Dataset Information

Treatment for chronic methicillin-sensitive Staphylococcus aureus pulmonary infection in people with cystic fibrosis.

ABSTRACT:

Background

Cystic fibrosis is an inherited life-threatening multisystem disorder with lung disease characterized by abnormally thick airway secretions and persistent bacterial infection. Chronic, progressive lung disease is the most important cause of morbidity and mortality in the condition and is therefore the main focus of clinical care and research. Staphylococcus aureus is a major cause of chest infection in people with cystic fibrosis. Early onset, as well as chronic, lung infection with this organism in young children and adults results in worsening lung function, poorer nutrition and increases the airway inflammatory response, thus leading to a poor overall clinical outcome. There are currently no evidence-based guidelines for chronic suppressive therapy for Staphylococcus aureus infection in cystic fibrosis such as those used for Pseudomonas aeruginosa infection. This is an update of a previously published review.

Objectives

To assess the evidence regarding the effectiveness of long-term antibiotic treatment regimens for chronic infection with methicillin-sensitive Staphylococcus aureus (MSSA) infection in people with cystic fibrosis and to determine whether this leads to improved clinical and microbiological outcomes.

Search methods

Trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, Embase, handsearching article reference lists and through contact with local and international experts in the field. Date of the last search of the Group's Cystic Fibrosis Trials Register: 09 February 2018.We also searched ongoing trials databases. Date of latest search: 20 May 2018.

Selection criteria

Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials used as suppressive therapy for chronic infection with methicillin-sensitive Staphylococcus aureus compared with placebo or no treatment.

Data collection and analysis

The authors independently assessed all search results for eligibility. No eligible trials were identified.

Main results

The searches identified 58 trials, but none were eligible for inclusion in the current version of this review.

Authors' conclusions

No randomised controlled trials were identified which met the inclusion criteria for this review. Although methicillin-sensitive Staphylococcus aureus is an important and common cause of lung infection in people with cystic fibrosis, there is no agreement on how best to treat long-term infection. The review highlights the need to organise well-designed trials that can provide evidence to support the best management strategy for chronic methicillin-sensitive Staphylococcus aureus infection in people with cystic fibrosis.

SUBMITTER: Ahmed MI

PROVIDER: S-EPMC6513196 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Laboratory models have been invaluable for the field of microbiology for over 100?years and have provided key insights into core aspects of bacterial physiology such as regulation and metabolism. However, it is important to identify the extent to which these models recapitulate bacterial physiology within a human infection environment. Here, we performed transcriptomics (RNA-seq), focusing on the physiology of the prominent pathogen Staphylococcus aureus in situ in human cystic fibrosis (CF) infection. Through principal-component and hierarchal clustering analyses, we found remarkable conservation in S. aureus gene expression in the CF lung despite differences in the patient clinic, clinical status, age, and therapeutic regimen. We used a machine learning approach to identify an S. aureus transcriptomic signature of 32 genes that can reliably distinguish between S. aureus transcriptomes in the CF lung and in vitro The majority of these genes were involved in virulence and metabolism and were used to improve a common CF infection model. Collectively, these results advance our knowledge of S. aureus physiology during human CF lung infection and demonstrate how in vitro models can be improved to better capture bacterial physiology in infection.IMPORTANCE Although bacteria have been studied in infection for over 100?years, the majority of these studies have utilized laboratory and animal models that often have unknown relevance to the human infections they are meant to represent. A primary challenge has been to assess bacterial physiology in the human host. To address this challenge, we performed transcriptomics of S. aureus during human cystic fibrosis (CF) lung infection. Using a machine learning framework, we defined a "human CF lung transcriptome signature" that primarily included genes involved in metabolism and virulence. In addition, we were able to apply our findings to improve an in vitro model of CF infection. Understanding bacterial gene expression within human infection is a critical step toward the development of improved laboratory models and new therapeutics.

