Pharmacokinetic optimisation of antibacterial treatment in patients with cystic fibrosis. Current practice and suggestions for future directions

Antibacterials play a central role in the medical management of patients with cystic fibrosis (CF). Administration of adequate dosages of antibacterials results in pronounced beneficial effects on the morbidity and mortality of this patient group. The dosage of the antibacterial that is needed for optimal treatment depends on the individual patient's pharmacokinetics and the pharmacokinetic-pharmacodynamic effect on the micro-organism of relevance in the host. In general, the disposition of antibacterial drugs in patients with CF is not as 'atypical' as once thought. Recent research with adequately matched controls demonstrated that, for a few beta-lactam antibacterials only, a CF-specific increase of the total body clearance seems to exist and that the large volumes of distribution observed are the result of malnutrition and the relative lack of adipose tissue. Pharmacokinetic-pharmacodynamic relationships in patients with CF are less well studied. Apart from the pharmacokinetics, there is a need for optimisation of antibacterial therapy. For the aminoglycosides, pharmacokinetic optimisation based on measured serum drug concentrations is common practice. The Sawchuk-Zaske method based on peak and trough drug concentrations is widely used. A more sophisticated approach is the 'goal-oriented model-based Bayesian adaptive control' method, where integration of mathematically determined optimally (D-optimally) sampled serum drug concentrations and a population model results in the most likely set of individual pharmacokinetic parameter values suitable for further pharmacokinetic optimisation of the therapy. A future development is the integration of changing serum drug concentrations and killing rates of the target micro-organism to a pharmacokinetic-pharmacodynamic surrogate relationship to optimise drug therapy. The latter approach may be extremely useful in deciding on the frequency of aminoglycoside administration as well as the optimal use of the beta-lactam antibacterials and fluoroquinolones.     

Use of aminoglycosides in elderly patients. Pharmacokinetic and clinical considerations

Aminoglycosides still represent a mainstay in the treatment of serious infections caused by Gram-negative bacilli in elderly patients. The aging process is accompanied by various physiological changes (e.g. alterations in body composition, impairments in certain organ functions), which may affect drug disposition and, subsequently, drug action. For aminoglycosides that are eliminated by the renal route, kidney function is the key parameter that should be taken into account when dosage regimens are calculated. Because there is a progressive decline in renal function with aging, the glomerular filtration rate should be estimated for each patient. Any change in creatinine clearance (CLCR) should result in a proportional correction of the dosage regimen. Such individualised dosage of aminoglycosides is particularly important because of their narrow therapeutic indices. There are no conclusive data which indicate that age per se affects the elimination of aminoglycoside antibiotics. Overdosage may result from overestimation of renal function if crude serum creatinine (SCr) levels are used as a guide. Nomograms for the relationship between SCr and CLCR have been developed. However, nomograms should be used with caution because substantial interindividual variability in the plasma concentration-clearance relationship is still observed. Therefore, the choice of a maintenance dose based on an assessment of renal function, which change rapidly, should always be considered as preliminary, and verification by serum concentration measurements is necessary. As a result, the use of aminoglycoside serum concentration monitoring during therapy as the most important guide for dosage adjustment is particularly important in the elderly, and is indispensable in conjunction with frequent assessment of renal function. Although a matter of debate, the value of serum concentration monitoring has been demonstrated. With traditional multiple daily dosage, monitoring peak and trough concentrations has been recommended. For once daily dosage, however, no guidelines relating to therapeutic and/or toxic concentrations are available yet. In the meantime, we recommend monitoring at least trough concentrations. Once daily administration of aminoglycosides has emerged as a new mode of treatment. Compared with multiple daily administration, once daily dosage may have a number of advantages, and many clinical trials comparing the efficacy or safety of both modes have shown either superiority or equivalence of the new mode in most indications. At present, however, no data from studies of once daily administration in young compared with elderly adults are available.     

