Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project)

REIPI/INCREMENT-SOT Group.[Background] Whether active therapy with β-lactam/β-lactamase inhibitors (BLBLI) is as affective as carbapenems for extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) bloodstream infection (BSI) secondary to urinary tract infection (UTI) in kidney transplant recipients (KTRs) remains unclear.[Methods] We retrospectively evaluated 306 KTR admitted to 30 centers from January 2014 to October 2016. Therapeutic failure (lack of cure or clinical improvement and/or death from any cause) at days 7 and 30 from ESBL-E BSI onset was the primary and secondary study outcomes, respectively.[Results] Therapeutic failure at days 7 and 30 occurred in 8.2% (25/306) and 13.4% (41/306) of patients. Hospital-acquired BSI (adjusted OR [aOR]: 4.10; 95% confidence interval [CI]: 1.50-11.20) and Pitt score (aOR: 1.47; 95% CI: 1.21-1.77) were independently associated with therapeutic failure at day 7. Age-adjusted Charlson Index (aOR: 1.25; 95% CI: 1.05-1.48), Pitt score (aOR: 1.72; 95% CI: 1.35-2.17), and lymphocyte count ≤500 cells/μL at presentation (aOR: 3.16; 95% CI: 1.42-7.06) predicted therapeutic failure at day 30. Carbapenem monotherapy (68.6%, primarily meropenem) was the most frequent active therapy, followed by BLBLI monotherapy (10.8%, mostly piperacillin-tazobactam). Propensity score (PS)-adjusted models revealed no significant impact of the choice of active therapy (carbapenem-containing vs any other regimen, BLBLI- vs carbapenem-based monotherapy) within the first 72 hours on any of the study outcomes.[Conclusions] Our data suggest that active therapy based on BLBLI may be as effective as carbapenem-containing regimens for ESBL-E BSI secondary to UTI in the specific population of KTR. Potential residual confounding and unpowered sample size cannot be excluded (ClinicalTrials.gov identifier: NCT02852902).This work was supported by: (1) Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III (ISCIII), Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases [RD16/0016/0001, RD16/0016/0002, REIPI RD16/0016/0008; RD16/0016/00010], co-financed by European Development Regional Fund “A way to achieve Europe”, Operative Program Intelligent Growth 2014-2020; (2) European Society of Clinical Microbiology and Infectious diseases Study Group for Infections in Compromised Hosts (ESGICH, grant to J.M.A.); (3) Sociedad Andaluza de Trasplante de Órgano Sólido (SATOT, grant to L.M.M.); (4) Research project PI16/01631 integrated into the Plan Estatal de I+D+I 2013-2016 and co-financed by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación and the Fondo Europeo de Desarrollo Regional (FEDER); (5) M.F.R. holds a research contract “Miguel Servet” (CP 18/00073) from ISCIII, Ministerio de Ciencia, Innovación y Universidades. The work was also supported by the following European Society of Clinical Microbiology and Infectious diseases (ESCMID) study groups: Infections in Compromised Hosts (ESGICH), Bloodstream Infections and Sepsis (ESGBIS) and Antimicrobial Resistance Surveillance (ESGARS).Peer reviewe

Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas

Background: Infections are well known complications of some targeted drugs used to treat solid organ cancer and hematological malignancies. Furthermore, Individual patient risk factors are associated with underlying pathologies, concomitant immunosuppressive treatment, prior treatment and use of anti-infective prophylaxis. Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Objectives: In this narrative review, we present the current state of knowledge concerning the infectious complications occurring in patients treated with immune checkpoint inhibitors (ICIs), Bruton’s tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors or CAR-T cell infusion. Sources: We searched for studies treating infectious complications of ICIs, BTK inhibitors, PI3K inhibitors, antiapoptotic protein BCL-2 inhibitors and CAR-T cell therapy. We included randomized, observational studies and case reports. Content: Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Treatment of irAEs with corticosteroids and other immunosuppressive agents can lead to opportunistic infections. Bruton’s tyrosine kinase (BTK) inhibitors are associated with higher rate of infections, including invasive fungal infections. Implications: Infections, particularly fungal ones, are common in patients treated with BTK inhibitors even though most of the complications occurring among patients treated by ICIs or CART-cells infusion are associated with the treatment of side effects related to the use of these new treatments. The diagnosis of these infectious complications can be difficult and may require extensive investigations

Frequency of surface bacterial contamination in family physicians’ offices

ObjectivesThe environment is perceived as a potential source of healthcare-associated infections. While this infection source has been well studied in hospital settings, little data on the risk of contamination in general medical practice is available. We aimed to assess the frequency of environmental contamination in family practice (FP), and to describe pathogens isolated, at-risk surfaces, and factors associated with this contamination.Patients and methodsWe conducted a cross-sectional point prevalence study over six months in 51 FP offices. In each office, six environmental samples were collected after and before consultations on high-touch surfaces (stethoscope, examination table, physician's desktop, blood pressure cuff, medical equipment tray, computer keyboard and mouse).ResultsA total of 580 samples were obtained. All offices were contaminated at any time with at least 2.5 colony forming units. The median rate of examination room bio-cleaning was twice a week. For all equipment and surfaces, a lower bacterial load was found before consultations when the last cleaning had occurred less than 24 hours prior to testing.ConclusionHigh environmental contamination was observed in FP offices. Less than one practice in five used an effective cleaning agent; family physicians’ awareness of practice hygiene is an important step for prevention

Empiric Treatment in HAP/VAP: “Don’t You Want to Take a Leap of Faith?”

