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Oral antibiotic therapy improves fat absorption in cystic fibrosis patients with small intestine bacterial overgrowth
Journal of Cystic Fibrosis 10 (2011) 418 – 421 www.elsevier.com/locate/jcf
Original Article
Oral antibiotic therapy improves fat absorption in cystic fibrosis patients with small intestine bacterial overgrowth☆ Aleksandra Lisowska a,⁎, Andrzej Pogorzelski b , Grzegorz Oracz c , Katarzyna Siuda a , Wojciech Skorupa d , Marta Rachel e, f , Szczepan Cofta g , Tomasz Piorunek g , Jarosław Walkowiak a, h a
1st Chair of Pediatrics, Department of Pediatric Gastroenterology & Metabolism, Poznań University of Medical Sciences, Szpitalna 27/33; 60-572 Poznań, Poland b Department of Bronchology & Cystic Fibrosis, National Institute for Tuberculosis & Lung Diseases, Pediatric Branch, Prof. J. Rudnika 3B; 34-700 Rabka Zdrój, Poland c Department of Pediatric Gastroenterology, Hepatology & Immunology, Child Memorial Health Institute, Al. Dzieci Polskich 20; 04-736 Warszawa, Poland d 1st Clinic of Lung Diseases, National Tuberculosis and Lung Diseases Research Institute, Płocka 26; 01-138 Warszawa, Poland e Institute of Physiotherapy, Medical Faculty, University of Rzeszów, ul. Warszawska 26a, 35-205 Rzeszów, Poland f Department of Pediatrics, Regional Hospital nr 2, ul. Lwowska 60, 35-301 Rzeszów, Poland g Department of Respiratory Diseases, Allergology & Lung Oncology, Poznań University of Medical Sciences, Szamarzewskiego 82/84, 60-569 Poznań, Poland h Department of Dietetics, Chair of Human Nutrition & Hygiene, Poznań University of Life Sciences, Wojska Polskiego 28; 60-637 Poznań, Poland Received 13 January 2011; received in revised form 15 April 2011; accepted 19 June 2011 Available online 20 July 2011
Abstract Background: The aim of the present study was to assess the influence of antibiotic therapy on fat assimilation in cystic fibrosis (CF) patients with small intestine bacterial overgrowth (SIBO). Materials and methods: Twenty six pancreatic insufficient CF patients with bronchopulmonary exacerbation and diagnosed SIBO (positive hydrogen–methane breath test) entered the study. 13C mixed triglyceride breath test was performed before and after antibiotic therapy. Sixteen subjects were treated intravenously (ceftazidime and amikacin), ten patients orally (ciprofloxacin). Results: Cumulative percentage dose recovery changed significantly in the subgroup receiving antibiotics orally [median (mean ± SEM): 3.6% (4.5 ± 1.3%) vs. 7.2 (6.9 ± 1.6%); p = 0.019]. In the subgroup with intravenous drug administration, the tendency towards improvement was noted [2.7 (4.3 ± 1.5%) vs. 5.2 (5.7 ± 0.8%); p = 0.109]. Conclusions: Antibiotic therapy applied in CF patients with SIBO in the course of pulmonary exacerbation results in a significant improvement of fat digestion and absorption. © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Small intestine bacterial overgrowth; Antibiotic therapy; Fat digestion and absorption; Stable isotope breath test
1. Introduction ☆
AL & JW designed the study. AL, AP, WS, MR, KS, SC, and TP included and supervised subjects studied. AL, GO & JW performed the breath test. JW performed the statistical analysis. AL, JW & KS wrote the manuscript with feedback from all authors. ⁎ Corresponding author at: Poznań University of Medical Sciences, 1st Chair of Pediatrics, Department of Pediatric Gastroenterology & Metabolism, Szpitalna 27/33, 60-572 Poznań, Poland. Tel.: +48 61 8480310. E-mail address: [email protected] (A. Lisowska).
