eCysticFibrosis Review eCysticFibrosis Review
HOMECME/CE INFORMATION PROGRAM DIRECTORSNEWSLETTER ARCHIVEEDIT PROFILERECOMMEND TO A COLLEAGUE
Subscribe to eCysticFibrosis Review Editor’s Note: Look out for eCysticFibrosis Review Special Edition; a two-part series highlighting on some of the key information presented at the European Cystic Fibrosis Society (ECFS) Conference in Lisbon, Portugal June 12-15, 2013.

eCysticFibrosis Review VOLUME 4, ISSUE 5

P. aeruginosa Eradication

In this Issue...

In patients with cystic fibrosis, chronic endobronchial infection with Pseudomonas aeruginosa (Pa) is associated with a greater morbidity and mortality. Early Pa isolates tend to be highly antibiotic-susceptible and present at low density. Thus, a "window of opportunity" exists to eradicate Pa before infection becomes chronic. Early Pa eradication is now standard of care around the world, but the most effective regimen remains a highly contested topic.

In this issue, we review the results of four important clinical trials of early Pa eradication therapies that, together, begin to answer the question, "How shall I most safely and effectively treat my patient who has new isolation of Pa from a respiratory culture?" The comparative efficacy of different treatment regimens is described, similarities and differences in study design of the four trials are identified, and potential negative consequences of early eradication therapy are discussed. Finally, suggested next steps in evaluating the safety and efficacy of early eradication therapy are outlined.
LEARNING OBJECTIVES
After participating in this activity, the participant will demonstrate the ability to:
Distinguish between existing, newly available, and investigational inhaled antibiotics for treating chronic pulmonary infections
Identify appropriate use and selection of inhaled therapies in combination
Evaluate current evidence describing the use of intermittent, continuous, cycled inhaled antibiotics therapies to suppress airway infections
Recognize and apply best practices in managing pulmonary exacerbations
Incorporate evidence-based strategies and newly available technologies to improve patient adherence to inhaled medication

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.


  IMPORTANT CME/CE INFORMATION
Program Begins Below
 accreditation statements
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

The Institute for Johns Hopkins Nursing and the American Nurses Credentialing Center do not endorse the use of any commercial products discussed or displayed in conjunction with this educational activity.

credit designations
Physicians
Newsletter: The Johns Hopkins University School
of Medicine designates this enduring material
for a maximum of 1.0 AMA PRA Category 1
Credit(s)
™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses
Newsletter: This 1 contact hour Educational Activity is provided by the Institute for Johns Hopkins Nursing. Each Newsletter carries a maximum of 1 contact hours or a total of 6 contact hours for the six newsletters in this program.

Respiratory Therapists
For United States: Visit this page to confirm that your state will accept the CE Credits gained through this program.

For Canada: Visit this page to confirm that your province will accept the CE Credits gained through this program.

intended audience
This activity has been developed for pulmonologists, pediatric pulmonologists, gastroenterologists, pediatricians, infectious disease specialists, respiratory therapists, dieticians, nutritionists, nurses, and physical therapists.

There are no fees or prerequisites for this activity.

launch date
This program launched on February 28, 2013 and is published monthly; activities expire two years from the date of publication.

hardware & software requirements
Pentium 800 processor or greater, Windows 98/NT/2000/XP or Mac OS 9/X, Microsoft Internet Explorer 5.5 or later, Windows Media Player 9.0 or later, 128 MB of RAM Monitor settings: High color at 800 x 600 pixels, Sound card and speakers, Adobe Acrobat Reader.

disclaimer statement
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.

