Oral Levofloxacin Versus Intravenous Cefotaxime in the Treatment of Patients with Spontaneous Bacterial Peritonitis: A Randomized Controlled Trial

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1 Med. J. Cairo Univ., Vol. 80, No. 2, December: 71-78, Oral Levofloxacin Versus Intravenous Cefotaxime in the Treatment of Patients with Spontaneous Bacterial Peritonitis: A Randomized Controlled Trial HAMDY M. MOUSTAFA, M.D.*; MOHAMED B. BASTTAWEY, M.D.**; KHALED A. EID, M.D.*** and MONA M. ABDEL MEGUID, M.D.**** The Departments of Hepatology and Gastroenterology*,**,*** Faculty of Medicine, Al-Azhar University Assiut*,***, Al-Azhar University, Cairo** & Clinical Pathology****, Qena Faculty of Medicine, South Valley University, Qena Abstract Objectives : Spontaneous bacterial peritonitis is a frequent complication in patients with liver cirrhosis and ascites. Intravenous Cefotaxime is a reasonable choice for suspected SBP but certain oral agents as oral oftoxacin, 400mg twice daily may be as effective as parenteral therapy. Aim of the Work : To compare the therapeutic and cost effectiveness of oral levofloxacin 750mg once daily versus intravenous cefotaxime 2gm/8h in the treatment of cirrhotic patients with SBP. Patients and Methods : 80 patients with decompensated chronic liver diseases and ascites confirmed to have SBP were enrolled in this study. Patients were randomized into two groups; each group consists of 40 patients. Group 1 treated with cefotaxime 2gm i.v/8h for 5 days and Group 2 treated with levofloxacin 750mg orally once daily also for 5 days. All patients were subjected to: Liver profile, serological tests for viral markers, abdominal ultrasound, modified Child's Pugh score, and ascitic fluid analysis (chemical, microscopical & microbiological) at baseline, after 48 hours and at the end from the start of treatment. Results : The baseline ascitic PML of group I was 640 cells/ml 3 and of group II was 655 cells/ml 3. The PML count was markedly decreased after 48 hours and after 5 days of treatment compared to the baseline count in both groups (p<0.001). Negative growth was found in 67.5% of the total patients, 70% of group I, and 65% of group II whereas positive growth was found in 32.5% of the total patients, 30% of group I, and 35% of group II. In group I, the number of negative growth increased from 28 before to 35 after treatment with no significant difference ( p>) and the positive ascitic fluid cultures were decreased from 12 to 5 after treatment also with no significant difference ( p>) while in group II, the number of negative growth were significantly increased from 26 before to 36 after treatment ( p<) and the positive ascitic fluid cultures were significantly decreased from 14 Correspondence to: Dr. Mona M. Abdel Meguid, The Department of Clinical Pathology, Qena Faculty of Medicine, South Valley University, Qena before to 4 after treatment ( p<). 7 cases in group I and 6 cases in group II failed to respond to treatment. Infection resolution occurred in 33 (82.5%) patients in group I and in 34 (85%) patients in group II. Conclusion: Oral levofloxacin is comparable to i.v. cefotaxime in the treatment of SBP. Oral levofloxacin is also cheeper than i.v. cefotaxime, and the oral route and single daily dose is more convenient to the patient than intravenous route. Key Words: Levofloxacin Cefotaxime Bacterial peritonitis Randomized Controlled trial. Introduction SPONTANEOUS Bacterial Peritonitis (SBP) is characterized by infection of the ascitic fluid in the absence of any primary focus of intra-abdominal infect on [1]. Spontaneous bacterial peritonitis is a frequent complication in patients with liver cirrhosis and ascites and associated with significant morbidity and mortality rate that approaches 100% if untreated [2]. Most cases of SBP are due to gut bacteria, such as Escherichia coli and Klebsiella; however, streptococcal and, infrequently, staphylococcal infections can also occur [3]. Cefotaxime or a similar third-generation cephalosporin, are a reasonable choice for suspected SBP. Nephrotoxic antibiotics should specifically be avoided because the under-perfused kidneys in cirrhosis tend to be exquisitely sensitive [4]. Certain oral agents (oral oftoxacin, 400mg twice daily) [5] and (oral ciprofloxacin) [6] may be as effective as parenteral therapy in the treatment of uncomplicated SBP. Levofloxacin is a fouroquinolone with a broad spectrum covering most of enterobacteriaceae, pseudomonas aeroginosa and some gram positive bacteria [7]. 71