Small intestine bacterial overgrowth (SIBO) may frequently occur in subjects with cystic fibrosis (CF) [1,2]. Its typical symptoms comprise abdominal discomfort, bloatening, flatulence, gasses and appear from several minutes to hours after meal [2,3]. Due to their similarity to typical gastrointestinal manifestation in CF, SIBO may remain undiagnosed unless specifically assessed. It is suggested that due to SIBO, the
1569-1993/$ - see front matter © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2011.06.008
A. Lisowska et al. / Journal of Cystic Fibrosis 10 (2011) 418–421
synthesis of enterotoxic and unabsorbable metabolites may result in mucosal damage and interfere with digestion and absorption [4,5]. Therefore, the presence of SIBO in CF subjects may potentially aggravate malabsorption. Intensive inflammation of the CF mouse small intestine was reported [6]. Results obtained in a subsequent study suggested, that bacterial overgrowth plays an important role in inflammation and contributes to the failure in thrive in this model of CF [7]. We have recently compared the effectiveness of fat absorption in CF patients with and without SIBO. No significant differences were observed [8]. In a following study we have also failed to document the effect of antibiotic therapy applied in non-selected cystic fibrosis (CF) patients in the course of pulmonary exacerbation on intestinal digestion and absorption as measured by 13C-labeled mixed triglyceride breath test ( 13C MTG-BT). Although observed changes of cumulative percentage dose recovery (CPDR) in the whole studied group were not significant, the tendency towards the improvement (p b 0.100) was observed [8]. Therefore, we aimed to assess the influence of antibiotic therapy on fat assimilation in CF patients with SIBO. 2. Materials and methods The study comprised 26 CF patients (15 females and 11 males) (Table 1). Diagnosis of CF was based on history, clinical manifestation and increased sweat chloride concentrations and in the majority of patients confirmed by the CFTR gene analysis. The genotypes of the studied patients were as follow: F508del/F508del (n = 12), F508del/CFTRdel2,3(21kB) (n = 2), F508del/R553X (n = 1), CFTRdel2,3(21kB)/CFTRdel2,3(21kB) (n = 2), F508del/2143delT (n = 1), F508del/2183AA-G (n = 1), F508del/W1282X (n = 1), 1717-1G-A/N1303K (n = 1), F508del/ unknown mutation (n = 4), and unknown mutation/unknown mutation (n = 1). Inclusion criteria comprised the willingness to participate in the study, exocrine pancreatic insufficiency (fecal elastase-1 concentration b 100 μg/g and the presence of steatorrhea), pulmonary exacerbation (demanding antibiotic therapy) and the presence of SIBO (based upon results of HMBT) [9,10]. Exclusion criteria comprised: antibiotic therapy (i.v. or p.os) six weeks prior to the test, liver cirrhosis, diabetes mellitus, oxygen dependency, the use of systemic corticosteroids, severe pulmonary exacerbation or any pulmonary complication. Glucose HMBT was performed after overnight fast. Patients were instructed not to eat or drink for at least 12 h before the test Table 1 Basic epidemiological and clinical data of cystic fibrosis patients (n = 26). Parameter
Range
Median (mean ± SEM)
Age (years) Body weight (Z-score) FEV1 (%) Fecal elastase-1 (μg/g) AlAT (U/l) GGTP (U/l)
12–32 − 2.42–0.78 54.4–112.4 BDL*–88 8–52 6–64
19 (20.8 ± 1.0) − 0.73 (− 0.70 ± 0.16) 81.2 (81.9 ± 2.6) 6 (10 ± 4) 23 (22.6 ± 2.0) 16 (18.4 ± 2.6)
*BDL — below detection limit.
