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Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice–web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of −1·0% (95% CI −7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. Astellas Pharma Global Development, Basilea Pharmaceutica International.

Background Bartonella quintana is an important cause of culture-negative endocarditis. Although humans have been considered as its only reservoir, recent studies showed that macaque species are also reservoirs of B. quintana . Based on multi-locus sequence typing (MLST) B. quintana strains have been classified into 22 sequence types (STs), with 7 STs exclusively found in humans. Data regarding the molecular epidemiology of B. quintana endocarditis is limited to only 3 STs identified in 4 patients from Europe and Australia. We studied B. quintana endocarditis acquired in Eastern Africa or Israel to investigate the genetic diversity and clinical relatedness of B. quintana from distinct geographic regions. Methods Eleven patients with B. quintana endocarditis, 6 from Eastern Africa and 5 from Israel, were studied. DNA was extracted from cardiac tissue or blood specimens and analyzed by MLST based on 9 genetic loci. An evolutionary relationship between STs was visualized by a minimum spanning tree. A phylogenetic tree was constructed with the concatenated sequences (4271 bp) of the 9 loci using the maximum-likelihood method. Results Six strains were classified into previously described STs while 5 strains were identified for the first time and classified into new STs 23–27 which clustered with the previously reported STs 1–7 from human strains found in Australia, France, Germany, the USA, Russia, and the former Yugoslavia, without indication of geographical structuring. ST2 was the most prevalent ST, found in 5 of 15 patients with endocarditis (33.3%). ST26 appears to be a primary founder of the human lineage. Conclusions The new and previously reported human STs form a single human lineage, clearly separated from the other 3 B. quintana lineages of cynomolgus, rhesus, and Japanese macaques. From evolutionary perspectives, these findings support the assumption that B. quintana has co-evolved with host species to form a host-speciation pattern. ST26 is suggested herein as a primary founder of the human lineage and may be key to explore where B. quintana had first originated; ST2 is a dominant genetic type associated with B. quintana endocarditis. To confirm these findings, additional worldwide molecular epidemiological studies are required.

Background Cranial nerve neuropathies represent a rare manifestation of cat scratch disease (CSD). Only a few case reports have been published, and the full clinical spectrum remains poorly characterized. We aimed to describe the clinical presentation, diagnostic approach, and prognosis of cat scratch disease (CSD)-associated cranial nerve neuropathies, a manifestation that is poorly characterized. Methods Using data from a national CSD surveillance study, we identified patients with CSD-associated cranial neuropathies confirmed by serology and/or PCR for Bartonella henselae. Clinical, epidemiological, and imaging data were analyzed. Follow-up was conducted. Results Seven immunocompetent patients with cranial nerve neuropathies were identified among approximately 4100 CSD patients diagnosed over a 28-year period (1997–2025). Affected cranial nerves included the facial ( n  = 3), abducens ( n  = 2), oculomotor ( n  = 1), and glossopharyngeal ( n  = 1) nerves, the latter two not previously reported in patients with CSD. All patients reported cat exposure. Neuropathies were accompanied by other CSD-related features, including fever (71%), lymphadenitis (57%), neuroretinitis (43%), and encephalitis (14%). Three patients received antibiotic therapy and five were treated with systemic corticosteroids. Six patients fully recovered within a median of 4 weeks; one patient showed marked improvement after 3 months and was subsequently lost to follow-up. Conclusion CSD-associated cranial neuropathies are rare and possibly underdiagnosed. Diagnostic clues include cat contact and concurrent CSD features such as fever, lymphadenopathy, or neuroretinitis. These findings are hardly observed in idiopathic cranial nerve palsies such as Bell’s palsy, for which guidelines recommend against routine serologic evaluation. Although outcomes are generally favorable, optimal treatment remains undefined. We suggest testing for B. henselae infection in patients with cranial neuropathies when CSD is suspected. Increased clinical awareness is warranted to facilitate timely diagnosis and management.

