Diagnosis, treatment and prevention of spontaneous bacterial peritonitis

BaillieÁre's Clinical Gastroenterology Vol. 14, No. 6, pp. 975±990, 2000

doi:10.1053/bega.2000.0142, available online at http://www.idealibrary.com on

7 Diagnosis, treatment and prevention of spontaneous bacterial peritonitis Javier FernaÂndez

MD

Research Fellow

Tilman M. Bauer

MD

Research Fellow

Miquel Navasa

MD

Senior Specialist

Juan RodeÂs

FRCP

Professor of Medicine Liver Unit, Institut de Malalties Digestives, Hospital Clinic, IDIBAPS, University of Barcelona, Spain

Spontaneous bacterial peritonitis (SBP) is a frequent complication in cirrhotic patients with ascites. Diagnosis of SBP is established by a polymorphonuclear cell count in ascitic ¯uid 5250 cells/mm3. The organism responsible for the infection is isolated in 60±70% of the cases. The remaining cases are considered to have a variant of SBP (culture-negative SBP) and are treated in the same way as those with a positive culture. The SBP resolution rate ranges between 70 and 90%, and hospital survival between 50 and 70%. An early diagnosis and the use of a more adequate antibiotic therapy are the most probable reasons for the improvement in prognosis for SBP in recent decades. Despite the resolution of the infection, SBP may trigger severe complications such as renal impairment, gastrointestinal bleeding and accentuation of hepatic insuciency which are responsible for the associated mortality. Patients recovering from an episode of SBP should be considered as potential candidates for liver transplantation. Key words: spontaneous bacterial peritonitis; bacterial infection; cirrhosis; bacterial translocation; cephalosporins; quinolones; selective intestinal decontamination.

Spontaneous bacterial peritonitis (SBP) is de®ned as the infection of a previously sterile ascitic ¯uid, without any apparent intra-abdominal source of infection. The prevalence of SBP in unselected cirrhotic patients with ascites admitted to a hospital ranges between 10 and 30%.1,2 Diagnosis of SBP is established by a polymorphonuclear cell count in ascitic ¯uid higher than 250 cells/mm3. In approximately 60±70% of the cases the organism responsible is isolated in ascitic ¯uid culture or in blood cultures. The remaining cases are considered as a variant of SBP and are treated in the same way as those with a positive culture.3 The outcome of cirrhotic patients with SBP has 1521±6918/00/060975‡16 $35.00/00

c 2000 Harcourt Publishers Ltd. *

976 J. FernaÂndez et al.

dramatically improved during the last 20 years. At present, the SBP resolution rate ranges between 70 and 90% and hospital survival ranges between 50 and 70%.1 An early diagnosis of SBP and, specially, the use of a more adequate antibiotic therapy, are the most probable reasons for the improvement in prognosis for SBP. However, despite the resolution of the infection, the mortality rate of SBP is still high (30%), due mainly to the development of some complications such as renal impairment, gastrointestinal bleeding and progressive liver failure. Cirrhotic patients recovering from an episode of SBP should be considered as potential candidates for liver transplantation because the survival expectancy after this bacterial infection is very poor. This chapter focuses on the pathogenesis, diagnosis, prophylaxis and treatment of this severe complication of cirrhosis. PATHOGENESIS Colonization of the ascitic ¯uid from an episode of bacteraemia is nowadays the most accepted hypothesis on the pathogenesis of SBP.1,4 Although the passage of microorganisms from the bloodstream to ascites has never been documented, it can be assumed that bacteria present in the circulation may pass easily to the ascites because of the constant ¯uid exchange between these two compartments. Once bacteria have reached the ascites, the development of SBP depends on the antimicrobial capacity of the ascitic ¯uid. Patients with a decreased defensive capacity of ascitic ¯uid develop SBP. Because most organisms causing SBP are Gram-negative bacteria of enteric origin1,2,4,5, several pathogenic mechanisms have been proposed to explain the passage of enteric organisms from the intestinal lumen to the systemic circulation: (1) the intestinal bacterial overgrowth that leads to an increase in aerobic Gram-negative bacilli in the jejunal ¯ora in cirrhosis and the possible alteration in gut permeability due to portal hypertension or to circumstances decreasing mucosal blood ¯ow (e.g. acute hypovolaemia or splanchnic vasoconstrictor drugs); (2) the depression of the hepatic reticuloendothelial system which allows the free passage of microorganisms from the bowel lumen to the systemic circulation via the portal vein; (3) bacterial translocation, or the process by which enteric bacteria normally present in the gastrointestinal tract can cross the mucosa and infect the mesenteric lymph nodes, and reach the bloodstream through the intestinal lymphatic circulation. The skin, the urinary tract and the upper respiratory tract may be the sites by which non-enteric bacteria enter the circulation and cause SBP. This pathogenic mechanism is favoured in many cases by diagnostic or therapeutic procedures which break the natural mucocutaneous barriers. Whatever the source of the bacteria reaching the bloodstream, a bacteraemic event may be more prolonged and, therefore, may more readily become clinically signi®cant, in cirrhotic patients compared to non-cirrhotic patients because of the marked depression of the reticulendothelial system in the former. As indicated above, once microorganisms have colonized the ascites, the development of SBP depends on the defensive capacity of the ascitic ¯uid (Figure 1). Changes in the intestinal ¯ora and in the intestinal barrier Overgrowth of Gram-negative bacilli has been demonstrated in the jejunal ¯ora of cirrhotic patients.6 The intestinal hypomotility caused by the sympathetic overactivity of cirrhotic patients could, at least partly, explain this fact.7 The change in the intestinal ¯ora may increase the chance of aerobic Gram-negative bacteria invading the

