-
PLoS Neglected Tropical Diseases Mar 2021Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs).
METHODS
For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression.
RESULTS
We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041-0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001-2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368-1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021-0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244-1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020-0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections.
CONCLUSION
Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.
Topics: Amphotericin B; Antimony; Antiprotozoal Agents; Deoxycholic Acid; Drug Combinations; Humans; Leishmaniasis, Visceral; Phosphorylcholine
PubMed: 33780461
DOI: 10.1371/journal.pntd.0009302 -
The Pediatric Infectious Disease Journal May 2013Candida is the third most common cause of late-onset neonatal sepsis in infants born at <1500 g. Candida parapsilosis infections are increasingly reported in preterm... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Candida is the third most common cause of late-onset neonatal sepsis in infants born at <1500 g. Candida parapsilosis infections are increasingly reported in preterm neonates in association with indwelling catheters.
METHODS
We systematically reviewed neonatal literature and synthesized data pertaining to percentage of C. parapsilosis infections and mortality by meta-analyses. We also reviewed risk factors, virulence determinants, antimicrobial susceptibility patterns and outlined clinical management strategies.
RESULTS
C. parapsilosis infections comprised 33.47% (95% confidence interval [CI]: 30.02, 37.31) of all neonatal Candida infections. C. parapsilosis rates were similar in studies performed before the year 2000, 33.53% (95% CI: 30.06, 37.40) (28 studies), to those after 2000, 27.00% (95% CI: 8.25, 88.37) (8 studies). The mortality due to neonatal C. parapsilosis infections was 10.02% (95% CI: 7.66, 13.12). Geographical variations in C. parapsilosis infections included a low incidence in Europe and higher incidence in North America and Australia. Biofilm formation was a significant virulence determinant and predominant risk factors for C. parapsilosis infections were prematurity, prior colonization and catheterization. Amphotericin B remains the antifungal drug of choice and combination therapy with caspofungin or other echinocandins may be considered in resistant cases.
CONCLUSION
C. parapsilosis is a significant neonatal pathogen, comprises a third of all Candida infections and is associated with 10% mortality. Availability of tools for genetic manipulation of this organism will identify virulence determinants and organism characteristics that may explain predilection for preterm neonates. Strategies to prevent horizontal transmission in the neonatal unit are paramount in decreasing infection rates.
Topics: Antifungal Agents; Biofilms; Candida; Candidiasis; Drug Resistance, Fungal; Humans; Infant, Newborn; Infant, Newborn, Diseases; Microbial Sensitivity Tests; Risk Factors; Virulence
PubMed: 23340551
DOI: 10.1097/INF.0b013e3182863a1c -
Journal of Fungi (Basel, Switzerland) Apr 2024Extrapulmonary infections by spp., though rare, can occur via dissemination, affecting singular or multiple sites, including the skin and musculoskeletal system.... (Review)
Review
Extrapulmonary infections by spp., though rare, can occur via dissemination, affecting singular or multiple sites, including the skin and musculoskeletal system. Skeletal involvement often manifests as osteomyelitis, particularly in the axial skeleton. The present systematic review evaluates all documented cases of skeletal coccidioidomycosis to assess the diagnostic and treatment strategies alongside the outcomes, drawing insights from an analysis of 163 verified cases. A systematic review following PRISMA guidelines identified all studies reporting skeletal infections by spp. up to 2023 from the PubMed and Scopus databases. Eligible studies evaluated osteoarticular infections from spp. Data extraction included demographics, microbiological data, diagnostic methods, and treatment outcomes. Of the 501 initially identified records, a total of 163 patients from 69 studies met the inclusion criteria. Most cases were from the USA, predominantly males, while the median age of the population was 36 years. Diabetes mellitus was the common comorbidity (14.7%). was the most prevalent pathogen. The spine and hand were common sites of infection (17.5% and 15.1%, respectively). Osteomyelitis by spp. was diagnosed, in most cases, by positive cultures ( = 68; 41.7%), while, in 49 (30.9%), both the histological examination and cultures yielded the fungus. Surgical debridement was performed in 80.9% of cases. A total of 118 (72.3%) patients were treated with monotherapy, while combination therapy with two or more antifungal agents was reported in 45 (17.7%). Amphotericin B (either liposomal or deoxycholate) was the most commonly given agent as monotherapy in 51 (31.2%) patients, while 30 (18.4%) patients received itraconazole as monotherapy. The rate of infection's resolution was higher in patients undergoing surgical debridement (79.5%), compared to those treated only with antifungal agents (51.6%, = 0.003). Treatment outcomes showed complete resolution in 74.2% of patients, with a mortality rate of 9.2%. Coccidioidal osseous infections present diagnostic and therapeutic challenges. Surgical intervention is often necessary, complementing antifungal therapy. Vigilance for spp. infections, especially in regions with endemicity, is crucial, particularly when bacterial cultures yield negative results.
