Cystic Fibrosis

Cystic Fibrosis Progression

Initiation of treatment early in life is critical to prevent disease progression

Cystic Fibrosis: Organ-System Disease

* Multiple organ-system disease
* Pulmonary
* Digestive
* Reproductive organs
* and more are affected

Cystic Fibrosis

Mortality usually due to lung disease

CF Diagnosis

* Newborn screening/ Immunoreactive Trypsinogen (IRT)
* Meconium Ileus (MI)
* Sweat Chloride test

CF Diagnosis: Newborn Screening/ Immunoreactive Trypsinogen (IRT)

* NOT diagnostic—only identifies infants at risk for CF
* High value necessitates genetic testing

CF Diagnosis: Meconium Ileus (MI)

* \~ 20% of CF cases present with MI
* 80-90% of patients with MI have CF

CF Diagnosis: Sweat Chloride Test

* Sweat Chloride test is diagnostic gold standard
* 2nd confirmatory test required
* ≥ 60 mmol/L: CF diagnosis
* Borderline sweat chloride ranges vary between infants and older children/adults
* Patients with borderline values may still have CF

Cystic Fibrosis (CF) Genetics

* Autosomal recessive disease
* 1 mutation on each allele of cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to CF
* Presentation on only 1 allele prevents full expression of CF

Cystic Fibrosis (CF) Genetic Testing

* 2 mutations identified on genetic testing of CF patient
* Most common genetic mutation is F508del

Cystic Fibrosis (CF) Severity

Disease severity depends on genetic mutation

Cystic Fibrosis (CF) Mutation Classes

* Class 1 is the most severe form
* F508del is a class 2 mutation
* Class 4-6 usually pancreatic sufficient

CF Pathophysiology

* Genetic mutations cause defect in the CFTR
* 2000 different genetic mutations identified


* CFTR normally regulates Na+ and Cl- transport across the cell membrane
* Defective CFTR → impaired chloride transport → dehydrated cell surface liquid → mucus plugging → organ dysfunction

Lung Disease

* Thickened mucus → decreased mucus clearance → bacterial overgrowth and colonization → plugging, increased cough, SOB → decreased O2 sats, lung scarring → eventual mortality

Lung Disease: Other Complications

* Pneumothorax
* Pleurisy

GI Disease: Bile Duct

Thick secretions in bile ducts → scarring → gallstones, decreased bicarbonate production, liver dysfunction

GI Disease: Pancreas

* Thick secretions in pancreas → plugged pancreatic ducts & scarring
* → decreased pancreatic enzyme secretion → poor digestion → poor nutrient absorption → decreased weight gain, malnutrition → worsened lung disease, osteoporosis
* → decreased or sporadic insulin secretion, impaired insulin sensitivity → hyperglycemia → microvascular complications (nephrotoxicity, neurotoxicity, retinopathy)

Reproductive Disease: Males

* In utero blockage of vas deferens leads to male infertility in CF
* **Do not assume infertility**
* Sperm may still be produced and may be retrieved for In-Vitro Fertilization (IVF)
* Recommend genetic counseling

Reproductive Disease: Females

* Females may be infertile due to thickened cervical mucus or malnutrition
* Medication counseling by the pharmacist
* Recommend genetic counseling

Cystic Fibrosis (CF) Diet

* High-calorie, high-protein, unrestricted fat diet
* Balance
* Nutritional supplements
* Scandishakes
* Boost, Kids Essentials, Ensure, etc.
* Good nutrition means better lung health, outcomes
* Goal BMI ≥ 50 percentile
* Hyperlipidemia is rare in CF

Cystic Fibrosis (CF) and Fat Soluble Vitamins

* Poor absorption of fat-soluble vitamins in CF
* AquADEK
* Contains A,D,E,K and other minerals
* Dosed Qday - BID
* Hydrophilic microsphere structure aids absorption
* 3 formulations: liquid, gelcap, and chewtab
* OTC; often not covered by insurance, cost \~$30/60 doses