International audienceVentilator-associated pneumonia is a frequent cause of ICU-acquired infections. These infections are associated with high morbidity and mortality. The increase in antibiotic resistance, particularly among Gram-negative bacilli, makes the choice of empiric antibiotic therapy complex for physicians. Multidrug-resistant organisms (MDROs) related infections are associated with a high risk of initial therapeutic inadequacy. It is, therefore, necessary to quickly identify the bacterial species involved and their susceptibility to antibiotics. New diagnostic tools have recently been commercialized to assist in the management of these infections. Moreover, the recent enrichment of the therapeutic arsenal effective on Gram-negative bacilli raises the question of their place in the therapeutic management of these infections. Most national and international guidelines recommend limiting their use to microbiologically documented infections. However, many clinical situations and, in particular, the knowledge of digestive or respiratory carriage by MDROs should lead to the discussion of the use of these new molecules, especially the new combinations with beta-lactamase inhibitors in empirical therapy. In this review, we present the current epidemiological data, particularly in terms of MDRO, as well as the clinical and microbiological elements that may be taken into account in the discussion of empirical antibiotic therapy for patients managed forventilator-associated pneumonia

Iatrogenic Cushing's Syndrome Induced by Posaconazole

International audienceIatrogenic Cushing's syndrome is an undesirable outcome of glucocorticoids treatment. It can be increased by pharmacologic interactions. Glucocorticoid therapy, given in association with ritonavir, and some azole treatments are causes of iatrogenic Cushing's syndrome. We present a patient with common-variable immunodeficiency who received 7 years of itraconazole therapy for bronchial colonization with Aspergillus in combination with inhaled fluticasone without any Cushingoid symptoms. After a switch to posaconazole, the patient developed Cushingoid symptoms. I atrogenic Cushing's syndrome is caused by exposure to gluco-corticoids and may be promoted by interaction with additional drugs that result in hypothalamic-pituitary-adrenal axis suppression. It is well documented in asthmatic, human immunodefi-ciency virus (HIV)-infected patients receiving inhaled steroids in combination with a ritonavir-containing antiretroviral regimen (1, 2). Steroids, whether inhaled or injected by intranasal or epi-dural routes, have usually minimal systemic effects at recommended dosages. They are metabolized mainly by CYP3A4. The combination of long-term inhaled steroids with azole derivatives, such as itraconazole, fluconazole, or voriconazole, has been reported to exacerbate hypothalamic-pituitary-adrenal axis suppression (3, 4, 5). Posaconazole is an orally active broad-spectrum antifungal triazole that inhibits cytochrome P450-dependent CYP3A4 and therefore decreases synthetic glucocorticoid hepatic metabolism (6). We report a case of a patient who presented with Cushing's syndrome following a treatment switch to posacona-zole after 7 years of itraconazole therapy without any Cushingoid symptoms. A 51-year-old woman with common-variable immunodefi-ciency associated with autoimmunity, bronchiectasis, asthma diagnosed in 1996, and a lymphoid follicular hyperplasia diagnosed in 2010 was treated by montelukast sodium (10 mg once daily), triamcinolone acetonide (55 g once daily), a long-acting ␤2-adrenergic agonist associated with inhaled glucocorticoid (salme-terol and fluticasone), risedronate (35 mg weekly), levothyroxine (75 g daily), desloratadine (5 mg daily), sertraline (25 mg daily), and intravenous immunoglobulins (IVIG). Since 2000, she was treated with itraconazole as prophylaxis for bronchial coloniza-tion with Aspergillus fumigatus without any radiologic signs of invasive aspergillosis or elevated fungal biomarkers (galactoman-nan or beta-D-glucan). In 2007, following the persistent bronchial colonization with Aspergillus fumigatus and the concomitant isolation of Aspergillus nidulans, a switch to posaconazole as prophy-laxis (200 mg three times daily) was done. She did not present any side effects during the first year of treatment. After 12 months of posaconazole treatment, she progressively presented at first a skin fragility and then a venous stasis dermatitis with weight gain (6 kg) and a moon face. Her blood pressure was 130/80 mm Hg with no postural drop, and she had a fasting blood glucose level of 5.1 mmol/liter. Initial investigations detected a low serum cortisol level (35.6 ng/ml) at 8 a.m. (normal range, Ͼ210 ng/ml). A standard short Synacthen test was abnormal, with a baseline serum cortisol concentration of 46 nmol/liter (normal, 170 to 740 nmol/liter), rising only to 206.9 nmol/liter (normal, Ͼ600 nmol/liter) at 60 min, leading to the diagnosis of corticotroph insufficiency. There was no evidence of impaired glucose tolerance. Search for antiadrenal autoantibodies was negative, with limits of interpretation in this patient in IVIG substitution, and pituitary MRI was normal. An adrenocorticotropin (ACTH; at 8 a.m.) concentration of Ͻ10 pg/ml reflects the corticotrop insuffi-ciency. Other hormonal investigations of the hypothalamic-pituitary axis were normal (at 8 a.m.): prolactin ϭ 11.1 g/liter (normal, 3 to 29 g/liter), T4 ϭ 4.7 pmol/liter (normal, 11 to 39 pmol/liter), IGF1 ϭ 91.9 g/ml (normal, ϭ 70 to 300 g/ ml). Corticosteroids supplementation was introduced by hy-drocortisone (40 mg per day), and inhaled steroids were stopped. Oral glucocorticoid therapy is a common cause of iatrogenic Cushing's syndrome. Other routes of steroid administration, such as inhalation, topical, ocular, nasal drops, or epidural injections, may also result in hypercorticism (7). This can be promoted by interaction between glucocorticoids and other drugs interfering with glucocorticoid metabolism, such as ritonavir, itraconazole, or fluconazole (8). We hypothesize that our patient probably developed clinical Cushing's syndrome as a result of elevated sys-temic concentrations of inhaled steroids, which led to cortico-troph insufficiency resulting from adrenocorticotrophic hormone suppression. Inhibition of the cytochrome P450 CYP3A4-type enzyme system by posaconazole leads to a reduction in fluticasone hepatic metabolism. With prolonged use, inhaled steroids have previously been associated with adrenal suppression. The combination of itraconazole, fluconazole, or voriconazole with inhaled steroids has occasionally been reported to cause Cushing's syndrome after a few months of combination therapy, often reversible after treatment interruption (9). Our patient was on 7 years of itraconazole therapy in combination with fluticasone and neve