PubMed: 38667941
DOI: 10.3390/jof10040270 -
International Journal of Infectious... Nov 2014A meta-analysis was performed to compare mold-active triazoles or lipid amphotericin B plus an echinocandin to non-echinocandin monotherapy for acute invasive... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
A meta-analysis was performed to compare mold-active triazoles or lipid amphotericin B plus an echinocandin to non-echinocandin monotherapy for acute invasive aspergillosis (IA).
METHODS
We searched PubMed, EMBASE, and other databases through May 2013 unrestricted by language. We included observational and experimental studies wherein patients with proven or probable IA by EORTC/MSG criteria underwent our comparative intervention. PRISMA and MOOSE guidelines were followed and quality was assessed using the Jadad and Newcastle-Ottawa criteria. Meta-regression with fixed and random effects and sensitivity analyses were performed. The primary study outcome measure was 12-week overall mortality. The secondary outcome assessed was complete and partial response.
RESULTS
Only observational studies of primary 12-week survival showed heterogeneity (I(2)=48.96%, p=0.05). For salvage IA therapy, fixed effects models demonstrated improved 12-week survival (Peto odds ratio (OR) 1.80, 95% confidence interval (CI) 1.08-3.01) and success (Peto OR 2.17, 95% CI 1.21-3.91) of combination therapy. Significance remained after applying random effects as a sensitivity analysis (12-week survival: Peto OR 1.90, 95% CI 1.04-3.46, and unchanged value for success). Restriction to high quality studies and including echinocandins as the comparator for refractory IA revealed an adjusted OR of 1.72 (95% CI 0.96-3.09; p=0.07) for global success, while the survival endpoint remained unaltered.
CONCLUSIONS
Combination antifungals for IA demonstrate improved outcomes over monotherapy in the salvage setting. Clinicians should consider this approach in certain situations.
Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Drug Therapy, Combination; Echinocandins; Female; Humans; Male; Middle Aged; Salvage Therapy; Survival Analysis; Treatment Outcome; Triazoles
PubMed: 25240416
DOI: 10.1016/j.ijid.2014.07.007 -
Clinical Oral Investigations Nov 2022To identify the antifungal susceptibility profile of Candida spp. isolated from the human oral cavity was assessed with meta-analyses of observational studies that... (Meta-Analysis)
Meta-Analysis Review
AIM
To identify the antifungal susceptibility profile of Candida spp. isolated from the human oral cavity was assessed with meta-analyses of observational studies that collected samples from the oral cavity of human subjects.
MATERIAL AND METHODS
Isolated Candida albicans tested by E-test®; disk diffusion test; microdilution and macrodilution; Sensititre YeastOne; and/or FungiTest. Search strategies were conducted on the MEDLINE, Embase, CINAHL, Dentistry, and Oral Sciences, Central, Scopus, and LILACS databases, and gray literature sources. Articles were initially screened by title and then their abstracts. Articles that met the conditions for inclusion were read in full, followed by data extraction. A descriptive analysis was conducted of each study, and the data were tabulated. A first meta-analysis was conducted to assess the resistance of antifungals regardless of systemic comorbidities. An additional stratified analysis was conducted by systemic comorbidity groups for the outcome "resistance" to the antifungals.