Project description:Chronic pulmonary bacterial infections and associated inflammation remain a cause of morbidity and mortality in people with cystic fibrosis (PwCF) despite new modulator therapies. Therapies targeting host factors that dampen detrimental inflammation without suppressing immune responses critical for controlling infections remain limited, while the development of lung infections caused by antimicrobial resistant bacteria is an increasing global problem, and a significant challenge in CF. Pharmacological compounds targeting the mammalian MAPK proteins MEK1 and MEK2, referred to as MEK1/2 inhibitor compounds, have potential combined anti-microbial and anti-inflammatory effects. Here we examined the immunomodulatory properties of MEK1/2 inhibitor compounds PD0325901, trametinib, and CI-1040 on CF innate immune cells. Human CF macrophage and neutrophil phagocytic functions were assessed by quantifying phagocytosis of serum opsonized pHrodo red E. coli, Staphylococcus aureus, and zymosan bioparticles. MEK1/2 inhibitor compounds reduced CF macrophage pro-inflammatory cytokine production without impairing CF macrophage or neutrophil phagocytic abilities. Wild-type C57BL6/J and Cftr tm1kth (F508del homozygous) mice were used to evaluate the in vivo therapeutic potential of PD0325901 compared to vehicle treatment in an intranasal methicillin-resistant Staphylococcus aureus (MRSA) infection with the community-acquired MRSA strain USA300. In both wild-type and CF mice, PD0325901 reduced inflammation associated body mass loss. Wild-type mice treated with PD0325901 had significant reduction in neutrophil-mediated inflammation compared to vehicle treatment groups, with preserved clearance of bacteria in lung, liver, or spleen 1 day after infection in either wild-type or CF mouse models. In summary, this study provides the first data evaluating the therapeutic potential of MEK1/2 inhibitor to modulate CF immune cells and demonstrates that MEK1/2 inhibitors diminish pro-inflammatory responses without impairing host defense mechanisms required for acute pathogen clearance.

Project description:Staphylococcus aureus is the most commonly identified airway colonizer of cystic fibrosis (CF) patients, and infections with methicillin-resistant S. aureus (MRSA) are associated with poor outcomes. Yet, little is known about the intrahost evolution of S. aureus among CF patients. We investigated convergent evolution and adaptation of MRSA among four CF patients with long-term respiratory carriage. For each patient, we performed whole-genome sequencing on an average of 21 isolates (range: 19-23) carried for a mean of 1,403 days (range: 903-1,679), including 25 pairs of isolates collected on the same day. We assessed intrahost diversity, population structure, evolutionary history, evidence of switched intergenic regions (IGRs), and signatures of adaptation in the context of patient age, antibiotic treatment, and co-colonizing microbes. Phylogenetic analysis delineated distinct multilocus sequence type ST5 (n = 3) and ST72 (n = 1) clonal populations in addition to sporadic, non-clonal isolates, and uncovered a putative transmission event. Variation in antibiotic resistance was observed within clonal populations, even among isolates collected on the same day. Rates of molecular evolution ranged from 2.21 to 8.64 nucleotide polymorphisms per year, and lineage ages were consistent with acquisition of colonization in early childhood followed by subsequent persistence of multiple sub-populations. Selection analysis of 1,622 core genes present in all four clonal populations (n = 79) found 11 genes variable in three subjects - most notably, ATP-dependent protease clpX, 2-oxoglutarate dehydrogenase odhA, fmtC, and transcription-repair coupling factor mfd. Only one gene, staphylococcal protein A (spa), was found to have evidence of gene-wide diversifying selection. We identified three instances of intrahost IGR switching events, two of which flanked genes related to quorum sensing. The complex microbial ecology of the CF airway poses challenges for management. We illustrate appreciable intrahost diversity as well as persistence of a dominant lineage. We also show that intrahost adaptation is a continual process, despite purifying selective pressure, and provide targets that should be investigated further for their function in CF adaptation.