Spontaneous bacterial peritonitis: a historical perspective: Kerr DNS, Pearson DT, Read AE. Infection of ascitic fluid in patients with hepatic cirrhosis [Gut 1963; 4: 394–398]; Conn HO. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome [Ann Intern Med 1964; 60: 568–580]

Abstract

Spontaneous bacterial peritonitis (SBP) is an infection of ascites characteristic of the cirrhotic patient that occurs in the absence of a contiguous source of infection (e.g. intestinal perforation, intraabdominal abscess) and in the absence of an intra-abdominal inflammatory focus such as an abscess, acute pancreatitis or cholecystitis. The first reports describing this entity appeared in the German and French literatures between 1907 and 1958 [1Krencker E. Bacterium coli commune als Sepsiserreger in 2 fallen von abdominaler krankungen.Munchen Med Wschr. 1907; 54: 2095Google Scholar, 2Brule M. Hillemand P. Goutner B. Septicemie a colibacille et peritonite terminale chez une cirrhotique.Bull Soc Med Hop Paris. 1939; 63: 1167Google Scholar, 3Cachin M. Sur un syndrome ictero-ascitique avec colibacillemie.Rev Med Chir Mal Foie. 1955; 30: 5PubMed Google Scholar, 4Caroli J. Platteborse R. Septicemie porto-cave. Cirrhoses du foie et septicemie a colibacille.Sem Hop Paris. 1958; 34: 112-127Google Scholar], including an extensive French study by Caroli and Platteborse that reported 15 patients with E. coli bacteremia [[4]Caroli J. Platteborse R. Septicemie porto-cave. Cirrhoses du foie et septicemie a colibacille.Sem Hop Paris. 1958; 34: 112-127Google Scholar], five of whom had an associated peritonitis. In the English medical literature, the entity was first recognized in two papers that appeared almost simultaneously, a paper by Kerr et al. from the UK in 1963 [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar], describing 11 episodes of SBP in nine cirrhotic patients, and a paper by Conn from the US in 1964 [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar], describing six episodes of SBP in five cirrhotic patients. It was in the latter paper that the term ‘spontaneous bacterial peritonitis’ was first utilized. It is timely that a review of the current knowledge of the epidemiology, diagnosis, treatment, prevention and possible pathogenesis of SBP be reviewed to underline advances in the area and to identify future areas of research. In the Kerr et al. [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar] and Conn [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar] reports, cases of SBP had presented in a 4–5-year period, with a prevalence of around 7%. In later studies, the prevalence of SBP in cirrhotic patients with ascites was around 15% [[7]Garcia-Tsao G. Spontaneous bacterial peritonitis.Gastro Clin North Am. 1992; 21: 257-275PubMed Google Scholar]. In a recent large prospective series of hospitalized cirrhotic patients in a 2-year period, SBP was the most frequent (138 of 572 or 24%) of the bacterial infections present at admission or that developed during hospitalization [[8]Fernandez J. Navasa M. Gomez J. Colmenero J. Vila J. Arroyo V. et al.Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (745) Google Scholar]. It appears that the prevalence of SBP is much lower (3.5%) in asymptomatic outpatients undergoing therapeutic paracentesis and its outcome seems to be better than SBP occurring in hospitalized patients [[9]Evans L.T. Kim W.R. Poterucha J.J. Kamath P.S. Spontaneous bacterial peritonitis in asymptomatic outpatients with cirrhotic ascites.Hepatology. 2003; 37: 897-901Crossref PubMed Scopus (186) Google Scholar]. In prospective studies, the 12-month incidence of first episode of SBP in cirrhotic patients with ascites has ranged between 11% [[10]Llach J. Rimola A. Navasa M. Gines P. Salmeron J.M. Gines A. et al.Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.Hepatology. 1992; 16: 724-727Crossref PubMed Scopus (179) Google Scholar] and 29% [[11]Andreu M. Sola R. Sitges-Serra A. Alia C. Gallen M. Vila C. et al.Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites.Gastroenterology. 1993; 104: 1133-1138Abstract PubMed Google Scholar], but this incidence is highly dependent on ascites total protein content (0% in patients with an ascites protein >1 g/dL vs. 20% in patients with an ascites protein <1 g/dL) [[10]Llach J. Rimola A. Navasa M. Gines P. Salmeron J.M. Gines A. et al.Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.Hepatology. 