Statement of Need
Based on a review of the current literature, including national and regional measures, detailed conversations with expert educators at Johns Hopkins, and a survey of potential program participants, this program will address the following core patient care gaps:
Disease-Modifying Therapies
Clinicians may be unfamiliar with recently introduced disease-modifying therapies and how they are altering the therapeutic landscape for patients with cystic fibrosis.
Clinicians may be uncertain how to integrate genotyping into therapeutic decisions and how to communicate with patients and families about the relationship between genotype and therapy
Nutrition
Many clinicians lack strategies to persuade patients to adhere to CF nutritional requirements, resulting in low body weight and nutritional failure in patients with cystic fibrosis.
Many clinicians remain uncertain how to optimize pancreatic function in patients with cystic fibrosis.
Treating CF Patients with Inhaled Antibiotics
Clinicians lack knowledge about the use of existing and emerging inhaled ABX to treat chronic pulmonary infections.
Clinicians need more information to make informed decisions about the use of inhaled ABX in combination.
Clinicians lack information about best practices for scheduling ABX therapy to suppress chronic airway infections.
Common clinician assumptions about treating pulmonary exacerbations lack supporting evidence.
CF clinicians are not aware of and/or are not actively advocating inhaled ABX patient-adherence strategies.



 planner disclosure
As a provider approved by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine Office of Continuing Medical Education (OCME) to require signed disclosure of the existence of financial relationships with industry from any individual in a position to control the content of a CME activity sponsored by OCME. Members of the Planning Committee are required to disclose all relationships regardless of their relevance to the content of the activity. Faculty are required to disclose only those relationships that are relevant to their specific presentation. The following relationships have been reported for this activity:

Michael P. Boyle, MD, FCCP discloses that he has served as a consultant for Vertex, Novartis, Genentech, Savara, Pharmaxis, and Gilead Sciences, Inc. He has also received grant/research support from Vertex.

No other planners have indicated that they have any financial interests or relationships with a commercial entity.

Guest Author’s Disclosures

This activity is supported by educational grants from Aptalis Pharma, Gilead Sciences, Inc, and Vertex Pharmaceuticals.

SUCCESSFUL COMPLETION
To successfully complete this activity, participants must read the content, and visit the Johns Hopkins University School of Medicine’s CME website and the Institute for Johns Hopkins Nursing . If you have already registered for other Hopkins CE programs at these sites, simply enter the requested information when prompted. Otherwise, complete the registration form to begin the testing process. A passing grade of 70% or higher on the post-test/evaluation is required to receive CE credit.

statement of responsibility
The Johns Hopkins University School of Medicine takes responsibility for the content, quality and scientific integrity of this CME activity.

CONFIDENTIALITY DISCLAIMER FOR CME CONFERENCE ATTENDEES
I certify that I am attending a Johns Hopkins University School of Medicine CME activity for accredited training and/or educational purposes.

I understand that while I am attending in this capacity, I may be exposed to "protected health information," as that term is defined and used in Hopkins policies and in the federal HIPAA privacy regulations (the "Privacy Regulations"). Protected health information is information about a person’s health or treatment that identifies the person.

I pledge and agree to use and disclose any of this protected health information only for the training and/or educational purposes of my visit and to keep the information confidential.

I understand that I may direct to the Johns Hopkins Privacy Officer any questions I have about my obligations under this Confidentiality Pledge or under any of the Hopkins policies and procedures and applicable laws and regulations related to confidentiality. The contact information is: Johns Hopkins Privacy Officer, telephone: 410-735-6509,
e-mail: HIPAA@jhmi.edu.

"The Office of Continuing Medical Education at the Johns Hopkins University School of Medicine, as provider of this activity, has relayed information with the CME attendees/participants and certifies that the visitor is attending for training, education and/or observation purposes only."

For CME Questions, please contact the CME Office at (410) 955-2959 or e-mail cmenet@jhmi.edu.
For CME Certificates, please call (410) 502-9634.

Johns Hopkins University School of Medicine
Office of Continuing Medical Education
Turner 20/720 Rutland Avenue
Baltimore, Maryland 21205-2195

Reviewed & Approved by:
General Counsel, Johns Hopkins Medicine (4/1/03)
Updated 4/09

internet cme/ce policy

The Office of Continuing Medical Education (CME) at the Johns Hopkins University School of Medicine is committed to protecting the privacy of its members and customers. The Johns Hopkins University SOM CME maintains its Internet site as an information resource and service for physicians, other health professionals and the public.