2 72 Oral Levofloxacin Versus Intravenous Cefotaxime Our aim is to compare the therapeutic and cost effectiveness of oral levofloxacin 750mg once daily versus intravenous cefotaxime 2gm/8h in the treatment of cirrhotic patients with spontaneous bacterial peritonitis. Patients and Methods This study was conducted on 80 patients with decompensated chronic liver disease with SBP admitted to Hepatology, Gastroenterology and Infectious Diseases Departments in Al-Hussein and Sayed Galal University Hospitals from February 2011 to November The study was approved by Ethical Research Committee of the Hospital, informed consent was obtained from all participants who met the eligibility criteria. Inclusion criteria: Patients with decompensated chronic liver diseases and ascites confirmed to have SBP (more than 250 PML/ml of ascitic fluid +/- positive ascitic fluid culture). Exclusion criteria : a- Patients with evidence of secondary bacterial peritonitis, tuberculous peritonitis or malignant ascites. b- Patients with other causes of ascites e.g. cardiac or renal diseases. c- Patients received antibiotics ten days prior to the hospital admission. d- Pregnant or lactating ladies. e- Patients younger than 18 year old. f- Patients with hypersensitivity to the prescribed antibiotic. All patients were subjected to the following : I- Thorough history taking with particular attention to: Manifestations of liver cell failure, history of previous attack of SBP, history of possible complications and history of iatrogenic procedures (cannula or catheter). II- Full general and local examination, looking for: signs of chronic liver disease and signs of SBP. III- Other investigations include : Liver profile: (Total and direct bilrubin, serum AST, ALT, ALP, total proteins, serum albumin and prothrombin profile). Serological tests for viral markers: (HBS-Ag, HCV-Abs), by ELISA technique. Abdominal ultrasonography: By using (ALO- CA) device, abdominal probe (3.5MHz). Ultrasonographic evaluation included: Liver, spleen, ascitic fluid, gall bladder and kidneys. Modified Child's Pugh score was calculated for all patients [8]. Diagnostic abdominal paracentesis: Thirty ml of ascitic fluid were aspirated from every patient under strict aseptic conditions then it was divided into 3 samples. The first sample (5ml) was for chemistry examination (Lactate dehydrogenase, total protein, albumin and glucose). The second sample (15ml) was for bacteriological examination (Gram stain, Leishman stain, Ziehl Neelsen, neutrophil count, culture for both aerobic and anaerobic organisms and their antibiotic sensitivity). Culture was done by inoculating 10ml of ascitic fluid in (BD BACTEC) blood culture bottle at the bedside. The third sample (1 0ml) was for cytological examination to exclude malignant cells. IV- Follow-up: Paracentesis was repeated for every patient 2 days after starting treatment and at the end of the course of the treatment. Patients were randomized by random assignment into two groups; each group consists of 40 patients: comprised of 40 cirrhotic patients with SBP receiving cefotaxime 2 gm i.v/8 h for 5 days and their sexes and ages were matched with group II which comprised of 40 cirrhotic patients with SBP receiving levofloxacin 750mg orally once daily [9] for 5 days. Treatment failure was considered when the condition of the patients rapidly deteriorated within the first hours of the antibiotic therapy (i.e. with development of shock), or when no significant decrease in the ascitic PMN count was observed in the follow-up paracentesis. A reduction in the PMN count of less than 25% as compared with the pre-treatment value was considered as suggestive of failure of the antibiotic treatment [10]. We modify antibiotic therapy for these patients according to in vitro susceptibility of isolated organisms. Infection resolution was defined as ascitic PMN leukocyte count <250/mm 3 and/or negative culture [5]. Statistical methodology : The collected data were analyzed using SPSS program (Statistical Package for Social Sciences) software version Descriptive statistics were done for numerical parametric data as mean, standard deviation and minimum & maximum of the range and for numerical non parametric data as median and 1 st & 3 rd inter-quartile range, while they were done for categorical data as number and

