A meropenem pharmacokinetics model in patients with haematological malignancies.

BACKGROUND: Optimal dosing of antibiotics is critical in immunocompromised patients suspected to have an infection. Data on pharmacokinetics (PK) of meropenem in patients with haematological malignancies are scarce. OBJECTIVES: To optimize dosing regimens, we aimed to develop a PK population model for meropenem in this population. METHODS: Patients aged ≥18 years, hospitalized in the haematology department of our 1500 bed university hospital for a malignant haematological disease and who had received at least one dose of meropenem were eligible. Meropenem was quantified by HPLC. PK were described using a non-linear mixed-effect model and external validation performed on a distinct database. Monte Carlo simulations estimated the PTA, depending on renal function, duration of infusion and MIC. Target for free trough concentration was set at >4× MIC. RESULTS: Overall, 88 patients (181 samples) were included, 66 patients (75%) were in aplasia and median Modification of Diet in Renal Disease (MDRD) CLCR was 117 mL/min/1.73 m2 (range: 35-359). Initial meropenem dosing regimen ranged from 1 g q8h to 2 g q8h over 30 to 60 min. A one-compartment model with first-order elimination adequately described the data. Only MDRD CLCR was found to be significantly associated with CL. Only continuous infusion achieved a PTA of 100% whatever the MIC and MDRD CLCR. Short duration of infusion (<60 min) failed to reach an acceptable PTA, except for bacteria with MIC < 0.25 mg/L in patients with MDRD CLCR below 90 mL/min/1.73 m2. CONCLUSIONS: In patients with malignant haematological diseases, meropenem should be administered at high dose (6 g/day) and on continuous infusion to reach acceptable trough concentrations.

Clinical and microbiological features associated with group B Streptococcus bone and joint infections, France 2004-2014.

This study describes the clinical and microbiological features associated with group B Streptococcus (GBS) bone and joint infections (BJIs). It was a retrospective analysis of adult cases of GBS BJIs reported to the French National Reference Center for Streptococci from January 2004 to December 2014. Clinical data and GBS molecular characteristics are reported. Strains were collected from 163 patients. The most frequent comorbidities were: solid organ cancer (n = 21, 21%) and diabetes mellitus (n = 20, 20%). The main infection sites were knee (47/155 = 30%) and hip (43/155 = 27%), and occurred on orthopedic devices in 71/148 cases (48%). CPS III (n = 47, 29%), Ia (n = 26, 16%) and V (n = 40, 25%) were predominant. Resistance to erythromycin, clindamycin and tetracycline was detected in 55/163 (34%), 35/163 (21%) and 132/163 (81%) strains, respectively. The most frequent sequence types were ST-1 (n = 21, 25%), ST-17 (n = 17, 20%) and ST-23 (n = 11, 13%). The rate of resistance to erythromycin was 0% for ST-17 strains, 52% (n = 11) for ST-1 and 44% (n = 7) for ST-23 (p < 0.001). GBS bone and joint infections predominantly occur in patients aged >50 years and/or with comorbidities such as cancer and diabetes mellitus. CPS type distribution and MLST are very similar to that of other adult GBS invasive infections.

Fighting the spread of AmpC-hyperproducing Enterobacteriaceae: beneficial effect of replacing ceftriaxone with cefotaxime.

OBJECTIVES: Considering the hypothesis that the high biliary elimination of ceftriaxone could be responsible for the selection of Enterobacteriaceae harbouring high-level AmpC ß-lactamase (HL-CASE), the use of ceftriaxone was discontinued in our hospital in 2006 and replaced with cefotaxime. METHODS: Antibiotic consumption, expressed as defined daily dose (DDD)/1000 patient-days (PD), and HL-CASE incidence, expressed as the number of patients carrying HL-CASE/1000 PD, were compared between the pre-intervention period (Period 1, 2001-05) and the post-intervention period (Period 2, 2006-12) using an interrupted time series analysis. RESULTS: The incidence of HL-CASE increased significantly from 0.32 to 0.69/1000 PD during Period 1 (coefficient = 0.082, P < 0.01). A significant inflection of the slope in the incidence curve occurred in Period 2 (coefficient = -0.061, P = 0.05), mainly owing to the stabilization of the HL-CASE incidence of Enterobacteriaceae harbouring chromosomally inducible cephalosporinase (Period 1, 0.27 to 0.64/1000 PD; Period 2, 0.58 to 0.61/1000 PD) and especially for Enterobacter cloacae (Period 1, 0.09 to 0.30/1000 PD; Period 2, 0.26 to 0.27/1000 PD). This deceleration was observed despite a significant increase in the slope of cefotaxime consumption over Period 2 (coefficient = 2.97, P < 0.01). CONCLUSION: Despite the disadvantages of using cefotaxime compared with ceftriaxone (administration three times daily versus once a day), the ecological benefits of this substitution seem sufficiently convincing to preferentially use cefotaxime. Control of HL-CASE incidence is crucial to limiting carbapenem use and preventing the selection of carbapenemase-producing Enterobacteriaceae.

