This prospective study was conducted at the Tropical Medicine Department, Zagazig University Hospitals, Zagazig, Sharkia Governorate, Egypt during the period from October 2010 to October 2011. This study was approved by the Ethical committee of our institution. Written informed consents were obtained from all patients. For patients with any grade of hepatic encephalopathy, the written informed consents were obtained from the first degree relatives.

All patients were inpatients and underwent diagnostic abdominal paracentesis with a differential leucocyte count, microbiological culture, and biochemical analysis at admission. Cefotaxime sodium 2 g/12 h (iv) was used as the initial empirical therapy because it is supported by the current guidelines as the first line of therapy for SBP[2]. It was subsequently maintained or replaced depending on the clinical course, a second abdominal paracentesis with PMNL count, and the in vitro susceptibility of the isolated microorganisms, up to a planned period of 5-7 d in a hospitalized basis.

After 48 h, a second abdominal paracentesis was done; cases with < 25% reduction in PMNL count were considered resistant to cefotaxime and were then randomly assigned to receive either meropenem 1 g/8 h (iv) or levofloxacin 1 g/12 h (iv drip). They were randomized by matching the sample (resistant group) and were classified into matched pairs; one from each pair was randomly enrolled into either the meropenem subgroup or the levofloxacin subgroup. One patient who was initially assigned to the levofloxacin subgroup was moved to the meropenem subgroup due to drug availability at the time of therapy. The final number was 11 patients in the meropenem subgroup and 8 in the levofloxacin subgroup.

The choice of these antibiotics was not only a matter of availability but also mainly due to previous reports of activity against bacterial species causing SBP[6,7] both in vitro[8] and in vivo[9] at national[10] and international[11] levels.

Five days after initiation of alternative antibiotic therapy an end of treatment diagnostic abdominal paracentesis was performed; cases with < 25% reduction in PMNL count from the second puncture counts were treated according to the results of in vitro culture and sensitivity that were available. All cases with initially positive ascitic fluid culture were re-cultured. Intravenous expansion was performed with human albumin 20 g iv infusion at the time of diagnosis and after 48 h.

All patients underwent a final diagnostic paracentesis with a differential leucocyte count at the end of therapy. The antibiotic dosage was adjusted to renal function throughout the treatment period. Diuretics were routinely discontinued at the time of diagnosis of SBP and therapeutic paracentesis was not allowed during the study.

All patients were subjected to history taking, complete clinical examination, laboratory tests (including a complete blood cell count, prothrombin time, biochemical tests of liver and kidney function, and fresh urine sediment), chest x-ray film, a diagnostic abdominal paracentesis, and the sample was subjected to total and differential cell count, chemical examination, aerobic and anaerobic culture. These were performed in all the cirrhotic patients with ascites on the day of admission and whenever they developed symptoms and signs suspicious for SBP (i.e., fever, change in mental status, abdominal pain, development of renal failure, hypotension, etc.) during the hospitalization period.

The ascitic fluid samples were collected under aseptic conditions in tubes containing ethylenediamine tetraacetic acid anticoagulant and then tested to determine white blood cell and PMNL counts by automated cell blood counter; chemical analysis for glucose, lactate dehydrogenase (LDH) and total protein were also done. All the specimens were analyzed within one hour. Moreover, 10 mL of ascitic fluid was inoculated directly at the patient’s bedside into aerobic and anaerobic blood culture bottles for bacteriological examination.

Ascitic fluid cultures were performed at the time of the initial paracentesis in the blood culture bottles (Remaux, France) at the bedside. All were incubated aerobically and anaerobically at 37  °C for 2 d before a subculture was done. Cases were considered negative after 7 d. All initially positive cases were re-cultured and cases were considered resolved from infection when PMNLs count had dropped to < 250/mm³ and all culture cases were negative.

Cirrhosis: Cirrhosis diagnosed based on clinical, biochemical, histological and/or radiological findings and Child class was assessed for each patient.

SBP: SBP was defined as the presence of ≥ 250 PMNLs/mm³ in the ascitic fluid[2].

Resolution of SBP: Resolution of SBP was defined as reduction of the elevated ascitic fluid PMNL count to < 250/mm³, negative culture in previously positive cases with resolution of the clinical manifestations and normalization of the impaired renal function.

Resistance: Resistance to empiric therapy was considered when < 25% reduction in PMNL count from the base line was achieved after 48 h[2].

Exclusion criteria: (1) Non-cirrhotic ascites (including malignant ascites); (2) Cases with secondary bacterial peritonitis; and (3) Bacterascites (i.e., positive ascitic fluid culture with < 250 neutrophils/mm³).

Data were checked, entered and analyzed using SPSS Version 15. Data were expressed as mean ± SD for quantitative variables, number and percentage for qualitative ones. χ² or Fisher exact, t test and paired t test were used when appropriate. P < 0.05 was considered significant.