Spontaneous bacterial peritonitis 977

Enteric Gram-negative bacilli

Other sources of organisms: skin, respiratory and urinary tract, etc.

Bacterial overgrowth Altered gut permeability Bacterial translocation

Mesenteric lymph nodes

Portal vein

Systemic circulation Ascites Bacteraemia Depression of systemic host defenses

Bacterascites Altered defensive capacity of ascitic fluid

Spontaneous bacteraemia

Spontaneous bacterial peritonitis Figure 1. Pathogenesis of spontaneous bacterial peritonitis.

bloodstream and cause infections of enteric origin in patients with cirrhosis. In addition, it has been shown that, in CCl4-induced cirrhotic rats with ascites there is an increased passage of bacteria from the intestinal lumen to extraintestinal sites, including regional lymph nodes and the systemic circulation.7±10 Causes of bacterial translocation are a disruption of the intestinal permeability barrier, bacterial overgrowth (IBO), and/or a decrease in host immune defences. The simultaneous presence of IBO and a severe disturbance in the intestinal barrier seem to be required for bacterial translocation to mesenteric lymph nodes (MLN).7 The alteration in gut permeability could be partially due to portal hypertension that causes marked oedema and in¯ammation in the submucosa of the cecum in cirrhotic rats with ascites, thus favouring bacterial translocation.10 Changed permeability of the intestinal mucosa has also been seen in haemorrhagic shock, sepsis, injury or administration of endotoxin.11 In portal hypertensive rats8,12 it has been shown that haemorrhagic shock is followed by increased bacterial translocation to MLN, suggesting that haemorrhagic shock, a not infrequent event in cirrhotic patients, could alter the intestinal barrier in these animals. Depression of activity of the reticuloendothelial system Although the reticuloendothelial system is widely distributed throughout the body, approximately 90% of this defensive system is in the liver, where Kup€er cells and endothelial sinusoidal cells are the major components.13 Several groups have demonstrated that cirrhotic patients may have marked depression of the reticuloendothelial system function. In addition, it has been shown that the risk of acquiring bacteraemia and SBP in cirrhosis is directly related to the degree of dysfunction of the reticuloendothelial system in these patients.14,15