Continuing Medical Education at the Johns Hopkins University School of Medicine will keep your personal and credit information confidential when you participate in a CME Internet-based program. Your information will never be given to anyone outside the Johns Hopkins University School of Medicine’s CME program. CME collects only the information necessary to provide you with the services that you request.

IN THIS ISSUE
Commentary
The ELITE trial: A comparison of 28 and 56 days of inhaled tobramycin to treat early Pseudomonas aeruginosa infection
The EPIC trial: A comparison of four regimens involving inhaled tobramycin to treat early Pseudomonas aeruginosa infection
Inhaled tobramycin and oral ciprofloxacin for 28 days vs inhaled colistin and oral ciprofloxacin for 28 days to treat early Pseudomonas aeruginosa infection
Inhaled tobramycin for 28 days versus inhaled colistin and oral ciprofloxacin for 3 months to treat early Pseudomonas aeruginosa infection
Planning Committee

Michael P. Boyle, MD, FCCP
Associate Professor of Medicine
Director, Adult Cystic Fibrosis Program
The Johns Hopkins University
Baltimore, MD

Peter J. Mogayzel, Jr., MD, PhD
Professor of Pediatrics
Director, Cystic Fibrosis Center
The Johns Hopkins University
Baltimore, MD

Donna W. Peeler, RN, BSN
Pediatric Clinical Coordinator
Cystic Fibrosis Center
The Johns Hopkins University
Baltimore, MD

Meghan Ramsay, MS, CRNP
Adult Clinical Coordinator
Cystic Fibrosis Center
The Johns Hopkins University
Baltimore, MD
GUEST AUTHORS OF THE MONTH
Commentary & Reviews:
DKristin A. Riekert, MD Margaret Rosenfeld, MD, MPH
Professor
Division of Pulmonary Medicine
Seattle Children’s Hospital Department of Pediatrics
University of Washington School of Medicine
Seattle, Washington
Guest Faculty Disclosures

The author has indicated that she has received grants/research support from Vertex and has served as a consultant for Genentech.

Unlabeled/Unapproved Uses

The author has indicated that there will be no references to unlabeled or unapproved uses of drugs or products.

Planning Committee Disclosures
Program Information
CME/CE Info
Accreditation
Credit Designations
Intended Audience
Learning Objectives
Internet CME/CE Policy
Faculty Disclosures
Disclaimer Statement

Length of Activity
1 hour Physicians
1 contact hour Nurses

Release Date
June 27, 2013

Expiration Date
June 26, 2015





TO COMPLETE THE
POST-TEST


Step 1.
Please read the newsletter.

Step 2.
See the post-test link at the end of the newsletter.

Step 3.
Follow the instructions to access the post-test.

Commentary

In patients with cystic fibrosis (CF), chronic endobronchial infection with Pseudomonas aeruginosa (Pa) is associated with a greater rate of pulmonary exacerbations, loss of lung function and greater mortality.1-3 Initial acquisition of Pa is generally from the environment, and early Pa isolates tend to be highly antibiotic- susceptible and present at low density. Thus, a "window of opportunity" exists to eradicate Pa before infection becomes chronic.4 The Danish CF Clinic pioneered early Pa eradication therapy more than 20 years ago5 and has demonstrated improved long-term outcomes.6 While early Pa eradication is now the standard of care around the world, the most effective regimen remains a highly contested topic. In many European countries, a combination of inhaled colistin and oral ciprofloxacin, often for three months, is employed,7 while in North America, 28 days of inhaled tobramycin is the most widely employed antibiotic, with or without oral ciprofloxacin.

