Meningitis and Bacteremia Due to Neisseria cinerea following a Percutaneous Rhizotomy of the Trigeminal Ganglion.

Neisseria cinerea is a human commensal. The first known case of meningitis and bacteremia due to Neisseria cinerea following percutaneous glycerol instillation of the trigeminal ganglion is reported. Conventional phenotypic methods and complete 16S RNA gene sequencing accurately identified the pathogen. Difficulties in differentiation from pathogenic neisseriae are discussed.

Randomized non-inferiority trial to compare trimethoprim/sulfamethoxazole plus rifampicin versus linezolid for the treatment of MRSA infection.

OBJECTIVES: The therapeutic arsenal for MRSA infections is limited. The aim of this study was to assess the non-inferiority of a combination of trimethoprim/sulfamethoxazole plus rifampicin versus linezolid alone for the treatment of MRSA infection. METHODS: We conducted a randomized, open-label, single-centre, non-inferiority trial comparing trimethoprim/sulfamethoxazole (160 mg/800 mg three times daily) plus rifampicin (600 mg once a day) versus linezolid (600 mg twice a day) alone in adult patients with various types of MRSA infection. Patients were allocated 1:1 to either regimen. The primary outcome was clinical cure at 6 weeks after the end of treatment (non-inferiority margin 20%) assessed by both ITT and PP analyses. Secondary outcomes included the microbiologically documented persistence of MRSA in clinical cultures, mortality and adverse events. The study protocol has been registered with ClinicalTrials.gov (NCT00711854). RESULTS: Overall, 150 patients were randomized to one of the two treatment arms between January 2009 and December 2013 and were included in the ITT analysis. Of these 56/75 (74.7%) in the linezolid group and 59/75 (78.7%) in the trimethoprim/sulfamethoxazole and rifampicin group experienced clinical success (risk difference 4%, 95% CI -9.7% to 17.6%). The results were confirmed by the PP analysis, with 54/66 (81.8%) cured patients in the linezolid group versus 52/59 (88.1%) in the trimethoprim/sulfamethoxazole and rifampicin group (risk difference 6.3%, 95% CI -6.8% to 19.2%). There were no statistically significant differences between the two groups in any of the secondary outcomes, including microbiologically documented failure. Four adverse drug reactions attributed to the study medication occurred in the linezolid group versus nine in the trimethoprim/sulfamethoxazole and rifampicin group. CONCLUSIONS: Compared with linezolid, trimethoprim/sulfamethoxazole and rifampicin seems to be non-inferior in the treatment of MRSA infection.

Ampicillin-resistant Haemophilus influenzae isolates in Geneva: serotype, antimicrobial susceptibility, and ß-lactam resistance mechanisms.

The purpose of this study was to analyze the molecular mechanisms of ampicillin-resistant Haemophilus influenzae isolated in Geneva, Switzerland. We investigated the association between specific patterns of amino acid substitutions in penicillin-binding protein 3 (with or without ß-lactamase production) and ß-lactam susceptibility. Another main focus for this study was to compare the accuracy of disk diffusion and Etest methods to detect resistance to ampicillin and amoxicillin/clavulanic acid. The antibiotic susceptibility to ß-lactam antibiotics of 124 H. influenzae isolates was determined by disk diffusion and Etest methods, and interpreted by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) breakpoints. Alterations in PBP3 were investigated by sequencing the ftsI gene. Of the 124 clinical isolates analyzed, ampicillin resistance was found in 36% (45 out of 124). The rate of resistance to amoxicillin/clavulanic acid was 9% and 0.8%, using EUCAST and CLSI breakpoints respectively. For the 78 ß-lactamase negative ampicillin-susceptible (BLNAS) isolates for which the Etest method indicated a high degree of susceptibility (MIC ≤ 1 mg/L), the disk diffusion method revealed resistance to ampicillin and amoxicillin/clavulanic acid in 33 cases (42%). Most common amino acid substitutions were Asn526Lys and Val547Ile, followed by Asp569Ser, Ala502Val, Asp350Asn, Met377Ile, Ile449Val, and Arg517His. The patterns observed were classified into six groups (IIa, IIb, IIc, IId, III-like, and miscellaneous). Continued characterization of both invasive and respiratory H. influenzae isolates is necessary in order to observe changes in the microbiology and epidemiology of this pathogen that could lead to clinical failure when treated by empirical antibiotic therapy.