RESULTS
When not grouping Candida albicans isolates by systemic conditions, the lowest resistance rates to the antifungals tested were observed for amphotericin B, nystatin, flucytosine, and caspofungin. In contrast, the highest resistance rates were observed for miconazole and econazole. There was a high degree of heterogeneity and low resistance in general in all analyses, except for the "several associated comorbidities" group, which had high resistance rates.
CONCLUSIONS
Clinical C. albicans isolates had low antifungal resistance.
CLINICAL RELEVANCE
The presence of concomitant systemic comorbidities appears to be an essential factor that should be considered when evaluating resistance to antifungals for oral isolates.
Topics: Humans; Antifungal Agents; Candida albicans; Candidiasis; Microbial Sensitivity Tests; Drug Resistance, Fungal; Mouth
PubMed: 36167858
DOI: 10.1007/s00784-022-04716-2 -
Antimicrobial Agents and Chemotherapy Jun 2010To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a... (Meta-Analysis)
Meta-Analysis
To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a systematic review and meta-analysis of randomized controlled trials published before 31 August 2009. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. We used the beta-binomial model to account for variation across studies and the maximum likelihood method to estimate the pooled risks. We identified 39 studies with more than 8,000 enrolled patients for planned comparisons. The incidence rates of treatment discontinuation due to adverse reactions and liver injury associated with antifungal therapy ranged widely. The pooled risks of treatment discontinuation due to adverse reactions were above 10% for amphotericin B formulations and itraconazole, whereas they were 2.5% to 3.8% for fluconazole, caspofungin, and micafungin. We found that 1.5% of the patients stopped itraconazole treatment due to hepatotoxicity. Furthermore, 19.7% of voriconazole users and 17.4% of itraconazole users had elevated serum liver enzyme levels, although they did not require treatment discontinuation, whereas 2.0% or 9.3% of fluconazole and echinocandin users had elevated serum liver enzyme levels but did not require treatment discontinuation. The results were similar when we stratified the data by empirical or definitive antifungal therapy. Possible explanations for antifungal agent-related hepatotoxicity were confounded by antifungal prescription to patients with a high risk of liver injury, the increased chance of detection of hepatotoxicity due to prolonged treatment, or the pharmacological entity.
Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Humans; Liver; Mycoses; Risk Factors
PubMed: 20308378
DOI: 10.1128/AAC.01657-09 -
The Journal of Antimicrobial... Sep 2022Trichoderma spp. are filamentous fungi causing invasive fungal diseases in patients with haematological malignancies and in peritoneal dialysis patients.
BACKGROUND
Trichoderma spp. are filamentous fungi causing invasive fungal diseases in patients with haematological malignancies and in peritoneal dialysis patients.
OBJECTIVES
To analyse clinical presentation, predisposing factors, treatment and outcome of Trichoderma infections.
METHODS
A systematic literature review was conducted for published cases of invasive Trichoderma infection in PubMed until December 2021 and by reviewing the included studies' references. Cases from the FungiScope® registry were added to a combined analysis.
RESULTS
We identified 50 invasive infections due to Trichoderma species, including 11 in the FungiScope® registry. The main underlying conditions were haematological malignancies in 19 and continuous ambulatory peritoneal dialysis (CAPD) in 10 cases. The most prevalent infection sites were lung (42%) and peritoneum (22%). Systemic antifungal therapy was administered in 42 cases (84%), mostly amphotericin B (n = 27, lipid-based formulation 13/27) and voriconazole in 15 cases (30%). Surgical interventions were performed in 13 cases (26%). Overall mortality was 48% (n = 24) and highest for allogeneic HSCT and solid organ transplantation (SOT) recipients [80% (4/5) and 77% (7/9), respectively]. In patients treated with amphotericin B, voriconazole and caspofungin, mortality was 55% (15/27), 46% (7/15) and 28% (2/7), respectively. Three out of four patients treated with a combination therapy of voriconazole and caspofungin survived.
