key: cord-0008375-evvyfytm
authors: Marks-Austin, Kathy A.; Fiel, Stanley B.; Campbell, Preston W.; Stull, Terrence L.
title: Infections in cystic fibrosis
date: 2006-05-31
journal: Semin Pediatr Infect Dis
DOI: 10.1016/s1045-1870(05)80045-7
sha: 5f420bf9153b31a79556884127a119200365ed7b
doc_id: 8375
cord_uid: evvyfytm

nan

death in CF patientsJ 5 This occurs less often now, presumably because of therapy with antist aphylccoccal antibiotics.

Several properties mediate the pathogenesis of S aureus in CF patients. The cell wall ofS au~eus is important in allowing it to colonize CF patients and avoid pfiagocytosis. It can smwive and grow in high NaCI concentrations, and the growth of S nut,us is enhmlced by p -hydr oxyphenylace tic acid mad oleic acid, both of which are elevated in CF respiratory secretiohsJ 6 It also produces exotoxins such as the alpha and delta toxins, winch cause tissue injury. Although the association is not well characterized, S aureus colonization in CF patients may ~,oredispose to co-infection withPseudomonas aeru~nosa.

The indications for treating S aureus are not clear because isolation from sputum may be due to either colonization or infection. Furthermore, sputum cultures may not be accurate because recovery from a sputum sample may indicate upper airway colonization. Therefore, it is not surprising that investigations of treatment show varied results. Some physicians have proposed the prophylactic use of antibiotics. However, one double-bllnded, placebo-controlled study showed a decrease in Ia~orbidity from S a~reus mad Haemophilus influenzae with a concomitant increase in mucoid P aeraginosa colonization. 17 Others recommend therapy ors aureus with an acute pulmonm T exacerbation or on isolation from a sputum sample. A current 6-year, double-blinded, placebo-controlled c finical trial of continuous cephalexin therapy-may" elucidate the value of early empiric antist aphylococcal therapy in young CIF patients.18

The role ofH influoLbae in CF remains unclear. 19 In addition to CF, nonencapsulated H influenzae also are found often in patients with other chronic pulmonary diseases, such as bronchitis and bronchiectasis. However, Rayner et al 2~ found that H i,.fluenzae was isolated more frequently in the lower respiratory tract of CF patients than in that of asthmatics. The investigators also found that an increase in the isolation ofH influenzae preceded exacerbations, and that colonization was reduced after antibiotic therapy. Isolation rates vary and tend to be related to culturing techniques. Previous studies detected biotype 1 most frequently, ~1 although other studies have questioned this result.2~ As with the S aureus, primary viral infection may precede colonization byHinjlu~ae. Hinfluenzae may infect the upper respiratory tract before the lower tract, and H b~uenzae enflotoxin may cause tissue injury and inflammatory reactions that predispose to Pseudomonas colonization. P acavginosa in previously undiagnosed patients should lead the physician to suspect the diagnosis of CF. 2s Colonization with S aureus and H i~ue*a.ae predisposes to colonization by rnucoid strains ofP aeruginosa not found in nature or in patients with other pulmonary diseasesY Eighty percent of CF patients older than age 26 years are colonized chronically with mucoid P aeruginosa. 13 The mucoid phenotype of Paeruginosa is due to the exopolysacchm-ide alginate. Alginate protects the organism from host defenses by preventing antibody coating and phagoc~osis. 242s Alginate also may maintain colony formation in the airway, e6 May et a127 have characterized the regulatory mechanisms governing alginate biosynthesis, and have identified factors in the CF lung that may participate in the transition from nonmucoid to mucoidPaeruginosa. Other factors also contribute to the virulence ofP aeruginosa. P aeruginosa adheres to respiratory, epithelium and to mucln in the respiratory tract. 28 P aeruginosa produces exoproducts and proteases, which produce an inflammatory response causing destruction of the ah~vays and decline in pulmonary function. Many strains are nontypeable secondary to a deficiency in lipopolysaccfiaride (LPS) sidechains, although the pathogenic significance of this finding is not clear. 29 Cystic fibrosis patients with 1 ) aeruginosa have elevated levels of antibodies directed against ,o aeruginos~ antigens; however, the antibodies do not protect against pulmonary infectionJ ~ Meconium ileus is an important predictor of early-colonization with P aeruginosa, sl There is, however, no correlation between genoWpe in CF and 19 aeruginosa colonization. Early acquisition may be due to more severe disease, earlier hospital stays, early antibiotic use, or cross-nifectionfl Antibiotic therapy does not eliminate the mucoid strains? 2 Winnie and Cowan 3s correlated m~ increased anti-P aeruginosa titer with decreased pulmonary-function tests. Impaired mucoclliary clearance due to chronic inflammation and ail~vay obstruction contributes to the inability to clear P aeruginosa; 28 however, disseminated P aeruginosa infections are rare. Several approaches to prevent chronic P aeruginosa colonization are being investigated. Cofiorting of noninfected patients has been used in attempts to prevent primary infections 4 Immuhizations with a lipopolysaccharide vaccine and a whole ceil vaccine agahist 1 ) aeruginosa have shown limited success)5-37

