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Contains fulltext : 193592.pdf (Publisher’s version ) (Open Access) Background: The international Innovative Medicines Initiative (IMI) project DRIVE-AB (Driving Reinvestment in Research and Development and Responsible Antibiotic Use) aims to develop a global definition of 'responsible' antibiotic use. Objectives: To identify consensually validated quantity metrics for antibiotic use in the outpatient setting. Methods: First, outpatient quantity metrics (OQMs) were identified by a systematic search of literature and web sites published until 12 December 2014. Identified OQMs were evaluated by a multidisciplinary, international stakeholder panel using a RAND-modified Delphi procedure. Two online questionnaires and a face-to-face meeting between them were conducted to assess OQM relevance for measuring the quantity of antibiotic use on a nine-point Likert scale, to add comments or to propose new metrics. Results: A total of 597 articles were screened, 177 studies met criteria for full-text screening and 138 were finally included. Twenty different OQMs were identified and appraised by 23 stakeholders. During the first survey, 14 OQMs were excluded and 6 qualified for discussion. During the face-to-face meeting, 10 stakeholders retained five OQMs and suggestions were made considering context and combination of metrics. The final set of metrics included defined daily doses, treatments/courses and prescriptions per defined population, treatments/courses and prescriptions per defined number of physician contacts and seasonal variation of total antibiotic use. Conclusions: A small set of consensually validated metrics to assess the quantity of antibiotic use in the outpatient setting was obtained, enabling (inter)national comparisons. The OQMs will help build a global conceptual framework for responsible antibiotic use.

Supplemental Digital Content is available in the text, Q fever is a neglected and potentially fatal disease. During acute Q fever, antiphospholipid antibodies are very prevalent and have been associated with fever, thrombocytopenia, acquired heart valve disease, and progression to chronic endocarditis. However, thrombosis, the main clinical criterion of the 2006 updated classification of the antiphospholipid syndrome, has not been assessed in this context. To test whether thrombosis is associated with antiphospholipid antibodies and whether the criteria for antiphospholipid syndrome can be met in patients with acute Q fever, we conducted a cross-sectional study at the French National Referral Center for Q fever. Patients included were diagnosed with acute Q fever in our Center between January 2007 and December 2015. Each patient's history and clinical characteristics were recorded with a standardized questionnaire. Predictive factors associated with thrombosis were assessed using a rare events logistic regression model. IgG anticardiolipin antibodies (IgG aCL) assessed by an enzyme-linked immunosorbent assay were tested on the Q fever diagnostic serum. A dose-dependent relationship between IgG aCL levels and thrombosis was tested using a receiver operating characteristic (ROC) analysis. Of the 664 patients identified for inclusion in the study, 313 (47.1%) had positive IgG aCL and 13 (1.9%) were diagnosed with thrombosis. Three patients fulfilled the antiphospholipid syndrome criteria. After multiple adjustments, only positive IgG aCL (relative risk, 14.46 [1.85–113.14], P = .011) were independently associated with thrombosis. ROC analysis identified a dose-dependent relationship between IgG aCL levels and occurrence of thrombosis (area under curve, 0.83, 95%CI [0.73–0.93], P

International audience; Invasive fungal infection is a serious complication following allogeneic hematopoietic stem cell transplantation. Pulmonary infection due to Hormographiella aspergillata is an uncommon condition associated with a high mortality rate. The susceptibility of H. aspergillata to available antifungal agents is not well established. We report for the first time a case of H. aspergillata lung infection that responded poorly to conventional treatment with liposomal amphotericin B (LAmB; 3 mg kg-1 of body weight per day) with renal damage at higher posology (5 mg kg-1 of body weight per day), but improved rapidly after addition of nebulized LAmB to intravenous LAmB (3 mg kg-1 of body weight per day). Successful treatment of our patient using nebulized LAmB would be worth evaluating in cases refractory to standard treatment or when the reference treatment may not be extended due to interaction or side effects.

Supplemental Digital Content is available in the text, Because Q fever is mostly diagnosed serologically, localizing a persistent focus of Coxiella burnetii infection can be challenging. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) could be an interesting tool in this context. We performed a retrospective study on patients diagnosed with C burnetii infection, who had undergone 18F-FDG PET/CT between 2009 and 2015. When positive 18F-FDG PET/CT results were obtained, we tried to determine if it changed the previous diagnosis by discovering or confirming a suspected focus of C burnetii infection. One hundred sixty-seven patients benefited from 18F-FDG PET/CT. The most frequent clinical subgroup before 18F-FDG PET/CT was patients with no identified focus of infection, despite high IgG1 serological titers (34%). For 59% (n = 99) of patients, a hypermetabolic focus was identified. For 62 patients (62.6%), the positive 18F-FDG PET/CT allowed the diagnosis to be changed. For 24 of them, (38.7%), a previously unsuspected focus of infection was discovered. Forty-two (42%) positive patients had more than 1 hypermetabolic focus. We observed 21 valvular foci, 34 vascular foci, and a high proportion of osteoarticular localizations (n = 21). We also observed lymphadenitis (n = 27), bone marrow hypermetabolism (n = 11), and 9 pulmonary localizations. We confirmed that18F-FDG PET/CT is a central tool in the diagnosis of C burnetii focalized persistent infection. We proposed new diagnostic scores for 2 main clinical entities identified using 18F-FDG PET/CT: osteoarticular persistent infections and lymphadenitis.