419
and to avoid slowly digesting foods like beans and similar vegetables, brans or high-fiber cereals the day before the test. Patients were not allowed to smoke, sleep or exercise vigorously for at last 1 h before or at any time during the test. Every patient received glucose dissolved in water orally in a dose of 1.5 g/kg up to maximum 75 g. Breath samples were collected at baseline (fasting) and at 15, 30, 45, 60, 90, and 120 min after glucose ingestion. Samples were analyzed with QuinTron MicroLyser DP Plus (Quintron, USA). A positive HMBT was defined as a rise of ≥ 20 ppm hydrogen or ≥ 12 ppm methane over baseline during the test. In all enrolled CF subjects, 13C MTG-BT was performed to assess lipid digestion and absorption, before and after antibiotic therapy. Sixteen patients were treated intravenously with amikacin and ceftazidime, in respective doses: 20–35 mg/kg/24 h and 150– 250 mg/kg/24 h, remaining 10 subjects were given ciprofloxacin in a dose of 35–50 mg/kg/24 h (in latter two in proper divided doses) according to existing CF standards. The assignment of patients to treatment groups was based upon psychological and social aspects (patients' abilities and wills). Patients did not differ in terms of their clinical status. The assignment of patients to treatment groups was based on sputum culture with bacterial sensitivity tests and psychological/social aspects (i.e. willingness/ permission for hospitalization). Patients did not differ significantly in terms of the nature of pulmonary exacerbations. 13 C MTG-BT was performed after overnight fast. Each of the studied subjects received 150 mg 13C mixed triglyceride with 0.25 g butter per kg body weight 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 min after test meal ingestion. The samples were analyzed with IRIS 13 C-Analyser System (Wagner, Bremen, Germany). CPDR was considered to reflect digestion and absorption of lipids. In healthy non-CF individuals it should be higher than 14.5%. Values are expressed as ranges, means (± SEM) and medians. The differences in CPDR before and after antibiotic therapy were determined with the use of Wilcoxon-rank test. The effectiveness of antibiotic therapy in curing SIBO was assessed using Fisher test. The level of significance was set at p b 0.05. The protocol of the investigation was approved by Ethical Committee of Poznań University of Medical Sciences, Poland.
3. Results Antibiotic therapy resulted in a significant reduction of hydrogen/methane production in both treated groups (p b 0.005 and p b 0.0015 for oral and intravenous therapy, respectively) as shown in Fig. 1A–B. The cure of SIBO was achieved respectively in 9 (90%) and 7 (43.8%) patients treated orally and intravenously, being more effective in the latter group (p b 0.037). The results of 13C MTG-BT have been presented in Table 2. The values of CPDR changed significantly in the subgroup receiving antibiotics orally (p b 0.019). In the subgroup receiving intravenously the tendency towards the improvement (p b 0.109) was observed.
420
A. Lisowska et al. / Journal of Cystic Fibrosis 10 (2011) 418–421
Hydrogen/methane* expiration (ppm)
A
40 35 30 25 20 15
Before
10
After
5 0
0
15
30
45
60
90
120
Minutes
Hydrogen/methane* expiration (ppm)
B
40 35 30 25 20 Before
15
After
10 5 0
0
15
30
45
60
90
120
Minutes
Fig. 1. A. Changes in mean values of hydrogen/methane expiration in CF patients receiving antibiotics orally. *The sum of hydrogen and doubled methane expiration has been given. B. Changes in mean values of hydrogen/ methane expiration in CF patients receiving antibiotics intravenously. *The sum of hydrogen and doubled methane expiration has been given.
4. Discussion We documented in the present study the positive influence of antibiotic therapy on fat assimilation in CF patients with SIBO. According to literature search it is the first study assessing such a relationship in a reliable way in humans. Reilly et al. attempted to assess the effect of an acute bronchopulmonary exacerbation on energy balance in a group Table 2 Lipid digestion and absorption in cystic fibrosis patients with small intestine bacterial overgrowth undergoing antibiotic therapy based upon cumulative 13C dose recovery (CDPR). Studied group (n) CF-IV ⁎⁎ (16) CF-PO ⁎⁎⁎ (10)
CPDR (%) Parameter
Before
After
Median Mean ± SEM Range Median Mean ± SEM Range
2.7 4.3 ± 1.5 BDL ⁎–20.2 3.6 4.5 ± 1.3 BDL ⁎–9.2
5.2 5.7 ± 0.8 1.8–11.4 7.2 6.9 ± 1.6 0.8–12.8
⁎ BDL — below detection limit. ⁎⁎ CF-IV — subjects receiving antibiotics intravenously. ⁎⁎⁎ CF-PO — subjects receiving antibiotics orally.
