cystic fibrosis treatment_ a review of antibiotics' mechanism of action and efficacy for...

7/27/2019 Cystic Fibrosis Treatment_ a Review of Antibiotics' Mechanism of Action and Efficacy for _em_Pseudomonas Aeruginosa__em

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Cystic Fibrosis Treatment: A Review of Antibiotics' Mechanism of Action and Efficacy for Pseudomonas aeruginosa CME/CE

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Release Date: December 8, 2008 ; Valid for credit through December 8, 2009

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This activity is intended for pulmonologists.

Goal

The goal of this activity is to provide pulmonologists with education on therapies for Pseudomonasaeruginosa management in cystic fibrosis.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Review the identification of airway infect ions in patients with cystic fibrosis (CF) throughoutthe patient life cycle from childhood to adulthood

2. Evaluate acute and chronic therapeutic recommendations, considering the efficacy andmechanism of action of current and investigational antimicrobial regimens for the treatment of Pseudomonas aeruginosa infections in patients with CF

3. Assess the potential effects of therapy on both forced expiratory volume in 1 second andquality of life in patients with CF

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Contents of This CME/CE Activity

Cystic Fibrosis Treatment: A Review of Antibiotics' Mechanism of Action and Efficacy for PseudomonasaeruginosaNoah Lechtzin, MD, MHS

Cystic Fibrosis Treatment: A Review of Antibiotics' Mechanism of Action and Efficacy forPseudomonas aeruginosa

Introduction and Overview of Cystic Fibrosis (CF)

Epidemiology of CF

CF is the most common life-shortening inherited disease in whites, affecting approximately 1 in 2500 live births.There are approximately 30,000 individuals in the United States who have CF. [1] This multisystem diseasefrequently affects the lungs, pancreas, and sinuses. CF also affects fertility, the liver, and bone health. Thedisease is caused by a genetic defect in a specific chloride channel, the CF transmembrane conductanceregulator (CFTR). [2] The CFTR gene was identified in 1989, [3] which led to immediate hope for a cure. Althoughthere is currently no curative treatment for CF, supportive care directed at treating lung disease and optimizingnutrition has been extremely successful. The median age of survival has increased from under 5 years in the1950s to more than 37 years currently. [1,4] CF was once considered only a pediatric disease, but now more than40% of all patients with CF are 18 years or older. [1] Nevertheless, 90% or more of individuals with CF eventuallydie from pulmonary complications. CF results in bronchiectasis, chronic pulmonary infection, and obstructive lungdisease.

Common symptoms of CF include cough, sputum production, chest tightness, sinus pressure, sinus drainage,failure to thrive, abdominal pain, steatorrhea, and meconium ileus or bowel obstruction. CF is similar to other chronic obstructive lung diseases such as asthma and chronic obstructive pulmonary disease in that it is markedby periods of relative stability interrupted by intermittent exacerbations. [5]

How well do you understand the pathophysiolo gy of cystic fibrosis ?

Very well

Moderately well

Limited understanding

Not at all

Pathophysiology

CF is inherited in an autosomal-recessive pattern and is caused by mutations in the CFTR gene, resulting inabsent or defective CFTR protein. The CFTR gene is located on the long arm of chromosome 7 and more than1000 different disease-causing mutations of this chromosome have been identified. [2,6,7] The CFTR is anadenosine triphosphate-dependent cell membrane chloride transport channel. Through its regulation of chloride iontransport and its effects on other ion channels, CFTR affects airway surface liquid, airway electrolyteconcentrations, and pH. [8] Although the physiology of CFTR dysfunction is complicated and the subject of muchscientific debate, the net effect is that individuals with CF have abnormally viscous secretions in organs thatexpress CFTR. These include the upper and lower respiratory tract, the pancreas, the biliary tree, the intestines,and the reproductive tract.

The overwhelming cause of morbidity and mortality in CF is from lung disease and chronic pulmonary infections.More than 90% of deaths in CF are the result of lung disease and its complications. [1,9] People with CF havemucous plugging, chronic bacterial infections of their airways, airway inflammation, and ultimately bronchiectasis ,as shown in Figure 1. [10]




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Figure 1. Complications of cystic fibrosis (CF). From Yankaskas JR, Knowles M, eds. Cystic Fibrosis in Adults . Philadelphia, Pa: Lippincott-Raven; 1999: chapter 3. [10] Reprinted withpermission.

