Spotlight on New Antibiotics for the Treatment of Pneumonia
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ABSTRACT:
SUBMITTER: Russo A
PROVIDER: S-EPMC7755939 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality both in the USA and globally. As the burden of CAP continues to increase due to several factors, the advances in its diagnosis, prevention, and treatment have taken on even greater interest and importance. The majority of CAP patients are treated empirically, and selection of appropriate antibiotic treatment is increasingly difficult because the epidemiology of CAP is changing, in part due to antimicrobial resistance, and the causative CAP pathogens differ between countries and regions. There is also an increasing prevalence of chronic co-morbid diseases among CAP patients. Treatment of CAP has become challenging because of these factors along with the varying safety profiles and efficacy of well-established antibiotics, as well as limited new therapeutic options. Recently, however, new antibiotics have been approved, which will expand the treatment options for CAP, particularly in those patients with underlying complications. Recently approved delafloxacin, an anionic fluoroquinolone, has a unique structure and distinct chemical characteristics; it demonstrated non-inferiority to moxifloxacin in a phase III clinical trial, but was shown to be superior to moxifloxacin at early clinical response in CAP patients who also have chronic obstructive pulmonary disease (COPD) or asthma as a co-morbidity, and in CAP patients who may have severe illness. Delafloxacin could offer an additional therapy against resistant isolates and among these difficult-to-treat patients. This review summarizes the development, latest research, and safety profile of the new antibiotic delafloxacin, and its potential future role in the treatment of CAP.
| S-EPMC7511281 | biostudies-literature
Project description:Heat shock protein 90 (Hsp90) is a promising cancer drug target as a molecular chaperone critical for stabilization and activation of several of the oncoproteins that drive cancer progression. Its actions depend upon its essential ATPase, an activity fortuitously inhibited with a very high degree of selectivity by natural antibiotics: notably the actinomycete-derived benzoquinone ansamycins (e.g. geldanamycin) and certain fungal-derived resorcyclic acid lactones (e.g. radicicol). The molecular interactions made by these antibiotics when bound within the ADP/ATP-binding site of Hsp90 have served as templates for the development of several synthetic Hsp90 inhibitor drugs. Much attention now focuses on the clinical trials of these drugs. However, because microbes have evolved antibiotics to target Hsp90, it is probable that they often exploit Hsp90 inhibition when interacting with each other and with plants. Fungi known to produce Hsp90 inhibitors include mycoparasitic, as well as plant-pathogenic, endophytic and mycorrhizal species. The Hsp90 chaperone may, therefore, be a prominent target in establishing a number of mycoparasitic (interfungal), fungal pathogen-plant and symbiotic fungus-plant relationships. Furthermore the Hsp90 family proteins of the microbes that produce Hsp90 inhibitor antibiotics are able to reveal how drug resistance can arise by amino acid changes in the highly conserved ADP/ATP-binding site of Hsp90.
