Impact of time to antibiotic therapy on clinical outcome in patients with bacterial infections in the emergency department: implications for antimicrobial stewardship.

BACKGROUND: Rapid initiation of antibiotic treatment is considered crucial in patients with severe infections such as septic shock and bacterial meningitis, but may not be as important for other infectious syndromes. A better understanding of which patients can tolerate a delay in start of therapy is important for antibiotic stewardship purposes. OBJECTIVES: To explore the existing evidence on the impact of time to antibiotics on clinical outcomes in patients presenting to the emergency department (ED) with bacterial infections of different severity of illness and source of infection. SOURCES: A literature search was performed in the PubMed/MEDLINE database using combined search terms for various infectious syndromes (sepsis/septic shock, bacterial meningitis, lower respiratory tract infections, urinary tract infections, intra-abdominal infections and skin and soft tissue infections), time to antibiotic treatment, and clinical outcome. CONTENT: The literature search generated 8828 hits. After screening titles and abstracts and assessing potentially relevant full-text papers, 60 original articles (four randomized controlled trials, 43 observational studies) were included. Most articles addressed sepsis/septic shock, while few studies evaluated early initiation of therapy in mild to moderate disease. The lack of randomized trials and the risk of confounding factors and biases in observational studies warrant caution in the interpretation of results. We conclude that the literature supports prompt administration of effective antibiotics for septic shock and bacterial meningitis, but there is no clear evidence showing that a delayed start of therapy is associated with worse outcome for less severe infectious syndromes. IMPLICATIONS: For patients presenting with suspected bacterial infections, withholding antibiotic therapy until diagnostic results are available and a diagnosis has been established (e.g. by 4-8 h) seems acceptable in most cases unless septic shock or bacterial meningitis are suspected. This approach promotes the use of ecologically favourable antibiotics in the ED, reducing the risks of side effects and selection of resistance.

Safety and immunogenicity of the epicutaneous reactivation of pertussis toxin immunity in healthy adults: a phase I, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Protection induced by acellular vaccines can be short, requiring novel immunization strategies. Objectives of this study were to evaluate safety and capacity of a recombinant pertussis toxin (PTgen) -coated Viaskin® epicutaneous patch to recall memory responses in healthy adults. METHODS: This double-blind, placebo-controlled randomized trial (Phase I) assessed the safety and immunogenicity of PTgen administered on days 0 and 14 to healthy adults using Viaskin® patches applied directly or after epidermal laser-based skin preparation. Patch administration was followed by Boostrix®dTpa on day 42. Antibodies were assessed at days 0, 14, 28, 42 and 70. RESULTS: Among 102 volunteers enrolled, 80 received Viaskin-PT (Viaskin-PT 25 µg (n = 25), Viaskin-PT 50 µg (n = 25), laser + Viaskin-PT 25 µg (n = 5), laser + Viaskin-PT 50 µg (n = 25)), Viaskin-placebo (n = 10) or laser + Viaskin-placebo (n = 2). Incidence of adverse events was similar across groups (any local event: 21/25 (84.0%), 24/25 (96.0%), 4/5 (80.0%), 24/25 (96.0%), 8/10 (80.0%), 10/12 (83.0%), respectively). Direct application induced no detectable response. On day 42, PT-IgG geometric mean concentrations were significantly higher following laser + Viaskin-PT 25 µg and 50 µg (139.87 (95% CI 87.30-224.10) and 121.76 (95% CI 95.04-156.00), respectively), than laser + Viaskin-placebo (59.49, 95% CI 39.37-89.90). Seroresponse rates were higher following laser + Viaskin-PT 25 µg (4/5 (80.0%), 95% CI 28.4-99.5) and 50 µg (22/25 (88.0%), 95% CI 68.8-97.5) than laser + Viaskin-placebo (0/12 (0.0%), 95% CI 0.0-26.5). CONCLUSIONS: Viaskin-PT applied after laser-based epidermal skin preparation showed encouraging safety and immunogenicity results: anti-PT booster responses were not inferior to those elicited by Boostrix®dTpa. This study is registered at ClinicalTrials.gov (NCT03035370) and was funded by DBV Technologies.

Primary melanotic tumors of the nervous system: a consecutive case series.

