant superbugs.

The mythological chimera and new era of relapse prediction post-transplant.

Allogeneic hemopoietic stem cell transplantation is the treatment of choice for high-risk or relapsed acute leukemia. However, unfortunately, relapse post-transplant continues to be the most common cause of treatment failure with 20-80% of patients relapsing based on disease risk and status at transplant. Advances in molecular profiling of different hematological malignancies have enabled us to monitor low level disease before and after transplant and develop a more personalized approach to the management of these disease including early detection post-transplant. While, in general, detectable disease by morphology remains the gold standard to diagnosing relapse, multiple approaches have allowed detection of cancer cells earlier, using peripheral blood-based methods with sensitivities as high as 1:106, together called minimal/measurable residual disease (MRD) detection. However, a in significant number of patients with acute leukemia where no such molecular markers exist it remains challenging to detect early relapse. In such patients who receive transplantation, chimerism monitoring remains the only option. An increase in mixed chimerism in post allogeneic HCT patients has been correlated with relapse in multiple studies. However, chimerism monitoring, while commonly accepted as a tool for assessing engraftment, has not been routinely used for relapse detection, at least in part because of the lack of standardized, high sensitivity, reliable methods for chimerism detection. In this paper, we review the various methods employed for MRD and chimerism detection post-transplant and discuss future trends in MRD and chimerism monitoring from the viewpoint of the practicing transplant physician.

Association of multidrug resistance behavior of clinical Pseudomonas aeruginosa to pigment coloration.

Pseudomonas aeruginosa is an adaptable bacterial pathogen that infects a variety of organs, including the respiratory tract, vascular system, urinary tract, and central nervous system, causing significant morbidity and mortality. As the primary goal of this study, we wanted to determine how pigment color production differed between clinical strains of P. aeruginosa, and whether or not that variation was associated with multidrug resistance or the ability to form biofilms. We screened in total 30.1% of yellow, 39.8% green and 30.1% of no pigment-producing P. aeruginosa strains from a total of 143 various clinical isolates. Yellow pigment-producing strains presented significant resistance to antibiotics groups, including ß-lactam (91.5%), aminoglycosides (70.5%), and carbapenems (51.9%) compared to green and non-pigmented strains. Notably, 16.3% of yellow pigment-producing strains were resistant to colistin which is used as a last-resort treatment for multidrug-resistant bacteria, whereas only 2.3% of non-pigmented and 1.8% of green pigmented strains were resistant to colistin. Aside from that, yellow pigment-producing strains were frequent producers of enzymes belonging to the lactamase family, including ESBL (55.6%), MBL (55.6%), and AmpC (50%). Compared to the green groups (7.14%) and non-pigmented groups (28.5%), they had a higher frequency of efflux positive groups (64.2%). Notably, when compared to non-pigmented groups, green pigment-producing strains also displayed antibiotic susceptibility behavior similar to yellow pigment-producing strains. The majority of yellow pigment-producing strains outperformed the green and non-pigmented strains in terms of MIC levels when compared to the other two groups of strains. Despite the fact that previous studies have demonstrated a direct correlation between multidrug resistance behaviors and biofilm production, no such statistically significant association between pigment and biofilm formation was found in our investigation. Our research has demonstrated that the correlation of bacterial pigments on their susceptibility to antimicrobial agents. Yellow pigment-producing P. aeruginosa strains posed a significant problem due to the lack of alternative agents against such transformed strains, which may be associated with the development of multidrug resistance.

Recent Advancements in Antifibrotic Therapies for Regression of Liver Fibrosis.

Cirrhosis is a severe form of liver fibrosis that results in the irreversible replacement of liver tissue with scar tissue in the liver. Environmental toxicity, infections, metabolic causes, or other genetic factors including autoimmune hepatitis can lead to chronic liver injury and can result in inflammation and fibrosis. This activates myofibroblasts to secrete ECM proteins, resulting in the formation of fibrous scars on the liver. Fibrosis regression is possible through the removal of pathophysiological causes as well as the elimination of activated myofibroblasts, resulting in the reabsorption of the scar tissue. To date, a wide range of antifibrotic therapies has been tried and tested, with varying degrees of success. These therapies include the use of growth factors, cytokines, miRNAs, monoclonal antibodies, stem-cell-based approaches, and other approaches that target the ECM. The positive results of preclinical and clinical studies raise the prospect of a viable alternative to liver transplantation in the near future. The present review provides a synopsis of recent antifibrotic treatment modalities for the treatment of liver cirrhosis, as well as a brief summary of clinical trials that have been conducted to date.

Disulfiram enhances meropenem activity against NDM- and IMP-producing carbapenem-resistant Acinetobacter baumannii infections.