CONCLUSIONS
Despite treatment with antifungal therapies and surgery, invasive Trichoderma infections are life-threatening complications in immunocompromised patients, especially after HSCT and SOT. In addition, Trichoderma spp. mainly affect the lungs in patients with haematological malignancies and the peritoneum in CAPD patients.
Topics: Amphotericin B; Antifungal Agents; Caspofungin; Hematologic Neoplasms; Humans; Registries; Trichoderma; Voriconazole
PubMed: 35929089
DOI: 10.1093/jac/dkac235 -
The Cochrane Database of Systematic... Jul 2018There remains uncertainty about the optimum timing of antiretroviral therapy (ART) initiation in HIV-positive people with cryptococcal meningitis. This uncertainty is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There remains uncertainty about the optimum timing of antiretroviral therapy (ART) initiation in HIV-positive people with cryptococcal meningitis. This uncertainty is the result of conflicting data on the mortality risk and occurrence of immune reconstitution inflammatory syndrome (IRIS) when ART is initiated less than four weeks after cryptococcal meningitis treatment is commenced.
OBJECTIVES
To compare the outcomes of early initiation of ART (less than four weeks after starting antifungal treatment) versus delayed initiation of ART (four weeks or more after starting antifungal treatment) in HIV-positive people with concurrent cryptococcal meningitis.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for trials published between 1 January 1980 and 7 August 2017. We additionally searched international trial registries, including ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP), and conference abstracts from the International AIDS Society (IAS) and the Conference on Retroviruses and Opportunistic Infections (CROI) for ongoing or unpublished studies between 2015 and 2017. We reviewed reference lists of included studies to identify additional studies.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) that compared early versus delayed ART initiation in HIV-positive people with cryptococcal meningitis. Children, adults, and adolescents from any setting were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two review authors independently applied the inclusion criteria and extracted data. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs). We presented time-to-death data as hazard ratios with 95% CIs. We assessed the certainty of the evidence using the GRADE approach.
MAIN RESULTS
Four trials including 294 adult participants met the inclusion criteria of this review. Participants were predominantly from low- and middle-income countries. Two trials treated cryptococcal meningitis with amphotericin B and fluconazole; a third trial used fluconazole monotherapy; and the fourth trial did not specify the antifungal used.Early ART initiation may increase all-cause mortality compared to delayed ART initiation (RR 1.42, 95% CI 1.02 to 1.97; 294 participants, 4 trials; low-certainty evidence). Early ART initiation may reduce relapse of cryptococcal meningitis compared to delayed ART initiation (RR 0.27, 95% CI 0.07 to 1.04; 205 participants, 2 trials, low-certainty evidence). We are uncertain whether early ART initiation increases or reduces cryptococcal IRIS events compared to delayed ART initiation (RR 3.56, 95% CI 0.51 to 25.02; 205 participants, 2 trials; I = 54%; very low-certainty evidence). We are uncertain if early ART initiation increases or reduces virological suppression at six months compared to delayed ART initiation (RR 0.93, 95% CI 0.72 to 1.22; 205 participants, 2 trials; I statistic = 0%; very low-certainty evidence).We were unable to pool results related to rate of fungal clearance for the two trials that reported this outcome; individual trial results indicated that there was no difference in cerebrospinal fluid fungal clearance between trial arms. Similarly, we were unable to pool results on adverse events for the trials reporting on this outcome; individual trial results indicated no difference in the occurrence of grade 3 to 5 adverse events between trial arms.Three of the four included trials had an overall low or unclear risk of bias related to the primary outcome of all-cause mortality. However, we assessed one trial as at high risk of bias due to selective outcome reporting and other bias. This, in addition to the few clinical events and imprecision of effect estimates, led to downgrading of the evidence to low or very low certainty.
