[The management and treatment of cystitis: same challenges, new strategies]. / Prise en charge et traitement des cystites : mêmes défis, nouvelles stratégies.

Cystitis is an inflammation of the bladder that is most often caused by bacterial infection and is the most common urinary tract infection. This lower urinary tract infection (UTI) is one of the most frequently encountered infections in women in outpatient practice. The concept of the urobiome, the microbiome of the urinary tract, has recently emerged and has improved our comprehension of the physiopathology of UTI. Recent studies have highlighted the potential limits of additional examinations used in our clinical practice. The emergence of delayed therapy is a novelty in the treatment of lower UTI; it likely allows for an overall reduction in antibiotic consumption while remaining an effective treatment. Alternatives to antibiotic treatment exist but most have yet to be tested in sufficiently powered randomized trials.

La cystite est une inflammation de la vessie, le plus souvent provoquée par une infection bactérienne, et est l'infection urinaire (IU) la plus fréquente. Par ailleurs, l'infection urinaire basse (IUB) est l'infection la plus souvent rencontrée chez la femme dans la pratique ambulatoire. L'étude de l'urobiome, le microbiome du tractus urinaire, a permis des avancées dans la compréhension de la physiopathologie des IU. Des études ont mis en avant les possibles limites des examens complémentaires utilisés dans notre pratique clinique. L'émergence du traitement différé (Delayed Therapy) est une nouveauté dans le traitement des IUB, dans le sens où il permettrait de diminuer la consommation d'antibiotiques tout en restant un traitement efficace. Les alternatives au traitement antibiotique existent, mais la majorité doit encore être validée dans des essais randomisés de meilleure qualité.

Impact of the 2019 Food and Drug Administration Guidance for Uncomplicated Urinary Tract Infection on Treatment Response Rates: A Reanalysis of a Clinical Trial of Nitrofurantoin vs Fosfomycin.

Background: Current US Food and Administration (FDA) guidance recommends that the primary efficacy endpoint for uncomplicated urinary tract infection (uUTI) clinical trials be a composite of clinical and microbiological responses. We applied these criteria to a previous clinical trial to determine the impact on treatment outcomes. Methods: We conducted a patient-level reanalysis of a randomized clinical trial of nitrofurantoin versus fosfomycin for treatment of uUTI in nonpregnant adult women. Women were included in the reanalysis if they had 2 or more signs/symptoms of uUTI and a single bacterial species isolated from baseline urine culture at ≥105 colony-forming units (CFU)/mL. The applied primary efficacy endpoint-therapeutic response-required both clinical resolution of signs/symptoms and reduction of the infecting bacterial pathogen to <103 CFU/mL at day 14 post-treatment completion. Results: Two hundred eleven of 513 (41%) patients were eligible for inclusion in the reanalysis. Among these patients, 74% (76/103) and 69% (75/108) in the nitrofurantoin and fosfomycin groups, respectively, achieved clinical resolution by day 14. Similarly, 70% (72/103) and 67% (72/108) in each group achieved microbiological success at day 14. As such, 59% (61/103) and 57% (62/108) of women in each group met the primary efficacy endpoint-therapeutic success-at day 14. In comparison, 75% and 66% of patients in each group achieved clinical resolution at day 14 in the initial clinical trial. Conclusions: Applying current FDA guidance resulted in lower composite efficacy rates than clinical resolution alone as observed in the initial clinical trial. This may limit the ability to compare antibiotic treatment effects between historical and future clinical trials.

How to use biomarkers of infection or sepsis at the bedside: guide to clinicians.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or aid clinicians to prognosticate patient risk. More than 250 biomarkers have been identified and evaluated over the last few decades, but no biomarker accurately differentiates between sepsis and sepsis-like syndrome. Published data support the use of biomarkers for pathogen identification, clinical diagnosis, and optimization of antibiotic treatment. In this narrative review, we highlight how clinicians could improve the use of pathogen-specific and of the most used host-response biomarkers, procalcitonin and C-reactive protein, to improve the clinical care of patients with sepsis. Biomarker kinetics are more useful than single values in predicting sepsis, when making the diagnosis and assessing the response to antibiotic therapy. Finally, integrated biomarker-guided algorithms may hold promise to improve both the diagnosis and prognosis of sepsis. Herein, we provide current data on the clinical utility of pathogen-specific and host-response biomarkers, offer guidance on how to optimize their use, and propose the needs for future research.

Robust innate responses to SARS-CoV-2 in children resolve faster than in adults without compromising adaptive immunity.