The CF airway is abnormally susceptible to infection with certain organisms including Pseudomonas aeruginosa,Staphylococcus aureus , Haemophilus influenzae, Burkholderia cepacia, S tenotrophomonas maltophilia, and

Achromobacter xylosoxidans .[11] Whereas all of these organisms have clinical relevance, Pseudomonas infectionappears to play a particularly central role in the pathophysiology of CF lung disease. Lung infections begin shortlyafter birth in individuals with CF and are accompanied by acute inflammation with a preponderance of neutrophils.This acute inflammation persists in CF and is mediated by interleukin -8, tumor necrosis factor-alpha, andinterleukin-1. [12]

The characteristics of the airway surface liquid are central to lung infections in CF. The airway surface liquid isdivided into 2 components: the periciliary liquid layer and the mucous layer. [13] The height of the liquid layer isregulated to allow free movement of the bronchial cilia and the mucous layer binds particles to aid in clearance.There are 2 conflicting theories to explain the high rate of Pseudomonas infection in CF airways, the "low-volume"hypothesis and the "high-salt" hypothesis, illustrated in Figure 2. [14] Most recent evidence suggests that the low-volume hypothesis is correct. [15] This hypothesis postulates that defective CFTR does not regulate epithelialsodium channels (ENaC), resulting in increased absorption of isotonic fluid and dehydration of the airway surfaceliquid. [16] This impairs mucociliary clearance. The opposing theory, the high-salt theory, proposes that as a resultof defective CFTR, salt is not absorbed into the cells appropriately and the airway surface liquid is "saltier" thannormal. [17]




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centers will not perform lung transplants on patients with CF who are infected with B cepacia .[19,20] P aeruginosais the most common airway infection in CF, and P aeruginosa infection is associated with shortened survival andmore frequent exacerbations. [21-24] Studies have demonstrated that eradication of early Pseudomonas infectionfrom individuals with CF results in better outcomes including slower decline in lung function. [25-27] Over time,however, P aeruginosa forms mucoid colonies that probably cannot be sterilized. Mucoid strains of P aeruginosaproduce a thick layer of an exopolysaccharide called alginate. These mucoid strains are nonmotile and grow inmicrocolonies imbedded in alginate. Alginate protects the bacteria from antibiotics and leukocytes. [28] Althoughabnormalities in the airway environment and mucociliary clearance contribute, they do not explain the extremely

high prevalence of P aeruginosa infection in people with CF. Other potential explanations include an increasedbinding affinity for P aeruginosa in the CF airways [29,30] and direct binding of P aeruginosa to mutant CFTR. [31] P aeruginosa is a common environmental organism and can be found on damp areas such as sinks, shower heads,hot tubs, sponges, nebulizers, and also fruits and vegetables. It is thought that the vast majority of people with CFare infected with their own unique environmental strain. [32] However, there are well-documented cases of person-to-person spread. This has been especially problematic with epidemic spread of highly antibiotic-resistantstrains. [33,34]

Figure 3. Age-specific prevalence of infections in patients with cyst ic fibrosis, 2006. Published withpermission from the Cystic Fibrosis Foundation Patient Registry, 2006 Annual Report to Center Directors, Bethesda, MD: Cystic Fibrosis Foundation, 2007. [1] B cepacia = Burkholderia cepacia; H influenza = Haemophilus influenzae; MRSA = methici llin-resist ant Staphylococcus aureus; P aeruginosa = Pseudomonas aeruginosa; S aureus = Staphylococcus aureus; S maltophilia =Stenotrophomonas maltophilia.

Detection of Pseudomonas Infection

How commonly do you test for Pseudomonas aeruginosa in patients with CF?

Always

Often

Occasionally

Not at all

Not applicable




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The accurate diagnosis of P aeruginosa infection in individuals with CF can be challenging. Patients frequentlyhave multiple morphologies of P aeruginosa present in respiratory isolates. Antibiotic susceptibilities frequentlydiffer between the different morphotypes and can vary greatly depending on sampling. It is time consuming andexpensive for microbiology laboratories to select multiple different strains from each respiratory sample.

