Pathogenesis of Cystic Fibrosis Lung Disease
Inhaled Antibiotics in Cystic Fibrosis
Resident Grand Rounds
November 24, 1998
by
Tony Poteat, M.D.
Case PresentationHPI
A 41-year-old white male with cystic fibrosis presents with a seven day history of increased shortness of breath and diaphoresis. The patient has noted an increase in his sputum production. He also states that his sputum is thicker and that it has become green. The patient denies any fever, chills, acute episodes of shortness of breath, chest pain, or hemoptysis. He admits to infrequent use of his pulmozyme and flovent. The patient had stopped his inhaled tobramycin seven days prior to admission.
PMH
Cystic Fibrosis diagnosed at age 28
Nasal Polyps
All: Tetracycline
Medications
Inhaled tobramycin 300 mg b.i.d. for 28 days then off for 28 days
Ventolin 3 puffs t.i.d.
Flovent 2 puffs b.i.d.
Serevent 2 puffs b.i.d.
Pulmozyme 2.5 mg nebulized q.d.
Home oxygen 3L by nasal cannula continuous
Pancreatic enzymes with meals and snacks
SH
10 pack year history of tobacco, quit at age 28
Occasional red wine
ROS
He feels that he has lost 5-10 pounds over the last month
Temp: 95.9 Pulse: 107 RR: 25 BP: 133/90 Weight: 152
Physical Exam
Gen: Anxious WM in mild respiratory distress
HEENT: EOMI, PERRL, OP clear
Neck: Supple, no LAD
CV: RRR no murmur, rubs, or gallops
Lungs: Crackles in the left base, decreased breath sounds and wheezes bilaterally
Abd: Benign
Ext: Clubbing in all extremities
Labs
WBC: 17.9, 71% segs, 18% lymphs, 10% monos. Hgb: 15.3. Plt: 416. SMAC: WNL
ABG: 7.406/49/49/30/83% on 3L NC
CXR: Cystic changes, peribronchial thickening, no focal infiltrates
Sputum culture from 4 months before grew 4+ Pseudomonas aeruginosa sensitive to Zosyn. Spirometry from 4 months earlier showed an FEV1 of 18% predicted and a FVC of 45% predicted.
The patient’s sats improved on 60% face shield and aggressive bronchodilators, and he was admitted to 8 RT. He was begun on IV Zosyn, Cipro, inhaled Tobramycin, PO prednisone, nebs, and postural drainage. Blood and sputum cultures were sent and a pediatric pulmonology consult was obtained. Their recommendations were to continue the antibiotics, get a nutrition consult and a breathing plus consult. The patient’s sputum cultures grew 4+ Pseudomonas aeruginosa, sensitive to the current antibiotics. The patient continued to improve with the above treatment and his oxygen demands returned to baseline. He was discharged after eight days on PO Cipro, IV Zosyn and inhaled Tobramycin.
The patient was readmitted one month latter for another pulmonary exacerbation requiring intubation. He was transferred to UNC for further management.
The term cystic fibrosis was first used in 1938, two years after its constitution of symptoms had first been described (1). Since that time much has been discovered about cystic fibrosis. Cystic fibrosis is transmitted by an autosomal recessive pattern. This disease leads to multiorgan disorders including the lung, pancreas, sweat glands, testes, and biliary ducts. The cystic fibrosis gene is located on chromosome 7 and codes for the cystic fibrosis transmembrane conductance regulator(CFTR). CFTR is a cyclic AMP mediated chloride channel. In Caucasians the carrier rate is 1 in 20. The incidence in this population is about 1 in 2,500 live births.
Since the discovery of cystic fibrosis the population of cystic fibrosis patients has changed dramatically. Cystic fibrosis was a disease of childhood but now of the 19,517 patients with cystic fibrosis in the US 34% are 18 years of age or older. This is also evidenced by the median age for disease free survival increasing to 31 years in 1996. Despite the many advances in the treatment of cystic fibrosis it remains one of the most common genetic killers in the US with more than 90% of patients dying of lung disease.
The introduction of antibiotics in the 1940’s significantly improved the prognosis for cystic fibrosis patients. Antibiotics directed against Pseudomonas and Staph aureus have been used to treat pulmonary exacerbations, and on a continuous basis to try and lengthen the interval between pulmonary exacerbations. Bacterial culture of the respiratory tract with antibiotic susceptibility testing guides antibiotic selection in patients with cystic fibrosis (2).
Pathogenesis of Cystic Fibrosis Lung Disease
At birth the cystic fibrosis lung is normal. Shortly after birth many patients acquire infection that begins an inflammatory response which continues throughout their disease. The lungs of cystic fibrosis patients become infected with distinctive bacteria, specifically Pseudomonas. The reason why Pseudomonas aeruginosa is selected in the cystic fibrosis lung is still unclear, but may relate to abnormalities in mucous sulfation or sodium content. This cascade of infection and inflammation ultimately destroys airways, impairs gas exchange, and leads to patient death. The proposed pathophysiologic cascade for the cystic fibrosis lung is seen in figure 1. The proposed treatments for each step are seen on the right hand side of the figure (2).
