Assessment of the Role of 1,3-ß-d-Glucan Testing for the Diagnosis of Invasive Fungal Infections in Adults.

Detection of 1,3-ß-d-glucan (BDG) in serum has been evaluated for its inclusion as a mycological criterion of invasive fungal infections (IFI) according to EORTC and Mycoses Study Group (MSG) definitions. BDG testing may be useful for the diagnosis of both invasive aspergillosis and invasive candidiasis, when interpreted in conjunction with other clinical/radiological signs and microbiological markers of IFI. However, its performance and utility vary according to patient population (hematologic cancer patients, solid-organ transplant recipients, intensive care unit patients) and pretest likelihood of IFI. The objectives of this article are to provide a systematic review of the performance of BDG testing and to assess recommendations for its use and interpretation in different clinical settings.

The impact of anti-mould prophylaxis on Aspergillus PCR blood testing for the diagnosis of invasive aspergillosis.

BACKGROUND: The performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined. OBJECTIVES: To determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA). METHODS: As part of the systematic review and meta-analysis of 22 cohort studies investigating Aspergillus PCR blood testing in 2912 patients at risk of IA, subgroup analysis was performed to determine the impact of AMP on the accuracy of Aspergillus PCR. The incidence of IA was calculated in patients receiving and not receiving AMP. The impact of two different positivity thresholds (requiring either a single PCR positive test result or ≥2 consecutive PCR positive test results) on accuracy was evaluated. Meta-analytical pooling of sensitivity and specificity was performed by logistic mixed-model regression. RESULTS: In total, 1661 (57%) patients received prophylaxis. The incidence of IA was 14.2%, significantly lower in the prophylaxis group (11%-12%) compared with the non-prophylaxis group (18%-19%) (P < 0.001). The use of AMP did not affect sensitivity, but significantly decreased specificity [single PCR positive result threshold: 26% reduction (P = 0.005); ≥2 consecutive PCR positive results threshold: 12% reduction (P = 0.019)]. CONCLUSIONS: Contrary to its influence on GM-EIA, AMP significantly decreases Aspergillus PCR specificity, without affecting sensitivity, possibly as a consequence of AMP limiting the clinical progression of IA and/or leading to false-negative GM-EIA results, preventing the classification of probable IA using the EORTC/MSGERC definitions.

Interlaboratory evaluation of Mucorales PCR assays for testing serum specimens: A study by the fungal PCR Initiative and the Modimucor study group.

Interlaboratory evaluations of Mucorales qPCR assays were developed to assess the reproducibility and performance of methods currently used. The participants comprised 12 laboratories from French university hospitals (nine of them participating in the Modimucor study) and 11 laboratories participating in the Fungal PCR Initiative. For panel 1, three sera were each spiked with DNA from three different species (Rhizomucor pusillus, Lichtheimia corymbifera, Rhizopus oryzae). For panel 2, six sera with three concentrations of R. pusillus and L. corymbifera (1, 10, and 100 genomes/ml) were prepared. Each panel included a blind negative-control serum. A form was distributed with each panel to collect results and required technical information, including DNA extraction method, sample volume used, DNA elution volume, qPCR method, qPCR template input volume, qPCR total reaction volume, qPCR platform, and qPCR reagents used. For panel 1, assessing 18 different protocols, qualitative results (positive or negative) were correct in 97% of cases (70/72). A very low interlaboratory variability in Cq values (SD = 1.89 cycles) were observed. For panel 2 assessing 26 different protocols, the detection rates were high (77-100%) for 5/6 of spiked serum. There was a significant association between the qPCR platform and performance. However, certain technical steps and optimal combinations of factors may also impact performance. The good reproducibility and performance demonstrated in this study support the use of Mucorales qPCR as part of the diagnostic strategy for mucormycosis.

Mortality from COVID-19.

Abstract: The differences of the epidemiology (incidence, case-to-death rate, mortality, etc) of COVID-19 between USA and Italy are analyzed taking into account the social, economic and sanitary characteristics of the two countries, both severely hit be the pandemic; and the causes of the so many different behaviors of the disease in each of them are discussed and explained.

