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Eefjan Breukink - One of the best experts on this subject based on the ideXlab platform.
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The expanding role of lipid II as a target for lAntibiotics
Future Microbiology, 2007Co-Authors: Nathaniel I. Martin, Eefjan BreukinkAbstract:Lipid II is an essential cell-wall precursor required for the growth and replication of both Gram-positive and Gram-negative bacteria. Compounds that use lipid II to selectively target bacterial cells for destruction represent an important class of Antibiotics. Clinically, vancomycin is the most important example of an Antibiotic that operates in this manner. Despite being considered the ‘Antibiotic drug of last resort’, significant bacterial resistance to vancomycin now manifests itself worldwide. In this paper we review recent progress made in understanding the lipid II-associated antibacterial characteristics of various naturally occurring compounds, with particular focus on the lAntibiotic peptides.
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Lipid II as a target for Antibiotics
Nature Reviews Drug Discovery, 2006Co-Authors: Eefjan Breukink, Ben De KruijffAbstract:The bacterial membrane-anchored cell-wall precursor Lipid II can be considered an Achilles' heel of bacteria, as it is an essential component of bacterial cell walls and is a relatively easily accessible target for Antibiotics. Lipid II is targeted by at least four classes of Antibiotic: glycopeptides (for example, vancomycin); lAntibiotics (for example, nisin); ramoplanin; and mannopeptimycins. There is no Antibiotic in clinical use today to which resistance has not developed, including vancomycin. This has led to increasing interest in the therapeutic potential of other classes of compound that target Lipid II, including ramoplanin and the mannopeptimycins. The lAntibiotic nisin binds to the pyrophosphate moiety of Lipid II, and this binding is thought to involve the formation of at least five hydrogen bonds between backbone amine functionalities of nisin and oxygen atoms of the phosphate groups of Lipid II. It is known that amino acids in the D -configuration are essential for this binding interaction. The mechanism of action of ramoplanin and the mannopeptimycins has yet to be elucidated, but it is thought that the unusual amino acids, such as D -amino acids and glycosylated amino acids, in the peptide backbones of these and other Antibiotics that target Lipid II are important in the binding of these Antibiotics to Lipid II. The Lipid-II-targeting Antibiotics have a broad spectrum of activity: they are suitably active against most, if not all, Gram-positive bacteria and the lAntibiotic nisin also has potent activity against some Gram-negative bacteria. Resistance of bacteria to nisin is generally achieved by a shielding mechanism in which incorporation of positive charges in the cell wall repels nisin from the bacterial cells, thereby preventing it from reaching Lipid II. However, resistance to ramoplanin or mannopeptimycins has not yet been reported. In vitro screening has shown that all the tested lAntibiotics show promising activity against multi-resistant and vancomycin-resistant strains. Lipid II production is restricted to bacteria, and so these Antibiotics should have low toxicity in humans. This highlights their potential as new clinical Antibiotics for the treatment of resistant infections. Lipid II is a membrane-anchored cell-wall precursor that is essential for bacterial cell-wall biosynthesis. The effectiveness of targeting Lipid II as an antibacterial strategy is highlighted by the fact that it is the target for at least four different classes of Antibiotic, including the clinically important glycopeptide Antibiotic vancomycin. However, the growing problem of bacterial resistance to many current drugs, including vancomycin, has led to increasing interest in the therapeutic potential of other classes of compound that target Lipid II. Here, we review progress in understanding of the antibacterial activities of these compounds, which include lAntibiotics, mannopeptimycins and ramoplanin, and consider factors that will be important in exploiting their potential as new treatments for bacterial infections. Lipid II is an essential component of bacterial cell-wall biosynthesis, and as such is an attractive therapeutic target. Breukink and de Kruijff review the modes of action of compounds targeting Lipid II, and discuss their potential as treatments to combat bacterial infections.
Christopher R Frei - One of the best experts on this subject based on the ideXlab platform.