In 1992 Eitan et al published a study on the prediction of mortality in patients with cystic fibrosis. The study cohort consisted of 673 patients followed between 1977 and 1989. These patients had assessments of pulmonary function, blood gas levels, nutritional status, and vital status. One hundred ninety patients died during the study period (28%). The risk of death increased as all values for lung-function decreased (FEV1 and FVC). Approximately 50% of the patients died within two years of measurements of; FEV1, below 30% predicted, and FVC, below 40% predicted. For every decrease in FEV1 of 10% the relative risk of death was 1.8. A decrease in the weight-for-height percentage to < 70% was also associated with a mortality rate greater than 50% within two years. Figures 2 and 3 show the one and two year mortality rates among patients with cystic fibrosis for FEV1, FVC, and weight for height percentage. The weight for height percentage figure is divided into those patients above and those below 18 years of age in the bottom portion of figure three (3).
Because cystic fibrosis is characterized by progressive loss in lung function, changes in FEV1 and FVC are important indicators of health status, and are directly related to morbidity and mortality.
Pseudomonas aeruginosa is a major contributor to obstructive airway disease in cystic fibrosis and is a major cause of morbidity and mortality among cystic fibrosis patients. Aminoglycosides active against Pseudomonas aeruginosa penetrate the sputum poorly, resulting in peak sputum concentrations equivalent to only 12% of serum concentrations. In addition, the bioactivity of aninoglycosides is even further reduced in the lower airways, secondary to the binding of aminoglycosides to DNA, mucin, and to the presence of increased concentrations of divalent cations. These lower levels require large IV doses of aminoglycosides to obtain effective bactericidal levels at the site of infection. The high doses of aminoglycoside place the patient at risk for ototoxic and nephrotoxic side effects. The direct delivery of aminoglycoside to the respiratory tract by aerosol administration is therefor attractive, because it produces high concentrations of antibiotic at the site of infection. Due to the limited absorption of aninoglycoside from the respiratory tract systemic toxicity will be minimized (4).
To administer antibiotics directly to the respiratory tract they need to be nebulized. In 1997 Eisenberg et al conducted a multicenter, open-label, randomized, crossover study to determine whether adequate concentrations of tobramycin could be delivered to the lower respiratory tract of cystic fibrosis patients using a jet nebulizer system. Their purpose was to determine if the delivery of tobramycin by this system was comparable to the UltraNeb 99/100, a delivery system previously found to deliver effective concentrations to the airways. In previous studies the UltraNeb 99/100 was efficacious, but problems with cost, inconvenience, and nebulizer maintenance have limited patient and physician acceptance of this regimen. This study found that the Pari LC and the Sidestream jet nebulizers were effective in delivering greater than 10 times the MIC of pseudomonas in 87% and 93% of patients respectively (4).
In 1995 Nikolaizik et al studied bronchial constriction after nebulized tobramycin. They found FEV1 and FVC to be significantly decreased from baseline after inhalation of tobramycin. This effect was significantly reduced by the use of inhaled beta agonist prior to tobramycin inhalation (p<0.001) (5).
In 1981 Hodson et al published a double-blind, randomized, cross-over trial of aerosolized carbenicillin and gentamicin treatment in young cystic fibrosis patients infected with Pseudomonas aeruginosa. Twenty patients with the diagnosis of cystic fibrosis were enrolled into the study. Pseudomonas aeruginosa had been cultured from the sputum of all 20 patients during the six months before entering the study. No patients had received IV antibiotics within two weeks prior to the trial. The purpose was to determine if this treatment could halt or slow the decline in lung function and reduce the frequency of hospitalizations.
Patients were randomly assigned to 6 month treatment with aerosol antibiotic and 6 months of placebo treatment. The antibiotics consisted of 1 gram of carbenicillin and 80 mg of gentamicin each b.i.d. administered via nebulizer. Patients were followed monthly throughout the study. Three patients withdrew, one during the first month with a rash, one with severe respiratory failure during placebo, and one with bilateral pneumothoracies in month 8. Blinding was broken in one patient in month 10 because during the first 6 months she had significant improvement but during 4 months on placebo she felt much worse.
Of the 17 patients that completed the study the mean FEV1 during antibiotic was 1566 ml verses 1300 ml for placebo (p<0.001). Mean FVC was 2656 ml during antibiotic and 2314 during placebo (p<0.02). A reduction in the number of hospitalizations was seen, with 3 during antibiotic treatment and 7 during placebo, but this was not statistically significant. Of the 17 patients at the end of the trial, 14 patients’ assessments favored the antibiotic period, 3 patients were undecided, and no one favored placebo.