Pregnancy in patients with cystic fibrosis

With increasing life span of patients with CF, more women with CF are becoming pregnant and others are seeking information about the risks involved during pregnancy and delivery. A striking limitation of the available information is the lack of large prospective studies of pregnant patients with CF matched for age and disease severity compared with their non-pregnant cohorts. A study investigating the effect of pregnancy on morbidity and mortality is being completed by the Cystic Fibrosis Foundation. We recommend that all women with CF be offered contraceptive measures and counseling on the maternal and fetal risks of pregnancy, including the genetic risks for the child. The issue of who will raise the child in the event of subsequent morbidity or maternal mortality should ideally be prospectively discussed.     

Basic therapies in cystic fibrosis. Does standard therapy work?

Epidemiologic data demonstrate a dramatic improvement in survival for cystic fibrosis (CF) over the last few decades and projections suggest that trend will continue. Standard therapy works and should be aggressively applied to this patient population. Although the specific therapies have evolved over the years, the basic tenets of CF care remain unchanged and include antibiotics to control infection, airway clearance, and adequate nutrition. This article focuses on treatment of the pulmonary disease and includes a discussion of the following specific components of a standard therapeutic approach to CF: (1) antibiotics, (2) airway clearance and exercise, (3) mucolytics, (4) bronchodilators, (5) oxygen, (6) anti-inflammatory therapies, and (7) nutritional support. Judicious application of these therapies coupled with careful monitoring of pulmonary, nutritional, and metabolic parameters results in most CF patients surviving into adulthood with an acceptable quality of life.     

Osteoporosis in patients with cystic fibrosis

Decreased bone density and increased risk of fractures are seen in patients with cystic fibrosis. Suboptimal vitamin D levels, nutrition problems, hypogonadism, inactivity, corticosteroid use, and cytokines may contribute to the low bone mass seen in these patients. Treatment recommendations must be individualized and may include nutrition, vitamin D, estrogen or testosterone, and exercise. In high-risk patients calcitonin or growth hormone could be considered.     

The prospects for gene therapy in cystic fibrosis

Gene therapy provides the best prospect of a fundamental new treatment for cystic fibrosis. The lungs are the most important target, because this organ is the most severely affected by the disease and is also accessible for topical treatment. Advances in this field have been very rapid, and the prospects remain good although a number of problems need to be overcome. The two main approaches to gene transfer, namely adenoviruses and liposomes, are efficient in vitro, but early clinical trials have shown that they work less well in vivo. A number of proof of concept studies have shown that gene transfer is possible, but full functional correction of the cystic fibrosis defect has not yet been achieved. Adenoviruses have provoked an inflammatory response, and new viral vectors are being developed to overcome this. Existing lipids are relatively inefficient, but new liposomes are being developed to enhance gene transfer. Much work needs to be done to improve safety and efficacy of gene transfer before materials are ready for large scale clinical trials. However, progress is very rapid, and there is a real prospect of developing an effective gene therapy for cystic fibrosis within the next decade.     

Effect of antibiotic treatment on inflammatory markers and lung function in cystic fibrosis patients with Pseudomonas cepacia

BACKGROUND: The acquisition of Pseudomonas cepacia in patients with cystic fibrosis is associated with increasing deterioration in lung function and more frequent hospital admissions. Pseudomonas cepacia is usually resistant to several antibiotics in vitro, but the response of patients colonised with the organism has not been extensively studied in vivo. METHODS: A three month prospective study was performed to investigate the response of 14 Ps cepacia positive patients and 10 Ps cepacia negative patients to a two week course of intravenous antibiotics. All those who were Ps cepacia negative and six of the 14 Ps cepacia positive patients had Ps aeruginosa in their sputum which was sensitive to the prescribed therapy. The inflammatory markers C-reactive protein, white blood cell count, serum lactoferrin, neutrophil elastase/alpha 1-antitrypsin complex, and tumour necrosis factor alpha were measured at the start and end of each antibiotic course. RESULTS: The median (range) % improvement in baseline FEV1 and FVC following treatment in the group as a whole was 15.2% (-23.5% to 156.3%) and 23.9% (-36.8% to 232.7%) respectively. There was no statistical difference in improvement in lung function, body weight, or inflammatory markers between individuals who were Ps cepacia positive and those who were Ps cepacia negative. CONCLUSIONS: Patients who are Ps cepacia positive appear to respond as well to intravenous antibiotics as those who are Ps cepacia negative, despite having lower lung function and a bacterium in their sputum which is resistant in vitro to the antibiotics used.     