International audience; no abstract

Pneumocystis jirovecii pneumonia (PCP) is emerging in HIV-negative patients, for whom the prognosis is significantly worse than in HIV-infected patients and risk factors are poorly characterized. We performed an observational, multi-centre, prospective study of 56 consecutive cases of documented PCP in HIV-negative patients, and found that: (1) the main underlying conditions were haematological malignancies (43%), solid tumours (25%), inflammatory diseases (20%), and solid organ transplantation (7%); (2) most patients (80%) had received prolonged corticosteroids, with a mean daily dose of 47.3 ± 32.8 mg equivalent prednisone when PCP was diagnosed, and a mean cumulative dose of 5807 ± 5048 mg over the last 12 months; and (3) the median CD4 cell count was 0.12 × 10⁹/l (range 0.0-1.42), with a median CD4/CD8 ratio of 1.32 (0.0-6.4). These findings may be used to better target PCP prophylaxis according to the level of risk and contribute to decrease the burden of PCP in HIV-negative patients.

To the Editor: Catabacter hongkongensis is a newly described anaerobic agent that is likely an intrinsic component of normal gut flora; it was first reported by Lau et al. in 2007 (1). We report a fatal case of infection caused by C. hongkongensis that was identified by 16S rRNA sequence. A man 52 years of age was admitted to an intensive care unit in France for septic shock. He was a retired service member, smoker, and alcohol drinker. He had a history of hypertension but no previously known gastrointestinal disease. He sought treatment for acute abdominal pain and diarrhea of several hours’ duration. On admission, he had persistent abdominal pain with generalized abdominal distension, arterial hypotension, and hypoxemia but was not febrile. Two sets of anaerobic and aerobic blood cultures were performed at a 1-hour interval, and empiric treatment with amoxicillin/clavulanic acid and gentamicin was started. Biochemical screening showed severe metabolic acidosis, acute renal insufficiency, and systemic inflammatory response syndrome. An abdominal radiograph revealed massive pneumoperitonitis. Laparotomy showed multiple lesions and intestinal perforation at the ascending and first part of the transverse colon, with a large amount of purulent fluid in the peritoneal cavity. A complete colectomy was performed, with rectum closure and end ileostomy. Despite fluid resuscitation and catecholamine infusions, hemodynamic instability worsened rapidly and led to the patient’s death. Microbiological analysis of abdominal fluid revealed the presence of Pseudomonas aeruginosa, Escherichia coli, and Enterococcus spp., but no anaerobic agent. On day 3 postincubation, 1 of the 2 anaerobic blood cultures grew a motile gram-positive bacillus, which grew only in strictly anaerobic conditions. Phenotypic analysis showed catalase production but not indole positivity or nitrate reduction. Standard phenotypic tests were performed with the rapid ID 32A and api20A strips (bioMerieux, Marcy l’Etoile, France). The numeric profiles obtained were 0002000010 and 4030121, respectively. The bacteria produced acid from arabinose, glucose, mannose, and xylose, was negative for glycerol fermentation and leucine arylamidase and positive for rhamnose fermentation. Despite these results, phenotypic tests failed to identify the isolate. Antimicrobial drug susceptibility was determined by disk diffusion method and Etest for MICs. The isolate showed susceptibility to metronidazole (MIC 32 µg/mL) according to Eucast clinical breakpoints (www.eucast.org). No other bacteria were isolated in the blood cultures. Genetic analysis was performed by 16S rRNA gene sequencing of a 1,265-bp fragment by using DG74 and RDRO80 primers (2). The nucleotide sequence obtained was compared with known sequences in GenBank by multiple sequence alignment using the ClustalW program (3). It was 100% identical to C. hongkongensis (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"AY574991","term_id":"46310217","term_text":"AY574991"}}AY574991). The first 4 case-patients with C. hongkongensis infection were described by Lau et al. in 2007 (1). Two of these patients lived in Hong Kong and the 2 others in Canada. As in our case, only 1 patient died. Since there was a high degree of phenotypic and genetic difference with other anaerobic agents, the authors proposed a new genus and species and affiliation with a new family, Catabacteriacae. The 2 isolates from Canada differed from the 2 others by being negative for glycerol fermentation and positive for rhamnose fermentation and leucine arylamidase, similar to our case, except for leucine arylamidase, which in our case was negative. In the previously reported cases, C. hongkongensis was susceptible to metronidazole, vancomycin, and kanamycin; variably susceptible to penicillin (MICs 0.5–4.0 µg/mL); and resistant to colistin and cefotaxime (1). Whether C. hongkongensis belongs to the intestinal flora, as do Bifidobacterium, Eggerthella, Eubacterium, and Lactobacillus spp., remains undetermined. Codony et al. recently investigated by real-time PCR the presence of Catabacteriaceae in 29 water samples in the vicinity of Barcelona, Spain. Four samples were positive, demonstrating presence of this organism in the European environment and its probable enteric origin (4). Because our patient sought treatment with severe infection associated with isolation of other pathogenic bacteria, whether blood infection by C. hongkongensis may be responsible for such a fatal outcome is unknown. Nevertheless, we can exclude sample contamination by this anaerobic bacteria for the 2 following reasons. First, anaerobic contaminants are rare in blood cultures and generally involve Propionibacterium acnes. Furthermore, the rapid growth of the present isolate in blood cultures within 3 days suggested a relatively high bacterial load in the blood sample. Our report confirms that C. hongkongensis can be found in blood culture associated with gastrointestinal disease and may reflect intestinal perforation. Identification may be difficult. Isolation of motile gram-positive anaerobic bacillus together with catalase positivity should lead to suspicion of C. hongkongensis in clinical laboratories. Full identification of this pathogen requires 16S sequencing. Environmental reports have demonstrated the presence of this organism in human wastewater in Europe, which suggests that it may be universally present as part of the normal human gastrointestinal flora.

