pulmonary complications of cystic fibrosis -...

Pulmonary Complications of Cystic Fibrosis

Salia Farrokh, Pharm.DPGY2 Critical Care Pharmacy ResidentYale-New Haven HospitalDecember 9, 2012

Objectives

Review the pathophysiology of Cystic Fibrosis (CF)

List clinical manifestations of the disease

Describe the pathogenesis of pulmonarycomplications

Define treatment of pulmonary complications

Provide evidence based clinical recommendationsregarding medication management of respiratorycomplications

Epidemiology

Currently 70,000 people are diagnosed with CF inthe world

30,000 in the US

54.9% men vs. 46.1% women

More than 70% are diagnosed by age 2

Epidemiology

Race Prevalence

Whites of northernEuropean origin *

93.7%

Hispanics 3.2%

African Americans 2.7%

Other ethnicity 0.4%

*Most common lethal genetic disease in the Caucasian population

Epidemiology

In the1950s, only few CF children lived to attendelementary school

In 2012, the estimated median age of survival for aCF patient is in the late 30’s

Currently, more than 45% of CF patients are 18 orolder

Background

Cystic Fibrosis (CF) isan inherited chronicdisease of thesecretary glands

CF is an autosomalrecessive trait

Source: http://www.healthtalkandyou.com/severity-of-cystic-fibrosis-linked-to-genetics/

Pathophysiology

Cystic fibrosis gene

Identified in 1989

Located on chromosome 7

Codes for Cystic FibrosisTransmembrane Regulator(CFTR) protein

Over 1000 cystic fibrosisassociated mutations

∆ F 508 allele is the mostcommon mutation

Pathophysiology

CFTR is a cAMPdependant chloridechannel

In CF, mutation leadsto defective cAMP-stimulated chloridetransport

Pathophysiology

In normal state,

epithelial cells transport

Cl - through CFTR channels

Mutant CFTR channelsresult in decreased Cl -

secretion and increasedsodium absorption

Source: http://www.epgonline.org/~cystic-fibrosis~understanding~understanding-cystic-fibrosis-definition.cfm~pageid~2193

Question #1

What organs are involved in CF?

1) Lungs

2) Liver

3) Pancreas

4) Intestine

5) All of the above

Pathophysiology

The defective gene and its protein product causethick, sticky mucus

Clogs the lungs life-threatening lung infections

Obstructs the pancreas deficiencies of digestiveenzymes malabsorption malnutrition

Mainly affects:

Respiratory system: sinuses and lungs

GI tract: pancreas, liver, and intestine

GU tract: reproductive organs

Clinical Manifestations of CF

Source: http://www.nutrimedical.com/news.jhtml

Diagnosis

Diagnosis

Newborn screening

Required in all states

Sweat chloride test

DNA analysis

Diagnosis

Sweat Chloride Test Gold standard

Reference range

Age Reference Range Interpretation

0-6 months≤29 mmol/L30 to 59 mmol/L≥60 mmol/L

UnlikelyIntermediateIndicative ofCF

> 6 months≤39 mmol/L40 to 59 mmol/L≥60 mmol/L

UnlikelyIntermediateIndicative ofCF

http://www.hopkinscf.org/main/whatiscf/diag_testsweat.html

Diagnosis

DNA Analysis

Used with intermediate sweat chloride values

Requires:

Appropriate testing techniques

Standardized criteria for defining CF-causing mutations

Mutation screening panels can identify 90% ofCFTR mutations

Currently 9.7% of genotyped individuals have at leastone un-identified mutation

Diagnosis

Ancillary Tests

Pancreas Insufficiency (PI)

Nasal Potential Difference (NPD)

Place electrodes on the lining of the nose

Measure electrical potential difference across the airwaylining

Instill 4 types of solutions Ringer’s saline solution

Amiloride

Chloride-free solution

Isoproterenol

Diagnosis

* Assessment should be done at a CF center at age 2 mos and sweat chloride test should be performed at age 2-6 mos

• CF Diagnostic Process for Screened Newborns

Sweat chloride30-59 mmol/L

Diagnosis

o Recommended General process for diagnosing CFRespiratory System

Why Lungs?

