Background. Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum ...triazole with in vitro and in vivo activity against Aspergillus species. Methods. We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. Results. Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee—assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50–11.04; P = .006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. Conclusions. Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.
Objectives: A multinational, multicentre, open-label clinical trial was conducted to evaluate the safety and efficacy of posaconazole, an extended-spectrum triazole antifungal agent, in subjects with ...invasive fungal infections who had refractory disease or who were intolerant of standard antifungal therapy. In this subanalysis, we report on those subjects in this trial who had a fungal infection that involved the CNS. Methods: Subjects received posaconazole oral suspension 800 mg/day in divided doses for up to 1 year; however, subjects could receive additional therapy as part of a treatment-use extension protocol. A blinded, third-party data review committee determined subject eligibility and outcome. Results: Of the 330 subjects who enrolled in the study, 53 had infections of the CNS, of which 39 were considered evaluable for efficacy. Most had refractory disease (37 of 39) and underlying HIV infection (29 of 39). Twenty-nine subjects had cryptococcal infections, and 10 had infections caused by other fungal pathogens Aspergillus spp. (four), Pseudallescheria boydii (two), Coccidioides immitis (one), Histoplasma capsulatum (one), Ramichloridium mackenziei (one), and Apophysomyces elegans plus a Basidiomycetes sp. (one). Successful outcomes were observed in 14 of 29 (48%) subjects with cryptococcal meningitis and five of 10 (50%) subjects with CNS infections due to other fungal pathogens. Posaconazole was well tolerated. Conclusions: These data suggest that posaconazole, as an oral medication, has clinical activity against fungal infections of the CNS and may provide a valuable alternative to parenteral therapy in patients failing existing antifungal agents.
The incidence of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients has increased during the past 20 years and is associated with significant morbidity and mortality. In ...this post hoc analysis of a large, open-label, multicenter study, we evaluated efficacy and safety of posaconazole, a new extended-spectrum triazole, as salvage therapy for IFIs in SOT recipients.
Twenty-three SOT recipients with proven or probable IFI and evidence of disease refractory to, or intolerant of, standard antifungal therapies received posaconazole oral suspension (40 mg/mL) 800 mg daily in divided doses. An independent, blinded data-review committee assessed patient diagnosis and outcome.
Complete or partial response was documented in 13 of 23 (57%) SOT recipients with proven or probable IFIs, including 1 of 2 (50%) refractory patients, 5 of 8 (63%) intolerant to prior therapy, and 7 of 13 (54%) who were both. Successes by type of IFI included 7 of 12 with invasive aspergillosis, 2 of 2 with invasive fusariosis, 1 of 1 with cryptococcosis, and 1 of 2 with zygomycosis. Treatment-related adverse events (TRAEs) were reported in 12 of 23 patients. Severe TRAEs occurred in 4 of 23 patients including increased levels of cyclosporine or tacrolimus requiring immunosuppressive dose adjustments in three patients and in one, termination of posaconazole. Severe TRAEs associated with renal and liver toxicities were uncommon.
Posaconazole was well tolerated and effective against IFIs including invasive aspergillosis, zygomycosis, fusariosis, and cryptococcosis in SOT recipients intolerant of or failing other antifungal therapies. Calcineurin inhibitor levels should be closely monitored in patients treated concomitantly with posaconazole to avoid toxicity from drug interaction.
