Zithromax- azithromycin is a macrolide antibiotic that is being found to be very helpful with the symptoms of Cystic Fibrosis. The interaction of this macrolide used as a long term maintenance medication helps the lung to preform more effectively with less inflammation and mucus production.
The following articles are worth copying and reading carefully and then discussing with your doctor. Some doctors have already started their patients on this therapy because of the early results in Cystic Fibrosis trials and some are hopeful because of even longer ongoing use of this drug in a disease called Diffuse Panbronchiolitis, which is very similar to it's presentation to CF.
My own son was beginning to have more frequent exhaserbations and the traditional treatment of IV antibiotics was not helping much anymore, transplant came up in conversation for the first time. A very wonderful mother on the internet who had done extensive research of her own, came to me with her research and said she believed this could help my son and many more if only the doctors would listen.
I read the work carefully, at this point this was not a drug used in Cystic Fibrosis, it was easy to see the parallels in the treatment and symptoms of the disease in Japan. I took the work to my sons doctor and after much discussion he agreed to let me try this medication on my son. This exchange that helped stabilize my son and give us hope happend over a year ago in the fall of 1998. Thankfully now there is work being done with this drug and it's benefit when used in Cystic Fibrosis. I hope the following work will help others as it has helped my son. The following papers are a collection of medical abstracts, published articles and information which could help many who suffer from this disease.
There are similarities between cystic fibrosis (CF) in white people and dffuse panbronchiolitis (DPB) in the Japanese. Long-term macrolides such as erythromycin and azithromycin have been poven to decrease symptoms and improve 10 year survival from 12-4% to greater than 90% in induviduals iwith DPB, even in those colonised with mucoid Pseudomonas aeruginosa.
Our index case was a teenager with CF on the heart-lung transplant waiting list who, when treated empirically with long-term azithromycin, had an improvement in forced vital capacity (FVC) from 840mL (26% predicted) to 2420mL(65%), forced expieratory volume in 1 s (FEV1) from 300mL (11%) to 940mL (26%), and oxygen saturation breathing air from 65% to 93%, which resulted in emoval from the list.
Subsequently, in an open study, we treated children with CF who had end-stage CF lung disease or chronic airflow limitation unresponsive to conventional therapy with long term azithromycin. The case notes of children who took azithromycin daily for more than 3 months were reviewed. We exluded those children unable to do lung-function test or who commenced steroids, recombinant human DNase, or intravenous immunoglobulin whilst on azithromycin were excluded. The average predicted FVC, FEV1, forced expiratory flow 25-75%, and peak expiratory flow rate in the 6 moths before the start of treatment were compared with their post-treatment average, together with oxygen saturation and height and weight z-scores. Results in the 2 months after starting azithromycin were exluded. All statistical analyses were done with Wilcoxon's signed rank test with a p value of less ttan 0.05 considered significant. Results were presented as median (range) values.
Seven children (three boys) were studied, all of whom were colonised with P aeruginosa. Median age at start of treatment was 12.1 years (5.8 to 16.8). Median treatment length was 0.6 years (0.3 to 1.2) The %FVC rose (p<0.03) by a median of 11.3% (-5.5 to 24.7) from 62.8 (33.9 to 95.9) to 70.3 (58.3 to 112.6). The median %FEV1, also rose by 11.0% (-3.6 to 13.4, p<0.03) from 47.5 (12.2 to 75.4) to 49.5 (23.2 to 88.8; figure). No other signigicant differences were observed.
Historical controls and clinical experience suggest that a deterioration would be more likely if only conventioal treatment had been given. These improvements are similar to those reported in patients with DPB treated with long-term macrolides. It has been suggested that the effect of macrolides in DPB on P aeruginosa is anti-inflammatory rather that antibacterial, since the effect is below the minimum inhibitory concentration althought the exact mechanisms reamain controversial. Hypotheses in patients with DPB include: a reduction in inteleukin (IL)-1ß, IL-8, and neutrophils in bronchoalveolar lavage fluid, a reduction in immune complexes directed toward the biofilm produced by mucoid P aruginosea, a decrease in mucus hypersecretion by airway tissue, less p aeruginosa adherence, and acceleration of apoptosis of neutrophils. Our findings suggest that long-term azithromycin may improve lung function in children wit CF and should be considered in CF patients with deteriorating lung function. This study supports the need for a controlled prospective trial.
