The role of systemic corticosteroids when treating infections in adult primary care.

Inflammatory response to aggressive infection is responsible not only for symptoms, especially pain, but also for severity, when the inflammatory cascade is violent, and provokes a deleterious cytokine storm. Due to their anti-inflammatory properties, corticosteroids are widely used in ambulatory medical practice. While their beneficial effects on some symptoms, particularly pain, are undeniable, so are the risks associated with their other properties (immunosuppression, neurostimulation, hypermetabolism), even during short-term administration at low doses. Following robust risk-benefit assessment, the role of corticosteroids in the treatment of a number of serious pathologies (septic shock, severe acute community-acquired pneumonia, and some forms of bacterial meningitis such as hypoxia-related pneumocystosis, etc.) is presently well-defined. The objective of this review is not to consider the role of corticosteroids in cases of severe infectious disease necessitating hospital-based management, or in contexts where there exists a clear consensus in favor of their utilization. This work represents an attempt to apprise the current state of knowledge on the interest of corticosteroids in the management of infections in adults in primary care. Corticosteroid treatment can be beneficial with regard to some of the infectious diseases treated in primary care. That said, when the benefit actually appears, it remains modest, and the level of evidence supporting the utilization of corticosteroids is low or moderate. In no situation is an indication for corticosteroid therapy official or even, at the very least, indisputable. With regard to the pathologies under consideration, corticosteroid prescription must imperatively be based on impeccable characterization of the clinical situation, diagnosis of severity, knowledge of the disease field, and risk-benefit assessment for a given patient.

Defining standard and high dosages for ß-lactam agents administered by intermittent, prolonged or continuous infusion: a PK/PD simulation study.

BACKGROUND: The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For injectable ß-lactams, standard and high dosages have been proposed for short-infusion regimens only. OBJECTIVES: To evaluate dosages for ß-lactams administered by prolonged infusion (PI) and continuous infusion (CI). METHODS: Monte Carlo simulations were performed for seven injectable ß-lactams: aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, piperacillin and temocillin. Various dosage regimens based on short infusion, PI or CI were simulated in virtual patients. Pharmacokinetic (PK) profiles and PTAs were obtained based on reference population PK models, as well as PK/pharmacodynamic targets and MIC breakpoints proposed by EUCAST. Alternative dosage regimens associated with PTA values similar to those of recommended dosages up to the breakpoints were considered acceptable. RESULTS: Adequate PTAs were confirmed for most EUCAST short-infusion dosage regimens. A total of 9 standard and 14 high dosages based on PI (3 to 4 h) or CI were identified as alternatives. For cefepime and aztreonam, only PI and CI regimens could achieve acceptable PTAs for infections caused by Pseudomonas spp.: 2 g q8h as PI of 4 h or 6 g/24 h CI for cefepime; 2 g q6h as PI of 3 h or 6 g/24 h CI for aztreonam. CONCLUSIONS: These alternative standard and high dosage regimens are expected to provide antibiotic exposure compatible with new EUCAST definitions of susceptibility categories and associated MIC breakpoints. However, further clinical evaluation is necessary.

Antibiotic Therapy for 6 or 12 Weeks for Prosthetic Joint Infection.

BACKGROUND: The management of prosthetic joint infection usually consists of a combination of surgery and antimicrobial therapy. The appropriate duration of antimicrobial therapy for this indication remains unclear. METHODS: We performed an open-label, randomized, controlled, noninferiority trial to compare 6 weeks with 12 weeks of antibiotic therapy in patients with microbiologically confirmed prosthetic joint infection that had been managed with an appropriate surgical procedure. The primary outcome was persistent infection (defined as the persistence or recurrence of infection with the initial causative bacteria, with an antibiotic susceptibility pattern that was phenotypically indistinguishable from that at enrollment) within 2 years after the completion of antibiotic therapy. Noninferiority of 6 weeks of therapy to 12 weeks of therapy would be shown if the upper boundary of the 95% confidence interval for the absolute between-group difference (the value in the 6-week group minus the value in the 12-week group) in the percentage of patients with persistent infection within 2 years was not greater than 10 percentage points. RESULTS: A total of 410 patients from 28 French centers were randomly assigned to receive antibiotic therapy for 6 weeks (205 patients) or for 12 weeks (205 patients). Six patients who withdrew consent were not included in the analysis. In the main analysis, 20 patients who died during follow-up were excluded, and missing outcomes for 6 patients who were lost to follow-up were considered to be persistent infection. Persistent infection occurred in 35 of 193 patients (18.1%) in the 6-week group and in 18 of 191 patients (9.4%) in the 12-week group (risk difference, 8.7 percentage points; 95% confidence interval, 1.8 to 15.6); thus, noninferiority was not shown. Noninferiority was also not shown in the per-protocol and sensitivity analyses. We found no evidence of between-group differences in the percentage of patients with treatment failure due to a new infection, probable treatment failure, or serious adverse events. CONCLUSIONS: Among patients with microbiologically confirmed prosthetic joint infections that were managed with standard surgical procedures, antibiotic therapy for 6 weeks was not shown to be noninferior to antibiotic therapy for 12 weeks and resulted in a higher percentage of patients with unfavorable outcomes. (Funded by Programme Hospitalier de Recherche Clinique, French Ministry of Health; DATIPO ClinicalTrials.gov number, NCT01816009.).