Baseline characteristics of patients are presented in Table 1. Age and gender were comparable in group I and group II. In group I, the numbers in Child class B and C were 21% and 79% while in group II they were 5.3% and 94.7%, respectively. This means that most cefotaxime resistance cases were associated with advanced liver disease.

Fever and abdominal pain were the most frequent manifestations and were reported in 82.7% and 94.7% of patients in group I and in 80.2% and 84.2% of patients in group II, respectively. Asymptomatic patients were found in 18.5% of the cefotaxime sensitive group, but all patients of the resistant group presented with symptoms and signs. Regarding the laboratory parameters (Table 2), patients in group II had a greater peripheral blood leucocyte response than group I.

Ascitic fluid culture was positive in only 32% of cases. There were 26 ascitic fluid culture positive cases within group I (out of 81); the isolated organisms were Escherichia coli (E. coli) in 13 (50%), Klebsiella in 7 (27%), Enterobacter, and Strep. viridans each in 2 (8%), Pneumococci and S. aureus each in 1 (4%) (Figure 1A). There were 6 ascitic fluid culture positive cases within group II (out of 19); the isolated organisms were E. coli in 2 (33%), Enterobacter, S. aureus, Enterococci and Acinetobacter each in one (16%) (Figure 1B).

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Figure 1 Isolated organisms in groups. A: Group I; B: Group II. E. coli: Escherichia coli.

Data for all patients are presented in Tables 2 and 3. Patients in group II had a more severe ascitic inflammatory response than group I and this was demonstrated by the more ascitic LDH and PMNL counts. In group I, apart from the significant reduction in PMNL count, none of the biochemical parameters showed significant changes at the end of therapy. In group II the meropenem subgroup had higher LDH and PMNL count at initiation of the alternative antibiotic therapy; there was no significant difference in the studied parameters between patients responsive to meropenem and levofloxacin at the end of therapy.

Cases were treated for a median of 5-12 d. Cases in group I (n = 81) were treated by cefotaxime for 5-7 d, while patients in group II were treated as follows: the meropenem subgroup was treated for 5 d, the levofloxacin subgroup was treated for 5 d, 2 cases who were resistant to levofloxacin were treated with vancomycin in one case and ampicillin/sulbactam in one case, according to the in vitro culture and sensitivity results, for further 5 d and were recultured and examined by an end of treatment ascitic PMNL count before being considered cured.

The clinical and laboratory parameters of group II patients showed no major improvement with the initial empirical therapy; whereas noticeable improvements in many of the parameters were achieved when the alterative antibiotic therapy was given. This was obvious in hepatic encephalopathy (HE) which was encountered in 30.9% of patients in group I and 63.2% of patients in group II (grade II-III HE), where an improvement of consciousness level was achieved after antibiotic treatment of SBP. All patients of group II, in spite of starting treatment of HE, showed no major improvement with cefotaxime, but improvement of consciousness level occurred after the resolution of SBP by the alternative antibiotic therapy.

Spontaneous bacterial peritonitis is infection of ascitic fluid in cirrhotic patients with high mortality rates. Cefotaxime has become the empiric antibiotic of choice for the treatment since 1985. Mortality rates reduced from 90% when cefotaxime was first described to around 20%-40%. Recent reports showed that resistance to third generation cephalosporins (including cefotaxime) is increasing and this may increase the need to develop alternative antibiotics.

Eradication of ascitic fluid infection is the goal of antibiotic therapy. This study confirmed the validity of cefotaxime as an empiric first line therapy for spontaneous bacterial peritonitis and identified meropenem as an effective alternative in cases of cefotaxime resistance.

Cefotaxime as the empiric first line therapy for spontaneous bacterial peritonitis is effective in 81% of cases. Meropenem is effective in 100% of cefotaxime-resistant cases, while levofloxacin is effective in 75% of cefotaxime-resistant cases.

This article emphasises the value of meropenem and levofloxacin as effective alternatives to cefotaxime in resistant cases.

Spontaneous bacterial peritonitis is infection of ascitic fluid in patients with cirrhosis; Cefotaxime (a third generation cephalosporin) is utilized primarily for its activity against Gram-negative aerobic organisms. The drug exhibits moderate activity against Gram-positive bacteria. Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a variety of infections. It is a beta lactam antibiotic and belongs to the subgroup of carbapenems; Levofloxacin is a synthetic chemotheraputic antibiotic which belongs to fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes.

The clinical study focused on the effect of cefotaxime as the empiric first line therapy for spontaneous bacterial peritonitis and effectiveness of meropenem and levofloxacin as alternatives in case of cefotaxime resistance. This will be useful for future planning of therapy and clinical application.