Over the past several years, the results of several important clinical trials of early Pa eradication therapies have been published. These studies begin to answer the question, "How shall I most safely and effectively treat my patient with new isolation of Pa from a respiratory culture?" As the studies reviewed herein describe, the results have not necessarily been those expected in this era of ever-increasing aggressiveness of care in our CF patients. These four studies all converge on the same conclusion: that 28 days of inhaled tobramycin is in general quite effective in eradicating Pa and that longer or repeated courses of inhaled tobramycin, adding oral ciprofloxacin, or using three months of inhaled colistin and oral ciprofloxacin, are no more effective. All regimens were safe in the short term, though with one potential cautionary note: in both the EPIC trial (comparing four regimens all including inhaled tobramycin) and the trial by Taccetti, et al (comparing 28 days of inhaled tobramycin and oral ciprofloxacin vs 28 days of inhaled colistin and oral ciprofloxacin), up to 20% of participants developed new respiratory infection with Stenotrophomonas maltophilia, a tobramycin-resistant, gram negative organism of unclear pathogenicity. Interestingly, this finding was not seen in the ELITE trial comparing 28 to 56 days of inhaled tobramycin (these three trials are reviewed in this issue). Thus, as is so often the case in CF, treatment directed toward one organism probably alters the homeostasis of the complex polymicrobial community in the CF airway. The impact on clinical outcomes of this microbiologic finding is currently unclear.

It should be mentioned that a limitation of all these studies is the reliance on throat swabs to diagnose Pa respiratory infection, because of the invasive nature of bronchoalveolar lavage. Treatment decisions based on the results of oropharyngeal cultures may lead to "overtreatment," as the low positive predictive value of throat swabs in this population means that throat swabs tend to overestimate the prevalence of Pa in the lower airway.8 Nonetheless, in many countries, treatment decisions are based on the results of throat swabs, as the presence of Pa in the upper airway may convey an increased risk of subsequent lower airway infection.3

What are the next steps in studying the safety and efficacy of Pa eradication regimens? First, while in general these regimens are highly effective, 10% to 30% of patients in each of these studies failed eradication therapy. Understanding how to treat these patients is critical to minimizing the burden of morbidity associated with chronic Pa infection. Second, and perhaps tied to the first step, is a better understanding of the role of intravenous antibiotics in early eradication therapy. In a small cohort of clinically stable children with CF and new Pa infection (N = 15, six of whom received IV antibiotics), Noah et al,9 performed bronchoalveolar lavage before and four to six weeks after treatment with two weeks of systemic antibiotics or four weeks of inhaled tobramycin. While both groups had similar reductions in bacterial load after therapy, those in the systemic group had a significantly greater reduction in markers of inflammation (Iower airway total cells and percent neutrophils). Though intriguing, a larger study would be required to change clinical practice. Last, longer-term follow-up of patients receiving early eradication therapy will be critical to monitoring both efficacy and safety of this approach. The participants in the clinical trials reviewed in this issue were in general healthy, with relatively preserved lung function and few pulmonary exacerbations. No differences between groups in short-term (up to two years) clinical outcomes was detected, but the effects over much longer time periods are relatively unknown.6 Finally, long-term effects on airway microbiology (such as the finding of possibly increased prevalence of Stenotrophomonas maltophilia) must be further evaluated.

In summary, on the whole, these studies demonstrate that early Pa eradication regimens are relatively effective, and that "less may be more," in that 28 days of inhaled tobramycin (or possibly colistin) appears as effective as any other regimen tested. Hopefully, we are ushering in an era in which early Pa eradication delays or prevents chronic Pa infection, resulting in fewer hospitalizations and better long-term outcomes for our CF patients.6,10