BACKGROUND AND PURPOSE: Primary melanotic tumors of the nervous system (PMTNS) are thought to be an exceedingly rare group of tumors not captured by tumor registries. We aimed to determine relative incidence, clinical presentation, diagnostic findings, patient management, and outcome. METHODS: We retrospectively searched the database of the Section of Neuro-Oncology at the Yale Cancer Center for patients with primary or metastatic melanotic lesions of the nervous system. For patients with PMTNS, we recorded demographic data, clinical presentation, histopathological and imaging findings, therapy, and outcome. RESULTS: A total of 116 patients with melanotic lesions were identified, including four patients with PMTNS. The relative incidence of PMTNS was therefore calculated as 3.4%. Histology of PMTNS patients revealed melanocytoma in three patients and psammomatous melanotic schwannoma in one patient. Symptoms were non-specific and attributed to tumor mass effect. Magnetic resonance imaging showed hyperintensity on pre-contrast T1-weighted imaging, hypointensity on T2-weighted imaging, and homogenous contrast enhancement in all PMTNS patients. Definitive diagnosis was based on tissue analysis, with detection of melanin-containing cells on conventional histology and S100-positivity on immunohistochemistry. Molecular analysis for GNAQQ209L mutation assisted in establishing diagnosis when only small amounts of tissue were available. Aggressive surgical treatment showed favorable outcomes in all cases; radiation therapy was used for residual or relapsed disease. The median follow-up was 7.5 ± 5 years, and all patients were alive on the day of database closure. CONCLUSION: Primary melanotic tumors of the nervous system are rare nervous system tumors. Outcome appears excellent, and complete surgical resection may form the basis for favorable outcome. Radiation therapy may represent a therapeutic approach for residual or relapsed disease.

Clinical characteristics of fibroblast growth factor receptor 3 antibody-related polyneuropathy: a retrospective study.

BACKGROUND AND PURPOSE: Autoantibodies are increasingly being used as a diagnostic biomarker of chronic inflammatory neuropathies. However, their role and associated clinical syndrome are not well defined. METHODS: This retrospective chart review evaluated the clinical presentation, diagnostic workup and therapeutic responses in fibroblast growth factor receptor 3 (FGFR3) antibody-associated neuropathy. RESULTS: A total of 27 patients [14 men, aged 29-87 (65 ± 14) years] with positive FGFR3 antibody were included. Distal lower-extremity paresthesia (66%), unsteady gait (26%) and foot drop (11%) were common presenting symptoms. Symptom onset was acute in four (15%) cases. Distal lower-extremity weakness (mild in eight and severe in three patients) was the most frequent motor finding. Decreased distal sensation to pinprick (59%) and loss of vibration sensation (37%) were observed. Titer of FGFR3 ranged between 3100 and 30 000 (normal < 3000) with a mean of 10 688 ± 7284. Apart from the occasional association of other neuropathy-related autoantibodies, comprehensive neuropathy workup was otherwise unrevealing. Six patients had other autoimmune disease and seven patients had a history of cancer. Electromyography reflected sensorimotor neuropathy with mixed axonal and demyelinating features in 11 cases. Pure sensory neuropathy was noted in three patients. Demyelination was found in five of six nerve biopsies. Intravenous immunoglobulin response was observed in 8/10 treated patients. CONCLUSIONS: The FGFR3 antibody appears not to be restricted to sensory neuropathy only. Its role in the pathogenicity of chronic inflammatory neuropathies is not yet well established and, although there may be a role for immunotherapy, larger studies are warranted.

Oral amoxicillin and amoxicillin-clavulanic acid: properties, indications and usage.

BACKGROUND: Amoxicillin has been in use since the 1970s; it is the most widely used penicillin both alone and in combination with the ß-lactamase clavulanic acid. OBJECTIVES: In this narrative review, we re-examine the properties of oral amoxicillin and clavulanic acid and provide guidance on their use, with emphasis on the preferred use of amoxicillin alone. SOURCES: Published medical literature (MEDLINE database via Pubmed). CONTENT: While amoxicillin and clavulanic acid have similar half-lives, clavulanic acid is more protein bound and even less heat stable than amoxicillin, with primarily hepatic metabolism. It is also more strongly associated with gastrointestinal side effects, including Clostridium difficile infection, and, thus, in oral combination formulations, limits the maximum daily dose of amoxicillin that can be given. The first ratio for an amoxicillin-clavulanic acid combination was set at 4:1 due to clavulanic acid's high affinity for ß-lactamases; ratios of 2:1, 7:1, 14:1 and 16:1 are currently available in various regions. Comparative effectiveness data for the different ratios are scarce. Amoxicillin-clavulanic acid is often used as empiric therapy for many of the World Health Organization's Priority Infectious Syndromes in adults and children, leading to extensive consumption, when some of these syndromes could be handled with a delayed antibiotic prescription approach or amoxicillin alone. IMPLICATIONS: Using available epidemiological and pharmacokinetic data, we provide guidance on indications for amoxicillin versus amoxicillin-clavulanic acid and on optimal oral administration, including choice of combination ratio. More data are needed, particularly on heat stability, pharmacodynamic effects and emergence of resistance in 'real-world' clinical settings.