Elimination of fluconazole during continuous renal replacement therapy. An in vitro assessment

International audienceIntroduction:Continuous renal replacement therapy (CRRT) efficiently eliminates fluconazole. However, the routes of elimination were not clarified. Adsorption of fluconazole by filters is a pending question. We studied the elimination of fluconazole in a model mimicking a session of CRRT in humans using the NeckEpur® model. Two filters were studied.Methods:The AV1000®-polysulfone filter with the Multifiltrate Pro. Fresenius and the ST150®-polyacrylonitrile filter with the Prismaflex. Baxter-Gambro were studied. Continuous filtration used a flowrate of 2.5 L/h in post-dilution only. Session were made in duplicate. Routes of elimination were assessed using the NeckEpur® model.Results:The mean measured initial fluconazole concentration (mean ± SD) for the four sessions in the central compartment (CC) was 14.9 ± 0.2 mg/L. The amount eliminated from the CC at the end of 6 h-session at a 2.5 L/h filtration flowrate for the AV1000®-polysulfone and the ST150®-polyacrylonitrile filters were 90%–93% and 96%–94%, respectively; the clearances from the central compartment (CC) were 2.5–2.6 and 2.4–2.3 L/h, respectively. The means of the instantaneous sieving coefficient were 0.94%–0.91% and 0.99%–0.91%, respectively. The percentages of the amount eliminated from the CC by filtration/adsorption were 100/0%–95/5% and 100/0%–100/0%, respectively.Conclusion:Neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in any significant adsorption of fluconazole

Impact of the beta-lacta test on the management of urinary tract infections at the emergency department

Introduction: Rapid detection of extended-spectrum β-lactamases is essential. In this study, we evaluated the potential impact of β-lacta test on both the times to appropriate antibiotic therapy and to the implementation of patient isolation measures.Patients and methods: We included prospectively all the patients admitted to the emergency department for clinical suspicion of urinary tract infection. Compared with physician's decision, we analysed the potential impact of β-lacta test on the initial antibiotic therapy and on the implementation of hygiene measures. This study has been registered under number NCT02897609.Results: We included 203 patients, 43% with acute pyelonephritis and 21% with acute prostatitis. The β-lacta test had a 95.2% sensitivity and a 99.5% specificity to detect extended-spectrum β-lactamases. Taking the β-lacta test results into account would have decreased significantly both the times to appropriate therapy and to isolation measures from 54 to 2.7 h and from 55.2 to 2.6 h, respectively.Conclusion: The β-lacta test could reduce significantly the times to appropriate therapy and implementation of isolations measure