Glucose tolerance in patients with cystic fibrosis

In order to define prevalence and incidence of diabetes mellitus in cystic fibrosis, we followed 191 unselected patients above two years of age (median 13.6) in a five-year prospective study with annual oral glucose tolerance tests. The prevalence of diabetes increased from 11 to 24% during the study period with an annual age-dependent incidence rate of 4-9%. Diabetes was diagnosed at a median age of 21 years (range 3-40). At diagnosis of diabetes, hyperglycaemia, fasting hyperglycaemia (> or = 7.8 mmol/l), and increased haemoglobin Alc levels (> 6.4) were present in 33%, 16% and 16% of the diabetic patients, respectively. Impaired glucose tolerance implied a higher risk than normal glucose tolerance for the development of diabetes (odds ratio 5.6). In 58% of cases with impaired glucose tolerance, however, glucose tolerance was normalised at the next annual test. Normal glucose tolerance was found in only 37% of the patients at all five tests. Within this group of patients, median fasting and two-hour post-load plasma glucose concentrations and haemoglobin Alc levels increased by 6-8% during five years. Thus, the prevalence and incidence of diabetes in patients with cystic fibrosis is very high and increases with age. Since symptoms of hyperglycaemia and increased fasting plasma glucose and haemoglobin Alc levels are inconstant findings in newly diagnosed diabetic cystic fibrosis patients, we recommend annual oral glucose tolerance tests in all cystic fibrosis patients above the age of 10 years.     

Lentiviral vectors for gene therapy of cystic fibrosis

A replication-defective vector based on human immunodeficiency virus (HIV) was evaluated for gene transfer directed to the lung. The tropism of this vector has been expanded through the incorporation of the vesticular stomatitis virus G protein into its envelope. The HIV vector effectively transduced nondividing airway epithelial cells in vitro whereas a murine-based retroviral vector did not. Experiments in a human bronchial xenograft model demonstrated high-level gene transduction with a cystic fibrosis transmembrane conductance regulator (CFTR) HIV vector into undifferentiated, cystic fibrosis (CF)-derived cells of the xenograft. CFTR expression was stable and capable of functional correction of the CF defect after the graft matured. The HIV vector did not effectively transduce cells of the xenograft when instilled after the epithelium had differentiated. This block to transduction appears to be at the level of entry, although post entry restrictions cannot be ruled out. Further development of this vector system for CF gene therapy should focus on a better understanding of potential entry and post entry blocks.     

Enhanced oxidative damage in cystic fibrosis patients

Antioxidant depletion and increased free radical production by inflammatory cells have been described in cystic fibrosis (CF) patients. To evaluate oxidative damage intensity, we measured plasma concentrations of malondialdehyde, hydroperoxides and protein carbon groups as markers of oxidative injury to lipids and proteins in a group of 101 CF patients free of acute exacerbation, and in 43-112 controls. Moreover, we estimated antioxidant function by measuring activities of erythrocyte superoxide dismutase, glutathione reductase and vitamin E concentrations. In CF patients, malondialdehyde and hydroperoxide plasma levels were significantly higher than in controls (p < 0.001). Increased lipid peroxidation was documented by these two markers. Parallel rises in protein carbonyls in plasma of CF patients were observed (p < 0.0001). These patients presented biochemical but not clinical vitamin E deficiency. Glutathione reductase and superoxide dismutase activities were significantly higher than in controls. These results show a serious imbalance of CF patients between oxidant-antioxidant status leading to oxidative stress.     

