Posts filed under ‘Antimicrobianos’

Omadacycline as a promising new agent for the treatment of infections with Mycobacterium abscessus.

Omadacycline: A Potential New Treatment for Mycobacterium abscessus

SOURCE

J Antimicrob Chemother. October 1, 2019 V.74 N.10 P.2930-2933.

Bax HI1,2, de Vogel CP2, Mouton JW2, de Steenwinkel JEM2.

Author information

1 Department of Internal Medicine, Division of Infectious Diseases, Erasmus University Medical Centre, Rotterdam, The Netherlands.

2 Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Abstract

BACKGROUND:

Despite intensive treatment regimens, the outcome of Mycobacterium abscessus infections is extremely poor and thus novel treatment regimens are needed. Although tigecycline seems to be one of the best options currently available, its long-term use is hampered by severe toxic side effects as well as the need for intravenous administration and the relatively high concentrations required for efficacy.

OBJECTIVES:

To assess the in vitro activity of omadacycline against M. abscessus and compare it with the activity of tigecycline.

METHODS:

The concentration- and time-dependent killing capacities of omadacycline and tigecycline against M. abscessus subspecies abscessus were determined using a time-kill kinetics assay. Time-kill curves as well as concentration-effect curves were generated.

RESULTS:

Time-kill curves showed strong concentration-dependent antimicrobial activity for both omadacycline and tigecycline. Omadacycline showed inhibition of mycobacterial growth at 4 mg/L and mycobacterial killing at concentrations ≥16 mg/L. Tigecycline showed mycobacterial killing at concentrations ≥4 mg/L, achieving elimination at concentrations ≥16 mg/L. The concentration-effect curves after 7 days of exposure showed stasis, 1 log mycobacterial killing and 2 log mycobacterial killing at 3.3, 4.0 and 4.8 mg/L for omadacycline and 2.2, 2.7 and 3.4 mg/L for tigecycline, respectively.

CONCLUSIONS:

The results of this in vitro study on omadacycline activity, together with its favourable (pharmacokinetic) properties, suggest that omadacycline is a potential new agent for the treatment of M. abscessus infections

FULL TEXT

https://academic.oup.com/jac/article/74/10/2930/5522506

PDF (CLIC en PDF)

November 18, 2019 at 7:07 pm

Cefiderocol, a Siderophore Cephalosporin for Gram-Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment.

J Clin Pharmacol. May 2017 V.57 N.5 P.584-591. doi: 10.1002/jcph.841. Epub 2016 Nov 22.

Katsube T1, Echols R2, Arjona Ferreira JC2, Krenz HK2, Berg JK3, Galloway C4.

Author information

1 Shionogi & Co, Ltd, Osaka, Japan.

2 Shionogi Inc, Florham Park, NJ, USA.

3 DaVita Clinical Research, Minneapolis, MN, USA.

4 DaVita Clinical Research, Lakewood, CO, USA.

Abstract

Cefiderocol, a new injectable siderophore cephalosporin antibiotic, has promising in vitro and in vivo activity against Gram-negative bacteria including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Cefiderocol is mainly renally eliminated. The pharmacokinetics and safety of cefiderocol in subjects with renal impairment were assessed following a single 1000-mg intravenous 1-hour infusion of cefiderocol. Subjects with mild, moderate, or severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis were compared with demographically (age, body mass index, and sex) matched healthy subjects with normal renal function. The effect of hemodialysis on the clearance of cefiderocol was also assessed. Total drug clearance from plasma (CL) and terminal half-life (t1/2 ) correlated with renal function. Ratios (90% confidence intervals) of area under the plasma concentration-time curve from 0 to infinity (AUC) in mild, moderate, severe, and ESRD groups compared to those with normal renal function were 1.0 (0.8-1.3), 1.5 (1.2-1.9), 2.5 (2.0-3.3), and 4.1 (3.3-5.2), respectively. Maximum plasma concentration (Cmax ) was similar between renal-impairment groups and the normal-renal-function group. Approximately 60% of cefiderocol was removed by hemodialysis for 3 to 4 hours. The plasma-protein-unbound fraction was similar between various renal function groups. The incidence of adverse events did not appear to have any correlation with the degree of renal impairment. Single 1000-mg intravenous doses of cefiderocol were generally well tolerated in subjects with impaired renal function except for 1 subject who discontinued due to urticaria. In conclusion, renal impairment impacted AUC, CL, and t1/2 without affecting Cmax . Cefiderocol was significantly removed by intermittent hemodialysis.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412848/pdf/JCPH-57-584.pdf

November 16, 2019 at 10:10 am

Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa.