HIV coreceptor tropism in paired plasma, peripheral blood mononuclear cell, and cerebrospinal fluid isolates from antiretroviral-naïve subjects.

A survey of HIV coreceptor usage in cerebrospinal fluid (CSF) samples, peripheral blood mononuclear cells (PBMCs), and plasma samples from naïve seropositive patients was conducted. One hundred patients were enrolled in this study. Of the 100 patients, 36 had a primary or recent infection (P-RI), 31 had an early chronic infection (>350 CD4 cells) (ECI), and 33 had a late chronic infection (LCI). All 3 compartments were sampled in a subset of 33 participants, while the remaining 67 patients provided plasma samples and PBMCs only. Seventy-seven patients harbored the R5 virus in plasma samples and had a significantly higher median and percentage of CD4(+) T cells than patients with X4 virus (437 and 281 cells/µl, respectively; P = 0.0086; 20.6% and 18.6%, respectively). The X4 strain was detected more frequently in patients with LCI than in patients with P-RI or ECI (39.3%, 19.4%, and 9.6%, respectively; P = 0.0063). PBMC and plasma tropism was concordant in 90 patients, and 73 had the R5 strain. Among patients with discordant results, 4 had the R5 virus in their plasma and the X4 virus in PBMCs; 6 showed the opposite profile. Plasma, PBMC, and CSF tropism determinations were concordant in 26/33 patients (21 patients had R5, and 5 had X4). The tropism was discordant in 5/33 patients, with the X4 virus in plasma and R5 in CSF; the HIV tropism in PBMCs was X4 in 3 patients. The remaining 2/33 patients had the R5 virus in plasma and PBMCs and the X4 virus in CSF; one of these patients had a P-RI. The discordant tropism in CSF and blood may have implications for chemokine (C-C motif) receptor 5 (CCR5) antagonist use in patients with limited response to antiretroviral therapy (ART) or in responding patients evaluated for simplification of treatment.

Immune tolerance with rituximab in congenital haemophilia with inhibitors: a systematic literature review based on individual patients' analysis.

Rituximab, a monoclonal antibody against the pan B-cell antigen CD20, has been successfully used in both adults and children for the management of malignant and non-malignant immune-mediated disorders including acquired haemophilia. On the basis of this positive experience, a number of investigators have recently used this agent in patients with congenital haemophilia and inhibitors refractory to first-line treatments. After a careful electronic and hand search, we have collected 29 studies that included 49 cases. A durable complete remission was obtained in 53% of the cases and no severe adverse events related to rituximab were recorded. A multivariate analysis applied to individual patients' data identified the diagnosis of a mild/moderate haemophilia and the concomitant treatment with factor VIII concentrates and immunosuppression agents as covariates associated with an increased response to rituximab. Large prospective randomized studies with an adequate follow-up are needed to confirm these preliminary findings.

Strong and persistent correlation between baseline and follow-up HIV-DNA levels and residual viremia in a population of naïve patients with more than 4 years of effective antiretroviral therapy.

In a longitudinal study on 181 naïve patients who responded to therapy (mean follow-up 4 years), high baseline human immunodeficiency virus (HIV)-RNA values correlated with high levels of cellular HIV-DNA at all time points (p < 0.0001, p 0.045, p 0.0055, and p 0.0025, respectively) and negatively correlated with undetectable residual viremia (URV; <2.5 copies/mL) at T1, T2, and T3 (p 0.026, p 0.0149, and p 0.0002, respectively). Baseline high HIV-DNA levels predicted the persistence of high values (p 0.0001) and negatively correlated with URV (p 0.0254, p 0.0481, and p 0.0085). These results suggest that baseline viral load, cellular HIV-DNA, and URV were strongly correlated over long-term follow-up of antiretroviral therapy responders.

The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring.