Automated techniques to determine antibiotic susceptibility are inadequate in the complicated bacterial milieu of CF. It is recommended that laboratories use selective media, MacConkey's agar, and the disc diffusion techniquefor susceptibility testing. [35] Clinicians treating individuals with CF should keep in mind that inhaled tobramycinreaches levels in the airways that are 20- to 50-fold higher than levels obtained from intravenous administration.Therefore, minimum inhibitory concentration cut-offs typically reported by microbiology laboratories indicatingtobramycin resistance should not deter one from using inhaled tobramycin. Additionally, for Pseudomonasisolates that are resistant to multiple c lasses of antibiotics , testing should be performed using combinations of antibiotics to assess whether some combinations act synergistically. [36] Although combination testing isrecommended and is commonly used, the existing literature has not shown it to be more effective than antibioticschosen based on clinical judgment. [37] Expectorated sputum is an accurate method to sample the microbiology of the lower respiratory tract in CF and correlates well with samples obtained by bronchoscopy. [38] However, infants,children, and some adults with more mild disease may not be able to expectorate sputum. The gold standardmethod of sampling in these patients is bronchoscopy and bronchoalveolar lavage (BAL); however, this invasiveprocedure requires sedation. Therefore, BAL is not performed routinely. Frequently, clinicians rely onoropharyngeal swabs as a surrogate for lower airway sampling. Results using oropharyngeal swabs have beencompared directly with BAL results, with one study reporting a positive predictive value of 44% and negativepredictive value of 95%. The authors concluded that a negative throat swab is adequate to exclude P aeruginosa

infection in the lower airways, but a positive throat swab was not sufficient to rule in infection.[39]

In spite of itsshortcomings, oropharyngeal swabs are frequently used to diagnose P aeruginosa infection in patients that cannotproduce sputum. Antipseudomonal serologies have been used clinically for the detection of P aeruginosa infectionin Europe but have remained largely a research tool in the United States. [40] Serologies are more sensitive thanoropharyngeal cultures for detecting early P aeruginosa infection but do not decrease in response to treatment inestablished infections. [41] Serial serologic testing may be useful to eradicate new P aeruginosa infection. [42]

Which of the following is the greatest barrier to providing optimal care to patients wi th CF?

Hypersens itivities as sociated with current treatment regimens

Cost of therapies

Patient compliance

Inaccessibi lity of novel therapies

Management of Pulmonary Sequelae of CF

The approach to the management of the pulmonary sequelae of CF includes both chronic and acute therapies.Patients persistently colonized with P aeruginosa and chronic stable pulmonary disease should be evaluated for treatment with either tobramycin solution for inhalation, USP and/or azithromycin. In addition, all patients with CFand chronic stable disease should also be evaluated for treatment with dornase alfa and/or 7% hypertonic saline(HS). These therapies have different mechanisms of action resulting in differential effects on lung function andquality of life. In patients with CF who have acute pulmonary exacerbations, the approach to management involvesaggressive antibiotic treatment.

Chronic Stable CF

Inhaled Antibiotics

Because 80% of patients with CF will eventually be positive for infection with P aeruginosa , and this infection leadsto increased morbidity and mortality, its control is of utmost importance. The most well-studied inhaled antibioticfor chronic suppression of P aeruginosa in CF is tobramycin solution for inhalation, USP.

In your experience, what is the correlation between respons e to intravenous aminoglycoside antibiotic therapy and thedevelopm ent of neph rotoxicity or ototoxicity?




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Strong correlation

Moderate correlation

Weak correlation

No correlation

Not applicable

Aminoglycoside antibiotics interfere with bacterial protein synthesis by binding to the 30S and 50S ribosomal

subunits, resulting in a defective bacterial cell membrane. In CF, large doses of intravenous antibiotics are requiredto penetrate the sputum. These high doses result in an increased risk for nephrotoxicity and ototoxicity . Nebulizedantibiotics allow the direct delivery of the antibiotic to the lower airway by aerosol administration. Nebulizedantibiotics, in contrast to intravenous antibiotics, offer the advantage of high concentrations of the antibiotic at thesite of infection, with minimal systemic absorption. [43]