3 Hamdy M. Moustafa, et al. 73 percentage. Indeferential analyses were done for quantitative variables using independent t-test in cases of two independent groups with parametric data, Mann whiteny test in cases of two independent groups with non parametric data, Wilcoxon signed rank test in cases of two dependent groups with non-parametric data and Friedman's test for more than two dependent groups with non parametric data. Indeferential analyses were done for qualitative data using Chi square test for independent variables and Fisher s Exact test for independent variables with small expected numbers as well as McNemar test for dependent categorical data. The level of significance was taken at p-value <0.001 is highly significant, < is significant and > is insignificant. Results Patients were randomized by random assignment into two groups; each group consists of 40 patients: comprised of 40 cirrhotic patients with SBP receiving cefotaxime 2gm i.v/8h for 5 days and their sexes and ages were matched with group II which comprised of 40 cirrhotic patients with SBP receiving levofloxacin 750mg orally once daily for 5 days. Fourteen patients (17.5%) of the total patients (9 in group I & 5 in group II) were found to have history of previous hospitalization due to ascetic fluid infection, 9 patients (11.2%) (5 in group I & 4 in group II) had a recent history of iatrogenic procedures as (cannula or catheter), 44 patients (55%) (19 in group I & 25 in group II) had history of diagnostic or therapeutic paracentesis. This clinical history and examination were illustrated in (Table 1) and the Descriptive data of laboratory investigations for studied patients were illustrated in (Table 2). Most of the cirrhotic patients were hepatitis C antibody positive (Table 3). Ascitic fluid analysis : - Chemistry: In the total patients, the mean total protein was (1.9 ± 1.36mg/dl), mean LDH was (72.2±75.4 IU/L), mean glucose was ( ± 37.2mg/dl) and the mean SAAG was (1.2 ±0.085) (Table 2). - PML cell count: The baseline ascitic PML of group I was 640 cells/ml 3 and in group II was 655 cells/ml 3. The PML count was markedly decreased with highly statistically significant difference after 48 hours and after 5 days of treatment compared to the baseline count in both groups (Table 4). - Culture: Negative growth was found in 67.5% of the total patients (Table 5), 70% of group I, and 65% of group II (Table 7) whereas positive growth was found in 32.5% of the total patients (Table 5), most of them (46.2%) were E Coli (Table 6), 30% of group I and 35% of group II (20% were E Coli) (Table 7). In group I patients treated with iv cefotaxime, the number of negative growth increased from 28 before to 35 after treatment with no significant difference and the positive ascitic fluid cultures were decreased from 12 to 5 after treatment also with no significant difference while in group II patients treated with oral levofloxacin, the number of negative growth were significantly increased from 26 before to 36 after treatment and the positive ascitic fluid cultures were significantly decreased from 14 before to 4 after treatment (Table 7). According to the Modified Child-Turcotte-Pugh classification for cirrhosis, 69 patients (86.2%) of the total patients (63 patients in group I & 33 in group II) were found to be Child C, 11 patients (11.7%) were Child B (4 patients in group I & 7 in group II) whereas no patients were Child A (Table 8). Seven cases in group I and 6 cases in group II failed to respond to treatment (Table 9). Infection resolution (defined as ascites PML count <250 cells/mm 3 and culture negativity at the end of treatment) occurred in 33 (82.5%) patients in group I and in 34 (85%) patients in group II (Fig. 1). Table (1): History and clinical examination of total patients and both groups. Variables Prior history of ascetic fluid infections History of iatrogenic procedures History of diagnostic or therapeutic paracentesis Total patients (N=80) (N=40) I (N=40) N % N % N % Abdominal tenderness Rebound tenderness Hepatic Encephalopathy Fever Gastrointestinal bleeding Bleeding tendency Jaundice

4 74 Oral Levofloxacin Versus Intravenous Cefotaxime Table (2): Descriptive data of laboratory investigations for studied patients. Variables Total patients I Mean±SD Mean±SD Mean±SD Total leucoucytic count (x10 3 /µl) 9.2± ± ±5.87 Blood indices Hemoglobin (gm/dl) 10.06± ± ± 1.82 Platelet count (x10 3 /µl) 96.1± ± ±58.64 Erythrocyte sedimentation rate (mm/hr) 35.9± ± ±76.5 Liver function tests Total bilirubin (mg/dl) 4.7± ± ±4.4 ALT (IU/L) 31.1± ± ± 11.9 AST (IU/L) 34.32± ± ±9.2 Albumin (gm/dl) 2.05± ± ±0.3 Total proteins (gm/dl) 6.4± ± ±0.77 Coagulation profile Prothrombin time (second) 21.3± ± ±4.8 INR 1.98± ± ±8.69 Prothrombin concentration (%) 45.3± ± ±8.69 Kidney function tests BUN (mg/dl) 37.15± ± ±26.6 Creatinine (mg/dl) 1.76± ± ±0.59 Na (mmol/l) ± ± ±5.6 K (mmol/l) 3.98± ± ±0.8 Ascitic fluid chemistry Total Proteins (gm/dl) 1.9± ± ±2.38 LDH (U/L) 72.2± ± ±64.6 Glucose (mg/dl) ± ± ±26.17 SAAG 1.2± ± ±0.09 Table (3): Viral markers in total patients and both groups. Variable HCV Ab +ve HBs Ag +ve HCV Ab and HBs Ag -ve Total patients N=80 N=40 N % N % N % I N=40 Table (5): Number and percentage of negative and positive growth in total SBP patients Table (4): Ascitic