Oral switch versus standard intravenous antibiotic therapy in left-sided endocarditis due to susceptible staphylococci, streptococci or enterococci (RODEO): a protocol for two open-label randomised controlled trials.

INTRODUCTION: Left-sided infective endocarditis (IE) is a serious infection with a heavy burden for patients and healthcare system. Oral switch after initial intravenous antibiotic therapy may reduce costs and improve patients' discomfort without increasing unfavourable outcomes. We describe the methodology of two simultaneously conducted open-label randomised trials aiming to assess non-inferiority of oral switch as compared with entirely intravenous antibiotic therapy for the treatment of left-sided IE. METHODS AND ANALYSIS: Two simultaneous multicentre open-label prospective randomised trials assessing non-inferiority of oral switch during antibiotic treatment as compared with entirely intravenous therapy in patients with left-sided IE are ongoing. One trial is dedicated to left-sided IE caused by multisusceptible staphylococci (Relais Oral Dans le traitement des Endocardites à staphylocoques ou streptOcoques (RODEO)-1) and the other is dedicated to left-sided IE caused by susceptible streptococci or enterococci (RODEO-2). It is planned to randomise 324 patients in each trial after an initial course of at least 10 days of intravenous antibiotic therapy either to continue intravenous antibiotic therapy or to switch to oral antibiotic therapy. The primary outcome is treatment failure within 3 months after the end of antibiotic treatment, a composite outcome defined by all-cause death and/or symptomatic embolic events and/or unplanned valvular surgery and/or microbiological relapse (with the primary pathogen). Secondary outcomes include patient quality of life, echocardiographic outcome, costs and efficiency associated with IE care. Statistical analysis will be performed with a non-inferiority margin of 10% and a one-sided 2.5% type I error. ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants. This study was approved by Tours Research ethics committee (CPP TOURS-Region Centre-Ouest 1, 2015-R26, 23 February 2016). Study findings will be published in peer-reviewed journals and disseminated through presentation at relevant national and international conferences. TRIAL REGISTRATION NUMBER: EudraCT Number: 2015-002371-16 and NCT02701608; NCT02701595.

Carbapenem use in French hospitals: A nationwide survey at the patient level.

The objective of this study was to evaluate the characteristics of carbapenem use in French healthcare settings in order to guide future actions. Healthcare facilities voluntarily participated in a nationwide cross-sectional survey in 2011. Medical data and reasons for carbapenem treatment (CPR) and discontinuation were recorded for all patients treated with carbapenems. A total of 2338 patients were recorded by 207 facilities. The median duration of CPR was 8 days, and 31.4% of patients received CPR for >10 days. An antibiotic consultant was involved in the initial choice of CPR in 36.8% of cases. CPR was chosen on an empirical (EP) basis for 1229 patients (52.6%), mainly because of severe sepsis (48.6%) or a perceived risk of bacterial resistance (33.7%). Among EP patients, de-escalation was more frequent in the case of intervention of an antibiotic consultant (35.1%) than without intervention (22.9%) (P<0.01). Among the 1109 patients receiving CPR initially based on bacteriological results, 607 (54.7%) had ESBL-producing Enterobacteriaceae and 397 (35.8%) had Gram-negative bacilli susceptible to at least one ß-lactam other than carbapenems or to fluoroquinolones. Among the latter, de-escalation was performed in 59 cases (14.9%). The intervention of an antibiotic consultant did not favour de-escalation in this group. In conclusion, carbapenems are frequently used for treating suspected or confirmed multidrug-resistant bacteria, and overall CPR duration is long. De-escalation is frequently not implemented despite isolates being susceptible to other drugs. More frequent antibiotic consultant intervention may help to decrease carbapenem use in the case of EP treatment.