Inhaled tobramycin has been shown to be both efficacious and safe. Ramsey and colleagues [43] performed 2multicenter, double-blind, placebo-controlled trials of intermittent administration of inhaled tobramycin in patientswith CF and P aeruginosa infection. The change in percent predicted forced expiratory volume in 1 second(FEV 1%) at week 20 compared with week 0 was 11.87% comparing inhaled tobramycin with nebulized saline, as

shown in Figure 4. [43]

Figure 4. Mean change in the percent predicted forced expiratory volume in 1 second (FEV 1%) inpatients receiving inhaled tobramycin or placebo. The mean change from week 0 in FEV 1%(expressed as the percentage of the value predicted on the basis of age, height, and sex) is shownfor each study visit. The shading denotes the periods when the subjects received tobramycin or placebo. The I bars represent 95% confidence intervals. FEV 1% values were available for 257patients in the tobramycin group and 262 in the placebo group at week 0 and for 232 patients in the

tobramycin group and 231 in the placebo group at week 20. From Ramsey BW, Pepe MS, QuanJM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. CysticFibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340:23-30. [43] Used with permission.

In addition, patients in the tobramycin group were 26% (95% confidence interval (CI), 2% to 43%) less likely to behospitalized. There was a small increase in minimum inhibitory concentrations of the P aeruginosa strainsinfecting the tobramycin-treated patients; however, because the concentrations of inhaled tobramycin are 100times as high as systemic therapies, the relevance of thresholds from intravenous therapy may not be applicableto inhalational therapies. In addition, there was no increase in the isolation of other resistant Gram-negativeorganisms such as B cepacia complex. There were no ototoxic or nephrotoxic effects in the intervention group.The Cystic Fibrosis Foundation strongly recommends the chronic use of inhaled tobramycin to improve lungfunction and reduce exacerbations in patients with CF who are > 6 years of age and have persistent infection with




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P aeruginosa and an FEV 1% < 70%. [42] In those patients with CF who have persistent P aeruginosa cultures and

FEV 1% 70%, only 2 small studies have been performed. [45,46] Based on these results, the Cystic FibrosisFoundation found a moderate amount of evidence to recommend the use of nebulized tobramycin to reduceexacerbations in this milder subgroup, as noted in the Table. [44]

Table. Cystic F ibrosis Foundation Committee Recommendations for Selected ChronicMedications in Patients With CF Aged 6 Years of Age and Older

ChronicMedication

Routeand Dose

Frequency CFDisease

Clinical OutcomesStudied

Estimateof NetBenefit*

CF FoundationCommitteeRecommendation

Inhaledtobramycin

Nebulized300 mg

twice aday

PersistentP aeruginosa

FEV 1% 70%

Improves lung functionand reducesexacerbations

Substantial A

FEV 1% >70%

Reduces exacerbations Moderate B

Dornase alfa Nebulized2.5 mg

Every day All patientswith CF

FEV 1% 70%


Substantial A

FEV 1% >70%


Moderate B

Azithromycin Orally

250 mg

Every day PersistentP aeruginosa


Substantial B

Hypertonicsaline

Nebulized

7%

Twice aday

All patientswith CF


Moderate B

* Benefit - Harms Recommendation levels: A, committee strongly recommends that clinicians routinely provide themedication to eligible patients; B, the committee recommends that clinicians routinely provide themedication to eligible patientsCF = cystic fibrosis; FEV 1% = percent predicted forced expiratory volume in 1 second; P aeruginosa = Pseudomonas aeruginosaFrom Flume PA, O'Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic

medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176:957-969. [44]

Other nebulized antibiotics have been studied in CF. Inhaled colistin is occasionally used in individuals with CFwho do not tolerate inhaled tobramycin or who have more respiratory complications in their tobramycin "off"months. Small studies evaluating inhaled colistin have been performed. One study [47] comparing nebulized colist inwith placebo demonstrated no difference in lung function and another study comparing nebulized colistin withnebulized tobramycin revealed improvement in lung function with tobramycin but not with colistin. [48] Finally,bronchospasm is a significant concern with nebulized colis tin, and thus it is used as a second-line agent. [49]

McCoy and colleagues [50] recently evaluated the effectiveness and safety of aztreonam lysine for inhalation (AZLI)as maintenance therapy for P aeruginosa airway infection in patients with CF. In this multicenter, double-blind,placebo-controlled trial, after randomization and completion of a 28-day course of tobramycin inhalation solution,