This study noted the drawbacks of taking 20 minutes twice a day to administer the antibiotics and the cost of the antibiotics. However, the cost of a 10 day treatment of IV antibiotics was equivalent to the cost of over 2 months’ inhaled antibiotics (6).
In 1987 Stead et al published a randomized, crossover study comparing nebulized ceftazidime verses a combination of gentamicin and carbenicillin verses saline. Each treatment was given for 4 continuous months to patients with cystic fibrosis and Pseudomonas aeruginosa in the sputum. Eighteen patients (median age 21) were enrolled into the study. Criteria for inclusion were the presence of Pseudomonas aeruginosa in the sputum over the last 6 months sensitive to the antibiotics in question. They also required frequent admissions for IV antibiotics for Pseudomonas aeruginosa or FVC less than 70% predicted or both of these features. Inhaled gentamicin and carbenicillin were open to the patients but the remainder of the study was blinded. The treatments were given in random order to reduce any carry-over effect. The goal of this study was to assess if ceftazidime would be as effective as gentamicin and carbenicillin. The possible benefits of being able to use it in patients with penicillin allergy, taking less time to nebulize, and to possibly treat patients who did not respond to the other treatment.
Of the eighteen patients studied 5 were withdrawn all during the first 4 months of treatment. Two patients were noncompliant (one on saline and one on ceftazidime), two patients who were receiving saline had deterioration of their condition and were changed to antibiotic with improvement, and one patient could not tolerate the taste of saline. The results showed that FEV1 increased with treatment. FEV1 on saline was 1.48 liters compared to 1.70 liters in both antibiotic groups (p<0.02 for ceftazidime and <0.01 for gentamicin and carbenicillin). Also peak expiratory flows were significantly increased (p<0.02) in the antibiotic groups, and body weight was significantly increased (p<0.01) compared to entry. In retrospect 10 patients required 16 hospital admissions in the year prior to admission, compared to only four patients requiring a total of 5 admissions during the study year (p<0.05).
The conclusions from this study are that inhaled antibiotics are effective in improving FEV1, weight, and reducing hospital admissions. In addition ceftazidime can be used as an alternative to gentamicin and carbenicillin in patients with a penicillin allergy, antibiotic resistance to gentamicin or carbenicillin, or in patients who fail to respond to gentamicin and carbenicillin after 2-3 months (7).
In 1989 Maclusky et al published a randomized controlled trial comparing
the long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized
with Pseudomonas aeruginosa. The aim of this study was to investigate the long-term
safety and effectiveness of tobramycin in suppressing pulmonary disease in cystic fibrosis
patients colonized with Pseudomonas aeruginosa. Twenty-eight patients were enrolled
into the study. All patients were colonized with Pseudomonas aeruginosa, between
the ages of 7 and 24 years, had FEV1 greater than 40% predicted, and were receiving
bronchodilators twice daily. Characteristics of patients were similar on entry into the
study and can be seen in table 1. Patients in the treatment group received 80 mg of
tobramycin three times daily in place of normal saline. Patients were aware of their
treatment regimen but the study physician was blinded. 
Results of this study showed that over the 32 month study the rate of decline of FEV1 and FVC in the treatment group verses the control group was statistically significant (p<0.01 for FEV1, and p<0.05 for FVC). Results of the study can be seen in table 2 and figure 4. Eleven of the 12 control patients had deterioration in their pulmonary function, while 9 of the 15 treatment patients had either no deterioration or actual improvement (p<0.01). No changes in hearing or renal function were observed during the study period (8).
In 1993 Ramsey et al. published a trial on the efficacy of aerosolized tobramycin in cystic fibrosis patients. This was a multicenter, double-blind, placebo-controlled, three period crossover trial to assess the safety and efficacy of aerosolized tobramycin. This design was to attempt to overcome some of the limitations of previous studies. Seventy-one patients were enrolled who all had the diagnosis of cystic fibrosis, sputum containing Pseudomonas aeruginosa sensitive to tobramycin, and FVC greater than 40% predicted. Patients were randomly assigned to one of two groups treated in the following sequences: group 1 received tobramycin for 28 days followed by placebo for 56 days; group 2
received placebo for 28 days followed by tobramycin for 56 days. The tobramycin was administered in 600 mg doses three times per day using an ultrasonic nebulizer. Patients were seen at weeks 2, 4, 8, and 12 during drug or placebo administration. At each visit pulmonary functions, complete blood count, and the density of bacteria in the sputum were measured. To determine compliance and to mask the taste of tobramycin quinine hydrochloride was added to the drug and placebo solutions. Random urine samples were assessed for quinine concentration, as a measure of compliance.