SARS-CoV-2 infection in children is less severe than it is in adults. We perform a longitudinal analysis of the early innate responses in children and adults with mild infection within household clusters. Children display fewer symptoms than adults do, despite similar initial viral load, and mount a robust anti-viral immune signature typical of the SARS-CoV-2 infection and characterized by early interferon gene responses; increases in cytokines, such as CXCL10 and GM-CSF; and changes in blood cell numbers. When compared with adults, the antiviral response resolves faster (within a week of symptoms), monocytes and dendritic cells are more transiently activated, and genes associated with B cell activation appear earlier in children. Nonetheless, these differences do not have major effects on the quality of SARS-CoV-2-specific antibody responses. Our findings reveal that better early control of inflammation as observed in children may be key for rapidly controlling infection and limiting the disease course.

A systematic review of phage therapy applied to bone and joint infections: an analysis of success rates, treatment modalities and safety.

Bone and joint infections are difficult to treat, and increasing antibiotic resistance has only made them more challenging. This has led to renewed interest in phage therapy (PT). The aim of this systematic review was to determine success rate, current treatment modalities and safety of PT in bone and joint infections.A systematic search of PubMed, EMBASE and Cochrane databases as well as the journal PHAGE for literature published between January 2000 and April 2021 was conducted according to PRISMA guidelines to identify all human studies assessing bacteriophages as therapy for bone and joint infections. All study designs and patient populations were eligible. The review's primary outcome was success rate.Twenty records describing a total of 51 patients and 52 treatment episodes were included. No randomized controlled studies were identified. The overall success rate was 71% (n = 37/52). Topical administration alone was the most frequent administration route (85%, n = 44/52). Antibiotics were administered concomitantly with PT in the majority of treatments (79%, n = 41/52), and surgery was performed for 87% (n = 45/52) of treatment episodes. Four minor adverse events related to PT were reported, representing 8% (n = 4/52) of treatment episodes.PT for bone and joint infections has not been evaluated in any randomized controlled clinical study, and current administration modalities are highly variable between case reports and case series. While publications included here show potential benefit and few adverse effects, clinical trials are warranted to assess the efficacy of PT for bone and joint infections and determine optimal treatment modalities. Cite this article: EFORT Open Rev 2021;6:1148-1156. DOI: 10.1302/2058-5241.6.210073.

Population Pharmacokinetics of Imipenem in Critically Ill Patients: A Parametric and Nonparametric Model Converge on CKD-EPI Estimated Glomerular Filtration Rate as an Impactful Covariate.

BACKGROUND: Population pharmacokinetic (popPK) models for antibiotics are used to improve dosing strategies and individualize dosing by therapeutic drug monitoring. Little is known about the differences in results of parametric versus nonparametric popPK models and their potential consequences in clinical practice. We developed both parametric and nonparametric models of imipenem using data from critically ill patients and compared their results. METHODS: Twenty-six critically ill patients treated with intravenous imipenem/cilastatin were included in this study. Median estimated glomerular filtration rate (eGFR) measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 116 mL/min/1.73 m2 (interquartile range 104-124) at inclusion. The usual dosing regimen was 500 mg/500 mg four times daily. On average, five imipenem levels per patient (138 levels in total) were drawn as peak, intermediate, and trough levels. Imipenem concentration-time profiles were analyzed using parametric (NONMEM 7.2) and nonparametric (Pmetrics 1.5.2) popPK software. RESULTS: For both methods, data were best described by a model with two distribution compartments and the CKD-EPI eGFR equation unadjusted for body surface area as a covariate on the elimination rate constant (Ke). The parametric population parameter estimates were Ke 0.637 h-1 (between-subject variability [BSV]: 19.0% coefficient of variation [CV]) and central distribution volume (Vc) 29.6 L (without BSV). The nonparametric values were Ke 0.681 h-1 (34.0% CV) and Vc 31.1 L (42.6% CV). CONCLUSIONS: Both models described imipenem popPK well; the parameter estimates were comparable and the included covariate was identical. However, estimated BSV was higher in the nonparametric model. This may have consequences for estimated exposure during dosing simulations and should be further investigated in simulation studies.

The pharmacokinetics of nitrofurantoin in healthy female volunteers: a randomized crossover study.