Statistical significance 0.109
0.019
of 14 CF children [11]. Since the relationship between timing of food intake and stool collection as well as between stable period and exacerbation was not clear, the obtained results raise some doubts. The data on the effectiveness of fat digestion and absorption as measured by the coefficient of fat absorption (CFA) were available in 10 out of 14 studied subjects. CFA improved during exacerbation in 7 subjects and worsened in 1 patient. However, no significant effect was observed. We have conducted a similar study assessing the influence of antibiotic therapy on fat assimilation with the use of reliable stable isotope breath test. The strict criteria of timing were used, the test was conducted directly before and after antibiotic therapy. Norkina et al. proved that intestinal bacterial overgrowth is related to intestinal inflammation and failure in thrive in the CF mouse model [6]. Significant CF mice weight gain at the end of a 3-weeks antibiotic treatment (ciprofloxacin and metronidazole) was observed. Having in mind this effect we aimed previously to assess the significance of SIBO for CF human lipid assimilation. We did not observe any differences between subjects with and without SIBO [8]. In a subsequent study, antibiotic therapy applied in non-selected CF patients resulted in the tendency towards the improvement of CPDR (p b 0.100). However, the effects observed in subgroups receiving antibiotics either orally or intravenously were less evident (p b 0.167 and p b 0.327, respectively). Therefore, we planned in the present study to determine fecal fat assimilation before and after antibiotic treatment exclusively in CF patients with documented SIBO [12]. Considering limited sensitivity and specificity of breath test for the detection of SIBO, we used very strict criteria including exclusively patients with a significant increase of hydrogen and or methane exhalation after glucose loading. We documented in the present study significant changes of CPDR due to oral antibiotic therapy with ciprofloxacin. Although significant improvement of fat digestion and absorption as measured by 13C MTG-BT was observed, the effects of antibiotic therapy were minor. The relationship documented in animal model does not seem to be so clear in humans [7]. Clinical significance of SIBO for lipid digestion and absorption in CF patients demands further studies. In conclusion, oral antibiotic therapy applied in CF patients with small intestine bacterial overgrowth in the course of pulmonary exacerbation results in statistically significant improvement of fat digestion and absorption. References [1] Lewindon PJ, Robb TA, Moore DJ, Davidson GP, Martin AJ. Bowel dysfunction in cystic fibrosis: importance of breath testing. J Pediatr Child Health 1998;34:79–82. [2] Fridge JL, Conrad C, Gerson L, Castillo RO, Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr 2007;44:212–8. [3] Di Stefano M, Miceli E, Missanelli A, Corazza GR. Treatment of small intestine bacterial overgrowth. Eur Rev Med Pharmacol Sci 2005;9:217–22. [4] Borowitz D, Durie PR, Clarke LL, Werlin SL, Taylor CJ, Semler J, et al. Gastrointestinal outcomes and confounders in cystic fibrosis. J Pediatr Gastroenterol Nutr 2005;41:273–85. [5] Gregg CR. Enteric bacterial flora and bacterial overgrowth syndrome. Semin Gastrointest Dis 2002;13:200–9.
A. Lisowska et al. / Journal of Cystic Fibrosis 10 (2011) 418–421 [6] Norkina O, Kaur S, Ziemer D, De Lisle RC. Inflammation of the cystic fibrosis mouse small intestine. Am J Physiol Gastrointest Liver Physiol 2004;286:G1032–41. [7] Norkina O, Burnett DG, De Lisle RC. Bacterial overgrowth in cystic fibrosis transmembrane conductance regulator null mouse small intestine. Infect Immun 2004;72:6040–9. [8] Lisowska A, Pogorzelski A, Oracz G, Skorupa W, Cofta S, Socha J, et al. Small intestine bacterial overgrowth and fat digestion and absorption in cystic fibrosis patients. Acta Sci Pol Technol Aliment 2010;9:477–83. [9] Walkowiak J, Nousia-Arvanitakis S, Henker J, Stern M, Sinaasappel M, Dodge JA. Indirect pancreatic function tests in children. J Pediatr Gastroenterol Nutr 2005;40:107–14.
421
[10] Walkowiak J. Assessment of maldigestion in cystic fibrosis. J Pediatr 2004;145:285–7. [11] Reilly JJ, Evans TJ, Wilkinson J, Paton JY. Adequacy of clinical formulae for estimation of energy requirements in children with cystic fibrosis. Arch Dis Child 1999;81:120–4. [12] Lisowska A, Pogorzelski A, Oracz G, Skorupa W, Cofta S, Szydłowski J, et al. No major effect of antibiotic therapy on fat digestion and absorption in cystic fibrosis. Acta Biochim Pol, PMID: 21738905 [2011 Jul 7, Electronic publication ahead of print].