Background.Musculoskeletal manifestations (MMs) are considered to be rare in cat scratch disease (CSD) and are not well characterized. We aimed to study MMs of CSD. Methods.A surveillance study performed over 11 years identified patients with CSD on the basis of compatible clinical presentation and confirmatory serological test or PCR results for Bartonella henselae. Patients with CSD who had MMs (i.e., myalgia, arthritis, arthralgia, tendinitis, osteomyelitis, and neuralgia) were compared with patients with CSD who did not have MMs (control subjects). Results.Of 913 patients with CSD, 96 (10.5%) had MMs. Myalgia (in 53 patients [5.8%]) was often severe, with a median duration of 4 weeks (range, 1–26 weeks). Arthropathy (arthralgia and/or arthritis; in 50 patients [5.5%]) occurred mainly in the medium and large joints and was classified as moderate or severe in 26 patients, with a median duration of 5.5 weeks (range, 1–240 weeks). In 7 patients, symptoms persisted for ⩾1 year; 5 developed chronic disease. Tendinitis, neuralgia, and osteomyelitis occurred in 7, 4, and 2 patients, respectively. Patients with MMs were significantly older than patients in the control group (median age, 31.5 years vs. 15.0 years; P < .001). In multivariate analysis, age >20 years was associated with having any MM (relative risk [RR], 4.96; 95% confidence interval [CI], 2.79–8.8), myalgia (RR, 4.69; 95% CI, 2.22–9.88), and arthropathy (RR, 11.0; 95% CI, 4.3–28.2). Arthropathy was also associated with female sex (RR, 1.89; 95% CI, 1.01–3.52) and erythema nodosum (RR, 4.07; 95% CI, 1.38–12.02). Conclusions.MMs of CSD are more common than previously thought and affect one-tenth of patients with CSD. MMs occur mostly in patients aged >20 years and may be severe and prolonged. Osteomyelitis, the most well known MM of CSD is, in fact, the rarest.

In recent years, dramatic changes in health care systems have shifted much of the care of sick individuals from hospitals to the community. Consequently, infections traditionally classified as community-acquired or hospital-acquired infections cannot now be readily classified into either category. We thus propose a new classification based on a wider spectrum of acquisition. A total of 1028 episodes of bloodstream infection (BSI) were divided into 5 categories: true community-acquired infections (370 episodes [36%]), infections in recently discharged patients (110 [11%]), infections associated with invasive procedures performed just before or at the time of admission (56 [5%]), infections in patients admitted from nursing homes (68 [7%]), and hospital-acquired infections (424 [41%]). Thus, 234 (39%) of the 604 bloodstream infections traditionally defined as community acquired were reclassified into 3 newly defined groups, each of which has distinct epidemiologic, clinical, and bacteriologic characteristics, as well as distinct antimicrobial susceptibility profiles. There is a conceptual and practical need for such a new classification.

Cat scratch disease (CSD), caused by Bartonella henselae, usually presents as regional lymphadenopathy/lymphadenitis, known as typical CSD or as atypical CSD, which includes, among others, neurological manifestations. Serology for anti-B. henselae IgG antibodies is the most commonly used diagnostic tests for CSD. Intravenous immunoglobulin (IVIG) is given for an increasing number of medical conditions and may cause interference with serological testing. We report six patients with neurological manifestations and two patients with Kawasaki disease mimicking typical CSD, mistakenly diagnosed as CSD due to false-positive serology following IVIG therapy. Bartonella IgG serology was positive one to six days after IVIG administration and reverted to negative in seven of eight patients or significantly decreased (1 patient) ≤30 days later. In patients with CSD, IgG titers remained essentially unchanged 15–78 days after the positive serum sample. An additional eight patients treated with IVIG for various conditions were evaluated prospectively. All were seronegative one day pre-IVIG infusion, five patients demonstrated an increase in the IgG titers one to three days after IVIG administration, one interpreted as positive and four as intermediate, whereas three patients remained seronegative, suggesting that false seropositivity after IVIG therapy may not occur in all patients. Treatment with IVIG can result in false-positive serology for B. henselae. Increased awareness to the misleading impact of IVIG is warranted to avoid misinterpretation. Repeat testing can distinguish between true and false serology. Preserving serum samples prior to IVIG administration is suggested.