[Allergies and adverse events associated with fluoroquinolones]. / Allergies et effets indésirabtes dus aux fluoroquinolones.

The prescription ot fluoroquinolones has been constantly increasing over the past decade. consequently, an increasing number of hyper-sensitivity reactions and adverse events have been reported. The aim of the review is to discuss the incidence of hypersensitivity reactions either IgE (immediate) or T cells mediated (delayed). We will make an overview ofthe diagnostic tools available to detect such hypersensitivity reactions. Finally, the specific adverse events associated with fluoroquinolones, including tendinopathy, chondrotoxicity, peripheral neuropathy or retinal detachment will be discussed.

[Diagnosis of bacterial gastroenteritis]. / Diagnostic de la gastroentérite bactérienne.

The etiologic agents of acute gastroenteritis are diverse. The diagnosis of bacterial pathogens is particularly challenging given the large amount of vastly diverse indigenous gastrointestinal organisms present in stool. Multiple methods must be used by the clinical microbiology laboratories to diagnose the cause of acute gastroenteritis, including bacterial cultures, ELISA, and microscopy. Due to the limitations of conventional methods, there is still room for improvement in the detection of pathogens by using the molecular methods. This paper discusses these different diagnostic approaches and limitations.

[Rapid tests during respiratory infection: an aid to non-prescription of antibiotics? ]. / Tests rapides lors d'infection respiratoire: une aide à la non-prescription d'antibiotiques?

Due to overuse, we are about to reach the end of the antibiotic era. Each of us is responsible to limit their usage to a minimum. Respiratory infections are the first cause of antibiotic prescriptions. The use of new simple tests available at the bedside can be very useful in this context. The development of sophisticated molecular diagnostic tools, such as "multiorganism" panels, may revolutionize our approach to respiratory infections. The key will be to interpret the results correctly, with due consideration of the statement, "Treat patients, not lab results".

[ESBL and carbapenemases in Enterobacteriaceae]. / Bêtalactamases à spectre étendu et carbapénémases chez les Enterobacteriaceae.

Carbapenemase-producing enterobacteria (CPE) spread all over the world during the last years, causing serious infections with increasing frequency. Very few new drugs active against CPE are expected to be clinically available. Studies summarized in this review show that there is yet room to improve our therapeutic approaches, in the treatment of infections due to CPE.

[Which benefits for the clinician to implement MALDI-TOF/MS in the bacteriology laboratory?]. / Quels bénéfices pour les cliniciens de la mise en place du MALDI-TOF/MS dans te taboratoire de bactériologie?

Mass spectrometry (MALDI-TOF/MS) is a recent technology especially adapted to identify microbial pathogens. It has rapidly established itself as a must for most medical bacteriology laboratories. Its ease of use and speed of execution typically permit providing pathogen identification one day earlier to the clinicians. MALDI-TOF/MS facilitates identification of filamentous fungi and mycobacteria that require particular lab expertise when using conventional methods. This paper highlights the multiple advantages that MALDI-TOF/MS can bring to the physicians in their practice.

[Corticosteroids in the treatment of infectious diseases]. / Quelle place pour les stéroïdes dans le traitement des maladies infectieuses?

The addition of a corticosteroid has become a common practice for the treatment of some infectious diseases, such as meningitis, septic shock, moderate to severe Pneumocystis jirovecii pneumonia. The belief that steroids may have a beneficial effect in the early stage of pro-inflammatory infections explains the renewed interest for these treatments. This review of recent literature helps determine the use of steroids in the treatment of infectious diseases as formal guidance, questionable or rather contraindicated. When there is a clear scientific indication for the use of corticosteroids regardless of the current infection, the latter is never a formal contraindication.

Fatal acute melioidosis in a tourist returning from Martinique Island, November 2010.