Auditory brainstem response: Key parameters for good-quality recording.

Auditory brainstem response (ABR) is widely used in ENT to investigate hearing loss. This test evaluates the response of the ascending auditory pathway, from cochlea to mesencephalon, following auditory stimulation. It provides precise analysis of waves numbered I to V according to location on the auditory pathway, in terms of amplitude, latency and inter-wave interval. Good-quality assessment requires familiarity with the parameters to be used and the factors likely to modify response. We describe the procedure for ABR examination and the recorded responses, with particular attention to factors influencing response to which the examiner must be vigilant. These factors are related to the individual (age, gender, hearing loss, body temperature, drug treatments), transducer (air or bone conduction), stimulation parameters (type, polarity, intensity, calibration, duration, cadence, number of clicks, background noise) and acquisition parameters (analysis window, scale, electrodes). We also briefly describe the clinical applications of this examination.

How have mathematical models contributed to understanding the transmission and control of SARS-CoV-2 in healthcare settings? A systematic search and review.

Since the onset of the COVID-19 pandemic, mathematical models have been widely used to inform public health recommendations regarding COVID-19 control in healthcare settings. The objective of this study was to systematically review SARS-CoV-2 transmission models in healthcare settings, and to summarize their contributions to understanding nosocomial COVID-19. A systematic search and review of published articles indexed in PubMed was carried out. Modelling studies describing dynamic inter-individual transmission of SARS-CoV-2 in healthcare settings, published by mid-February 2022 were included. Models have mostly focused on acute-care and long-term-care facilities in high-income countries. Models have quantified outbreak risk, showing great variation across settings and pandemic periods. Regarding surveillance, routine testing rather than symptom-based was highlighted as essential for COVID-19 prevention due to high rates of silent transmission. Surveillance impacts depended critically on testing frequency, diagnostic sensitivity, and turn-around time. Healthcare re-organization also proved to have large epidemiological impacts: beyond obvious benefits of isolating cases and limiting inter-individual contact, more complex strategies (staggered staff scheduling, immune-based cohorting) reduced infection risk. Finally, vaccination impact, while highly effective for limiting COVID-19 burden, varied substantially depending on assumed mechanistic impacts on infection acquisition, symptom onset and transmission. Modelling results form an extensive evidence base that may inform control strategies for future waves of SARS-CoV-2 and other viral respiratory pathogens. We propose new avenues for future models of healthcare-associated outbreaks, with the aim of enhancing their efficiency and contributions to decision-making.

Potential impact of real-time processing and rapid susceptibility testing of blood samples in Gram-negative bloodstream infections in intensive care patients.

INTRODUCTION: Timely and appropriate therapy is critical in patients with Gram-negative bloodstream infections (GNBSI). Most bacteriology laboratories process blood specimen in the daytime, during laboratory operating hours, and use conventional culture for antimicrobial susceptibility testing (AST). We simulated the potential impact of real-time processing and rapid AST (7 hours) on early adaptation of the antibiotic regimen in intensive care unit (ICU) patients with GNBSI. METHODS: All GNBSI episodes occurring in the ICUs of 2 hospitals in Paris were included. Data were collected. For each episode of bacteremia, we simulated the impact of three strategies: (1) Real-time processing coupled with conventional techniques (Gram stain and standard AST); (2) Standard processing coupled with rapid AST; and (3) Real-time processing coupled with rapid AST. RESULTS: We included 109 episodes in 98 patients. Forty-two patients (48%) died during ICU stay. AST results led to a change of the antibiotic regimen in 66 (61%) episodes, mainly de-escalation (54/109, 55%). In standard care, median time from sample collection to definitive AST result was 65.9 hours (±26.7). The three strategies would have reduced time-to-result by 9.2 hours (±7.1), 30.8 hours (±19.7) and 40.0 hours (±20.6) respectively. Compared to standard care, strategies 1, 2 and 3 would have avoided 20, 69 and 90 patient-days of broad-spectrum antibiotics respectively. CONCLUSION: In addition to real-time processing of blood samples, rapid AST would be the most effective strategy to shorten time-to-result in critical patients with GNBSI.