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outpatient Antibiotic prescribing in the united states 2000 to 2010
BMC Medicine, 2014Co-Authors: Kelly R Reveles, Russell T Attridge, Kenneth A Lawson, Ishak A Mansi, James S Lewis, Christopher R FreiAbstract:The use of Antibiotics is the single most important driver in Antibiotic resistance. Nevertheless, Antibiotic overuse remains common. Decline in Antibiotic prescribing in the United States coincided with the launch of national educational campaigns in the 1990s and other interventions, including the introduction of routine infant immunizations with the pneumococcal conjugate vaccine (PCV-7); however, it is unknown if these trends have been sustained through recent measurements. We performed an analysis of nationally representative data from the Medical Expenditure Panel Surveys from 2000 to 2010. Trends in population-based prescribing were examined for overall Antibiotics, broad-spectrum Antibiotics, Antibiotics for acute respiratory tract infections (ARTIs) and Antibiotics prescribed during ARTI visits. Rates were reported for three age groups: children and adolescents (<18 years), adults (18 to 64 years), and older adults (≥65 years). An estimated 1.4 billion Antibiotics were dispensed over the study period. Overall Antibiotic prescribing decreased 18% (risk ratio (RR) 0.82, 95% confidence interval (95% CI) 0.72 to 0.94) among children and adolescents, remained unchanged for adults, and increased 30% (1.30, 1.14 to 1.49) among older adults. Rates of broad-spectrum Antibiotic prescriptions doubled from 2000 to 2010 (2.11, 1.81 to 2.47). Proportions of broad-spectrum Antibiotic prescribing increased across all age groups: 79% (1.79, 1.52 to 2.11) for children and adolescents, 143% (2.43, 2.07 to 2.86) for adults and 68% (1.68, 1.45 to 1.94) for older adults. ARTI Antibiotic prescribing decreased 57% (0.43, 0.35 to 0.52) among children and adolescents and 38% (0.62, 0.48 to 0.80) among adults; however, it remained unchanged among older adults. While the number of ARTI visits declined by 19%, patients with ARTI visits were more likely to receive an Antibiotic (73% versus 64%; P <0.001) in 2010 than in 2000. Antibiotic use has decreased among children and adolescents, but has increased for older adults. Broad-spectrum Antibiotic prescribing continues to be on the rise. Public policy initiatives to promote the judicious use of Antibiotics should continue and programs targeting older adults should be developed.
Kerenza Hood - One of the best experts on this subject based on the ideXlab platform.
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Antibiotic prescription strategies for acute sore throat a prospective observational cohort study
Lancet Infectious Diseases, 2014Co-Authors: Paul Little, Beth Stuart, F Richard D Hobbs, Christopher C Butler, Alastair D Hay, Brendan Delaney, John L Campbell, Sue Broomfield, Paula Barratt, Kerenza HoodAbstract:Summary Background Data from trials suggest that Antibiotics reduce the risk of complications of sore throat by at least 50%, but few trials for complications have been done in modern settings, and datasets of delayed Antibiotic prescription are underpowered. Observational evidence is important in view of poor compliance with Antibiotic treatment outside trials, but no prospective observational cohort studies have been done to date. Methods We generated a large prospective cohort from the DESCARTE study, and the PRISM component of DESCARTE, of 12 829 adults presenting with sore throat (≤2 weeks duration) in primary care. Our follow-up of the cohort was based on a detailed and structured review of routine medical records, and analysis of the comparison of three Antibiotic prescription strategies (no Antibiotic prescription, immediate Antibiotic prescription, and delayed Antibiotic prescription) to control for the propensity to prescribe Antibiotics. Information about Antibiotic prescription was recorded in 12 677 individuals (4805 prescribed no Antibiotics, 6088 prescribed Antibiotics immediately, and 1784 prescribed delayed Antibiotics). We documented by review of patients' notes (n=11 950) the development of suppurative complications (eg, quinsy, impetigo and cellulitis, otitis media, and sinusitis) or reconsultation with new or non-resolving symptoms). We used multivariate analysis to control for variables significantly related to the propensity to prescribe Antibiotics and for clustering by general practitioner. Findings 164 (1·4%) of the 11 950 patients with information available developed complications; otitis media and sinusitis were the most common complications (101 patients [62%]). Compared with no Antibiotic prescription, immediate Antibiotic prescription was associated with fewer complications (adjusted risk ratio [RR] 0·62, 95% CI 0·43–0·91, estimated number needed to treat [NNT 193) as was delayed prescription of Antibiotics (0·58, 0·34–0·98; NNT 174). 1787 of the 11 950 patients (15%) reconsulted with new or non-resolving symptoms; the risk of reconsultation was also reduced by immediate (0·83, 0·73–0·94; NNT 40) or delayed Antibiotics (0·61, 0·50–0·74; NNT 18). Interpretation Suppurative complications are not common in primary care and most are not serious. The risks of suppurative complications or reconsultation in adults are reduced by Antibiotics, but not as much as the trial evidence suggests. In most cases, no Antibiotic is needed, but a delayed prescription strategy is likely to provide similar benefits to an immediate Antibiotic prescription. Funding UK Medical Research Council.