978 J. FernaÂndez et al.

Several mechanisms have been proposed to explain the impairment of the phagocytic activity of the reticuloendothelial system in cirrhosis, including intrahepatic shunting, a reduction in the phagocytic capacity of monocytes, which are considered as the Kup€er cell precursors, and an impaired function of macrophage Fc gamma receptors in alcoholic cirrhosis.13,16,17 Serum opsonic activity has been found to be markedly reduced in most cirrhotic patients, probably as a consequence of a decreased serum concentration of complement and ®bronectin, substances that normally stimulate the phagocytosis of microorganisms by enhancing their adhesiveness to the reticuloendothelial cell surface. Decreased opsonic activity of the ascitic ¯uid The non-speci®c antimicrobial capacity of ascitic ¯uid in cirrhosis varies greatly from patient to patient and this variability may be involved in the pathogenesis of SBP. Runyon et al have recently reported the existence of a highly signi®cant inverse correlation between the opsonic activity of ascitic ¯uid and the risk of developing SBP in patients admitted to hospital with ascites.18 The opsonic activity of ascitic ¯uid in cirrhosis is directly correlated with the total protein level in ascites and with the concentration of defensive substances, such as immunoglobulins, complement, and ®bronectin.18±22 Interestingly, several investigators have found that the concentration of total protein in ascitic ¯uid, a very easy measurement in clinical practice, correlates directly with the risk of SBP in cirrhosis with ascites. It has been demonstrated that patients with protein concentration in ascitic ¯uid below 10 g/l develop peritonitis during hospital stay with a signi®cantly higher frequency than those with a higher protein content in ascites (15 versus 2%, respectively)19 and that the cumulative 1-year probability of developing peritonitis during long-term follow-up is signi®cantly greater in this subgroup of cirrhotic patients than in those with an ascitic protein concentration over 10 g/l (20 versus 2%, respectively).21 Finally, the probability of the ®rst episode of SBP in cirrhotic patients with ascites is signi®cantly in¯uenced by the antimicrobial capacity of ascitic ¯uid and by hepatic function, with ascitic ¯uid protein levels, platelet count and serum bilirubin levels being the most useful indicators of high risk of spontaneous peritonitis.22,23 The variation in the antimicrobial properties could be related to (a) the serum levels of the defensive proteins involved in antibacterial mechanisms of ascitic ¯uid; (b) the degree of portal hypertension and hepatic insuciency, and (c) the volume of water diluting ascitic ¯uid solutes. This last possibility is supported by the ®nding that diuretic-induced reduction of water in ascitic ¯uid increases the total protein concentration and the antibacterial power of ascites24, and by the common observation in clinical practice that SBP occurs predominantly in cirrhotic patients with largevolume ascites. Neutrophil leukocyte dysfunction A high proportion of cirrhotic patients show altered neutrophil leukocyte function at di€erent levels. The most frequent disturbance is a marked reduction of chemotaxis, probably caused by the presence of chemotactic inhibitory substances in the serum. The nature of these substances has not yet been determined. Furthermore, the phagocytic and bacterial killing capacity of neutrophils has been found to be reduced in cirrhosis.25 However, because infections frequently developed by patients with congenital or acquired neutrophil-function abnormalities (mainly chronic

Spontaneous bacterial peritonitis 979

granulomatous diseases and recurrent staphylococcal and fungal infections) are very di€erent from those developed by cirrhotic patients, it seems very unlikely that leukocyte dysfunction plays a major role in the susceptibility of cirrhosis to bacterial infections. Iatrogenic factors In addition to procedures well known to predispose to infection, such as intravenous or urethral catheters, cirrhotic patients are frequently subjected to other diagnostic or therapeutic manoeuvres which may alter the natural defence barriers and, therefore, increase the risk of bacterial infection. Endoscopic sclerotherapy for bleeding oesophageal varices, particularly emergency sclerotherapy, seems to be associated with bacteraemia, with an incidence ranging from 5 to 30%.26,27 Although, in some cases, sclerotherapy has been implicated in the development of serious infectious complications such as purulent meningitis28 and bacterial peritonitis29, bacteraemia is usually a transient phenomenon and the use of prophylactic antibiotics is not recommended. The placement of a transjugular intrahepatic portosystemic stent for the treatment of bleeding oesophageal varices is not associated with the development of signi®cant bacterial infections. However, cirrhotic patients with a peritoneovenous shunt (LeVeen shunt) frequently develop infectious complications, particularly spontaneous bacterameia and peritonitis. In several series the incidence of bacterial infections after the insertion of a LeVeen shunt for the treatment of ascites was approximately 20%.30,31 Finally, there is a very low risk of clinically relevant infection with other invasive techniques often performed in these patients, such as diagnostic or therapeutic paracentesis and endoscopy. DIAGNOSIS Clinical characteristics The clinical presentation of SBP probably depends on the stage at which the infection is diagnosed. Most patients present with signs or symptoms clearly suggestive of peritoneal infection, although SBP may be asymptomatic, especially in the initial stages. Abdominal pain and fever are the most characteristic symptoms. Other signs and symptoms such as alterations in gastrointestinal motility (vomiting, ileus, diarrhoea), hepatic encephalopathy, gastrointestinal bleeding, renal impairment, septic shock and hypothermia may be present in a high number of patients.32,33 Diagnostic paracentesis should be performed on hospital admission in all cirrhotic patients with ascites to investigate the presence of SBP, and in hospitalized patients with ascites whenever they present with any of the following: (a) abdominal pain, vomiting, diarrhoea, ileus or rebound tenderness; (b) systemic signs of infection such as fever, leukocytosis or septic shock, and (c) hepatic encephalopathy or impairment in renal function32,33 (Table 1). Laboratory and microbiological data The diagnosis of SBP is based on clinical suspicion and on ascitic ¯uid analysis. An ascitic ¯uid polymorphonuclear (PMN) count of 5250 cells per mm3 is nowadays considered diagnostic of SBP and constitutes an indication to initiate empirical antibiotic treatment. In patients with haemorrhagic ascites a subtraction of one PMN per 250 red blood cells