Outcome of spontaneous and iatrogenic pneumothoraces managed with small-bore chest tubes.

BACKGROUND: Little is known about the efficacy of management of iatrogenic pneumothoraces with small-bore chest tubes. The aim of this study was to assess the outcome of iatrogenic pneumothoraces requiring drainage managed with a small-bore chest tube and to compare the results to spontaneous pneumothoraces treated in the same unit with the same device. The primary outcome was requirement of video-assisted thoracoscopic surgery for drainage failure; secondary outcomes were length of drainage and number of inserted chest tubes. METHODS: Patients with pneumothorax admitted between 1997 and 2007 were retrospectively identified. Traumatic pneumothoraces and those occurring under mechanical ventilation were excluded. All pneumothoraces were drained using the same small-bore chest tube (8 French) according to our local protocol. RESULTS: Five hundred sixty-one pneumothoraces were analysed, 431 (76.8%) were spontaneous pneumothoraces and 130 (23.2%) were iatrogenic. Iatrogenic pneumothoraces were associated with less requirement of video-assisted thoracoscopic surgery for drainage failure [adjusted odds ratio= 0.24 (0.04, 0.86)]. Length of drainage of iatrogenic pneumothoraces was longer than for primary spontaneous pneumothoraces (3.8 ± 3.1 vs. 2.7 ± 1.8 days, P < 0.001) and shorter than for secondary spontaneous pneumothoraces (4.6 ± 2.3 days, P = 0.004). Number of inserted chest tubes per patient was not significantly different according to pneumothoraces' aetiology. CONCLUSION: Small-bore chest tubes are feasible for treatment of iatrogenic pneumothoraces and have a better rate of success and slightly longer drainage duration than when used for spontaneous pneumothoraces.

3D-printed simulator for nasopharyngeal swab collection for COVID-19.

OBJECTIVES: Diagnosis of COVID-19 is essential to prevent the spread of SARS-CoV-2. Nasopharyngeal swabs (NPS) remain the gold standard in screening, although associated with false negative results (up to 30%). We developed a 3D simulator of the nasal and pharyngeal cavities for the learning and improvement of NPS collection. PATIENTS AND METHODS: Simulator training sessions were carried out in 11 centers in France. A questionnaire assessing the simulator was administered at the end of the sessions. The study population included both healthcare workers (HCW) and volunteers from the general population. RESULTS: Out of 589 participants, overall satisfaction was scored 9.0 [8.9-9.1] on a scale of 0 to 10 with excellent results in the 16 evaluation items of each category (HCWs and general population, NPS novices and experienced). The simulator was considered very realistic (95%), easy to use (97%), useful to understand the anatomy (89%) and NPS sampling technique (93%). This educational tool was considered essential (93%). Participants felt their future NPS would be more reliable (72%), less painful (70%), easier to perform (88%) and that they would be carried out more serenely (90%). The mean number of NPS conducted on the simulator to feel at ease was two; technical fluency with the simulator can thus be acquired quickly. CONCLUSION: Our simulator, whose 3D printing can be reproduced freely using a permanent open access link, is an essential educational tool to standardize the learning and improvement of NPS collection. It should enhance virus detection and thus contribute to better pandemic control.

Rapid diagnostic tests for infectious diseases in the emergency department.