OBJECTIVES: To assess whether the neurological or gastrointestinal adverse effects of ritonavir correlate with parameters of ritonavir systemic exposure. METHODS: Peak (Cmax) and trough (Cmin) ritonavir plasma levels were compared in 11 patients experiencing side-effects (group A) versus 10 patients without side-effects (group B). Ritonavir was administered with the following escalation dosing scheme: 300, 400, 500 mg twice a day for 3, 4, and 5 days, respectively, then the full dose of 600 mg twice a day. Blood sampling was done in group A within 24 h of the occurrence of side-effects and in group B after at least 3 days of the full dosage regimen. RESULTS: Both Cmax and Cmax were significantly higher (Mann-Whitney U test) in patients with side-effects. Cmax was [median (interquartile range)] 26.7 (22.7-33.3) mg/l versus 16.2 (13.4-17.0) mg/l (P = 0.001) and Cmin was 12.6 (9.1-13.9) versus 7.5 (4.9-8.6) mg/l (P = 0.002). CONCLUSION: Patients with higher ritonavir concentrations are at a higher risk of experiencing neurological or gastrointestinal side-effects. Individualization of the dosage regimen, e.g. a downward titration of the ritonavir dose in patients with side-effects, guided by plasma level monitoring, may result in a substantial increase in the percentage of patients tolerating ritonavir without increasing the risk of treatment failure as a result of suboptimal systemic exposure.

The impact of human immunodeficiency virus type 1 on infectiousness of tuberculosis: a meta-analysis.

To assess if the relative infectiousness of patients with tuberculosis is enhanced by coinfection with human immunodeficiency virus type 1 (HIV-1), data from 6 studies of 1240 health care workers who had contact with tuberculosis patients were analyzed. Overall rates of tuberculin skin test conversion were similar regardless of HIV-1 positivity of tuberculosis patients (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.23-1.84). However, when only 3 studies during nosocomial outbreaks of multidrug-resistant Mycobacterium tuberculosis were analyzed, rates of skin test conversion were higher among contacts of HIV-1-positive index cases (OR, 2.85; 95% CI, 1.85-3.85; P=.0002). A second meta-analysis included data from 11 studies of 10,714 household contacts of tuberculosis patients. Prevalence of both skin test positivity (OR, 0.45; 95% CI, 0.20-1.03) and active disease (OR, 1.17; 95% CI, 0.78-1.56) were similar regardless of HIV-1 positivity of index cases. These data suggest that tuberculosis patients with HIV-1 infection are not intrinsically more infectious to their contacts than are HIV-1-negative tuberculosis patients.

Pharmacokinetics and pharmacodynamics of nelfinavir administered twice or thrice daily to human immunodeficiency virus type 1-infected children.

We studied the pharmacokinetics and pharmacodynamics of nelfinavir administered 2 or 3 times per day to human immunodeficiency virus type 1 (HIV-1)-infected children receiving highly active antiretroviral therapy containing nelfinavir. The geometric mean trough concentrations of nelfinavir for the thrice- and twice-daily regimens were 1.55 mg/L and 1.11 mg/L, respectively (P=not significant). Nelfinavir concentrations did not correlate with total daily dose, dose per kilogram of weight, age, weight, previous protease inhibitor (PI) experience, or CD4(+) cell percentage. In the 25 PI-naive children, the virus load reductions at 24 weeks of treatment with the twice- and thrice-daily regimens were comparable. A significantly higher percentage of children in the twice-daily group had a trough concentration of nelfinavir of less than the inhibitory concentration of 95% (P=.042). The decrease in the virus load at 24 weeks of treatment was not correlated with the trough concentration of nelfinavir. The variability of trough concentrations was extremely high, particularly among recipients of the twice-daily regimen, resulting in a higher number of patients with subinhibitory concentrations of nelfinavir in this group.

T cell blastogenic responses to Toxoplasma gondii trophozoites among HIV-infected patients.