Chloride conduction of nasal fibroblasts in polyposis patients with cystic fibrosis and in patients without cystic fibrosis. Relevance for the ENT physician]

Cystic fibrosis (CF) is a complex systemic disease that has pathological alterations in the upper airways, including the recurrent formation of nasal polyps. Although the fibroblast is the predominant cell type in nasal stroma and nasal polyps, little is known about the electrophysiological properties of nasal fibroblasts. We investigated whether fibroblasts possess a cAMP-regulated chloride conductance which is impaired in patients with CF. Thus far the few studies concerning conductance in fibroblasts have been performed on skin fibroblasts using indirect methods and have yielded conflicting results. Therefore we studied chloride conductance in fused nasal fibroblasts by employing conventional microelectrodes. We have demonstrated that a cAMP-regulated chloride conductance is present in fibroblasts. However, this chloride conductance cannot be activated in fibroblasts from CF-patients. Thus, we present direct evidence that the impairment of the cAMP-regulated chloride conductance in CF is not confined to epithelial cells but also affects the fibroblast. We discuss how this conductance might modulate fibroblast proliferation to produce polyp formation.     

Correlates of osteopenia in patients with cystic fibrosis

The responses to heat shock in Tritrichomonas mobilensis, a squirrel monkey parasite and Tritrichomonas augusta, an amphibian trichomonad, were evaluated by means of metabolic labeling with [35S]methionine. Electrophoretically separated trichomonad proteins synthesized at different temperatures were visualized by autoradiography and the label incorporation quantitated by a trichloroacetic acid precipitation procedure. A considerable difference in thermotolerance between the two species was found as the protein synthesis reached a maximum at 41 C in T. mobilensis and 37 C in T. augusta. The latter tolerated temperature increases 13 C above normal cultivation temperatures as compared to only 4 C thermotolerance range above normal in T. mobilensis. Major heat shock proteins (Hsps) were expressed in both T. mobilensis (with apparent Mr 94, 72, and 58 kDa) and T. augusta (Mr 94, 70, and 56 kDa) as revealed by autoradiography. Western blot analysis with polyclonal antibody against DnaK of Escherichia coli showed the presence of antigenic Hsp70 homologs in both trichomonads. Similarly, a polyclonal antibody against Hsp60 with broad interspecies cross-reactivity detected Hsp60 homologs in both T. mobilensis and T. augusta. The anti-DnaK antibody cross-reacted with a T. mobilensis protein localized in Golgi apparatus as demonstrated by immunoelectron microscopy. Immunocytochemistry on trichomonad frozen sections revealed the presence of the Hsp60 homolog in light-microscopic granules corresponding to hydrogenosomes.     

Pharmacokinetics of famotidine in patients with cystic fibrosis

Famotidine pharmacokinetics were studied in 13 patients with severe cystic fibrosis (CF) ranging from 10 to 47 years of age and 25 to 72 kg in weight. Patients were randomized to first receive famotidine either 20 mg intravenously or 40 mg orally. Twelve patients were crossed over to the alternate treatment. Repeated blood samples were obtained over 12 hours after intravenous and oral administration and urine was collected over 24 hours for quantitation of famotidine by means of high-performance liquid chromatography (HPLC). A compartment model-dependent approach was used to characterize the disposition of famotidine. From the intravenous data, the mean +/- standard deviation elimination half-life (t1/2) was 2.11 +/- 0.75 hours, the total clearance (Cl) was 0.79 +/- 0.41 L/kg/hr, the renal clearance was 0.57 +/- 0.26 L/kg/hr, the fraction eliminated unchanged in the urine was 83% +/- 16%, and the apparent volume of distribution (Vdss) was 1.33 +/- 0.53 L/kg. The bioavailability determined from comparison of intravenous and oral area under the curve data was 71% +/- 27%. Results of this study support an initial famotidine dose of 20 mg intravenously or 40 mg orally every 12 hours in patients with CF who are older than 9 years of age.     