Guidelines for management of intra-abdominal infections.

Intra-abdominal infections are one of the most common gastrointestinal emergencies and a leading cause of septic shock. A consensus conference on the management of community-acquired peritonitis was published in 2000. A new consensus as well as new guidelines for less common situations such as peritonitis in paediatrics and healthcare-associated infections had become necessary. The objectives of these Clinical Practice Guidelines (CPGs) were therefore to define the medical and surgical management of community-acquired intra-abdominal infections, define the specificities of intra-abdominal infections in children and describe the management of healthcare-associated infections. The literature review was divided into six main themes: diagnostic approach, infection source control, microbiological data, paediatric specificities, medical treatment of peritonitis, and management of complications. The GRADE(®) methodology was applied to determine the level of evidence and the strength of recommendations. After summarising the work of the experts and application of the GRADE(®) method, 62 recommendations were formally defined by the organisation committee. Recommendations were then submitted to and amended by a review committee. After 2 rounds of Delphi scoring and various amendments, a strong agreement was obtained for 44 (100%) recommendations. The CPGs for peritonitis are therefore based on a consensus between the various disciplines involved in the management of these patients concerning a number of themes such as: diagnostic strategy and the place of imaging; time to management; the place of microbiological specimens; targets of empirical anti-infective therapy; duration of anti-infective therapy. The CPGs also specified the value and the place of certain practices such as: the place of laparoscopy; the indications for image-guided percutaneous drainage; indications for the treatment of enterococci and fungi. The CPGs also confirmed the futility of certain practices such as: the use of diagnostic biomarkers; systematic relaparotomies; prolonged anti-infective therapy, especially in children.

Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.

BACKGROUND: Duration of treatment for patients with vertebral osteomyelitis is mainly based on expert recommendation rather than evidence. We aimed to establish whether 6 weeks of antibiotic treatment is non-inferior to 12 weeks in patients with pyogenic vertebral osteomyelitis. METHODS: In this open-label, non-inferiority, randomised controlled trial, we enrolled patients aged 18 years or older with microbiologically confirmed pyogenic vertebral osteomyelitis and typical radiological features from 71 medical care centres across France. Patients were randomly assigned to either 6 weeks or 12 weeks of antibiotic treatment (physician's choice in accordance with French guidelines) by a computer-generated randomisation list of permuted blocks, stratified by centre. The primary endpoint was the proportion of patients who were classified as cured at 1 year by a masked independent validation committee, analysed by intention to treat. Non-inferiority would be declared if the proportion of cured patients assigned to 6 weeks of treatment was not less than the proportion of cured patients assigned to 12 weeks of treatment, within statistical variability, by an absolute margin of 10%. This trial is registered with EudraCT, number 2006-000951-18, and Clinical Trials.gov, number NCT00764114. FINDINGS: Between Nov 15, 2006, and March 15, 2011, 359 patients were randomly assigned, of whom six in the 6-week group and two in the 12-week group were excluded after randomisation. 176 patients assigned to the 6-week treatment regimen and 175 to the 12-week treatment regimen were analysed by intention to treat. 160 (90·9%) of 176 patients in the 6-week group and 159 (90·9%) of 175 of those in the 12-week group met the criteria for clinical cure. The difference between the groups (0·05%, 95% CI -6·2 to 6·3) showed the non-inferiority of the 6-week regimen when compared with the 12-week regimen. 50 patients in the 6-week group and 51 in the 12-week group had adverse events, the most common being death (14 [8%] in the 6-week group vs 12 [7%] in the 12-week group), antibiotic intolerance (12 [7%] vs 9 [5%]), cardiorespiratory failure (7 [4%] vs 12 [7%]), and neurological complications (7 [4%] vs 3 [2%]). INTERPRETATION: 6 weeks of antibiotic treatment is not inferior to 12 weeks of antibiotic treatment with respect to the proportion of patients with pyogenic vertebral osteomyelitis cured at 1 year, which suggests that the standard antibiotic treatment duration for patients with this disease could be reduced to 6 weeks. FUNDING: French Ministry of Health.