PML count after 48 hours and after 5 days of treatment compared to the baseline count in both groups. Ascitic fluid PML Day 0 Day 2 Day 5 Reduction of PML between Day 0/2 Day 2/5 Day 0/2/5 Z^ IQR ( ) 60.0 (40-170) 35.0 ( ) IQR=Interquartile range. Z^=Wilcoxon test. p p<0.001* p<0.001* χ 2# =104 p<0.001* I IQR 655 ( ) 77.0 ( ) Z^ 50.0 ( ) p p<0.001* p<0.001* χ 2# =81 p<0.001* χ 2 # = Friedman test. Ascitic bacterial culture Total negative growth Total positive growth Total patients N=80 N % Table (6): Number and percentage of the isolated microorganisms in culture with positive growth. Organism Culture with positive growth No (26) % E-coli Gram negative Klebsiella pneumoniae Acinobacter Gram positive Staphylococcus epidermidis Streptococcus pneumoniae

5 Hamdy M. Moustafa, et al. 75 Table (7): Comparison between baseline ascitic fluid cultures of the studied groups. N=40 I N=40 Ascitic bacterial culture Before After Before After Treatment Treatment p-value Treatment Treatment p-value (N & %) (N & %) (N & %) (N & %) Negative growth 28 (70%) 35 (87.5%) 26 (65 %) 36 (90%) Gram negative E-coli Klebsiella pneumoniae Acinobacter 4 (10%) 3 (7.5%) 1 (2.5%) 8 (20%) Positive growth Gram positive Total positive culture Staphylococcus epidermidis Streptococcus pneumoniae 1 (2.5%) 12 (30%) 5 (7.5%) 14 (35%) 1 (2.5%) 1 (2.5%) 4 (10%) Table (8): Modified Child-Turcotte-Pugh classification in total patients and the studied groups. Total patients I Variable N=80 N=40 N= N % N % N % Child A Child B Child C Table (9): Comparison between the studied groups as regard Treatment failure along the course of treatment Treatment failure 0-48 hours 48 hr-5days p-value 5 (12.5%) N=7 (17.5%) I 1 (2.5%) 5 (12.5%) > N=6 (15%) p-value > > lnfection resolution I Fig. (1): Infection resolution in the studied groups at the end of treatment. Discussion The prevalence of spontaneous bacterial peritonitis of hospitalized patients ranges between 10% and 30% [9]. The older literature on spontaneous bacterial peritonitis reported that it was a commonly fatal complication [11]. The mortality rate has declined with the diagnostic and therapeutic improvement but mortality is still over 20%, mainly due to hepato-renal syndrome [12]. We had a good selection of our patients by exclusion of ascites due to causes other than portal hypertension as the mean SAAG ratio is (1.2g/dl) in total patients and both groups (Table 2). Fourteen out of 80 SBP patients (17.5%), in this study (Table 1), had previous attacks of SBP which is one of the risk factors for recurrence of infection [9]. This result is comparable to the 19.2% surviving patients of an episode of SBP observed by [13] but is much lower than that of [14] who found that more than 25% of hospitalized patients due to SBP had history of previous attack of SBP. History of paracentesis (diagnostic or therapeutic) was found in 55% of our patients (Table 1). Angeloni et al., (2008) [15] found that more than (50%) of patients had history of diagnostic or therapeutic paracentesis which alter the host defense barrier and predispose to ascetic fluid infection [16]. Since fever is recorded only in 42.5% of our patients and leukocytosis is rare; the identification of the infection of ascitic fluid is, therefore, based only on the result of the diagnostic paracentesis. A PMN cell count >250 cell/mm 3 has been proposed as the most important parameter for the diagnosis of SBP. The low proportion of positive ascitic fluid cultures in our study (32.5%) (Table

6 76 Oral Levofloxacin Versus Intravenous Cefotaxime 5) is probably due to the relatively low concentration of bacteria in the ascitic fluid as compared with the infections in other organic fluids (e.g. urine) [9]. For the same reason, a therapy based on the isolation of the responsible bacteria is seldom achievable and the antibiotic treatment cannot be delayed to the moment when microbiological results are available [10,17]. In this study, 67.5% of SBP patients had negative acetic fluid culture and only 32.5% had positive culture (Table 5). Low rates of positive SBP cultures have been reported in other studies, with proportions ranging from 39% to 59% [5] while the rest of cases were reported as culture negative neutrocytic ascites (CNNA) which is considered a variant of SBP with the same prognosis [18]. The Gram negative Escherichia coli account for 46.2% of the total SBP patients with positive growth which is the most common organism followed by Klebsiella species and acinobacter microorganisms (Table 6). Park et al., 2007 [19] found Escherichia coli in nearly 50% of all cases of SBP, and it is the most common Gram negative organism followed by Klebsiella species and other Gram negative bacteria. We found