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are patient views about Antibiotics related to clinician perceptions management and outcome a multi country study in outpatients with acute cough
PLOS ONE, 2013Co-Authors: Samuel Coenen, Paul Little, Kerenza Hood, Nick A Francis, Mark James Kelly, J Nuttall, Theo J M Verheij, Hasse Melbye, Herman Goossens, Christopher C ButlerAbstract:Background: Outpatients with acute cough who expect, hope for or ask for Antibiotics may be more unwell, benefit more from Antibiotic treatment, and be more satisfied with care when they are prescribed Antibiotics. Clinicians may not accurately identify those patients. Objective: To explore whether patient views (expecting, hoping for or asking for Antibiotics) are associated with illness presentation and resolution, whether patient views are accurately perceived by clinicians, and the association of all these factors with Antibiotic prescribing and patient satisfaction with care. Methods: Prospective observational study of 3402 adult patients with acute cough presenting in 14 primary care networks. Correlations and associations tested with multilevel logistic regression and McNemar ‘s tests, and Cohen’s Kappa, positive agreement (PA) and negative agreement (NA) calculated as appropriate. Results: 1,213 (45.1%) patients expected, 1,093 (40.6%) hoped for, and 275 (10.2%) asked for Antibiotics. Clinicians perceived 840 (31.3%) as wanting to be prescribed Antibiotics (McNemar’s test, p,0.05). Their perception agreed modestly with the three patient views (Kappa’s=0.29, 0.32 and 0.21, PA’s=0.56, 0.56 and 0.33, NA’s=0.72, 0.75 and 0.82, respectively). 1,464 (54.4%) patients were prescribed Antibiotics. Illness presentation and resolution were similar for patients regardless their views. These associations were not modified by Antibiotic treatment. Patient expectation and hope (OR:2.08, 95% CI:[1.48,2.93] and 2.48 [1.73,3.55], respectively), and clinician perception (12.18 [8.31,17.84]) were associated with Antibiotic prescribing. 2,354 (92.6%) patients were satisfied. Only those hoping for Antibiotics were less satisfied when Antibiotics were not prescribed (0.39 [0.17,0.90]). Conclusion: Patient views about Antibiotic treatment were not useful for identifying those who will benefit from Antibiotics. Clinician perceptions did not match with patient views, but particularly influenced Antibiotic prescribing. Patients were generally satisfied with care, but those hoping for but not prescribed Antibiotics were less satisfied. Clinicians need to more effectively elicit and address patient views about Antibiotics.
Paul Little - One of the best experts on this subject based on the ideXlab platform.