Lung disease accountsfor nearly 85% of themortality in CF

Yankaskas JR. et al. CHEST 2004; 125:1S–39S

Lungs in Cystic Fibrosis

In later stages, due to sustained hypoxemia, pulmonary hypertension can occur

Lungs in Cystic Fibrosis

Altered or absent CFTR decreased surfaceliquid and impairedciliary clearance of themucus layer

Abnormal CFTRincreased levels ofasialylated glycolipids

Defective CFTR lowlevels of nitric oxide

Question #2

Which of the following is the most common organismseen in the sputum of a 35 YO cystic fibrosis male?

1) Haemophilus influenzae

2) Burkholderia cepacia

3) Stenotrophomonas maltophilia

4) Pseudomonas aeruginosa

5) MRSA

Most Common Organisms

Staphylocccus aureus Pseudomonas aeruginosa

Mucoid vs. non-mucoidstrains

Haemophilus influenzae Burkholderia cepacia Achromobacter

xylosoxidans Stenotrophomonas

maltophilia MRSA

Mucoid (left) vs. non-mucoid (right) PSA

Source: http://www.cfmicrobiology.org.uk/introduction

Most Common Organisms

Hauser AR. et al. Clin. Microbiol. Rev. 2011; 24 (1): 29-70

Goals?1)Slow or stop the progression of the disease2)Allow young patients to grow and developnormally

Treatment

Assessment

Pulmonary function test FEV1 is the single most useful objective measure of

pulmonary status

Complete microbiological assessment of expectoratedsputum At least annually Preferably on a quarterly basis

Chest imaging Every 2-4 years in stable patients No support for annual assessment Except for patients with acute exacerbations, pneumothorax,

atelectasis, or hemoptysis

Treatment

Treatment

CF flareChronicPhase

Bacterialeradicatio

n

Antibiotics

Reductionof

inflammation

Sterilizationof the

pulmonarytree

Treatment

Two anti-pseudomonalagents

eg. A beta lactam andan aminoglycoside

S. aureus Coverageincluding MRSA

Aerosolized antibiotics Recombinant Human

Dornase (DNase) Hypertonic saline Anti-inflammatory

agents Macrolide antibiotics

Bronchodilators N-acetylcysteine

Acute Exacerbation Chronic Suppressive Therapy

Antibiotics for Acute Exacerbation

Antibiotic Selection

Appropriate coverage

Appropriate dose and frequency

Pharmacokinetics considerations

Appropriate duration

unknown

Question #3

JT is 40 YO male with PMH significant for CF,anemia, and depression. He was admitted toBridgeport Hospital, with CC of SOB andtemperature of 38.4˚C. His sputum culture isgrowing PSA susceptible to tobramycin, doripenem,and ciprofloxacin.

JT has a normal renal function (Clcr ~ 70 mL/min)and NKDA Wt: 65 Kg

Ht: 170 cm

Question #3

How would you dose tobramycin for JT?

1) 450 mg IV every 24 hours




5) None of the above

Pathogen Specific Treatment

Pathogen Drug Amount Route Frequency

S. aureus

Oxacillin 2 gm IV Q4 h

Vancomycin 15 mg/kg IV Q6, Q8h,Q12

PSA Amikacin 7.5 mg/kg30 mg/kg

IV Q 8hDaily

Tobramycin 1.7 mg/kg10 mg/kg

IV Q 8hDaily

Ciprofloxacin 400 mg500- 750 mg

IVPO

Q 8h, Q12h

Ceftazidime 2 gm IV Q 8h

Pip/tazo 4.5 gm IV Q 6h

H.flu Amoxicillin 500-1000 mg PO Q12h

Amox/clav 875 mg (Amox) PO Q 12h

Ceftriaxone 1gm IV Q24h

Rare OrganismsOrganism Drug Amount Route Frequenc

y

B. cepacia complex Meropenem plus(choose one)MinocyclineAmikacinCeftazidimeChloramphenicolTimeth/sulf

2 gm

100 mg5-7.5 mg/kg2 gm15-20 mg/kg4-5 mg/kg

IV

IV/POIVIVIVIV

Q8h

Q12hQ8hQ8hQ6hQ12h

Stenotrophomonasmaltophilia

Ticarcillin/clav orTrimeth/sulf or(Ticarcillin/clavplus aztreonam)