Commentary References

1. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34(2):277-287.
2. Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, Green CG, Collins J, Farrell PM. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32(4):277-287.
3. Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, Collins J, Rock MJ, Splaingard ML. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis.JAMA 2005;293 5:581-588.
4. Rosenfeld M, Ramsey BW, Gibson RL. Pseudomonas acquisition in young patients with cystic fibrosis: pathophysiology, diagnosis, and management. Curr Opin Pulm Med. 2003;9(6):492-497.
5. Steinkamp G, Tummler B, Malottke R, von der Hardt H. Treatment of Pseudomonas aeruginosa colonisation in cystic fibrosis. Arch Dis Child. 1989;64:1022-1028.
6. Frederiksen B, Koch C, Hoiby N. Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol. 1997;23(5):330-335.
7. Elborn JS, Hodson M, Bertram C. Implementation of European standards of care for cystic fibrosis - provision of care. J Cyst Fibros. 2009;8:348-355.
8. Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R, Grimwood K, Hiatt P, McCoy K, McNamara S, Ramsey B, Wagener J. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol. 1999;28(5):321-328.
9. Noah TL, Ivins SS, Abode KA, Stewart PW, Michelson PH, Harris WT, Henry MM, Leigh MW. Inhaled versus systemic antibiotics and airway inflammation in children with cystic fibrosis and Pseudomonas. Pediatr Pulmonol. 2010;45(3):281-290.
10. Lillquist YP, Cho E, Davidson AG. Economic effects of an eradication protocol for first appearance of Pseudomonas aeruginosa in cystic fibrosis patients: 1995 vs. 2009. .J Cyst Fibros. 2011;10(3):175-180.
back to top




The ELITE trial: A comparison of 28 and 56 days of inhaled tobramycin to treat early Pseudomonas aeruginosa infection
Ratjen F, Munck A, Kho P, Angyalosi G. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax. 2010;65(4):286-291.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract  View journal abstract  View full article  View full article
The aim of the EarLy Inhaled Tobramycin for Eradication (ELITE) study was to evaluate the safety and efficacy of two regimens of tobramycin solution for inhalation (TSI) – 28 and 56 days of TSI 300 mg 5/mL twice daily – for the treatment of early onset Pseudomonas aeruginosa (Pa) infection in patients with CF. The investigation was a two-arm, randomized study conducted at 21 European centers between 2003 and 2008. Participants had to be at least 6 months of age with first or early Pa infection (defined as new isolation of Pa from a respiratory culture after four negative cultures in the preceding year or two years without antipseudomonal therapy). All participants received TSI for 28 days, at which point they were randomized 1:1 to either stop study drug (28-day group) or receive an additional 28 days of TSI (56-day group). In addition, patients were excluded from randomization if anti-pseudomonal serology collected at day 1 was positive (any titer ≥ 1000 for IgG against exotoxin A, alkaline protease, or elastase). Of the studies reviewed in this issue, this is the only one that incorporated Pa serology in the eligibility criteria. Randomized participants had regular study visits, monthly for the first year and then quarterly, until either a respiratory culture was positive for Pa or for 26 months. The primary outcome was the median time to recurrence of Pa.

A total of 123 patients were recruited into the study, and 88 were randomized (31 patients were excluded because of positive Pa serology and four for other reasons). Of the 88 randomized participants, 65 were included in the efficacy evaluable population, 34 and 31 in the 28- and 56-day TSI groups, respectively. The median time to Pa recurrence was similar between the two groups (26.1 and 25.8 months after TSI in the 28- and 56-day groups, respectively, HR 0.81, 95% CI 0.37 to 1.75, P = 0.59). At the final study visit, 66% and 69% of participants remained Pa-free in the 28-day (n = 36) and 56-day (n = 41) groups, respectively. Results were similar for sputum producers and nonproducers. Results were similar in participants with normal vs reduced lung function at baseline. Among the 21 patients in whom paired Pa isolates were available, the isolates had the same genotype in 12 and different genotypes in 9. Adverse events were similar between the two groups, as were treatment-emergent respiratory pathogens.

This study demonstrates that 28 and 56 days of TSI are both highly effective in eradicating early Pa infection, and there is no advantage to a longer course of therapy. Over 90% of participants had negative cultures for Pa one month after the end of treatment, and two-thirds were still Pa-negative for up to 27 months in both groups. While inhaled antibiotics may not reach all areas of the lungs because of mucus plugging or peripheral airway obstruction, in this population with relatively mild disease (mean FEV1 ~ 83% predicted), efficacy of TSI was high. The primary endpoint was microbiologic efficacy rather than clinical outcomes. Lung function on average remained stable in both groups during the study period, but a longer term trial would be required to evaluate clinical efficacy.
back to top




The EPIC trial: A comparison of four regimens involving inhaled tobramycin to treat early Pseudomonas aeruginosa infection
Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011;165(9):847-856.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract  View journal abstract  View full article  View full article

