-
Microbiology Spectrum Jul 2024and are both known urease producers and have the potential to cause hyperammonemia. We hypothesized that the risk of hyperammonemia is increased by renal failure,...
and are both known urease producers and have the potential to cause hyperammonemia. We hypothesized that the risk of hyperammonemia is increased by renal failure, burden of cryptococcal infection, and fungal strain characteristics. We performed a retrospective review of plasma ammonia levels in patients with cryptococcal infections. Risk factors for hyperammonemia were statistically compared between patients with and without hyperammonemia (>53 µmol/L). Cryptococcal cells from three patients included in the study were recovered from our biorepository. Strain characteristics including urease activity, ammonia production, growth curves, microscopy, melanin production, and M13 molecular typing were analyzed and compared with a wild-type (WT) strain. We included 29 patients, of whom 37.9% had hyperammonemia, 59% had disseminated cryptococcal infection (DCI), and 41% had isolated central nervous system infection. Thirty-eight percent of patients had renal failure and 28% had liver disease. Renal failure was associated with 4.4 times (95% confidence interval [CI] 1.5, 13.0) higher risk of hyperammonemia. This risk was higher in DCIs (RR 6.2, 95% CI 1.0, 40.2) versus isolated cryptococcal meningitis (RR 2.5, 95% CI, 0.40, 16.0). Liver disease and cryptococcal titers were not associated with hyperammonemia. from one patient with extreme hyperammonemia demonstrated a 4- to 5-fold increase in extracellular urease activity, slow growth, enlarged cell size phenotypes, and diminished virulence factors. Hyperammonemia was strongly associated with renal failure in individuals with DCI, surpassing associations with liver failure or cryptococcal titers. However, profound hyperammonemia in one patient was attributable to high levels of urease secretion unique to that cryptococcal strain. Prospective studies are crucial to exploring the significance of this association.IMPORTANCE produces and secretes the urease enzyme to facilitate its colonization of the host. Urease breaks down urea into ammonia, overwhelming the liver's detoxification process and leading to hyperammonemia in some hosts. This underrecognized complication exacerbates organ dysfunction alongside the infection. Our study investigated this intricate relationship, uncovering a strong association between the development of hyperammonemia and renal failure in patients with cryptococcal infections, particularly those with disseminated infections. We also explore mechanisms underlying increased urease activity, specifically in strains associated with extreme hyperammonemia. Our discoveries provide a foundation for advancing research into cryptococcal metabolism and identifying therapeutic targets to enhance patient outcomes.
Topics: Humans; Cryptococcosis; Hyperammonemia; Cryptococcus neoformans; Female; Retrospective Studies; Male; Cryptococcus gattii; Middle Aged; Urease; Adult; Aged; Ammonia; Risk Factors; Renal Insufficiency; Aged, 80 and over
PubMed: 38842310
DOI: 10.1128/spectrum.03902-23 -
Frontiers in Cellular and Infection... 2024Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for and a promising therapeutic target. This study reveals previously unknown roles of TPS1...
Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for and a promising therapeutic target. This study reveals previously unknown roles of TPS1 in evasion of host defenses during pulmonary and disseminated phases of infection. In the pulmonary infection model, TPS1-deleted () are rapidly cleared by mouse lungs whereas TPS1-sufficent WT (H99) and revertant (:) strains expand in the lungs and disseminate, causing 100% mortality. Rapid pulmonary clearance of mutant is T-cell independent and relies on its susceptibility to lung resident factors and innate immune factors, exemplified by but not H99 inhibition in a coculture with dispersed lung cells and its rapid clearance coinciding with innate leukocyte infiltration. In the disseminated model of infection, which bypasses initial lung-fungus interactions, strain remains highly attenuated. Specifically, mutant is unable to colonize the lungs from the bloodstream or expand in spleens but is capable of crossing into the brain, where it remains controlled even in the absence of T cells. In contrast, strains H99 and rapidly expand in all studied organs, leading to rapid death of the infected mice. Since the rapid pulmonary clearance of mutant resembles a response to acapsular strains, the effect of deletion on capsule formation and was examined. cryptococci form capsules but with a substantially reduced size. In conclusion, TPS1 is an important virulence factor, allowing evasion of resident pulmonary and innate defense mechanisms, most likely its role in cryptococcal capsule formation.