| S-EPMC3603443 | biostudies-literature
Project description:BackgroundChildren with acute pneumonia may be vitamin D deficient. Clinical trials have found that prophylactic vitamin D supplementation decreases the risk of developing pneumonia in children. Data on the therapeutic effects of vitamin D in acute childhood pneumonia are limited.ObjectivesTo evaluate the efficacy and safety of vitamin D supplementation as an adjunct to antibiotics for the treatment of acute childhood pneumonia.Search methodsWe searched CENTRAL (2017, Issue 7), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register; Ovid MEDLINE Epub Ahead of Print; In-Process & Other Non-Indexed Citations; Ovid MEDLINE Daily and Ovid MEDLINE (1946 to July Week 4, 2017); and Embase (2010 to 28 July 2017). We also searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 28 July 2017. There were no language restrictions.Selection criteriaRandomised controlled trials (RCTs) including children (aged over one month and up to five years) hospitalised with acute community-acquired pneumonia, as defined by the WHO acute respiratory infection guidelines, that compared vitamin D supplementation with control.Data collection and analysisTwo review authors independently assessed studies for inclusion and extracted data. For dichotomous data, we extracted the number of participants experiencing the outcome and the total number of participants in each treatment group. For continuous data, we used the arithmetic mean and standard deviation (SD) for each treatment group together with numbers of participants in each group. We used standard methodological procedures expected by Cochrane.Main resultsWe included seven RCTs conducted in low-income countries that involved 1529 children (780 with pneumonia and 749 with severe or very severe pneumonia). Four studies used a single 100,000 IU dose of vitamin D₃ at the onset of illness or within 24 hours of hospital admission; two used a daily dose of oral vitamin D₃ (1000 IU for children aged up to one year and 2000 IU for children aged over one year) for five days; and one used a daily dose of oral vitamin D₃ (50,000 IU) for two days. One study reported microbiological and radiological diagnosis of pneumonia.The effects of vitamin D on outcomes were inconclusive when compared with control: time to resolution of acute illness (hours) (mean difference (MD) -0.95, 95% confidence interval (CI) -6.14 to 4.24; 3 studies; 935 children; low-quality evidence) mortality rate (risk ratio (RR) 0.97, 95% CI 0.06 to 15.28; 1 study; 193 children; very low-quality evidence); duration of hospitalisation (MD 0.49, 95% CI -8.41 to 9.4; 4 studies; 835 children; very low-quality evidence) and time to resolution of fever (MD 1.66, 95% CI -2.44 to 5.76; 4 studies; 584 children; very low-quality evidence).No major adverse events were reported.The GRADE assessment found very low-quality evidence (due to serious study limitations, inconsistencies, indirectness, and imprecision) for all outcomes except time to resolution of acute illness.One study was funded by the New Zealand Aid Corporation; one study was funded by an institutional grant; and five studies were unfunded.Authors' conclusionsWe are uncertain as to whether vitamin D has an important effect on outcomes because the results were imprecise. No major adverse events were reported. We assessed the quality of the evidence as very low to low. Several trials are ongoing and may provide additional information.
| S-EPMC6513535 | biostudies-literature
Project description:BackgroundPneumonia remains the leading cause of paediatric infectious mortality globally. Treatment failure, which can result from non-adherence to oral antibiotics, can lead to poor outcomes and therefore improving adherence could be a strategy to reduce pneumonia related morbidity and mortality. However, there is little published evidence from low-resource settings for the drivers of non-adherence to oral antibiotics in children.ObjectiveWe aimed to investigate reasons for adherence and non-adherence in children diagnosed and treated in the community with fast-breathing pneumonia in rural Malawi.MethodsWe conducted focus group discussions (FGDs) with caregivers of children known to have been diagnosed and treated with oral antibiotics for fast-breathing pneumonia in the community and key informant interviews with community healthcare workers (CHW). FGDs and interviews were conducted within communities in Chichewa, the local language. We used a framework approach to analyze the transcripts.ResultsWe conducted 4 FGDs with caregivers and 10 interviews with CHWs. We identified four themes, which were common across caregivers and CHWs: knowledge and understanding, effort, medication perceptions and community influences. Caregivers and CHWs demonstrated good knowledge of pneumonia and types of treatment, but caregivers showed confusion around dosing and treatment durations. Effort was needed to seek care, prepare medication and understand regimens, acting as a barrier to adherence. Perceptions of how well the treatment was working influenced adherence, with both quick recovery and slow recovery leading to non-adherence. Community influences were both supportive, with transport assistance for referrals and home visits to improve adherence, and detrimental, with pressure to share treatments.ConclusionAdherence to oral antibiotic treatment for fast-breathing pneumonia was understood to be important, however considerable barriers we described within this rural low-resource setting, such as the effort preparing and administering medication, community pressures to share drugs and potential complexity of regimens.
| S-EPMC6209296 | biostudies-literature
Project description:Dysregulation of the innate immune system drives lung injury and its systemic sequelae due to breakdown of vascular barrier function, harmful hyperinflammation and microcirculatory failure, which contribute to the unfavourable outcome of patients with severe pneumonia. A variety of promising therapeutic targets have been identified and numerous innovative therapeutic approaches demonstrated to improve lung injury in experimental preclinical studies. However, at present specific preventive or curative strategies for the treatment of lung failure in pneumonia in addition to antibiotics are still missing. The aim of this mini-review is to give a short overview of some, but not all, adjuvant therapeutic strategies for pneumonia and its most important complications, sepsis and acute respiratory distress syndrome, and briefly discuss future perspectives.