Original Article
Oral antibiotic therapy improves fat absorption in cystic fibrosis patients with small intestine bacterial overgrowth☆ Aleksandra Lisowska a,⁎, Andrzej Pogorzelski b , Grzegorz Oracz c , Katarzyna Siuda a , Wojciech Skorupa d , Marta Rachel e, f , Szczepan Cofta g , Tomasz Piorunek g , Jarosław Walkowiak a, h a
1st Chair of Pediatrics, Department of Pediatric Gastroenterology & Metabolism, Poznań University of Medical Sciences, Szpitalna 27/33; 60-572 Poznań, Poland b Department of Bronchology & Cystic Fibrosis, National Institute for Tuberculosis & Lung Diseases, Pediatric Branch, Prof. J. Rudnika 3B; 34-700 Rabka Zdrój, Poland c Department of Pediatric Gastroenterology, Hepatology & Immunology, Child Memorial Health Institute, Al. Dzieci Polskich 20; 04-736 Warszawa, Poland d 1st Clinic of Lung Diseases, National Tuberculosis and Lung Diseases Research Institute, Płocka 26; 01-138 Warszawa, Poland e Institute of Physiotherapy, Medical Faculty, University of Rzeszów, ul. Warszawska 26a, 35-205 Rzeszów, Poland f Department of Pediatrics, Regional Hospital nr 2, ul. Lwowska 60, 35-301 Rzeszów, Poland g Department of Respiratory Diseases, Allergology & Lung Oncology, Poznań University of Medical Sciences, Szamarzewskiego 82/84, 60-569 Poznań, Poland h Department of Dietetics, Chair of Human Nutrition & Hygiene, Poznań University of Life Sciences, Wojska Polskiego 28; 60-637 Poznań, Poland Received 13 January 2011; received in revised form 15 April 2011; accepted 19 June 2011 Available online 20 July 2011
Abstract Background: The aim of the present study was to assess the influence of antibiotic therapy on fat assimilation in cystic fibrosis (CF) patients with small intestine bacterial overgrowth (SIBO). Materials and methods: Twenty six pancreatic insufficient CF patients with bronchopulmonary exacerbation and diagnosed SIBO (positive hydrogen–methane breath test) entered the study. 13C mixed triglyceride breath test was performed before and after antibiotic therapy. Sixteen subjects were treated intravenously (ceftazidime and amikacin), ten patients orally (ciprofloxacin). Results: Cumulative percentage dose recovery changed significantly in the subgroup receiving antibiotics orally [median (mean ± SEM): 3.6% (4.5 ± 1.3%) vs. 7.2 (6.9 ± 1.6%); p = 0.019]. In the subgroup with intravenous drug administration, the tendency towards improvement was noted [2.7 (4.3 ± 1.5%) vs. 5.2 (5.7 ± 0.8%); p = 0.109]. Conclusions: Antibiotic therapy applied in CF patients with SIBO in the course of pulmonary exacerbation results in a significant improvement of fat digestion and absorption. © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Small intestine bacterial overgrowth; Antibiotic therapy; Fat digestion and absorption; Stable isotope breath test
1. Introduction ☆
AL & JW designed the study. AL, AP, WS, MR, KS, SC, and TP included and supervised subjects studied. AL, GO & JW performed the breath test. JW performed the statistical analysis. AL, JW & KS wrote the manuscript with feedback from all authors. ⁎ Corresponding author at: Poznań University of Medical Sciences, 1st Chair of Pediatrics, Department of Pediatric Gastroenterology & Metabolism, Szpitalna 27/33, 60-572 Poznań, Poland. Tel.: +48 61 8480310. E-mail address: [email protected] (A. Lisowska).