Topics: Animals; Cryptococcus neoformans; Cryptococcosis; Mice; Glucosyltransferases; Lung; Virulence; Virulence Factors; Disease Models, Animal; Host-Pathogen Interactions; Brain; Spleen; Female; Mice, Inbred C57BL; Immunity, Innate; Immune Evasion; Gene Deletion
PubMed: 38841113
DOI: 10.3389/fcimb.2024.1392015 -
Southern African Journal of HIV Medicine 2024The high burden of cryptococcal meningitis (CM) among people living with HIV persists despite widespread access to antiretroviral therapy. Efforts to prevent CM among...
BACKGROUND
The high burden of cryptococcal meningitis (CM) among people living with HIV persists despite widespread access to antiretroviral therapy. Efforts to prevent CM among people living with HIV could be hindered by a limited understanding of their lived experiences of CM and its diagnosis.
OBJECTIVES
To explore and describe the experiences of people diagnosed with HIV-associated CM in routine care. Two public healthcare facilities in Johannesburg, South Africa.
METHOD
This was a qualitative-methods exploratory, descriptive, phenomenological study. We conducted semi-structured, individual in-depth interviews with nine purposively sampled participants (comprising 5 men and 4 women). Data were analysed using the Moustakas phenomenological approach.
RESULTS
Five themes and several sub-themes emerged from the data. Participants described their experiences of being diagnosed, which were marked by intense headaches. Diagnosis of CM led to reduced quality of life, fear of death, and loss of income. Participants described their CM treatment experience and health-seeking behaviour including self-medication, seeking help from traditional healers and general practitioners and utilising public health facilities as a last resort. Barriers to care included negative healthcare workers' attitudes, unhealthy lifestyles, and poor knowledge of CM.
CONCLUSION
People with HIV-associated CM face negative impacts prior to and after diagnosis. These patients struggled to access timely quality healthcare. Patients starting or restarting antiretroviral therapy, and thus at risk for CM, should receive CM education as part of HIV counselling.
PubMed: 38840713
DOI: 10.4102/sajhivmed.v25i1.1560 -
BMC Infectious Diseases Jun 2024Treatment of carbapenem-resistant Enterobacterales (CRE) infections in low-resource settings is challenging particularly due to limited treatment options. Colistin is...
The impact of colistin-based regimens on mortality compared to other antimicrobials in patients with carbapenem-resistant Enterobacterales bacteremia in South African hospitals: a cross-sectional study.
BACKGROUND
Treatment of carbapenem-resistant Enterobacterales (CRE) infections in low-resource settings is challenging particularly due to limited treatment options. Colistin is the mainstay drug for treatment; however, nephrotoxicity and neurotoxicity make this drug less desirable. Thus, mortality may be higher among patients treated with alternative antimicrobials that are potentially less efficacious than colistin. We assessed mortality in patients with CRE bacteremia treated with colistin-based therapy compared to colistin-sparing therapy.
METHODS
We conducted a cross-sectional study using secondary data from a South African national laboratory-based CRE bacteremia surveillance system from January 2015 to December 2020. Patients hospitalized at surveillance sentinel sites with CRE isolated from blood cultures were included. Multivariable logistic regression modeling, with multiple imputations to account for missing data, was conducted to determine the association between in-hospital mortality and colistin-based therapy versus colistin-sparing therapy.
RESULTS
We included 1 607 case-patients with a median age of 29 years (interquartile range [IQR], 0-52 years) and 53% (857/1 607) male. Klebsiella pneumoniae caused most of the infections (82%, n=1 247), and the most common carbapenemase genes detected were bla (61%, n=551), and bla (37%, n=333). The overall in-hospital mortality was 31% (504/1 607). Patients treated with colistin-based combination therapy had a lower case fatality ratio (29% [152/521]) compared to those treated with colistin-sparing therapy 32% [352/1 086]) (p=0.18). In our imputed model, compared to colistin-sparing therapy, colistin-based therapy was associated with similar odds of mortality (adjusted odds ratio [aOR] 1.02; 95% confidence interval [CI] 0.78-1.33, p=0.873).