Vitamin Supplementation

* Additional supplementation of A, D, E, K may be necessary
* Vitamin K (Mephyton): 5 or 10mg PO Qday to BID

Percentage of Bone Disease in Cystic Fibrosis (CF)

\~50-75% of CF patients

Cystic Fibrosis (CF): Risk Factors of Bone Disease

* Poor Calcium, Vit D & K absorption
* Glucocorticoid, PPI, H2 blocker therapy
* Low activity levels
* Chronic inflammation

Cystic Fibrosis (CF): Bone Disease Monitoring

Bone density scans and vitamin levels recommended for monitoring

Cystic Fibrosis (CF): Bone Disease Treatment

* Consider bisphosphonates if T/Z score ≤ -2.0
* IV better than oral?? No data, but worry about absorption
* Calcium, Vitamin D & K supplementation
* Exercise

Pancreatic Enzyme Replacement Therapy (PERT) Administration

Administered with all meals and snacks

Pancreatic Enzyme Replacement Therapy (PERT) Capsules

* Capsules contain microtablets or microspheres
* Enteric-coated
* Role of H2 blockers & PPIs

Pancreatic Enzyme Replacement Therapy (PERT) Dosing

* Dose usually based on units of lipase/kg
* \~1500 lipase units/kg/meal
* Usual max dosage = 2,500 units of lipase/kg/meal, 10,000 units of lipase/kg/day
* Colonic strictures associated with lipase >6000 units/kg/meal

Pancreatic Enzyme Replacement Therapy (PERT) Brands

DO NOT SUBSTITUTE

* Cotazyme
* Zenpep
* Creon
* Pancreaz
* Pertzye
* Ultresa
* Viokace

Pancreatic Enzyme Replacement Therapy (PERT): Options for Tube Feed Patients

* New options may be coming out soon
* Jejunally-placed tube: Dissolve capsule contents in Sodium Bicarbonate
* Gastrically-placed tube: distribute contents in acidic juice such as nectar-thick (don’t crush)

Airway Clearance Techniques

* Percussion vest
* Manual chest percussion therapy (CPT)
* Positive Expiratory Pressure
* Flutter device
* Acapella
* Postural drainage
* Aerobic exercise

Goals of Respiratory Treatments

* Clear mucus from lungs
* Reduce bacterial concentration in sputum
* Improve quality of life & survival

Goals of Respiratory Treatments: Clear Mucus from Lungs

* Improve respiratory function
* Prevent further colonization
* Prevent further lung damage

Goals of Respiratory Treatments: Reduce Bacterial Concentration in Sputum

* Reduce inflammation in the lungs
* Prevent exacerbations

Correct Order of Respiratory Meds

1) Albuterol (MDI or neb)

2) Hypertonic saline (not used frequently)

3) Pulmozyme

* Vest simultaneously

4) Inhaled antibiotic

5) Steroid nebulizer or inhaler

Correct Order of Respiratory Meds Goals

Goal is open, clear airways for better drug distribution and absorption into lung tissue

Drugs for t-piece Nebulizer

As recommended by your physician

Drugs for Sidestream Nebulizer

* Pulmozyme® (dornase alpha)
* Albuterol (salbutamol)Albuterol (salbutamol

Drugs for PARI LC PLUS® Breath-Enhanced Nebulizer

**Use with 25 psi compressor**

* TOBI®
* Colymycin (sterile colistimethate sodium, USP)
* Albuterol
* Pulmozyme®
* Pulmicort® (budesonide)

Drugs for PARI LC STAR® Breath-Enhanced Nebulizer

**Use with 25 psi compressor**

* Colymycin
* AlbuterolAlbuterol
* Pulmozyme®
* Pulmicort®

Drugs for Altera® with eFlow® Technology Breath-Enhanced Nebulizer

Cayston®

E-Rapid®

* E-Rapid® nebulizer handset now available for use with Altera® compressor
* A substitute for the Pari-LC Plus® nebulizer that allows for rapid administration of meds