Small intestine bacterial overgrowth (SIBO) may frequently occur in subjects with cystic fibrosis (CF) [1,2]. Its typical symptoms comprise abdominal discomfort, bloatening, flatulence, gasses and appear from several minutes to hours after meal [2,3]. Due to their similarity to typical gastrointestinal manifestation in CF, SIBO may remain undiagnosed unless specifically assessed. It is suggested that due to SIBO, the
1569-1993/$ - see front matter © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2011.06.008
A. Lisowska et al. / Journal of Cystic Fibrosis 10 (2011) 418–421
synthesis of enterotoxic and unabsorbable metabolites may result in mucosal damage and interfere with digestion and absorption [4,5]. Therefore, the presence of SIBO in CF subjects may potentially aggravate malabsorption. Intensive inflammation of the CF mouse small intestine was reported [6]. Results obtained in a subsequent study suggested, that bacterial overgrowth plays an important role in inflammation and contributes to the failure in thrive in this model of CF [7]. We have recently compared the effectiveness of fat absorption in CF patients with and without SIBO. No significant differences were observed [8]. In a following study we have also failed to document the effect of antibiotic therapy applied in non-selected cystic fibrosis (CF) patients in the course of pulmonary exacerbation on intestinal digestion and absorption as measured by 13C-labeled mixed triglyceride breath test ( 13C MTG-BT). Although observed changes of cumulative percentage dose recovery (CPDR) in the whole studied group were not significant, the tendency towards the improvement (p b 0.100) was observed [8]. Therefore, we aimed to assess the influence of antibiotic therapy on fat assimilation in CF patients with SIBO. 2. Materials and methods The study comprised 26 CF patients (15 females and 11 males) (Table 1). Diagnosis of CF was based on history, clinical manifestation and increased sweat chloride concentrations and in the majority of patients confirmed by the CFTR gene analysis. The genotypes of the studied patients were as follow: F508del/F508del (n = 12), F508del/CFTRdel2,3(21kB) (n = 2), F508del/R553X (n = 1), CFTRdel2,3(21kB)/CFTRdel2,3(21kB) (n = 2), F508del/2143delT (n = 1), F508del/2183AA-G (n = 1), F508del/W1282X (n = 1), 1717-1G-A/N1303K (n = 1), F508del/ unknown mutation (n = 4), and unknown mutation/unknown mutation (n = 1). Inclusion criteria comprised the willingness to participate in the study, exocrine pancreatic insufficiency (fecal elastase-1 concentration b 100 μg/g and the presence of steatorrhea), pulmonary exacerbation (demanding antibiotic therapy) and the presence of SIBO (based upon results of HMBT) [9,10]. Exclusion criteria comprised: antibiotic therapy (i.v. or p.os) six weeks prior to the test, liver cirrhosis, diabetes mellitus, oxygen dependency, the use of systemic corticosteroids, severe pulmonary exacerbation or any pulmonary complication. Glucose HMBT was performed after overnight fast. Patients were instructed not to eat or drink for at least 12 h before the test Table 1 Basic epidemiological and clinical data of cystic fibrosis patients (n = 26). Parameter
Range
Median (mean ± SEM)
Age (years) Body weight (Z-score) FEV1 (%) Fecal elastase-1 (μg/g) AlAT (U/l) GGTP (U/l)
12–32 − 2.42–0.78 54.4–112.4 BDL*–88 8–52 6–64
19 (20.8 ± 1.0) − 0.73 (− 0.70 ± 0.16) 81.2 (81.9 ± 2.6) 6 (10 ± 4) 23 (22.6 ± 2.0) 16 (18.4 ± 2.6)
*BDL — below detection limit.