AUTHORS' CONCLUSIONS
The results of this review are relevant to HIV-positive adults with cryptococcal meningitis in low- and middle-income countries. These data suggest a higher risk of mortality among people who initiate ART within four weeks of cryptococcal meningitis diagnosis. However, it is unclear if this higher mortality risk is related to cryptococcal meningitis-IRIS.
Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Anti-HIV Agents; Antifungal Agents; Cause of Death; Drug Administration Schedule; Fluconazole; HIV Infections; Humans; Meningitis, Cryptococcal; Randomized Controlled Trials as Topic
PubMed: 30039850
DOI: 10.1002/14651858.CD009012.pub3 -
Journal of the International AIDS... Jan 2020HIV-associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub-Saharan Africa (SSA). We performed a systematic review and... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
HIV-associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub-Saharan Africa (SSA). We performed a systematic review and meta-analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings.
METHODS
We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized-controlled trials (RCTs) or investigator-managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short-term (in-hospital or two weeks), medium-term (up to 10 weeks) and long-term (up to six months).
RESULTS AND DISCUSSION
Seventy-nine studies met inclusion criteria. In routine care settings, pooled short-term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole-based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short-term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short-term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized-controlled trials. Few studies evaluated long-term outcomes.
CONCLUSIONS
Mortality rates from HIV-associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV-associated meningitis in the region.
Topics: Adult; Africa South of the Sahara; Aged; Amphotericin B; Antifungal Agents; Female; Fluconazole; HIV Infections; Humans; Male; Meningitis, Cryptococcal; Middle Aged; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 31957332
DOI: 10.1002/jia2.25416 -
Isolated Colonic Histoplasmosis in Patients Undergoing Immunomodulator Therapy: A Systematic Review.Journal of Investigative Medicine High... 2023Gastrointestinal histoplasmosis remains an inconspicuous clinicopathologic entity. It is predominantly considered a protean manifestation of disseminated disease. We... (Review)
Review
Gastrointestinal histoplasmosis remains an inconspicuous clinicopathologic entity. It is predominantly considered a protean manifestation of disseminated disease. We hereby delineate a unique case of biopsy-proven isolated colonic histoplasmosis in a patient undergoing methotrexate therapy. Furthermore, we present the first systematic review of the MEDLINE, Google Scholar, Embase, and Scopus databases regarding isolated colonic histoplasmosis in adult patients receiving immunomodulator therapy (IMT). A total of 13 case reports (level of clinical evidence: IV) were identified. The mean age was 55.6 ± 11.1 years, with 9 (69.2%) cases reported in women. Patients with subclinical disease (5, 38.5%) were often incidentally diagnosed by screening colonoscopy. Symptomatic individuals predominantly presented with diarrhea (4, 30.8%), weight loss (3, 23.1%), and/or abdominal pain (3, 23.1%). IMT was mainly administered for liver transplant (4, 30.8%), renal transplant (4, 30.8%), and ulcerative colitis (2, 15.4%). Common colonoscopy features included colonic ulcerations (7, 53.8%), polyps or pseudopolyps (3, 23.1%), and/or mass-like lesions (3, 23.1%). Diagnosis was made by histology of colonic biopsy in 11 (84.6%) and resected specimens in 2 (15.4%) patients. Treatment consisted of a combination of amphotericin B with oral itraconazole in 6 (46.2%), oral itraconazole alone in 5 (38.5%), and amphotericin B alone in 2 (15.4%) patients. Complete clinical recovery was achieved in all patients. This article illustrates that isolated colonic involvement can be the only clinical presentation of histoplasmosis. It may masquerade as other bowel disorders, presenting diagnostic and therapeutic conundrums. Gastroenterologists should rule out colonic histoplasmosis in IMT recipients who develop unexplained colitis symptoms.
Topics: Adult; Humans; Female; Middle Aged; Aged; Histoplasmosis; Itraconazole; Amphotericin B; Colon; Immunologic Factors
PubMed: 37293945
DOI: 10.1177/23247096231179448