Antimicrob Agents Chemother. November 21, 2016 V.60 N.12 P. 7396-7401. Print 2016 Dec.

Ito A1, Nishikawa T2, Matsumoto S2, Yoshizawa H2, Sato T2, Nakamura R2, Tsuji M2, Yamano Y2.

Author information

1 Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan akinobu.ito@shionogi.co.jp.

2 Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.

Abstract

Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the third-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole-14C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in P. aeruginosa cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not observed when one of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119021/pdf/zac7396.pdf

November 16, 2019 at 10:09 am

Present and future of siderophore-based therapeutic and diagnostic approaches in infectious diseases.

Infect Dis Rep. October 1, 2019 V.11 N.2 P.8208. doi: 10.4081/idr.2019.8208. eCollection 2019 Sep 18.

Tonziello G1, Caraffa E1, Pinchera B2, Granata G1, Petrosillo N1.

Author information

1 National Institute for Infectious Diseases “L. Spallanzani” – IRCCS, Rome.

2 University of Naples “Federico II”, Naples, Italy.

Abstract

Iron is an essential micronutrient required for the growth of almost all aerobic organisms; the iron uptake pathway in bacteria therefore represents a possible target for novel antimicrobials, including hybrids between antimicrobials and siderophores. Siderophores are low molecular weight iron chelators that bind to iron and are actively transported inside the cell through specific binding protein complexes. These binding protein complexes are present both in Gram negative bacteria, in their outer and inner membrane, and in Gram positive bacteria in their cytoplasmic membrane. Most bacteria have the ability to produce siderophores in order to survive in environments with limited concentrations of free iron, however some bacteria synthetize natural siderophore-antibiotic conjugates that exploit the siderophore-iron uptake pathway to deliver antibiotics into competing bacterial cells and gain a competitive advantage. This approach has been referred to as a Trojan Horse Strategy. To overcome the increasing global problem of antibiotic resistance in Gram negative bacteria, which often have reduced outer membrane permeability, siderophore-antibiotic hybrid conjugates have been synthetized in vitro. Cefiderocol is the first siderophore-antibiotic conjugate that progressed to late stage clinical development so far. In studies on murine models the iron-siderophore uptake pathway has been also exploited for diagnostic imaging of infectious diseases, in which labelled siderophores have been used as specific probes. The aim of this review is to describe the research progress in the field of siderophore-based therapeutic and diagnostic approaches in infectious diseases.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778818/pdf/idr-11-2-8208.pdf

November 16, 2019 at 10:08 am

Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America.

Am J Respir Crit Care Med. October 1, 2019  V.200 N.7  e45-e67.

Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al.

Background

This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia.

Methods

A multidisciplinary panel conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.

Results

The panel addressed 16 specific areas for recommendations spanning questions of diagnostic testing, determination of site of care, selection of initial empiric antibiotic therapy, and subsequent management decisions. Although some recommendations remain unchanged from the 2007 guideline, the availability of results from new therapeutic trials and epidemiological investigations led to revised recommendations for empiric treatment strategies and additional management decisions.

Conclusions

The panel formulated and provided the rationale for recommendations on selected diagnostic and treatment strategies for adult patients with community-acquired pneumonia.

 

Este documento proporciona pautas de práctica clínica basadas en evidencia sobre el manejo de pacientes adultos con NAC.

Métodos

Un panel multidisciplinario realizó revisiones sistemáticas pragmáticas de la investigación relevante y aplicó la metodología de calificación de recomendaciones, evaluación, desarrollo y evaluación para recomendaciones clínicas.

Resultados

El panel abordó 16 áreas específicas para recomendaciones que abarcan preguntas sobre pruebas de diagnóstico, determinación del sitio de atención, selección de terapia ATB empírica inicial y decisiones de manejo posteriores. Aunque algunas recomendaciones permanecen sin cambios con respecto a la guía de 2007, la disponibilidad de resultados de nuevos ensayos terapéuticos e investigaciones epidemiológicas condujo a recomendaciones revisadas para estrategias de tratamiento empírico y decisiones de manejo adicionales.

