Unexpected activity of oral fosfomycin against resistant strains of Escherichia coli in murine pyelonephritis

International audienceFosfomycin tromethamine activity is well established for oral treatment of uncomplicated lower urinary tract infections, but little is known about its potential efficacy in pyelonephritis. Ascending pyelonephritis was induced in mice infected with 6 strains of Escherichia coli (fosfomycin MICs, 1 μg/ml to 256 μg/ml). The urine pH was 4.5 before infection and 5.5 to 6.0 during infection. Animals were treated for 24 h with fosfomycin (100 mg/kg of body weight subcutaneously every 4 h), and the CFU were enumerated in kidneys 24 h after the last fosfomycin injection. Peak (20.5 μg/ml at 1 h) and trough (3.5 μg/ml at 4 h) levels in plasma were comparable to those obtained in humans after an oral dose of 3 g. Fosfomycin treatment significantly reduced the bacterial loads in kidneys (3.65 log10 CFU/g [range, 1.83 to 7.03 log10 CFU/g] and 1.88 log10 CFU/g [range, 1.78 to 5.74 log10 CFU/g] in start-of-treatment control mice and treated mice, respectively; P < 10−6). However, this effect was not found to differ across the 6 study strains (P = 0.71) or between the 3 susceptible and the 3 resistant strains (P = 0.09). Three phenomena may contribute to explain this unexpected in vivo activity: (i) in mice, the fosfomycin kidney/plasma concentration ratio increased from 1 to 7.8 (95% confidence interval, 5.2, 10.4) within 24 h in vitro when the pH decreased to 5, (ii) the fosfomycin MICs for the 3 resistant strains (64 to 256 μg/ml) decreased into the susceptible range (16 to 32 μg/ml), and (iii) maximal growth rates significantly decreased for all strains and were the lowest in urine. These results suggest that local fosfomycin concentrations and physiological conditions may favor fosfomycin activity in pyelonephritis, even against resistant strains

Novel Chromosomal Mutations Responsible for Fosfomycin Resistance in Escherichia coli

International audienceFosfomycin resistance in results from chromosomal mutations or acquisition of plasmid-mediated genes. Because these mechanisms may be absent in some resistant isolates, we aimed at decipher the genetic basis of fosfomycin resistance in . Different groups of isolates were studied: fosfomycin-resistant mutants selected from CFT073 (MIC = 1 mg/L) and two groups (wildtype and non-wildtype) of clinical isolates. Single-nucleotide allelic replacement was performed to confirm the implication of novel mutations into resistance. Induction of expression by glucose-6-phosphate (G6P) was assessed by RT-qPCR. The genome of all clinical isolates was sequenced by MiSeq (Illumina). Two first-step mutants were obtained from CFT073 (MICs, 128 mg/L) with single mutations: G469R in (M3); F384L in (M4). Second-step mutants (MICs, 256 mg/L) presented additional mutations: R282V in (M7 from M3); Q558 in (M8 from M4). Introduction of or mutations by site-directed mutagenesis conferred a 128-fold increase in fosfomycin MICs, whereas single mutations in or were only responsible for a 2-fold increase. Also, these mutations abolished the induction of expression by G6P. All 14 fosfomycin-susceptible clinical isolates (MICs, 0.5-8 mg/L) were devoid of any mutation. At least one genetic change was detected in all but one fosfomycin-resistant clinical isolates (MICs, 32 - >256 mg/L) including 8, 17, 18, 5, and 8 in , , , , and genes, respectively. In conclusion, novel mutations in and are associated with fosfomycin resistance in clinical isolates

More complications in cervical than in non-cervical spine tuberculosis

International audiencePurpose: Cervical spine tuberculosis (CST) is a rare disease that may lead to severe neurological complications. The goal of the study was to compare the characteristics of patients with CST with those of patients with non-cervical spine tuberculosis (NCST).Methods: Between 1997 and 2016, we reviewed all cases of proven tuberculosis from a cohort of spine infections in a tertiary care hospital. Clinical, biological, and imaging data were collected at baseline and after treatment.Results: Fifty-one cases of spine tuberculosis were included: 14 with CST on imaging (27%) and 37 with no cervical localization. Median age was 39 y. Demographic characteristics, duration of symptoms and neurological findings of spine compression were similarly present at presentation in CST and NCST patients. On imaging, lesions were more often multifocal in CST than in NCST patients (9/14 [64%] versus 10/37 [27%], p = .014). Spinal surgery was required in 32/51 (63%) patients. At the end of follow-up (median: 20 months), cure rates were similar in CST and NCST patients but motor and/or sensitive functional sequel were more frequent in CST than NCST patients (6/14 [43%] versus 2/37 [5%], p = .003).Conclusions: Cervical involvement is present in more than a quarter of patients with spinal tuberculosis. Patients with CST had more frequent neurological sequelae than patients with NCST. This was mainly due to a more multifocal disease at presentation. Screening for cervical localization should be systematic in patients with spinal tuberculosis even in the absence of cervical symptoms

