Hot Topics in Antibiotic Management of Pediatric CF Lung Disease Mike Tracy, MD Fellow, Pediatric Pulmonary

Overview Origins CF lung disease Conventional CF bacteria Treatment of 3 major CF bacteria –Staphylococcus aureus –Pseudomonas –Non-tuberculous Mycobacteria Future of CF pulmonary infections

Origins of CF Lung Disease Stolz et al, NEJM, 2015, 372;4

Origins of CF Lung Disease Stolz et al. NEJM, 2015, 372;4

Prevalence of Conventional Respiratory Bacteria by year in CF, Annual Data Report 2014 CFF Patient Registry

Prevalence of Respiratory Bacterial Organisms by Age in CF, 2014 Annual Data Report 2014 CFF Patient Registry

Airway Bacterial Changes over Time Chmiel JF et al. Annal ATS 2014; 11(7):1120

Impact of Antibiotic treatment in CF Patrick Flume (various sources) Predicted Median Survival (US), years Antibiotic Era : Doubling of predicted survival LiPuma, NACFC Plenary Session II, 2014

Current Testing & Treatment Insufficient Routine culture techniques easily identify only ~1% of known bacteria –Limited use as most bacteria in CF lung exist in biofilms When we identify & target conventional pathogens: –25% of patients with pulmonary exacerbations do not reach pre-exacerbation values in lung function Sanders DB, et al. AJRCCM 2010;182(5):627 Chmiel JF et al. Annal ATS 2014; 11(7):1120

Staphylococcus aureus MSSA MRSA Many types infections –Skin –Bones –Blood –Lungs

Prevalence of Conventional Respiratory Bacteria by year in CF, Annual Data Report 2014 CFF Patient Registry

S. Aureus in CF by age Annual Data Report 2014 CFF Patient Registry

Is S. aureus bad for people with CF? In children –Increased inflammation –Worse lung function decline –Increased 10 yr mortality In older adolescents & adults –Decreased 5-yr mortality –Better lung function –Lower risk exacerbations Hoffman L, NACFC 2015

MRSA Methicillin-resistant Staphylococcus aureus Chronic MRSA associated with worse outcomes –Cause or marker? No conclusive studies for how to treat (or not to treat) MRSA in CF –Eradication Protocols Staph Aureus Resistance – treat or observe trial (STAR-too) So who and how do we treat? Dasenbrook EC, et al. JAMA 2010;303:

MRSA: Treatment + MRSA NewChronic No Symptoms Eradication protocol? None? Eradication Protocol? Mild Pulmonary Symptoms Eradication protocol? Oral antibiotics? Inhaled antibiotics? Acute Pulmonary Exacerbation Oral/IV antibiotics

Pseudomonas Common bacteria Opportunistic Many strains –P. aeruginosa most common Spread by direct or indirect contact Initial colonization  how can we stop chronic infection?

P. aeruginosa: CFF Guidelines 2014 Recommendation 1 –Inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture –Inhaled tobramycin (300 mg twice daily) for 28 days Recommendation 2 –Recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa Mogayzel PJ et al, AATS, 2014

P. aeruginosa by Age, 1988–2014 Annual Data Report 2014 CFF Patient Registry

P. aeruginosa: Initial Treatment No clear benefit of one treatment over another –CFF recommends TOBI nebs as most studied Treatment is successful based on microbiology results Sustained eradication  less likely chronic infection –Clinical long term benefit unclear Some groups less likely to clear –Based on type of P. aeruginosa? Mayer-Hamblett et al. CID 2015:61 Mayer-Hamblett et al. CID 2014:59

P. aeruginosa: Ongoing Research OPTIMIZE –TOBI +/- Azithromycin –Decrease pulmonary exacerbations? Torpedo-CF –IV vs Oral antibiotics + Inhaled antibiotic (Colistin) –Increase success of prolonged eradication?

Non-tuberculous Mycobacterium (NTM) Major emerging pathway “Cousins” to bacteria that cause TB Opportunistic >100 types NTM Acquired from soil, dust, water Person-to-person transmission may be important –Likely indirect, through environment Concern for accelerated decline in lung function

Mycobacterial species 2014 Annual Data Report 2014 CFF Patient Registry

New NTM Guidelines Floto RA, et al. Thorax 2016;71:i1–i22

New NTM Guidelines: Screening Recommendation 2 –Cultures for NTM be performed annually in spontaneously expectorating individuals with a stable clinical course Recommendation 3 –In the absence of clinical features suggestive of NTM pulmonary disease, individuals who are not capable of spontaneously producing sputum do not require screening cultures for NTM Floto RA, et al. Thorax 2016;71:i1–i22

New NTM Guidelines: Diagnosis NTM Pulmonary Disease (NTM-PD) Symptoms of NTM similar to other CF organisms A single positive culture of NTM does not necessarily mean NTM-PD –Need to rule out other common CF bacteria –Need radiology studies, and repeat cultures Floto RA, et al. Thorax 2016;71:i1–i22

New NTM Guidelines: Treatment Floto RA, et al. Thorax 2016;71:i1–i22

Future of CF pulmonary infections Bacteria Microbiome - Many species undetected Fungi Aspergillus Interactions with bacteria Viruses Associated w/ 30-40% Pulmonary Exacerbations

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