More recently, investigations have focused on characterizing the potential role of defined polysaccfiaride vaccines, including conjugated vaccines? ~,s9 In this group, certain vaccines induce antibodies and are safe. However, the efficacy of these vaccines is still under investigation.

The prevalence of chronic P aeruginosa colonization was reduced using a 3-week course of oral ciprofloxacin and inhaled colistin given to CF patients at the time of their first positive sputum culture for P aeruginosa. ~ The duration of this study was short (27 months) , and more studies are needed before this approach cart be recommended as part of routine CF care. Species-specific polymerase chain reaction (PCR) ribotyping has been proposed to overcome the limitations of culture methods. 4s

As with P aeruginosa, attempts at eradication of B cepacia usually are unsuccessful. The organism contains an inducible [Mactamase, 5~ and in vitro susceptibility testing does not necessarily reflect in vivo response?

The gram-negative bacillus Xant/lomonas maltophilia was classified initially as jo maltophilia. However, a more detalIed taxonomic analysis resulted in reclassification? 2 This organism has been associated with meningitis, pneumonia, mastoiditis, endocarditis, and urinary tract infections.

Xanthomonca" is isolated increasingly from compromised hosts. 53 The organism has been described with increasing fi'equency in mechanically ventilated patients in the intensive care unit and in patients with previous antimicrobial therapy. 54

Several studies have shown that X maltophi[ia is isolated increasingly from CF patients. 55,56 The increased detection may be due in part to improved selective media. 

Other bacteria have been isolated from the sputum of CF patients. However, they less frequently cause disease than the previously discussed organisms. Enterobacteriaceae are isolated from the sputum of CF patients, and these include Escherichia coli, Klebsiella, Proteus, E~t~robacler, and Citrobacter. 11 H parainfluenzae as well as Streptococcus pneumoniae also are isolated. 20,61 Previously, Legionella pneumophilia had been considered to cause exacerbations in CF patients, based on increasing serum antibody titersY However, it was later shown that L pneumophilia antibodies cross-react with Pseudonwnas antibodies, e4 Therefore, the actual incidence of Legio,ella in CF remains to be characterized.

The incidence of Mycobacteria tuberculosis is not increased in CF 

Although Candida altncans is isolated from CF patients, it usually does not require therapy, because it rm'ely is considered pathologic. 7~ Isolation usually is related to antibiotic or steroid use.

Aspergillusfumigatus is another fungns isolated fi-om CF patients.