Thirty-six patients were assigned to group 1, and 35 to group 2. The groups were not significantly different. Characteristics of the study groups can be seen in table 3. Sixty-six of the 71 patients completed the study. The frequency of noncompliance ranged from 7 to 20 percent across the three periods, but was comparable between each group (p>0.35). FEV1 and FVC during the first 28 day period was greater in the tobramycin group than in placebo (p<0.015). For the three-period crossover the difference in the tobramycin group verses the placebo group continued to be significant (p<0.005). These results are summarized in figure 5 where open symbols represent placebo treatment and solid symbols represent tobramycin treatment. Pulmonary exacerbations and antibiotic use were also decreased by the third period of the study. Of the patients in the tobramycin group only 3% had pulmonary exacerbations compared to 20% in the placebo group (P=0.06, number needed to treat is 5.9). Another outcome is antibiotic use where 49% of placebo patients required antibiotics verses 15% in the tobramycin group (p=0.006, number needed to treat is 3.0). No renal or ototoxicity was observed during the study. The emergence of tobramycin-resistant Pseudomonas aeruginosa species was found in 10 of 71 patients (14%). There was no significant difference in the frequency of emergence of resistant strains between placebo and tobramycin administration during the study period (p>0.5) (9).
In 1998 Wiesemann et al published a double-blind, placebo-controlled, randomized trial of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis. Twenty-two patients were enrolled into the study and received either placebo or 80 mg b.i.d. of aerosolized tobramycin for 12 months shortly after acquiring Pseudomonas aeruginosa lung colonization. Eleven patients were randomized to each group. They found that the tobramycin group converted from Pseudomonas aeruginosa positive to a Pseudomonas aeruginosa negative culture in a significantly shorter time than the placebo group (p<0.05). This is also shown in figure 6. They did not find any significance in the difference in pulmonary function tests between the two groups (10).
Two multicenter, randomized, double-blind, placebo-controlled studies yet to be published on TOBIŪ (Tobramycin Solution for Inhalation), were recently made available in a technical monograph by the Pathogenesis Corporation. For these studies a total of 520 cystic fibrosis patients with Pseudomonas aeruginosa at 69 cystic fibrosis treatment centers were enrolled. Both studies employed the identical design seen in figure 7.
Patients were randomly assigned to receive taste-masked placebo or TOBI 300 mg b.i.d. given by jet nebulizer. Demographics for the two groups can be seen in table 4. Investigators were allowed to treat patients according to the standard of care for cystic fibrosis patients. The studies were done to answer questions on clinical and microbiologic endpoints as well as health outcomes.
Results show that FEV1 improved significantly on TOBI and is displayed in table 5 and figures 8a and 8b.
Other outcomes that were evaluated were the number of hospitalizations, anti-pseudomonal antibiotic use, and absenteeism from work or school. Patients treated with TOBI were 26% less likely to be hospitalized than patients on placebo were (p=0.014, relative risk 0.74). The length of hospitalization for TOBI patients averaged 5.1 days compared to 8.1 days for placebo patients (p<0.001). Patients on TOBI were also less likely to require IV anti-pseudomonal antibiotics than placebo patients (p<0.001). TOBI patients also missed fewer days from work or school than the placebo group, 5.15 days verses 6.96 days respectively (p=0.031).
Of importance to the case presentation was this studies subgroup analysis. This analysis shows equal benefit in patients with FEV1 less than 50%, age greater than 18, and male gender, seen in table 6.
This study is also the first to use the PARA LC PLUSŪ jet nebulizer. This nebulizer has a valve that directs the entire inspiration through the nebulization chamber. This design is approximately two times more efficient than a standard jet nebulizer. Using this nebulizer the tobramycin dose can be nebulized in approximately 15 minutes (11).
In reviewing the articles used in this paper the User’s Guides to the Medical Literature were used to assess the validity of these articles (12, 13).
Inhaled antibiotics have proven to slow or reverse the progression of pulmonary disease and to promote weight gain in cystic fibrosis patients with Pseudomonas aeruginosa. They are effective in decreasing antibiotic use, hospitalizations, and pulmonary exacerbations. They may also help to prolong the time to onset of chronic persistent Pseudomonas aeruginosa infection of the respiratory tract. It remains to be seen whether prolonged administration verses intermittent courses of inhaled antibiotics are more effective for the cystic fibrosis patient. The amount of antibiotic to be administered has also been variable. Future studies will be needed to determine the optimal dose of antibiotic and the optimal dosing regimen (b.i.d. verses t.i.d.). If a more efficient nebulizer or an inspiration-activated nebulizer can be developed it would greatly decrease the cost of this treatment, by reducing the amount of antibiotic lost and therefor the amount needed to achieve adequate levels at the site of infection.
Bibliography