Therapeutic drug monitoring of imipenem and the incidence of toxicity and failure in hospitalized patients: a retrospective cohort study.

OBJECTIVES: Therapeutic drug monitoring (TDM) of beta-lactam antibiotics is increasingly employed to ensure adequate antibiotic exposure and slow emergence of resistance. Imipenem's therapeutic range has not been defined; we report plasma concentrations and clinical outcomes of patients receiving imipenem for bacterial infections. METHODS: All hospitalized adult patients undergoing imipenem TDM during therapy for suspected or confirmed bacterial infections between 1 January 2013 and 28 February 2017 were included in this single-centre retrospective cohort. The primary outcome was incidence of clinical toxicity; secondary outcomes included incidence of clinical failure and median imipenem concentrations in those with and without toxicity and/or failure. Total imipenem concentrations were measured via high-performance liquid chromatography with ultraviolet detection. RESULTS: A total of 403 imipenem levels were drawn from 300 patients. Fifteen (5%) patients experienced an adverse event considered at least possibly related to imipenem. Eighty-eight (29%) patients had clinical failure; augmented renal clearance appeared to emerge as a protective factor against failure (OR 0.42; 95% CI 0.20-0.89). Median first-measure trough concentration was 3.2 mg/L (IQR 1.7-6.5). Patients with suspected toxicity did not have higher concentrations. Patients whose dose was not increased after a trough level <2 mg/L was returned trended towards increased clinical failure (3/28 (11%) vs. 12/63 (19%)), though the difference was not statistically significant. CONCLUSIONS: Toxicity was rare and clinical failure frequent in this cohort of patients whose imipenem concentrations were generally low and occasionally undetectable. Larger trials are needed to define optimal imipenem exposure.

The development and early clinical testing of the ExPEC4V conjugate vaccine against uropathogenic Escherichia coli.

OBJECTIVES: In this 'how it was done' narrative review, we provide a description of, and context for, the early development of a conjugate vaccine targeting extra-intestinal, pathogenic Escherichia coli (ExPEC), from its creation in the laboratory to its testing in a large, first-in-human phase Ib trial. SOURCES: We searched the Pubmed database for previous attempts to develop vaccines against ExPEC, and we provide data from laboratory and trial databases established during the development of ExPEC4V, the tetravalent conjugate vaccine candidate. CONTENT: Earlier attempts at ExPEC vaccines had mixed success: whole-cell or cell-lysate preparations have limited effectiveness, and though an early conjugate vaccine was immunogenic in animal models, its development stalled before extensive clinical testing could occur. The development of the current conjugate vaccine candidate, ExPEC4V, began at a population level, with an epidemiological survey to determine the most common E. coli serotypes causing urinary tract infections (UTI) in Switzerland, Germany and the USA. The O antigens of the four most prevalent serotypes were selected for inclusion in ExPEC4V. After its creation in the laboratory by means of an in vivo bioconjugation process engineered to occur within E. coli cells, ExPEC4V underwent toxicity and immunogenicity testing in animal models. It then underwent safety and immunogenicity testing in a first-in-human, phase Ib multicentre trial, whose population of healthy women with a history of recurrent UTI allowed for an additional, preliminary assessment of the candidate's clinical efficacy. IMPLICATIONS: Laboratory development and early phase I testing were successful, as the vaccine candidate emerged with strong safety and immunogenicity profiles. The clinical trial was ultimately underpowered to detect a significant reduction in vaccine-specific E. coli UTI, though it showed a significant decrease in the incidence of UTI caused by E. coli of any serotype. We discuss the findings, including the lessons learned.

New and improved? A review of novel antibiotics for Gram-positive bacteria.

