Acute respiratory infections are amongst the leading causes of childhood morbidity and mortality globally. Viruses are the predominant cause of such infections, but mixed etiologies with bacteria has for decades raised the question of the interplay between them in causality and determination of the outcome of such infections. In this review, we examine recent microbiological, biochemical, and immunological advances that contribute to elucidating the mechanisms by which infections by specific viruses enable bacterial infections in the airway, and exacerbate them. We analyze specific domains in which viruses play such facilitating role including enhancement of bacterial adhesion by unmasking cryptic receptors and upregulation of adhesion proteins, disruption of tight junction integrity favoring paracellular transmigration of bacteria and loss of epithelial barrier integrity, increased availability of nutrient, such as mucins and iron, alteration of innate and adaptive immune responses, and disabling defense against bacteria, and lastly, changes in airway microbiome that render the lung more vulnerable to pathogens. Separate exhaustive analysis of each domain focuses on individuals with cystic fibrosis (CF), in whom viruses may play a key role in paving the way for the primary injury that leads to permanence of bacterial pathogens, viruses may then serve as triggers for “CF exacerbations”; these constituting the signature and ultimately the outcome determinants of these patients.

BackgroundCystic fibrosis (CF) is associated with significant morbidity and early mortality due to recurrent acute and chronic lung infections. The chronic use of multiple antibiotics increases the possibility of multidrug resistance (MDR). Antibiotic susceptibility determined by culture-based techniques may not fully represent the resistance profile. The study objective was to detect additional antibiotic resistance using molecular methods and relate the presence of MDR to airway microbiome diversity and pulmonary function.MethodsBacterial DNA was extracted from sputum samples and amplified for the V4 region of the 16S rRNA gene. An qPCR array was used to detect antibiotic resistance genes. Clinical culture results and pulmonary function were also noted for each encounter.ResultsSix study participants contributed samples from 19 encounters. Those samples with MDR (n = 7) had significantly lower diversity measured by inverse Simpson's index than those without (n = 12) (2.193 ± 0.427 vs 6.023 ± 1.564, p = 0.035). Differential abundance showed that samples with MDR had more Streptococcus (p = 0.002) and Alcaligenaceae_unclassified (p = 0.002). Pulmonary function was also decreased when MDR was present (FEV1, 51 ± 22.9 vs 77 ± 26.7, p = 0.054; FVC, 64.5 ± 22.7 vs 91.6 ± 27.7, p = 0.047).ConclusionsThe presence of MDR within the CF airway microbiome was associated with decreased microbial diversity, the presence of Alcaligenes, and decreased pulmonary function.

OBJECTIVES To determine the frequency of subtherapeutic exposure to intravenously administered β-lactam antibiotics in a cohort of cystic fibrosis (CF) patients who were treated for a pulmonary exacerbation, and its impact on pulmonary function. METHODS Nineteen CF patients between the ages of 5 and 21 years treated at Children's National Health System for a pulmonary exacerbation were followed between March 2015 and August 2016 in a prospective, longitudinal study. Pharmacokinetic modeling and minimum inhibitory concentrations (MICs) of the involved pathogens were used to determine therapeutic or subtherapeutic β-lactam antibiotic exposure based on the time the antibiotic concentration was above the MIC. Clinical outcomes were measured by spirometry values. RESULTS The 19 participants were treated with a total of 29 courses of antibiotics. The most common β-lactam antibiotics used in a treatment course were ceftazidime (62%) and meropenem (45%). There was no difference in age, CF genotype, or creatinine clearance between the 9 participants (47%) who reached therapeutic concentrations versus the 10 (53%) who did not. Those who achieved sufficiently high antibiotic exposure had more significant improvement of their pulmonary function tests. CONCLUSIONS We found that sufficient antibiotic exposure during treatment of CF pulmonary exacerbations was associated with improved pulmonary function. Moreover, it was impossible to predict, solely from the dosing regimen used, which patients were going to reach therapeutic β-lactam antibiotic serum concentrations. This suggests that CF patients may benefit from closer monitoring of their β-lactam exposure and bacterial MIC for optimal clinical outcomes.

In persons with cystic fibrosis (CF), decreased airway microbial diversity is associated with lower lung function. Conflicting data exist on the impact of short-term antibiotics for treatment of acute pulmonary exacerbations. However, whether differences in antibiotic exposure impacts airway microbiome changes has not been studied. We hypothesized that subtherapeutic beta-lactam antibiotic exposure, determined by the pharmacokinetics and pharmacodynamics (PK/PD) after intravenous (IV) antibiotic administration, would be associated with different patterns of changes in CF airway microbial diversity. eligible children were enrolled when well; study assessments were performed around the time of pulmonary exacerbation. plasma drug concentrations and bacterial minimum inhibitory concentrations (MICs) were used to determine therapeutic versus subtherapeutic beta-lactam antibiotic exposure. Respiratory samples were collected from children, and extracted bacterial DNA was amplified for the V4 region of the 16S rRNA gene. Twenty children experienced 31 APEs during the study; 45% (n = 14) of antibiotic courses were deemed therapeutic. Those in the therapeutic group had more significant decreases in alpha diversity at end of treatment and post-recovery compared to baseline than those in the subtherapeutic group. therapeutic and subtherapeutic beta-lactam use is associated with different patterns of changes in CF airway microbial diversity following antibiotic administration. More than 30,000 people in the United States are living with cystic fibrosis (CF), a severe autosomal recessive disease that leads to recurrent lung infections and chronic suppurative lung disease associated with significant morbidity and mortality 1,2. Children and adults frequently require hospitalization for severe recurrent lung infections, known as acute pulmonary exacerbations (APE) 3,4. Antibiotic use is typically directed at specific pathogens, such as Pseudomonas aeruginosa 5. However, prior studies have shown that in vitro susceptibilities do not correlate with clinical outcomes 6. This inconsistency may be due in part to the numerous other bacteria such as Prevotella spp., Veillonella spp., and Gemella spp. that have commonly been identified in CF airways by culture-independent sequencing 7-13 .

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