BACKGROUND: Use of nitrofurantoin has increased significantly since its recent repositioning as a first-line agent for uncomplicated cystitis by multiple guidelines. However, current dosing regimens were developed in an era before robust pharmacokinetic testing and may not be optimal. Furthermore, formulations have been modified over the years. OBJECTIVES: To reassess the plasma and urinary pharmacokinetic profile of macrocrystalline nitrofurantoin in two commonly used dosing regimens. METHODS: In this open-label, randomized crossover pharmacokinetic trial, 12 healthy adult female volunteers were randomized to receive oral nitrofurantoin 100 mg q8h on days 1 and 2 and, after a washout period, 50 mg q6h on days 30 and 31, or the same dosing schemes in reversed order. Urine and blood were collected at steady state and analysed by UPLC. Pharmacokinetic analysis was performed by WinNonlin. RESULTS: Plasma peak concentrations were low (mean 0.33 mg/L, SD 0.08, and 0.69 mg/L, SD 0.35, after 50 and 100 mg, respectively) and dose dependent. The AUC0-24 was higher (6.49 versus 4.43 mg·h/L, P = 0.021) for the 100 mg q8h dosing regimen, but the dose-normalized AUC was similar for the two regimens. In contrast, urinary concentrations were dose independent: increasing the nitrofurantoin dose delayed the time to peak urinary concentration, while steady-state AUC0-24 values remained unchanged (943.49 and 855.95 mg·h/L at 50 mg q6h and 100 mg q8h, respectively). CONCLUSIONS: Plasma concentrations were relatively low and dose dependent. The dose-independent urinary concentrations suggest that excretion of nitrofurantoin into the urine is saturable. Pharmacodynamic studies are urgently required to determine the impact of these findings.

Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial.

Importance: The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI). Objective: To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis. Design, Setting, and Participants: Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel. Interventions: Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection. Main Outcomes and Measures: The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events. Results: Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively). Conclusions and Relevance: Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion. Trial Registration: ClinicalTrials.gov Identifier: NCT01966653.

[Lower urinary tract infections in men. Urethritis, cystitis and prostatitis]. / Infections urinaires basses non associées aux sondes urinaires chez l'homme. Urétrite, cystite et prostatite.

Recommendations for the treatment of lower non-catheter-related urinary tract infection (UTI) in men are rarely evidence-based. Their management requires the localization of the site of infection, whether it be the urethra, bladder or prostate, and includes antibiotic therapy and in most cases urological assessment. They are often associated with urinary tract procedures or anatomical or functional abnormalities. Nearly 80 % of male UTIs are caused by Enterobacteriaceae. The prevalence of broad-spectrum beta-lactamase-producing strains (ESBL) and quinolone-resistant strains is increasing. The aim of this article is to define three types of lower, non-catheter-related UTI in men - urethritis, cystitis and prostatitis - their microbiology and management in Switzerland.

Les recommandations de traitement des infections des voies urinaires (IVU) basses masculines non associées aux sondes souffrent d'un manque d'évidence. Leur prise en charge implique la distinction entre urétrite, cystite et prostatite, et comprend une antibiothérapie associée dans certains cas à un bilan urologique anatomique et fonctionnel. Elles sont souvent associées aux instrumentations du tractus urinaire ou à des anomalies anatomiques ou fonctionnelles. Les Entérobactéries en sont la cause dans près de 80 % des cas ; la prévalence de souches productrices de bêtalactamases à spectre élargi (BLSE) et résistant aux quinolones augmente. Cet article a pour but de clarifier les définitions, la microbiologie et la prise en charge en Suisse de trois types d'IVU basses masculines non associées aux sondes ­ urétrite, cystite et prostatite.

A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa.

The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1ß/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines.

Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).

Therapeutic drug monitoring of the ß-lactam antibiotics: what is the evidence and which patients should we be using it for?

Traditional antibiotic dosing was not designed for today's escalating antibiotic resistance, lack of novel antibiotics and growing complexity in patient populations. Dosing that ensures optimal antibiotic exposures should be considered essential to increase the likelihood of effective patient treatment. Given the variability in these exposures across different patients, a 'one-dose-fits-all' approach is increasingly problematic. Therapeutic drug monitoring (TDM) of the ß-lactams, the most widely used antibiotic class, is underutilized in certain populations. Clinical experience with ß-lactam TDM remains relatively scarce. Patients most likely to benefit from such an intervention include the critically ill, the obese, the elderly and those with cystic fibrosis. Most centres actively performing ß-lactam TDM target a minimum 100% of the time during the dosing interval that the free (unbound) concentration of antibiotic exceeds the MIC of the pathogen (100% fT>MIC), which is higher than a traditional target supported by in vitro data. Ideally, isolated pathogens should undergo MIC testing along with TDM on a regular basis, allowing clinicians to address the triad of bug, drug and patient ('mug') in equal measure.

[Infections disease update: 2014 is viral]. / Infectiologie en 2014: une année virale.

Chikungunya's phenomenal dissemination imposes now infection suspicion when returning from endemic areas. Colorectal cancer screening may be dependent of the microbiome. Even a small amount of E. coli in catheter sampled urine is predictive for a urinary infection. Prevention of pharyngitis suppurated late complications doesn't justify systematic antimicrobial therapy. A bitherapy is probably better for severe community acquired pneumonias. Due to epidemiology and resistances, management of gonorrhoea has changed. Enterovirus 68 is particular because of its almost exclusive lung tropism in children. The question is no longer how to treat hepatitis C but which patients to treat and when. Pritelivir clearly improves herpes genitalis symptoms. The first confirmed case of Ebola has reach our contry.