Antibiotic Treatment and Age Are Associated With Staphylococcus aureus Carriage Profiles During Persistence in the Airways of Cystic Fibrosis Patients

Background Staphylococcus aureus is one of the most isolated pathogens from the airways of cystic fibrosis (CF) patients. There is a lack of information about the clonal nature of S. aureus cultured from CF patients and their impact on disease. We hypothesized that patients would differ in their clinical status depending on S. aureus clonal carriage profiles during persistence. Methods During a 21-months prospective observational multicenter study (Junge et al., 2016), 3893 S. aureus isolates (nose, oropharynx, and sputa) were cultured from 183 CF patients (16 German centers, 1 Austrian center) and subjected to spa-sequence typing to assess clonality. Data were associated to lung function, age, gender, and antibiotic treatment by multivariate regression analysis. Results Two hundred and sixty-five different spa-types were determined with eight prevalent spa-types (isolated from more than 10 patients): t084, t091, t008, t015, t002 t012, t364, and t056. We observed different carriage profiles of spa-types during the study period: patients being positive with a prevalent spa-type, only one, a dominant or related spa-type/s. Patients with more antibiotic cycles were more likely to be positive for only one spa-type (p = 0.005), while older patients were more likely to have related (p = 0.006), or dominant spa-types (p = 0.026). Two percent of isolates were identified as methicillin-resistant S. aureus (MRSA) and evidence of transmission of clones within centers was low. Conclusion There was a significant association of antibiotic therapy and age on S. aureus carriage profiles in CF patients indicating that antibiotic therapy prevents acquisition of new clones, while during aging of patients with persisting S. aureus, dominant clones were selected and mutations in the spa-repeat region accumulated.

[1]  M. Mei-Zahav,et al.  Changing epidemiology of the respiratory bacteriology of patients with cystic fibrosis-data from the European cystic fibrosis society patient registry. , 2020, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[2]  A. Mellmann,et al.  High Nuclease Activity of Long Persisting Staphylococcus aureus Isolates Within the Airways of Cystic Fibrosis Patients Protects Against NET-Mediated Killing , 2019, Front. Immunol..

[3]  A. Mellmann,et al.  In vivo competition and horizontal gene transfer among distinct Staphylococcus aureus lineages as major drivers for adaptational changes during long-term persistence in humans , 2018, BMC Microbiology.

[4]  D. Görlich,et al.  Staphylococcus aureus in the airways of cystic fibrosis patients - A retrospective long-term study. , 2018, International journal of medical microbiology : IJMM.

[5]  J. Empel,et al.  Emergence and spread of worldwide Staphylococcus aureus clones among cystic fibrosis patients , 2018, Infection and drug resistance.

[6]  P. Palange,et al.  Cystic fibrosis , 2016, The Lancet.

[7]  J. Mainz,et al.  Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus , 2016, PloS one.

[8]  H. Rohde,et al.  Dynamic in vivo mutations within the ica operon during persistence of Staphylococcus aureus in the airways of cystic fibrosis patients , 2016, PLoS pathogens.

[9]  H. Völzke,et al.  Molecular Epidemiology of Staphylococcus aureus in the General Population in Northeast Germany: Results of the Study of Health in Pomerania (SHIP-TREND-0) , 2016, Journal of Clinical Microbiology.

[10]  A. Mellmann,et al.  Real-Time Genome Sequencing of Resistant Bacteria Provides Precision Infection Control in an Institutional Setting , 2016, Journal of Clinical Microbiology.

[11]  J. Suaya,et al.  spa Typing and Multilocus Sequence Typing Show Comparable Performance in a Macroepidemiologic Study of Staphylococcus aureus in the United States , 2016, Microbial drug resistance.

[12]  S. Jensen-Fangel,et al.  Intravenous antibiotics given for 2 weeks do not eradicate persistent Staphylococcus aureus clones in cystic fibrosis patients. , 2014, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[13]  Dag Harmsen,et al.  Bacterial Whole-Genome Sequencing Revisited: Portable, Scalable, and Standardized Analysis for Typing and Detection of Virulence and Antibiotic Resistance Genes , 2014, Journal of Clinical Microbiology.

[14]  S. Ranganathan,et al.  Staphylococcus aureus in early cystic fibrosis lung disease , 2013, Pediatric pulmonology.

[15]  A. Bragonzi,et al.  Extended Staphylococcus aureus persistence in cystic fibrosis is associated with bacterial adaptation. , 2013, International journal of medical microbiology : IJMM.

[16]  A. Prince,et al.  The length of the Staphylococcus aureus protein A polymorphic region regulates inflammation: impact on acute and chronic infection. , 2012, The Journal of infectious diseases.

[17]  S. Stanojevic,et al.  Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations , 2012, European Respiratory Journal.

[18]  P. Sly,et al.  Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  B. Spratt,et al.  Geographic Distribution of Staphylococcus aureus Causing Invasive Infections in Europe: A Molecular-Epidemiological Analysis , 2010, PLoS medicine.

[20]  Francis J. Martin,et al.  Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A. , 2009, The Journal of clinical investigation.

[21]  J. Emerson,et al.  Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis. , 2009, The Journal of pediatrics.

[22]  J. Stoye,et al.  Based Upon Repeat Pattern (BURP): an algorithm to characterize the long-term evolution of Staphylococcus aureus populations based on spa polymorphisms , 2007, BMC Microbiology.

[23]  A. Witney,et al.  Microarrays Reveal that Each of the Ten Dominant Lineages of Staphylococcus aureus Has a Unique Combination of Surface-Associated and Regulatory Genes , 2006, Journal of bacteriology.

[24]  Michael C. Wendl,et al.  Argonaute—a database for gene regulation by mammalian microRNAs , 2005, BMC Bioinformatics.

[25]  Georg Peters,et al.  Variation of the Polymorphic Region X of the Protein A Gene during Persistent Airway Infection of Cystic Fibrosis Patients Reflects Two Independent Mechanisms of Genetic Change in Staphylococcus aureus , 2005, Journal of Clinical Microbiology.

[26]  Bharat Reddy,et al.  Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1 , 2004, Nature Medicine.

[27]  James M. Musser,et al.  spa Typing Method for Discriminating among Staphylococcus aureus Isolates: Implications for Use of a Single Marker To Detect Genetic Micro- and Macrovariation , 2004, Journal of Clinical Microbiology.

[28]  J. Rothgänger,et al.  Typing of Methicillin-Resistant Staphylococcus aureus in a University Hospital Setting by Using Novel Software for spa Repeat Determination and Database Management , 2003, Journal of Clinical Microbiology.

[29]  R. Proctor,et al.  Population Dynamics of Persistent Staphylococcus aureus Isolated from the Airways of Cystic Fibrosis Patients during a 6-Year Prospective Study , 2003, Journal of Clinical Microbiology.

[30]  F. Ratjen,et al.  Cystic fibrosis , 2003, The Lancet.

[31]  R. Proctor,et al.  Persistent infection with small colony variant strains of Staphylococcus aureus in patients with cystic fibrosis. , 1998, The Journal of infectious diseases.