OBJECTIVES: To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii. METHODS: Chequerboard and antibiotic resistance reversal analysis were performed using 25 clinical isolates producing different MBLs. Three representative strains harbouring NDM, IMP or non-MBL genes were subjected to a time-kill assay to further evaluate this synergistic interaction. Dose-dependent inhibition by disulfiram was assessed to determine IC50 for NDM-1, IMP-7, VIM-2 and KPC-2. Further, to test the efficacy of meropenem monotherapy and meropenem in combination with disulfiram against NDM- and IMP-harbouring A. baumannii, an experimental model of systemic infection and pneumonia was developed using BALB/c female mice. RESULTS: Chequerboard and antibiotic reversal assay displayed a synergistic interaction against MBL-expressing A. baumannii strains with 4- to 32-fold reduction in MICs of meropenem. In time-kill analysis, meropenem and disulfiram exhibited synergy against NDM- and IMP-producing carbapenem-resistant A. baumannii (CRAb) isolates. In vitro dose-dependent inhibition analysis showed that disulfiram inhibits NDM-1 and IMP-7 with IC50 values of 1.5 ± 0.6 and 16.25 ± 1.6 µM, respectively, with slight or no inhibition of VIM-2 (<20%) and KPC-2. The combination performed better in the clearance of bacterial load from the liver and spleen of mice infected with IMP-expressing CRAb. In the pneumonia model, the combination significantly decreased the bacterial burden of NDM producers compared with monotherapy. CONCLUSIONS: These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.

Potential Synergistic Antibiotic Combinations against Fluoroquinolone-Resistant Pseudomonas aeruginosa.

The rise in multiple-drug-resistant (MDR) phenotypes in Gram-negative pathogens is a major public health crisis. Pseudomonas aeruginosa is one of the leading causes of nosocomial infections in clinics. Treatment options for P. aeruginosa have become increasingly difficult due tdo its remarkable capacity to resist multiple antibiotics. The presence of intrinsic resistance factors and the ability to quickly adapt to antibiotic monotherapy warrant us to look for alternative strategies like combinatorial antibiotic therapy. Here, we report the frequency of P. aeruginosa multidrug-resistant and extensively drug-resistance (XDR) phenotypes in a super-specialty tertiary care hospital in north India. Approximately 60 percent of all isolated P. aeruginosa strains displayed the MDR phenotype. We found highest antibiotic resistance frequency in the emergency department (EMR), as 20 percent of isolates were resistant to 15 antipseudomonal antibiotics. Presence of plasmids with quinolone-resistance determinants were major drivers for resistance against fluoroquinolone. Additionally, we explored the possible combinatorial therapeutic options with four antipseudomonal antibiotics-colistin, ciprofloxacin, tobramycin, and meropenem. We uncovered an association between different antibiotic interactions. Our data show that the combination of colistin and ciprofloxacin could be an effective combinatorial regimen to treat infections caused by MDR and XDR P. aeruginosa.

Serum ferritin as a predictive biomarker in COVID-19. A systematic review, meta-analysis and meta-regression analysis.

Ferritin is a known inflammatory biomarker in COVID-19. However, many factors and co-morbidities can confound the level of serum ferritin. This current metaanalysis evaluates serum ferritin level in different severity levels in COVID-19. Studies evaluating serum ferritin level in different clinical contexts (COVID-19 vs. control, mild to moderate vs. severe to critical, non-survivor vs. survivor, organ involvement, ICU and mechanical ventilation requirement) were included (total 9 literature databases searched). Metaanalysis and metaregression was carried out using metaphor "R" package. Compared to control (COVID-19 negative), higher ferritin levels were found among the COVID-19 patients [SMD -0.889 (95% C.I. -1.201, -0.577), I2 = 85%]. Severe to critical COVID-19 patients showed higher ferritin levels compared to mild to moderate COVID-19 patients [SMD 0.882 (0.738, 1.026), I2 = 85%]. In meta-regression, high heterogeneity was observed could be attributed to difference in "mean age", and "percentage of population with concomitant co-morbidities". Non-survivors had higher serum ferritin level compared to survivors [SMD 0.992 (0.672, 1.172), I2 = 92.33%]. In meta-regression, high heterogeneity observed could be attributed to difference in "mean age" and "percentage of male sex". Patients requiring ICU [SMD 0.674 (0.515 to 0.833), I2 = 80%] and mechanical ventilation [SMD 0.430 (0.258, 0.602), I2 = 32%] had higher serum ferritin levels compared to those who didn't. To conclude, serum ferritin level may serve as an important biomarker which can aid in COVID-19 management. However, presence of other co-morbid conditions/confounders warrants cautious interpretation.

Pyogenic liver abscess: Clinical features and microbiological profiles in tertiary care center.