CONCLUSION
In our resource-limited setting, the mortality risk in patients treated with colistin-based therapy was comparable to that of patients treated with colistin-sparing therapy. Given the challenges with colistin treatment and the increasing resistance to alternative agents, further investigations into the benefit of newer antimicrobials for managing CRE infections are needed.
Topics: Humans; Colistin; Cross-Sectional Studies; Male; South Africa; Female; Middle Aged; Adult; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Bacteremia; Young Adult; Adolescent; Enterobacteriaceae Infections; Child, Preschool; Infant; Child; Infant, Newborn; Hospital Mortality; Carbapenems; Hospitals
PubMed: 38840122
DOI: 10.1186/s12879-024-09459-x -
MSphere Jun 2024Superficial infections of the skin, hair, and nails by fungal dermatophytes are the most prevalent of human mycoses, and many infections are refractory to treatment. As...
UNLABELLED
Superficial infections of the skin, hair, and nails by fungal dermatophytes are the most prevalent of human mycoses, and many infections are refractory to treatment. As current treatment options are limited, recent research has explored drug synergy with azoles for dermatophytoses. Bisphosphonates, which are approved to treat osteoporosis, can synergistically enhance the activity of azoles in diverse yeast pathogens but their activity has not been explored in dermatophytes or other molds. Market bisphosphonates risedronate, alendronate, and zoledronate (ZOL) were evaluated for antifungal efficacy and synergy with three azole antifungals: fluconazole (FLC), itraconazole (ITR), and ketoconazole (KET). ZOL was the most active bisphosphonate tested, displaying moderate activity against nine dermatophyte species (MIC range 64-256 µg/mL), and was synergistic with KET in eight of these species. ZOL was also able to synergistically improve the anti-biofilm activity of KET and combining KET and ZOL prevented the development of antifungal resistance. Rescue assays in revealed that the inhibitory effects of ZOL alone and in combination with KET were due to the inhibition of squalene synthesis. Fluorescence microscopy using membrane- and ROS-sensitive probes demonstrated that ZOL and KET:ZOL compromised membrane structure and induced oxidative stress. Antifungal activity and synergy between bisphosphonates and azoles were also observed in other clinically relevant molds, including species of and . These findings indicate that repurposing bisphosphonates as antifungals is a promising strategy for revitalising certain azoles as topical antifungals, and that this combination could be fast-tracked for investigation in clinical trials.
IMPORTANCE
Fungal infections of the skin, hair, and nails, generally grouped together as "tineas" are the most prevalent infectious diseases globally. These infections, caused by fungal species known as dermatophytes, are generally superficial, but can in some cases become aggressive. They are also notoriously difficult to resolve, with few effective treatments and rising levels of drug resistance. Here, we report a potential new treatment that combines azole antifungals with bisphosphonates. Bisphosphonates are approved for the treatment of low bone density diseases, and in fungi they inhibit the biosynthesis of the cell membrane, which is also the target of azoles. Combinations were synergistic across the dermatophyte species and prevented the development of resistance. We extended the study to molds that cause invasive disease, finding synergy in some problematic species. We suggest bisphosphonates could be repurposed as synergents for tinea treatment, and that this combination could be fast-tracked for use in clinical therapy.
Topics: Antifungal Agents; Drug Synergism; Arthrodermataceae; Microbial Sensitivity Tests; Humans; Diphosphonates; Azoles; Biofilms; Drug Resistance, Fungal; Fungi
PubMed: 38837382
DOI: 10.1128/msphere.00248-24 -
Frontiers in Cellular and Infection... 2024
Topics: Mucormycosis; Mucorales; Humans; Antifungal Agents; Animals
PubMed: 38836052
DOI: 10.3389/fcimb.2024.1427252 -
BMC Infectious Diseases Jun 2024Kidney transplant recipients (KTRs) are at an elevated risk of progressing to severe infections upon contracting COVID-19. We conducted a study on risk factors and...