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knowledge attitude and practice with respect to Antibiotic use among chinese medical students a multicentre cross sectional study
International Journal of Environmental Research and Public Health, 2018Co-Authors: Xiaomin Wang, Paul Little, Joseph D Tucker, Michael Moore, Keiji Fukuda, Xudong ZhouAbstract:Objective: Inappropriate Antibiotic use leads to Antibiotic resistance. This has become a serious global crisis, with more multi-drug resistant infections and fewer effective Antibiotics available. This study aims to understand knowledge, attitude, and practice (KAP) with respect to Antibiotic use for self-limiting illnesses among medical students in China. Methods: An online cross-sectional survey instrument questionnaire was distributed in six regional universities in China from September to November 2015. Overall, 1819 medical students were enrolled. A pre-tested questionnaire was delivered by the researchers. KAP scores were calculated to determine the appropriation. Chi-squared and multivariable logistic regression and adjusted odd ratios (aORs) with 95% confidence interval (CI) were used to assess the relationship between the demographic characteristics and Antibiotic use knowledge and behaviour. Results: In total, 11,192 students completed the questionnaires, with a response rate of 95%. In total, 529 (29%) medical students reported at least one self-limiting illness in the prior month. Of those with a self-limiting illness, 285 (54%) self-medicated, with 77 (27%) using Antibiotics; 111 (21%) went to see a doctor, of which 64 (58%) were prescribed Antibiotics, and 133 did nothing (25%). In the past year, 279 (15%) of medical students had used Antibiotics as prophylaxis, and 273 (15%) of medical students had demanded an Antibiotic from a doctor. Meanwhile, 1166 (64%) of them kept a personal stock of Antibiotics, and 1034 (57%) of them had bought Antibiotics at a pharmacy, of which 97% were purchased without a prescription. Students with high KAP scores with respect to Antibiotics were significantly less likely to self-medicate with Antibiotics (aOR 0.37, 95% CI 0.15–0.91, p = 0.031), use Antibiotics for prophylaxis (aOR 0.35, 95% CI 0.21–0.60, p < 0.0001), or demand an Antibiotic (aOR 0.46, 95% CI 0.26–0.81, p = 0.007) from the doctor. Logistical regression showed that students whose fathers had a higher education level, whose mothers had medical background, who were from urban areas were more likely to stock Antibiotics and self-medicate with Antibiotics. Conclusion: High rates of Antibiotic self-medication for self-limiting illness and stocking of Antibiotics among medical students were observed. Along with the high rates of medical students receiving unnecessary Antibiotics from their doctors were observed. The students’ knowledge and attitude towards to Antibiotics, which drive prescribing, highlight the urgent need for effective Antibiotic stewardship and training programs in Chinese healthcare institutes and medical schools.
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Antibiotic prescription strategies for acute sore throat a prospective observational cohort study
Lancet Infectious Diseases, 2014Co-Authors: Paul Little, Beth Stuart, F Richard D Hobbs, Christopher C Butler, Alastair D Hay, Brendan Delaney, John L Campbell, Sue Broomfield, Paula Barratt, Kerenza HoodAbstract:Summary Background Data from trials suggest that Antibiotics reduce the risk of complications of sore throat by at least 50%, but few trials for complications have been done in modern settings, and datasets of delayed Antibiotic prescription are underpowered. Observational evidence is important in view of poor compliance with Antibiotic treatment outside trials, but no prospective observational cohort studies have been done to date. Methods We generated a large prospective cohort from the DESCARTE study, and the PRISM component of DESCARTE, of 12 829 adults presenting with sore throat (≤2 weeks duration) in primary care. Our follow-up of the cohort was based on a detailed and structured review of routine medical records, and analysis of the comparison of three Antibiotic prescription strategies (no Antibiotic prescription, immediate Antibiotic prescription, and delayed Antibiotic prescription) to control for the propensity to prescribe Antibiotics. Information about Antibiotic prescription was recorded in 12 677 individuals (4805 prescribed no Antibiotics, 6088 prescribed Antibiotics immediately, and 1784 prescribed delayed Antibiotics). We documented by review of patients' notes (n=11 950) the development of suppurative complications (eg, quinsy, impetigo and cellulitis, otitis media, and sinusitis) or reconsultation with new or non-resolving symptoms). We used multivariate analysis to control for variables significantly related to the propensity to prescribe Antibiotics and for clustering by general practitioner. Findings 164 (1·4%) of the 11 950 patients with information available developed complications; otitis media and sinusitis were the most common complications (101 patients [62%]). Compared with no Antibiotic prescription, immediate Antibiotic prescription was associated with fewer complications (adjusted risk ratio [RR] 0·62, 95% CI 0·43–0·91, estimated number needed to treat [NNT 193) as was delayed prescription of Antibiotics (0·58, 0·34–0·98; NNT 174). 1787 of the 11 950 patients (15%) reconsulted with new or non-resolving symptoms; the risk of reconsultation was also reduced by immediate (0·83, 0·73–0·94; NNT 40) or delayed Antibiotics (0·61, 0·50–0·74; NNT 18). Interpretation Suppurative complications are not common in primary care and most are not serious. The risks of suppurative complications or reconsultation in adults are reduced by Antibiotics, but not as much as the trial evidence suggests. In most cases, no Antibiotic is needed, but a delayed prescription strategy is likely to provide similar benefits to an immediate Antibiotic prescription. Funding UK Medical Research Council.