BACKGROUND: Pyogenic liver abscess (PLA) is the end result of a number of pathologic processes that cause a suppurative infection of the liver parenchyma. MATERIALS AND METHODS: Sixty-five patients of age more than 18 years and radiologically confirmed cases of liver abscess were included in this study. Pus and blood samples were collected. Pus was processed for microscopy of trophozoite of Entamoeba histolytica and aerobic and anaerobic bacterial culture. Blood was processed for antibody ELISA for Entamoeba histolytica and aerobic bacterial culture. Identification of aerobic and anaerobic isolates was done by Vitek2 and antibiotic sensitivity test for aerobic bacterial isolates was done by Vitek2. RESULT: Out of sixty five, twenty five were confirmed as PLA. All patients were male with mean age 37.9 years. Fever and upper abdominal pain were the most common symptoms. Right lobe comprised 80% of the abscess. Pus sample was more sensitive than blood sample for diagnosis. There were a total of 33 isolates in our study. Klebsiella pneumoniae (6/33) was the most common aerobic isolate and Clostridium spp. (7/33) was the anaerobic isolate. All gram-negative bacteria were showing good sensitivity for 3rd and 4th generation cephalosporins, fluoroquinolones, amikacin, gentamicin, piperacillin-tazobactam, imipenem and meropenem. Abscess >5 cm was treated with percutaneous drainage while abscess <5 cm was treated with antibiotics only. CONCLUSION: Diagnosis should be made with the combination of clinical suspicion, radiology, and microbiology. Empirical therapy should include anaerobic coverage too. Only antibiotic therapy can be given under consideration of size of abscess, persistence of fever after giving antibiotics, and any suspected complications.

Immune Dysfunction and Multiple Treatment Modalities for the SARS-CoV-2 Pandemic: Races of Uncontrolled Running Sweat?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic threat with more than 11.8 million confirmed cases and more than 0.5 million deaths as of 3 July 2020. Given the lack of definitive pharmaceutical interventions against SARS-CoV-2, multiple therapeutic strategies and personal protective applications are being used to reduce the risk of high mortality and community spread of this infection. Currently, more than a hundred vaccines and/or alternative therapeutic regimens are in clinical trials, and some of them have shown promising results in improving the immune cell environment and controlling the infection. In this review, we discussed high-performance multi-directory strategies describing the uncontrolled deregulation of the host immune landscape associated with coronavirus disease (COVID-19) and treatment strategies using an anti-neoplastic regimen. We also followed selected current treatment plans and the most important on-going clinical trials and their respective outcomes for blocking SARS-CoV-2 pathogenesis through regenerative medicine, such as stem cell therapy, chimeric antigen receptors, natural killer (NK) cells, extracellular vesicular-based therapy, and others including immunomodulatory regimens, anti-neoplastic therapy, and current clinical vaccine therapy.

Assessment of polymyxin B-doxycycline in combination against Pseudomonas aeruginosa in vitro and in a mouse model of acute pneumonia.

The increasing prevalence of antibiotic resistance in Pseudomonas aeruginosa has created an urgent need for suitable therapy. This study explored the pairing of doxycycline with other antipseudomonal antibiotics, and found that polymyxin B in combination with doxycycline had a synergistic effect against clinical strains of P. aeruginosa. This synergistic combination was studied by checkerboard assays and time-kill curve analysis. Further, in-vitro biofilm disruption, pyoverdine inhibition assays were performed. The efficacy of polymyxin B-doxycycline in combination, administered by inhalation, was evaluated using a mouse model of acute pneumonia. The combination was found to have a synergistic effect in both in-vitro and in-vivo studies. The combination decreased biofilms of P. aeruginosa and reduced the level of pyoverdine, an important siderophore of P. aeruginosa. In addition, the combination decreased the P. aeruginosa population by 3 log10 (P<0.01) in the mouse model of acute pneumonia, and showed an improvement in lung function by inhalation. To the best of the authors' knowledge, this is the first in-vivo study to evaluate the efficacy of polymyxin B in combination with doxycycline against P. aeruginosa, showing a possible promising option for acute pneumonia due to multi-drug-resistant P. aeruginosa.

Detection of extended-spectrum beta-lactamase (ESBL) production by disc diffusion method among Pseudomonas species from various clinical samples.

AIM/OBJECTIVES: This study was aimed to detect extended-spectrum beta-lactamase (ESBL) producing Pseudomonas species isolated from various clinical samples by phenotypic methods with their susceptibility testing. MATERIALS AND METHODS: Hundred Pseudomonas isolates were taken from various clinical samples of patients attending outpatient department (OPD) and inpatient department (IPD). Antimicrobial susceptibility test and ESBL detection were assessed using CLSI guidelines on Mueller Hinton agar. RESULTS: Out of 100 Pseudomonas isolates, 46 isolates were from female and 54 were from male patients. More cases of pseudomonal infection were in the age group between 46 and 60 years (34%), and 59% of Pseudomonas species were isolated from patients belongs to urban areas and the rest 41% were from rural. The isolates collected from OPD were 61% and rest 39% from IPD. Pseudomonas species showed maximum resistance to cephalosporin group of antibiotics and showed least resistance to imipenem, and showed 100% susceptibility to colistin. ESBL production was detected in 42% of total isolates. CONCLUSION: The present study highlights that the Pseudomonas species remains an important cause of nosocomial infections. ESBL producing Pseudomonas species continue to be an important organism causing life-threatening infections. Multidrug resistance was seen in most of the strains. Resistance is developing even to combination of ceftazidime clavulanic acid. Resistance is developing to last resort of antibiotic, i.e. imipenem also. This gives the alarming signal for the future, making the therapeutic options more difficult. Strict infection control measures are to be taken to contain this so-called water and soil organisms as Pseudomonas.