1992; 16: 724-727Crossref PubMed Scopus (179) Google Scholar]. In early series, E. coli was the predominant organism isolated from ascites (8/11 of the cases reported by Kerr et al. [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar] and 4/6 of the cases reported by Conn [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar]). Even in the most recent series by Fernandez et al. [[12]Fernandez J. Navasa M. Gomez J. Colmenero J. Vila J. Arroyo V. et al.Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (378) Google Scholar], gram-negative bacteria (GNB) were isolated in 80% of the cases of SBP that were culture-positive. A recent study performed in a US hospital showed that the frequency of multiple-antibiotic resistance in bacteria isolated from cirrhotic ascites increased from 8 to 38% in an earlier (1991–1995) compared to a later (1996–2001) cohort [[13]Singh N. Wagener M.M. Gayowski T. Changing epidemiology and predictors of mortality in patients with spontaneous bacterial peritonitis at a liver transplant unit.Clin Microbiol Infect. 2003; 9: 531-537Crossref PubMed Scopus (53) Google Scholar]. This is most probably the result of the widespread use of antibiotic prophylaxis, as shown in a recent study in which 65% of GNB isolated from patients on long-term norfloxacin prophylaxis were quinolone-resistant compared to only 29% of GNB from patients not on long-term norfloxacin [[12]Fernandez J. Navasa M. Gomez J. Colmenero J. Vila J. Arroyo V. et al.Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (378) Google Scholar]. Notably, trimethoprim-sulfamethoxazole-resistance was also significantly more frequent in GNB isolated from patients on long-term norfloxacin (68% vs. 44%). Early diagnosis of SBP is key in its management. Kerr et al. noted that symptoms of SBP were distinct from the classical picture of (surgical) peritonitis, as fever, abdominal pain and typical local features of peritonitis were present in only 4 of 11 episodes [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar]. Both Kerr et al. [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar]and Conn [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar] recorded that all patients presented with hepatic encephalopathy, that ascites protein was of no diagnostic value and that there was an ‘obvious excess’ of ascites polymorphs. All these findings have been borne through the years. Although the typical features of SBP consist of symptoms and signs of a generalized peritonitis, patients rarely present with the complete picture and single elements of the typical presentation are more frequent, with isolated fever or abdominal pain being the most frequent presenting manifestations. Patients may present with other less typical signs and symptoms such as unexplained encephalopathy. An Ascites Club consensus recommendation is the performance of a diagnostic paracentesis to rule out SBP in patients with ascites presenting with encephalopathy [[14]Rimola A. Garcia-Tsao G. Navasa M. Piddock L.J.V. Planas R. Bernard B. et al.Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document.J Hepatol. 2000; 32: 142-153Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar]. As mentioned previously, ascites protein has been found to be predictive of the development of SBP but, unlike pleural fluid in which an exudative fluid (protein >2.9 mg/dL) is indicative of inflammation/infection, ascites protein does not rise in SBP and is therefore of no diagnostic value. An entity akin SBP, spontaneous bacterial empyema represents passage of peritoneal fluid into the pleural space and in this entity, as in SBP, pleural fluid protein remains stable among samples obtained before, during or after the infection [[15]Xiol X. Castellvi J.M. Guardiola J. Sese E. Castellote J. Perello A. et al.Spontaneous bacterial empyema in cirrhotic patients: a prospective study.Hepatology. 1996; 23: 719-723Crossref PubMed Google Scholar]. In early reports, the diagnosis of SBP was established with a positive ascites bacteriological culture. However, the paper by Conn [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar] was the first to recognize that bacteria may not always be isolated from ascites. In his report, a patient developed culture-positive SBP after two similar episodes of fever, abdominal pain and ‘neutrocytic peritonitis’ but with negative ascites cultures. Although the sensitivity of ascites culture improves when the fluid is inoculated in blood culture bottles [[14]Rimola A. Garcia-Tsao G. Navasa M. Piddock L.J.V. Planas R. Bernard B. et al.Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document.J Hepatol. 2000; 32: 142-153Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar], it is still apparent that a significant proportion of cases of SBP remain culture-negative (60% in the recent series by Fernandez et al. [[12]Fernandez J. Navasa M. Gomez J. Colmenero J. Vila J. Arroyo V. et al.Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (378) Google Scholar]). This has led to the use of the polymorphonuclear cell (PMN) count as the main element in the diagnosis of SBP and it has been determined that the best cutoff is a PMN count >250 mm−3 [[14]Rimola A. Garcia-Tsao G. Navasa M. Piddock L.J.V. Planas R. Bernard B. et al.Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document.J Hepatol. 2000; 32: 142-153Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar]. The PMN count is performed manually and may not be available in all hospitals after hours. An alternative to manual counting is the use of reactive strips for leukocyte esterase that have been shown to be useful when results are extreme (0 or 3–4+) but less so for middle results of 1–2+[[16]Castellote J. Lopez C. Gornals J. Tremosa G. Farina E.R. Baliellas C. et al.Rapid diagnosis of spontaneous bacterial peritonitis by use of reagent strips.Hepatology. 2003; 37: 893-896Crossref PubMed Scopus (129) Google Scholar]. It has however been suggested that strips from different manufacturers may have different diagnostic value and should be tested locally. Isolating an organism is important in guiding the management of patients with SBP. All of the cases reported by Conn had positive blood cultures and in five of the six episodes, the same bacteria was isolated from ascites and blood [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar]. Currently, blood cultures are positive in about half of the cases of SBP and to maximize the possibilities of isolating an infecting organism, blood cultures should also be obtained in patients in whom SBP is suspected. It must be kept in mind that a small group of patients have a peritonitis that is secondary to hollow viscus perforation, a contiguous abscess or an intraabdominal inflammatory process. In fact, the autopsy of two of the cases described by Kerr et al. revealed bile duct obstruction in one and intestinal necrosis in another [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar]. Therefore, these two were episodes of secondary peritonitis rather than SBP. The presence of secondary bacterial peritonitis should be suspected when a suspected SBP fails to respond to antibiotic therapy or when more than one organism is isolated from ascites, particularly when anaerobic bacteria and/or fungi are isolated. Interestingly, in the case described by Kerr et al. associated with intestinal necrosis, Candida albicans was the organism isolated from ascites [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar]. In the study by Conn [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar], the administration of systemic antibiotics (tetracycline and streptomycin) led to resolution of SBP in all but one case. The paper by Kerr et al. [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar] mentioned that, given an equilibration time of several hours between blood and ascites, it was logical to start treatment by both the intravenous and intraperitoneal routes and they did so with cloramphenicol. However, the routine intraperitoneal instillation of antibiotics was deemed unnecessary after a study of 31 paired specimens showed that the ascitic fluid antibiotic concentration was about one half or more of the simultaneous serum level and in all but one it was above the minimal inhibitory concentration [[17]Gerding D.N. Hall W.H. Schierl E.A. Antibiotic concentrations in ascitic fluid of patients with ascites and bacterial peritonitis.Ann Intern Med. 1977; 86: 708-713Crossref PubMed Scopus (54) Google Scholar]. In fact, an SBP resolution rate of around 90% has been demonstrated in several studies in which cefotaxime (or another third generation cephalosporin) was used intravenously, and this is currently the antibiotic of choice [[14]Rimola A. Garcia-Tsao G. Navasa M. Piddock L.J.V. Planas R. Bernard B. et al.Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document.J Hepatol. 2000; 32: 142-153Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar] although the combination amoxicillin/clavulanate is equally effective and is therefore an alternative [[18]Ricart E. Soriano G. Novella M. Ortiz J. Sabat M. Kolle L. et al.Amoxicillin-clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients.J Hepatol. 2000; 32: 596-602Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar]. Once improvement is demonstrated, intravenous antibiotics can be switched to an oral regime [18Ricart E. Soriano G. Novella M. Ortiz J. Sabat M. Kolle L. et al.Amoxicillin-clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients.J Hepatol. 