3gm4-5 mg/kg3 gm2 gm

IVIVIVIV

Q6hQ12hQ6hQ8h

Achromobacterxylosoxidans

Chloramphenicalplus MinocyclineCipro plus(choose one)ImipnemMeropenem

15-20 mg/kg100 mg400 or 500-750 mg

500-1000 mg2 gm

IVIV/POIV/PO

IVIV

Q6hQ12 hQ12 h

Q6hQ8h

Aminoglycoside Dosing in CF

Smyth AR. and Bhatt J.

Compared once a day vs. three times a day dosingof amingolycosides

Trial #1 Trial #2 Trail #3

N total: 22 N total: 49 N total: 244

Total daily dose in eachgroups: tobramycin 15mg/kg/day

Total daily dose in eachgroup: tobramycin 10mg/kg/day

Total daily dose in eachgroup: tobramycin 10mg/kg/day

Duration: 14 days Duration:12 days Duration: 14 days

Smyth AR. Bhatt J. Cochrane Database of Systemic Reviews 2012, Issue2. Art. No: CD002009

Aminoglycoside Dosing in CF

Outcomes:

Pulmonary function: no significant difference

Nutrition status: no significant difference

Ototoxicity: no significant difference

Nephrotoxicity: significant worsening of renal functionin children in three times a day dosing

Resistance: no reports

Pharmacokinetics in Cystic Fibrosis

Drug T ½(elimination)

Vd Cl (total) Cl (renal)

Piperacillin Decreased Increased Increased Not reported

Ceftazidime Decreased Increased Increased Increased

Aztreonam Decreased Increased Increased Increased

Ciprofloxacin Decreased Decreased No change No change

Gentamicin No change Increased Increased Not reported

Tobramycin No change Increased Increased No change

Amikacin No change Increased Increased Increased

Meropenem Decreased Decreased Increased Increased

Doripenem No change No change No change No change

Antibiotics for Chronic Suppressive Therapy

Aerosolized Antibiotics

Rationale: to eradicate initial and suppress chronic PSAinfectionDrug Dose Patient Population CFF

Recommendation

Aerosolizedtobramycin (Tobi®) 300 mg BID

≥ 6 YO with +respiratory PSAculture and moderate– severe disease

Strongrecommendation forchronic use

≥ 6 YO with +respiratory PSAculture and milddisease

Recommendation forchronic use

Aerosolizedcolistin

50-75 mg2-3/day

≥ 6 YO with +respiratory PSAculture

Insufficient evidenceto recommend for oragainst chronic use

Aerosolizedaztreonam(Cayston®)

75 mg TID ≥ 7 YO with +respiratory PSAculture

?

Evidence

Two large, multicenter, double blind,placebo controlled trials

Method: 520 patients received 300mg of inhaled tobramycin orplacebo BID (3 on–off cycles for atotal of 24 weeks)

Primary endpoints:

Improved FEV1

Increase by 10% at week 20

Reduced sputum PSA density

Decrease by an average of0.8 log 10

26% less hospitalization

Ramsey BW. et al. N Engl J Med 1999;340:23-30

P < 0.001

Evidence

A multicenter, randomized clinical trial of nebulizedtobramycin or colistin in CF

Method: 115 patients received either Tobramycinor colistin, BID x 4 weeks

Primary Endpoints

Tobramycin improved FEV 1 by 6.7%

No improvement was observed with colistin

Both agents significantly reduced sputum PSA density

Eur Respir J 2002; 20:658-664

Evidence

Inhaled aztreonam trials

Trial N Dosing Regimen Results

Phase II doubleblinded

105 75 mg and 225 mg BID vs.placebo for 14 days

75 mg was selected forfuture studies due to doserelated respiratoryadverse effects