980 J. FernaÂndez et al. Table 1. Indications for diagnostic paracentesis. . Cirrhotic patients with ascites at admission . Cirrhotic patients with ascites and signs or symptoms of infection: fever, leukocytosis, abdominal pain . Cirrhotic patients with ascites who present with a clinical condition that is deteriorating during hospitalization: renal function impairment, hepatic encephalopathy, gastrointestinal bleeding . Patients with new-onset ascites

Table 2. Microorganisms responsible for spontaneous bacterial peritonitis (SBP). Positive culture SBP Gram-negative bacilli Escherichia coli Klebsiella sp Others

67% 50% 37% 6% 7%

Gram-positive cocci Streptococcus pneumoniae Other streptococci Staphylococcus aureus

17% 10% 6% 1%

Negative culture SBP

33%

should be made to adjust for the presence of blood in ascites.32 The measurement of lactic dehydrogenase concentration, glucose levels and total protein concentration in ascitic ¯uid is important to establish a di€erential diagnosis between spontaneous and secondary peritonitis. Secondary peritonitis should be suspected when at least two of the following features are present in ascitic ¯uid: glucose levels 550 mg/dl, protein concentration 410 g/dl, lactic dehydrogenase concentration 4normal serum levels. Gram's stain of a smear of sediment obtained after centrifugation of ascitic ¯uid is frequently negative in SBP as the concentration of bacteria is usually low (one organism/ ml or less). Nevertheless, it may be helpful in identifying patients with gut perforation in whom multiple types of bacteria can be seen.33 Culture of ascitic ¯uid directly into blood culture bottles (aerobic and anaerobic media) at the bedside is positive in between 50 and 70% of cases. Moreover, blood cultures are positive in a signi®cant proportion of patients with SBP.33 Table 2 shows the most common organisms isolated in patients with SBP. Other alterations in systemic laboratory parameters such as leukocytes, azotaemia and acidosis can be seen in cirrhotic patients with SBP. TREATMENT Antibiotic therapy must be started once the diagnosis of SBP is established. Empirical treatment should cover all potential organisms responsible for SBP without causing adverse e€ects. At present, third-generation cephalosporins are considered the gold standard in the treatment of SBP in cirrhosis. However, other antibiotics are also e€ective in the treatment of this infective complication (Table 3).

Spontaneous bacterial peritonitis 981 Table 3. Spontaneous bacterial peritonitis outcome depending on the di€erent antibiotic therapy employed. Antibiotic Cefotaxime (i.v.) 2 g/4 hours 2 g/6 hours 2 g/12 hours 2 g/8 hours/5 days 2 g/8 hours/10 days

SBP resolution rate (%)

Superinfection (%)

Hospital survival (%)

86 77 79 93 91

0 1 1 0 0

73 69 79 67 58

Ceftriaxone (i.v.)

91

0

70

Cefonicid (i.v.)

94

0

63

Amoxicillin-clavulanic acid (i.v.)

85

7

63

Aztreonam (i.v.)

71

14

57

O¯oxacin (oral)

84

1

81

Treatment of SBP with third-generation cephalosporins In 1985 Felisart et al34 published the ®rst investigation assessing the ecacy of cefotaxime in patients with SBP. It consisted of a randomized controlled trial comparing cefotaxime versus the combination of ampicillin plus tobramycin in a large series of cirrhotic patients with SBP or other severe bacterial infections. Cefotaxime was more e€ective than ampicillin plus tobramycin in achieving resolution of SBP, and whereas no patient treated with cefotaxime developed nephrotoxicity and superinfections, these two adverse e€ects occurred in more than 10% of the patients treated with ampicillin plus tobramycin. Following this study, cefotaxime is considered to be one of the ®rst-choice antibiotic therapies in the empirical treatment of SBP in patients with cirrhosis. Two randomized controlled trials have assessed the optimal duration of therapy and dosage of cefotaxime in cirrhotic patients with SBP. Runyon et al35 randomized 90 patients with SBP to receive cefotaxime (2 g i.v. every 8 hours) during 10 days or during 5 days. Resolution of the infection (93.1 versus 91.2%), recurrence of SBP during hospitalization (11.6 versus 12.8%) and hospital mortality (32.6 versus 42.5%) were comparable in the two groups. Short-course treatment with cefotaxime is, therefore, as ecacious as long-course therapy in cirrhotic patients with SBP. Rimola et al36 reported the results of a randomized multicentre controlled trial in 143 patients with SBP treated with cefotaxime comparing two di€erent dosages: 2 g every 6 hours versus 2 g every 12 hours. The rate of SBP resolution (77 versus 79%) and patient survival (69 versus 79%) were similar in both groups. Therefore, doses of cefotaxime lower than those usually recommended are very e€ective in SBP. Recent studies have demonstrated that ceftriaxone (2 g i.v. every 24 hours) is highly e€ective in the treatment of SBP, with a resolution rate of 100% and a hospital mortality rate of 30%.37,38 Treatment of SBP with other parenteral antibiotics Several investigations have been carried out to assess the ecacy of other antibiotic regimes in these patients. Aztreonam was evaluated in 16 episodes of SBP caused by