2000; 32: 596-602Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 19Terg R. Cobas S. Fassio E. Landeira G. Rios B. Vasen W. et al.Oral ciprofloxacin after a short course of intravenous ciprofloxacin in the treatment of spontaneous bacterial peritonitis: results of a multicenter, randomized study.J Hepatol. 2000; 33: 564-569Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. In fact, a study performed in patients with ‘uncomplicated SBP’ showed that oral ofloxacin, a quinolone that is widely bioavailable after oral administration, is as effective as intravenous cefotaxime in the treatment of SBP [[20]Navasa M. Follo A. Llovet J.M. Clemente G. Vargas V. Rimola A. et al.Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis.Gastroenterology. 1996; 111: 1011-1017Abstract Full Text PDF PubMed Scopus (236) Google Scholar]. However, the emergence of quinolone-resistant organisms limits the usefulness of ofloxacin. Importantly this study identified a subgroup of patients with 100% SBP resolution and 100% survival with either oral or intravenous antibiotics that could be potentially treated as outpatients and these were patients with community-acquired SBP, no GI hemorrhage or encephalopathy and a normal renal function. One of the most important predictors of death in patients with SBP is the development of renal impairment, which occurs in about a third of the patients. It has been considered that renal impairment occurs as a result of a decrease in effective arterial blood volume. Plasma volume expansion with albumin has been shown to be an effective adjuvant to antibiotic therapy, particularly in patients with renal dysfunction and jaundice [[21]Sort P. Navasa M. Arroyo V. Aldeguer X. Planas R. Ruiz-del-Arbol L. et al.Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.N Engl J Med. 1999; 341: 403-409Crossref PubMed Scopus (1243) Google Scholar]. In addition to significantly lower rates of renal dysfunction, patients who received albumin had significantly lower rates of in-hospital mortality (10% vs. 29%) and 3-month mortality (22% vs. 41%) compared to patients who did not receive albumin. This in-hospital mortality rate of 10% is the lowest reported for SBP and is in clear contrast with a mortality rate ≥80% in initial studies in which 8/9 [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar] and 4/5 [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar] patients died within 30 days of the last episode of SBP. The decreasing mortality of SBP is most probably the result of early detection and early antibiotic therapy. Once SBP occurs, the possibility of recurrence is high and this is clearly demonstrated in the paper by Conn in which SBP recurred in two of five patients: once within a month in one and twice within 3 months in another. A prospective study showed that the 1-year cumulative probability of developing a recurrent episode of SBP is 69% [[22]Tito L. Rimola A. Gines P. Llach J. Arroyo V. Rodes J. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors.Hepatology. 1988; 8: 27-31Crossref PubMed Scopus (348) Google Scholar]. This rate could be reduced significantly to 20% with the use of oral norfloxacin at a dose of 400 mg/day [[23]Gines P. Rimola A. Planas R. Vargas V. Marco F. Almela M. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Google Scholar]. A recent study confirmed these results and demonstrated that the use of weekly quinolones was not as effective and led to a greater emergence of E. coli resistant to quinolones in feces compared to daily norfloxacin [[24]Bauer T.M. Follo A. Navasa M. Vila J. Planas R. Clemente G. et al.Daily norfloxacin is more effective than weekly rufloxacin in prevention of spontaneous bacterial peritonitis recurrence.Dig Dis Sci. 2002; 47: 1356-1361Crossref PubMed Scopus (52) Google Scholar]. Even though studies of secondary prophylaxis have not been designed to demonstrate an effect on survival, it is now considered a routine practice to initiate antibiotic prophylaxis, prior to discharge from the hospital, in patients who have survived an episode of SBP [[14]Rimola A. Garcia-Tsao G. Navasa M. Piddock L.J.V. Planas R. Bernard B. et al.Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document.J Hepatol. 2000; 32: 142-153Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar]. The development of infections due to antibiotic-resistant organisms and the change in the spectrum of microorganisms causing infection speaks against the widespread use of prophylactic antibiotics in cirrhosis [12Fernandez J. Navasa M. Gomez J. Colmenero J. Vila J. Arroyo V. et al.Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (378) Google Scholar, 25Campillo B. Dupeyron C. Richardet J.P. Mangeney N. Leluan G. Epidemiology of severe hospital-acquired infections in patients with liver cirrhosis: effect of long-term administration of norfloxacin.Clin Infect Dis. 1998; 26: 1066-1070Crossref PubMed Scopus (129) Google Scholar]. Long-term prophylaxis should be restricted to patients at a high risk of developing SBP, as is the case of those with a prior history. Another group of patients in whom the incidence of SBP (and other bacterial infections) is high, is the group of cirrhotic patients admitted for gastrointestinal hemorrhage [[26]Deschenes M. Villeneuve J.P. Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis.Am J Gastroenterol. 1999; 94: 2193-2197Crossref PubMed Google Scholar]. A meta-analysis of five prospective randomized trials demonstrates that short-term antibiotic prophylaxis in cirrhotic patients admitted with gastrointestinal hemorrhage has resulted not only in a decrease in infection rate but also in an improvement in survival [[27]Bernard B. Grange J.D. Khac E.N. Amiot X. Opolon P. Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis.Hepatology. 1999; 29: 1655-1661Crossref PubMed Scopus (640) Google Scholar]. More recently, antibiotic prophylaxis has been shown to significantly decrease the rate of variceal rebleeding [[28]Hou M.C. Lin H.C. Liu T.T. Kuo B.I. Lee F.Y. Chang F.Y. et al.Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial.Hepatology. 2004; 39: 746-753Crossref PubMed Scopus (328) Google Scholar]. A more controversial area is that of the primary prophylaxis of SBP. Previous studies of prophylaxis in patients with low ascites protein either included patients with prior SBP or were not placebo-controlled. The only placebo-controlled, double-blind trial of oral norfloxacin in the primary prophylaxis of SBP in cirrhotic patients with low ascites protein failed to demonstrate a significant difference in the incidence of SBP between the placebo group (9%) and the norfloxacin group (0%) [[29]Grange J.D. Roulot D. Pelletier G. Pariente E.A. Denis J. Ink O. et al.Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites—A double-blind randomized trial.J Hepatol. 1998; 29: 430-436Abstract Full Text PDF PubMed Scopus (146) Google Scholar]. Therefore, before quinolone prophylaxis can be widely recommended, the results of further placebo-controlled trials are awaited, particularly in the subgroup of patients with ascites at a higher risk of developing SBP. In addition to a low ascites protein, patients with high serum bilirubin (>3.2 mg/dL) and low platelet counts (<98,000 mm−3) have been identified as having an even greater risk of developing first SBP, with a 1-year probability of 55% (compared to 20–25% for those with only a low ascites protein) [[30]Guarner C. Sola R. Soriano G. Andreu M. Novella M.T. Vila C. et al.Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.Gastroenterology. 1999; 117: 414-419Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. Future investigations will be directed at searching for alternatives to antibiotics in the prophylaxis of SBP. Both studies theorized on the possible pathogenesis of SBP. Since five of eight episodes of SBP in the Kerr et al. series had been preceded within 10 days by the performance of a paracentesis, the authors proposed this as the most important factor in the pathogenesis of SBP and described safer paracentesis techniques, recognizing that infection in the three remaining cases could have reached the ascitic fluid via the blood stream [[5]Kerr D.N.S. Pearson D.T. Read A.E. Infection of ascitic fluid in patients with hepatic cirrhosis.Gut. 1963; 4: 394-398Crossref PubMed Scopus (60) Google Scholar]. Alternatively, in the study by Conn and given the finding of a concomitant bacteremia in all six episodes, the pathogenesis of SBP was assumed to be ‘escape of bacteria from the intestinal tract into the blood, causing transient bacteremia’, going on to state that ‘in the cirrhotic patient in whom the bacterial filtering mechanism of the liver is impaired, the duration of such bacteremia is prolonged offering the organisms a greater opportunity to invade the ascitic fluid and to cause bacterial peritonitis’ [[6]Conn H.O. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome.Ann Intern Med. 1964; 60: 568-580Crossref PubMed Scopus (196) Google Scholar]. The pathogenetic elements put forward by Conn have been explored and confirmed experimentally. Bacterial translocation (BT), the passage of bacteria from the gut to extraintestinal sites, has been shown to be increased in cirrhotic rats with ascites [[31]Garcia-Tsao G. Lee F.Y. Barden G.E. Cartun R. West A.B. Bacterial translocation to mesenteric lymph nodes is increased in cirrhotic rats with ascites.Gastroenterology. 