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patients were treated with either AZLI 75 mg twice daily, AZLI 75 mg 3 times daily, or placebo 2 or 3 times dailyfor 28 days, followed by monitoring for 56 days. Compared with placebo, significant improvements in respiratoryquality-of-life scores (5.01 points; 95% CI, 0.81 to 9.21), FEV 1% (6.3%; 95% CI, 2.5 to 10.1) and time tointravenous antibiotics (92 days vs 71 days, P < .007) were reported with nebulized aztreonam. AZLI was welltolerated, improved respiratory symptoms and pulmonary function, and delayed time to need for intravenous or inhaled antibiotics. Currently, this product is awaiting approval by the US Food and Drug Administration. There areother inhaled antibiotics for use in CF under investigation. A liposomal formulation of amikacin inhaled once dailyyielded positive results in a phase 2 trial in Europe (data presented at the European CF meeting 2008). A drypowder inhaled form of tobramycin and inhaled fluoroquinolones are under development.

Macrolide Antibiotics

Another treatment for patients with CF who are chronically infected with P aeruginosa is azithromycin. Themechanism of action through which macrolide antibiotics improve lung function in CF is unclear. As previouslydiscussed, CF lung disease is characterized by inflammation and recurrent infection, shown in Figure 1. Twopossible explanations for the efficacy of azithromycin include a direct antimicrobial effect and/or suppression of inflammation that is seen in CF. [51,52]

Three studies have compared azithromycin with placebo and all have shown clinical benefit. [53-55] The largest wasperformed by Saiman and colleagues, [54] who conducted a 24-week multicenter, double-blind, placebo-controlledstudy and found azithromycin given 3 times per week was efficacious and safe. In this study, approximately half of the patients were older than 18, mean FEV

1was approximately 70%, and most patients were receiving therapy

with inhaled tobramycin or dornase alfa. The azithromycin group had an increase in FEV 1% of 6.2% (95% CI,2.6% to 9.8%) at day 168 compared with the placebo group. In addition, compared with the placebo arm, theazithromycin group had fewer exacerbations (hazard ratio, 0.65; 95% CI, 0.44-0.95) and improvement in physicalfunctioning on the CF quality-of-life questionnaire (mean difference, 2.7; 95% CI, 0.1 to 5.3). There were noepisodes of macrolide-resistant nontuberculosis mycobacteria, but this result should be interpreted with caution,as follow-up time in the study was relatively short. To prevent development of resistance, all patients initiated andcontinued on macrolide therapy should have respiratory cultures for nontuberculous mycobacteria every 6 to 12months. The Cystic Fibrosis Foundation recommends the chronic use of azithromycin for patients with CF aged 6 with persistent P aeruginosa infection to reduce exacerbations and improve lung function (Table). [44]

Dornase Alfa

Deoxyribonuclease (DNase) and mucus glycoproteins contribute to the increased viscosi ty of thickenedsecretions in CF. Extracellular DNase is released by the leukocytes that accumulate in the airways in response tochronic bacterial infection. The increased viscosity contributes to decreased mucociliary clearance. Dornase alfa,administered by nebulizer, is a recombinant human enzyme that selectively cleaves extracellular DNase intosmaller parts. [56] Dornase alfa is recommended in patients with and without P aeruginosa infection.

Fuchs and colleagues [5] performed a randomized, double-blind, placebo-controlled trial comparing 24 weeks of nebulized dornase alfa with placebo in 968 patients whose average FEV 1% was 61%. Once-daily administrationimproved the age-adjusted relative risk for an exacerbation by 28% (95% CI, 2% to 48%) and lung function by5.8%. The primary side effect was voice alteration. Other studies have been performed and found a significantimprovement in FEV 1% at 3 months,