We report the fatal case of acute melioidosis in a patient returning from Martinique with fever in November 2010. Gram-negative rods were isolated from a blood culture and Burkholderia pseudomallei identified within 24 hours after first medical contact. The patient died two days after admission to hospital despite intravenous therapy with high doses of imipenem/cilastatin and intensive care. Clinicians seeing travellers returning from the subtropics or tropics with severe pneumonia or septicaemia should consider the possibility of acute melioidosis.

[An update on Lassa virus]. / Le virus lassa, état des lieux.

Lassa virus, the etiologic agent of Lassa hemorrhagic fever, infects 100,000 to 300,000 people every year in West Africa with an overall mortality rate ranging from 1 to 2%. It was discovered in 1969 and remains a significant public health risk in endemic areas. Because airborne transmission is possible and mortality can be high under certain conditions, Lassa virus has been classified as a category A bioterrorism agent. Early diagnosis is difficult due to insidious non-specific onset and to the great genetic divergence of the virus that makes RT-PCR assays unreliable. The lack of proper diagnostic tools promotes nosocomial infection and diminishes the efficacy of treatment. Recently, numerous advances have been made in the development of both diagnostic and vaccination techniques. The purpose of this review is to present an update on that research as well as the current epidemiology of Lassa virus.

[Melioidosis: a poorly known tropical disease]. / Mélioïdose: une pathologie tropicale méconnue.

A 35 year-old man was admitted to the hospital for fever upon returning from the Caribbean area. He died 48 hours later, after developing pulmonary lesions that were complicated by multi-organ failure, despite rapid diagnosis of melioidosis by mass spectrometry on blood cultures. Melioidosis is a rare bacterial disease in the traveller that is caused by Burkholderia pseudomallei. Although the clinical presentation is variable, pneumonia is the most frequent finding. Diagnosis may be considered in travellers returning from tropical and subtropical regions, especially during rainy seasons. Accordingly, when confronted with a patient who presents with fever after travelling, it is important to carefully specify the regions visited, potential expositions, and rapidly offer adequate laboratory testing.

Posttraumatic ankle arthritis due to a novel Nocardia species.

INTRODUCTION: Nocardial arthritis in immunocompetent patients is rare, and the optimum duration of antimicrobial therapy is unknown, although several months of antibiotic treatment is often recommended. CASE REPORT: We here report the first case of human infection with a novel Nocardia sp., summarise the epidemiology of nocardial arthritis and outline the feasibility of relatively short antibiotic treatments after careful surgical drainage.

Association between treatment duration and mortality or relapse in adult patients with Staphylococcus aureus bacteraemia: a retrospective cohort study.

OBJECTIVES: The aim was to evaluate the effect of duration of therapy (DOT) on mortality and relapse for patients with Staphylococcus aureus bacteraemia (SAB). METHODS: We performed a retrospective single-centre cohort study including adult patients with SAB. We determined the association between DOT (≤14 days versus >14 days) and mortality by adjusted hazard ratios (aHR) and 95% confidence intervals through Cox regression adjusted for immortal-time bias and confounding by indication, stratified by presence of complicated SAB (any of: endocarditis, implant, duration of SAB >2 days, fever >3 days). The primary outcome was 90-day all-cause mortality, and the secondary outcome was 90-day relapse. RESULTS: Between January 2010 and December 2015, we included 530 patients, of whom 94 out of 530 (17.7%) had methicillin-resistant SAB and 305 out of 530 (57.6%) had complicated SAB. Ninety-day mortality was 27.0% (143/530), with no significant trend across the study period; median time to death was 17 days (interquartile range (IQR) 8-30) after onset of SAB. Median DOT was 20 days (IQR 13-39). Patients with complicated SAB had significantly reduced mortality with DOT >14 days (aHR 0.32, 95% CI 0.16-0.64). DOT was not associated with mortality in patients with uncomplicated SAB (aHR 0.85; 0.41-1.78). Eighteen (18/530) patients (3.4%) relapsed; on univariate analysis, DOT was not associated with relapse (HR 1.01; 0.97-1.06). CONCLUSIONS: DOT >14 days is associated with higher survival in patients with complicated SAB, but not for patients with uncomplicated SAB. No association was found for relapse, but 90-day relapse was very low in this cohort. Importantly, 90-day mortality remained high across the study period.