982 J. FernaÂndez et al.

enterobacteria.39 The overall mortality during hospitalization was 62%. Superinfections due to resistant organisms were detected in three cases (19%). These results, together with the fact that aztreonam is capable of covering only approximately 75% of the potential organisms causing SBP, clearly establish that this antibiotic is not adequate for the empirical treatment of cirrhotic patients with SBP. More recently, it has been demonstrated that cefonicid (2 g/12 hours i.v.) is e€ective in the treatment of SBP, with a resolution rate of 94% and a hospital mortality rate of 37%.38 Finally, two studies have shown that the parenteral administration of amoxicillin associated with clavulanic acid is e€ective and safe in the treatment of SBP.40,41 The low cost of this antibiotic regime is one important advantage.

Treatment of SBP with oral antibiotics In most instances, patients with SBP are in relatively good clinical condition and could be treated orally. Two studies have been reported assessing the e€ectiveness of oral antibiotics in SBP. Both studies used wide-spectrum quinolones which are almost completely absorbed after oral administration and rapidly di€use to the ascitic ¯uid. Silvain et al42 reported the e€ectiveness of oral pe¯oxacin alone (one case) or in combination with other oral antibiotics (cotrimoxazole, nine cases; amoxicillin, three cases; cefadroxil, one case; and cotrimoxazole plus metronidazole, one case) in 15 SBP episodes. The rate of infection resolution was 87%, two patients developed superinfections and survival at the end of hospitalization was 60%. Navasa et al43 reported the results of a randomized controlled trial in patients with non-severely complicated SBP (no septic shock, ileus or serum creatinine 43 mg/dl) comparing oral o¯oxacin (400 mg/12 hours) versus intravenous cefotaxime (2 g every 6 hours). The rate of infection resolution and patient survival were similar in the two groups. In addition, the incidence of superinfections and the length of antibiotic treatment were also similar in both groups, suggesting that oral o¯oxacin is as e€ective as intravenous cefotaxime in the treatment of non-severely complicated SBP in cirrhosis.

Intravenous albumin infusion in SBP In a randomized multicentre controlled trial, Sort et al44 have recently demonstrated that, in patients with SBP, treatment with intravenous albumin in addition to an antibiotic reduces the incidence of renal impairment and improves hospital survival. The study included 126 patients with SBP who were randomly assigned to treatment with intravenous cefotaxime (63 patients) or with cefotaxime and intravenous albumin (63 patients). Albumin was given at a dose of 1.5 g per kilogram of body weight at the time of diagnosis, followed by 1 g per kilogram of body weight on day 3. Renal impairment developed in 21 patients in the cefotaxime group (33%) and in six in the cefotaxime-plus-albumin group (10%). The hospital mortality rate was 29% in the cefotaxime group in comparison to 10% in the cefotaxime-plus-albumin group. The results of this study suggest that cirrhotic patients with SBP should be expanded with albumin. However, further studies are needed to determine whether lower doses of albumin have the same e€ects on renal function and survival, whether albumin can be substituted by arti®cial plasma expanders and whether all cirrhotic patients with SBP may bene®t from albumin infusion or whether this e€ect is limited to a subgroup of SBP patients.