The aim of the Early Pseudomonas Infection Control (EPIC) Trial was to compare the efficacy and safety of 4 anti-pseudomonal antibiotic regimens in children with CF with new Pseudomonas aeruginosa (Pa) infection. The study was a four-arm, randomized study conducted at 35 US centers between 2004 and 2009. Duration of study participation was 18 months. Participants had to be 1 to 12 years of age with new isolation of Pa from a respiratory tract culture within the six months preceding randomization. New isolation of Pa was defined as first lifetime documented pa-positive culture or a Pa-positive culture after at least a two-year absence of Pa. Participants were allowed one course of intravenous or inhaled antipseudomonal antibiotics before enrollment.

The study was designed to compare culture-based therapy (antibiotics administered quarterly regardless of results of respiratory cultures) vs cycled therapy (antibiotics administered only during quarters in which respiratory cultures were positive for Pa) as well as the addition of systemic antibiotics (ciprofloxacin) to inhaled antibiotics (tobramycin inhalation solution, TIS). Thus, participants were randomized equally to one of four groups: (1) cycled TIS and oral ciprofloxacin, (2) cycled TIS and oral placebo, (3) culture-based TIS and oral ciprofloxacin, (4) culture-based TIS and oral placebo. The antibiotic regimen administered during treatment cycles consisted of TIS 300 mg nebulized twice daily for 28 days and either ciprofloxacin 15 to 20 mg/kg twice daily or oral placebo for the first 14 days. At the beginning of the study, all participants received an initial treatment cycle according to their assigned group, and a second consecutive 28-day course of TIS if cultures obtained during the third week of the first cycle were positive for Pa. The primary clinical endpoint was time to first pulmonary exacerbation requiring IV antibiotics or hospital admission. The primary microbiological endpoint was the proportion of Pa-positive respiratory cultures among all quarterly cultures obtained after the initial treatment cycle.

A total of 304 participants were randomized equally to each of the 4 treatment groups (76 per arm) and included in the intent-to-treat population. While all study participants, as defined by the eligibility criteria, had a Pa-positive respiratory culture within six months before enrollment, 46% received antipseudomonal therapy during the six months preceding enrollment, and only 40% had Pa-positive cultures at the time of randomization. After the initial course of TSI, participants in the cycled-therapy group received on average six additional 28-day courses of TSI over the 18 month study period, while those in the culture-based group received on average only one additional course.

Overall, there was no difference between groups in the proportion of participants experiencing a pulmonary exacerbations requiring IV antibiotics or hospitalization: 24/152 (16%) in the cycled therapy group, 26/152 (17%) in the culture-based group, 29/152 (19%) in the ciprofloxacin group, and 21/152 (14%) in the placebo group. Similarly, the odds of a Pa-positive culture were similar between treatment groups (OR 0.78, 95% CI 0.49 to 1.23 comparing cycled vs culture-based therapy and OR 1.10, 95% CI 0.71 to 1.71 comparing ciprofloxacin vs placebo). All four regimens were effective in eradicating Pa. The majority of participants had no Pa-positive cultures after the first treatment cycle (57 to 74%, depending on the arm), and among those who did have recurrence of Pa, the majority had no more than two Pa positive cultures over the 18-month study. Growth and lung function outcomes were also similar between groups. The emergence of mucoid Pa, tobramycin-resistant and ciprofloxacin-resistant Pa was low and similar in all 4 groups (0 to 4%). Although not different between groups, the rate of treatment-emergent acquisition of Stenotrophomonas maltophilia was up to 20%. The clinical implications of acquiring this tobramycin-resistant gram-negative organism are unclear. Adverse events and safety were similar between groups, except participants assigned to ciprofloxacin had a greater frequency of cough than those assigned to placebo.