Invasive aspergillus or mycetoma is uncommon in CF, and amphotericin treatment usually is not needed. 7't However, the nc dence of a ergic bronchopulmonarv aspergillosis (ABPA) is 5% to 15% among CF patients. 75 exacerbations associated with viruses generally-were indistinguishable from those in which no virus was isolated; however, exacerbations associated with influenza virus generally were more severe than those associated with other vilqlses or exacerhations in which viruses were not isolated. 83 Likewise, infection with respiratory syncitial virus (RSV) has been shown to cause frequent early-hospitalizations for respiratory distress, be associated with increased morbidity (prolonged hospitalizations and mechanical ventilation), and result in an increased frequency, of chronic respiratory, symptoms and worse chest radiograph scores. 81 Although vaccnies for RSV currently are not available, commonly used vaccines include the inactivated egg-grown influenza vaccine and the live attenuated measles vaccine. The influenza vaccine is given yem-Iy as a spfit-viron vaccine to patients younger than age 19 years and the whole virus to patients older than age 12 years. Its efficacy-is approximately 80%. The measles vaccine is given as a single initial dose at 15 months and provides durable immunity, for 90% of patients; a second dose is recommended to stimulate immunity among vaccine failures.

A CF pulmonary exacerbation is an acute or subacute change in pulmonary symptoms related to increased airway secretions. An exacerbation usually is characterized by several of the following findings: (1) increase in productive cough; (2) change in the volume and character of sputum; (3) dyspnea; (4) reduced exercise ability; (5) decreased activity or lack of energy-; (6) increased respiratory rate; (7) new chest auscultative findings; (8) new infiltrates on chest radiograph; (9) deterioration in pulmonary, function tests or oxygen saturation; and (10) decreased appetite or weight loss. a5 Although there is not a universally accepted definition of an exacerbation, most CF clinicians would begin antibiotic therapy, aggressive chest physiotherapy, nutritional support and, in selected patients, bronchodilators if five or more of the above findings were present. For the clinician to select appropriate antimicrobial therapy, all of the significant lower respiratory tract organisms must be identified and their sensitivity patterns determined. In young CF patients, adequate lower tract sampling is difficult, and most clinicians rely on throat swabs to detect pathogens. The throat swab is performed by placing the swab against the phalTr~x to collect secretions. Coughing may occur, resuhing in lung secretions being coughed onto the swab. Therefore, the throat swab may contain only oropharyngeal flora, or if cough occurs, a lower airway specimen may be collected. Ramsey et al86 evaluated the predictive value of oropha~lgeal cultures for identifying lower airway bacterial colonization by simultaneously performing oropharyngeal cultures and bronchoseopy. The positive predictive value of a positive oropharyngeal culture in patients who could not cough and expectorate sputum was 83% for P aeruginosa and 91% for S aureus. Unfortunately, the sensitMty of the upper airway cuhure was only 46% forPaeruginosa and 77% for S au~rus. Therefore, oropharyngeal cultures ~ielding .P aeruginosa or S aureus are higialy predictive of lower allvcay colonization, but a negative culture does not rule out the presence of these organisms. In patients with CF who can expectorate sputum, sputum samples contain the same bacterial species as simultaneously collected bronchial secretions, s7

Because P aeruginosa is a frequent colonizer of the CF lung, special media are used to preven~ its rapid growth from obscuring other significant co-pathogens. For the recovery ors aureus, the use of mannitol-salt agar is recommended. PC agar, which contains antibiotics to suppress P aeruginosa, is used routinely for isolating the fastidious but typically multiresistant B cepacia. Decontamination of sputum using sodium hydroxide and oxalic acid is recommended before obtaining cultures for mycobacteria. 71 Other pathogens may be uncuhurable using these teclmiques. For example, the role of anaerobic bacteria, viruses, fungal agents, and other fastidious bacteria in CF lung disease is characterized poorly because of the detection difficulties associated ~4th culturing them. The development of PCRbased detection methods may enable epidemiologic studies of these potentially difficult to culture pathogens. Currently, CF sputum or throat samples are cultured on routine media (blood agar plate, chocolate agar, MacConkey agar), mannitol-sMt agar, and PC agar.

