This study was directed to evaluate the role of sparfloxacin and pentoxifylline in the prophylaxis of spontaneous bacterial peritonitis in cirrhotic patients. Forty cirrhotic patients with ascites were included in the study. Patients were randomized into four groups in a blind fashion; each group consists of ten patients. Group one received ciprofloxacin (control group), group two received sparfloxacin, group three received pentoxifylline, and group four received a combination of sparfloxacin and pentoxifylline. Treatment duration was six months. Serum TNF-α level was the primary inflammatory marker of the study to evaluate the effect of the used medications. In group two, TNF-α level showed a statistically significant decrease in comparison with group one ( ), while in group three, TNF-α level showed nonsignificant difference in comparison with the control group ( ). In addition, group four showed a statistically significant decrease in TNF-α level compared to the other three groups ( ). The finding from our study indicates that sparfloxacin as well as pentoxifylline could be used in prophylaxis of spontaneous bacterial peritonitis. Combination of sparfloxacin and pentoxifylline showed some of synergism which may be useful in decreasing emergence of resistant strains. 1. Introduction Spontaneous bacterial peritonitis (SBP) is a common and severe complication of cirrhotic patients having ascites with a prevalence rate between 10 and 30% characterized by spontaneous infection of ascitic fluid which occurs in the absence of any infection or perforation of intra-abdominal organs [1]. Approximately 20% of patients are already infected at the time of admission and nearly 50% develop an infection during hospitalization [2]. Patients with the greatest risk for the development of SBP are those who have recovered from the first episode. In these patients, the recurrence rate is very high; the probability of developing a new episode of SBP ranges from 40% to 70% within the first-year followup [3, 4]. SBP is now associated with in-hospital mortality rates ranging from 20% to 40% [5]. Furthermore, mortality rates one and two years after an episode of SBP are reported to be 50–70% and 70–75%, respectively [6]. However, mortality after SBP is improved owing to early diagnosis and prompt treatment with empiric antibiotics. Bacterial translocation (BT) and migration of viable microorganisms from the intestinal lumen to the mesenteric lymph nodes and other extraintestinal sites have been postulated as the main mechanism in the pathogenesis of SBP [7–9]. Translocation of
References
[1]
A. Rimola and M. Navasa, “Infections in liver disease,” in Oxford Textbook of Clinical Hepatology, J. Bircher, J. P. Benhamou, N. McIntyre, M. Rizzetto, and J. Rode’s, Eds., pp. 1861–1876, Oxford University Press, Oxford, UK, 2nd edition, 1999.
[2]
J. Lata, O. Stiburek, and M. Kopacova, “Spontaneous bacterial peritonitis: a severe complication of liver cirrhosis,” World Journal of Gastroenterology, vol. 15, no. 44, pp. 5505–5510, 2009.
[3]
B. A. Runyon, “Spontaneous bacterial peritonitis: an explosion of information,” Hepatology, vol. 8, no. 1, pp. 171–175, 1988.
[4]
L. Titó, A. Rimola, P. Gines, J. Llach, V. Arroyo, and J. Rodes, “Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors,” Hepatology, vol. 8, no. 1, pp. 27–31, 1988.
[5]
P. J. Thuluvath, S. Morss, and R. Thompson, “Spontaneous bacterial peritonitis—in-hospital mortality, predictors of survival, and health care costs from 1988 to 1998,” The American Journal of Gastroenterology, vol. 96, no. 4, pp. 1232–1236, 2001.
[6]
A. Rimola, G. García-Tsao, M. Navasa et al., “Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document,” Journal of Hepatology, vol. 32, no. 1, pp. 142–153, 2000.
[7]
C. Guarner and G. Soriano, “Bacterial translocation and its consequences in patients with cirrhosis,” European Journal of Gastroenterology and Hepatology, vol. 17, no. 1, pp. 27–31, 2005.
[8]
R. D. Berg and A. W. Garlington, “Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model,” Infection and Immunity, vol. 23, no. 2, pp. 403–411, 1979.
[9]
B. A. Runyon, S. Squier, and M. Borzio, “Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis,” Journal of Hepatology, vol. 21, no. 5, pp. 792–796, 1994.
[10]
J. Fernández, M. Navasa, J. Gómez et al., “Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis,” Hepatology, vol. 35, no. 1, pp. 140–148, 2002.
[11]
P. Ginès, P. Angeli, K. Lenz et al., “EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis,” Journal of Hepatology, vol. 53, no. 3, pp. 397–417, 2010.
[12]
E. Pestova, J. J. Millichap, G. A. Noskin, and L. R. Peterson, “Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones,” Journal of Antimicrobial Chemotherapy, vol. 45, no. 5, pp. 583–590, 2000.
[13]
D. C. Hooper, “Mechanisms of action and resistance of older and newer fluoroquinolones,” Clinical Infectious Diseases, vol. 31, supplement 2, pp. S24–S28, 2000.