Conclusiones

El panel formuló y proporcionó la justificación de las recomendaciones sobre estrategias seleccionadas de diagnóstico y tratamiento para pacientes adultos con NAC.

FULL TEXT

https://www.atsjournals.org/doi/10.1164/rccm.201908-1581ST#_i6

PDF

https://www.atsjournals.org/doi/pdf/10.1164/rccm.201908-1581ST

November 15, 2019 at 7:59 am

Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomised, non-inferiority trial.

Ann Rheum Dis. August 2019 V.78 N.8 P.1114-1121. doi: 10.1136/annrheumdis-2019-215116. Epub 2019 Apr 16.

Gjika E1, Beaulieu JY1, Vakalopoulos K1, Gauthier M1, Bouvet C1, Gonzalez A1, Morello V1, Steiger C1, Hirsiger S1, Lipsky BA2,3, Uçkay I4,5.

Author information

1 Hand Surgery Unit, Hopitaux Universitaires de Geneve, Geneva, Switzerland.

2 Service of Infectious Diseases, Hopitaux Universitaires de Geneve, Geneva, Switzerland.

3 Division of Medical Sciences, University of Oxford, Oxford, UK.

4 Service of Infectious Diseases, Hopitaux Universitaires de Geneve, Geneva, Switzerland ilker.uckay@balgrist.ch.

5 Uniklinik Balgrist, Zurich, Switzerland.

Abstract

OBJECTIVE:

The optimal duration of postsurgical antibiotic therapy for adult native joint bacterial arthritis remains unknown.

METHODS:

We conducted a prospective, unblinded, randomised, non-inferiority study comparing either 2 or 4 weeks of antibiotic therapy after surgical drainage of native joint bacterial arthritis in adults. Excluded were implant-related infections, episodes without surgical lavage and episodes with a follow-up of less than 2 months.

RESULTS:

We enrolled 154 cases: 77 in the 4-week arm and 77 in the 2-week arm. Median length of intravenous antibiotic treatment was 1 and 2 days, respectively. The median number of surgical lavages was 1 in both arms. Recurrence of infection was noted in three patients (2%): 1 in the 2-week arm (99% cure rate) and 2 in the 4-week arm (97% cure rate). There was no difference in the number of adverse events or sequelae between the study arms. Of the overall 154 arthritis cases, 99 concerned the hand and wrist, for which an additional subgroup analysis was performed. In this per-protocol subanalysis, we noted three recurrences: one in the 2-week arm (97 % cure); two in the 4-week arm (96 % cure) and witnessed sequelae in 50% in the 2-week arm versus 55% in the 4-week arm, of which five (13%) and six (13%) needed further interventions.

CONCLUSIONS:

After initial surgical lavage for septic arthritis, 2 weeks of targeted antibiotic therapy is not inferior to 4 weeks regarding cure rate, adverse events or sequelae and leads to a significantly shorter hospital stay, at least for hand and wrist arthritis.

TRIAL REGISTRATION NUMBER: NCT03615781.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691865/pdf/annrheumdis-2019-215116.pdf

November 13, 2019 at 7:27 am

British Thoracic Society community acquired pneumonia guideline and the NICE pneumonia guideline: how they fit together.

BMJ Open Respir Res. May 13, 2015 V.2 N.1 :e000091. doi: 10.1136/bmjresp-2015-000091.

Lim WS1, Smith DL2, Wise MP3, Welham SA4.

Author information

1 Department of Respiratory Medicine , Nottingham City Hospital , Nottingham , UK.

2 Southmead Hospital , North Bristol Lung Centre , Bristol , UK.

3 Department of Adult Critical Care , University Hospital of Wales , Cardiff , UK.

4 British Thoracic Society , London , UK.

Abstract

The British Thoracic Society (BTS) guideline for the management of adults with community acquired pneumonia (CAP) published in 2009 was compared with the 2014 National Institute for Health and Care Excellence (NICE) Pneumonia Guideline. Of the 36 BTS recommendations that overlapped with NICE recommendations, no major differences were found in 31, including those covering key aspects of CAP management: timeliness of diagnosis and treatment, severity assessment and empirical antibiotic choice. Of the five BTS recommendations where major differences with NICE were identified, one related to antibiotic duration in low and moderate severity CAP, two to the timing of review of patients and two to legionella urinary antigen testing.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442154/pdf/bmjresp-2015-000091.pdf

November 13, 2019 at 7:17 am

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