Antinffcrobial therapy usually is guided by the identification and sensitivity, patterns of isolated bacterial pathogens. Exacerbations associated with P aeruginosa usually are treated with a two-drug regimen consisting of an aminogiyzoside and either a third-generation cephalosporin or semisyntbetic penicillin. Additional therapy may be added if coverage for H bfiuenzae or S aureus is needed. Muhiresistant P aeruginosa is a special problem. Often, combinations of antibiotics may be synergistic and clinically effective, despite the pathogen's being resistmat to each one individually, a~

In general, the pharmacokinetics of CF patients indicate a larger volume of distribution and an increased total body clearance of aminoglycosides and [~qactams; 89 therefore, recommended dosages of antimicrobials for CF patients reflect this difference (Table 1) . Antibiotics usually are given for 2 weeks, although trims supporting tiffs approach are lacking. Longer courses (3 or 4 weeks) may be needed for sicker patients.

The fluoroquinolones, ciprofloxacin and ofloxacin, have be-9 come important agents for the treatment ofbronchopulmonary infections in CF patients for several reasons: (1) they have broad-spectrum antibacterial actMty including P aeruginosa, S aureus, and //" b~uenzae; (2) they can be given orally, their bioavallability being 70%; and (3) they have remarkable properties of diffusion into the pulmonary tissue and hroncbial secretions. 9~ The pharmacokinetics of the flouroquinolones are similar in CF and non-CF patients, and therefore dosing is similar. Adverse reactions occur in 4% to 8% of patients and are reversible when the drug is discontinued. The most common adverse reactions are gastrointestinal, skin reactions, photosensitivity, mad minor central nervous system disorders. Unfortunately, monotherapy with these agents is commonly associated with the development of drug resistance byP aeruginosa after 3 to 

Traditional therapy for exacerbations has included antibiotics, physician therapy, nutritional support, and specific therapy for organ failure. Several newly accepted and investigational approaches may significantly improve the prognosis of CF.

Recombinant human DNase (rh DN~e) has been developed recently for use in CF patients. Sputum from CF patients contains large amounts of extracelhilar DNA from degenerated polymorphonucleax neutrophils, adding to the viscosityP 3 In the 1950s, bovine DNase was shown to reduce the viscosity, of respiratory secretions by degrading DNA, 94 but its use was associated with severe reactions. 05 Therapeutic administration of rh DNase was made possible by the cloning of human pancreatic DNase I from a human pancreatic cDNA library. 96 Human recombinant DNase has fewer side effects, 97-99 and early phase I and phase II trials demonstrated improvement in pulmonary function tests when given by" aerosolizatinn to CF patients. A 24-week, phase III, parallel-design, placebo-controlled, double-blind study of rh DNase therapy-in 968 adults and children with CF demonstrated both safety and effmaey. I~176 The administration of rh DNase at a dose of 2.5 mg daily or 2.5 mg twice daily improved the mean forced expiratory volume in 1 second (FEVI) by 5% to 6% and reduced the age-adjusted risk of respiratory exacerbations by-approximately 30%.

Recently, aerosolized antibiotics have been used to provide direct delivery of aminoglycosides to" the lower alrway~ of CF patients. By inhalation of aerosolized antibiotics, high concentrations of antiblotlcs reach the site of infection with decreased risk of systemic effects because of midimal absorption. TM Ramsey et a199 recently compared aerosolized tobramycin to placebo and demonstrated improvements in forced vital capacity (FVC), FEVI, and forced expiratory flow during the middle half of the forced vital capacity (FEF~5~o.75%), as well as a decrease in the density ofl ) aeruginosa in the sputum. Aerosol administration is safe as indicated by" the lack of detectable ototoxicity or nephrotoxicity.99,1~

Chronic infection in CF results in chronic inflammation and associated lung destruction. Antl-inflammatory agents have been studied in the CF population to limit the host response. AhernateMay therapy with preddisone has been tested in several clinical trials. In I985, Auerbach et alm~ reported encouraging results with improved respiratory status and increased patient weight. However~ a subsequent study by Rosenstein and Eigan I~ reported that prednisone 2 mg/kg on alternate days was associated with cataracts, growth retardation, and glucose abnormalities. Ibuprofen currently is being investigated as an antiinflammatory agent that inhibits neutrophil function and has fewer side effects than corticosteroids. A placebo-controlled, double-bhnd study demonstrated that ibuproIen caw be safely dosed in children, m5 Pouprofen administered consistently for four years slowed the growth of lung disease without serious adverse effects in a population of CF patients aged 15 to 39 years, m6

