Antibiotic therapy and fat digestion and absorption in cystic fibrosis

11st Chair of Pediatrics, Department of Pediatric Gastroenterology & Metabolism, Poznań University of Medical Sciences, Poznań, Poland; 2Department of Bronchology & Cystic Fibrosis, National Institute for Tuberculosis & Lung Diseases, Pediatric Branch, Rabka, Poland; 3Department of Pediatric Gastroenterology, Hepatology & Immunology, Child Memorial Health Institute, Warszawa, Poland; 41st Clinic of Lung Diseases, National Tuberculosis and Lung Diseases Research Institute, Warszawa, Poland; 5Department of Respiratory Medicine, 6Department of Pediatric Otorhinolaryngology, Poznań University of Medical Sciences, Poznań, Poland; 7Department of Dietetics, Chair of Human Nutrition & Hygiene, Poznań University of Life Sciences, Poznań, Poland


InTRoDuCTIon
Cystic fibrosis (CF) is an inflammatory and destructive disease with differentiated clinical expression.Bronchopulmonary disease is the major clinical manifestation which frequently demands antibiotic therapy.Available data suggests that such treatment applied in CF patients improves not only respiratory function but also nutritional status, which has been related to increased energy intake and decreased energy expenditure (Vic et al., 1997;Castro et al., 2002;Hankard et al., 2002;Béghin et al., 2003).Interestingly, antibiotic therapy in the CF mouse model resulted in the reduction of bacterial load of the small intestine, decreased intensity of intestinal inflammation and significant body mass gain.The effect was suggested to be linked to the improvement of intestinal digestion and absorption (Norkina et al., 2004a;2004b).Therefore, we aimed in the present study to assess the influence of routinely applied antibiotic therapy in CF patients on fat digestion and absorption.
Inclusion criteria for subjects comprised the willingness to participate in the study and exocrine pancreatic insufficiency (fecal elastase-1 concentration < 100 μg/g and the presence of steatorrhea) (Walkowiak, 2004;Walkowiak et al., 2005).Exclusion criteria comprised: intravenous and oral antibiotic therapy six weeks prior to the test, liver cirrhosis, diabetes mellitus, oxygen dependency, the use of systemic corticosteroids.
In all enrolled CF subjects, 13 C-labelled mixed triglyceride breath test ( 13 C MTG-BT) was performed to assess lipid digestion and absorption, before and after antibiotic therapy (on the day preceding antibiotic therapy and on the last day of antibiotic administration).Sixteen patients were treated intravenously with ceftazidime and amikacin, in respective doses: 150-250 mg/kg per 24 h and 20-35 mg/kg per 24 h, the remaining eight subjects were given ciprofloxacin orally in a dose of 35-50 mg/ kg per 24 h.The antibiotics were administered for 14 days.
13 C MTG-BT was performed after overnight fast.Each of the studied subjects received 150 mg of 13 C mixed triglyceride with 0.25 g butter per kg body mass mixed on a slice of bread.Breath samples were collected at baseline (fasting) and at 30,60,90,120,150,180,210,240,270,300,330 and 360 minutes after test meal ingestion.The samples were analyzed with an IRIS 13 C-Analyser System (Wagner, Bremen, Germany).Cumulative percentage dose recovery (CPDR) was considered to reflect digestion and absorption of lipids.
Values are expressed as ranges, means and medians.The statistical significance of differences in CPDR before and after antibiotic therapy was determined with the use of Wilcoxon-rank test.The level of significance was set at p < 0.05.Statistical analysis was performed using STATISTICA 8.0.(StatSoft Inc. 2008).
The protocol of the investigation was approved by the Bioethical Committee of Poznań University of Medical Sciences, Poland.

RESulTS
The values of CPDR before and after antibiotic therapy did not differ in the whole studied group or in either of the subgroups differing in the mode of drug administration (Table 2).

DISCuSSIon
No significant influence of the antibiotic treatment applied on lipid digestion and absorption was observed in the present study.To the best of our knowledge this is the first study assessing such a relationship in humans in a reliable way.Reilly et al. (1999) made an attempt to assess the effect of an acute respiratory exacerbation on energy balance.The exacerbation was associated with a significant reduction in energy intake.A trend towards lower total energy expenditure was observed.No statistical differences in fat absorption and resting energy expenditure as well as body mass and composition were documented.However, the power of the study was rather low, as only 14 children were studied.The data on the effectiveness of fat digestion and absorption (coefficient of fat absorption -CFA) were available for ten of them.CFA was better during exacerbation in seven subjects and worse in one patient.The authors attributed some CFA changes to a better compliance with the pancreatic enzyme replacement therapy under supervision.However, they finally concluded that the changes were negligible.With the methodology applied in their study it is difficult to determine the reliability of the findings.Fat intake was assessed during exacerbation for 6-7 days and for one weekend and two week days during the stable period.Fecal fat output was calculated from a three-day stool collection made during each period.Nevertheless, the relationship between the timing of food intake and stool collection as well as between stable period, antibiotic treatment and exacerbation was not precised.According to the authors' discussion they aimed to assess the difference in CFA between well-being and exacerbation.In contrast to their study, we assessed the effect of both oral and intravenous antibiotic therapies.In addition, we determined fat assimilation on fixed days before and after antibiotic treatment (reflecting in a reliable way appropriate time points) to assess its potential influence on the efficacy of digestion and absorption.
There is a strong association of bacterial infection and inflammation in CF, at least in the airways.Accumulating evidence indicates that susceptibility to inflammation may be inherent to the tissue involved even in the absence of specific pathogenic microbial colonization (Muhlebach et al., 1999).The CFTR-null mouse model does not express CFTR and is not expected to have inherent inflammation due to protein misfolding.The observed inflammation in the CF mouse intestine most likely occurs as a result of altered luminal environment with subsequent bacterial overgrowth (Norkina et al., 2004a;2004b).The body weight of CF mice at the end of 3-week antibiotic treatment (ciprofloxacin and metronidazole) was significantly increased compared to untreated CF mice and not significantly different from that of wild-type animals.The antibiotic treatment had no effect on the body mass of control wild-type animals (Norkina et al., 2004b).
The obtained results suggest that antibiotic therapy may have a significant impact on digestion and absorption in CF patients, thereby influencing the energy balance during treatment of pulmonary exacerbations.The doses used in the animal model are not easy to be translated into a human study.Moreover, ciprofloxacin doses used in bronchopulmonary exacerbation in CF are well established.Therefore, we applied its typical  doses.Although intravenous therapy in such cases is more commonly used, we also assessed the effects of oral antibiotic administration on lipid assimilation.The observed changes did not reach the level of significance.However, a tendency towards an improvement of fat absorption was noted.
In conclusion, routinely applied antibiotic therapy in the course of pulmonary exacerbation in CF patients does not seem to result in an improvement of fat digestion and absorption.

Table 2 . lipid digestion and absorption in cystic fibrosis (CF) patients undergoing antibiotic therapy based upon cumulative 13 C dose recovery (CPDR)
*CF-IV, subjects receiving antibiotics intravenously; **CF-PO, subjects receiving antibiotics orally