| S-EPMC9487679 | biostudies-literature
Project description:ObjectiveTo compare hospital outcomes associated with commonly used antibiotic therapies for aspiration pneumonia in children with neurologic impairment (NI).Design/methodsA retrospective study of children with NI hospitalized with aspiration pneumonia at 39 children's hospitals in the Pediatric Health Information System database. Exposure was empiric antibiotic therapy classified by antimicrobial activity. Outcomes included acute respiratory failure, intensive care unit (ICU) transfer, and hospital length of stay (LOS). Multivariable regression evaluated associations between exposure and outcomes and adjusted for confounders, including medical complexity and acute illness severity.ResultsIn the adjusted analysis, children receiving Gram-negative coverage alone had two-fold greater odds of respiratory failure (odds ratio [OR] 2.15; 95% CI: 1.41-3.27), greater odds of ICU transfer (OR 1.80; 95% CI: 1.03-3.14), and longer LOS [adjusted rate ratio (RR) 1.28; 95% CI: 1.16-1.41] than those receiving anaerobic coverage alone. Children receiving anaerobic and Gram-negative coverage had higher odds of respiratory failure (OR 1.65; 95% CI: 1.19-2.28) than those receiving anaerobic coverage alone, but ICU transfer (OR 1.15; 95% CI: 0.73-1.80) and length of stay (RR 1.07; 95% CI: 0.98-1.16) did not statistically differ. For children receiving anaerobic, Gram-negative, and P. aeruginosa coverage, LOS was shorter (RR 0.83; 95% CI: 0.76-0.90) than those receiving anaerobic coverage alone; odds of respiratory failure and ICU transfer rates did not significantly differ.ConclusionsAnaerobic therapy appears to be important in the treatment of aspiration pneumonia in children with NI. While Gram-negative coverage alone was associated with worse outcomes, its addition to anaerobic therapy may not yield improved outcomes.
| S-EPMC7641495 | biostudies-literature
Project description:Plastid transformation has become an attractive tool in biotechnology. Because of the prokaryotic nature of the plastid's gene expression machinery, expression elements (promoters and untranslated regions) that trigger high-level foreign protein accumulation in plastids usually also confer high expression in bacterial cloning hosts. This can cause problems, for example, when production of antimicrobial compounds is attempted. Their bactericidal activity can make the cloning of the corresponding genes in plastid transformation vectors impossible. Here, we report a general solution to this problem. We have designed a strategy (referred to as toxin shuttle) that allows the expression in plastids of proteins that are toxic to Escherichia coli. The strategy is based on blocking transcription in E. coli by bacterial transcription terminators upstream of the gene of interest, which subsequently are excised in planta by site-specific recombination. We demonstrate the applicability of the strategy by the high-level expression in plastids (to up to 30% of the plant's total soluble protein) of 2 phage-derived protein antibiotics that are toxic to E. coli. We also show that the plastid-produced antibiotics efficiently kill pathogenic strains of Streptococcus pneumoniae, the causative agent of pneumonia, thus providing a promising strategy for the production of next-generation antibiotics in plants.
| S-EPMC2662961 | biostudies-literature
Project description:The burden of hospital admission for pneumonia in internal medicine wards may not be underestimated; otherwise, cases of pneumonia are a frequent indication for antimicrobial prescriptions. Community- and hospital-acquired pneumonia are characterized by high healthcare costs, morbidity and non-negligible rates of fatality. The overcoming prevalence of resistant gram-negative and positive bacteria (e.g., methicillin-resistant Staphylococcus aureus, penicillin and ceftriaxone-resistant Streptococcus pneumoniae, extended-spectrum β-lactamases and carbapenemases producing Enterobacteriaceae) has made the most of the first-line agents ineffective for treating lower respiratory tract infections. A broad-spectrum of activity, favourable pulmonary penetration, harmlessness and avoiding in some cases a combination therapy, characterise new cephalosporins such as ceftolozane/tazobactam, ceftobiprole, ceftazidime/avibactam and ceftaroline. We aimed to summarise the role and place in therapy of new cephalosporins in community- and hospital-acquired pneumonia within the setting of internal medicine wards. The "universal pneumonia antibiotic strategy" is no longer acceptable for treating lung infections. Antimicrobial therapy should be individualized considering local antimicrobial resistance and epidemiology, the stage of the illness and potential host factors predisposing to a high risk for specific pathogens.