BACKGROUND: Rapid diagnostic tests (RDTs) for infectious diseases, with a turnaround time of less than 2 hours, are promising tools that could improve patient care, antimicrobial stewardship and infection prevention in the emergency department (ED) setting. Numerous RDTs have been developed, although not necessarily for the ED environment. Their successful implementation in the ED relies on their performance and impact on patient management. OBJECTIVES: The aim of this narrative review was to provide an overview of currently available RDTs for infectious diseases in the ED. SOURCES: PubMed was searched through August 2019 for available studies on RDTs for infectious diseases. Inclusion criteria included: commercial tests approved by the US Food and Drug Administration (FDA) or Conformité Européenne (CE) in vitro diagnostic devices with data on clinical samples, ability to run on fully automated systems and result delivery within 2 hours. CONTENT: A nonexhaustive list of representative commercially available FDA- or CE-approved assays was categorized by clinical syndrome: pharyngitis and upper respiratory tract infection, lower respiratory tract infection, gastrointestinal infection, meningitis and encephalitis, fever in returning travellers and sexually transmitted infection, including HIV. The performance of tests was described on the basis of clinical validation studies. Further, their impact on clinical outcomes and anti-infective use was discussed with a focus on ED-based studies. IMPLICATIONS: Clinicians should be familiar with the distinctive features of each RDT and individual performance characteristics for each target. Their integration into ED work flow should be preplanned considering local constraints of given settings. Additional clinical studies are needed to further evaluate their clinical effectiveness and cost-effectiveness.

Variable impact of an antimicrobial stewardship programme in three intensive care units: time-series analysis of 2012-2017 surveillance data.

BACKGROUND: Preprescription authorization (PPA) and postprescription review with feedback (PPRF) were successively implemented in 2012 and 2016 in our 1500-bed hospital. AIM: The impact of PPA and PPRF on carbapenems use and resistance levels of Pseudomonas aeruginosa was assessed in three intensive care units (ICUs). METHODS: Carbapenems use (in DDDs/1000 occupied bed-days) and resistance of P. aeruginosa (percentage of non-susceptible (I+R) isolates to imipenem and/or meropenem) were analysed using a controlled interrupted time-series method. Two periods were compared: 2012-2015 (PPA) and 2016-2017 (PPA+PPRF). Models were adjusted on the annual incidence of extended-spectrum ß-lactamase-producing enterobacteriacae. FINDINGS: Carbapenem use was stable over the PPA period in all ICUs, with a significant change of slope over the PPA+PPRF period only in ICU1 (ß2 = -12.8, 95% confidence interval (CI) = -19.5 to -6.1). There was a switch from imipenem to meropenem during the PPA period in all three units. Resistances of P. aeruginosa were stable over the study period in ICU1 and ICU2, and significantly decreased over the PPA+PPRF period in ICU3 (ß2 = -0.18, CI = -0.3 to -0.03). CONCLUSION: In real-life conditions and with the same antimicrobial stewardship programme (AMSP) led by a single team, the impact of PPRF was heterogeneous between ICUs. Factors driving the impact of AMSPs should be further assessed in comparable settings through real-life data, to target where they could prove cost-effective.

Six-week antibiotic therapy after one-stage replacement arthroplasty for hip and knee periprosthetic joint infection.

OBJECTIVES: One-stage replacement arthroplasty for treatment of periprosthetic joint infection (PJI) results in similar cure rate than two-stage (around 85-92%), but antibiotic therapy duration is not well established. The aim of this study was to evaluate the efficacy of a short six-week antibiotic course in periprosthetic joint infections after onstage exchange. PATIENTS AND METHODS: Retrospective, observational study conducted at Orthopaedic Department of Cochin Hospital, Paris, between 1st January 2010 and 31 December 2015. Patients with a microbiologically proven PJI, treated with one-stage replacement and 6 weeks (+/1week) of antimicrobial therapy were included. Pearson's-χ2 and Wilcoxon tests were used to compare categorical and continuous variables. RESULTS: Fifty patients with periprosthetic joint infections (42 hip, 8 knee PJI) treated with one-stage replacement arthroplasty were included. Median age was 69.3 years (IQR 24.5-97.4). Infections occurred after a mean of 36 months (IQR 1-216). Bone biopsy cultures were positive for Staphylococcus spp. in 29 patients (58%), Cutibacterium acnes in 19 (38%), Gram-negative bacilli in 6 (12%). Polymicrobial infections occurred in 12 (24%). Intravenous antibiotics were administered for a median of 11 days (IQR 4-45) and 46 patients (92%) were switched to an oral therapy. Medium follow-up was of 32 months (IQR 12-101). Overall remission rate was 90%. CONCLUSIONS: A six-week course of antibiotics in knee and hip PJIs treated with one-stage RA has a satisfactory remission rate in this open study.