We reviewed 153 episodes of invasive pneumococcal disease involving 147 hospitalized patients with and without human immunodeficiency virus (HIV) disease to examine and compare epidemiologic and ...clinical features, capsular serotypes, and antibiotic susceptibility patterns. HIV infection was the most common risk factor for invasive pneumococcal disease. Pneumococcal disease in HIV-infected individuals was characterized by the greater frequency with which pneumonia was the source of bacteremia (90% vs. 63%) (P < .01) and an increased recurrence rate (15% vs. < 1%) (P < .01). The overall mortality rate was 12% and did not vary by HIV serostatus. Capsular-type data were available for 149 episodes; 90% of the types were among those found in the polyvalent pneumococcal vaccine. The four most common capsular types causing invasive disease were 14, 6b, 9v, and 22f; capsular type 9v was significantly more common among HIV-infected patients (P < .01). Penicillin-resistant isolates were identified in 7.2% of all cases, and their presence did not vary by HIV status; 20% of isolates from cerebrospinal fluid were resistant. The majority of the resistant isolates were of capsular type 9v. Given the worldwide increase in both HIV and penicillin-resistant pneumococcal infections, better preventative and therapeutic strategies are greatly needed.
Tedizolid phosphate is an oxazolidinone antibacterial agent approved for the treatment of Gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To ...support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate treatment in adolescents (12 to <18 years) with ABSSSIs, along with emerging data from a phase 1 trial (PN013) in children (2 to <12 years). Updated PK parameter estimates remained similar to those of the previous model. Body weight was a statistically significant covariate on clearance and volume parameters, with no clinically meaningful effects on exposure in adolescents. Tedizolid exposures in adolescents from PN012 were slightly higher with largely overlapped area under the concentration-time curve distribution compared with adults from previous phase 2 and 3 trials. The probability of PK/pharmacodynamic target attainment at the MIC susceptibility breakpoint of 0.5 μg/ml for Staphylococcus and Streptococcus sp. was 100%. As most participants from the PN012 trial were cured, no significant exposure-efficacy relationship was identified. Tedizolid exposures were similar between participants with and without a safety event from PN012; no clear relationship was detected between exposure and safety. Despite lower body weight and higher exposures in adolescents, safety profiles in adolescents were similar those in adults. These results support the 200-mg, once-daily intravenous or oral dose of tedizolid phosphate in adolescents with ABSSSIs.
We report a case of granulocytic ehrlichiosis in a 71-year-old man who presented with an acute febrile illness and subsequently developed multisystem organ dysfunction and sudden severe anemia with ...thrombocytopenia requiring intensive care, mechanical ventilation, hemodialysis, and transfusions. The diagnosis was suspected on the fifth hospital day after a peripheral blood smear was examined; intracytoplasmic inclusion bodies were present in granulocytes only. Results of serological tests of acute and convalescent sera confirmed the diagnosis of granulocytic ehrlichiosis. We discuss the features of this case that were similar to those of published case reports as well as the course and outcome of treatment. This, to our knowledge, represents the first documented case of human granulocytic ehrlichiosis to occur outside the Upper Midwest. Because of the possible epidemiological association of Ehrlichia species with the deer tick Ixodes scapularis (dammini), this case raises additional concern for clinicians and patients in regions where Lyme disease is endemic.
Abstract
Pseudomonas aeruginosa is an ubiquitous environmental bacterium. It can be recovered, often in high numbers, in common food, especially vegetables. Moreover, it can be recovered in low ...numbers in drinking water. A small percentage of clones of P. aeruginosa possesses the required number of virulence factors to cause infection. However, P. aeruginosa will not proliferate on normal tissue but requires previously damaged organs. Further narrowing the risk to human health is that only certain specific hosts are at risk, including patients with profound neutropenia, cystic fibrosis, severe burns, and those subject to foreign device installation. Other than these very well-defined groups, the general population is refractory to infection with P. aeruginosa. Because of its ubiquitous nature, it is not only not practical to eliminate P. aeruginosa from our food and drinking water, but attempts to do so would produce disinfection byproducts more hazardous than the species itself. Moreover, because there is no readily available sensitive and specific means to detect and identify P. aeruginosa available in the field, any potential regulation governing its control would not have a defined laboratory test measure of outcome. Accordingly, attempts to regulate P. aeruginosa in drinking water would not yield public health protection benefits and could, in fact, be counterproductive in this regard.
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