BACKGROUND
Kidney transplant recipients (KTRs) are at an elevated risk of progressing to severe infections upon contracting COVID-19. We conducted a study on risk factors and multi-pathogen infections in KTRs with SARS-CoV-2 Omicron variant.
METHODS
KTRs were subjected to a thorough etiological evaluation. Whenever feasible, they were also provided with bronchoscopy and bronchoalveolar lavage to enable metagenomic next-generation sequencing (mNGS), ideally within a 48-hour window post-admission. We performed a retrospective analysis for pathogens and risk factors of KTRs with the COVID-19 virus variant Omicron.
RESULTS
We included thirty patients in our study, with sixteen exhibiting single infection of COVID-19 and fourteen experiencing co-infections, predominantly with Pneumocystis jirovecii. Notably, patients with severe cases demonstrated significantly elevated levels of C-reactive protein (CRP) and interleukin-6 compared to those with moderate cases (P < 0.05). Furthermore, individuals whose conditions progressed had markedly higher baseline serum creatinine levels than those without such progression (P < 0.05). The presence of heart failure, acute exacerbation of renal dysfunction, and a history of opportunistic infections were significantly associated with a higher likelihood of deterioration and hospital admission due to the SARS-CoV-2 Omicron variant, as compared to the control group (P < 0.05). In subsequent follow-up analysis, the all-cause rehospitalization rate was observed to be 21.4%, with Pneumocystis jirovecii infection accounting for half of these cases.
CONCLUSION
Among KTRs, a significant coinfection rate of 47% was observed, with Pneumocystis jirovecii emerging as the predominant pathogen in these cases. The development of heart failure, acute exacerbation of chronic renal dysfunction, and a prior history of opportunistic infections have been identified as potential risk factors that may contribute to clinical deterioration in KTRs. Additionally, Pneumocystis jirovecii infection has been established as a critical factor influencing the rate of all-cause rehospitalization within this patient population.
Topics: Humans; Kidney Transplantation; COVID-19; Male; Female; Retrospective Studies; Middle Aged; SARS-CoV-2; Risk Factors; Transplant Recipients; Adult; Coinfection; Aged; Pneumocystis carinii; Pneumonia, Pneumocystis
PubMed: 38834974
DOI: 10.1186/s12879-024-09444-4 -
Microbiology Spectrum Jul 2024Coccidioidomycosis, also known as Valley fever, is a disease caused by the fungal pathogen . Unfortunately, patients are often misdiagnosed with bacterial pneumonia,...
UNLABELLED
Coccidioidomycosis, also known as Valley fever, is a disease caused by the fungal pathogen . Unfortunately, patients are often misdiagnosed with bacterial pneumonia, leading to inappropriate antibiotic treatment. The soil -like species exhibits antagonistic properties against ; however, the antagonistic capabilities of host microbiota against are unexplored. We sought to examine the potential of the tracheal and intestinal microbiomes to inhibit the growth of . We hypothesized that an uninterrupted lawn of microbiota obtained from antibiotic-free mice would inhibit the growth of while partial depletion through antibiotic disk diffusion assays would allow a niche for fungal growth. We observed that the microbiota grown on 2×GYE (GYE) and Columbia colistin and nalidixic acid with 5% sheep's blood agar inhibited the growth of , but microbiota grown on chocolate agar did not. Partial depletion of the microbiota through antibiotic disk diffusion revealed diminished inhibition and comparable growth of to controls. To characterize the bacteria grown and identify potential candidates contributing to the inhibition of , 16S rRNA sequencing was performed on tracheal and intestinal agar cultures and murine lung extracts. We found that the host bacteria likely responsible for this inhibition primarily included and . The results of this study demonstrate the potential of the host microbiota to inhibit the growth of and suggest that an altered microbiome through antibiotic treatment could negatively impact effective fungal clearance and allow a niche for fungal growth .