Anaesthesia for liver transplantation in cystic fibrosis patients

INTRODUCTION: Cystic fibrosis (CF) is a disease caused by an inherited genetic defect. While pulmonary and pancreatic abnormalities predominate the clinical spectrum, other organ involvement is common, including liver. The severity of liver disease does not appear to be related to the severity of exocrine pancreatic or lung function. We discuss anaesthesia in four CF patients undergoing liver transplantation. METHODS: We studied haemodynamic and oxygenation modifications during anaesthesia in four patients affected by CF with end-stage liver disease and mild to moderate pulmonary abnormalities. The patients received pancreatic enzyme prior to transplantation and two had insulin-dependent diabetes mellitus. All patients were treated with broad-spectrum antibiotic therapy. After a waiting time ranging one week to three months, all patients were successfully transplanted. General anaesthesia was induced with fentanyl, thiopental and pancuronium, and maintained with isoflurane supplemented by fentanyl in O2:air. Haemodynamic and oxygenation evaluations were made during the main phases of the transplant. After the intubation and at the end of the procedure all patients received a broncho-alveolar toilet through fiberoptic bronchoscopy. RESULTS: During anaesthesia for liver transplantation, PaO2 increased proportionally to the decreasing of Qs/Qt. In postoperative follow-up, Fev1 and FVC improved from preoperative time in all patients. In conclusion, even if cystic fibrosis is a multisystem disease, liver transplantation can be offered to CF patients with endstage liver disease and mild to moderate pulmonary function abnormalities. The four patients are still alive, enjoying good health. The improved respiratory function and quality of life of these children is remarkable.     

Is gene therapy in cystic fibrosis a realistic expectation?

To date there are 11 human protocols either ongoing or approved for gene therapy for cystic fibrosis (CF) in the United States. There are also two protocols in the United Kingdom and one in France. Of these, results have been published in four. The protocols vary in the cells targeted, the vectors used, and the frequency of administration, but despite these differences all have contributed toward answering the key questions that will determine the future of gene therapy for CF: the questions of efficacy and safety. These studies have demonstrated that it is feasible to transfer the normal human CF transmembrane conductance regulator complementary DNA to the respiratory epithelium and that this will lead to production of normal CF transmembrane conductance regulator protein and in some cases to a physiologic response. The most frequently used vector is the adenovirus. Obstacles to be overcome with this system include the need for improved and prolonged expression, efficacy on repeat administration, and decreased inflammation. Recent work on the immune response to adenoviral vectors may help achieve these goals. The cationic lipid method of gene delivery is less likely than adenovirus to cause inflammation, at least in the nose, but improved efficacy of gene transfer is necessary as well as improved complex stability. Furthermore, this system has yet to be tested in the lungs of individuals with CF. Finally, the adeno-associated virus, the other vector approved for human gene therapy studies in CF, has shown some promise in preclinical studies but remains to be tested in humans. The results of these studies give some cause for guarded optimism, but point out a number of problems that must be overcome before gene therapy for CF delivers on the promise of a safe effective treatment for this condition.     

Chemotactic factors in bronchial secretions of cystic fibrosis patients

To understand chronic neutrophil attraction into cystic fibrosis airways, both global chemotactic activity and individual chemotactic factors were studied in bronchial secretions. Bronchial secretions of 8 cystic fibrosis patients, collected on the first day of admission for antibiotic treatment, showed a high chemotactic index (19.4 +/- 5.7, n = 8). Fractionation by gel filtration of bronchial secretions resulted in three chemotactic fractions. The first factor corresponded to interleukin-8, and the second activated neutrophils via the FMLP receptor. The third factor, which was of lower molecular weight, did not activate FMLP or leukotriene B4 receptors, and its nature is still under investigation. Treating patients with antibiotics reduced global chemotactic activity, mainly by reducing the activity due to stimulation of the FMLP receptor.     

Composition of nasal secretion in patients with cystic fibrosis

Quantitative examination of nasal secretion in patients with cystic fibrosis revealed a significantly greater than normal concentration of calcium, a finding in keeping with the hypothesized importance of this ion in the pathophysiology of the disease.