[57] 12 months, [58] and 24 months. [59] The 2-year study was performed inchildren with mild CF. Although FEV 1% improves with dornase alfa, quality-of-life outcomes have shown conflicting

results. Fuchs and colleagues [5] found dornase alfa to be associated with significant improvements in the dyspnea

scale, overall well-being score, and CF-related symptom score compared with placebo. Another study foundimprovement in quality of life, but the study duration was only 10 days. [60] Two other studies have either found noimprovement, [61] or found significant improvement only in general well-being, cough, and congestion. [62] Based onthe results of these studies, the Cystic Fibrosis Foundation strongly recommends the use of dornase alfa inpatients with CF who are aged 6 with FEV 1% < 70% to improve lung function and reduce exacerbations. For those with milder disease (FEV 1% > 70%), the Cystic Fibrosis Foundation recommends dornase alfa as shown in

the Table. [44]

7% HS




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Another approach to treat the pathophysiology of CF lung disease involves rehydrating the volume of liquid on theairway surface with HS, as noted in Figure 2. The osmotic gradient created by the HS draws water from the airwayto hydrate the aqueous surface layer and therefore improves mucociliary clearance. HS is recommended inpatients with and without P aeruginosa infection.

Nebulized 7% HS has been shown to improve lung function, decrease exacerbations, and improve quality of life.Elkins and colleagues [63] performed a multicenter, randomized, double-blind, placebo-controlled trial comparingnebulized 7% HS with placebo in 164 patients for 48 weeks. HS did not improve the rate of change of lungfunction; however FEV 1 was significantly higher in the HS arm at the end of the study (68 mL; 95% CI, 3 mL to132 mL). HS significantly improved 48-week exacerbation-free survival rate (76% vs 62%; P = .03). Quality of lifewas significantly improved in the HS group in the role, emotional, and health domains of the CF questionnaire for adults. Perhaps most importantly, participants in the HS group had significantly fewer days absent from work or school (7 days vs 24 days, P < .001). HS is well-tolerated when pretreatment with a bronchodilator is given. Themost common side effects were cough or bronchospasm. Based on this and other studies, the Cystic FibrosisFoundation recommends the chronic use of hypertonic saline for individuals > 6 years of age to improve lungfunction and reduce exacerbations (Table). [44]

Eradication

Once P aeruginosa becomes a chronic colonizer in the respiratory tract of individuals with CF, it is very difficult toeradicate. Persistent infection is associated with worse morbidity and mortality, and therefore, there has beeninterest in aggressively treating the first P aeruginosa culture, even in asymptomatic patients. The benefits of eradication must be weighed against the potential harms of prolonged antibiotic therapy. Most of the support for eradication comes from the experience in Denmark where historic controls were used to compare outcomes after the institution of ciprofloxacin and nebulized colistin with the first P aeruginosa culture. [40] Compared with historiccontrols, patients undergoing the protocol had lower antibody responses and longer survival after acquisition of chronic P aeruginosa lung infection. Based on the results of this and other studies, the National Heart, Lung, andBlood Institute and Cystic Fibrosis Foundation are conducting an 18-month placebo-controlled trial comparingculture-based treatment with consistent treatment with nebulized tobramycin for inhalation and oral ciprofloxacin,with the goal of reducing P aeruginosa infection in children with CF. The study should be completed in August of 2009. [64] This trial will help in the management of these patients, but until this trial is completed, it is notunreasonable to treat patients with a new P aeruginosa culture with a course of nebulized tobramycin and oralciprofloxacin.

Acute Pulmonary Exacerbation Caused by P aeruginosa

In patients with P aeruginosa and an acute CF exacerbation, close attention to antibiotic therapy, airwayclearance, and nutritional support should be undertaken. Antibiotic therapy options include oral, inhaled, and/or intravenous routes. Aggressive antibiotic treatment is warranted because P aeruginosa has been associated withan increased risk for morbidity and mortality. [23,65] The definition of an acute exacerbation varies from study tostudy and even from center to center. A scoring system to determine treatment of a pulmonary exacerbation in theCF clinic has been shown to improve outcomes. [66] Patients with CF have differences in volume of distribution andrate of elimination for many antibiotics, and thus higher doses and shorter intervals may be required. [67]

Those with mild exacerbations and P aeruginosa sensitive to oral antibiotics can initiate treatment with oralantibiotics plus or minus a nebulized antibiotic for 2 to 3 weeks. In the small studies that have been performed,oral and intravenous antibiotic therapy have equivalent outcomes. [68] Oral therapy beyond 4 weeks is notrecommended as ciprofloxacin monotherapy has been associated with the development of resistant P

aeruginosa. [69] Treatment with intravenous antibiotics should begin in those individuals who fail oral antibiotictherapy, who have a culture that is resistant to oral antibiotics, or who are having a moderate-to-severeexacerbation. The initial antibiotic choice should be guided by sensit ivities from sputum cultures.