As noted above, active immunization of CF children has been " unsuccessfully attempted to prevent acquisition of Pseudomonas. Antipseudornonas therapy ~,Ath passive immunization also has been examined. Infusion of intravenous immunoglobdiin (MG) into CF patients has been recently tested for efficacy, in reducing Pseudomo,m" infection and acute exacerbation in a double-blind study-. Transient improvement in expiratory flow measurements in the treated group was detected. However, the length of hospital stay was not shortened.l~ Further investigations of passive and active immunization are needed.

Amiioride, a sodimn transport blocker, ameliorates the basic CF airway defect in epithelial ion transport. Preliminary studies have shown improved mucociliary clearance and pulmonary function tests. 108

Several groups are actively investigating somatic gene therapy for CF. The current strategyis to deliver the normal gene to the epithelium of the CF airway. Several viral vectors are being investigated for their utility in disseminating the genes into the airway. Preliminary studies are underway to determine the safe~ and efficacy-of such therapy. Gene therapy may provide a significant advancement in redudng the need for antibiotics to treat the infections of CF by locally correcting the genetic defect.

Antibiotics may be important in extending the survival of CF patients; however, the widespread use of antibiotics has been associated with the emergence of m~tiblotic-resistant bacteria.

Because?seudomonas has emerged as the most important pathogen in CF, resistance has been extensively studied in P aeraginosa. Resistance to [3-1actam antibiotics, aminoglycosides, and quinolones has emerged. I~,]I~ It is sometimes difficult to determine the significance of antibiotic resistance. Total eradication of antibiotic-sensitive bacterial species from CF patients treated with antibiotics rarely is achieved. However, these patients experience improvement in clinical symptoms and pulmonary function. Despite reduction in the sputum concentration of sensitive species, mortality in CF frequently is secondary to respiratory-decompensation and infection. Multiresistant organisms may contribute to this unfortunate scenario. 45

Modes of transmission of infections in CF appear to be varied. LiPuma et a146 demonstrated person-to-person transmission of B cepado, and other studies have implicated acquisition at CF summer camps. Occasional contamination of equipment also bas occured, nI Govan et al 112 examined transmission within CF social groups, and also detailed B cepada contaminating environmental surfaces within their clinics. Another study examined the transmission ofP aeruginosa among CF patients and found a high rate of acquisition among CF siblings and patients attending CF camps and clinics. I13 Based on these and other similar studies, cohor ting of CF patients with muhiresistant organisms now is recommended.

More definitive therapy in CF includes lung transplantion. Despite antibiotic therapy, CF patients develop severe pulmonary impairment, and lung transplantion becomes a consideration. The indications for CF lung transplantation are similar to those for other diseases. Patients usually have severe hy-poxemia, oxygen dependence, reduced exercise tolerance, mean FEV less than 30%, and respiratory failure. These are accompa-nied by repeated pulmonary infections, continued weight loss despite nutritional support, psychological instability, and other irreversible organ damage.I/4

After lung transplantation, CF patients develop opportunistic infections similar to those of non-CF patients. Initial reports did not show an increased incidence of Paeudomonas pneumonia. However, recent reports show that P aeruginosa is the predominant pathogen.B cepacia is an important source of morbidity and mortality, especially in patients who were not colonized with B cepacia before transplantion3 Is Certain groups have begun an aggressive program to limit this organism after transplantion by cohorting, antibiotic prophylaxis, aggressive antibiotic therapy for infections, and sinus drainage surgery. H~ The long-term efficacy of lung transplantation for patients with CF is not yet known. 