| S-EPMC7399401 | biostudies-literature
Project description:Guidelines recommend administration of antibiotics with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa for treatment of healthcare-associated pneumonia (HCAP). It is unclear if this therapy improves outcomes for patients with HCAP.To determine if administration of guideline-similar therapy (GST) was associated with a reduction in 30-day mortality for HCAP.Multi-center retrospective study.Thirteen hundred and eleven admissions for HCAP in six Veterans Affairs Medical Centers.Each admission was classified as receiving GST, anti-MRSA or anti-pseudomonal components of GST, or other non-HCAP therapy initiated within 48 hours of hospitalization. Association between 30-day mortality and GST was estimated with a logistic regression model that included GST, propensity to receive GST, probability of recovering an organism from culture resistant to antibiotics traditionally used to treat community-acquired pneumonia (CAP-resistance), and a GST by CAP-resistance probability interaction.Odds ratios and 95% confidence intervals [OR (95% CI)] of 30-day mortality for patients treated with GST and predicted probability of recovering a CAP-resistant organism, and ratio of odds ratios [ROR (95% CI)] for treatment by CAP-resistance probability interaction.Receipt of GST was associated with increased odds of 30-day mortality [OR = 2.11 (1.11, 4.04), P = 0.02)] as was the predicted probability of recovering a CAP-resistant organism [OR = 1.67 (1.26, 2.20), P < 0.001 for a 25% increase in probability]. An interaction between predicted probability of recovering a CAP-resistant organism and receipt of GST demonstrated lower mortality with GST at high probability of CAP resistance [ROR = 0.71(?1.00) for a 25% increase in probability, P = 0.05].For HCAP patients with high probability of CAP-resistant organisms, GST was associated with lower mortality. Consideration of the magnitude of patient-specific risk for CAP-resistant organisms should be considered when selecting HCAP therapy.
| S-EPMC3378737 | biostudies-literature
Project description:Background and objectiveNarrow-spectrum antibiotics are recommended as the first-line agent for children hospitalized with community-acquired pneumonia (CAP). There is little scientific evidence to support that this consensus-based recommendation is as effective as the more commonly used broad-spectrum antibiotics. The objective was to compare the effectiveness of empiric treatment with narrow-spectrum therapy versus broad-spectrum therapy for children hospitalized with uncomplicated CAP.MethodsThis multicenter retrospective cohort study using medical records included children aged 2 months to 18 years at 4 children's hospitals in 2010 with a discharge diagnosis of CAP. Patients receiving either narrow-spectrum or broad-spectrum therapy in the first 2 days of hospitalization were eligible. Patients were matched by using propensity scores that determined each patient's likelihood of receiving empiric narrow or broad coverage. A multivariate logistic regression analysis evaluated the relationship between antibiotic and hospital length of stay (LOS), 7-day readmission, standardized daily costs, duration of fever, and duration of supplemental oxygen.ResultsAmong 492 patients, 52% were empirically treated with a narrow-spectrum agent and 48% with a broad-spectrum agent. In the adjusted analysis, the narrow-spectrum group had a 10-hour shorter LOS (P = .04). There was no significant difference in duration of oxygen, duration of fever, or readmission. When modeled for LOS, there was no difference in average daily standardized cost (P = .62) or average daily standardized pharmacy cost (P = .26).ConclusionsCompared with broad-spectrum agents, narrow-spectrum antibiotic coverage is associated with similar outcomes. Our findings support national consensus recommendations for the use of narrow-spectrum antibiotics in children hospitalized with CAP.
| S-EPMC4535024 | biostudies-literature