1. Hoiby N. Diffuse panbonchiolitis and CF: East meets West. Thaoaz 1994; 49:531-32
2. Nafai H, Shishido H, Yoneda R, Yamaguchi E, Tamua A, Kurashima A, Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration 1991; 58: 145-49
3. Sakito O, Kadota J, Kohmo S, Abe K, Shirai Rm Hara K Interleukin 1 beta, tumor nevrosis factor alpha, and intereukin 8 in bronchoalveolar lavage fluid of patints with diffuse panbronchiolits: a patentioal mecanism of macrolide therapy. Respiration 1996; 63: 42-48
4. Koyama H, Geddes DM, Erythromycin and diffuse panbronchiolitis, Thoarx 1997; 52: 915-18
5. Kabayashi H. Biofilm disease: its clinical manifestation and theraputic possibilities of macrolides. AmF Med 1995; 9926S-30S
Sir - Adam Jaffe and co-workers (Feb 7, p 420) report on an open study that shows the long-term use of the macrolide antibiotic azithromycin improved lung function in cystic fibrosis. The mechanism by which azithromycin might work is unknown. The doses of azithromycin used in this study were below the doses that might be effective against pseudomonas aeruginosa, a bacterium which affects patients with cystic fibrosis. Based on their work, Jaffe and colleagues call for controlled prospective studies on the efficacy of long-term use of azithromycin for cystic fibrosis. Understanding the method by which azithromycin works might give further impetus to do such trails, and could be helpful in finding other drugs that might be beneficial to patients with cystic fibrosis.
The key may lie in a report by Lallemand and colleagues of a patient with cystic fibrosis and fibroscarcoma of the left femoral biceps. The patient was treated with surgical resection, radiation, and chemotherapy which included cyclophosphamide and epirubicin. The patient's cancer was cured by treatment, and surprisingly, the patient's lung function improved substantially. Lallemand and co-workers suggested that the improvement in lung function was caused by upregulation (due to the chemotherapy) of a P-glycogenprotein, the multdrug-resistant-asssociated protein (MDR), which transports various compounds out of cells. MDR is homologus to CFTR (the chloride channel mutated in cf) and in-vitro experiments have shown that MDR and CFTR can complement each other. In support of their theory, Lallemmand and co-workers found detectable concentrations of MDR mRNA in nasal epitheilial cells from the patient with cystic fibrosis and the fibrosarcoma, but not in the cystic fibrosis patient who had never had chemotherapy. The only difficulty in implementing the work of Lallemand and co-workers' is that it would be difficult to use toxic drugs such as cyclophosphamide and epirubicin in most patients to try to upregulate MDR. OF course, the situation would be different if a less toxic drug could be found to upregulate MDR in patients with cf. Perhaps azithromycin was helpful in Jaffe's trial because it upregulated MDR. The macrolide antibiotic erythromycin p-glycoprotein expression. One result consistent with this hypothesis would be the finding that nasal epithelial cells in the patients treated by Jaffe had high concentrations of MDR mRNA, whereas nasal epithelial cells from controls did not. If azithromycin is efficacious in cystic fibrosis because it upregulates MDR, the reports of Lallemand and Jaffe could herald a new age of treatment for cystic fibrosis through the use of known drugs to upregulate proteins already within the cell (a form of "intracellular archeology" ) rather, for example, than gene therapy which attempts to insert new genes or proteins into cells. Another safe drug in the current formulary known to upregulate MDR is colchicine. In addition, it might also be useful to look for other know or new non-toxic compounds that upregulate MDR.