[Pediatric osteo-articular infections with negative culture results: what about Kingella kingae?]. / Infections ostéo-articulaires septiques à culture négative chez l'enfant: avez-vous pensé à Kingella kingae?

Kingella kingae is an emerging pathogen that is recognized as a causative agent of septic arthritis and osteomyelitis, primarily in infants and children. The bacterium is best detected by rapid inoculation in blood culture systems or by real-time PCR assays. Pathogenesis of the agent was linked recently to the production of a potent cytotoxin, known as RTX, which is toxic to a variety of human cell types. The locus encoding the RTX toxin is thought to be a putative virulence factor, and is, apparently, essential for inducing cytotoxic effects on respiratory epithelial, synovial and macrophage-like cells. Herein, we describe a novel real-time PCR assay that targets the RTX toxin gene. The assay exhibited a sensitivity of 30 c.f.u., which is 10-fold more sensitive than a previously published semi-nested broad-range 16S rRNA gene PCR, and showed no crossreactivity with several related species and common osteoarticular pathogens. Its clinical impact is illustrated by three pediatric cases.

Arenaviruses.

The Arenaviridae family contains 22 recognized virus species, each of them strongly associated with a rodent species (except Tacaribe virus which is associated with a species of bat), suggesting an ancient co-evolutionary process. Although the concept of co-evolution between rodents and arenaviruses is now largely accepted, little has been uncovered in terms of dating the phenomenon and the mechanisms of evolution, including speciation and pathogenicity. These questions are targeted in the present chapter. Old World arenaviruses are associated with the Eurasian rodents in the family Muridae. New World arenaviruses are associated with American rodents in the subfamily Sigmodontinae. The correlation between the rodent host phylogeny and the viruses suggests a long association and a co-evolutionary process. Furthermore, three distinct New World arenaviruses share a common ancestor, demonstrating a unique recombination event that probably occurred in that ancestor. This shows that recombination among arenaviruses of different lineages might occur in nature. Recombination and co-evolutionary adaptation appear as the main mechanisms of arenavirus evolution, generating a high degree of diversity. The diversity among rodent host reservoir and virus species and the potential to exchange genomic material provide a basis for the emergence of new viruses and the risk of these becoming pathogenic for humans.

Imipenem heteroresistance in nontypeable Haemophilus influenzae is linked to a combination of altered PBP3, slow drug influx and direct efflux regulation.

OBJECTIVE: To investigate the potential roles of PBPs, efflux pumps and slow drug influx for imipenem heteroresistance in nontypeable Haemophilus influenzae (NTHi). METHODS: Fifty-nine NTHi clinical isolates examined in this study were collected at Geneva University Hospitals between 2009 and 2014. Alterations in PBPs were investigated by gene sequencing. To evaluate the affinities of the PBPs to imipenem, steady-state concentration-response experiments were carried out using imipenem in a competition assay with Bocillin-FL. The effect of the carbonyl cyanide m-chlorophenylhydrazone (CCCP) on imipenem susceptibility was assessed using broth dilution and viable cell counting. Using whole-genome sequencing, we explored the potential roles of outer membrane protein P2 (OmpP2), LytM proteins and the dcw gene cluster in imipenem heteroresistance. RESULTS: All 46 imipenem-heteroresistant isolates (IMIhR) harboured amino acid substitutions in the ftsI gene, which encodes PBP3, corresponding to 25 different mutation patterns that varied from the ftsI gene mutation patterns found in imipenem-susceptible isolates. Among all PBPs, the highest affinity to imipenem was documented for PBP3 (IC50, 0.004 µg/mL). Different amino acid substitutions and insertions were noted in OmpP2, suggesting a relationship with imipenem heteroresistance. The IMIhR isolates were affected by CCCP differently and displayed a higher percentage of killing by imipenem in CCCP-treated cells at concentrations ranging between 0.5 and 8 µg/mL. CONCLUSIONS: The present study provides robust evidence indicating that in combination with the altered PBP3, the slowed drug influx and its enhanced efflux due to the loss of regulation led to the development of imipenem heteroresistance in NTHi.