This study demonstrates that cycled and culture-based therapy are equally effective in terms of clinical endpoints (pulmonary exacerbations, growth, lung function) and microbiologic efficacy. All treatment regimens were highly effective, and the addition of oral ciprofloxacin to inhaled tobramycin did not improve outcomes. Thus, this study suggests that treatment of new Pa with inhaled tobramycin monotherapy is as effective as more aggressive culture-based regimens or adding oral ciprofloxacin.

back to top






Inhaled tobramycin and oral ciprofloxacin for 28 days vs inhaled colistin and oral ciprofloxacin for 28 days to treat early Pseudomonas aeruginosa infection
 
Taccetti G, Bianchini E, Cariani L, et al. Early antibiotic treatment for Pseudomonas aeruginosa eradication in patients with cystic fibrosis: A randomised multicentre study comparing two different protocols. Thorax. 2012;67(10):853-859.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract  View journal abstract  View full article  View full article
The aim of the study by Taccetti and colleagues was to compare the efficacy of two 28-day anti-pseudomonal antibiotic regimens in children with CF with new Pseudomonas aeruginosa infection: inhaled tobramycin and oral ciprofloxacin (tobra-cipro) vs inhaled colistin and oral ciprofloxacin (colistin-cipro). The study was a two-arm, open-label randomized investigation conducted at 13 European centers between 2008 and 2010. Participants had to be > 1 year of age with first or new Pa infection, defined as a Pa-positive culture after three negative cultures in the previous six months.

The primary endpoint was Pa eradication, defined as three successive negative cultures in six months. Participants were randomized to receive oral ciprofloxacin (30 mg/kg/day in two divided doses) and either colistin (1 million IU nebulized twice daily) or tobramycin inhalation solution (300 mg nebulized twice daily) for 28 days. Participants were evaluated two, four, and six months after the study treatment and then monitored during routine clinic visits for variable periods (median length of observation 16 months, range 12-28 months).

A total of 223 patients were randomized, 105 to colistin-cipro and 118 to tobra-cipro. About half the participants in each group had previous Pa infection before trial entry: 54% and 47% in the colistin-cipro and tobra-cipro groups, respectively. Forty percent of participants were expectorators at enrollment. Pa eradication (as defined by three successive negative cultures in six months) was achieved in 63% and 65% of participants in the colistin-cipro and tobra-cipro groups, respectively. Note that the definition of eradication is stricter than in the other trials, so a direct comparison of microbiologic efficacy cannot be made. The proportion achieving eradication was similar in those with first-ever Pa infection (66%) and those with prior Pa-positive cultures (62%). Genotyping was performed on paired Pa isolates from 47 participants at baseline and within 6 months after treatment. The same genotype was found in 36 isolate pairs and a different genotype in 11 isolate pairs. Similar to the EPIC trial, treatment-emergent Stenotrophomonas maltophilia was found in 18% of participants during the follow-up period (median length of follow up 16 months) and Achromobacter xylosoxidans in 6%.

This study demonstrates that 28 days of inhaled tobramycin and oral ciprofloxacin or inhaled colistin and oral ciprofloxacin appear equally effective in terms of microbiologic efficacy. Efficacy of the two regimens was not significantly different in those with first-ever Pa infection and those with prior Pa infection, nor in strata of high vs lower lung function or of age. The overall microbiologic efficacy rate in this study appears lower than in either the ELITE or EPIC trials. However, this statement must be interpreted with caution because of different eligibility criteria (the ELITE and EPIC trials both required at least one year with negative cultures in those with prior Pa infection, whereas Taccetti and colleagues required only six months), participant characteristics and definition of microbiologic efficacy. The ELITE trial evaluated time to first recurrence of Pa, the EPIC trial evaluated the proportion of Pa-positive respiratory cultures among all quarterly cultures obtained after the initial treatment cycle, and Taccetti and colleagues evaluated Pa eradication, defined as three successive negative cultures in six months. In addition, similar to the EPIC trial, Stenotrophomonas maltophilia was newly isolated from respiratory cultures in about 20% of participants after treatment. This observation was not found in the ELITE trial, and its clinical significance remains unclear.
back to top