Eric Lewing Altshuler
School of Medicine, Univ. Of Cal. At San Diego and
Brain and Perception Laboratory, La Jolla. Ca
92093-0606
Abstract:
Lallemand et al propose that possible long-term expression of Multidrug Resistance-associated Protein (MRP) and Multidrug Resistance protein induced by chemotherapy may complement unfunctional CFTR protein and provide an unexpected therapeutic approach in cystic fibrosis.Full Text: Copyright Lancet Ltd. Sep 6, 1997
Cystic fibrosis is caused by mutations in the cystic fibrosis gene encoding CFTR, a chloride channel belonging to the ATP-Binding Cassette (ABC) family. MultiDrug Resistance protein (MDR) and the Multidrug Resistanceassociated Protein (MRP) also belong to this family of transmembrane transporters. CFTR shares 50% sequence homology with MRP, and 30% sequence homology with MDR. Complementations between proteins of these close subfamilies have been reported.1,2
A patient with cystic fibrosis born in 1968 had a deletion AF508 on one allele, and a stop mutation G673X on the second, which correspond to two allelic forms of CFTR expected to remain inactive. He had had symptoms since birth, including an infection by Pseudomonas aeruginosa. In April, 1993, he developed a fibrosarcoma of the left femoral biceps, which was treated by surgery, radiotherapy, and chemotherapy with cyclophosphamide and epirubicin. After chemotherapy, his lung function improved and P aeruginosa infection cleared. Now, he has a forced vital capacity of 89% and physiotherapy is no longer required. A sweat test in January, 1997, was still clearly positive. Because cancer chemotherapy induces overexpression of MDR and MRP, complementation of CFTR by these close ABC proteins could explain improved lung function in this patient. Nasal epithelial cells were collected and analysed for the corresponding mRNAs by RT-PCR in the patient (patient A) and in a patient with cystic fibrosis never exposed to antitumour drugs (patient B). The mRNAs of MDR and MRP were undetectable in patient B, but were clearly identified in patient A.
Hence, complementation of defective CFTR by MRP and /or MDR might explain this unusual case. Given the persistent positive sweat test, a still undescribed CFTR function has probably been complemented. Because most severe cystic fibrosis patients have a deletion of the GSTMl gene encoding an enzyme which produces glutathione adducts;3 MRP transports glutathione adducts, of pro-inflammatory agents (leukotriene LTC4), and of metals or oxidants; MRP is the closest human ABC protein to CFTR, and close ABC proteins can have related functions,'2 we propose that CFTR and MRP share the function of detoxifying natural or xenobiotic toxic species by exporting glutathione adducts. Unlike the chloride-channel function, this new function would account for the primary inflammation disorder observed in cystic fibrosis (clearance of leukotrienes). This hypothesis relies on a single observation; reports of other cases of cystic fibrosis during cancer treatment are needed.
We propose that possible long-term expression of MRP and MDR induced by chemotherapy5 may complement unfunctional CFTR protein and provide an unexpected therapeutic approach in cystic fibrosis.
This work was supported by the Association Franqaise de Lutte contre la Mucoviscidose (AFLM) and the Association Francaise contre la Myopathie(AFM).
[Footnote]
1 Tommasini R, Evers R, Vogt E, et al. The human multidrug resistance-associated protein functionally complements the yeast cadmium resistance factor 1. Proc Natl Acad Sci USA 1996; 93: 6743-48.
2 Ruetz S, Brault M, Kast C, et al. Functional expression of the multidrug resistance-associated protein in yeast Saccharomyces ceredae. ,F Biol Chem 1996; 271: 4154-60.
3 Baranov VS, Ivaschenko T, Bakay B, et al. Proportion of the GSTM1 0/0 genotype in some Slavic populations and its correlation with cystic fibrosis and some multifactorial diseases. Hum Genet 1996; 97: 516-20.
4 Leier I, Jedlitschky G, Buchholz U, Cole SPC, Deeley RG, Keppler D. The MRP gene encodes an ATP-dependent export pump for leukotriene C) and structurally related conjugates. J Biol Chem 1994; 245: 27807-10.