Combination therapy with an aminoglycoside and either a beta-lactam or carbapenem antibiotic withantipseudomonal activity should be started at pseudomonal doses and continued for 14 to 21 days. Combinationtherapy, compared with single-agent therapy, results in a greater decrease in the sputum density of P aeruginosaand a longer time to next exacerbation requiring hospitalization (30% vs 62% at 80 days, P < .01). [70] For thosewith multiple-antibiotic-resistant P aeruginosa , synergy panels have not been shown to improve clinical or bacteriologic outcomes when compared with usual care. [37] Synergy panels may prove helpful in antibioticselection in those individuals who do not respond to treatment for a pulmonary exacerbation or a patient with CF




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who has extensive drug allergies. [71]

The initial choice of aminoglycoside is usually tobramycin because it has higher sputum concentrations, [72] hasbeen studied the most, and was shown to be superior to gentamicin in a small trial of patients who did not haveCF. [73] Amikacin should be considered if P aeruginosa is resistant to tobramycin as a recent case control studyhas shown an increased risk for acute renal failure with gentamicin. [74] When dosing tobramycin, once-dailydosing is preferred to 3-times-daily dosing. [75] Advantages of once-daily dosing include decreased burden of treatment to patients and their families and potential for less nephrotoxicity. [76] Smyth and colleagues [75]

performed a multicenter, double-blind, randomized, controlled trial of 244 patients comparing once-daily vs 3-times-daily dosing of tobramycin. The results showed equal efficacy between the 2 regimens in terms of lung andrenal function. Subgroup analysis revealed once-daily dosing had a slightly protective effect on serum creatinine inchildren.

Impact of Treatment on Health-Related Quality of Life (QOL)

There has been increasing recognition that patient-reported outcomes including health related QOL are importantto assess. The US Food and Drug Administration has issued a guidance document concerning use of patient-reported outcomes [PRO] in clinical trials and will accept them as primary or secondary outcomes. [77] Pulmonaryexacerbations have been shown to have a large negative effect on QOL. [78] The early landmark inhaled tobramycinand dornase alfa trials did not use state-of-the-art validated measures of QOL. However, a 3-point global measureof QOL was significantly higher in patients receiving inhaled tobramycin in the 1999 tobramycin trial. [79] In the trialof dornase alfa by Fuchs and colleagues, [5] overall well-being measured on a 5-point scale was significantly better in the dornase alfa group compared with the placebo group.

More recent clinical trials have placed greater emphasis on QOL measures and have generally used well-validatedmeasures s uch as the Cyst ic Fibrosis Questionnaire-Revised (CFQ-R) or the Cystic Fibrosis Quality of Life(CFQoL) questionnaire. The CFQ-R is a PRO tool to measure health-related QOL. Chronic macrolide therapy hasbeen shown to improve the physical functioning domain of the CFQ-R. [35] Inhaled hypertonic saline use resulted insignificant improvements in multiple QOL domains. [63] McCoy and colleagues [50] reported that, compared withpatients who received placebo, patients who received aztreonam for inhalation had improvements in time to needfor additional inhaled or antipseudomonal antibiotics and improved respiratory symptoms, as measured by CFQ-Rrespiratory scores, FEV 1, and sputum P aeruginosa density.

Although multiple treatments have been shown to improve QOL in clinical t rials and avoiding exacerbations should

translate to better QOL, the impact of treatment should not be overlooked. In the Australian trial of HS, [63]although symptoms and other QOL domains improved, use of HS resulted in a higher treatment burden.Fortunately, many agents currently under investigation should be easier and less time consuming for patients touse. These include a dry powder inhaler for tobramycin, once-daily inhaled amikacin, and aztreonam for inhalation.