Ceftaroline for the treatment of prosthetic valve endocarditis due to methicillin-resistant Staphylococcus aureus.

The case is described of a frail patient who developed prosthetic valve endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA). Conventional antimicrobial treatments either failed or were contraindicated, and the patient was judged unsuitable for a further valve replacement. A salvage therapy with high doses of a new cephalosporin, ceftaroline, given three times daily was undertaken; subsequently, the patient had not relapsed at two months after completing a six-week course of ceftaroline. Ceftaroline deserves major attention as an alternative choice in difficult-to-treat MRSA endocarditis.

Fosfomycin: efficacy against infections caused by multidrug-resistant bacteria.

OBJECTIVE: To analyze the indications for and the efficacy of parenteral fosfomycin, especially against multidrug-resistant (MDR) and pan-resistant bacterial infections. PATIENTS AND METHODS: During a unique crisis in fosfomycin production, the supply of this antibiotic had to be carefully monitored in France over a 10-week period. One hundred and sixteen assessable patients were included in a prospective cohort study. RESULTS: The main indications for use were osteoarthritis, lung infection, urinary tract infection, and bacteraemia. The 2 bacteria most frequently involved were Pseudomonas aeruginosa and methicillin-resistant Staphylococcus. MDR bacteria were seen in 71.5% (83/116) of cases, especially MDR P. aeruginosa (n = 28). Critical situations were common, with 44.0% (51/116) of hospitalizations occurring in an intensive care unit and 22.4% (26/116) of patients with septic shock. The overall outcome was favourable in 76.8% of cases (76/99 assessable patients). CONCLUSION: This study provided a unique opportunity to describe the use of fosfomycin and assess its efficacy, especially against MDR bacterial infections, even in critical situations.

Value of preoperative investigations in diagnosing prosthetic joint infection: retrospective cohort study and literature review.

The diagnosis of a prosthetic joint infection is difficult, but crucial for appropriate treatment. Scintigraphy with specific markers for infection (labelled white cells or immunoglobulin-G) has been reported as a more reliable diagnostic tool than clinical assessment (fever, fistula), laboratory studies (polynuclear neutrophil count, erythrocyte rate sedimentation, and C-reactive protein), and preoperative aspiration. In the first part of this study, we retrospectively reviewed 230 patients admitted with a suspected prosthetic joint infection, and examined the validity of the different diagnostic tools for the group as a whole and for subgroups according to the Coventry classification. In the second part, we reviewed 35 articles about preoperative evaluation of infection in prosthetic joints and compared them to our findings. Our study indicates that C-reactive protein and joint aspiration are the most useful tools to diagnose prosthetic joint infection even in situations of chronic infection (Coventry type II).

[Update on the role of levofloxacin in the management of acute community-acquired pneumonia]. / Actualités et place de la lévofloxacine dans la prise en charge des pneumonies aiguës communautaires.

THE EFFICACY OF LEVOFLOXACIN: In treating community-acquired pneumonia (CAP) has been assessed during 5 large clinical trials (including 4 controlled randomized trials). 1067 PATIENTS HAVE BEEN TREATED BY LEVOFLOXACIN: And 645 by a comparator. Success rates were identical between levofloxacin and comparator ranging from 70.6% to 84.2% for levofloxacin treated patients, and from 75% to 85.7% for comparators treated patients. 549 PRESUMED OR PROVED PNEUMOCOCCAL PNEUMONIA: Have been treated by levofloxacin with a success rate ranging from 83% to 100%, and 379 have been treated by a comparator with a success rate ranging from 90% to 95%. Success rates for the 310 pneumococcal-documented infections, including 96 bacteraemia, were identical between levofloxacin and comparator. The severity of the patients ranged between studies from moderate to severe. PROOFS COMING FROM THOSE CLINICAL TRIALS: Show the efficiency of levofloxacin in the treatment of moderate to severe community acquired pneumonia in adults, and in the treatment of presumed or proved pneumonia, with or without bacteraemia.