5 Giaccone G, van Ark-Otte J, Rubio GJ, et al. MRP is frequently expressed in human lung-cancer cell lines, in non-small-cell lung cancer and in normal lungs. Int,J' Cancer 1996; 66: 760-67. Laboratoire de RMN, DCSO, URA CNRS 1308 (V Stoven), Laboratoire de Biochimie, BlOC, URA 1370, Ecole Polytechnique, F-91128 Palaiseau, France; and Dipartement de Pediatrie, Hopital NeckerEnfants Malades, Pads
Most recent papers from the CF Convention on the use of azithromycin
Anstead MI, Kuhn RJ, Hartford LH, Craigmyle L, Halsey S, Kanga JF University of Kentucky, Lexington, KY, USA Diffuse panbronchiolitis (DPB) and cystic fibrosis (CF) are both diseases characterized by chronic endobronchial infection with Pseudomonas aeruginosa, and intense airway inflammation. Chronic treatment with macrolide antibiotics has resulted in a dramatic improvement in survival in DPB by an anti-inflammatory mechanism. Macrolide antibiotics may be useful for chronic therapy in cystic fibrosis by slowing the progression of endobronchial destruction by anti-inflammatory and anti-bacterial mechanisms. We utilized chronic azithromycin therapy in 20 CF patients with very severe or rapidly progressive obstructive lung disease. Patients were treated for an average of 9.4 months (range = 2 - 18 months) with azithromycin (dose = 250mg every other day). Therapy was initiated at the end of a hospitalization for pulmonary exacerbation or in the outpatient clinic at a follow-up visit. All patients were infected with Pseudomonas aeruginosa. The mean FEV1 at initiation of therapy was 0.94 ±0.41L and at the end of therapy was 1.14 ±0.51L, a 21% improvement in FEV1 during therapy (p = .0006). Liver and renal functions were monitored closely during the study period. No patient suffered any significant side effects during the study period. Based on its theoretical efficacy and the potential role for chronic macrolide therapy in cystic fibrosis demonstrated by this data, we are conducting a randomized double blind, controlled trial to evaluate the effect of chronic azithromycin therapy on lung function, inflammatory markers, and bacterial products in cystic fibrosis patients with mild to moderate obstructive lung disease. Supported by the American Lung Association
Fischer JJ, Baumann U, Gudowius P, Tummler B, von der Hardt H Hanover Medical School, Hannover, Germany
Long term treatment with macrolides was proven beneficial for patients with diffuse panbronchiolitis (DPB), that are chronically infected with Pseudomonas aeruginosa. The mechanisms, however, are still unclear. Adherence of P. aeruginosa to buccal epithelial cells is increased in chronically infected patients with cystic fibrosis (CF), indicating a compromised epithelial barrier. We assessed the effect of long term treatment (250 mg AZM twice weekly for 3 months) with azithromycin (AZM) on adherence of P. aeruginosa on buccal epithelial cells in patients with CF in an open prospective study. 11 children (mean age 14,6 yrs) chronically infected with P. aeruginosa, participated. Mean (SD) adherence prior the study was 8.0 (4.8) bacteria per cell. Following treatment with AZM, adherence was reduced in all patients by 5.6 (95% confidence interval 1.9 to 9.3, p = 0.007) to 2.4 (1.1) bacteria per cell, reaching near normal levels. In addition, adherence started to increase in 3 out of 4 patients tested after termination of treatment with AZM, apparently in a time dependent manner. Since macrolides do not necessarily eradicate P. aeruginosa in DPB, modifying host defence may be responsible for the improved prognosis in this disease. Here, we show that AZM may improve the epithelial barrier function in CF. Our findings provide a new model for a beneficial effect of macrolides in CF, that may lead to a preventive strategy prior infection with P. aeruginosa.
Tai S1, Sudo E1, Sun F1, King M1, App EM2, Sextro W3, Von der Hardt H4, Baumann U4
1. University of Alberta, Edmonton, AB, Canada
2. Albert-Ludwigs-University, Freiburg, Germany
3. Altonaer Krankenhaus, Hamburg, Germany
4. Hanover Medical School, Hanover, Germany
Macrolide antibiotics have been shown to be of significant clinical value in the treatment of chronic hypersecretion associated with panbronchiolitis and chronic bronchitis. Their benefit to cystic fibrosis patients has not yet been proven. Our study examined the effect of three months of low-dose oral azithromycin treatment (250 mg AZM twice weekly, except for one patient who received 250 mg AZM daily) on sputum rheological properties. Ten patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa and regular treatment with i.v. antibiotics every three months (4 male / 6 female participants, age range 10 to 19 years, mean age 15.1 ± 2.4 (SD)) completed a three month trial including sputum collection. Sputum viscoelasticity was determined by magnetic rheometer analysis of aliquots of expectorated respiratory tract secretion, deep frozen and shipped to the analytical laboratory. Viscoelasticity of the thawed samples (G*, dyn/cm2, over 1-100 rad/s measurement frequency) decreased significantly in 9 of 10 paired samples, comparing pretreatment value with the value at the end of the treatment period. Log G* at 10 rad/s pretreatment was 2.824 ± 0.255 (SD) compared with 2.501 ± 0.247 at the end of the 3-month azithromycin treatment period. The difference (0.323 log units, a factor of 2.10 on a linear scale) was statistically significant (p = 0.0004) and predictive of improved mucociliary clearance, based on laboratory model studies. These results indicate one possible mechanism whereby long-term, low-dose oral azithromycin therapy could improve mucociliary clearance and decrease mucus retention in cystic fibrosis.