419
and to avoid slowly digesting foods like beans and similar vegetables, brans or high-fiber cereals the day before the test. Patients were not allowed to smoke, sleep or exercise vigorously for at last 1 h before or at any time during the test. Every patient received glucose dissolved in water orally in a dose of 1.5 g/kg up to maximum 75 g. Breath samples were collected at baseline (fasting) and at 15, 30, 45, 60, 90, and 120 min after glucose ingestion. Samples were analyzed with QuinTron MicroLyser DP Plus (Quintron, USA). A positive HMBT was defined as a rise of ≥ 20 ppm hydrogen or ≥ 12 ppm methane over baseline during the test. In all enrolled CF subjects, 13C MTG-BT was performed to assess lipid digestion and absorption, before and after antibiotic therapy. Sixteen patients were treated intravenously with amikacin and ceftazidime, in respective doses: 20–35 mg/kg/24 h and 150– 250 mg/kg/24 h, remaining 10 subjects were given ciprofloxacin in a dose of 35–50 mg/kg/24 h (in latter two in proper divided doses) according to existing CF standards. The assignment of patients to treatment groups was based upon psychological and social aspects (patients' abilities and wills). Patients did not differ in terms of their clinical status. The assignment of patients to treatment groups was based on sputum culture with bacterial sensitivity tests and psychological/social aspects (i.e. willingness/ permission for hospitalization). Patients did not differ significantly in terms of the nature of pulmonary exacerbations. 13 C MTG-BT was performed after overnight fast. Each of the studied subjects received 150 mg 13C mixed triglyceride with 0.25 g butter per kg body weight 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 min after test meal ingestion. The samples were analyzed with IRIS 13 C-Analyser System (Wagner, Bremen, Germany). CPDR was considered to reflect digestion and absorption of lipids. In healthy non-CF individuals it should be higher than 14.5%. Values are expressed as ranges, means (± SEM) and medians. The differences in CPDR before and after antibiotic therapy were determined with the use of Wilcoxon-rank test. The effectiveness of antibiotic therapy in curing SIBO was assessed using Fisher test. The level of significance was set at p b 0.05. The protocol of the investigation was approved by Ethical Committee of Poznań University of Medical Sciences, Poland.
3. Results Antibiotic therapy resulted in a significant reduction of hydrogen/methane production in both treated groups (p b 0.005 and p b 0.0015 for oral and intravenous therapy, respectively) as shown in Fig. 1A–B. The cure of SIBO was achieved respectively in 9 (90%) and 7 (43.8%) patients treated orally and intravenously, being more effective in the latter group (p b 0.037). The results of 13C MTG-BT have been presented in Table 2. The values of CPDR changed significantly in the subgroup receiving antibiotics orally (p b 0.019). In the subgroup receiving intravenously the tendency towards the improvement (p b 0.109) was observed.
420
A. Lisowska et al. / Journal of Cystic Fibrosis 10 (2011) 418–421
Hydrogen/methane* expiration (ppm)
A
40 35 30 25 20 15
Before
10
After
5 0
0
15
30
45
60
90
120
Minutes
Hydrogen/methane* expiration (ppm)
B
40 35 30 25 20 Before
15
After
10 5 0
0
15
30
45
60
90
120
Minutes
Fig. 1. A. Changes in mean values of hydrogen/methane expiration in CF patients receiving antibiotics orally. *The sum of hydrogen and doubled methane expiration has been given. B. Changes in mean values of hydrogen/ methane expiration in CF patients receiving antibiotics intravenously. *The sum of hydrogen and doubled methane expiration has been given.
4. Discussion We documented in the present study the positive influence of antibiotic therapy on fat assimilation in CF patients with SIBO. According to literature search it is the first study assessing such a relationship in a reliable way in humans. Reilly et al. attempted to assess the effect of an acute bronchopulmonary exacerbation on energy balance in a group Table 2 Lipid digestion and absorption in cystic fibrosis patients with small intestine bacterial overgrowth undergoing antibiotic therapy based upon cumulative 13C dose recovery (CDPR). Studied group (n) CF-IV ⁎⁎ (16) CF-PO ⁎⁎⁎ (10)
CPDR (%) Parameter
Before
After
Median Mean ± SEM Range Median Mean ± SEM Range
2.7 4.3 ± 1.5 BDL ⁎–20.2 3.6 4.5 ± 1.3 BDL ⁎–9.2
5.2 5.7 ± 0.8 1.8–11.4 7.2 6.9 ± 1.6 0.8–12.8
⁎ BDL — below detection limit. ⁎⁎ CF-IV — subjects receiving antibiotics intravenously. ⁎⁎⁎ CF-PO — subjects receiving antibiotics orally.