Phase III doubleblinded

164 75 mg TID vs. placebo for28 days

↑ FEV1 by 10.3%,

Phase III doubleblinded

211 75 mg BID or TID vsplacebo for 28 days (openlabel TIS)

↑ time-to- need abx by21 days

Elbon S. and Henig NR. Expert Opinion Pharmacotherapy 2010;11(8): 1373-1385

TIS vs. AZLI

A multicenter, randomized, parallel group study

28 day, intermittent, repeating cycles of Tobramycin InhalationSolution (TIS) vs. Aztreonam for Inhalation Solution (AZLI)

300 mg BID vs. 75 mg TID

N total = 268 CF patients with PSA

N aztreonam = 136

N tobramycin = 132

Oermann, CM et al. Ped Pulm 2010 in press

TIS vs. AZLI

Results: mean ∆ in FEV1% predicted at day 28 AZLI (8.35) vs. TIS (0.55)

AZLI TIS % ↓ p

Total number of respiratory hospitalizations 40 58 31% 0.044

Total number of respiratory events requiringIV and/or inhaled anti PSA abx

84 121 31% 0.004

Recombinant Human DNase

Rationale: to improve airway clearance bydegrading large amount of free DNA

Drug Dose Patient Population CFFRecommendation

Dornase alpha(Pulmozyme®)

2.5 mg once a day(BID?)

≥ 6 YO withmoderate –severe disease

Strongrecommendationfor chronic use

≥ 6 YO withmild disease

Recommendationfor chronic use

Evidence for moderate-severe disease

Trial Number o patients Duration FEV1 end points

Fuchs et al. 968 24 weeks ↑ by 5.8%

McCoy et al. 320 12 weeks ↑ by 7.3%

Total of 19 trials in moderate-severe CF patients Long term vs. short term Better FEV1 outcomes with long term trials Better FEV1 outcomes with larger trials

Evidence for mild disease

A 2 year randomized,multicenter, placebo-controlled trial

Method: 474 patientsreceived DNase orplacebo

Results: Respiratory

exacerbation wasreduced by 34%

Mean FEV1 improved by3.2% ± 1.2%(p=0.006)

Quan JM. et al. J Pedi 2001;139:831-820

Hypertonic Saline

Rationale: to increase hydration of respiratory tractand improve mucocilliary clearance

Drug Dose PatientPopulation

CFFRecommendation

Hypertonic Saline 4 ml BID ≥ 6 YO CFpatients


Evidence

Multiple trials with conflicting results

Eng et al.

Effects of 6% inhaled saline BID in 58 patients x14 days

Mean FEV1 increase of 15% vs. 2.8% seen in 0.9% saline

Elkins et al.

Effects of 7% inhaled saline BID in 164 patients x 48 weeks

No change in FEV1 compared with 0.9% saline

56% reduction in pulmonary exacerbations

Anti-inflammatory Agents

Rationale: to prevent inflammation and subsequentobstruction and infection Excessive inflammatory response in CF patients

Drug Drug/Dose Patient Population Recommendation

Oral corticosteroids Prednisone 1mg/kg (maxdose: 60 mg)

6-18 YO CF patients withoutasthma or ABPA

Against the chronic use

> 18 YO CF patients withoutasthma or ABPA

Insufficient data torecommend for oragainst chronic use

Inhaled corticosteroids Variable agents/doses ≥ 6 YO CF patients withoutasthma or ABPA

Against the chronic use

Macrolide antibiotics Azithromycin ≥ 6 YO CF patients withpersistent PSA present inairways


Evidence

Four trials to identify role of macrolides in CF

Clarithromycin

One trial

Ten adult patients

Six weeks

Did not show to improve lung function

Azithromycin

Larger patient population (50-100)

All trials improved FEV1 (3.6%-6.2%)

Evidence

A multicenter, randomized,double-blind, placebo-controlled

Method: 185 patients withCF and PSA for > 1 year Azithromycin 250 mg (wt <

40 kg) or 500 mg (wt≥ 40kg) 3 days a week orplacebo for 168 days

Primary Endpoints: Improved FEV1by 4.4% Reduced exacerbation Increased body wt by 0.7 kg