A highly specific enzyme immunoassay (EIA) was recently described for use in the diagnosis of cat scratch disease (CSD). However, data regarding EIA antibody kinetics or its correlation with long-term clinical follow-up data are lacking. The association between antibody kinetics, clinical spectrum, and disease duration were studied in 98 patients with CSD. The median duration of follow-up was 35.3 weeks (range, 2–211.3 weeks). Results of EIA testing for detection of anti-Bartonella henselae immunoglobulin M (IgM) antibodies (detected in 53% of the patients) remained positive for ⩽3 months. Therefore, the presence of IgM indicated acute infection. Titers of immunoglobulin G (IgG) also decreased over time; 25% of the patients remained seropositive for >1 year after the onset of CSD. Onset of CSD in patients with an IgG titer with an optical density of ⩾1.0 occurred within the prior 12 months. No association was found between antibody titers or their kinetics and the clinical manifestations or duration of disease. EIA allows for the identification of atypical manifestations of CSD that were unrecognized before the use of serological assays. Complete recovery from these manifestations may take months. Results of this study provide additional data supporting the utility of EIA in the serodiagnosis of CSD.

Bartonella henselae is a zoonotic pathogen and the causative agent of cat scratch disease and a variety of other disease manifestations in humans. Previous investigations have suggested that a limited subset of B. henselae isolates may be associated with human disease. In the present study, 182 human and feline B. henselae isolates from Europe, North America and Australia were analysed by multi-locus sequence typing (MLST) to detect any associations between sequence type (ST), host species and geographical distribution of the isolates. A total of 14 sequence types were detected, but over 66% (16/24) of the isolates recovered from human disease corresponded to a single genotype, ST1, and this type was detected in all three continents. In contrast, 27.2% (43/158) of the feline isolates corresponded to ST7, but this ST was not recovered from humans and was restricted to Europe. The difference in host association of STs 1 (human) and 7 (feline) was statistically significant (P< or =0.001). eBURST analysis assigned the 14 STs to three clonal lineages, which contained two or more STs, and a singleton comprising ST7. These groups were broadly consistent with a neighbour-joining tree, although splits decomposition analysis was indicative of a history of recombination. These data indicate that B. henselae lineages differ in their virulence properties for humans and contribute to a better understanding of the population structure of B. henselae.

Background. Cat-scratch disease (CSD) is mostly contracted by children and young adults. To our knowledge, CSD in elderly patients has never been characterized, and it may be underrecognized in this age group. Methods. The study population included all patients with CSD diagnosed at our reference laboratory during 1991–2002. Demographic, clinical, and laboratory data for patients with CSD aged ⩾60 years (elderly group) were compared with data for patients with CSD aged <60 years (nonelderly group). Results. There were 846 immunocompetent patients with CSD included in this study. Fifty-two patients (6%) were ⩾60 years old. Lymphadenopathy was less common in elderly patients than in nonelderly patients (76.5% vs. 94.4%; P < .001), and general malaise was more frequent in elderly patients (70.8% vs. 51.4%; P = .009). Atypical CSD was more common in elderly patients than in nonelderly patients (32.7% vs. 13.6%), including endocarditis (odds ratio [OR], 61.6; P < .001), encephalitis (OR, 6.3; P = .013), and fever of unknown origin (OR, 7.3; P < .001). The time period from onset of symptoms to diagnosis was >6 weeks for 29.5% of elderly patients versus 13.3% of nonelderly patients (P = .003). Conclusions.CSD affects elderly persons as well as nonelderly persons, but clinical features differ between the patient groups. Atypical CSD, including endocarditis, is more frequent in elderly than in nonelderly patients. Conversely, lymphadenitis, the hallmark of typical CSD, is often absent in elderly patients. Lack of awareness among clinicians may delay the diagnosis of CSD in elderly persons and result in unnecessary and often invasive diagnostic procedures.

Hospital-acquired infective endocarditis (IE) is a growing health-care problem. Hospital-acquired IE, according to the commonly used definition, is IE manifesting ⩾72 h after admission to the hospital or within several weeks after a hospital-based invasive procedure. To assess the validity of this definition, we evaluated 87 episodes of IE, with special attention to recent hospitalizations. The incidence rate of IE in the 6-month period after discharge from the hospital was 27 cases per 100,000 person-years, compared with 1.1 cases per 100,000 person-years in a population with no recent hospitalizations. Furthermore, episodes of IE manifesting during this 6-month period were notable for a high proportion of typically hospital-acquired pathogens (26% vs. 0%; P = .001) and a low proportion of viridans streptococci (0% vs. 36%; P < .001), compared with community-acquired episodes that did not involve recent hospitalization. We conclude that characteristics of hospital-acquired IE extend to episodes arising within 6 months after discharge from the hospital and suggest that the definition of hospital-acquired IE be broadened to include these episodes.