[14]
H. Harada, A. Ishizaka, M. Yonemaru et al., “The effects of aminophylline and pentoxifylline on multiple organ damage after Escherichia coli sepsis,” The American Review of Respiratory Disease, vol. 140, no. 4, pp. 974–980, 1989.
[15]
G. E. Chalkiadakis, A. Kostakis, P. E. Karayannacos, et al., “Pentoxifylline in the treatment of experimental peritonitis in rats,” Archives of Surgery, vol. 120, no. 10, pp. 1141–1144, 1985.
[16]
M. M. Schonharting and U. F. Schade, “The effect of pentoxifylline in septic shock—new pharmacologic aspects of an established drug,” Journal of Medicine, vol. 20, no. 1, pp. 97–105, 1989.
[17]
D.-Z. Xu, Q. Lu, R. Kubicka, and E. A. Deitch, “The effect of hypoxia/reoxygenation on the cellular function of intestinal epithelial cells,” The Journal of Trauma: Injury, Infection and Critical Care, vol. 46, no. 2, pp. 280–285, 1999.
[18]
F. Corradi, C. Brusasco, J. Fernández et al., “Effects of pentoxifylline on intestinal bacterial overgrowth, bacterial translocation and spontaneous bacterial peritonitis in cirrhotic rats with ascites,” Digestive and Liver Disease, vol. 44, no. 3, pp. 239–244, 2012.
[19]
R. N. H. Pugh, I. M. Murray-Lyon, and J. L. Dawson, “Transection of the oesophagus for bleeding oesophageal varices,” The British Journal of Surgery, vol. 60, no. 8, pp. 646–649, 1973.
[20]
H. U. Bergmeyer, M. H？rder, and R. Rej, “International Federation of Clinical Chemistry (IFCC) scientific committee, analytical section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 2. IFCC method for aspartate aminotransferase (L-aspartate: 2-oxoglutarate aminotransferase, EC 2.6.1.1),” Journal of Clinical Chemistry and Clinical Biochemistry, vol. 24, no. 7, pp. 497–510, 1986.
[21]
H. U. Bergmeyer, M. Horder, and R. Rej, “International Federation of Clinical Chemistry (IFCC) scientific committee, analytical section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 3. IFCC method for alanine aminotransferase (L-alanine: 2-oxoglutarate aminotransferase, EC 2.6.1.2),” Journal of Clinical Chemistry and Clinical Biochemistry, vol. 24, no. 7, pp. 481–495, 1986.
[22]
B. T. Doumas, P. P. Kwok-Cheung, and B. W. Perry, “Candidate reference method for determination of total bilirubin in serum: development and validation,” Clinical Chemistry, vol. 31, no. 11, pp. 1779–1789, 1985.
[23]
B. T. Doumas, W. A. Watson, and H. G. Biggs, “Albumin standards and the measurement of serum albumin with bromcresol green,” Clinica Chimica Acta, vol. 31, no. 1, pp. 87–96, 1971.
[24]
A. J. Quick, “Quick on “Quick agglutination venostasis” bleeding time technique,” The Journal of Laboratory and Clinical Medicine, vol. 26, article 1812, 1973.
[25]
A. J. Taylor and P. Vadgama, “Analytical reviews in clinical biochemistry: the estimation of urea,” Annals of Clinical Biochemistry, vol. 29, no. 3, pp. 245–264, 1992.
[26]
K. Spencer, “Analytical reviews in clinical biochemistry: the estimation of creatinine,” Annals of Clinical Biochemistry, vol. 23, no. 1, pp. 1–25, 1986.
[27]
R. F. Henry, D. C. Cannon, and J. W. Winklemen, Clinical Chemistry: Principles and Techniques, Harper and Row, Hagerstown, Md, USA, 2nd edition, 1974.
[28]
G. Goldman, D. Soffer, L. Heller, D. Aderka, A. Lahat, and J. M. Klausner, “Tumour necrosis factor mediates bacterial translocation after haemorrhagic shock and endotoxaemia,” European Journal of Surgery, vol. 167, no. 4, pp. 299–304, 2001.
[29]
J. Fernández, M. Navasa, J. Gómez et al., “Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis,” Hepatology, vol. 35, no. 1, pp. 140–148, 2002.
[30]
E. Cholongitas, G. V. Papatheodoridis, A. Lahanas, A. Xanthaki, C. Kontou-Kastellanou, and A. J. Archimandritis, “Increasing frequency of Gram-positive bacteria in spontaneous bacterial peritonitis,” Liver International, vol. 25, no. 1, pp. 57–61, 2005.
[31]
S. Saleh, M. Mohammad, S. Mashallah, et al., “Inhibition of DPP IV is a suggested mechanism of the immunomodulatory effects of sparfloxacin,” Scientific Research and Essays, vol. 7, no. 3, pp. 310–317, 2012.
[32]
Y. Matsunaga, H. Miyazaki, N. Nomura, and M. Hashimoto, “Disposition and metabolism of [14C]sparfloxacin after repeated administration in the rat,” Arzneimittel-Forschung, vol. 41, no. 7, pp. 760–763, 1991.