Conversion by Peyer's patch lymphocytes of human enterocytes into M cells that transport bacteria.

The epithelium that lines the gut is impermeable to macromolecules and microorganisms, except in Peyer's patches (PPs), where the lymphoid follicle-associated epithelium (FAE) contains M cells that transport antigens and microorganisms. A cultured system that reproduces the main characteristics of FAE and M cells was established by cultivation of PP lymphocytes with the differentiated human intestinal cell line Caco-2. Lymphocytes settled into the epithelial monolayer, inducing reorganization of the brush border and a temperature-dependent transport of particles and Vibrio cholerae. This model system could prove useful for intestinal physiology, vaccine research, and drug delivery studies.

Assessing the benefit of the 72-hour antibiotic therapy reassessment documentation.

OBJECTIVES: To assess the documentation of the 72-hour antibiotic therapy reassessment in medical records. METHODS: One-day prevalence evaluation of curative antibiotic therapies≥72hours. The documentation of the reassessment was defined according to three criteria: (1) "clear" documentation (clinical or microbiological comment associated with a comment on the need to adjust the antibiotic therapy or on the lack of need); (2) "tacit" documentation (only based on a clinical or microbiological comment); (3) no documentation. RESULTS: We assessed 114 antibiotic therapies in 26 hospital departments. A clear reassessment at 72hours was observed in only 45 (39%) records and 31 (27%) records had no reassessment. The planned duration of treatment was written in 63 (55%) records. At 72hours, among the 71 antibiotic therapies with a microbiological documentation, 69 (97%) were active and 44 (62%) had a narrow spectrum. Among the 48 antibiotic therapies with a broad spectrum on day 1, only 21 (44%) benefited from a de-escalation at 72hours. A clearly recorded reassessment at 72hours was associated with de-escalation (P=0.025) and the prescription of a planned duration of treatment was associated with antibiotic therapy compliance with local or national guidelines (P=0.018). CONCLUSION: Although reassessment was observed in 73% of records, it was correctly recorded at 72hours in only 39% of cases. The documentation of the reassessment and the prescription of a planned duration were associated with a better quality of antibiotic prescription (de-escalation, compliance with guidelines) and are relevant indicators for monitoring the proper use of antibiotics.

Risk factors for development of desmoid tumours in familial adenomatous polyposis.

BACKGROUND: Desmoid tumours (DTs) are the primary cause of death of patients with familial adenomatous polyposis (FAP) following restorative proctocolectomy. The aim of this study was to identify risk factors for DT in a French population. METHODS: Clinical data for 442 patients with FAP from 1983 to 2004 were reviewed retrospectively. RESULTS: A total of 124 DTs were documented in 50 patients (25 female). DT sites were mesenteric (73 tumours), abdominal wall (44) and extra-abdominal (seven). Female patients developed DT earlier than males. Although DTs appeared after colectomy in 34 patients, the type of surgery did not influence the risk of DT. An identified point mutation in the adenomatous polyposis coli (APC) gene after codon 1444 was a significant risk factor (hazard ratio 3.3 (95 per cent confidence interval 1.5 to 7.3)). Belonging to a family affected by DT did not increase the individual's risk in this population. CONCLUSION: No risk factor for life-threatening mesenteric DT could meaningfully modify the management of patients with FAP.

[A study comparing previous induced abortion rates in populations of newly delivered women and infertile women]. / Etude comparative sur les antécédents d'interruption volontaire de grossesse dans une population de femmes infertiles et dans une population de femmes accouchées.