Saiman L. et al. JAMA. 2003;290:1749-1756

Bronchodilators

Rationale: to provide symptomatic relief and tofacilitate clearance of the airways

Standard component of therapy

Drug Drug/Dose Population CFFRecommendation

Beta 2 receptoragonist

Albuterol neb (0.5-5mg/day)

≥ 6 YO CFpatients


Inhaledanticholinergicagents

Ipratropium neb ( 50-500 mcg/day)

≥ 6 YO CFpatients

Insufficient evidenceto recommend for oragainst chronic use

N-acetylcysteine

Rationale: to improve mucus clearance by breakingdisulfide bonds

Clinical trials showed no benefit from inhaled ororal NAC

Drug Dose Patient Population CFF population

N-acetylcysteine oral ? ≥ 6 YO CF Insufficient evidenceto recommend for oragainst chronic use

N-acetylcysteineinhalation

3-5 ml of 20%6-10 ml of 10%

≥ 6 YO CF Insufficient evidenceto recommend for oragainst chronic use

Future Direction

Personalized Medicine

Kalydeco® by Vertex pharmaceuticals

Newest agent approved (January 31, 2012)

First to target the genetic defect

Targets G551d mutation

Makes CFTR protein structure open too slowly

Price? $294,000 for the BID dosing tablet/year

Duration? Life long!

Currently Vertex is studying a compound that will targetF∆508 mutation

F∆508 is the most common mutation

Thank you!

References

Farrell PM, Rosenstein BJ, White TB, et al. guidelines for diagnosis of cystic fibrosis innewborns through older adults: cystic fibrosis foundation consensus report. J Pediatr 2008:153 (2): S4-S14

Yankaskas JR, Marshall BC, Sufian B, et al. Cystic fibrosis adult care. Consensus conferencereport. Chest 2004; 125: 1s-39s

Touw DJ. Clinical Pharmacokinetics of antimicrobial drugs in cystic fibrosis. Pharm World Sci1998;20(4):149-160

Flume PA, O’Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Am J RspirCrit CareMed 2007; 176: 957-969

Ross LF. A re-examination of the use of ethnicity in prenatal carrier testing. Am J Med GenetPart A 2011;158A: 19-23

Quan JM, Tiddens HA, Sy JP, et al. A two-year randomized, placebo-controlled trial ofdornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. JPediatr 2001;139:813–20

Saiman L, Marshall BC, Mayer Hamblett N. et al. Azithromycin in Patients With Cystic FibrosisChronically Infected With Pseudomonas aeruginosa. JAMA. 2003;290:1749-1756

Ramsey BW, Pepe Ms, Quan JM, et al. Intermittent administration of inhaled tobramycin inpatients with cystic fibrosis. N Engl J Med 1999;340:23-30

References

Smyth AR, Bhatt J. Once daily versus multiple daily dosing with intravenous aminoglycosidesfor cystic fibrosis. Cochrane Database of Systemic Reviews 2012. Issue 2. Art. No.: CD002009.DOI: 10.1002/14651858.CD002009.pub4.

Gibson RL, Burns JL, Ramsey BW. Pathophysiology and Management of Pulmonary Infectionsin Cystic Fibrosis. Am J Respir Crit Care Med 2003;168: 918-951.

Cirillo I. Vaccaro N, Redman R. et al. Pharmacokinetics of Single-Dose Doripenem in Adultswith Cystic Fibrosis. Journal of Clinical Pharmacology2011; 1-9.

Miall LS, McGinley NT, Brownlee KG, et al. Methicillin resistant Stphylococcus aureus (MRSA)infection in cystic fibrosis. Arch Dis Child 2001;84:160-162.

Ballmann M, Smyth A, and Geller DE. Therapeutic Approaches to chronic cystic fibrosisrespiratory infections with available, emerging aerosolized antibiotics. Respiratory Medicine2011; 105 (S2): S2-S8.

Acknowledgment

Jeff Topal MD

Gina Bliss Pharm.D

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