Statistical significance 0.109
0.019
of 14 CF children [11]. Since the relationship between timing of food intake and stool collection as well as between stable period and exacerbation was not clear, the obtained results raise some doubts. The data on the effectiveness of fat digestion and absorption as measured by the coefficient of fat absorption (CFA) were available in 10 out of 14 studied subjects. CFA improved during exacerbation in 7 subjects and worsened in 1 patient. However, no significant effect was observed. We have conducted a similar study assessing the influence of antibiotic therapy on fat assimilation with the use of reliable stable isotope breath test. The strict criteria of timing were used, the test was conducted directly before and after antibiotic therapy. Norkina et al. proved that intestinal bacterial overgrowth is related to intestinal inflammation and failure in thrive in the CF mouse model [6]. Significant CF mice weight gain at the end of a 3-weeks antibiotic treatment (ciprofloxacin and metronidazole) was observed. Having in mind this effect we aimed previously to assess the significance of SIBO for CF human lipid assimilation. We did not observe any differences between subjects with and without SIBO [8]. In a subsequent study, antibiotic therapy applied in non-selected CF patients resulted in the tendency towards the improvement of CPDR (p b 0.100). However, the effects observed in subgroups receiving antibiotics either orally or intravenously were less evident (p b 0.167 and p b 0.327, respectively). Therefore, we planned in the present study to determine fecal fat assimilation before and after antibiotic treatment exclusively in CF patients with documented SIBO [12]. Considering limited sensitivity and specificity of breath test for the detection of SIBO, we used very strict criteria including exclusively patients with a significant increase of hydrogen and or methane exhalation after glucose loading. We documented in the present study significant changes of CPDR due to oral antibiotic therapy with ciprofloxacin. Although significant improvement of fat digestion and absorption as measured by 13C MTG-BT was observed, the effects of antibiotic therapy were minor. The relationship documented in animal model does not seem to be so clear in humans [7]. Clinical significance of SIBO for lipid digestion and absorption in CF patients demands further studies. In conclusion, oral antibiotic therapy applied in CF patients with small intestine bacterial overgrowth in the course of pulmonary exacerbation results in statistically significant improvement of fat digestion and absorption. References [1] Lewindon PJ, Robb TA, Moore DJ, Davidson GP, Martin AJ. Bowel dysfunction in cystic fibrosis: importance of breath testing. J Pediatr Child Health 1998;34:79–82. [2] Fridge JL, Conrad C, Gerson L, Castillo RO, Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr 2007;44:212–8. [3] Di Stefano M, Miceli E, Missanelli A, Corazza GR. Treatment of small intestine bacterial overgrowth. Eur Rev Med Pharmacol Sci 2005;9:217–22. [4] Borowitz D, Durie PR, Clarke LL, Werlin SL, Taylor CJ, Semler J, et al. Gastrointestinal outcomes and confounders in cystic fibrosis. J Pediatr Gastroenterol Nutr 2005;41:273–85. [5] Gregg CR. Enteric bacterial flora and bacterial overgrowth syndrome. Semin Gastrointest Dis 2002;13:200–9.
A. Lisowska et al. / Journal of Cystic Fibrosis 10 (2011) 418–421 [6] Norkina O, Kaur S, Ziemer D, De Lisle RC. Inflammation of the cystic fibrosis mouse small intestine. Am J Physiol Gastrointest Liver Physiol 2004;286:G1032–41. [7] Norkina O, Burnett DG, De Lisle RC. Bacterial overgrowth in cystic fibrosis transmembrane conductance regulator null mouse small intestine. Infect Immun 2004;72:6040–9. [8] Lisowska A, Pogorzelski A, Oracz G, Skorupa W, Cofta S, Socha J, et al. Small intestine bacterial overgrowth and fat digestion and absorption in cystic fibrosis patients. Acta Sci Pol Technol Aliment 2010;9:477–83. [9] Walkowiak J, Nousia-Arvanitakis S, Henker J, Stern M, Sinaasappel M, Dodge JA. Indirect pancreatic function tests in children. J Pediatr Gastroenterol Nutr 2005;40:107–14.
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[10] Walkowiak J. Assessment of maldigestion in cystic fibrosis. J Pediatr 2004;145:285–7. [11] Reilly JJ, Evans TJ, Wilkinson J, Paton JY. Adequacy of clinical formulae for estimation of energy requirements in children with cystic fibrosis. Arch Dis Child 1999;81:120–4. [12] Lisowska A, Pogorzelski A, Oracz G, Skorupa W, Cofta S, Szydłowski J, et al. No major effect of antibiotic therapy on fat digestion and absorption in cystic fibrosis. Acta Biochim Pol, PMID: 21738905 [2011 Jul 7, Electronic publication ahead of print].