OBJECTIVE: For years, induced abortions (IA) have been deemed responsible for altered fertility. The implication of various mechanisms including tubal infertility, intra-uterine adhesions, spontaneous abortion, ectopic pregnancy, cervical incompetence, shortened gestations, and any psychological trouble leading to anovulation has been raised. Though many authors find no evidence of an increased risk on fertility for women, whose IA is not complicated by infection, it might sometimes be insinuated that infertility is the consequence of previous abortion. Thus, we compared the rate of patients with any prior IA in a population of newly delivered women and in women ongoing IVF. PATIENTS AND METHODS: A retrospective study was conducted at Sèvres hospital, comparing two populations of women, newly delivered women (n=1738) between January 1st and December 31st 2005, and women ongoing IVF at the same period (n=430). We reported the number of previous medical or surgical induced abortions and compared it in both groups. Another analysis compared these rates, among two subgroups of women with one or more prior pregnancy (secondary infertility (n=148), and secondary gestation (n=1088). RESULTS: The rate of prior IA was not different in the two populations. In the IVF group, 13% (n=56) had undergone one or more IA, versus 16.7% (n=291) in the newly delivered group (P=0.06). Among women with previous pregnancy, 37.8% (56) women of the IVF group had undergone one or more previous IA, versus 26.7% (291) of the newly delivered women (P=0.007). DISCUSSION AND CONCLUSION: As expected by literature data on IA and fertility, rates of prior induced abortions were not different in the population of fertile women versus infertile. However, women with one or more previous pregnancy are more likely to have undergone previous IA in the IVF group than in the newly delivered group, possibly due to a bias of age. More data are requested to eliminate linkage between IA and infertility.

[Cholinesterase inhibitor therapy in long term care settings]. / Les anticholinestérasiques en soins de longue durée: analyse des pratiques actuelles à partir d'une étude observationnelle francoquébécoise.

PURPOSE: Cholinesterase Inhibitors (ChEIs) have proven efficacy in outpatients with mild to moderate Alzheimer's Disease (AD). The benefits of maintaining this treatment once patients are institutionalised remain controversial. The aim of this study was to present current therapeutic strategies regarding ChEIs use in long-term care settings (LTC). METHODS: A multicentric, retrospective, observational study was conducted on currently available ChEIs (donezepil, rivastigmine, galantamine) prescribed in LTC. Data were obtained from medical records. Judgement was based on three criteria: ChEIs indication, follow-up, and justification for maintenance of treatment. RESULTS: Among the 1,373 patients evaluated, 6% (N=81) were receiving ChEIs. They represented various stages of the disease, with cognitive and functional decline ranging from severe (18%) to very mild (10%). Among patients receiving ChEIs, 29% met neither the indication for which these drugs were approved, nor professional guidelines. Patient evaluation at entry was of high quality, with 90% of records including cognitive, functional and behavioural evaluation. Follow-up evaluations were weaker, with at least one assessment domain missing in 40% of the medical records. ChEIs treatment was maintained, although almost half of patients experienced a worsening of their clinical state. CONCLUSION: This study shows that follow-up of institutionalised patients receiving ChEIs could be improved. While treatment maintenance seems to be the rule, it should be questioned on ethical, efficacy, and economic grounds. The rationale for use and discontinuation of these therapeutic strategies in institutional settings requires urgent review.

Switch to oral antibiotics in the treatment of infective endocarditis is not associated with increased risk of mortality in non-severely ill patients.

Although many international guidelines exist for the management of infective endocarditis (IE), recommendations are lacking on the opportunity of switching antibiotics from the intravenous (IV) to oral route during treatment. We present a cohort study of 426 cases of IE over a period of 13 years (2000-2012), including 369 cases of definite IE according to the Duke criteria. Predictors of mortality were identified using the Cox proportional hazard analysis. The median (range) age at diagnosis was 64.5 (7-98) years. One hundred six patients (25%) had healthcare-associated IE. Oral streptococci (n = 99, 23%) and Staphylococcus aureus (n = 81, 19%) were the predominant microorganisms. Ninety-two patients (22%) died during follow-up. After an initial phase of IV antibiotherapy, 214 patients (50%) were switched to oral route a median (range) of 21 (0-70) days after diagnosis of IE. Patients in the oral group had fewer comorbidities, and criteria of severity at inclusion and were less frequently infected by S. aureus. Oral antibiotics were amoxicillin alone in 109 cases or a combination therapy of clindamycin, fluoroquinolone, rifampicin and/or amoxicillin in 46 cases, according to the susceptibility of the microorganisms. In the multivariate analysis, a switch to oral route was not associated with an increased risk of mortality. During follow-up, only two relapses and four reinfections were observed in the oral group (compared to nine and eight in the IV group, respectively). In this study, switching to oral administration was not associated with an increased risk of relapse or reinfection. These promising results need to be confirmed by prospective studies.