that Streptococcus pneumonia is the most common Gram positive organism followed by Staphylococcus epidermidis. This agrees with other studies [20,21] who found an increase in Gram positive bacteria in culture positive acitic fluid of SBP patiens. All the culture positive specimens were monomicrobial which agree with Parsi et al., 2007 [22] who found that more than 92% of all cases of SBP are monomicrobial, with aerobic Gram negative bacilli being responsible for more than two thirds of all cases. Early diagnosis and treatment is the gold standard approach in the management of patients with SBP [23]. The changes in the microbiological characteristics reported are impacting the choice of antibiotics used in the treatment. Cefotaxime has been the most extensively studied antibiotic for this infection. It was considered to be one of the first choice antibiotics because of its low toxicity and excellent efficacy [1]. Treatment of spontaneous bacterial peritonitis by intravenous cefotaxime should be administered for a minimum of 5 days [12]. Oral levofloxacin was comparable (in this study) to cefotaxime in the treatment of SBP (Table 7) as levofloxacin therapy significantly increased the number of culture negative cases from 65% before treatment to 90% after treatment and significantly reduced the number of culture positive cases from 35% before to 10% after treatment. It also significantly reduced the number of E. coli positive growth from 20% before to 5% after treatment (Table 7) while cefotaxime failed to do so. Yakar et al., 2010 [24] demonstrated that levofloxacin showed in vitro reasonable activity against E. coli (71%). In this study, there was no significant difference between both groups as regard treatment failure along the course of treatment, evaluated by failure to reduce the PMN count to less than 25% as compared with the pre-treatment values (Table 9). We switched the treatment of these patients to the prescribed antibiotics according to the culture and sensitivity of their acitic fluid [25]. The failure of cefotaxime is probably due to the fact that the isolated organisms were intrinsically resistant to cefotaxime (as enterococci) or capable of degrading the expanded-spectrum cephalosporins (as Extended spectrum B-lactamases (ESBL)-producing E. coli or Amp C ß-lactamase producing Enterobacter species) or bacteria with an inherent insufficient susceptibility to cefotaxime (as Staphylococcus aureus). Other explanation came from the fact that cirrhotic patients have frequent need of hospital assistance including outpatient visits, diagnostic invasive examinations, day-hospital admissions, which may facilitate contact with nosocomial antibiotic-resistant pathogens [15]. Levofloxacin was comparable to cefotaxime in bacteriological eradication (infection resolution) (85% versus 82.5%) (Fig. 1). This result can be better assessed by studying the efficacy of both drugs on a large scale. However, some authors [26] found that the levofloxacin bacteriological eradication was 100% while others [27] reported in their study that cefotaxime revealed bacteriologic cure of (91.2%). In the present study, we found that no significant difference between both groups as regard treatment failure after 48 hours of treatment, (5% in group I and 2.5% in group II) due to failure in the reduction in the PMN count of less than 25% as compared with the pre-treatment value. This reinforces with the need for changing antibiotic treatment according to culture and sensitivity tests of the acitic fluid as reported by Angeloni et al., 2008 [15]. Levofloxacin tablets may be orally administered (convenient oral route) without regard to meals with rapid and complete absorption and minimal

7 Hamdy M. Moustafa, et al. 77 hepatic metabolism. Its oral bioavailability is nearly 99% and the time to peak serum concentration is 1-2 hours. It is primarily eliminated through the renal route as unchanged drug and its half-life of elimination is 6-8 hours [7]. Levofloxacin is cheaper than cefotaxime as the cost of intravenous cefotaxime was six times higher than the oral therapy of levofloxacin. We concluded that oral levofloxacin is comparable to i.v. cefotaxime. Oral Levofloxacin is cheaper than i.v. cefotaxime, where the cost of intravenous cefotaxime was six times higher than the oral therapy of levofloxacin. The oral route and single daily dose of Levofloxacin is a convenient mean of therapy so, Levofloxacin is recommended for the treatment of uncomplicated Spontaneous Bacterial Peritonitis. References 1- OZMEN S., DURSUN M. and YILMAZ S.: Spontaneous bacterial peritonitis: Pathogensis, diagnosis, and anagement. Acta. Gastroenterol. 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