1995; 108: 1835-1841Abstract Full Text PDF PubMed Scopus (215) Google Scholar] and in cirrhotic patients with severe liver disease [[32]Cirera I. Bauer T.M. Navasa M. Vila J. Grande L. Taura P. et al.Bacterial translocation of enteric organisms in patients with cirrhosis.J Hepatol. 2001; 34: 32-37Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar]. In experimental studies, cirrhotic rats with positive ascites cultures have all had concurrent BT, often with the same organism, suggesting a causal relationship [[33]Llovet J.M. Bartoli R. March F. Planas R. Vinado B. Cabre E. et al.Translocated intestinal bacteria cause spontaneous bacterial peritonitis in cirrhotic rats: molecular epidemiologic evidence.J Hepatol. 1998; 28: 307-313Abstract Full Text PDF PubMed Scopus (134) Google Scholar]. However, the most compelling evidence regarding a causal relationship between BT and development of bacterial infections in cirrhosis comes from studies showing that the use of oral non-absorbable antibiotics decreases the development of SBP and other spontaneous infections in cirrhotic patients [34Rimola A. Bory F. Teres J. Perez-Ayuso R.M. Arroyo V. Rodes J. Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage.Hepatology. 1985; 5: 463-467Crossref PubMed Scopus (236) Google Scholar, 35Soriano G. Guarner C. Tomas A. Villanueva C. Torras X. Gonzalez D. et al.Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage.Gastroenterology. 1992; 103: 1267-1272Abstract PubMed Google Scholar, 36Gines P. Rimola A. Planas R. Vargas V. Marco F. Almela M. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Scopus (518) Google Scholar]. The presence of bacteremia in half the cases of SBP suggest that bacteria gain access to the systemic circulation prior to infecting the peritoneal fluid. For BT to become clinically significant, i.e. for it to lead to SBP or bacteremia, a failure of local and systemic immune defenses should also be present. The reticuloendothelial system (RES) is the main defensive system against bacteremia and other infections acquired through a hematogenous route. Most of the RES activity is located in the liver where Kupffer cells (tissue macrophages) are the major components. In cirrhosis, this activity is impaired because of porto-systemic shunting that bypasses the liver (thereby escaping the action of the RES) and because of an impaired phagocytic activity of Kupffer cells [[37]Rimola A. Soto R. Bory F. Arroyo V. Piera C. Rodes J. Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis.Hepatology. 1984; 4: 53-58Crossref PubMed Scopus (432) Google Scholar]. Additionally, low serum complement levels, more pronounced in patients with the most severe liver disease, lead to decreased peripheral bactericidal activity [[38]Homann C. Varming K. Hogasen K. Mollnes T.E. Graudal N. Thomsen A.C. et al.Acquired C3 deficiency in patients with alcoholic cirrhosis predisposes to infection and increased mortality.Gut. 1997; 40: 544-549Crossref PubMed Scopus (89) Google Scholar]. This decreased antibacterial activity would explain how a transient bacteremia would become persistent. In the patient with ascites, bacteria present in the systemic circulation will reach ascites and, once microorganisms colonize ascites, the development of SBP will depend on the defensive capacity of the fluid. Low ascites complement lead to decreased ascites bactericidal activity and to a greater risk for SBP [[39]Runyon B.A. Morrissey R.L. Hoefs J.C. Wyle F.A. Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis.Hepatology. 1985; 5: 634-637Crossref PubMed Scopus (156) Google Scholar] The mechanism for the increased BT observed in cirrhosis has not been fully established. The three factors that have been implicated in the development of BT, impaired immunity, intestinal bacterial overgrowth (IBO) and increased intestinal permeability, have all been found to be present in cirrhosis [[40]Garcia-Tsao G. Wiest R. Gut microflora in the pathogenesis of the complications of cirrhosis.Best Pract Res Clin Gastroenterol. 2004; 18: 353-372Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar]. Of these, the most susceptible to manipulation is IBO. The use of antibiotics that will selectively eliminate GNB (selective intestinal decontamination) should be effective in eliminating IBO and BT. Long-term administration of orally administered norfloxacin, a poorly absorbed quinolone, has been shown to produce a marked reduction in GNB from the fecal flora of cirrhotic patients without significant effects on gram-positive cocci or anaerobic bacteria [[23]Gines P. Rimola A. Planas R. Vargas V. Marco F. Almela M. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Google Scholar]. As mentioned previously, selective intestinal decontamination has been used in cirrhotic patients in different clinical settings with positive results, however, long-term prophylaxis is not ideal given its association with the development of antibiotic-resistant organisms. It is therefore important to find non-antibiotic methods to eliminate BT and prevent SBP. Recent studies performed in cirrhotic rats, demonstrate that IBO and BT can be decreased by accelerating intestinal transit, either with propranolol [[41]Perez-Paramo M. Munoz J. Albillos A. Freile I. Portero F. Santos M. et al.Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites.Hepatology. 2000; 31: 43-48Crossref PubMed Scopus (203) Google Scholar] or with cisapride [42Pardo A. Bartoli R. Lorenzo-Zuniga V. Planas R. Vinado B. Riba J. et al.Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis.Hepatology. 2000; 31: 858-863Crossref PubMed Scopus (160) Google Scholar, 43Zhang S.C. Wang W. Ren W.Y. He B.M. Zhou K. Zhu W.N. Effect of cisapride on intestinal bacterial and endotoxin translocation in cirrhosis.World J Gastroenterol. 2003; 9: 534-538PubMed Google Scholar]. Two studies in cirrhotic patients, show that a 6-month course of oral cisapride decreases orocecal transit time and eliminates IBO in 80% of patients with IBO at baseline [42Pardo A. Bartoli R. Lorenzo-Zuniga V. Planas R. Vinado B. Riba J. et al.Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis.Hepatology. 2000; 31: 858-863Crossref PubMed Scopus (160) Google Scholar, 44Madrid A.M. Hurtado C. Venegas M. Cumsille F. Defilippi C. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function.Am J Gastroenterol. 2001; 96: 1251-1255Crossref PubMed Google Scholar]. Although neither experimental studies nor studies in humans have shown a decrease in SBP or other infections in treated subjects, one of them showed that 2/10 patients on placebo developed SBP and urinary infection while infections do not seem to have occurred in patients on antibiotics or cisapride [[44]Madrid A.M. Hurtado C. Venegas M. Cumsille F. Defilippi C. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function.Am J Gastroenterol. 2001; 96: 1251-1255Crossref PubMed Google Scholar]. These results are encouraging and should stimulate further studies using prokinetics. Bacteriotherapy with Lactobacilli has been reported to correct IBO, stabilize mucosal barrier function and decrease BT in rat models of acute liver injury and failure. However, studies performed both in portal hypertensive rats [[45]Wiest R. Chen F. Cadelina G. Groszmann R.J. Garcia-Tsao G. Effect of Lactobacillus-fermented diets on bacterial translocation and intestinal flora in experimental prehepatic portal hypertension.Dig Dis Sci. 2003; 48: 1136-1141Crossref PubMed Scopus (39) Google Scholar] and in cirrhotic rats with ascites [[46]Bauer T.M. Fernandez J. Navasa M. Vila J. Rodes J. Failure of Lactobacillus spp. to prevent bacterial translocation in a rat model of experimental cirrhosis.J Hepatol. 2002; 36: 501-506Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar], have shown that the oral administration of Lactobacilli failed to prevent BT. The usefulness of other pro or prebiotics remains to be determined. Bile acids are bacteriostatic and may contribute to the sterility of small intestinal content in health. In cirrhosis there is a decrease in bile acid secretion and a recent study showed that orally administered conjugated bile acids, cholylsarcosine and cholylglycine, in ascitic cirrhotic rats reduced intestinal bacterial content, BT and endotoxemia and improved survival [[47]Lorenzo-Zuniga V. Bartoli R. Planas R. Hofmann A.F. Vinado B. Hagey L.R. et al.Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats.Hepatology. 2003; 37: 551-557Crossref PubMed Scopus (234) Google Scholar]. These compelling findings require further exploration in humans. In the 40 years since SBP was first described in the English literature as a ‘rarely recognized syndrome’, SBP has become a frequently recognized and investigated syndrome in patients with cirrhosis. Significant advances have been made in its pathogenesis, diagnosis, treatment and prevention. The recommendation by Conn that ‘this potentially lethal infection be recognized and treated promptly’ has been mostly accomplished and has led to a decrease in its mortality. It is now important to move forward into the area of prevention and to further develop alternatives to antibiotic prophylaxis.