Cystic Fibrosis Foundation Patient Regist~ Annual Data Report

etal: Identification of the cystic fibrosis gene: Chromosome walking and jumping

Identification of the cystic fibrosis gone: Genetic analysis

Identification of the cystic fibrosis gone: cloning and characterization of complementary DIX-A

Generation of c.~iP-activated chloride currents by expression of CFTR

Abnormal apical cell membrane in cystic fibrosis respiratory epithelium: An in vitro elect rophysiologic analysis

Abnormal ion permeation through cystic fibrosis respiratory epithelium

Pbarmacotberapy of airway disease in cystic fibrosis

Pathogenesis of cystic fibrosis

Cystic fibrosis: State of the art

Evolution of ail~'ay microbiology in the infant Mth cystic fibrosis: Role of nonpseudomonal and pseudomcnal pathogens

Marks 1'vii: Pulmonary infections in cystic fibrosis: Pathogenesis and therapy

The changing epidemiology of cystic fibrosis

Stopbylo~s ameus capsular types and antibody response to lung infections in patients with cystic fibrosis

Therapy and prognosis of fibroeystic disease of the pancreas

Bronchial infection in cystic fibrosis

A placebo-controlled trial of cephalexin therapy in the ambulatory management of patients with cystic fibrosis

Marks MI: Clinical significance of Staphylococcus aureus in cystic fibrosis

Temporal changes in biotypes of Haemophilus influenzae isolated from patients with cystic fibrosis

Biotype ofHaemophilus fi~uenzae: Correlation with virulence and anapid0in resistance

Doggett Re-: Incidence of mucold Pseudomonas aerugfilosa from clinical sources

Natural history of pulmonary infections in cystic fibrosis, in SturgessJM

Alginate biosyzathesis and other unusual characteristics associated with the pathogenesis ofPseudomon~ aemginosa in cystic fibrosis

Influence of mucnidy on antibody coating of2seudomonas aeruginosa

Role ofPseudor~onas a~ughwsa mucoid exopolysaccharide in adherence to tracheal cells

Al~nate synthesis by Pseudomonas aeruginosa: A key pathogenic factor in chronic pulmonary infections of cystic fibrosis patients

Interaction between Pseudomonas aevvgi nosa and host defenses in cystic fibrosis

Comparative inmaunochenilstry of llpopalysacchafdes from typable and polyagglutinable Pseudomonas aeri~nosa strains isolated fi-om patients w~tb cystic flbrosis

Cystic fibrosis Pseudomonas opsonins: Inhibitory nature in an in vitro phagocytic assay

Risk factors for Pseudomonas aeruginosa colonization in cystic fibrosis patients

Longitudinal study of immune response to Pseudomonas ae*~ginosa antigens in cystic fibrosis

Respiratory tract colonization withPseudomonas aeruginosa in cystic fibrosis: Correlation between anti-Pseudomonas aeraginosa antibody levels and palmonary function

Estimated risk of cross-infection with Pseudornonas aeruginosa in Danish cystic fibrosis patients

Prospective, controlled study of a polyvalent Pseudomonas vaccine in cystic fibrosis: Three year result

A new polyvalent ~Pseudomo-has vaceine

Use of Pseudomonas aeruginosa vaccine in patients with acute leukemia and cystic fibrosis

Immunizatin of noncolo nized cystic fibrosis patients against Pseudornonas aeruginosa

Human immune response to fibrosis and children with other diseases

Importance of viruses and LegiorMla pneumophila in respiratory exacerbations of young adults with cystic fibrosis

et ah Comparison of cross-staining reactions by Pseudomonas spp. and flouresceindabeled polyclonal and monoclonal antibodies directed against Leginella pneumopbilia

Prospective study of myeobacterial infections in patients with cystic fibrosis

Hodson ME, et ah Fatal pulmonary infection with mycobacyerium fortnitum in cystic fibi'osis

Myeobact efi~l isolations in young adults with cystic fibrosis

Isolation of rapidly growing mpzobact eria in patients with cystic fibi'osis

Microbiology of lung infection in cystic fibrosis patients

Nontuberculous mycobacterial disease in adult cystic fibrosis patients

Nontuberculous lnycobacteria in adult patients with cystic fibrosis

Improved recovery of mycobacteria from respiratory secretions of patients with cystic fibrosis