Hypertonic Saline

* 7% NaCl via nebulizer (some pts use 3% or 10%)
* Increases hydration of airway surface liquid

Hypertonic Saline Dosing

Qday-BID

Hypertonic Saline ADE

* Can cause airway irritation and bronchospasm
* Use bronchodilator pre-treatment

Hypertonic Saline Studies

Studies show improved lung function and reduced frequency of exacerbations, to lesser extent than dornase alfa

Hypertonic Saline Indication

* Not FDA approved for CF, but used by >50% of pts
* CF Foundation recommends chronic therapy with hypertonic saline

Pulmozyme (dornase alfa) MOA

Mucolytic; breaks up long white blood cell DNA strands, decreases mucus viscosity

Pulmozyme (dornase alfa) Dosing

* Nebulized liquid
* Dosed 2.5mg Qday – BID

Pulmozyme (dornase alfa) Studies

Studies show improved PFTs, decreased risk of infections requiring IV antibiotics

Pulmozyme (dornase alfa) ADE

* May cause:
* Increased cough
* Wheeze
* Hoarseness
* Skin rash
* Fever
* HA
* Malaise

Pulmozyme (dornase alfa) Indications

CF Foundation recommends using dornase alfa even in asymptomatic patients with mild lung disease

Anti-inflammatory/Other Therapies

* Ibuprofen
* Azithromycin

Anti-inflammatory/Other Therapies: Ibuprofen

* Traditional dosing 200-400mg q 4-6 hours
* High dose 20-30mg/kg/day, divided twice daily
* Requires PK monitoring of Ibuprofen levels
* Goal peak 50-100mcg/mL

Anti-inflammatory/Other Therapies: Azithromycin

* 250mg (

Cultures

* Sputum or throat
* Usually done quarterly
* Often multiple organisms on culture

Cultures: Commonly Isolated Organisms

* MSSA (methicillin-sensitive staph aureus)


* MRSA
* __**Pseudomonas aeruginosa**__
* Stenotrophomonas maltophilia
* Achromobacter
* Burkholderia cepacia

Cultures Complications

* Full eradication is rare; methods being studied
* Antibiotic resistance is common

Inhaled Antipseudomonal Antibiotics

* Tobi (tobramycin) & Tobi Podhaler
* Cayston (aztreonam)
* Off-label:
* Colistimethate
* Ceftazidime
* Meropene

Oral Antipseudomonal Antibiotics

* Ciprofloxacin
* Cipro suspension cannot be given per tube

Oral Antipseudomonal Antibiotics: Ciprofloxacin Dosing

* Children: 40mg/kg/day PO divided q12 hours
* Lower bioavailability

Antipseudomonal Antibiotics: Counseling Points

* Benefit outweighs risk of joint/connective tissue toxicity
* Counsel to separate from dairy, enteral feeds, Ca, Fe, Zn

Inhaled Tobramycin

Generic tobramycin neb solution now available (do not sub without authorization from MD)

Inhaled Tobramycin Indication

Treatment of CF patients with pseudomonas

Inhaled Tobramycin MOA

* Aminoglycoside
* Inhibits protein synthesis
* Bactericidal
* Concentration-dependent

Inhaled Tobramycin: Tobi Dosing

300mg (5mL ampule) BID via neb

Inhaled Tobramycin: Bethkis Dosing

300mg (4mL ampule) BID via neb

Inhaled Tobramycin: Tobi Podhaler Dosing

* 4 caps (2 inhalations per cap; 112mg total)
* Inhaled BID via device

Inhaled Tobramycin Durations

* Usually 28 days on, 28 days off
* Some patients alternate with Cayston or Colistimethate

Inhaled Tobramycin Counseling Points

Do not mix Tobi in nebulizer with any other meds

Inhaled Tobramycin ADE

* May cause
* Coughing
* Wheeze
* Sore throat
* Hoarseness

Cayston (aztreonam lysine) Dosing

Dose is 75mg inhaled TID via Altera nebulizer

Cayston (aztreonam lysine) Duration

Usually 28 days on, 28 days off

Cayston (aztreonam lysine) MOA

* Binds to PBP-3 on gram(-) aerobes
* Inhibits cell wall synthesis
* Bactericidal