Inhaled tobramycin for 28 days versus inhaled colistin and oral ciprofloxacin for 3 months to treat early Pseudomonas aeruginosa infection
Proesmans M, Vermeulen F, Boulanger L, Verhaegen J, De Boeck K. Comparison of two treatment regimens for eradication of Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros. 2013;12(1):29-34.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract  View journal abstract  View full article  View full article
The most common Pseudomonas aeruginosa (Pa) eradication regimen in Europe is inhaled colistin and oral ciprofloxacin, closely followed by inhaled tobramycin. In North America, the most common Pa eradication regimen is inhaled tobramycin. Proesmans and colleagues undertook a study to compare the microbiologic efficacy of these 2 regimens via a single-center open label trial conducted between 2004 and 2010. Participants were CF patients at their clinic < 18 years of age with first-ever Pa infection or new Pa infection after at least six months Pa-free (as documented by at least three negative cultures). Participants were randomized to oral ciprofloxacin (30 mg/kg/day) combined inhaled colistin, 2 million units inhaled twice daily for three months (cipro-colistin), or tobramycin inhalation solution (TIS) 300 mg nebulized twice daily for 28 days. Study duration was one year with follow-up for Pa status for two years. The primary outcome was Pa eradication at the end of the treatment (ie, at three months [cipro-colistin] or 28 days [TIS]). If the respiratory culture was still Pa-positive at the end of the treatment period, participants were changed to other treatment group.

A total of 58 participants were enrolled, 29 in each group. Ten participants in the cipro-colistin group and 8 in the TIS group had first-ever Pa infection, a lower proportion than in the other three studies reviewed. Pa eradication at the end of treatment was similar in both groups: 90% in the cipro-colistin group and 79% in the TIS group (relative risk 0.88, 95% CI 0.71-1.11). Three participants failed eradication in the cipro-colistin group and six participants failed eradication in the TIS group. Median time to Pa recurrence was nine months for the cipro-colistin group and five months for the TIS group, shorter than the median time to Pa recurrence of 26 months in the ELITE study. In participants with successful eradication with the study drug, Pa status at one year after treatment was Pa-free/intermittent/chronic in 13/13/0 patients, respectively, in the cipro-colistin group and 13/8/1 in the TIS group (P = 0.46). Of the 47 participants followed for two years, five (10%) developed chronic Pa infection. There was no difference between the two groups in the number of days of either oral or IV antibiotics for a pulmonary exacerbation, lung function or nutritional status. Adverse events were not described, except for one participant who was intolerant of TIS and changed to cipro-colistin. Treatment-emergent respiratory pathogens were not described.

This study demonstrates that three months of inhaled colistin plus oral ciprofloxacin and 28 days of inhaled tobramycin monotherapy both have high and similar microbiologic efficacy, with 80-90% eradication at the end of therapy. However, median time to relapse was relatively short, nine and five months, respectively. In the ELITE trial, inhaled tobramycin for 28 days was associated with a median time to relapse of 26 months. The apparent longer duration of efficacy in the ELITE trial may be related to their entry criteria, with 60% of ELITE trial participants having first-ever Pa infection and a requirement for one to two years Pa-free and negative Pa antibodies for randomization. In this study by Proesmans and colleagues, only one-third of participants had a first-ever Pa infection, and in 25% of patients with previous Pa isolation this occurred < 12 months before enrollment.
back to top






COMPLETE THE
POST-TEST


Step 1.
Click on the appropriate link below. This will take you to the post-test.

Step 2.
If you have participated in a Johns Hopkins on-line course, login. Otherwise, please register.

Step 3.
Complete the post-test and course evaluation.

Step 4.
Print out your certificate.

Physicians Post-Test
Nurse Post-Test
* (The post-test for the newsletter is 1 credit hour.)

Respiratory Therapists
Visit this page to confirm that your state will accept the CE Credits gained through this program or click on the link below to go directly to the post-test.


Respiratory Therapist Post-Test
© 2013 JHUSOM, IJHN and eCysticFibrosis Review

Presented by JHUSOM and IJHN in collaboration with DKBmed.
Illustration © Michael Linkinhoker