Spontaneous bacterial peritonitis 983

Predictors of SBP resolution and survival Several studies have been performed in order to identify predictors of infection resolution and patient survival in SBP. Toledo et al45 retrospectively analysed 213 consecutive episodes of SBP empirically treated with cefotaxime in 185 cirrhotic patients. In the multivariate analysis four out of 51 clinical and laboratory variables considered at the time of diagnosis of infection (band neutrophils in white blood cell count, community-acquired versus hospital-acquired SBP, blood urea nitrogen and serum aspartate aminotransferase levels) were identi®ed as independent predictors of infection resolution, and six (blood urea nitrogen and serum aspartate aminotransferase level, community-acquired versus hospital-acquired SBP, age, Child±Pugh score and ileus) as independent predictors of survival. A study by Follo et al46 in 252 consecutive episodes of SBP showed that the development of renal impairment following diagnosis of SBP is the strongest independent predictor of patient mortality in episodes responding to cefotaxime. Renal impairment occurred in 83 episodes (33%) and in every instance it ful®lled the criteria of functional renal failure. Renal impairment was progressive in 35 episodes, steady in 27 and transient in 21. The mortality rate was 100% in episodes associated with progressive renal impairment, 31% in episodes associated with steady renal impairment, 5% in episodes with transient renal impairment and 7% in episodes without renal impairment. Other independent predictors of mortality in this series were age, blood urea nitrogen level at diagnosis, isolation of the organism responsible in the ascitic ¯uid culture and peak serum bilirubin during antibiotic treatment. A recent study has shown that the development of renal impairment in SBP is related to the degree of in¯ammatory response triggered by the infection and estimated by cytokine levels (tumour necrosis factor and interleukin-6) in serum or in ascitic ¯uid. In addition, it has been shown that plasma and ascitic ¯uid cytokine levels also have prognostic value in patients with SBP.47±49

PROPHYLAXIS Current indications of selective intestinal decontamination in SBP prevention are summarized in Table 4. Cirrhotic patients with gastrointestinal haemorrhage are predisposed to develop severe bacterial infections during or immediately after the bleeding episode. Rimola et al50 and Soriano et al51 have shown that short-term intestinal decontamination is e€ective in preventing SBP in cirrhotic patients with gastrointestinal haemorrhage. The usefulness of systemic administration of prophylactic antibiotic agents in cirrhotic patients with gastrointestinal haemorrhage has also been Table 4. Indications and duration of selective intestinal decontamination for the prevention of SBP in cirrhotic patients. Indications

Duration of prophylaxis

Cirrhotic patients recovering from a previous episode of SBP (secondary prophylaxis)

Inde®nitely or until liver transplantation

Cirrhotic patients with gastrointestinal bleeding

Seven days

Cirrhotic patients with ascites and low ascitic ¯uid protein levels 4 10 g/l)

During hospitalization (no consensus)

984 J. FernaÂndez et al.

investigated in three more recent controlled studies. In these studies the treated groups received o¯oxacin (initially intravenously and then orally) plus amoxicillinclavulanic acid (before each endoscopy), cipro¯oxacin plus amoxicillin-clavulanic acid (®rst intravenously and then orally once the bleeding was controlled), and oral cipro¯oxacin, respectively.52±54 The incidence of bacterial infections was signi®cantly lower in the treated groups (10±20%) than in the corresponding control groups (45±66%). A relative limitation in these studies was the inability to assess the e€ect of antibiotic prophylaxis speci®cally on SBP because the incidence of both SBP and bacteraemia were analysed together. Nevertheless, the marked decrease in the rate of overall infections and the improvement in survival in the groups receiving antibiotic prophylaxis support such prophylaxis, being strongly recommended in cirrhotic patients with gastrointestinal haemorrhage independently of their speci®c risk of SBP.32 Furthermore, a meta-analysis by Bernard et al55, including all the above mentioned studies, showed a signi®cant bene®t in the subgroup of cirrhotic patients with gastrointestinal haemorrhage: 95% of patients were free of SBP in the treated group versus 87% in the control group. Cases with low ascitic ¯uid total protein concentration may be a second group of cirrhotic patients who may bene®t from selective intestinal decontamination. Soriano et al56 included 63 patients admitted to hospital for the treatment of an episode of ascites with an ascitic ¯uid total protein concentration lower than 15 g/l, some of whom had had a previous episode of SBP. The continuous administration of nor¯oxacin, 400 mg/day throughout the hospitalization period (32 patients), decreased the in-hospital incidence of SBP from 22% in the control group to 0% in the treated group. Grange et al57 included cirrhotic patients with ascitic ¯uid protein concentration 515 g/l and no previous episodes of SBP. In this study, the 6-month incidence of SBP was 0% in the group of patients prophylactically treated with nor¯oxacin, 400 mg/day for 6 months, compared to 9% in patients treated with placebo. Nevertheless, the incidence of SBP caused by Gram-negative organisms (the only one which theoretically can be prevented by nor¯oxacin prophylaxis) in the two groups was not statistically signi®cant: 0% in the nor¯oxacin-treated group and 5% in the placebo-treated group. Other antibiotic regimes have been evaluated in the prevention of SBP in high-risk patients. A placebo-controlled study demonstrated that 6-month prophylaxis with cipro¯oxacin, 750 mg weekly, was e€ective in reducing the incidence of SBP in cirrhotic patients with low ascitic ¯uid concentration: 4% in the treated group and 22% in the placebo-control group.58 In this study, patients with and without a prior history of SBP were included together and no attempt was made to evaluate the development of SBP in these two subgroups of patients separately. Singh et al have shown that trimethoprim±sulfamethoxazol (one double-strength tablet 5 days a week) is also e€ective in the prevention of SBP in cirrhotic patients with ascites.59 In this randomized controlled trial with a median duration of follow-up of only 90 days, the incidence of SBP was 26.7% in the control group and 3.3% in the group of patients receiving trimethoprim±sulfamethoxazole prophylaxis. Again, patients with di€erent risk for SBP were analysed together: patients with low and high ascitic ¯uid protein and patients who had and who had not had previous SBP episodes. Patients recovering from an episode of SBP represent a unique population for assessing the e€ect of long-term intestinal decontamination in the prophylaxis of SBP. In a double-blind placebo-controlled trial GineÁs et al60 investigated the e€ect of longterm administration of nor¯oxacin in 80 cirrhotic patients who had recovered from an episode of SBP. The overall probability of SBP recurrence at 1 year of follow-up was