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are patient views about Antibiotics related to clinician perceptions management and outcome a multi country study in outpatients with acute cough
PLOS ONE, 2013Co-Authors: Samuel Coenen, Paul Little, Kerenza Hood, Nick A Francis, Mark James Kelly, J Nuttall, Theo J M Verheij, Hasse Melbye, Herman Goossens, Christopher C ButlerAbstract:Background: Outpatients with acute cough who expect, hope for or ask for Antibiotics may be more unwell, benefit more from Antibiotic treatment, and be more satisfied with care when they are prescribed Antibiotics. Clinicians may not accurately identify those patients. Objective: To explore whether patient views (expecting, hoping for or asking for Antibiotics) are associated with illness presentation and resolution, whether patient views are accurately perceived by clinicians, and the association of all these factors with Antibiotic prescribing and patient satisfaction with care. Methods: Prospective observational study of 3402 adult patients with acute cough presenting in 14 primary care networks. Correlations and associations tested with multilevel logistic regression and McNemar ‘s tests, and Cohen’s Kappa, positive agreement (PA) and negative agreement (NA) calculated as appropriate. Results: 1,213 (45.1%) patients expected, 1,093 (40.6%) hoped for, and 275 (10.2%) asked for Antibiotics. Clinicians perceived 840 (31.3%) as wanting to be prescribed Antibiotics (McNemar’s test, p,0.05). Their perception agreed modestly with the three patient views (Kappa’s=0.29, 0.32 and 0.21, PA’s=0.56, 0.56 and 0.33, NA’s=0.72, 0.75 and 0.82, respectively). 1,464 (54.4%) patients were prescribed Antibiotics. Illness presentation and resolution were similar for patients regardless their views. These associations were not modified by Antibiotic treatment. Patient expectation and hope (OR:2.08, 95% CI:[1.48,2.93] and 2.48 [1.73,3.55], respectively), and clinician perception (12.18 [8.31,17.84]) were associated with Antibiotic prescribing. 2,354 (92.6%) patients were satisfied. Only those hoping for Antibiotics were less satisfied when Antibiotics were not prescribed (0.39 [0.17,0.90]). Conclusion: Patient views about Antibiotic treatment were not useful for identifying those who will benefit from Antibiotics. Clinician perceptions did not match with patient views, but particularly influenced Antibiotic prescribing. Patients were generally satisfied with care, but those hoping for but not prescribed Antibiotics were less satisfied. Clinicians need to more effectively elicit and address patient views about Antibiotics.