“Chronic Disseminated Aspergillosis,” a Novel Fungal Immune Reconstitution Inflammatory Syndrome

International audienceWe report a case of chronic hepatosplenic aspergillosis following immune reconstitution complicating colic aspergillosis in an AIDS patient with multicentric Castleman disease. Symptoms mimicked the clinical presentation of chronic disseminated candidiasis and responded to corticosteroid. This emerging entity enlarges the spectrum of fungal immune reconstitution inflammatory syndrome in the HIV setting

Sternal Wound Infection after Cardiac Surgery: Management and Outcome.

Sternal Wound Infection (SWI) is a severe complication after cardiac surgery. Debridement associated with primary closure using Redon drains (RD) is an effective treatment, but data on RD management and antibiotic treatment are scarce.We performed a single-center analysis of consecutive patients who were re-operated for SWI between 01/2009 and 12/2012. All patients underwent a closed drainage with RD (CDRD). Patients with endocarditis or those who died within the first 45 days were excluded from management analysis. RD fluid was cultured twice weekly. Variables recorded were clinical and biological data at SWI diagnosis, severity of SWI based on criteria for mediastinitis as defined by the Centers for Disease Control (CDC), antibiotic therapy, RD management and patient's outcome.160 patients developed SWI, 102 (64%) fulfilled CDC criteria (CDC+) and 58 (36%) did not (CDC- SWI). Initial antibiotic treatment and surgical management were similar in CDC+ and CDC- SWI. Patients with CDC+ SWI had a longer duration of antibiotic therapy and a mortality rate of 17% as compared to 3% in patients with CDC- SWI (p = 0.025). Rates of superinfection (10% and 9%) and need for second reoperation (12% and 17%) were similar. Failure (death or need for another reoperation) was associated with female gender, higher EuroScore for prediction of operative mortality, and stay in the ICU.In patients with SWI, initial one-stage surgical debridement with CDRD is associated with favorable outcomes. CDC+ and CDC- SWI received essentially the same management, but CDC+ SWI has a more severe outcome

Surgical and Medical Management in 137 Patients with Sternal Wound Infection Requiring Reoperation after Cardiac Surgery according to the Definition.

<p>Surgical and Medical Management in 137 Patients with Sternal Wound Infection Requiring Reoperation after Cardiac Surgery according to the Definition.</p

Flow chart of Patients with Sternal Wound Infection Requiring Reoperation after Cardiac Surgery.

<p>Flow chart of Patients with Sternal Wound Infection Requiring Reoperation after Cardiac Surgery.</p

Microbiological Data in 160 Patients with Sternal Wound Infection Requiring Reoperation after Cardiac Surgery, n (%).

<p>Abbreviation: MRSA, Methicillin-resistant staphylococcus aureus; CoNS, Coagulase-negative staphylococci</p><p>Microbiological Data in 160 Patients with Sternal Wound Infection Requiring Reoperation after Cardiac Surgery, n (%).</p

Initial Presentation of 160 Patients with Sternal Wound Infection Requiring Reoperation after Cardiac Surgery.

<p>* The two last modalities were brought together for the test because the conditions of validity for a Chi-square test at 3 degrees of freedom were not verified</p><p>Initial Presentation of 160 Patients with Sternal Wound Infection Requiring Reoperation after Cardiac Surgery.</p

Variables Associated with Failure (n = 36), Cox Proportional Hazard Model.

<p>Abbreviation: HR, Hazard ratio; BMI, Body Mass Index; SWI, CABG, Coronary Artery Bypass Grafting; SWI, Sternal Wound Infection; <i>S</i>. <i>aureus</i>, <i>Staphylococcus aureus</i>, CoNS, coagulase-negative staphylococci; CDC, Centers for Diseases control and Prevention; ICU, Intensive care unit</p><p>Variables Associated with Failure (n = 36), Cox Proportional Hazard Model.</p