Spontaneous bacterial peritonitis 985

20% in the nor¯oxacin group and 68% in the placebo group and the probability of SBP caused by aerobic Gram-negative bacilli at 1 year of follow-up was 3 and 60%, respectively. Only one patient treated with nor¯oxacin experienced side-e€ects related to treatment (oral and oesophageal candidiasis). Long-term selective intestinal decontamination, therefore, dramatically decreases the rate of SBP recurrence in patients with SBP. Three recent economic analyses have calculated that long-term antibiotic prophylaxis in cirrhotic patients is associated with a reduced cost compared with the `diagnosis and treat' strategy, suggesting that prophylaxis is cost-e€ective when applied to patients at high risk of developing SBP.61±63 Taking into account all these prophylactic studies it can be assumed that antibiotic prophylaxis in cirrhotic patients with ascites is indicated in patients who have had a previous episode of SBP because they are at high risk of SBP recurrence and because prophylaxis is cost-e€ective. In patients with low protein content in ascitic ¯uid who have never had SBP the recommendation is dicult to establish owing to the heterogeneity of the published studies which included patients with low and high risk of SBP together. This is the main reason for the lack of consensus because, despite the positive results of all the studies investigating di€erent antibiotics in the prophylaxis of SBP in patients with cirrhosis, they have been unable to identify subsets of patients who clearly bene®t from this therapy. On the other hand, it should be noted that three studies have been performed assessing the incidence and predictive factors of the ®rst episode of SBP in cirrhotic patients with ascites and they may help in deciding whether a patient should initiate antibiotic prophylaxis. In a series of 127 patients admitted to hospital for the treatment of an episode of ascites Llach et al21 showed that the probability of the appearance of the ®rst episode of SBP was 11% at 1 year and 15% at 3 years of follow-up. Five variables obtained at admission were signi®cantly associated with a higher risk of SBP appearance during follow-up (poor nutritional status, increased serum bilirubin levels, decreased prothrombin activity, increased serum AST levels and low ascitic ¯uid protein concentration) but only one (low ascitic ¯uid protein concentration) showed an independent predictive value. The 1-year and 3-year probabilities of the ®rst episode of SBP in patients with ascitic ¯uid protein content lower than 10 g/l and equal to or greater than 10 g/l were 0, 4, 20 and 24%, respectively. A clear conclusion from this study is that long-term prophylactic administration of antibiotic is not necessary in patients with a protein content in ascitic ¯uid 410 g/l, in whom the risk of developing SBP is negligible. In a similar study performed in 110 consecutive cirrhotic patients hospitalized for the treatment of an episode of ascites, Andreu et al22 identi®ed six variables associated with a higher risk of ®rst SBP appearance during follow-up (serum bilirubin 42.5 mg/dl, prothrombin activity 560%, ascitic ¯uid total protein concentration 510 g/l, serum sodium concentration 5130 mEq/l, platelet count 5116 000/mm3 and serum albumin concentration 526 g/ l) but only two (ascitic ¯uid protein concentration and serum bilirubin) showed an independent predictive value. Using these two variables, a relative risk index of a ®rst SBP episode was constructed. The 1-year cumulative probability for a ®rst episode of SBP in all patients was 29%. The corresponding values in the 55 patients with a risk index higher and lower than the median value were 8 and 50%, respectively. In a recent study, Guarner et al23 have identi®ed a subgroup of patients at high risk of developing a ®rst episode of SBP. Cirrhotic patients with low ascitic ¯uid protein levels (410 g/l) and high serum bilirubin level (43.2 mg/dl) and/or low platelet count (598 000/mm3) present a 1-year probability of developing a ®rst SBP of 55% in comparison with 24% of patients with only low ascitic ¯uid protein levels. Three studies, therefore, indicate that cirrhotic patients with ascites who are at risk of developing a ®rst episode of SBP can be