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a randomised controlled trial of management strategies for acute infective conjunctivitis in general practice
BMJ, 2006Co-Authors: Hazel Everitt, Paul Little, Pete SmithAbstract:Abstract Objective To assess different management strategies for acute infective conjunctivitis. Design Open, factorial, randomised controlled trial. Setting 30 general practices in southern England. Participants 307 adults and children with acute infective conjunctivitis. Intervention One of three Antibiotic prescribing strategies—immediate Antibiotics (chloramphenicol eye drops; n = 104), no Antibiotics (controls; n = 94), or delayed Antibiotics (n = 109); a patient information leaflet or not; and an eye swab or not. Main outcome measures Severity of symptoms on days 1-3 after consultation, duration of symptoms, and belief in the effectiveness of Antibiotics for eye infections. Results Prescribing strategies did not affect the severity of symptoms but duration of moderate symptoms was less with Antibiotics: no Antibiotics (controls) 4.8 days, immediate Antibiotics 3.3 days (risk ratio 0.7, 95% confidence interval 0.6 to 0.8), delayed Antibiotics 3.9 days (0.8, 0.7 to 0.9). Compared with no initial offer of Antibiotics, Antibiotic use was higher in the immediate Antibiotic group: controls 30%, immediate Antibiotics 99% (odds ratio 185.4, 23.9 to 1439.2), delayed Antibiotics 53% (2.9, 1.4 to 5.7), as was belief in the effectiveness of Antibiotics: controls 47%, immediate Antibiotics 67% (odds ratio 2.4, 1.1 to 5.0), delayed Antibiotics 55% (1.4, 0.7 to 3.0), and intention to reattend for eye infections: controls 40%, immediate Antibiotics 68% (3.2, 1.6 to 6.4), delayed Antibiotics 41% (1.0, 0.5 to 2.0). A patient information leaflet or eye swab had no effect on the main outcomes. Reattendance within two weeks was less in the delayed compared with immediate Antibiotic group: 0.3 (0.1 to 1.0) v 0.7 (0.3 to 1.6). Conclusions Delayed prescribing of Antibiotics is probably the most appropriate strategy for managing acute conjunctivitis in primary care. It reduces Antibiotic use, shows no evidence of medicalisation, provides similar duration and severity of symptoms to immediate prescribing, and reduces reattendance for eye infections. Trial registration Current Controlled Trials ISRCTN32956955
Hans-peter Grossart - One of the best experts on this subject based on the ideXlab platform.
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The multifaceted roles of Antibiotics and Antibiotic resistance in nature.
Frontiers in microbiology, 2013Co-Authors: Saswati Sengupta, Madhab K. Chattopadhyay, Hans-peter GrossartAbstract:Antibiotics are chemotherapeutic agents, which have been a very powerful tool in the clinical management of bacterial diseases since the 1940s. However, benefits offered by these magic bullets have been substantially lost in subsequent days following the widespread emergence and dissemination of Antibiotic resistant strains. While it is obvious that excessive and imprudent use of Antibiotics significantly contributes to the emergence of resistant strains, Antibiotic-resistance is also observed in natural bacteria of remote places unlikely to be impacted by human intervention. Both Antibiotic biosynthetic genes and resistance-conferring genes have been known to evolve billions of years ago, long before clinical use of Antibiotics. Hence it appears that Antibiotics and Antibiotics resistance determinants have some other roles in nature, which often elude our attention because of overemphasis on the therapeutic importance of Antibiotics and the crisis imposed by the Antibiotic-resistance in pathogens. In the natural milieu, Antibiotics are often found to be present in subinhibitory concentrations acting as signalling molecules supporting quorum sensing and biofilm formation. They also play an important role in the production of virulence factors and influence host-parasite interactions (e.g., phagocytosis, adherence to the target cell and so on). The evolutionary and ecological aspects of Antibiotics and Antibiotic-resistance in the naturally occurring microbial community are little understood. Therefore, the actual role of Antibiotics in nature warrants in-depth investigations. Studies on such an intriguing behaviour of the microorganisms promise insight into the intricacies of the microbial physiology and are likely to provide some lead in controlling the emergence and subsequent dissemination of Antibiotic resistance. This article highlights some of the recent findings on the role of Antibiotics and genes that confer resistance to Antibiotics in nature.