BACKGROUND: The number of antibiotics in the pipeline targeting Gram-positive pathogens has increased in recent years. AIMS: This narrative review aims to provide a summary of existing evidence on efficacy, microbiological spectrum and safety of novel systemic antibiotics that have either recently been licensed or completed phase III trials, and possess activity predominantly against Gram-positive organisms. SOURCES: A review of the published literature via the MEDLINE database was performed. In addition, ongoing trials were identified through a search of the clinical trial registration platform clinicaltrials.gov, and when necessary, pharmaceutical companies responsible for the development of the drug were contacted for further information. CONTENT: Data on development, microbiological spectrum, pharmacokinetic/pharmacodynamic properties, clinical efficacy, safety and cost are presented for the new cephalosporins ceftaroline and ceftobiprole; the lipoglycopeptides dalbavancin, oritavancin and telavancin; the fluoroquinolones delafloxacin, nemonoxacin and zabofloxacin; the dihydrofolate-reductase inhibitor iclaprim; the pleuromutilin lefamulin; and the tetracycline omadacycline. IMPLICATIONS: Although promising, these new antibiotics have so far been tested in non-severe infections whose treatment is generally uncomplicated and whose aetiologies were not predominantly multidrug-resistant pathogens. None of the new antibiotics have shown superiority to standard care, and none have been investigated for patient-relevant outcomes. Safety and pharmacokinetic data continue to be lacking. How these new drugs are to be integrated into the current armamentarium remains to be established.

Clonal or not clonal? Investigating hospital outbreaks of KPC-producing Klebsiella pneumoniae with whole-genome sequencing.

OBJECTIVES: Whole-genome sequencing (WGS) is a promising tool for identifying transmission pathways in outbreaks caused by multidrug-resistant bacteria. However, it is uncertain how the data produced by WGS can be best integrated into epidemiologic investigations. METHODS: We tested various genomic analyses to identify clonal groups in two distinct outbreaks of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae that occurred in Switzerland in 2013 and 2015. In blinded fashion, we sequenced 12 strains involved in the two outbreaks, respectively, and six that were epidemiologically unrelated. We analysed genomic commonalities from conserved genes to plasmid-borne antibiotic resistance genes (ARGs) and contrasted these results with available epidemiologic evidence. RESULTS: Using WGS, blinded analysts correctly identified the two clusters of strains from the two outbreaks. Nonetheless, the 2015 index strain was found to be slightly different (1-3 single nucleotide variants) from the strains recovered from secondary cases, likely because prior long-term carriage (3 years) by the index patient allowed for genetic mutations over time. Also, we observed occasional loss of ARG-bearing plasmidic fragments in outbreak-causing strains. CONCLUSIONS: Retrospective WGS analysis was successful in identifying clonal groups in both outbreaks. Still, data should be analysed with caution in cases of previous long-term carriage of the studied bacteria.

Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study.

OBJECTIVES: Cefepime remains an important antibiotic for severe bacterial infections, yet some meta-analyses have shown elevated mortality among patients randomized to it. Therapeutic drug monitoring (TDM) of ß-lactam antibiotics is increasing, but optimal plasma concentrations remain unknown. We examined clinical outcomes of patients undergoing cefepime TDM in an initial effort to define the drug's toxicity threshold. METHODS: In this single-centre retrospective cohort study, we enrolled all adult hospitalized patients receiving cefepime and undergoing TDM from January 2013 through July 2016. The primary outcome was the incidence of clinical toxicity; a secondary outcome was clinical failure. Plasma samples were analysed via high-performance liquid chromatography with ultraviolet detection. RESULTS: A total of 161 cefepime concentrations were drawn from 93 patients. Roughly half (82/161, 51%) and one-third (49/161, 30%) were trough and steady-state levels from patients receiving intermittent and continuous infusions, respectively; median concentrations were 17.6 mg/L (IQR 9.7-35.2) and 29.2 mg/L (IQR 18.9-45.9). Ten patients (11%) experienced a neurologic event considered at least possibly related to cefepime; neurotoxicity was associated with poorer renal function (median creatinine clearance 54 (IQR 39-97) vs. 75 mL/min/1.732 (IQR 44-104)) and longer cefepime durations (mean 8.3 (SD±6.7) vs. 13.3 days (± 14.2), p = 0.071). Patients with trough levels >20 mg/L had a fivefold higher risk for neurologic events (OR 5.05, 95% CI 1.3-19.8). CONCLUSIONS: Neurotoxicity potentially related to cefepime occurred at plasma concentrations >35 mg/L. For those receiving intermittent infusions, trough concentrations >20 mg/L should be avoided until further information is available from prospective studies.