North American Cystic Fibrosis Conference 2008: Updates on Treatments forPseudomonas in CF

At the 2008 North American Cystic Fibrosis Conference in Orlando, future treatment possibilities for individualswith CF infected with Pseudomonas aeruginosa were presented. These treatments are in varying stages of development. The European ELITE (Early Inhaled Tobramycin for Eradication) investigators reported that 28 daysof treatment with nebulized tobramycin at the time of the first (or early) Pseudomonas culture resulted in a mediantime to next Pseudomonas culture of more than 2 years. [80] Other studies examined patients with CF who are

already chronically infected with Pseudomonas sp. Sustained improvement in lung function at 14 days of follow-upwas shown with 75 mg of inhaled aztreonam 3 times a day, but not with twice-daily dosing. [81] Aztreonam has adifferent mechanism of action from tobramycin; tobramycin binds to bacterial 30S and 50S ribosome sites,whereas aztreonam binds to the penicillin-binding proteins. Aztreonam lysine for inhalation is a new formulationthat does not contain arginine, which is associated with airway inflammation if inhaled and is found in aztreonamfor injection. [50] Aztreonam has strong activity against Gram-negative organisms, especially Pseudomonas . Aphase 2 randomized, placebo-controlled trial of nebulized amikacin showed that this medication was safe andimproved multiple clinical endpoints, including lung function. [82] Amikacin is an aminoglycoside and has a similar mechanism of action to tobramycin. Finally, other studies of interest in patients with CF who are chronicallyinfected with P aeruginosa included dry powder ciprofloxacin, liposomal ciprofloxacin, combinationfosfomycin/tobramycin, and macerated garlic oil. Fluroquinolones target bacterial topoisomerases, while




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fosfomycin inhibits bacterial wall synthesis. Both fluoroquinolones and fosfomycin have activity againstPseudomonas as well as against Gram-positive organisms. Further studies on these potentially promisingtherapies are warranted, and in the future, patients with CF who are infected with Pseudomonas will likely benefitfrom different therapeutic options with multiple mechanisms of action.

P aeruginosa is the most common respiratory pathogen in patients with CF and appears to be central to theprogression of lung disease in CF. Research continues to improve our understanding of the high prevalence of P aeruginosa infection in CF, and new agents are being tested to diminish the effects of CFTR dysfunction.

This activity is supported by an independent educational grant from Gilead.

References

[ CLOSE WINDOW ]

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Authors and Disclosures As an organization accredited by the ACCME, Medscape, LLC requires everyone who is in a position to controlthe content of an education activity to disclose all relevant financial relationships with any commercial interest.The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within thepast 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated bythe US Food and Drug Administration, at first mention and where appropriate in the content.

Author

Noah Lechtzin, MD, MHS

Ass is tant Profess or, Department of Medicine, Johns Hopkins U niversity School of Medicin e,Baltimore, Maryland; Associate Director, Adult Cystic Fibrosis Program, Johns HopkinsHospital, Baltimore, Maryland

Disclos ure: Noah Lechtzin, MD, MHS, has dis closed that he has received grants for clinicalresearch from Transave. Dr. Lechtzin has also disclos ed that he has s erved as an advisor or consultant to Transave.

Reviewer

Michael P. Boyle, MD

Ass ociate Profes sor of Medicine, Johns Hopkins U niversi ty School of Medicine, Baltim ore,Maryland; Director, Adult Cystic Fibrosis Program, Johns Hopkins Hosp ital, Baltimore,

Maryland

Disclos ure: Michael P. Boyle, MD, has dis closed that he has served as an advisor or consultant to Novartis and Gilead.

Editor

Nancy Otto, PharmD

Editorial Director, Medscape Pulm onary Medicine

Disclos ure: Nancy Otto, PharmD, has disclosed no relevant financial relationship s.




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Jennifer Brown, PhD

Scientific Director, Medscape, LLC

Disclos ure: Jennifer Brown, PhD, has dis closed no relevant financial relationships.

Writer

Elliot C. Dasenbrook, MD, MHS

Fellow, Division of Pulmonary and Critical Care Medicine, Department of Medicine, JohnsHopkins University, Baltimore, Maryland

Disclos ure: Elliot C. Dasenbrook, MD, MHS, has dis closed n o relevant financial relationships .

Regis tration for CME credit, the pos t test and the evaluation mus t be completed online.To access the activity Post Tes t and Evaluation link, please go to:http://www.medscape.com/viewprogram/17747_index


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