OBJECTIVE: To evaluate the cell-mediated immune response to Toxoplasma gondii (T. gondii) among HIV-infected patients. METHODS: Forty HIV-infected patients were studied. Of them, 35 had antibodies to T. gondii and 5 had not. Nine of 35 patients with detectable serum Toxoplasma antibodies were classified as group A1 (CDC 1993), 10 as group B2, 6 as group B3, and 10 as group C3. Peripheral blood mononuclear cells (PBMCs) were obtained by Ficoll-Hypaque gradient centrifugation. Living Toxoplasma gondii trophozoites, herpes simplex virus (HSV), tetanus toxoid, and phytohemoagglutinin (PHA) were used in standard proliferation assays. Toxoplasma-responding blasts were expanded and assayed for antigen specificity and HLA restriction by proliferation assays. T cell subsets were analyzed using two-color flow cytometry. RESULTS: Among patients with detectable Toxoplasma serum antibodies, significant PBMC proliferation in response to T. gondii trophozoites was observed in those classified in group A1 or B2 but not in those in groups B3 and C3. Toxoplasma-induced blasts from five of six patients after 7 days of culture and from five patients after 15 days of culture proliferated in response to T. gondii in the presence of either autologous or allogeneic PBMCs as antigen-presenting cells (APCs) and/or also proliferated in response to HSV. The surface markers of T. gondii-induced blasts showed a variable percentage of CD4 and CD8 activated cells. CONCLUSIONS: T cell proliferative response to living trophozoites of T. gondii is lost only in patients with severe depletion of CD4 cells. PBMC proliferation was observed only in patients with previous T. gondii infection, but the T cell blasts generated showed a strong alloreactivity (proliferating in response to allogeneic irradiated PBMCs) and were apparently not antigen specific (proliferating also in response to HSV).

In vitro activity of a Combretum micranthum extract against herpes simplex virus types 1 and 2.

The authors demonstrate in vitro antiviral activity of a methanolic extract of Combretum micranthum leaves against HSV-1 and HSV-2. This activity is present only in the extract dissolved 7 days before the assay, but not in the freshly prepared extract, thus indicating the presence of inactive precursors which undergo spontaneous transformations into active compounds. The alkaline autooxidation of the methanolic extract promotes this rapid transformation. The precursors have been identified as condensed catechinic tannins, which, under alkaline conditions, suffer rapid cleavage, intramolecular rearrangement to catechinic acid and autooxidation. The alkaline autooxidation products of the methanolic extract of C. micranthum and those of the synthetic catechinic acid show similar I.R. and U.V. absorption curves, as well as similar anti-HSV-1 and -HSV-2 activities. EC50s of catechinic acid autooxidation products against HSV-1 and HSV-2 replication were 2 micrograms/ml and 4 micrograms/ml, respectively, when cell cultures were treated with the compound during virus infection.

Antibacterial prophylaxis.

Bacterial infections remain an important cause of morbidity and mortality in neutropenic patients. A number of prophylactic strategies have been used in order to reduce the risk of infection during severe granulocytopenia. The measures that have been investigated include isolation of the patient, granulocyte transfusion, active or passive immunisation, acceleration of granulocyte recovery and prophylactic use of antibacterial agents. However, many of these approaches have fallen out of favour, mostly because of concerns about the long lasting efficacy. This paper focuses on the available prophylactic strategies, with emphasis on the use of antibacterial agents.

Use of antibiotics in an Italian children's hospital, 1993-1995; clinical and economic considerations.

Antibiotic consumption and expenditure was studied during 1993 and 1995 in G. Gaslini children's hospital, an Italian 400-bed paediatric hospital, to see if any changes in use had occurred. There was an increase in the cost of antibacterial agents from 1993 to 1995, with a decrease in the daily cost of antibiotics and in the consumption of antiviral, antifungal and antiparasitic agents. There was a notable increase in the use of glycopeptides and carbapenems between 1995 and 1993 especially in specialities such as onco-haematology and intensive care. We suggest a basis for an antibiotic management programme aimed at reducing costs while still providing a high standard of care for patients.

Linezolid treatment of prosthetic hip Infections due to methicillin-resistant Staphylococcus aureus (MRSA).

Prosthetic joint infection is an infrequent but serious complication of total joint arthroplasty. Complete removal of all foreign material is essential, however when prosthesis removal is not possible or contraindicated, suppressive antibiotic therapy with retention of the functioning hip arthroplasty may be considered. Linezolid, the first approved oxazolidinone, appears to be a promising new agent for the treatment of serious Gram-positive infections. We report two cases of Methicillin-resistant Staphylococcus aureus (MRSA) prosthetic hip infections successfully treated with a long course of linezolid. This observation suggest that linezolid is a promising drug for the treatment of prosthetic joint infections due to MRSA or other Gram-positive pathogens, particularly when other therapeutic approaches are not feasible or a long-term antibiotic therapy is required.