Mycobactefium avium complex in a patient with cystic fibrosis: Disease vs. colonization

Serologic response to Candida albicam and Aspogillusfumigatus in cystic fibrosis

Precipitating antibodies to Aspergillusfumigatus in cystic fibrosis

Allergic broncbopulmonary mycc~is complicating cystic fibrosis

Respiratory infections in cystic fibrosis patients caused by virus, ChIamydia and Mycoplasma--Possible synergism with Pseudomonas aemginosa

Acquired ciliary defects in nasal epithelium of children with acute viral upper respiratory infections

Long term prospective study in children after respiratory sy~cyrial vlms infection

The impact of respiratory viral infections in patients with cystic fibrosis

et ah Evaluation of the safety of amantadine-HCl and the role of respiratory viral infections in cbildren with cystic fibrosis

Role of respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis

Association of Epstaln-Barr virus bifection and puhnonary exacerbations in patients with cystic fibrosis

Clinical manifestations of exacerbations of cystic fibrosis associated with non-bacterial infections

Association of respiratory viral infections with pulmonary deterioration in patients with cystic fibrosis

Sputum changes associ ated with therapy-for endobronehial exacerbation in cystic

Predictive value of oroptaaryngeal cultures for identifying lower air.ray bacteria in cystic fibrosis patients

Respiratory, tract bacteriology, in cystic fibrosis

Antibiotic strategies to treat multi-resistant Pseudomonc~ aeruginosa~ Program and Papers of the 6th Annual North American Cystic Fibrosis Conference, Washington, DC, Cystic Fibrosis Foundation

Antibiotic pharmacokinetics in cystic fibrosis: Differences and clinical significance

Use of the qufimlones in cystic fibrosis

Ciprofloxacln monotherapy for acute pulmonary exacerbations of cystic fibrosis

Ciprofloxacin therapy in cystic fibrosis

Studies in pulmonary secretions. 3. The nucleic acids in whole pulmovoary secretions h-ore patients with cystic fibrosis, bronchiectasis and lats'ngcctomy

Deoxyrifionuclease in treatment of purulent bronchitis

Bronchospasm after inhalation of pancreatic dornase

Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum

Recombinant humane DNase inhalation in normal sul?]ects and patients with cystic fibrosis: A phase I study

A pr eliminate, study of aerosolized recombinant human deox~Tibonuctease I in the treatment of cystic fibrosis

Efficacy and safbty of short-tern] administration ofaerosoilzed recombinant human deoxyribomlclease in patients with cystic fibi-osis

Effect of aerosolized recombinant human DNase on exacerbations of respiratol T symptoms and on pulmonary function in patients with cystic fibrosis

Inhaled antibiotics in cystic fibrosis: Is there a therapeutic effect

Absolute bioavailabifity and absorption characteristics of aerosolized t obramycin in adults with cystic fibrosis

Alternate-day prednisone reduces morbidity and improves palmona~ function cystic fibrosis

Risks of alternate day prednisone in patients with cystic fibrosis

Ibuprofen in children with cystic fibrosis: Pharmacokinetics and adverse effects

et ah Effects of bighm~ose ibuprofen in patients with cystic fibrosis

Intravenous immune globulin treatment of pulmonal?" exacerbations in cystic fibrosis

A pilot study" of aerosolized amiloride for treatment of lung disease in cystic fibrosis

Anthulcrobials in cystic fibrosis: Emergence of resistance and implications for treatment

Clinical and bacteriological responses to three antibiotics regimens for acute exacerbation of cystic fibrosis: Ticarcillin tobramycln, azlodllin tobramycin, and azlocillbi-placebo

P~'eudomonas cepacia in patients with cystic fibrosis

Evidence for transmission ofPseudomonas cepacia by social contact in cystic fibrosis

Ix-osocomial acquisi tion of pseudomonos aeruginosa by cystic fibrosis patients

Current status of cystic fibrosis lung transplant

Pseudomonm" cepaz~ in lung transplant recipients with cystic fibrosis