Cayston (aztreonam lysine) ADE

* Cough
* Bronchospasm
* Hoarseness

Cayston (aztreonam lysine): Pre-Treatment

Always pre-treat with albuterol or other beta-agonist

Colistin (colistimethate) Dosing

* Dosing is 150mg (diluted in 2 mL of sterile water) inhaled BID via nebulizer
* Use injectable colistin in the nebulizer (off label)

Colistin (colistimethate) Duration

* Usually a 28-day course
* May alternate with tobramycin or aztreonam inhalation for 28d on, 28d off

Colistin (colistimethate) MOA

* Cationic detergent
* Damages bacterial cytoplasmic membrane causing leaking of intracellular substances and cell death

Colistin (colistimethate) Pre-Treatment

Pre-treat with bronchodilator

IV Antipseudomonal Antibiotics

* Penicillins
* Cephalosporins
* Carbapenems
* Tobramycin
* Ciprofloxacin
* Aztreonam

IV Antipseudomonal Antibiotics: Penicillins

Piperacillin-Tazobactam (Zosyn)

IV Antipseudomonal Antibiotics: Cephalosporins

* Ceftazidime (Fortaz)
* Cefepime

IV Antipseudomonal Antibiotics: Carbapenems

* Meropenem (Merem
* 1st choice among carbapenems
* Doripenem (Doribax) or Imipenem-cilastatin (Primaxin)
* Resistance may develop more quickly to Primaxin

IV Antipseudomonal Antibiotics: Ciprofloxacin Dosing

10mg/kg Q8H IV required for CF children due to increased clearance

IV Tobramycin Dosing

* Traditional vs. extended interval dosing (EID)
* EID is preferred at the Sacred Heart CF Clinic (q24h dosing)

Why is extended interval dosing (EID) preferred?

* Provides higher peak:MIC ratio
* Maximizes concentration-dependent post-antibiotic effect
* 2.5-fold higher sputum Cmax vs TID dosing
* Lengthens drug-free interval
* Theoretically decreasing risk of nephro- & ototoxicity
* Increased resistance?
* Improved quality of life?

IV Tobramycin PK Monitoring: Initial Starting Dose

Initial starting dose \~10mg/kg q24h

IV Tobramycin PK Monitoring: Volume & Clearance

Vd & clearance rates are higher in CF

IV Tobramycin PK Monitoring: Tobramycin Levels After 1st or 2nd Dose

**Difficult to obtain consistent levels; much adjustment** **required**

* 2 & 6 hours post-dose for patients

Oral Antibiotics for MRSA

* High-dose Septra
* Clindamycin
* Minocycline, doxycycline (CI

Oral Antibiotics for MRSA: High-dose Septra Dosing

* 20mg/kg divided BID for children
* Septra DS: 2 tabs BID for adults

IV Antibiotics for MRSA

* Vancomycin, linezolid
* Daptomycin not appropriate (poor lung penetration)

Stenotrophomonas Maltophilia

* Bactrim is drug of choice (DOC)
* Levofloxacin, minocycline are alternatives
* Often resistant to aminoglycosides & carbapenems

Burkholderia Cepacia

* Bactrim is drug of choice
* Levofloxacin, minocycline are alternatives
* May be resistant to aminoglycosides, piperacillin, ceftazidime

Ursodiol Indication

Treats & prevents CF liver disease

Ursodiol Dosing

* Children: 20-30mg/kg/day, divided BID
* Adults: 600mg BID

Ursodiol Counseling Points

Give with food

Ursodiol ADE

* Constipation


* N/V
* Diarrhea
* Backache
* Dizziness
* Rash
* Cough
* Pharyngitis/bronchitis

Ursodiol MOA

Decreased biliary cholesterol concentration → breakdown of gallstones → increases bile flow → protects liver by decreasing toxicity of bile acid