[33]
M. Nadai, Y. L. Zhao, L. Wang et al., “Endotoxin impairs biliary transport of sparfloxacin and its glucuronide in rats,” European Journal of Pharmacology, vol. 432, no. 1, pp. 99–105, 2001.
[34]
G. A. P. Nieuwenhuijzen, Y. Haskel, Q. Lu et al., “Macrophage elimination increases bacterial translocation and gut-origin septicemia but attenuates symptoms and mortality rate in a model of systemic inflammation,” Annals of Surgery, vol. 218, no. 6, pp. 791–799, 1993.
[35]
J. V. Reynolds, P. Murchan, H. P. Redmond et al., “Failure of macrophage activation in experimental obstructive jaundice: association with bacterial translocation,” The British Journal of Surgery, vol. 82, no. 4, pp. 534–538, 1995.
[36]
X. Wang, R. Andersson, V. Soltesz, P. Leveau, and I. Ihse, “Gut origin sepsis, macrophage function, and oxygen extraction associated with acute pancreatitis in the rat,” World Journal of Surgery, vol. 20, no. 3, pp. 299–308, 1996.
[37]
K. Josaki, J. Contrino, J. Kristie, P. Krause, and D. L. Kreutzer, “Pentoxifylline-induced modulation of human leukocyte function in vitro,” The American Journal of Pathology, vol. 136, no. 3, pp. 623–630, 1990.
[38]
P. J. Krause, J. Kristie, W.-P. Wang et al., “Pentoxifylline enhancement of defective neutrophil function and host defense in neonatal mice,” The American Journal of Pathology, vol. 129, no. 2, pp. 217–222, 1987.
[39]
C. Wenisch, K. Zedtwitz-Liebenstein, B. Parschalk, and W. Graninger, “Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability assessed by flow cytometry,” Clinical Drug Investigation, vol. 13, no. 2, pp. 99–104, 1997.
[40]
U. F. Schade, “Pentoxifylline increases survival in murine endotoxin shock and decreases formation of tumor necrosis factor,” Circulatory Shock, vol. 31, no. 2, pp. 171–181, 1990.
[41]
S. Heller, K. Weber, A. Heller, R. Urbaschek, and T. Koch, “Pentoxifylline improves bacterial clearance during hemorrhage and endotoxemia,” Critical Care Medicine, vol. 27, no. 4, pp. 756–763, 1999.
[42]
V. K. Shukla, A. K. Ojha, M. Pandey, and B. L. Pandey, “Pentoxifylline in perforated peritonitis: results of a randomised, placebo controlled trial,” European Journal of Surgery, vol. 167, no. 8, pp. 622–624, 2001.
[43]
D. Lebrec, D. Thabut, F. Oberti et al., “Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis,” Gastroenterology, vol. 138, no. 5, pp. 1755–1762, 2010.
[44]
E. Ernst, “Pentoxifylline for intermittent claudication—a critical review,” Angiology, vol. 45, no. 5, pp. 339–345, 1994.
[45]
E. Akriviadis, R. Botla, W. Briggs, S. Han, T. Reynolds, and O. Shakil, “Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial,” Gastroenterology, vol. 119, no. 6, pp. 1637–1648, 2000.
[46]
J. Han, P. Thompson, and B. Beutler, “Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway,” The Journal of Experimental Medicine, vol. 172, no. 1, pp. 391–394, 1990.
[47]
M. Navasa, A. Follo, X. Filella et al., “Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality,” Hepatology, vol. 27, no. 5, pp. 1227–1232, 1998.
[48]
A. Cooper, A. Mikhail, M. W. Lethbridge, D. M. Kemeny, and I. C. Macdougall, “Pentoxifylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure,” Journal of the American Society of Nephrology, vol. 15, no. 7, pp. 1877–1882, 2004.
[49]
A. Rames, J.-M. Poirier, F. LeCoz et al., “Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients,” Clinical Pharmacology and Therapeutics, vol. 47, no. 3, pp. 354–359, 1990.
[50]
P. Neuner, G. Klosner, E. Schauer et al., “Pentoxifylline in vivo down-regulates the release of IL-1β, IL-6, IL-8 and tumour necrosis factor-α by human peripheral blood mononuclear cells,” Immunology, vol. 83, no. 2, pp. 262–267, 1994.
[51]
F. Corradi, J. Fernandez, M. Navasa, et al., “Pentoxifylline prevents Small Intestinal Bacterial Overgrowth (SIBO), Bacterial Translocation (BT), and Spontaneous Bacterial Peritonitis (SBP) in experimental cirrhosis,” Journal of Hepatology, vol. 40, supplement 1, p. 14, 2004.
[52]
S. Bailly, M. Fay, Y. Roche, and M. A. Gougerot-Pocidalo, “Effects of quinolones on tumor necrosis factor production by human monocytes,” International Journal of Immunopharmacology, vol. 12, no. 1, pp. 31–36, 1990.