Sir, Plasma exchange (PE) is a therapeutic procedure aimed at reducing the amount of abnormal or toxic substances in the blood, e.g. immunoglobulins. It consists in removing a large volume of plasma from a patient and replacing it with some form of replacement fluid. PE is non-selective and may also remove circulating medications from blood (both protein-bound and unbound drug). Darunavir is a synthetic non-peptidic HIV protease inhibitor (PI) metabolized mainly by CYP3A4 isoenzymes and 95% bound by plasma proteins, primarily a-1-acid glycoprotein. Increased clearance of atazanavir, another PI, during PE has already been reported, but the effect of PE on darunavir disposition is unknown. Since darunavir exhibits concentration–effect relationships, knowledge of this effect is critical for treatment efficacy. We report here the case of a white woman in her 50s receiving highly active antiretroviral therapy (HAART) including darunavir and requiring PE treatment. Consent for publication was obtained from the patient. She was diagnosed HIV-1 positive in 2001 and started HAART in 2005. Viral load (VL) and CD4 count were 720956 copies/mL and 13 cells/mm, respectively, when she was hospitalized for visceral leishmaniasis with polyclonal hypergammaglobulinaemia. She then started a new HAART combination consisting of darunavir/ritonavir (600/100 mg twice daily) with emtricitabine/tenofovir (200/245 mg once daily). Despite good virological response (VL ,20 copies/mL), immunological restoration was not achieved (CD4 count1⁄4150 cells/mm and CD4/CD8 ratio1⁄40.08) and hypergammaglobulinaemia increased. Because of hyperviscosity syndrome, she underwent PE sessions twice a week during which darunavir pharmacokinetics (PK) were explored. Several blood samples were drawn over the dosing interval, i.e. just before, during and immediately after a 2 h PE session, in order to estimate the elimination rate constant during PE (keon); a plasma sample collected during PE was also assayed in order to determine the amount of darunavir eliminated by PE. Three additional samples were drawn after PE in order to estimate the darunavir elimination rate constant after a PE session (keoff). Plasma darunavir concentrations were determined using a validated HPLC-UV method and ke values were estimated as the slope from the linear regression of log-concentrations on sample times. Corresponding t1 2 were estimated as loge2 divided by ke. In order to demonstrate the impact of PE on steady-state darunavir PK profiles, PK simulations were performed using Nonmem population PK software (Monte Carlo simulation, n1⁄41000 concentration –time profiles). Calculated keon and mean estimated PK parameters obtained from the literature (CL/F1⁄410.7 L/h, V/F1⁄4198 L and ka1⁄40.95 h) were used for that purpose. PK analysis was performed during three PE sessions. The mean+SD plasma volume and darunavir amount removed per session were 2.51+0.03 L and 9.3+8.3 mg, respectively. Actual darunavir concentrations measured before, during and after PE sessions were 8802+4835, 4505+2930 and 3314+2103 ng/mL, respectively. Estimated keoff and keon were 0.10+0.1 and 0.53+0.13 h, respectively. These data