986 J. FernaÂndez et al.

identi®ed by using routine biochemical parameters and suggest that these patients might bene®t from selective intestinal decontamination. However, the ecacy of antibiotic prophylaxis in these high-risk patients should be adequately investigated. A concern with the use of prolonged antibiotic prophylaxis is that it will lead to selection of antibiotic-resistant bacteria which can be disseminated within the general community and, in particular, hospital environments. Di€erent studies have evaluated the emergence of antibiotic-resistant bacteria in cirrhotic patients undergoing selective intestinal decontamination for the prevention of SBP. Although the development of SBP or other infections caused by quinolone-resistant organisms, mainly Pseudomonas spp and Gram-positive bacteria, in cirrhotic patients on quinolone prophylaxis was scarcely reported in initial controlled trials56,58,60, more recently the frequency of such infections has been found to be increased.64±67 One recent study showed clear di€erences in the type of bacteria causing infections in cirrhotic patients on chronic quinolone prophylaxis: while 67% of infections in untreated cirrhotic patients were due to Gram-negative organisms, infections in patients receiving quinolone prophylaxis were due mostly to Gram-positive organisms (79%). This study also showed the emergence of severe nosocomial staphylococcal infections due to methicillin-resistant strains.64 This concern about the safety of this prophylaxis reinforces the necessity of restricting the administration of prophylactic antibiotics to patients at greatest risk of SBP. Finally, it should be kept in mind that SBP carries a poor prognosis. The 1-year and 2-year probability of survival after an episode of SBP is 30±50% and 25±30%, respectively.20,68,69 Therefore, patients recovering from an episode of SBP should be considered as potential candidates for liver transplantation. SUMMARY Spontaneous bacterial peritonitis is a frequent, severe complication of cirrhotic patients with ascites. Its diagnosis is established on the basis of polymorphonuclear cell count in ascitic ¯uid higher than 250 cells/mm3. The routine use of diagnostic paracentesis whenever a cirrhotic patient with ascites is admitted to hospital usually allows an early diagnosis of the infection. At present, third-generation cephalosporins are considered the gold standard in the treatment of SBP. Because of the high incidence of quinolone-resistant Gram-negative bacilli isolated in cirrhotic patients on long-term nor¯oxacin prophylaxis, SBP in these patients should not be treated with quinolones as empirical therapy. Although SBP prognosis has improved in recent years, the mortality rate associated with this bacterial infection is still high. The development of severe complications such as renal impairment and gastrointestinal bleeding is responsible for this poor prognosis. The mechanisms involved in the pathogenesis of these complications are still unknown. Selective intestinal decontamination with quinolones has been demonstrated to be e€ective in SBP prophylaxis of patients who have recovered from a previous episode of SBP and in patients with gastrointestinal bleeding. The increasing emergence of quinolone-resistant organisms clearly establishes the necessity of restricting the primary prophylaxis to those subsets of patients at high risk of developing a ®rst episode of SBP. The identi®cation of these patients and the evaluation of alternative prophylactic measures such as other antibiotic regimes and non-antibiotic procedures are still under investigation. Because of the poor survival expectancy after this bacterial infection, cirrhotic patients recovering from an episode of SBP should be considered as potential candidates for liver transplantation.

Spontaneous bacterial peritonitis 987

Practice points . diagnosis: use of diagnostic paracentesis whenever a cirrhotic patient with ascites is admitted to hospital or when his/her clinical condition deteriorates during hospitalization . treatment: third-generation cephalosporins as the elective empirical treatment of SBP avoidance of quinolones in the treatment of SBP in patients undergoing SID with nor¯oxacin . prophylaxis is at present restricted to: cirrhotic patients recovering from a previous episode of SBP (inde®nitely) cirrhotic patients with gastrointestinal bleeding (during 7 days) cirrhotic patients with ascitic ¯uid protein levels 410 g/l during hospitalization (no consensus)

Research agenda The following data need further investigation: . establishment of the real role of bacterial translocation in the pathogenesis of SBP in cirrhotic patients . investigation on the pathogenesis of complications triggered by SBP: renal impairment, gastrointestinal bleeding, hepatic encephalopathy . identi®cation of cirrhotic patients at high risk of developing a ®rst episode of SBP . evaluation of alternative measures in SBP prophylaxis, such as other antibiotic regimes and non-antibiotic procedures

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