Stability of cefodizime in solution and compatibility with other injectable drugs.

The stability of cefodizime in five intravenous infusion fluids (0.9% sodium chloride, 5% dextrose in water, 10% dextrose in water, 5% amino acid injection, 3% polygeline) was studied at room temperature and at 4 degrees C. The compatibility of cefodizime with commonly used injectable drugs (ranitidine, metoclopramide, folinic acid, furosemide, aminophilline, methylprednisolone, betamethasone, hydrocortisone, dexamethasone, ketoprofen, noramidopyrine, acetylcysteine, digoxin, diazepam, acetylsalicylic acid, chlorpromazine, clonidine, clomipramine) was studied in 0.9% sodium chloride and 5% dextrose at room temperature. At intervals during the storage periods (up to 24 hrs at room temperature; up to 6 days at 4 degrees C) color, clarity and solution pH were examined; cefodizime content was determined by a microbiological method. Cefodizime concentrations remained greater than 90% of the initial concentrations in all infusion fluids for at least 24 hrs at room temperature and 6 days at 4 degrees C. No visual changes or appreciable changes in pH were observed for any of the solutions. Immediate clouding was observed when chlorpromazine was combined with the solution of cefodizime. A color change was observed when acetylcysteine was mixed with cefodizime. An increase in pH was noted when aminophilline was added to the solution of cefodizime. However, cefodizime concentrations remained greater than 90% of the initial concentrations of the solutions after mixture with all the tested drugs for at least 24 hrs at room temperature.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibacterial activity after a single-dose of norfloxacin, ofloxacin and pipemidic acid detected in urine of volunteers.

Six healthy volunteers received in a triple-crossover design a single oral dose of norfloxacin, ofloxacin or pipemidic acid. Urine samples were collected during the 24 h following the administration and were tested for inhibitory and bactericidal activity against selected strains of Enterobacteriaceae and Pseudomonas aeruginosa. Norfloxacin and ofloxacin inhibited the urinary growth of sensitive strains during the 24 h of sampling time at dilutions much higher than those generally considered satisfactory. Nalidixic acid was less effective and did not achieve bactericidal activity against Ps. aeruginosa over the interval of 12 to 24 h.

In vitro antibacterial activity of cefotaxime and desacetylcefotaxime, alone or in combination, against gram-positive cocci.

The in vitro activity of cefotaxime and desacetylcefotaxime against Staphylococcus aureus, Staph. epidermidis and Streptococcus pyogenes was investigated. Synergy studies were performed using time-kill curves and the chequerboard test. The time-kill curves were performed on five strains each of Staph. aureus, Staph. epidermidis and Strep. pyogenes; cefotaxime and desacetylcefotaxime were tested alone or in combination at MIC and sub-MIC values. The chequerboard test was performed in microtitre plates on ten strains each of Staph. aureus, Staph. epidermidis and Strep. pyogenes: the results were interpreted by the fractional inhibitory concentration index. In some cases both methods showed synergistic interaction against the staphylococci tested. Indifference was observed against Strep. pyogenes.

Cefonicid concentration in lung tissue after intramuscular administration.

A long-acting cephalosporin, cefonicid, was given as a single 1 g dose to sixteen patients hospitalized for lung carcinoma and undergoing thoracic surgery. Lung and serum specimens were obtained approximately 2, 4, 6 and 12 h after injection. Antibiotic assay was made by means of a microbiological method. Effective concentrations of cefonicid in the serum and lung tissue were achieved during the sampling time (12 h). The data suggest that a single dose of cefonicid may be useful for antibiotic prophylaxis in thoracic surgery.

Penetration of cefonicid in skin suction blister fluid in healthy volunteers.

A new cephalosporin, cefonicid (1 g) was given intramuscularly to six healthy volunteers 12 h after induction of skin suction blister. Serum and blister fluid were collected during a 24 h period. Antibiotic assay was made by a microbiological method. The data were analysed by a one-compartment kinetic model. Despite the high protein binding, cefonicid penetrated in microbiologically effective concentration into blister fluid. Blister fluid concentrations were higher than the serum concentrations at 24 h.