Rapid molecular determination of methicillin resistance in staphylococcal bacteraemia improves early targeted antibiotic prescribing: a randomized clinical trial.

Empiric therapy of methicillin-susceptible Staphylococcus aureus (MSSA) infections with vancomycin is associated with poorer outcome than targeted therapy with ß-lactams. Our objective was to evaluate whether rapid determination of methicillin resistance shortens the time from Gram stain to targeted antimicrobial therapy in staphylococcal bacteraemia, thereby reducing vancomycin overuse. This was a single-centre open parallel RCT. Gram-positive cocci in clusters in positive blood culture underwent real-time PCR for rapid species and methicillin resistance determination parallel to conventional microbiology. Patients were randomized 1:1 so that clinicians would be informed of PCR results (intervention group) or not (control group). Eighty-nine patients (intervention 48, control 41) were analysed. MRSA was identified in seven patients, MSSA in 46, and CoNS in 36. PCR results were highly concordant (87/89) with standard microbiology. Median time (hours) from Gram stain to transmission of methicillin-susceptibility was 3.9 (2.8-4.3) vs. 25.4 (24.4-26-7) in intervention vs. control groups (p <0.001). Median time (hours) from Gram stain to targeted treatment was similar for 'all staphylococci' [6 (3.8-10) vs. 8 (1-36) p 0.13] but shorter in the intervention group when considering S. aureus only [5 (3-7) vs. 25.5 (3.8-54) p <0.001]. When standard susceptibility testing was complete, 41/48 (85.4%) patients in the intervention group were already receiving targeted therapy compared with 23/41 (56.1%) in the control group (p 0.004). There was no significant effect on clinical outcomes. Rapid determination of methicillin resistance in staphylococcal bacteraemia is accurate and reduces significantly the time to targeted antibiotic therapy in the subgroup of S. aureus, thereby avoiding unnecessary exposure to vancomycin.

Unusual staphylococcal toxic shock syndrome presenting as a scarlet-like fever.

Diagnosis of nonmenstrual staphylococcal toxic shock syndrome (TSS) is often challenging. A female medical colleague had a rare entity, a staphylococcal pharyngitis complicated by TSS. The diagnosis was confirmed by isolation of tst-positive Staphylococcus aureus in throat culture and by identification of a specific Vß2 expansion pattern of her T lymphocytes. Recent improvements in microbiology can be of great help for the diagnosis of nonmenstrual TSS.

Evaluation of Crimean-Congo hemorrhagic fever virus in vitro inhibition by chloroquine and chlorpromazine, two FDA approved molecules.

Crimean-Congo hemorrhagic virus (CCHFV) causes hemorrhagic fever with high case mortality rates and is endemic in south-eastern Europe, Africa, and Asia. The limited catalog of specific treatment, highlight the necessity to look for additional therapeutic solutions. Previous experiments suggested that CCHFV enters the cells via a clathrin dependent pathway. Therefore, we have evaluated the potential anti-CCHFV activity of several molecules targeting this entry possibility. We identified two molecules chloroquine and chlorpromazine. Neutralization and virus yield reduction assays were tested in Vero E6 and Huh7 cells on two different CCHFV strains. Several combinations, including ribavirin, were assayed to test a potential synergistic effect. The two molecules inhibited CCHFV, and depending on the virus and the cell lines, the 50% inhibitory concentration (IC50) values for chloroquine and chlorpromazine ranged from 28 to 43 and 10.8-15.7 µM, respectively. Time-of-addition studies demonstrated that these molecules had a direct effect on CCHFV infectivity and spread. The antiviral activity of the two molecules was still effective even when added up to 6h post-infection and up to 24h. The selectivity index ranging from 3 to 35 lead us to evaluate combinations with ribavirin. Combinations of ribavirin and chloroquine or chlorpromazine were synergistic against CCHFV. Though the low chlorpromazine selectivity index suggests the need for a chemical improvement, our present study highlights chloroquine as the main drug having the potential for drug repurposing.