Saiman L1, Liu Z1, Chen Y1, San Gabriel P1, Knirsch C2
1. Columbia University, New York, NY, USA
2. Pfizer Pharmaceuticals, Inc., New York, NY, USA
There is increasing interest in the use of macrolide antibiotics for treatment of CF patients. While these agents are not bactericidal, they may have synergistic activity when combined with conventional antimicrobial agents. We used a microbroth dilution assay to test the in vitro activity of azithromycin and clarithromycin paired with 11 agents against 100 P. aeruginosa strains [non-mucoid (n=50) and mucoid (n=50)] isolated from unique CF patients, and 35 P. aeruginosa strains isolated from 35 non-CF patients. The single agents meropenem (MIC <4 mg/ml), trovafloxacin (MIC <2 mg/ml), and tobramycin (MIC <4 mg/ml) were most active; 36 - 66% of strains isolated from CF patients were susceptible to these agents. As expected, all strains were resistant to azithromycin and clarithromycin (MIC >8 mg/ml). The most active combinations demonstrating synergy (Fractional Inhibitory Concentration <0.5) were azithromycin/bactrim and azithromycin/doxycycline which inhibited 28% and 20% of mucoid strains, 18% and 14% of non-mucoid strains, and 0% and 26% of non-CF strains, respectively. Azithromycin paired with timentin, piperacillin/tazobactam, ceftazidime, meropenem, imipenem, ciprofloxacin, travofloxacin, chloramphenicol, and tobramycin had synergistic activity against 0 - 12% of isolates. The same agents paired with clarithromycin had synergistic activity against 0 - 18% of strains. These in vitro studies do not directly address the role of macrolides in decreasing alginate biosynthesis, disrupting the biofilm, or decreasing exoproduct expression. However, these studies confirm the synergistic activity of macrolides with conventional anti-pseudomonal agents. Consideration should be given to clinical trials of macrolides in CF patients. Funded by Pfizer Pharmaceuticals, Inc.
BALTIMORE (Reuters Health) Nov 14 - Azithromycin is a promising new treatment for cystic fibrosis because it reduces inflammation and also restores some degree of chloride transport in CF airway epithelial cells, researchers reported Friday at the 14th annual North American Cystic Fibrosis Conference.
Experts now believe that the drug's anti-inflammatory and chloride-transport effects may be more important than its antibiotic activity in this setting.
Dr. Simon Bowler, of Mater Hospital in South Brisbane, Australia, reported on the first prospective, randomized, placebo-controlled trial of long-term azithromycin in adult patients with stable CF. He and a multicenter team found that azithromycin greatly reduced the overzealous inflammatory responses that contribute to lung damage in CF patients.
Peripheral blood monocytes from 60 patients treated for 3 months with low-dose (250 mg/day) azithromycin released significantly less tumor necrosis factor-alpha (TNF-alpha) in response to mitogen challenge than did cells from patients treated with placebo.
In vitro work conducted by the Australian research group showed that TNF-alpha levels were higher at baseline and after stimulation in CF-affected cells than in cells from normal subjects. TNF-alpha secretion was reduced in cells cultured with azithromycin.
Dr. Scott Bell of The Prince Charles Hospital in Brisbane, Queensland, Australia, reported that inducible TNF-alpha secretion is influenced by gene polymorphisms and that cells from patients homozygous for the TNF1 allele respond more strongly to azithromycin than do cells from patients with other genotypes.
The benefits of azithromycin often seem out of proportion to its anti-inflammatory activity, which led Dr. Ugo Pradal to suspect that it might be doing something else in addition to reducing inflammation. Dr. Pradal, who is at the Cystic Fibrosis Center in Verona, Italy, and colleagues measured the drug's effect on ion transport in respiratory epithelia of patients with CF and found that it caused surprisingly large corrections in the chloride transport defect that characterizes the disease.
Dr. Pradal's group studied nasal potential differences in 10 adolescents and adults whose clinical status had improved after 1 month of daily azithromycin (500 mg). Before treatment, all patients had the chloride ion transport abnormalities characteristic of CF. After 1 month of treatment, chloride secretion had been restored in six of 10 patients, and some aspects of chloride transport approached values seen in nasal epithelia of normal control subjects.
"Our data suggest that the clinical improvement observed in some CF patients may be due not only to the antimicrobial and anti-inflammatory properties of azithromycin but also to the partial restoration of chloride conductance in the airway mucosa," Dr. Pradal said.