IMPORTANCE
Coccidioidomycosis is caused by a fungal pathogen that invades the host lungs, causing respiratory distress. In 2019, 20,003 cases of Valley fever were reported to the CDC. However, this number likely vastly underrepresents the true number of Valley fever cases, as many go undetected due to poor testing strategies and a lack of diagnostic models. Valley fever is also often misdiagnosed as bacterial pneumonia, resulting in 60%-80% of patients being treated with antibiotics prior to an accurate diagnosis. Misdiagnosis contributes to a growing problem of antibiotic resistance and antibiotic-induced microbiome dysbiosis; the implications for disease outcomes are currently unknown. About 5%-10% of symptomatic Valley fever patients develop chronic pulmonary disease. Valley fever causes a significant financial burden and a reduced quality of life. Little is known regarding what factors contribute to the development of chronic infections and treatments for the disease are limited.
Topics: Animals; Coccidioides; Mice; Gastrointestinal Microbiome; Trachea; Coccidioidomycosis; Microbiota; Bacteria; Female; Anti-Bacterial Agents; RNA, Ribosomal, 16S
PubMed: 38832766
DOI: 10.1128/spectrum.02978-23 -
Scientific Reports Jun 2024Dermatophytes show a wide geographic distribution and are the main causative agents of skin fungal infections in many regions of the world. Recently, their resistance to...
Dermatophytes show a wide geographic distribution and are the main causative agents of skin fungal infections in many regions of the world. Recently, their resistance to antifungal drugs has led to an obstacle to effective treatment. To address the lack of dermatophytosis data in Iraq, this study was designed to investigate the distribution and prevalence of dermatophytes in the human population and single point mutations in squalene epoxidase gene (SQLE) of terbinafine resistant isolates. The identification of 102 dermatophytes isolated from clinical human dermatophytosis was performed through morphological and microscopic characteristics followed by molecular analysis based on ITS and TEF-1α sequencing. Phylogeny was achieved through RAxML analysis. CLSI M38-A2 protocol was used to assess antifungal susceptibility of the isolates to four major antifungal drugs. Additionally, the presence of point mutations in SQLE gene, which are responsible for terbinafine resistance was investigated. Tinea corporis was the most prevalent clinical manifestation accounting for 37.24% of examined cases of dermatophytosis. Based on ITS, T. indotineae (50.98%), T. mentagrophytes (19.61%), and M. canis (29.41%) was identified as an etiologic species. T. indotineae and T. mentagrophytes strains were identified as T. interdigitale based on TEF-1α. Terbinafine showed the highest efficacy among the tested antifungal drugs. T. indotineae and T. mentagrophytes showed the highest resistance to antifungal drugs with MICs of 2-4 and 4 μg/mL, while M. canis was the most susceptible species. Three of T. indotineae isolates showed mutations in SQLE gene PheLeu substitution. A non-previously described point mutation, PheLeu was identified in T. indotineae and mutations LysAsn, PheLeu and LeuPhe were diagnosed in T. mentagrophytes XVII. The results of mutation analysis showed that PheLeu was a destabilizing mutation; protein stability has decreased with variations in pH, and point mutations affected the interatomic interaction, resulting in bond disruption. These results could help to control the progression of disease effectively and make decisions regarding the selection of appropriate drugs for dermatophyte infections.
Topics: Humans; Antifungal Agents; Iraq; Point Mutation; Tinea; Drug Resistance, Fungal; Microbial Sensitivity Tests; Male; Arthrodermataceae; Female; Squalene Monooxygenase; Adult; Phylogeny; Terbinafine; Middle Aged; Adolescent; Young Adult; Child; Fungal Proteins; Aged
PubMed: 38830918
DOI: 10.1038/s41598-024-63425-w -
CMAJ : Canadian Medical Association... Jun 2024
Topics: Humans; Male; Alopecia; Child; Tinea; Scalp; Antifungal Agents; Scalp Dermatoses
PubMed: 38830674
DOI: 10.1503/cmaj.231613-f